Clinical trial NCT02869438
Conditions: Asthma
Keywords: Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases
Sponsor: AstraZeneca
Start date: 2016-11-09; Completion date: 2018-08-01
Enrollment: 233 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the onset and maintenance of effect of benralizumab on lung function, blood eosinophils, asthma control metrics and quality of life during 12-week treatment in patients with uncontrolled, severe asthma with eosinophilic inflammation. A subset of patients will take part in body plethysmography substudy to further investigate the effect on lung function.

Detailed description:

Arms: arm 1: Benralizumab administered subcutaneously arm 2: Placebo administered subcutaneously
Interventions: intervention 1: Benralizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Benralizumab administered subcutaneously at Visit 1 (Day 0), Visit 8 (Day28 +/- 3 days) and Visit 9 (Day 56 +/- 3 days) intervention 2: Placebo administered subcutaneously at Visit 1 (Day 0), Visit 8 (Day28 +/- 3 days) and Visit 9 (Day 56 +/- 3 days)

Protocol documents:
Prot_001.pdf: 
1(99)
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
D3250C00038
Version
1.0
Date
02 Aug 2016
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-
controlled, Phase 3b Study to Evaluate the Onset of Effect and Time Course 
of Change in Lung Function with Benralizumab in Severe, Uncontrolled 
Asthma Patients with Eosinophilic Inflammation
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden


Clinical Study Protocol Synopsis
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
2(99)
VERSION HISTORY
Version 1.0, 07 July 2016
Initial creation


Clinical Study Protocol Synopsis
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
3(99)
PROTOCOL SYNOPSIS
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-
controlled, Phase 3b Study to Evaluate the Onset of Effect and Time Course 
of Change in Lung Function with Benralizumab in Severe, Uncontrolled 
Asthma Patients with Eosinophilic Inflammation
International Coordinating Investigator 
Study site(s) and number of subjects planned
This study will be conducted worldwide in approximately 55 study centers. Target is to 
randomize 230 patients.
Study period
Phase of development
Estimated date of first subject enrolled
Q3 2016
Phase 3b
Estimated date of last subject completed
Q4 2017


Clinical Study Protocol Synopsis
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
4(99)
Study design
This is a randomized, double-blind, parallel group, placebo-controlled study designed to 
evaluate the onset of effect and the safety of a fixed 30 mg dose of benralizumab administered 
subcutaneously (SC) to patients with severe, uncontrolled asthma. Approximately 230
patients with peripheral blood eosinophil counts ≥300 cells/μL will be randomized globally to 
receive SC benralizumab 30 mg or placebo. 
After enrolment, eligible patients will enter a 5-week screening/run-in period. Patients who 
meet eligibility criteria will enter a 12-week treatment period and receive 30 mg benralizumab 
or placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days). An End-of-Treatment (EOT) 
visit will be conducted at Day 84 (Week 12) and a follow-up (FU) visit will be conducted at 
Day 112 (Week 16).
Objectives
Primary objective
Outcome measure
To determine the effect of benralizumab on the 
time course of change (onset and maintenance 
of effect) on lung function
The average over the mean differences between 
benralizumab and placebo for the change from 
baseline (Visit 4) at Day 28 (Visit 8), Day 56 (Visit 9) 
and Day 84 (Visit 10) in pre-bronchodilator (BD) 
forced expiratory volume in 1 second (FEV1) will be 
used to determine if the study is positive and to 
determine maintenance of effect. The first post 
baseline timepoint where the p-value for the mean 
difference between benralizumab and placebo is less 
than or equal to 0.05 will be used to determine time to 
onset of effect.
Secondary objectives
Outcome measure 
To determine time course of effect of 
benralizumab on blood eosinophils and 
correlate changes in eosinophil depletion with 
lung function
Change from baseline in blood eosinophils (from 
hematology) to end of treatment together with the 
correlation with lung function
To determine the effect of benralizumab on the 
time course of change and maintenance on 
lung function.
Change from baseline (Visit 4) in pre-BD FEV1 at all 
clinic visits compared to placebo 
Change from baseline (Visit 4) in pre-BD forced vital 
capacity (FVC) at all clinic visits compared to 
placebo 
To determine the time course of the effect of 
benralizumab on asthma control metrics
Change from baseline (Visit 4) in Asthma Control 
Quesitonnaire-6 (ACQ-6) score at all post-baseline 
assessment timepoints
To determine the time course of effect of 
benralizumab on health related quality of life
Change from baseline (Visit 4) in St. George's 
Respiratory Questionnaire (SGRQ) score at all post-
baseline assessment timepoints


Clinical Study Protocol Synopsis
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
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To determine the effect of benralizumab on the 
time course of change in exhaled nitric oxide 
(FeNO) 
Change from baseline in FeNO (ppb) compared to 
placebo to end of treatment (Visit 10)
Safety objectives:
Outcome measure 
To evaluate the pharmacokinetics (PK) and 
immunogenicity of benralizumab
!
Serum PK
!
Anti-drug antibodies
To assess the safety and tolerability of 
benralizumab
!
Adverse events (AEs) and serious adverse events 
(SAEs)
!
Laboratory variables
!
Physical Examination
Other objectives:
Outcome measure 
To evaluate patient impression of overall 
asthma severity (PGI-S) and overall change 
from baseline as reported by the patient (PGI-
C) and clinician (CGI-C)
!
Change from baseline (Visit 4) in PGI-S at all 
post-baseline assessment timepoints
!
Clinician-reported global change in asthma from 
baseline (Visit 4) as measured by CGI-C
!
Patient-reported global change in asthma from 
baseline (Visit 4) as measured by PGI-C
Body plethysmography sub-study objectives
Sub-study primary objective
Outcome Measure 
To determine the effect of benralizumab on the 
time course of change in lung function as 
assessed through body plethysmography
Change from baseline (Visit 4) to end of treatment 
(Visit 10) in the following measures compared to 
placebo:
!
Residual volume (RV)


Clinical Study Protocol Synopsis
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
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Sub-study secondary objectives
Outcome measure 
To determine the effect of benralizumab on the 
time course of change in lung function as 
assessed through body plethysmography
Change from baseline (Visit 4) to end of treatment  
(Visit 10) in the following measures compared to 
placebo :
!
Total lung capacity TLC)
!
RV/TLC ratio
!
Inspiratory capacity (IC)
!
Functional residual capacity (FRC) 
!
Vital capacity (VC)
Sub-study other objectives
Outcome measure
To determine the effect of benralizumab on the 
time course of change in lung function as 
assessed through body plethysmography
Change from baseline (Visit 4) to end of treatment 
(Visit 10) in the following measures compared to 
placebo:
!
Specific airway resistance (SGaw)
!
Airway resistance (Raw)
Target subject population
Male and female patients 18 to 75 years of age with severe uncontrolled asthma will be 
enrolled.
Duration of treatment
After enrolment, eligible patients will enter a 5-week screening/run-in period.  Patients who 
meet eligibility criteria will enter a 12-week treatment period and receive 30 mg benralizumab 
or placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).  An End-of-Treatment (EOT) 
visit will be conducted at Day 84 (Week 12) and a follow-up (FU) visit will be conducted at 
Day 112 (Week 16).
The total planned study duration for patient is a maximum of 22 weeks.
Investigational product, dosage and mode of administration
Benralizumab 30 mg/mL solution for injection in an accessorized pre-filled syringe (APFS) 
will be administered at the study center subcutaneously (SC) every 4 weeks for 3 doses (Day 
0, Day 28 [±3 days], and Day 56 [±3days]).
Statistical methods
Approximately 230 subjects in total and 115 subjects in each treatment group are needed for 
this study based on the primary objective of the study to determine the effect of benralizumab 
on the time course of change (onset and maintenance of effect) of pre-bronchodilator (BD) 
FEV1.


Clinical Study Protocol Synopsis
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
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Subjects will be randomized in a 1:1 ratio to benralizumab or placebo. In order to have 
balanced number of subjects for region and the body plethysmography sub-study the 
randomization will be stratified for these variables.
The primary analysis method for primary endpoint, the change from baseline in pre-BD FEV1
will be compared between benralizumab and placebo using a repeated measures analysis. 
Treatment group will be fitted as the explanatory variable; region, visit and treatment*visit 
interaction as fixed effects and baseline pre-bronchodilator FEV1 as a covariate. The first 
post-baseline timepoint where the p-value for the mean difference between benralizumab and 
placebo is less than or equal to 0.05 will be used to determine time to onset of effect. The 
average over the mean differences between benralizumab and placebo based on the change 
from baseline (Visit 4, Day 0) to Days 28 (Visit 8), 56 (Visit 9) and 84 (Visit 10) in pre-BD 
FEV1 will be used to determine if the study is positive as well as maintenance of effect. 
Contrasts will be used to obtain estimates of the treatment differences over Days 28, 56 and 84 
as well as at each timepoint separately.
Efficacy analysis for the main study will be performed using the full analysis set, which 
consists of all randomized subjects who received at least 1 dose of investigational product.
Efficacy analyses for the body plethysmography sub-study will include the subset of patients 
who are randomized as part of the sub-study as described for the full analysis set.
All safety variables will be summarized descriptively. The safety analysis will be performed 
using the safety analysis set.


Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
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TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
VERSION HISTORY..............................................................................................2
PROTOCOL SYNOPSIS.........................................................................................3
TABLE OF CONTENTS.........................................................................................8
1.
INTRODUCTION .................................................................................................16
1.1
Background and rationale for conducting this study .............................................16
1.2
Rationale for study design, doses and control groups............................................18
1.3
Rationale for the sub-study design, doses and control groups...............................18
1.4
Benefit/risk and ethical assessment........................................................................18
1.5
Study design...........................................................................................................19
2.
STUDY OBJECTIVES..........................................................................................22
2.1
Primary objective...................................................................................................22
2.2
Secondary objectives .............................................................................................22
2.3
Safety objectives ....................................................................................................23
2.4
Other objectives for the main study.......................................................................23
2.5
Body plethysmography sub-study primary objectives...........................................23
2.6
Body plethysmography sub-study secondary objectives .......................................24
2.7
Body plethysmography sub-study other objectives ...............................................24
3.
SUBJECT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................24
3.1
Inclusion criteria ....................................................................................................24
3.1.1
Additional inclusion criteria applicable for the Body Plethysmography sub-
study.......................................................................................................................26
3.2
Exclusion criteria ...................................................................................................26
3.3
Eligibility criteria to be confirmed at randomization Visit 4.................................28
3.3.1
Inclusion criteria at randomization Visit 4.............................................................28
3.3.2
Exclusion criteria at randomization Visit 4............................................................29
3.4
Subject enrolment and randomization ...................................................................29
3.5
Procedures for handling incorrectly enrolled or randomized subjects...................29
3.6
Methods for assigning treatment groups................................................................30


Clinical Study Protocol
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Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
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3.7
Methods for ensuring blinding...............................................................................30
3.7.1
Maintaining the blind to the patient's blood eosinophils counts............................30
3.8
Methods for unblinding..........................................................................................30
3.9
Restrictions ............................................................................................................31
3.9.1
Asthma medication restrictions..............................................................................31
3.9.1.1
Other medication restrictions.................................................................................32
3.9.1.2
Other restrictions....................................................................................................32
3.10
Discontinuation of investigational product............................................................32
3.10.1
Procedures for discontinuation of a subject from investigational product ............33
3.11
Criteria for withdrawal...........................................................................................34
3.11.1
Screen failures........................................................................................................34
3.11.2
Withdrawal of the informed consent......................................................................34
3.12
Discontinuation of the study..................................................................................34
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................35
4.1
Enrolment/screening period...................................................................................41
4.1.1
Enrolment (Visit 1) Day -35 ..................................................................................41
4.1.2
Screening/run-in (Visit 2) Day -21 ........................................................................42
4.1.3
Screening/run-in (Visit 3) Day -7 ..........................................................................42
4.1.4
Re-screening ..........................................................................................................43
4.1.4.1
Procedures for patients who experience an exacerbation during   
screening/run-in .....................................................................................................43
4.2
Treatment period....................................................................................................43
4.3
Follow-up period....................................................................................................44
5.
STUDY ASSESSMENTS .....................................................................................44
5.1
Efficacy assessments..............................................................................................44
5.1.1
Spirometry..............................................................................................................44
5.1.1.1
Reversibility testing ...............................................................................................46
5.1.2
Fractional exhaled nitric oxide measurement ........................................................48
5.2
Safety assessments.................................................................................................48
5.2.1
Laboratory safety assessments...............................................................................48
5.2.1.1
Pregnancy test ........................................................................................................49
5.2.2
Physical examination .............................................................................................50
5.2.2.1
Complete physical examination.............................................................................50
5.2.2.2
Brief physical examination ....................................................................................50
5.2.3
Electrocardiogram..................................................................................................50
5.2.3.1
Resting 12-lead electrocardiogram ........................................................................50
5.2.4
Vital signs ..............................................................................................................51
5.2.4.1
Pulse and blood pressure........................................................................................51
5.2.4.2
Body temperature...................................................................................................51
5.3
Other assessments ..................................................................................................51


Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
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5.3.1
Weight and height..................................................................................................51
5.3.2
Patient reported outcomes......................................................................................51
5.3.2.1
Asthma Control Questionnaire ..............................................................................51
5.3.2.2
St. George’s Respiratory Questionnaire ................................................................52
5.3.2.3
Patient Global Impression of Severity assessments...............................................52
5.3.2.4
Clinician and Patient Global Impression of Change assessments .........................52
5.3.3
Other screening/run-in assessments.......................................................................53
5.3.3.1
Serology .................................................................................................................53
5.3.3.2
Serum immunoglobulin E......................................................................................53
5.3.4
Pharmacokinetics ...................................................................................................53
5.3.4.1
Collection of samples.............................................................................................53
5.3.4.2
Determination of drug concentration.....................................................................53
5.3.4.3
Storage and destruction of pharmacokinetic samples............................................53
5.3.5
Pharmacodynamics ................................................................................................54
5.3.5.1
Collection of samples.............................................................................................54
5.3.5.2
Immunogenicity.....................................................................................................54
5.3.5.3
Anti-drug antibodies ..............................................................................................54
5.3.5.4
Neutralizing antibodies ..........................................................................................54
5.3.6
Pharmacogenetics ..................................................................................................54
5.3.7
Biomarker analysis.................................................................................................54
5.3.8
Handling of biological samples .............................................................................54
5.3.8.1
Labelling and shipment of biological samples.......................................................54
5.3.8.2
Chain of custody of biological samples.................................................................55
5.4
Additional assessments applicable for the subset of subjects – body 
plethysmography sub-study ...................................................................................55
5.4.1
Body plethysmography ..........................................................................................55
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................56
6.1
Definition of adverse events ..................................................................................56
6.2
Definitions of serious adverse event......................................................................56
6.3
Recording of adverse events ..................................................................................57
6.3.1
Time period for collection of adverse events.........................................................57
6.3.2
Follow-up of unresolved adverse events................................................................57
6.3.3
Variables ................................................................................................................57
6.3.4
Causality collection................................................................................................58
6.3.5
Adverse events based on signs and symptoms.......................................................58
6.3.6
Adverse events based on examinations and tests...................................................58
6.3.6.1
Symptoms of the disease under study....................................................................59
6.3.7
Hy’s Law................................................................................................................59
6.3.8
Disease progression ...............................................................................................59
6.4
Reporting of serious adverse events.......................................................................59
6.5
Overdose ................................................................................................................60
6.6
Pregnancy...............................................................................................................60


Clinical Study Protocol
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Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
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6.6.1
Maternal exposure..................................................................................................61
6.6.2
Paternal exposure...................................................................................................61
6.7
Management of investigational product-related reactions.....................................61
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................62
7.1
Identity of investigational product(s).....................................................................62
7.2
Dose and treatment regimens.................................................................................62
7.3
Labelling ................................................................................................................64
7.4
Storage ...................................................................................................................64
7.5
Compliance ............................................................................................................65
7.6
Accountability........................................................................................................65
7.7
Concomitant and other treatments .........................................................................65
7.7.1
Background medication .........................................................................................65
7.7.2
Rescue medication .................................................................................................66
7.7.3
Other concomitant treatment..................................................................................66
8.
STATISTICAL ANALYSES BY ASTRAZENECA............................................66
8.1
Statistical considerations........................................................................................66
8.2
Sample size estimate..............................................................................................66
8.3
Definitions of analysis sets ....................................................................................67
8.3.1
All patients analysis set..........................................................................................67
8.3.2
Full analysis set......................................................................................................67
8.3.3
Body plethysmography sub-study analysis set ......................................................67
8.3.4
Safety analysis set..................................................................................................67
8.3.5
Pharmacokinetic analysis set .................................................................................67
8.4
Outcome measures for analyses.............................................................................68
8.4.1
Calculation or derivation of efficacy variables......................................................68
8.4.1.1
Pre-bronchodilator forced expiratory volume in 1 second ....................................68
8.4.1.2
Eosinophils counts in the blood .............................................................................68
8.4.1.3
Forced vital capacity..............................................................................................68
8.4.1.4
Asthma Control Questionnaire ..............................................................................68
8.4.1.5
St. George's Respiratory Questionnaire .................................................................69
8.4.1.6
Exhaled nitric oxide...............................................................................................69
8.4.1.7
Patient Global Impression of Severity...................................................................69
8.4.1.8
Patient and Clinician Global Impression of Change..............................................69
8.4.2
Body plethysmography sub-study..........................................................................70
8.4.2.1
Body lung function as assessed through body plethysmography ..........................70
8.4.3
Calculation or derivation of safety variable(s).......................................................70
8.4.3.1
Safety variables......................................................................................................70
8.4.4
Calculation or derivation of pharmacokinetic variables ........................................70
8.4.5
Calculation or derivation of immunogenicity variables.........................................70


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Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
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8.5
Methods for statistical analyses .............................................................................71
8.5.1
Analysis of the primary variable(s)........................................................................71
8.5.2
Analysis of the secondary variable(s)....................................................................72
8.5.2.1
Analysis methods for secondary efficacy variables...............................................72
8.5.2.2
Analysis for the Body plethysmography sub-study...............................................74
8.5.2.3
Analysis of the safety variables .............................................................................74
8.5.3
Subgroup analysis ..................................................................................................75
8.5.4
Interim analysis......................................................................................................75
8.5.5
Sensitivity analysis.................................................................................................75
8.5.6
Exploratory analysis...............................................................................................75
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ..........................75
9.1
Training of study site personnel.............................................................................75
9.2
Monitoring of the study .........................................................................................76
9.2.1
Source data.............................................................................................................76
9.2.2
Recording of data...................................................................................................76
9.2.3
Study agreements...................................................................................................77
9.2.4
Archiving of study documents...............................................................................77
9.3
Study timetable and end of study...........................................................................77
9.4
Data management by AstraZeneca ........................................................................77
10.
ETHICAL AND REGULATORY REQUIREMENTS.........................................78
10.1
Ethical conduct of the study...................................................................................78
10.2
Subject data protection...........................................................................................78
10.3
Ethics and regulatory review..................................................................................78
10.4
Informed consent ...................................................................................................79
10.5
Changes to the protocol and informed consent form.............................................79
10.6
Audits and inspections ...........................................................................................80
11.
LIST OF REFERENCES.......................................................................................80
LIST OF TABLES
Table 1
List of abbreviations.................................................................................14
Table 2
Study plan - Run-in period; Visit 1 to Visit 3 ..........................................35
Table 3
Study Plan - Randomization, treatment period, follow-up; Visit 4 
to Visit 11 .................................................................................................37
Table 4
Laboratory safety variables ......................................................................49


Clinical Study Protocol
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Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
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LIST OF FIGURES
Figure 1
Main study flow chart...............................................................................20
Figure 2
Body plethysmography sub-study flow chart...........................................21
Figure 3
Reversibility testing algorithm .................................................................47
Figure 4
Injection sites and rotation scheme...........................................................63
LIST OF APPENDICES
Appendix A
Additional Safety Information..................................................................85
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document .................................................................................87
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law............................................................................88
Appendix D
Anaphylaxis: signs and symptoms, management.....................................93
Appendix E
PROHIBITED AND RESTRICTED MEDICATIONS...........................97
Appendix F
BACKROUND THERAPY EQUIVALENCE TABLE ..........................99


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Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
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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.
Table 1
List of abbreviations
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
AST
Aspartate aminotransferase
ATS/ERS
American Thoracic Society/European Respiratory Society
Beta-hCG
Beta- human chorionic gonadotropin
BP
Blood pressure
BUN
Blood urea nitrogen
CO2
Carbon dioxide
COPD
Chronic obstructive pulmonary disease
CGI-C
Clinician Global Impression of Change
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report
DMP
Data Management Plan
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOT
End of treatment
ePRO
Electronic patient reported outcome
EU
European Union
FeNO
Fractional exhaled Nitric Oxide
FEV1
Forced expiratory volume in 1 second
FRC
Functional Residual Capacity
FSH
Follicle-stimulating hormone


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Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
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Table 1
List of abbreviations
Abbreviation or 
special term
Explanation
FVC
Forced vital capacity
Gamma-GT
Gamma-glutamyl transpeptidase
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
GMP
Good Manufacturing Practice
GLI 
The Global Lung Function Initiative
HIV
Human immunodeficiency virus
IATA
International Air Transport Association
IC
Inspiratory Capacity
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICS
Inhaled corticosteroids
IL
Interleukin
IL-5
Interleukin-5
IL-5R
Interleukin-5 receptor
IL-5Rα
Interleukin-5 receptor alpha subunit
ICI
International Coordinating Investigator
IM
Intramuscular
IP
Investigational product
IPD
Premature IP Discontinuation
IRB
Institutional Review Board
IV
Intravenous
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
nAb
Neutralizing antibodies
OCS
Oral corticosteroids
PD
Pharmacodynamic(s)
PEF
Peak expiratory flow


Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00038
Version 1.0
Date 02 Aug 2016
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Table 1
List of abbreviations
Abbreviation or 
special term
Explanation
PK
Pharmacokinetic(s)
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PN
Predicted normal
Post-BD
Post-bronchodilator
Pre-BD
Pre-bronchodilator
PRO
Patient reported outcome
Raw
Airway resistance
RBC
Red blood cell
RV
Residual Volume
SABA
Short-acting β2 agonists
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SGaw
Specific Airway conductance
SGRQ
St. George’s Respiratory Questionnaire
SUSARs
Suspected Unexpected Serious Adverse Reactions
TLC
Total Lung Capacity
ULN
Upper limit of normal
VC
Vital Capacity
WBC
White blood cell
WBDC
Web-based Data Capture
WOCBP
Women of childbearing potential
1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Asthma is a syndrome characterized by airway inflammation, reversible airway obstruction, 
and airway hyperresponsiveness.  Patients present clinically with recurrent wheezing, 
shortness of breath, cough, and chest tightness.  Asthma is a leading cause of morbidity with a 
global prevalence of approximately 300 million; it is estimated that the number of people with 
asthma may increase to 400-450 million people worldwide by 2025 (Masoli et al 2004).


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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 2016, NAEPP 2007).  Despite treatment 
per management guidelines, up to 50% of patients have asthma that is not well controlled 
(ATS 2005; 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, Saito 
et al 2015, Simpson et al 2006). 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 2011, Ortega et al 2014). These promising results support continued development 
of therapies targeting eosinophils 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 2010).  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, 
Molfino et al 2012, 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).  
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. The dose being studied for 
these trials is 30 mg, a dose derived from pharmacokinetic/pharmacodynamic (PK/PD) 
modeling of the Phase 2 dose finding study, administered in 2 dosing regimens – either 30 mg 
every 4 weeks (Q4W) or 30 mg every 4 weeks (Q4W) for the first 3 doses followed by dosing 
every 8 weeks (Q8W) thereafterThe primary endpoint in each study is the annual rate of 
asthma-related exacerbations with key secondary endpoints being FEV1 and asthma symptoms 
as defined by a daily patient diary. 


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The effect of benralizumab on depletion of blood eosinophils is rapid, with time to maximum 
effect on depletion of eosinophils in blood (ie, below level of detection) within 24 hours in 
asthmatic subjects (Laviolette et al 2013; Busse et al 2010) and within 6 hours in healthy 
subjects (Saito et al 2015). Benralizumab also depletes eosinophils in lung tissue and sputum 
in mild to moderate asthmatics (Laviolette et al 2013) where benralizumab showed a median 
61% reduction in lung tissue eosinophils at 28 days post dosing (at 1 mg/kg i.v.) and a median 
96% reduction at 84 days post dosing (combined 100 mg and 200 mg s.c.). This study is 
designed to characterize the time of onset of changes in lung function relative to the depletion 
of eosinophils in the peripheral blood.
1.2
Rationale for study design, doses and control groups
This is a randomized, double blind, placebo controlled global study designed to investigate the 
onset of effect of benralizumab (30 mg) administered subcutaneously (SC) on lung function in 
severe asthmatics still uncontrolled on standard of care therapy(-ies). Three doses will be 
given every 4 weeks on Day 0, Day 28 (±3 days) and Day 56 (±3 days). 
The dose chosen, 30 mg SC, is based on all available efficacy and safety data, as well as 
population exposure-response modelling and stochastic simulations from earlier benralizumab 
trials.
A 12 week treatment duration, with 3 doses of benralizumab given every 4 weeks, will 
characterize the full time course of effect of benralizumab on lung function profiling the effect 
on FEV1 from onset to the estimated plateau of effect at 12 weeks, as observed in the Ph2b 
study.
1.3
Rationale for the sub-study design, doses and control groups
For the sub-study, the primary efficacy variable is the change from baseline in Residual 
volume (RV) as assessed through body plethysmography up until the EOT at Visit 10. 
Secondary variables will characterize a change from baseline until V10 in lung volume 
subdivisions which include total lung capacity (TLC), RV/TLC ratio, inspiratory capacity 
(IC), functional residual capacity (FRC), and vital capacity (VC).
Other variables will characterize a change in airway resistance (Raw) and specific airway 
resistance (SGaw)
Previous studies have shown an improvement in FEV1, the substudy will evaluate the effect of 
benralizumab on the different lung subdivisions.
1.4
Benefit/risk and ethical assessment
Benralizumab is being studied in severe asthma where there are few treatment options for 
patients whose asthma remains uncontrolled on high dose ICS/LABA and oral corticosteroids 
(GINA 2016). 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 


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Study Code D3250C00038
Version 1.0
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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). 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 efficacy and safety data obtained to date support the continued clinical development of 
benralizumab in patients with asthma. 
A detailed assessment of the overall risk/benefit of benralizumab is given in the Investigator’s 
Brochure.
1.5
Study design 
This is a randomized, double-blind, parallel group, placebo-controlled study designed to 
evaluate the onset of effect and the safety of a fixed 30 mg dose of benralizumab administered
subcutaneously (SC) to patients with severe, uncontrolled asthma.  Approximately 230 
patients with peripheral blood eosinophil counts ≥300 cells/μL will be randomized globally to 
receive SC benralizumab 30 mg or placebo. 
After enrolment, eligible patients will enter a 5-week screening/run-in period.  Patients who 
meet eligibility criteria will enter a 12-week treatment period and receive 30 mg benralizumab 
or placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).  An End-of-Treatment (EOT) 
visit will be conducted at Day 84 (Week 12) and a follow-up (FU) visit will be conducted at 
Day 112 (Week 16).  


Clinical Study Protocol
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Study Code D3250C00038
Version 1.0
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Figure 1
Main study flow chart
Enrollment
Run-in period
Treatment period
Follow-up period
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Day -35
Day -21
Day -7
Day 0
Day 3
Day 7
Day 14
Day 28
Day 56
Day 84
Day 112
±0 d
±2 d
±2 d
±0 d
±1 d
±1 d
±3 d
±3 d
±3 d
±7 d
±7 d
Post BD 
Onlya
Post BDa
Post BDa
-
-
-
-
-
-
-
-
-
Pre-BD 
FEV1
b
Pre-BD 
FEV1
b
Pre-BD
FEV1
Pre-BD
FEV1
Pre-BD
FEV1
Pre-BD
FEV1
Pre-BD
FEV1
Pre-BD
FEV1
Pre-BD
FEV1
Pre-BD
FEV1
-
-
-
Dose 1
-
-
-
Dose 2
Dose 3
-
-
a
In case patient meets maintenance medication restrictions for the respiratory testing at Visit 1, only reversibility testing can be performed at Visit 1. If a 
patient fails the protocol-specified reversibility criterion (≥ 12% and 200 ml) at Visit 1, a second attempt is allowed at Visit 2 or Visit 3. 
b
Pre BD FEV1 spirometry should be recorded at Visit 2 as well as at Visit 3, irrespective of whether the patient has met protocol specified pre-
bronchodilator FEV1  criterion (<80%) at Visit 2 or not. The Pre BD FEV1 criteria must be met at either Visit 2 or at Visit 3.
d  days; FEV1 Forced Expiratory Volume in 1 sec measurement (spirometry); pre-BD  pre-bronchodilator; post-BD  post bronchodilator.


Clinical Study Protocol
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Study Code D3250C00038
Version 1.0
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Figure 2
Body plethysmography sub-study flow chart
Enrollment
Run-in period
Treatment period
Follow-up period
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Day -35
Day -21
Day -7
Day 0
Day 3
Day 7
Day 14
Day 28
Day 56
Day 84
Day 112
±0 d
±2 d
±2 d
±0 d
±1 d
±1 d
±3 d
±3 d
±3 d
±7 d
±7 d
Post BD 
Onlya 
Post BDa
-
-
-
-
-
-
-
-
-
-
Pre-BD 
FEV1
b
Pre-BD 
FEV1
b
Pre-BD
FEV1
Pre-BD
FEV1
Pre-BD
FEV1
Pre-BD
FEV1
Pre-BD
FEV1
Pre-BD
FEV1
Pre-BD
FEV1
Pre-BD
FEV1
-
-
BB
BB
-
BB
BB
BB
BB
BB
-
-
-
-
Dose 1
-
-
-
Dose 2
Dose 3
-
-
a
In case patient meets maintenance medication restrictions for the respiratory testing at Visit 1, only reversibility testing can be performed at Visit 1. If a 
patient fails the protocol-specified reversibility criterion (≥ 12% and 200 ml) at Visit 1, a second attempt is allowed only at Visit 2
b
Pre BD FEV1 spirometry should be done at Visit 2. If a patient fails the protocol-specified pre-bronchodilator FEV1 criterion (<80%) at Visit 2, a 
second attempt is allowed at Visit 3 for patients in main study as well as the sub-study. For the patients participating in the body plethysmography sub 
study a second attempt is allowed only at Visit 2.
BB  Body Box for whole body plethysmography; d  days; FEV1   Forced Expiratory Volume in 1 sec measurement (spirometry); pre-BD  pre-bronchodilator; 
post-BD  post bronchodilator.


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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary objective:
Outcome measure:
To determine the effect of benralizumab on the 
time course of change (onset and maintenance 
of effect) on lung function
The average over the mean differences between 
benralizumab and placebo for the change from 
baseline (Visit 4) at Day 28 (Visit 8), Day 56 (Visit 9) 
and Day 84 (Visit 10) in pre-BD FEV1 will be used 
to determine if the study is positive and to determine 
maintenance of effect. The first post baseline 
timepoint where the p-value for the mean difference 
between benralizumab and placebo is less than or 
equal to 0.05 will be used to determine time to onset 
of effect.
2.2
Secondary objectives
Secondary objectives
Outcome measure 
To determine time course of effect of 
benralizumab on blood eosinophils and 
correlate changes in eosinophil depletion with 
lung function
Change from baseline in blood eosinophils (from 
hematology) to end of treatment together with the 
correlation with lung function
To determine the effect of benralizumab on the 
time course of change and maintenance on 
lung function.
Change from baseline (Visit 4) in pre-BD FEV1 at all 
clinic visits compared to placebo 
Change from baseline (Visit 4) in pre-BD forced vital 
capacity (FVC) at all clinic visits compared to 
placebo 
To determine the time course of the effect of 
benralizumab on asthma control metrics
Change from baseline (Visit 4) in Asthma Control 
Quesitonnaire-6 (ACQ-6) score at all post-baseline 
assessment timepoints
To determine the time course of effect of 
benralizumab on health related quality of life
Change from baseline (Visit 4) in St. George's 
Respiratory Questionnaire (SGRQ) score at all post-
baseline assessment timepoints
To determine the effect of benralizumab on the 
time course of change in exhaled nitric oxide 
(FeNO) 
Change from baseline in FeNO (ppb) compared to 
placebo to end of treatment (Visit 10)


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2.3
Safety objectives
2.4
Other objectives for the main study
Other objectives:
Outcome measure 
To evaluate patient impression of overall 
asthma severity (PGI-S) and overall change 
from baseline as reported by the patient (PGI-
C) and clinician (CGI-C)
!
Change from baseline (Visit 4) in PGI-S at all 
post-baseline assessment timepoints
!
Clinician-reported global change in asthma from 
baseline (Visit 4) as measured by CGI-C
!
Patient-reported global change in asthma from 
baseline (Visit 4) as measured by PGI-C
2.5
Body plethysmography sub-study primary objectives
Sub-study primary objective
Outcome measure 
To determine the effect of benralizumab on the 
time course of change in lung function as 
assessed through body plethysmography
Change from baseline (Visit 4) to end of treatment 
(Visit 10) in the following measures compared to 
placebo:
!
Residual volume (RV)
Safety objectives:
Outcome measure 
To evaluate the pharmacokinetics (PK) and 
immunogenicity of benralizumab
!
Serum PK
!
Anti-drug antibodies
To assess the safety and tolerability of 
benralizumab
!
Adverse events (AEs) and serious adverse events 
(SAEs)
!
Laboratory variables
!
Physical Examination


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2.6
Body plethysmography sub-study secondary objectives
Sub-study secondary objectives
Outcome measure 
To determine the effect of benralizumab on the 
time course of change in lung function as 
assessed through body plethysmography
Change from baseline (Visit 4) to end of treatment  
(Visit 10) in the following measures compared to 
placebo :
!
Total lung capacity TLC)
!
RV/TLC ratio
!
Inspiratory capacity (IC)
!
Functional residual capacity (FRC) 
!
Vital capacity (VC)
2.7
Body plethysmography sub-study other objectives
Sub-study other objectives
Outcome measure
To determine the effect of benralizumab on the 
time course of change in lung function as 
assessed through body plethysmography
Change from baseline (Visit 4) to end of treatment 
(Visit 10) in the following measures compared to 
placebo:
!
Specific airway resistance (SGaw)
!
Airway resistance (Raw)
3.
SUBJECT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study. Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study subjects should meet the following criteria:
1.
Written informed consent for study participation must be obtained prior to any 
study related procedures being performed and according to international guidelines 
and/or applicable European Union (EU) guidelines. 
2.
Female and male aged 18 to 75 years inclusively at the time of Visit 1
3.
Documented current treatment with ICS and LABA for at least 30 days prior to 
Visit 1. 
!
For ICS/LABA combination preparations, high-strength maintenance doses approved 
in the given country will meet this criterion.


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!
If the ICS and LABA therapies are given by separate inhalers, the ICS dose must be 
>500 μg fluticasone propionate dry powder formulation or equivalent daily (see 
Appendix F).
!
Additional asthma controller medications, eg, oral corticosteroids, long-acting anti-
muscarinics (LAMAs), LTRAs, theophylline etc. are allowed if they have been used 
for at least 30 days prior to Visit 1. 
4.
History of at least 2 asthma exacerbations that required treatment with systemic 
corticosteroids (intramuscular (IM), intravenous (IV), or oral) in the 12 months 
prior to Visit 1. For patients receiving corticosteroids as a maintenance therapy, the 
corticosteroid treatment for the exacerbation is defined as a temporary increase of 
their maintenance dose.
5.
Pre-bronchodilator (pre-BD) FEV1 of < 80% predicted at Visit 2 or Visit 3
6.
ACQ-6 score ≥1.5 at Visit 1
7.
Evidence of asthma as documented by airway reversibility (FEV1 ≥12% and 
200 ml) demonstrated at Visit 1, Visit 2 or Visit 3 (as described in Section 5.1.1.1). 
For patients entering the body plethysmography sub-study, reversibility must be 
demonstrated at Visit 1 or at Visit 2 only.
8.
Peripheral blood eosinophil count of ≥300 cells/μL assessed by central lab at Visit 1
9.
Women of childbearing potential (WOCBP) must use an effective form of birth 
control (confirmed by the Investigator), eg, 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 birth control, as defined above, from enrolment, 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.
Women not of childbearing potential are defined as women who are either 
permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or who are postmenopausal.  Women will be considered 
postmenopausal if they have been amenorrheic for 12 months prior to the planned 
date of randomization without an alternative medical cause.  The following age-
specific requirements apply:
!
Women <50 years old are considered postmenopausal if they have been amenorrheic 
for 12 months or more following cessation of exogenous hormonal treatment and 
follicle stimulating hormone (FSH) levels in the postmenopausal range.


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!
Women ≥50 years old are considered postmenopausal if they have been amenorrheic 
for 12 months or more following cessation of all exogenous hormonal treatment.
10.
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.
11.
Weight of ≥40 kg
3.1.1
Additional inclusion criteria applicable for the Body Plethysmography sub-
study
1.
Residual volume ≥125% of predicted at Visit 3.
Patients who do not meet this criterion and/or are not able to take body 
plethysmography assessments, should continue in the main study only. 
3.2
Exclusion criteria
Subjects should 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, 
COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation 
syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and 
primary ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic 
disease, other than asthma, that are associated with elevated peripheral eosinophil 
counts (eg, allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss 
syndrome, hypereosinophilic syndrome)
2.
Life-threatening asthma defined as episodes requiring intubation associated with 
hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal 
episodes within the 12 months prior to Visit 1.
3.
Acute upper or lower respiratory infections requiring antibiotics or antiviral 
medication within 30 days prior to the date informed consent is obtained or during 
the screening/run-in period
4.
An upper respiratory tract infection or an asthma exacerbation that required 
treatment with systemic corticosteroids or an increase in regular maintenance dose 
of OCS  during the screening/run-in  period prior to randomization Visit 4
5.
Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, 
haematological, psychiatric, or major physical impairment that is not stable in the 
opinion of the Investigator and could:
!
Affect the safety of the patient throughout the study


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!
Influence the findings of the studies or their interpretations
!
Impede the patient’s ability to complete the entire duration of study
6.
Known history of allergy or reaction to any component of the investigational 
product formulation
7.
History of anaphylaxis to any biologic therapy
8.
History of Guillain-Barré syndrome
9.
A helminth parasitic infection diagnosed within 24 weeks prior to the date informed 
consent is obtained that has not been treated with, or has failed to respond to 
standard of care therapy
10.
Any clinically significant abnormal findings in physical examination, vital signs, 
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
11.
Any clinically significant cardiac disease or any electrocardiogram (ECG) 
abnormality obtained during the screening/run-in period, which in the opinion of the 
Investigator may put the patient at risk or interfere with study assessments
12.
History of alcohol or drug abuse within 12 months prior to the date informed 
consent is obtained
13.
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
14.
A history of known immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test
15.
Current smokers or former smokers with a smoking history of ≥10 pack years. 
A former smoker is defined as a patient who quit smoking at least 6 months prior to 
Visit 1. 
16.
Current malignancy, or history of malignancy, except for:
!
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 was obtained.


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!
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 was obtained.
17.
Use of immunosuppressive medication (including but not limited to: oral 
corticosteroids [for reasons other than asthma], methotrexate, troleandomycin, 
cyclosporine, azathioprine, intramuscular long-acting depot corticosteroids or any 
experimental anti-inflammatory therapy) within 3 months prior to the date informed 
consent 
18.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥1.5 
times the upper limit of normal (ULN) confirmed during screening period.
19.
Receipt of immunoglobulin or blood products within 30 days prior to the date 
informed consent is obtained
20.
Receipt of any marketed (eg, omalizumab, mepolizumab etc.) or investigational 
biologic within 4 months or 5 half-lives prior to the date informed consent is 
obtained, whichever is longer
21.
Receipt of live attenuated vaccines 30 days prior to the date of randomization.    
22.
Receipt of any investigational medication within 30 days or 5 half-lives prior to 
randomization, whichever is longer
23.
Previously received benralizumab (MEDI-563) 
24.
Planned surgical procedures during the conduct of the study
25.
Currently breastfeeding or lactating women
26.
Previous randomization in the present study
27.
Concurrent enrolment in another interventional or post-authorization safety study 
(PASS).
28.
AstraZeneca staff involved in the planning and/or conduct of the study
29.
Employees of the study center or any other individuals involved with the conduct of 
the study or immediate family members of such individuals
3.3
Eligibility criteria to be confirmed at randomization Visit 4.
3.3.1
Inclusion criteria at randomization Visit 4 
1.
At least 1 of the following within 7 days prior to randomization:
∀
Daytime or nighttime asthma symptoms for 2 or more days; 


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∀
Rescue SABA use for 2 or more days;
∀
Nighttime awakenings due to asthma at least 1 night during the 7-day period 
2.
ACQ >0.75 at Visit 4 prior to randomization. 
3.
A negative urine pregnancy test in WOCBP prior to administration of IP
3.3.2
Exclusion criteria at randomization Visit 4
1.
Greater than/equal to 20% change in mean Pre BD FEV1 value (mean of the Pre 
BD FEV1 taken 30 min (+/- 10 min) and 60 min (+/- 10 min) prior to dosing) at 
randomization Visit 4 (Day 0) from the mean pre BD FEV1 calculated from the pre 
BD FEV1 recorded at Visit 2 and Visit 3.
Procedures for withdrawal of incorrectly enrolled subjects see Section 3.5.
3.4
Subject enrolment and randomization
Investigator(s) should keep a record of all subjects who entered study screening (subject 
screening log).
The Investigator(s) will:
1.
Obtain signed informed consent from the potential subject before any study specific 
procedures are performed.
2.
Assign potential subject a unique enrolment number, beginning with ‘E#’ via 
interactive web/voice response system (IWRS/IVRS).
3.
Determine subject eligibility. See Section 2.7–Section 3.3.
4.
Assign eligible subject a unique randomization code via IWRS/IVRS
If a subject 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 the investigational product administration will not be replaced.
3.5
Procedures for handling incorrectly enrolled or randomized 
subjects
Patients who fail to meet the eligibility criteria should not, under any circumstance, be 
randomized 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.


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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 AstraZeneca Study 
Physician immediately, and a discussion should occur between the AstraZeneca Study 
Physician and the Investigator regarding whether to continue or discontinue the patient from 
treatment. The AstraZeneca Study Physician must ensure all decisions are appropriately 
documented.
3.6
Methods for assigning treatment groups
Patients will be stratified by geographical region and also by whether patients enter the whole 
body plethysmography sub-study. Randomization codes will be assigned strictly sequentially 
in each stratum as patients become eligible for randomization.
3.7
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). 
3.7.1
Maintaining the blind to the patient's blood eosinophils counts
While not entirely specific, patients on active benralizumab treatment are expected to have
lower blood eosinophil counts than patients on placebo. In order to mitigate potential 
unblinding on this basis, per protocol hematology will be run by the central laboratory. From 
Visit 4 on, eosinophil, basophil and monocyte counts will be redacted from any central 
laboratory reports sent to investigative sites to prevent the Principal Investigator/designee 
from possibly deducing the 'eosinophil + basophil' contribution to the complete blood count. 
3.8
Methods for unblinding 
Individual treatment codes, indicating the treatment randomization for each randomized 
subject, will be available to the Investigator(s) or pharmacists from the IVRS/IWRS. Routines 
for this will be described in the IVRS/IWRS user manual that will be provided to each centre.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomization. 
The Investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to subject to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product 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 
subject have been made and documented.


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3.9
Restrictions
3.9.1
Asthma medication restrictions
(a)
Use of SABA
Regularly scheduled or prophylactic SABA use is discouraged from enrolment and 
throughout the study duration. 
(b)
Use of short-acting anticholinergics (eg, ipratropium) as a rescue treatment for 
worsening asthma symptoms is not allowed from enrolment and throughout the 
study duration.
(c)
Use of long-acting beta-agonists as a reliever (eg, Symbicort Maintenance And 
Reliever Treatment) is not allowed from enrolment and throughout the study 
duration.
(d)
Maintenance of asthma controller medications
Changes to the patient's background medications are not allowed during the study.
Asthma exacerbations should be treated with oral or other systemic corticosteroids 
according to standard practice.
(e)
Asthma medication restrictions on the days of scheduled lung function 
assessment visit
Lung function assessments include FeNO, spirometry and whole body 
plethysmography (for a subset of patients). Procedures will be performed at the 
study center per the study plan and procedures in the following order: FeNO, 
spirometry, body plethysmography (if applicable). Restrictions to the patient’s 
background medication prior to the assessments are described below.
Patients should withhold their usual maintenance therapies on the day(s) when lung 
function testing is being performed. 
SABAs should be withheld for 6 or more hours before spirometry. Twice daily 
LABA- or LAMA-containing therapies should be withheld for 12-24 hours and 
once daily LABA- or LAMA-containing therapies for >24 hours before spirometry. 
LTRA should be restricted for >24 hours and twice daily theophyllines should be 
withheld for at least 12- 24 hours and once daily for >24 hours before spirometry 
assessments. 
If the patient has taken rescue SABA within 6 hours of the planned center visit 
spirometry, they should remain at the center until the 6 hour withholding time has 
been reached (as long as that does not exceed the 1.5 hour spirometry window). On 


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Visits 1, 2, 3 and visits 5 to Visit 11 they can return on another day within the visit 
window.
3.9.1.1
Other medication restrictions
(a)
Use of immunosuppressive medications is not allowed. Topical administration of 
immunosuppressive medication may be allowed at the discretion of the Investigator. 
Refer to section 3.2 and exclusion criterion 17 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
A table with medication-related restrictions is presented in Appendix E.
3.9.1.2
Other restrictions
(a)
Fertile and sexually active patients or their partners should use 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, and for 16 weeks (5 half-
lives) after last dose of IP (see Inclusion criterion 10)
(b)
Patients must abstain from donating blood and plasma from the time of informed 
consent, and for 16 weeks (5 half-lives) after last dose of IP.
(c)
Patients should avoid engaging in strenuous exertion for at least 30 minutes prior to 
all lung function assessments at the center.
(d)
Patients should avoid eating a large meal for at least 2 hours prior to all lung 
function assessments at the center.  
3.10
Discontinuation of investigational product
Subjects may be discontinued from investigational product (IP) in the following situations:
(a)
Patient decision. The patient is free to discontinue treatment at any time, without 
prejudice to further treatment (see Section 3.10.1)
(b)
Adverse event (AE) that in the opinion of the Investigator contraindicates further 
dosing
(c)
Risk to patient as judged by the Investigator or AstraZeneca
(d)
Pregnancy


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(e)
Lost to follow-up1
(f)
Severe non-compliance to the study protocol
(g)
Development of any study specific criteria for discontinuation
∀
Anaphylactic reaction to the investigational product requiring administration of 
epinephrine
∀
Development of helminth parasitic infestations requiring hospitalization
∀
An asthma-related event requiring mechanical ventilation
3.10.1
Procedures for discontinuation of a subject from investigational product 
At any time, subjects are free to discontinue investigational product or withdraw from the 
study (ie, investigational product and assessments – see Section 3.11), without prejudice to 
further treatment. A subject that decides to discontinue investigational should always be asked 
about the reason(s) and the presence of any adverse events. 
All patients must be administered the first dose of IP. If the patient misses the first IP 
administration they must be discontinued from the study and should return for IPD visit. If the 
patient receives the first IP administration but misses both the 2nd and the 3rd dose they must 
be discontinued from the study and should return for the IPD visit. If the patient receives the 
first IP administration but misses either the 2nd or 3rd dose they need not discontinue from the 
study
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 after the last dose of IP. At that visit, although no longer on IP, 
patients should be encouraged to remain in the study to complete all subsequent study visits, 
procedures, and assessments. Note that in this case, the IPD visit replaces the nearest regular 
visit while the following visits continue as possible
If the patient is not willing to participate further in the study after the IPD visit, the patient 
should still return for a follow up visit 8 weeks ±3 days after the last dose of IP for final study-
related assessments.
The reasons for premature discontinuation of IP should be recorded in the eCRF.
                                                
1 'Patient is considered lost to follow up when any of the following attempts of contact are failed: 3 attempts of 
either phone calls, faxes or emails; having sent 1 registered letter/certified mail; or 1 unsuccessful effort to check 
the vital status of the patient using publicly available sources, if allowed by local regulations.


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If a subject is withdrawn from study, see Section 3.11.
3.11
Criteria for withdrawal 
3.11.1
Screen failures 
Screen failures are patients who do not fulfil the eligibility criteria for the study, and therefore 
must not be randomized.  These patients should have the reason for study withdrawal recorded 
as ‘Incorrect Enrolment’ (ie, patient does not meet the required inclusion/exclusion criteria).  
This reason for study withdrawal is only valid for screen failures (not randomized patients).
3.11.2
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow up AEs outside of the clinical study. 
If a subject withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused. Withdrawn subjects will not be replaced. 
3.12
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed at 
undue risk because of clinically significant findings that:
!
meet individual stopping criteria or are otherwise considered significant 
!
are assessed as causally related to study drug, 
!
are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.


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4.
STUDY PLAN AND TIMING OF PROCEDURES 
Table 2
Study plan - Run-in period; Visit 1 to Visit 3
Assessment/Activity
Refer to
Enrolment
Run-in
Visit 1
Visit 2
Visit 3
D -35
D -21 (+/-2 days)
D -7 (+/- 2 days)
General procedures:
Informed consent
10.4
X
Inclusion/exclusion 
criteria
3.1/3.2
X
X
X
Demographics
4.1.1
X
Medical and asthma 
history
4.1.1
X
Patient Reported Outcome assessments:
ACQ-6
5.3.2.1
Xc
Safety assessments:
Complete physical 
examination
5.2.2.1/5.2.2.2
X
Vital signs
5.2.4
X
X
Weight, height, BMI
5.3.1
X
ECG
5.2.3.1
X
Adverse events
6
X
X
X
Concomitant medication
7.7/3.9.1/3.9.1.1
X
X
X
Laboratory assessments:
Clinical chemistry
5.2.1
X
Hematology
5.2.1
X
Urinanalysis
5.2.1
X
Serum pregnancy test
5.2.1.1
X
Serology (Hepatitis B, C, 
HIV-1, HIV-2)
5.3.3.1
X
FSH
5.2.1.1
Xb
Lung function assessments:


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Table 2
Study plan - Run-in period; Visit 1 to Visit 3
Assessment/Activity
Refer to
Enrolment
Run-in
Visit 1
Visit 2
Visit 3
D -35
D -21 (+/-2 days)
D -7 (+/- 2 days)
Exhaled NO (FeNO)
5.1.2
X
  
Spirometry (Pre-BD 
FEV1)
5.1.1
Xd
Xd
Reversibility (post-BD 
FEV1)
5.1.1.1
Xe,f
Xe,f
Xe
Sub-study assessments (if applicable):
Whole body 
plethysmography
5.4.1
X
a
This analysis will be only applicable for WOCBP patients.
b
FSH test done only for female patients to confirm postmenopausal status in women <50 years who have 
been amenorrheic for >=12 months
c
All patients must meet ACQ6 ≥1.5 at Visit 1. If this criteria is not met the patient must be screen failed and 
will not be allowed to rescreen.
d
For patients in the main study and the sub-study: The Pre BD FEV1 must be conducted at Visit 2 and at 
Visit 3. The Pre-BD FEV1 criteria must be met at either Visit 2 or at Visit 3.
e
For patients in the main study: If the patient did not meet Reversibility criteria at Visit 1, further attempts 
may be conducted at Visit 2 and at Visit 3. Reversibility testing must be performed using the algorithm as 
detailed in section 5.1.1.1.
f
For patients in the Body plethysmography sub-study: If the patient did not meet the reversibility criteria 
(using the algorithm as per section 5.1.1.1) at Visit 1, a further attempt may be conducted at Visit 2 only.
ACQ-6 Asthma Control Questionnaire 6; BMI Body Mass Index; FeNO Fractional exhaled Nitric Oxide; FEV1 
Forced expiratory volume in 1 sec; FSH Follicle-stimulating hormone; HIV Human Immunodeficiency 
virus; pre-BD pre-bronchodilator; post-BD post-bronchodilator; D Day; ECG Electrocardiogram; NO nitric 
oxide; V Visit; W Week; WOCBP Women of childbearing potential 


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Table 3
Study Plan - Randomization, treatment period, follow-up; Visit 4 to Visit 11
Assessment/
activity
Refer to
Treatment
EOT
IPD
FU
Unsb
V4
(D0)
V5
(D3)
V6
(D7)
V7
(D14)
V8
(D28)
V9
(D56)
V10
(D84)
V11
(D112)
Visit window (days)a)
+1
±1
±3
±3
±3
±7
±7
±7
N/A
General procedures:
Inclusion/
exclusion criteria
3.1/3.2/
3.3.1/ 
3.3.2
X
Randomization
4.2/3.6
X
Patient and clinician Reported Outcome assessments:
ACQ-6
5.3.2.1
Xg
X
X
X
X
X
SGRQ
5.3.2.2
X
X
X
X
X
PGI-S
5.3.2.3
X
X
X
X
X
X
X
PGI-C
5.3.2.4
X
X
X
X
X
X
CGI-C
5.3.2.4
X
X
X
X
X
X
X
Safety assessments:
Complete physical 
examination
5.2.2.1
X
X
X
Brief physical 
examination
5.2.2.2
X
X
X
X
Xb


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Table 3
Study Plan - Randomization, treatment period, follow-up; Visit 4 to Visit 11
Assessment/
activity
Refer to
Treatment
EOT
IPD
FU
Unsb
V4
(D0)
V5
(D3)
V6
(D7)
V7
(D14)
V8
(D28)
V9
(D56)
V10
(D84)
V11
(D112)
Visit window (days)a)
+1
±1
±3
±3
±3
±7
±7
±7
N/A
ECG
5.2.3.1
X
Vital signs
5.2.4
X
X
X
X
X
X
X
X
X
Xb
Adverse events
6
X
X
X
X
X
X
X
X
X
Xb
Concomitant 
medication
7.7/3.9.1
/3.9.1.1
X
X
X
X
X
X
X
X
X
Xb
Laboratory assessments:
Clinical chemistry
5.2.1
X
X
X
X
Hematology
5.2.1
X
X
X
X
Blood for eosinophil 
countc
5.2.1/ 
3.7.1
X
X
X
X
X
X
X
X
X
Total IgE
5.3.3.2
X
Serum pregnancyd
5.2.1.1
X
X
X
Urinanalysis
5.2.1
X
X
Urine pregnancy test, 
dipstick
5.2.1.1
X
X
X
X
X
X
PKe
5.3.4
X
X
X
X
X
X
X
X
ADA/nAbf
5.3.5.3
X
X
X


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Table 3
Study Plan - Randomization, treatment period, follow-up; Visit 4 to Visit 11
Assessment/
activity
Refer to
Treatment
EOT
IPD
FU
Unsb
V4
(D0)
V5
(D3)
V6
(D7)
V7
(D14)
V8
(D28)
V9
(D56)
V10
(D84)
V11
(D112)
Visit window (days)a)
+1
±1
±3
±3
±3
±7
±7
±7
N/A
Lung function assessments:
Spirometry 
(pre-BD FEV1)
5.1.1
Xh)
X
X
X
X
X
X
X
X
Exhaled NO 
(FeNO)
5.1.2
X
X
X
X
X
X
X
X
Sub-study assessments: (if applicable)
Whole body 
plethysmography
5.4.1
X
X
X
X
X
X
X
Randomization:
Randomization
4.3/3.6
X
Investigational Product administration
Benralizumab/ 
placebo
7.2/7.5/
7.6
X
X
X
a
All visits are to be scheduled from the date of randomization, not from the date of previous visit, except for early discontinuation from IP (see Section 
3.10 for details)
b
Unscheduled visits may be initiated as needed, and any additional assessments may performed at these visits, at the discretion of the Investigator. 
Procedures listed in the table are mandatory for each UNS visit.
c
Blood eosinophil count will assessed in central laboratory as a part of the hematology panel but eosinophil, basophil and monocyte count will be 
redacted from the reports available for investigative sites
d
This analysis will be only applicable for WOCBP patients.


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e
On dosing visits PK will be collected pre-dose
f
Neutralizing antibody (nAb) testing will occur for all samples that are ADA positive. Samples that are ADA negative will not be tested for nAb.
g
The patient must have an ACQ 6 >0.75 prior to randomization. If not the patient must be screen failed and cannot be rescreened
h
Pre-BD FEV1 must be conducted 60 min (+/- 10 min) and 30 min (+/- 10 min) prior to randomization and assessed against exclusion criteria in section 
3.3.2. 
ACQ-6 Asthma Control Questionnaire 6; ADA anti-drug antibodies; CGI-C Clinician Global Impression of Change; D Day; ECG Electrocardiogram; FeNO 
Fractional exhaled Nitric Oxide; FEV1 Forced expiratory volume in 1 sec; IgE Immunoglobulin E; IPD Premature Investigational Product 
Discontinuation; nAb Neutralizing antibodies; NO nitric oxide; PK Pharmacokinetics; PGI-C Patient Global Impression of Change; PGI-S Patient 
Global Impression of Severity; pre-BD pre-bronchodilator; post-BD post-bronchodilator; SGRQ St. George’s Respiratory Questionnaire; UNS 
Unscheduled visit; V Visit; W Week; WOCBP Women of childbearing potential


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4.1
Enrolment/screening period
4.1.1
Enrolment (Visit 1) Day -35
Each potential patient will provide written informed consent prior to any study specific 
procedures and undergo assessments applicable for the visit (see Table 2).
Demographics data collected will include date of birth/age, sex, race and ethnicity.
Patient must sign the Informed Consent Form (ICF) prior to any Visit 1 procedures and prior 
being instructed to withhold any medication. Registration of patient’s enrolment via 
IWRS/IVRS should occur on the day of ICF signature.
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 prior to 
enrolment. A patient’s verbal history suggestive of asthma symptoms, but without supporting 
documentation, is not sufficient to satisfy this inclusion criterion.
The following procedures are to be performed and/or data to be collected at Visit 1 (please 
refer to the schedule of assessments for details):
!
Informed consent process
!
Confirmation of eligibility criteria
!
Height/Weight/BMI
!
Complete physical examination
!
Medical and asthma history (including prior medication use)
!
A record of at least 2 asthma exacerbations within the previous 12 months must also be 
documented in source prior to enrolment
!
ACQ-6 score must be ≥1.5. If this criteria is not met the patient must be screen failed 
and will not be allowed to rescreen. 
!
ECG
!
Vital signs
!
Laboratory assessments (including clinical chemistry, hematology, urinalysis, serum 
pregnancy test, FSH (if needed) and serology for Hepatitis B, C, HIV-1, HIV-2)


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!
Reversibility testing - can be performed only in case the patient meets appropriate 
medication restrictions. If a patient has not met the required medication restrictions or 
fails the protocol-specified reversibility criterion (≥12% and 200 ml) at Visit 1, further 
attempts are allowed at Visit 2 or at Visit 3. If participating in the body 
plethysmography sub-study, the patient must meet reversibility criteria at Visit 1 or 2. 
No further attempt is allowed at Visit 3
4.1.2
Screening/run-in (Visit 2) Day -21
Assessments applicable for the period are listed in Table 2.
Visit 2 is primarily concerned with evaluating whether lung function meets study eligibility 
criteria.
Ensure that the patient has met the required medication restrictions. Fractional exhaled NO 
measurements must be performed prior to any spirometry assessments. 
Spirometry - Pre-bronchodilator FEV1 criterion (<80%) will be tested for the first time at 
Visit 2. If reversibility testing was not performed at Visit 1 or a patient fails the protocol 
specified reversibility criterion (≥12% and 200 ml) a second attempt is allowed at Visit 2. For
patients participating in the main study only - another attempt is allowed at Visit 3.
The following key procedures are to be performed and/or data to be collected on Visit 2 
(please refer to the schedule of assessments for details):
!
Revision of inclusion/exclusion criteria 
!
Collection of adverse events
!
Concomitant medication review
!
Vital signs measurement
!
Fractional exhaled nitric oxide (FeNO) level measurement
!
Pulmonary function tests (including Pre-BD FEV1 testing, reversibility testing, if the 
reversibility criterion was not met at Visit 1). 
4.1.3
Screening/run-in (Visit 3) Day -7
For main study only:
A pre BD FEV1 should be recorded at Visit 2 as well as at Visit 3, irrespective of whether the 
patient has met protocol specified pre-bronchodilator FEV1 criterion (<80%) at Visit 2 or not. 
If a patient fails the protocol specified reversibility criterion (≥ 12% and 200 ml) at Visit 1 or 
at Visit 2, a further attempt is allowed at Visit 3.


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For sub study only:
Visit 3 is primarily concerned with body plethysmography assessments. Please ensure that all 
required medication restrictions are adhered to prior to performing these assessments.
A pre BD FEV1 should be recorded at Visit 2 as well as at Visit 3, irrespective of whether the 
patient has met protocol specified pre-bronchodilator FEV1 criterion (<80%) at Visit 2 or not. 
Please ensure that inclusion criteria #5 and #7 are met prior to performing body 
plethysmography assessments.
Reversibility testing cannot be performed at Visit 3. This criteria must be met at either Visit 1 
or at Visit 2 for those patients participating in the sub-study.
4.1.4
Re-screening
If the reason for screen failure was transient (including but not limited to study-supplied 
equipment failure or unforeseen personal events that mandate missed screening visits), 
rescreening can be allowed only once. 
Re-screened patient should re-sign informed consent on the re-screening Visit 1.  All 
procedures from screening/run-in period should be repeated.
4.1.4.1
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. Once the exacerbation has been fully treated and the patient has 
returned back to their usual maintenance dose and remained on this dose for at least 2 weeks 
they can be rescreened (only once). 
4.2
Treatment period
Inclusion criteria at randomization will be confirmed at Day 0. Adherence to all criteria listed 
in section 3.3 must be confirmed prior to randomization on Visit 4 (Day 0)
Patients confirmed to be eligible will be randomized at Day 0. 
During the Day 0 visit, the patient should complete the following assessments: SGRQ and 
ACQ-6 completion, and then pre-BD spirometry 60 min and 30 min prior to IP administration. 
Patients will be randomized to either placebo or benralizumab 30 mg every 4 weeks 
throughout the treatment period.
Patients will have more frequently scheduled visits in the 2 weeks after the first IP 
administration and then more infrequent visits for the rest of study duration (refer Table 3). 
Restrictions as set out in Section 3.9 will continue to apply throughout the treatment period. In 
case of an asthma worsening/exacerbation (see Section 4.1.4.1) patients should be evaluated at 
the study center when feasible.


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At Visit 10 (Day 84±7), patients will come to the center for the End of Treatment (EOT) visit.
For patients who prematurely discontinued IP and are not willing to continue to participation 
in the study refer to Section 3.10 and 3.11. 
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 have follow-up visit 
at Visit 11 (Day 112±7). For study assessments schedule during this visit please refer to Table 
3.
5.
STUDY ASSESSMENTS
Medidata Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling. The investigator will ensure that data are recorded on the electronic Case 
Report Forms as specified in the study protocol and in accordance with the instructions 
provided.
The investigator ensures the accuracy, completeness and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed electronic Case Report Forms. A copy of the completed 
electronic Case Report Forms will be archived at the study site.
5.1
Efficacy assessments
5.1.1
Spirometry
General requirements
Lung function (FEV1 and forced vital capacity [FVC]) at the study center will be measured by 
spirometry using equipment provided by central vendor.  Spirometry will be performed by the 
Investigator or authorized delegate according to American Thoracic Society/European 
Respiratory Society (ATS/ERS) guidelines (Miller et al 2005).
The central spirometry vendor is responsible for assuring that the spirometer meets ATS/ERS 
recommendations and that the study center personnel who will be performing the testing are 
properly certified.  Spirometry calibration will be detailed in a separate spirometry procedures 
manual.
Important! Patients should withhold their SABA medication(s) for at least 6 hours prior to all 
scheduled lung function assessments. Twice daily LABA- or LAMA-containing therapies 
should be withheld for 12-24 hours and once daily LABA- or LAMA-containing therapies for 
>24 hours before spirometry. LTRA should be restricted for >24 hours and twice daily 


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theophyllines should be withheld for at least 12- 24 hours and once daily for >24 hours before 
spirometry assessments.
Options for handling patients who have inadvertently taken their asthma medication within the 
restricted window are described in Section 3.9.1.
Time of day for scheduled center visit spirometry
Spirometry testing should be done initiated in the morning between 6:00 AM and 11:00 AM 
according to the schedule provided in Table 2 and Table 3. All post-randomization spirometry 
assessments should be performed within ±1.5 hours of the time at which the qualifying pre-
BD FEV1 spirometry was performed either at Visit 2 or Visit 3. 
For example, if the spirometry (pre-BD FEV1) was started at 08:00 AM at Visit 3 and this 
spirometry met inclusion #5, then all subsequent spirometry testing needs to be initiated 
between 06:30 AM and 9:30 AM.
Spirometry technique
Patients should avoid engaging in strenuous exertion for at least 30 minutes prior to 
spirometry measurements. Patients should avoid eating a large meal for at least 2 hours prior 
to spirometry measurements at the center. Forced expiratory maneuvers should be performed 
with the patient seated in an upright position.  If this is not comfortable for the patient, 
standing is permitted.  The same position should be used by the patient for each forced 
expiratory maneuver from enrolment throughout the study. The head must not be tilted during 
maneuvers and the thorax should be able to move freely; hence, tight clothing should be 
loosened. A nose-clip should be used for the maneuver. 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 (PN) 
value (Quanjer et al 2012) will be recorded. The highest FVC will also be reported regardless 
of the effort in which it occurred (even if the effort did not result in the highest FEV1).
Order of administration of usual asthma controller medication and IP relative to 
scheduled pre- and post-bronchodilator spirograms
The patient’s usual morning asthma controller therapy must not be given until after the 
exhaled NO and pre-BD spirometry are complete. 


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For sites participating in the body plethysmography sub-study the usual asthma controller 
medication must be withheld till all the plethysmography assessments are completed. 
Investigational product dosing should also be not performed until pre-BD spirometry is 
complete. 
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, patient enrolment 
code, date and time of measurement, and visit number.
Spirometry references
The Global Lung Function Initiative (GLI) equations will be used to determine the patients 
PN values and are pre-programmed into your spirometer (Quanjer et al 2012).
FEV1 expressed as percent of the PN value will be calculated as follows:
FEV1% of PN = FEV1 measured/FEV1PN x 100
5.1.1.1
Reversibility testing
The procedure described in this section refers to the reversibility testing that can be performed 
at either Visit 1, Visit 2 or Visit 3. If a patient is participating in the body plethysmography 
sub-study, reversibility testing can only be performed either at Visit 1 or Visit 2 only.
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 4 inhalations). It is 
highly recommended to use a spacer device for this procedure. The algorithm for reversibility 
testing is outlined in Figure 3.


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Figure 3
Reversibility testing algorithm


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A lower total dose, eg, 2 inhalations instead of 4 puffs, can be used if there is a concern about 
any effect on the patient’s heart rate, tremor, or safety.
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
5.1.2
Fractional exhaled nitric oxide measurement
Airway inflammation will be evaluated using a standardized single-breath fractional exhaled 
nitric oxide (FeNO) test (ATS 2005). 
Since spirometry can potentially impact the nitric oxide measurement, the FeNO test needs be 
completed prior to spirometry. In addition, subjects should not eat or drink 1 hour prior to 
having the FeNO, as this may affect the results. 
While sitting, subjects are to inhale to total lung capacity through the NIOX MINO® Airway 
Inflammation Monitor (Aerocrine, New Providence, New Jersey) and then exhale for 10 
seconds at 50 mL/sec (assisted by visual and auditory cues). The value obtained will be 
recorded and the process repeated twice for a total of 3 measurements. The 3 measurements 
will be printed to serve as a source document. 
NIOX MINO® sensors will be replaced as recommended by the manufacturer.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Safety laboratory tests (list provided in Table 4 below) will be performed in a central 
laboratory. For information on methods of collection, assessment, labelling, storage, and 
shipment of samples please refer to the separate Laboratory Manual. Safety samples will be 
collected in accordance with the schedules provided in Table 2 and Table 3.
Hematology and urinalysis will be assessed in line with the schedules provided in Table 2 and 
Table 3.
The following laboratory variables will be measured:


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Table 4
Laboratory safety variables
Hematology/hemostasis 
(whole blood)
Clinical chemistry (serum or plasma)
Urinalysis
Hematocrit
Alkaline phosphatase (ALP)
Appearance
Hemoglobin (Hb)
Aspartate transaminase (AST)
Blood
Mean corpuscular volume 
(MCV)
Alanine transaminase (ALT)
Color
Platelet count
Blood urea nitrogen (BUN)
Ketones
Red blood cell (RBC)
Calcium
Microscopy including
WBC/high power field
(HPF), RBC/HPF
White blood cell (WBC) 
count with differential
Chloride
pH
Creatinine
Specific gravity
Gamma-GT (gamma-glutamyl transpeptidase)
Glucose
Phosphorus
Potassium
Sodium
Bilirubin, total
Cholesterol, total
Uric acid
a
Eosinophils, basophils and monocytes counts will be redacted from central laboratory reports except for 
Visit 1 (see Section 3.7).
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables.  For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.3.
NB. In case a subject shows an AST or ALT ≥3xULN and total bilirubin ≥2xULN please 
refer to Appendix D ‘Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law’, for further instructions.
5.2.1.1
Pregnancy test
The following tests are applicable to female patients only and will be conducted in accordance 
with the schedules provided in Table 2 and Table 3.


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!
Serum beta-hCG: To be done at screening Visit 1, Visit 10 and premature IP 
discontinuation visit (IPD), for WOCBP (analyzed at central laboratory) 
!
FSH: To be done at screening Visit 1 only, for female patients to confirm 
postmenopausal status in women <50 years who have been amenorrheic for ≥12 
months 
!
Urine HCG: To be performed at the study center for WOCBP at each treatment visit 
(before IP administration on Visit 4, Visit 8, Visit 9, Visit 10, IPD and Visit 11) using 
a dipstick. A positive urine test result must be confirmed with serum beta HCG.
5.2.2
Physical examination
Physical examination will be done in accordance with the schedules provided in Table 2 and 
Table 3.
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 6.3.
5.2.2.1
Complete physical examination
A complete physical examination will be performed and include an assessment of the 
following: general appearance, respiratory, cardiovascular, abdomen skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, abdomen, musculo-skeletal 
(including spine and extremities) and neurological systems.
5.2.2.2
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.
5.2.3
Electrocardiogram
5.2.3.1
Resting 12-lead electrocardiogram
Electrocardiograms (ECG) are to be performed in accordance with the schedule provided in 
Table 2 and Table 3. 
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 and administration of the asthma-related medications and IP).
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, 


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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. 
ECG data and evaluation will be recorded in the eCRF.
5.2.4
Vital signs
5.2.4.1
Pulse and blood pressure
Pre-dose vital signs (pulse, blood pressure, respiration rate, and body temperature) are to be 
obtained in accordance with schedule provided in Table 2 and Table 3
Vital signs are to be taken prior to IP administration, and, if possible, before blood drawing 
and usual asthma controller medication.  Vital signs should also be taken prior to 
bronchodilator administration if applicable for that visit.
5.2.4.2
Body temperature
Body temperature is to be recorded in degrees Celsius. 
5.3
Other assessments
5.3.1
Weight and height
Weight and height will be measured, and BMI calculated in accordance with schedules 
provided in Table 2.
The patient's weight will be recorded in kilograms; height will be recorded in centimeters.
Weight and height measurements will be performed in light clothing and with shoes off.
5.3.2
Patient reported outcomes
Patients will complete patient-reported outcome (PRO) assessments using a tablet ePRO 
device at the site. Patients will complete a training module prior to the first assessment to 
ensure that they understand how to use the device.
PRO assessments should be done before other visit procedures. 
5.3.2.1
Asthma Control Questionnaire 
The ACQ-6 is a shortened version of the Asthma Control Questionnaire (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.
Patients are asked to recall how their asthma has been during the previous week by responding 
to 1 bronchodilator use question and 5 symptom questions.
Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely 
uncontrolled). The mean ACQ-6 score is the mean of the responses. Mean scores of ≤0.75 


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indicate well-controlled asthma, scores between 0.75 and ≤1.5 indicate partly controlled 
asthma, and a score >1.5 indicates not well controlled asthma (Juniper et al 2006). Individual 
changes of at least 0.5 are considered to be clinically meaningful.
By omitting the ACQ-6 bronchodilator use question from the scoring algorithm, an ACQ-5 
score can be calculated.
The questionnaire will be completed at the study center via provided site tablet (ePRO) in 
accordance with schedule provided in Table 2 and Table 3
5.3.2.2
St. George’s Respiratory Questionnaire 
The St. George’s Respiratory Questionnaire (SGRQ) is a 50-item PRO instrument developed 
to measure the health status of subjects with airway obstruction diseases (Jones et al 1991). 
The questionnaire is divided into 2 parts: part 1 consists of 8 items pertaining to the severity of 
respiratory symptoms in the preceding 4 weeks; part 2 consists of 42 items related to the daily 
activity and psychosocial impacts of the individual’s respiratory condition. The SGRQ yields 
a total score and 3 domain scores (symptoms, activity, and impacts). The total score indicates 
the impact of disease on overall health status. This total score is expressed as a percentage of 
overall impairment, in which 100 represents the worst possible health status and 0 indicates 
the best possible health status. Likewise, the domain scores range from 0 to 100, with higher 
scores indicative of greater impairment. Specific details on the scoring algorithms are 
provided by the developer in a user manual (Jones et al 2009).
5.3.2.3
Patient Global Impression of Severity assessments
The Patient Global Impression of Severity (PGI-S) is a single item designed to capture the 
patient’s perception of overall symptom severity at the time of completion using a 6-point 
categorical response scale (no symptoms to very severe symptoms). For the time of 
completion, refer to Table 3.
The PGI-S should be completed on the site tablet by the patient before other study 
assessments and IP administration per the schedule provided in Table 3
5.3.2.4
Clinician and Patient Global Impression of Change assessments
Clinician Global Impression of Change (CGI-C) and Patient Global Impression of Change 
(PGI-C) instruments are used for an overall evaluation of response to treatment. The 
Investigator (clinician) and the patient will be asked to rate the degree of change in the overall 
asthma status compared to the start of treatment, ie, randomization visit. A 7-point rating scale 
will be used: 1= Very Much Improved; 2= Much Improved; 3= Minimally Improved; 4= No 
Changes; 5=Minimally Worse; 6=Much Worse and 7= Very Much Worse.
The CGI-C and PGI-C should be completed on the site tablet by the patient before other study 
assessments and IP administration per the schedule provided in Table 3


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5.3.3
Other screening/run-in assessments
5.3.3.1
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.
5.3.3.2
Serum immunoglobulin E
The levels of total immunoglobulin E (IgE) will be evaluated by a central laboratory. These 
tests will be performed at Visit 4 (Week 0) (see Table 3).
Instructions for sample collection, processing, storage, and shipment can be found in the 
separate laboratory manual provided to the centres.
5.3.4
Pharmacokinetics
5.3.4.1
Collection of samples
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 every visit from Visit 4 to Visit 10. On the dosing days, ie, Visit 4, 8 
and 9, the serum will be collected as pre-dose.
5.3.4.2
Determination of drug concentration
Samples for determination of drug concentration in serum will be analyzed by a central 
laboratory on behalf of AstraZeneca, using a validated bioanalytical method.  Full details of 
the analytical method used will be described in bioanalytical report.
5.3.4.3
Storage and destruction of pharmacokinetic samples
The PK samples will be retained at AstraZeneca or designee for a maximum of 3 years 
following publication of the CSR to properly address potential questions from regulatory 
authorities (RAs).
A summary of PK analysis results will be reported in the Clinical Study Report (CSR).


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5.3.5
Pharmacodynamics
5.3.5.1
Collection of samples
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]).
5.3.5.2
Immunogenicity
Instructions for immunogenicity (ADA and nAb) sample collection, processing, storage, and 
shipment can be found in the separate laboratory manual provided to the centers.
The immunogenicity samples will be retained at AstraZeneca or designee for a maximum of 3 
years following publication of the CSR to properly address potential questions from RAs.
A summary of the analysis will be presented in the CSR. Details of the analytical method used 
will be described in a bioanalytical report.
5.3.5.3
Anti-drug antibodies  
Serum samples for analysis of anti-drug antibodies (ADA) will be collected pre-dose at 
selected visits according to the study plan (see Table 3).
The presence or absence of ADA will be determined in the serum samples using validated 
bioanalytical methods.
5.3.5.4
Neutralizing antibodies
In vitro neutralizing antibody (nAb) activity is to be tested at all ADA collection time points 
of Week 16 and later in samples that are ADA-positive. Samples that are ADA-negative will 
not be tested for nAb. 
The presence or absence of neutralizing antibodies will be determined using a validated 
bioanalytical method.
5.3.6
Pharmacogenetics
Pharmacogenetic samples will not be taken during the study
5.3.7
Biomarker analysis 
Samples for biomarker analysis will not be collected during the study. 
5.3.8
Handling of biological samples
5.3.8.1
Labelling and shipment of biological samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see IATA 6.2 Guidance Document’.


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Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the subject unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved.
5.3.8.2
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each center keeps full traceability of collected biological samples 
from the subjects while in storage at the center until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival (where applicable).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca biobank system during the 
entire life cycle.
5.4
Additional assessments applicable for the subset of subjects – body 
plethysmography sub-study
Additional assessments will be performed for a subset of subjects at designated sites, 
approximately 50 subjects in the study, to determine the effect of benralizumab on the time 
course of change in lung function as assessed through body plethysmography.
Patients who participate in the sub-study will perform other lung function assessments as 
mentioned in sections 4.1.1, 4.1.2, 4.1.3, 4.2 and 4.3.
5.4.1
Body plethysmography
Body plethysmography is to be performed only by sites participating in the body 
plethysmography sub-study and will be performed on approximately 50 patients. 
Lung volume subdivisions which include total lung capacity (TLC), residual volume (RV), 
vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well 
as airway resistance (Raw and SGaw) measurements, will be performed at study sites by the 
Investigator or qualified designee according to ATS/ERS guidelines (Wanger et al 2005) 
according to the study schedule (see Table 2 and Table 3).
Lung volumes will be determined by body plethysmography. The test will be performed by 
qualified pulmonary function technicians with experience performing this assessment. At least 
3 FRC values that agree within 5% (ie, the difference between the highest and lowest value 
divided by the mean is <0.05) should be obtained and the mean value reported.


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It is expected that medication restrictions required for spirometry assessments (see section 3.9) 
are met for body plethysmography too. To enable that, body plethysmography assessments 
should be done soon after pre-BD spirometry assessments are complete, and before 
medications are given to patient.
Each site is expected to use their own body boxes to conduct assessments provided they meet 
the quality and experience criteria set by AstraZeneca. Details related to this procedure are 
provided in a separate body plethysmography manual provided to the designated study 
centers.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product.  An 
undesirable medical condition can be symptoms (eg. nausea, chest pain), signs (eg, 
tachycardia, enlarged liver) or the abnormal results of an investigation (eg, laboratory 
findings, electrocardiogram). In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, 
treatment, wash-out, follow-up), that fulfils 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 subject or may require medical 
intervention to prevent 1 of the outcomes listed above


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For further guidance on the definition of a SAE, see Appendix B to the clinical study protocol
(CSP).
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse events will be collected from time of signature of informed consent throughout the 
treatment period and including the follow-up period (through Day 112 [±7days]).
Serious adverse events will be recorded from the time of informed consent.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at follow-up in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in 
the case report form (CRF). AstraZeneca retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary.
6.3.3
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 Investigational Product (yes or no)
!
Action taken with regard to investigational product
!
AE caused subject’s withdrawal from study (yes or no)
!
Outcome.
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE
!
Date Investigator became aware of serious AE
!
AE is serious due to
!
Date of hospitalization


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!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
Description of AE
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, 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 A to the Clinical 
Study Protocol.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the CRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarized in the 
clinical study report.  Deterioration as compared to baseline in protocol-mandated laboratory 


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values, vital signs should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the investigational product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
6.3.6.1
Symptoms of the disease under study
6.3.7
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. Please refer to Appendix D for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
6.3.8
Disease progression
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 6.1
•
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.
Asthma exacerbation should be recorded as an AE or SAE only if it fulfills any of the above 
criteria.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, 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 site personnel inform 
the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.


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The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 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 adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day ie, immediately but no later than 24 hours of when he or she becomes 
aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed. 
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure (IB) for the AstraZeneca drug.
6.5
Overdose
!
An overdose with associated AEs is 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 is only reported on the Overdose CRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.


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6.6.1
Maternal exposure
If a subject becomes pregnant during the course of the study investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product 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 subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
6.6.2
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.
6.7
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 (Lieberman et al 2010).  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:


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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. 
In order to help understand the potential drug-relatedness of any acute reaction, a blood 
sample should be drawn during 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.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
All investigational products will be manufactured in accordance with Good Manufacturing 
Practice (GMP).
Benralizumab and placebo administered in the study will be a clear to opalescent, colorless to 
yellow solution
Investigational product
Dosage form and strength
Manufacturer
Benralizumab
30 mg/mL solution for injection 
in accessorized pre-filled 
syringe, 1 mL fill volume
MedImmune
Placebo
Matching placebo solution for 
injection in accessorized pre-
filled syringe, 1 mL fill volume
MedImmune
7.2
Dose and treatment regimens
The IP will be administered at the study center on treatment visits and within visit windows as 
specified in Table 3.
Before investigational product administration
Prior to each IP administration:


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!
Investigator/authorized delegate will assess injection site as per standards of medical 
care
!
For WOCBP, urine pregnancy test will be done; IP will be administered only when the 
result of the test is negative (see Section 5.2.1.1)
Investigational product administration
The IP will be administered by the Investigator/authorized delegate. It is advised that the site 
of injection of the IP be rotated such that the patient receives IP at a different anatomical site 
at each treatment visit. Suggested injection site rotation sequence is presented below (see 
Figure 4).
Figure 4
Injection sites and rotation scheme
In the case when rotation of the injection site is not favorable for the patient and/or 
Investigator, the reason should be recorded in the source documents.  The injection site of the 
IP should be recorded in the source documents and eCRF at each treatment visit.
Further details on IP administration are provided in the IP Handling Instruction.  
Investigational product administration must be carried out in line with the Instruction.
After investigational product administration
After IP administration the patient should be observed for a minimum of 2 hours for the 
appearance of any acute drug reactions.
Conditions requiring investigational product administration rescheduling 
If any of the following 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)


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!
The patient, in the opinion of the Investigator, is experiencing an acute or emerging 
asthma exacerbation
!
The patient is febrile (≥38°C; ≥100.4°F) within 72 hours prior to the IP administration
7.3
Labelling
Labelling of the IP will be carried out by AstraZeneca or desingee in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines of each country participating in 
the study. The labels will fulfil GMP Annex 13 requirements for labelling. Label text will be 
translated into local language. 
The label will include the following information:
!
study code
!
Investigational product/study drug dosage form, route of administration and quantity 
of dosage units
!
kit ID
!
P Lot ID
!
Expiry date
!
Investigator Name (to be written on the label)
!
E-code (to be written in the label)
!
Sponsor name and contact details
!
Directions for use
!
Storage condition
!
Standard statements required by regulatory authorities
7.4
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 the center staff should not use affected IP and should immediately 
contact an AstraZeneca representative for further guidance:


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•
Temperature excursion upon receipt or during storage at the study
•
Damaged kit upon receipt
•
Damaged syringe/cartridge
Damaged IP should be documented via IWRS/IVRS (refer to IWRS/IVRS manual for further 
details).
7.5
Compliance
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the CRF.
The IP will be administered at the study center on treatment visits and within visit windows as 
specified in Table 3. 
7.6
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 subject.
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.
7.7
Concomitant and other treatments 
Information about any treatment in the 3 months prior to the date of the informed consent, 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 2 and Table 
3) and recorded in the eCRF.
Note: To satisfy inclusion criterion 3 (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. 
7.7.1
Background medication
All patients are required to be treated with stable dose ICS/LABA for at least 30 days prior to 
Visit 1 and during the course of the study. For ICS/LABA combination preparations, high-
strength maintenance doses approved in the local country will meet this criterion. If the ICS 
and LABA therapies are given by separate inhalers, the ICS dose must be >500 μg fluticasone 
proprionate dry powder formation or equivalents daily.


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The background asthma controller medications should be maintained at a stable dose from 
Visit 1 until the end of the study. No changes are allowed to background medications 
throughout the duration of the study except during the treatment of an asthma exacerbation.
7.7.2
Rescue medication
Short-acting bronchodilators (SABAs) may be used as rescue medication during the study in 
the event of a worsening of asthma symptoms.
7.7.3
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
subject’s safety and well-being, may be given at the discretion of the Investigator and 
recorded in the appropriate sections of the CRF.
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violators identified.
Analyses will be performed by AstraZeneca or its representatives. 
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first subject 
randomized and any subsequent amendments will be documented, with final amendments 
completed prior to unblinding of the data.
8.2
Sample size estimate
The study is powered for the primary objective of the study to determine the effect of 
benralizumab on the time course of change (onset and maintenance of effect) of pre-BD FEV1. 
The first post baseline timepoint where the p-value for the mean difference between 
benralizumab and placebo is less than or equal to 0.05 will be used to determine time to onset 
of effect. The average over the mean differences between benralizumab and placebo based on 
the change from baseline (Visit 4) to Days 28 (Visit 8), 56 (Visit 9) and 84 (Visit 10) in pre-
BD FEV1 will be used to determine if the study is positive as well as maintenance of effect. 
The benralizumab Phase 2b study MI-CP220 (Castro et al 2014) as well as results from the 
benralizumab Phase 3 asthma exacerbation studies were used as a basis for the sample sizing. 
From these studies, it is expected that around 115 patients per treatment arm (230 in total) will 
provide approximately 90% power for the primary endpoint pre-BD FEV1 with type I error 
controlled at a two-sided alpha level of 0.05 if the true average over the mean treatment 
differences (benralizumab – placebo) across Days 28 (Visit 8), 56 (Visit 9) and 84 (Visit 10) is 
138 mL. The sample size will also be sufficient to have approximately 80% power for an 
average over the mean treatment difference of 120 mL. The assumed variability has a within 
group standard deviation of 375 mL and within subject correlation of 0.6. If the within 


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subject variability is reduced to 350 mL the sample size would be sufficient to have 80% 
power for an average of 110 mL. In addition, it is expected that around 115 patients per 
treatment arm will have 80% power to detect a true treatment difference (benralizumab –
placebo) of 130 mL assuming a within-group standard deviation of 350 ml or a true treatment 
difference of 140 mL assuming a standard deviation of 375 mL. Based on these assumptions, 
the minimum difference that would be statistically significant at the 0.05 level range from 
approximately 85 to 100 mL. The sample size was estimated using nQuery+nTerim version 
3.0 using methodology in (Liu et al 2005)
8.3
Definitions of analysis sets
All efficacy will be performed according to the Intent-to-Treat (ITT) principle based on the 
full analysis set. For consistency, demographic and baseline characteristics will be presented 
using the full analysis set. Safety objectives 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, and 
assent when applicable, to participate in the study will be included up to the date of their study 
termination.
8.3.3
Body plethysmography sub-study analysis set
The subset of patients who are randomized as part of the body plethysmography sub-study and 
receive any IP will be analyzed as described for the full analysis set.
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 1 or several occasions received active treatment will be classified as active. All safety 
summaries will be based on this analysis set
8.3.5
Pharmacokinetic analysis set
All patients who received benralizumab and from whom PK blood samples are assumed not to 
be affected by factors such as protocol violations and who had at least 1 quantifiable serum 
PK 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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8.4
Outcome measures for analyses
Definition of baseline
In general, the last measurement prior to the first dose of study treatment will serve as the 
baseline measurement. If time is collected, assessments performed the same day but at a time 
prior the first dose of study treatment will be included in baseline definition. If there is no 
value prior to the first dose of study treatment, then the baseline value will not be imputed and 
will be set to missing.
Visit 4 is the planned baseline visit, for all assessments carried out at a center, except for 
physical examination. The baseline visit for physical examination will be Visit 1.
The pre-BD FEV1 measurement recorded at Visit 4 will be used as baseline FEV1. If the Visit 
4 pre-BD measurement is missing, the last non-missing pre-BD value before Visit 4 will be 
used as baseline instead.
Change from baseline will be calculated as the post-baseline assessment value minus the 
baseline assessment value. If either value is missing, then the change from baseline value will 
be missing.
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 Visit 4 and the conclusion of EOT visit, 
inclusive.
8.4.1.1
Pre-bronchodilator forced expiratory volume in 1 second
Time to onset of effect in Pre-BD FEV1 is the primary objective of this study. The mean 
change from baseline to each of the post-randomization visits (post Visit 4) up to and 
including the end of double-blind treatment visit at day 84 (Visit 10) of pre-BD FEV1 will be 
the primary efficacy variable of this study. 
8.4.1.2
Eosinophils counts in the blood
Eosinophil counts in the blood as well as percentage change from baseline (Visit 4) at each 
post-baseline visit will be secondary efficacy variables for this study. These variables will 
also be used to assess the treatment effect over time of eosinophils in the blood.
8.4.1.3
Forced vital capacity 
The mean change from baseline (Visit 4) in FVC to each of the post-baseline visits will be a 
secondary efficacy variable for this study.
8.4.1.4
Asthma Control Questionnaire
The change in mean score from baseline (Visit 4) in ACQ-6 to each of the post-randomization 
periods will be a secondary efficacy variable for this study.


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Patients will also be categorized according to the following limits (Juniper et al 2005):
•
ACQ-6 (End of treatment –baseline) ≤-0.5 → Improvement
•
0.5<ACQ-6 (End of treatment –baseline) <0.5 → No change
•
ACQ-6 (End of treatment –baseline) ≥0.5 → Deterioration.
An ACQ-6 responder will be defined as a patient who had improvement on ACQ-6, ie, an 
ACQ-6 responder variable takes value 1 if change from baseline to end of treatment in ACQ-6 
≤-0.5 and 0 otherwise.
Furthermore, patients will be categorized according to their ACQ-6 end of treatment score as 
follows (Juniper et al 2006):
•
ACQ-6 (End of treatment) ≤0.75 → Well controlled
•
0.75<ACQ-6 (End of treatment) <1.5 → Partly controlled
•
ACQ-6 (End of treatment) ≥1.5 → not well controlled
8.4.1.5
St. George's Respiratory Questionnaire 
The  change in mean total score in SGRQ from baseline (Visit 4) to each of the post-
randomization periods in total score will be a secondary efficacy variable for this study.
For the responder analysis of SGRQ a responder will be defined as an individual with a ≥4-
point decrease (improvement) in SGRQ total score.
8.4.1.6
Exhaled nitric oxide 
The mean change from baseline (Visit 4) of FeNO to each post-baseline visit will be a 
secondary efficacy variable for this study.
8.4.1.7
Patient Global Impression of Severity
Patient Global Impression of Severity (PGI-S) is a single question asking the patient to rate 
the severity of their symptoms using a 6-point categorical response scale (0=no symptoms,
5=very severe symptoms). Improvement using the PGI-S will include changes from 
moderate, severe, and very severe to no symptoms, very mild, mild as well as patients who 
have improvements in their responses from baseline. 
8.4.1.8
Patient and Clinician Global Impression of Change
Clinician Global Impression of Change (CGI-C) and Patient Global Impression of Change 
(PGI-C) instruments are used for an overall evaluation of response to treatment. The 
Investigator (clinician) and the patient will be asked to rate the degree of change in the overall 
asthma status compared to the start of treatment, ie, randomization visit. A 7-point rating 


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scale will be used: 1=Very Much Improved; 2=Much Improved; 3=Minimally Improved; 
4=No Changes; 5=Minimally Worse; 6=Much Worse and 7=Very Much Worse.
The clinician and patient will be asked, separately, to rate the degree of change in the overall 
asthma status compared to the randomization visit. Calculation of percentages will be based 
on the number of subjects in the full analysis set with a completed assessment. There will be 
no imputation for missing values.
Patients will also be categorized according to the following responses post-baseline, 
separately for both the CGI-C and PGI-C:
!
Very much improved, much improved, minimally improved → Improved
!
Very much improved, much improved → Much improved
!
Very much improved → Very much improved
8.4.2
Body plethysmography sub-study
8.4.2.1
Body lung function as assessed through body plethysmography
The mean change from baseline to each of the post-randomization visits (post Visit 4) up to 
and including the end of 12-week double-blind treatment visit (Visit 10) will be used as 
efficacy variables within the body plethysmography sub-study analysis set. The level 
recorded at Visit 4 will be used as baseline. The primary variable for the sub-study will the 
change from baseline in residual volume (RV).  Secondary variables for the sub-study will be 
the change from baseline in total lung capacity (TLC), RV/TLC ratio, vital capacity (VC), 
inspiratory capacity (IC) and functional residual capacity (FRC). Other variables for the sub-
study are SGaw and Raw.
8.4.3
Calculation or derivation of safety variable(s)
8.4.3.1
Safety variables
The following safety data will be collected: vital signs, physical examination and ECG, 
haematology, clinical chemistry, urinalysis, reported AEs and SAEs.
8.4.4
Calculation or derivation of pharmacokinetic variables
Summary statistics of the PK will be generated for each visit where serum samples are 
collected.  In addition, estimation of PK parameters, ie, Cmax, tmax, and AUC[0,28d] will be 
computed for the first dosing cycle using noncompartmental estimation method.  Cmax and 
Tmax are direct measurements of the maximum observed concentration and the time to reach 
the Cmax respectively during the first dosing cycle. 
8.4.5
Calculation or derivation of immunogenicity variables
Assessments of anti-drug antibodies (ADA) will be conducted using a tiered approach (screen, 
confirm, titer). The presence of in vitro neutralizing antibody (nAb) activity will be tested in 
all ADA-positive samples time points using a ligand binding assay.


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8.5
Methods for statistical analyses
Demographics and subject characteristics will be summarized by treatment group using 
frequency and percentages (for categorical variables) and descriptive statistics of mean, 
standard deviation, minimum, median and maximum (for continuous variables) using the full 
analysis set.
The analysis of the primary and secondary endpoints will include all data captured during the 
84-day treatment period, including follow-up (where applicable), unless the patient withdraws 
consent to study participation, regardless of whether study treatment was prematurely 
discontinued, or delayed, and/or irrespective of protocol adherence. To emphasize the 
importance of collecting complete primary and secondary outcome data in all patients, the
informed consent form (ICF) form will ask that patients continue study assessments for the 
whole 84-day double-blind treatment period, including follow-up, even if they discontinue 
study treatment prematurely.
Descriptive statistics will also be provided for safety and efficacy data. Unless otherwise 
stated, the data analysis include subjects in the full analysis set. Descriptive statistics on 
continuous variables will be summarized by treatment group using mean, standard deviation, 
minimum, median and maximum, while categorical data were summarized using frequency 
counts and percentages. When data are summarized by time, the values recorded against the 
scheduled time points listed in the protocol will be used. When assessing minimum/maximum 
increases or decreases during the study, all assessments, including unscheduled assessments 
will be used. For analysis assessing change from baseline, only subjects with both baseline 
and at least 1 evaluable post-baseline measure will be included. 
Given there is a single primary endpoint and treatment comparison no formal testing strategy 
will be used for the analysis in this study.
The prior medications, categorized according to the WHO Drug Reference List dictionary 
which employs the Anatomical Therapeutic Chemical (ATC) classification system, will be 
summarized by treatment group as frequency and percentage of subjects reporting usage.
The concomitant medication will be categorized according to the WHO Drug Reference List 
dictionary which employs the Anatomical Therapeutic Chemical (ATC) classification system. 
The frequency and percentage of subjects taking concomitant medications and non-drug 
therapies during the treatment period will be summarized by drug class and drug name using 
ATC code.
8.5.1
Analysis of the primary variable(s)
The change from baseline in pre-BD FEV1 up until the EOT at Visit 10 will be compared 
between the 30 mg benralizumab group and placebo using a repeated measures analysis on 
patients with a baseline pre-BD FEV1 and at least 1 post-randomization pre-BD FEV1 in the 
full analysis set. The dependent variable will be the change from baseline in pre-BD FEV1 at 
post-baseline protocol specific visits (up to and including the EOT Visit). Treatment group 
will be fitted as the explanatory variable, region, visit and treatment*visit interaction as fixed 


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effects and baseline pre-bronchodilator FEV1 as a covariate.  The variance-covariance matrix 
will be assumed to be unstructured. If the procedure does not converge then a compound 
symmetric variance-covariance matrix will be used instead. The model is:
Change in FEV1=Treatment group+ baseline pre-BD FEV1+ region + visit+ treatment*visit
The primary objective of the study is to determine the effect of Benralizumab on the time 
course of change (onset and maintenance of effect) of pre-BD FEV1 using the model 
described above. The first post baseline timepoint where the p-value for the mean difference 
between benralizumab and placebo is less than or equal to 0.05 will be used to determine time 
to onset of effect. The average over the mean differences between benralizumab and placebo 
based on the change from baseline (Visit 4) to Days 28 (Visit 8), 56 (Visit 9) and 84 (Visit 10) 
in pre-BD FEV1 will be used to determine if the study is positive as well as maintenance of 
effect. Contrasts will be used to obtain estimates of the treatment differences over Days 28, 56 
and 84 as well as at each timepoint separately.  
Additional supportive analyses to the primary objective of the study will be carried out as 
detailed below.
The modelled treatment response as well as differences between benralizumab and placebo 
using the mean change from baseline in pre-BD FEV1 endpoint using an exponential model 
over time will be estimated. The model will be used determine the modelled time to onset of 
effect where the pre-BD FEV1 reaches thresholds for improvement in both mean differences 
between benralizumab and placebo as well as within treatment change from baseline 
differences. If the exponential model does not fit the time profile alternative models will be 
assessed.
The first timepoint using the repeated measures analyses where the observed mean treatment 
difference between benralizumab and placebo is first greater than different thresholds for 
improvement will also be presented.  In addition for each treatment group time to event 
analyses will be carried out to present the proportion of patients with onset of effect over time 
using different within patient change from baseline thresholds. 
8.5.2
Analysis of the secondary variable(s)
8.5.2.1
Analysis methods for secondary efficacy variables
Secondary efficacy variables in this study include:
!
Absolute and percentage change from baseline of peripheral blood eosinophil counts 
until EOT at Visit 10
!
Change from baseline in FVC until EOT at Visit 10
!
Change from baseline in ACQ-6 score until EOT at Visit 10
!
Change from baseline in SGRQ score until EOT at Visit 10


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!
Change from baseline in FeNO (ppb) until EOT at Visit 10 
For each variable, the objective is to determine the effect of benralizumab on the time course 
of change (onset and maintenance of effect).  
Other variables include:
!
Change from baseline in Patient Global Impression of Severity until EOT at Visit 10
!
Patient and Clinical Global Impression of Change until EOT at Visit 10
For the following variables:
!
Peripheral blood eosinophil counts 
!
Exhaled nitric oxide (FeNO)
!
FVC
!
ACQ-6 score
!
SGRQ
!
Change from baseline in PGI-S as a continuous measure.
The change from baseline at each timepoint will be compared between benralizumab and 
placebo using a repeated measures analysis. The dependent variable will be change from 
baseline for each endpoint. Treatment group will be fitted as the explanatory variable, region, 
visit and treatment*visit interaction as fixed effects and corresponding baseline as a covariate. 
The variance-covariance matrix will be assumed to be unstructured. If the procedure does not 
converge the compound symmetric variance-covariance matrix will be used instead. The least 
squares mean for the difference in treatment groups using the interaction between visit and 
treatment group its 95% CI, and the 2-sided p-values will be reported for each post baseline 
visit.
As for the primary endpoint the first post baseline timepoint where the p-value for the mean 
difference between benralizumab and placebo is less than or equal to 0.05 from the repeated 
measures analysis will be used to determine time to onset of effect. The average over the mean 
differences between benralizumab and placebo based on the change from baseline (Visit 4) to 
Days 28 (Visit 8), 56 (Visit 9) and 84 (Visit 10) will be used to determine maintenance of 
effect. Contrasts will be used to obtain estimates of the average treatment differences over 
Days 28, 56 and 84 as well as for each timepoint separately. 
In addition supportive analyses to using the modelled treatment difference between 
benralizumab and placebo using the mean change from baseline as well as the first timepoint 
using the repeated measures analyses where the observed mean treatment difference between 


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benralizumab and placebo are first greater than different thresholds for improvement will be 
presented.
Patients with a CGI-C improved, much improved and very much improved will be analysed 
using a logistic regression model with covariates of treatment and region. The percentage and 
number of patients in each category for these endpoints will also be summarised over time.  
This analysis will be repeated for the PGI-C well as for those patient with have an 
improvement using the PGI-S.  In addition the number and percentage of patients within each 
of the PGI-S, CGI-C and PGI-C categories as well as a shift tables demonstrating how patients 
change their categories throughout the study will be presented.
As supportive analyses to the repeated measures analyses the responder variables for ACQ-6 
and SGRQ will be analyzed as for the PGI-C, CGI-C and PGI-S endpoints. 
8.5.2.2
Analysis for the Body plethysmography sub-study
For the body plethysmography sub-study the primary efficacy variable is the change from 
baseline in body lung function RV as assessed through body plethysmography until EOT at 
Visit 10
Secondary efficacy variables for the body plethysmography sub-study are:
!
Change from baseline in body lung function (TLC, RV/TLC ratio, VC, IC, and FRC) 
as assessed through body plethysmography until EOT at Visit 10
Other endpoints for the body plethysmography sub-study are change from baseline in SGaw 
and Raw.
These endpoints will be analysed as for the primary endpoint however in the subset of patients 
in the body plethysmography sub-study population.
8.5.2.3
Analysis of the safety variables
Adverse events will be coded using the MedDRA dictionary. Number of subjects with events
and percentages will be tabulated by preferred term and system organ class. An event that 
occurred once or more times during the study treatment period will contribute 1 observation to 
the numerator of the proportion. The denominator of the proportion will comprise all subjects 
in the Safety set. Adverse events will also be summarized by intensity/severity and separately, 
by causality/relatedness (as determined by the investigator). Should a subject report the same 
preferred term/system organ class within multiple intensity/severity or causality/relatedness 
categories, the subject’s worst occurrence (most severe/most related) will be tabulated. 
Serious AEs, AEs leading to discontinuation, and commonly occurring AEs will be 
summarized in a generally similar manner. Adverse events, SAEs, AEs leading to death, and 
AEs leading to study discontinuation will be summarized for each treatment group as 
applicable.


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Laboratory data will be summarized by presenting shift tables using normal ranges (baseline 
to most extreme post-baseline value) and by presenting summary statistics of observed and 
change from baseline values (means, medians, quartiles, ranges). The incidence of clinically 
notable lab abnormalities will be summarized.
Vital sign data will be summarized by presenting summary statistics of observed and change 
from baseline values. The incidence of clinically notable vital sign abnormalities will be 
summarized.
Electrocardiogram intervals will be summarized by presenting summary statistics of observed 
and change from baseline values. The (uncorrected) QT interval will be corrected according to 
the Fridericia’s formula. The incidence of clinically notable ECG abnormalities will be 
summarized.
8.5.3
Subgroup analysis 
Full details of subgroup analyses will be pre-specified in the SAP.
8.5.4
Interim analysis
No interim analyses are planned.
8.5.5
Sensitivity analysis
Full details of any sensitivity analysis will be pre-specified in SAP.
8.5.6
Exploratory analysis 
The exploratory analysis of the PK of benralizumab in sputum will be analysed and reported 
outside of the CSR.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and WBDC, 
IWRS/IVRS, ePROs, and other systems to be utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator (PI) will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).


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9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:
!
Provide information and support to the Investigator(s)
!
Confirm that facilities remain acceptable
!
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed
!
Perform source data verification (a comparison of the data in the CRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating subjects. This will 
require direct access to all original records for each subject (eg, clinic charts)
!
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, 
and the action is documented, and reported to the subject.
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.


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9.2.3
Study agreements
The PI at each/the center should comply with all the terms, conditions, and obligations of the 
CSA, or equivalent, for this study.  In the event of any inconsistency between this Clinical 
Study Protocol and the CSA, the terms of CSP shall prevail with respect to the conduct of the 
study and the treatment of subjects and in all other respects, not relating to study conduct or 
treatment of subjects, the terms of the CSA shall prevail.
Agreements between AstraZeneca and the PI should be in place before any study-related 
procedures can take place, or subjects are enrolled.
9.2.4
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last subject undergoing the study’.
The study is expected to start in Q3 2016 and to end by Q4 2017.
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (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 AstraZeneca Data Management Centre 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.  Classification coding will be performed by the Medical 
Coding Team at the AstraZeneca Data Management Centre.
The data collected through third party sources will be obtained and reconciled against study 
data.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version MedDRA.  Medications will be classified according to the AstraZeneca 
Drug Dictionary.  All coding will be performed by the Medical Coding Team at the 
AstraZeneca Data Management Centre.
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the data management plan (DMP).  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 


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and have been processed correctly.  The DMP will also clarify the roles and responsibilities of 
the various functions and personnel involved in the data management process
When all data have been coded, validated, signed and locked, clean file will be declared. Any 
treatment revealing data may thereafter be added and the final database will be locked.
Serious adverse event reconciliation
Serious adverse event reconciliation reports are produced and reconciled with the Patient 
Safety database and/or the investigational site. 
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH)/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy 
on Bioethics and Human Biological Samples.
10.2
Subject data protection
The informed consent form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
10.3
Ethics and regulatory review
An Ethics Committee (EC) should approve the final study protocol, including the final version 
of the ICFand any other written information and/or materials to be provided to the subjects.  
The Investigator will ensure the distribution of these documents to the applicable EC, and to 
the study site staff.
The opinion of the EC should be given in writing. The Investigator should submit the written 
approval to AstraZeneca before enrolment of any subject into the study. 
The EC should approve all advertising used to recruit subjects for the study.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the EC annually.


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Before enrolment of any subject into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide RAs, ECs, and PIs with safety updates/reports according to local 
requirements.
Each PI is responsible for providing the ECs/institutional review boards (IRBs) with reports of 
any serious and unexpected adverse drug reactions from any other study conducted with the 
investigational product.  AstraZeneca will provide this information to the PI so that he/she can 
meet these reporting requirements.
10.4
Informed consent
The PI(s) at each centre will:
!
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study
!
Ensure each subject is notified that they are free to discontinue from the study at any 
time
!
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided
!
Ensure each subject provides signed and dated informed consent before conducting 
any procedure specifically for the study
!
Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File
!
Ensure a copy of the signed ICF is given to the subject
!
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the informed consent form that is approved by an EC.
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 AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (revised CSP).


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The amendment is to be approved by the relevant EC and if applicable, also the national RA
approval, before implementation.  Local requirements are to be followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each PI(s). For distribution to EC, see Section 10.3.
If a protocol amendment requires a change to a center’s ICF, AstraZeneca and the center’s EC
are to approve the revised ICF 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
Authorised representatives of AstraZeneca, a regulatory authority, or an EC may perform 
audits or inspections at the 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, 
analysed, and accurately reported according to the protocol, GCP, ICH guidelines, and any 
applicable regulatory requirements.  The Investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the center.
11.
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Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. 
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Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the 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 1 or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
!
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
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.


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!
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?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


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Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are 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 
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable
!
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.


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Appendix C
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.  Specific guidance on the managing liver abnormalities can 
be found in Section 6.3.7 of the protocol.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication  irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥ 3x ULN  together with 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.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
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


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!
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). 
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:
!
Notify the AstraZeneca representative
!
Request a repeat of the test (new blood draw) by the central laboratory
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
!
Determine whether the patient meets PHL criteria (see Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results)
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative
!
Determine whether the patient meets PHL criteria (see Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory CRF
Follow-up
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the patient has not met PHL criteria.
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.


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Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
!
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Actions Required When Potential Hy’s Law Criteria are Met Before 
and After Starting Study Treatment)
!
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. << For studies using a central laboratory add: This includes 
deciding which the tests available in the Hy’s law lab kit should be used>> 
!
Complete the 3 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
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


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!
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
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment 
This section is applicable to patients << with liver metastases>> 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 met the Investigator will:
!
Determine if there has been a significant change in the patients’ condition# compared 
with the last visit where PHL criteria were met#
∀
If there is no significant change no action is required
∀
If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Potential Hy’s Law Criteria met 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 


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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.
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 found 
to be the disease under study, eg, chronic or progressing malignant disease, severe 
infection or liver disease, << or did the patient meet PHL criteria prior to starting study 
treatment and at their first on study treatment visit as described in Actions Required 
When Potential Hy’s Law Criteria are Met Before and After Starting Study Treatment
>>?
If No: follow the process described in Potential Hy’s Law Criteria met of this Appendix
If Yes:
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met
!
If there is no significant change no action is required
!
If there is a significant change follow the process described in Section 4.2 of this 
Appendix
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf


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Appendix D
Anaphylaxis: signs and symptoms, management
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 1 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 lipstongue- uvula)
AND AT LEAST 1 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).


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


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


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(h) Consider transportation to an emergency department or an intensive care facility.
(i) For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged 
resuscitation efforts are encouraged, if necessary.
Adapted from: Kemp SF, Lockey RF, Simons FE; World Allergy Organization ad hoc 
Committee on Epinephrine in Anaphylaxis. Epinephr
5.
REFERENCES
Johansson et al 2004
Johansson SGO, 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; 113(5): 832-6.


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Version 1.0
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Appendix E
PROHIBITED AND RESTRICTED MEDICATIONS
Asthma medication restrictions
Table 1
Asthma medications restrictions
Medication
Prohibited/restricted
Details
Long-acting beta-agonists as
a reliever (eg, Symbicort
Maintenance and Reliever
Treatment)
Prohibited
Not allowed from enrolment and
throughout the study duration
Zileuton
Prohibited
Not allowed 30 days prior to Visit
1; during treatment period
Other medication restrictions
Table 2
Other medication restrictions
Medication
Prohibited/restricted
Details
Live Attenuated Vaccines
Prohibited
Not allowed 30 days prior to
randomization; during treatment
period, and 16 weeks (5 half-lives)
after the last dose of the investigational 
product
Inactive/killed vaccinations
(eg, inactive influenza)
Restricted
Not allowed within the 7 days before or 
within the 7 days  after any study visit
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
Any immunomodulators or
immunosuppressives –
topical
Restricted
Topical administration of
Immunosuppressive medication may
be allowed at the discretion of the
Investigator after discussion with the
AstraZeneca Study Physician
Blood products or
immunoglobulin therapy
Prohibited
Not allowed 30 days prior to date of
ICF; during treatment period


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Table 2
Other medication restrictions
Medication
Prohibited/restricted
Details
Any marketed (eg,
Omalizumab, mepolizumab) 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
Prohibited
Not allowed 30 Days or 5 Half Lives
(whichever is longer) prior to Visit 1;
during treatment period
Allergen Immunotherapy
Restricted
Allowed if on stable therapy for at
least 30 days prior to date of ICF; no
anticipated changed during treatment
Herbal remedies for the
treatment of allergic,
inflammatory, or respiratory
Prohibited
Not allowed 30 days prior to Visit
1 or during the treatment period
Roflumilast
Prohibited
Not allowed 30 days prior to Visit
1 and during the treatment period
Oral or ophthalmic β-
adrenergic antagonist (eg,
propranolol)
Prohibited
Patients currently using any oral or 
ophthalmic β-adrenergic antagonist at 
the time of enrolment are not eligible 
for the study.
Not allowed during treatment period


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Version 1.0
Date 02 Aug 2016
99(99)
Appendix F
BACKROUND THERAPY EQUIVALENCE TABLE
Table 1
Estimated daily dosage for inhaled corticosteroids
Asthma therapy:
Inhaled corticosteroid
Total daily dose (μg/day)
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
>400 to 800
>800
Budesonide, if as delivered dose (eg, Symbicort)
>320 to <640
≥640
Mometasone furoate
>220 - 440
>440


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Server Date
(dd-MMM-yyyy HH:mm ‘GMT’Z)
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SAP_000.pdf: 
1
Statistical Analysis Plan
Study Code
D3250C00038
Edition Number
2.0
Date
13 Aug 2018
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-
controlled, Phase 3b Study to Evaluate the Onset of Effect and Time Course 
of Change in Lung Function with Benralizumab in Severe, Uncontrolled 
Asthma Patients with Eosinophilic Inflammation






Statistical Analysis Plan 
Study Code D3250C00038
Edition Number 2.0
Date 13 Aug 2018
4
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................3
TABLE OF CONTENTS.....................................................................................4
LIST OF ABBREVIATIONS ..............................................................................7
AMENDMENT HISTORY..................................................................................9
1.
STUDY DETAILS............................................................................................. 10
1.1
Study objectives................................................................................................. 10
1.1.1
Primary objective............................................................................................... 10
1.1.2
Secondary objectives.......................................................................................... 10
1.1.3
Safety objective..................................................................................................11
1.1.4
Exploratory objectives .......................................................................................11
1.1.5
Body plethysmography sub-study objectives...................................................... 11
1.2
Study design ...................................................................................................... 12
1.3
Number of subjects ............................................................................................12
2.
ANALYSIS SETS ............................................................................................. 13
2.1
Definition of analysis sets .................................................................................. 13
2.1.1
All patients analysis set...................................................................................... 14
2.1.2
Full analysis set..................................................................................................14
2.1.3
Body plethysmography sub-study analysis set....................................................14
2.1.4
Safety analysis set..............................................................................................14
2.1.5
Pharmacokinetic analysis set.............................................................................. 14
2.2
Violations and deviations ................................................................................... 14
2.2.1
Important protocol deviations............................................................................. 14
2.2.2
Visit window definitions .................................................................................... 15
2.2.3
The definition of baseline................................................................................... 16
2.2.4
Prior/concomitant medications ...........................................................................17
3.
EFFICACY AND SAFETY VARIABLES ........................................................ 18
3.1
Primary efficacy outcome variable..................................................................... 18
3.2
Secondary efficacy outcome variables................................................................18
3.2.1
FEV1 responder................................................................................................. 18
3.2.2
Eosinophil counts in the blood ...........................................................................18
3.2.3
Pre-bronchodilator forced vital capacity............................................................. 18
3.2.4
Asthma Control Questionnaire-6........................................................................18
3.2.5
St. George’s Respiratory Questionnaire..............................................................20


Statistical Analysis Plan 
Study Code D3250C00038
Edition Number 2.0
Date 13 Aug 2018
5
3.2.6
Fractional exhaled nitric oxide measurement......................................................20
3.3
Exploratory efficacy outcome variables.............................................................. 21
3.3.1
Patient Global Impression of Severity ................................................................ 21
3.3.2
Clinician Global Impression of Change and Patient Global Impression of 
Change...............................................................................................................21
3.4
Sub-study efficacy outcome variables ................................................................ 21
3.4.1
Primary efficacy variable ................................................................................... 22
3.4.2
Secondary efficacy variables..............................................................................22
3.4.3
Exploratory efficacy variables............................................................................22
3.5
Safety outcome variables.................................................................................... 22
3.5.1
Adverse events...................................................................................................22
3.5.2
Laboratory variables .......................................................................................... 23
3.5.3
Local electrocardiogram..................................................................................... 24
3.5.4
Physical examination ......................................................................................... 24
3.5.5
Vital signs.......................................................................................................... 24
3.6
Pharmacokinetic variables.................................................................................. 25
3.7
Immunogenicity variables .................................................................................. 25
4.
ANALYSIS METHODS....................................................................................25
4.1
General principles.............................................................................................. 25
4.2
Analysis methods............................................................................................... 26
4.2.1
Patient disposition..............................................................................................26
4.2.2
Demography data and patient characteristics ...................................................... 27
4.2.3
Prior and concomitant medications..................................................................... 27
4.2.4
Study Treatments ...............................................................................................28
4.2.4.1
Exposure............................................................................................................ 28
4.2.4.2
Study treatment compliance ...............................................................................28
4.2.5
Primary outcome variable ..................................................................................28
4.2.5.1
Primary analysis................................................................................................. 28
4.2.5.2
Sensitivity analysis.............................................................................................29
4.2.5.3
Subgroup analysis.............................................................................................. 29
4.2.5.4
Supportive analyses............................................................................................ 30
4.2.6
Secondary efficacy outcome variables................................................................ 38
4.2.6.1
Secondary analyses ............................................................................................ 38
4.2.6.2
Proportion of responders by PRO measures........................................................ 40
4.2.7
Exploratory efficacy outcome variable ............................................................... 40
4.2.7.1
Exploratory analysis of PGI-S............................................................................ 40
4.2.7.2
Exploratory analysis of CGI-C and PGI-C.......................................................... 40
4.2.8
Sub-study body plethysmography outcome variable........................................... 40
4.2.8.1
Sub-study primary analysis ................................................................................ 41
4.2.8.2
Sub-study secondary analysis............................................................................. 41
4.2.8.3
Sub-study explorative analysis ...........................................................................41
4.2.9
Safety outcome variables....................................................................................41


Statistical Analysis Plan 
Study Code D3250C00038
Edition Number 2.0
Date 13 Aug 2018
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4.2.9.1
Adverse events .................................................................................................. 41
4.2.9.2
Laboratory data.................................................................................................. 42
4.2.9.3
Electrocardiograms ............................................................................................ 43
4.2.9.4
Physical examination ......................................................................................... 43
4.2.9.5
Vital signs.......................................................................................................... 43
4.2.10
Pharmacokinetic analyses................................................................................... 43
4.2.11
Immunogenicity analyses................................................................................... 44
5.
INTERIM ANALYSES ..................................................................................... 45
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 45
7.
REFERENCES ..................................................................................................45
8.
APPENDIX ....................................................................................................... 46
8.1
Accounting for missing data for pre-bronchodilator FEV1.................................. 46
8.2
Partial dates for adverse events and prior/concomitant medication and 
medical history................................................................................................... 52
8.3
Important protocol deviations............................................................................. 54
LIST OF TABLES
Table 1
Visit windows for assessments ..............................................................16
Table 2
Vital signs reference ranges...................................................................24


Statistical Analysis Plan 
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Edition Number 2.0
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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 
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomic Therapeutic Chemical
ATS/ERS
American Thoracic Society/European Respiratory Society
BD
Bronchodilator
BMI
Body Mass Index
CGI-C
Clinical global impression of change
CI
Confidence interval
CSP
Clinical study protocol
CSR
Clinical study report
ECG
Electrocardiogram
eCRF
Electronic case report form
EOT
End of treatment
ePRO
Electronic patient reported outcome
ERT
eResearch Technology, Inc.
FeNO
Fractional exhaled Nitric Oxide
FEV1
Forced expiratory volume in 1 second
FRC
Functional residual capacity
FSH
Follicle-stimulating hormone
FVC
Forced vital capacity
Gamma-GT
Gamma-glutamyl transpeptidase
GCP
Good clinical practice
IC
Inspiratory capacity
ICF
Informed Consent Form
ICS
Inhaled corticosteroids
IP
Investigational product
IPD
Premature IP Discontinuation


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Abbreviation or 
special term
Explanation
ITT
Intent-to-Treat
IVRS
Interactive Voice Response System
LABA
LOCF
Long-acting β2 agonists
Last observation carried forward
LSMEANS
Least Square Means
MedDRA
Medical Dictionary for Regulatory Activities
nAb
Neutralizing antibodies
PK
Pharmacokinetic(s)
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
Post-BD
Post-bronchodilator
Pre-BD
Pre-bronchodilator
PRO
Patient reported outcome
PT
Preferred term
Raw
Airway resistance
RBC
Red blood cell
RV
Residual volume
SABA
Short-acting β2 agonists
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SGaw
Specific airway conductance
SGRQ
St. George’s Respiratory Questionnaire
SOC
System Organ Class
TLC
Total lung capacity
ULN
Upper limit of normal
VC
Vital capacity
WBC
White blood cell
WBDC
Web-based Data Capture
WHODD
WHO drug dictionary


Statistical Analysis Plan 
Study Code D3250C00038
Edition Number 2.0
Date 13 Aug 2018
9
AMENDMENT HISTORY
Date
Brief description of change
27 November 2016
Initial version
(v1.0)
13 August 2018 (v 
2.0)
SAP amendment for the following:
!
Clarification that no visit window will be applied for summary of 
ADA or safety labs other than WBC counts and differentials
!
Update that no upper bound will be applied for follow up visit in
Table 1
!
Update that no post-baseline mean score will be derived for ACQ6 
!
Added FEV1 responder definition and analysis as secondary 
endpoint
!
Updated visit schedule for ACQ6, ACQ5 responder analysis and 
ACQ6 control status summary
!
Clarification that on-study summary of AE will be provided, but not 
on-treatment or post-treatment summaries
!
Added supportive analysis of onset of effect modelling in FEV1
!
Details of analysis method is added for overall standardized effect 
plot 
!
Subgroup analysis by baseline FeNO was added, and cutoffs for 
subgroup analysis by baseline IgE updated 
!
Added correlation plot of baseline EOS and FeNO
!
Clarification on how BLQ values to be included in PK summary, 
and subjects to be included in NCA
!
Simplified MI analysis approaches in Appendix 8.1
!
Clarified imputation for missing dates in medical history in 
Appendix 8.2
!
Specifications on IPD were added


Statistical Analysis Plan 
Study Code D3250C00038
Edition Number 2.0
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1.
STUDY DETAILS
This statistical analysis plan (SAP) outlines the analyses to be generated for the global clinical 
study report (CSR). Additional analyses required for regional submissions will be pre-
specified in a separate analysis plan and will be submitted to the appropriate authorities.
1.1
Study objectives
1.1.1
Primary objective
Primary Objective
Outcome Measure
To determine the effect of benralizumab on the 
time course of change (onset and maintenance 
of effect) on lung function
The average over the mean differences between 
benralizumab and placebo for the change from 
baseline (Visit 4) at Day 28 (Visit 8), Day 56 (Visit 
9) and Day 84 (Visit 10) in pre-BD FEV1 will be 
used to determine if the study is positive and to 
determine maintenance of effect. The first post 
baseline timepoint where the p-value for the mean 
difference between benralizumab and placebo is less 
than or equal to 0.05 will be used to determine time 
to onset of effect.
1.1.2
Secondary objectives
Secondary Objectives
Outcome Measures
To determine time course of effect of 
benralizumab on blood eosinophils and correlate 
changes in eosinophil depletion with lung 
function.
Change from baseline in blood eosinophils (from
hematology) to end of treatment together with the
correlation with lung function
To determine the effect of benralizumab on the 
time course of change and maintenance on lung 
function.
!
Change from baseline (Visit 4) in pre-BD 
FEV1 at all clinic visits compared to placebo
!
Percent of responders in pre-BD FEV1 by 
pre-specified cutoffs compared to placebo at 
all visits.
!
Change from baseline (Visit 4) in pre-BD 
forced vital capacity (FVC) at all clinic visits 
compared to placebo
To determine the time course of the effect of 
benralizumab on asthma control metrics
Change from baseline (Visit 4) in Asthma Control
Questionnaire-6 (ACQ-6) score at all post-
baseline assessment timepoints
To determine the time course of effect of
benralizumab on health-related quality-of-life
Change from baseline (Visit 4) in St. George's
Respiratory Questionnaire (SGRQ) score at all 
post-baseline assessment timepoints


Statistical Analysis Plan 
Study Code D3250C00038
Edition Number 2.0
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Secondary Objectives
Outcome Measures
To determine the effect of benralizumab on the 
time course of change in exhaled nitric oxide
(FeNO)
Change from baseline in FeNO (ppb) compared to 
placebo to end of treatment (Visit 10)
1.1.3
Safety objective
Safety Objectives
Outcome Measures
To evaluate the pharmacokinetics and 
immunogenicity of benralizumab
!
Serum PK
!
Anti-drug antibodies
To assess the safety and tolerability of 
benralizumab
!
Adverse events (AEs) and serious adverse 
events (SAEs)
!
Laboratory variables
!
Physical Examination
1.1.4
Exploratory objectives
Exploratory Objective
Outcome Measures
To evaluate patient impression of overall asthma 
severity (PGI-S) and overall change from baseline 
as reported by the patient (PGI-C) and clinician 
(CGI-C)
!
Change from baseline (Visit 4) in PGI-S 
at all post-baseline assessment timepoints
!
Clinician-reported global change in 
asthma from baseline (Visit 4) as 
measured by CGI-C
!
Patient-reported global change in asthma 
from baseline (Visit 4) as measured by 
PGI-C
1.1.5
Body plethysmography sub-study objectives
Sub-study Primary Objective
Outcome Measure
To determine the effect of benralizumab on the 
time course of change in lung function as assessed 
through body plethysmography
Change from baseline (Visit 4) to end of 
treatment (Visit 10) in the following measures 
compared to placebo:
!
Residual volume (RV)
Sub-study Secondary Objectives
Outcome Measures


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To determine the effect of benralizumab on the 
time course of change in lung function as assessed 
through body plethysmography
Change from baseline (Visit 4) to end of 
treatment (Visit 10) in the following measures 
compared to placebo:
!
Total lung capacity (TLC)
!
RV/TLC ratio
!
Inspiratory capacity (IC)
!
Functional residual capacity (FRC)
!
Vital capacity (VC)
Sub-study Exploratory Objective
Outcome Measures
To determine the effect of benralizumab on the 
time course of change in lung function as assessed 
through body plethysmography
Change from baseline (Visit 4) to end of 
treatment (Visit 10) in the following measures 
compared to placebo:
!
Specific airway conductance (SGaw)
!
Airway resistance (Raw)
1.2
Study design
This is a randomized, double-blind, parallel group, placebo-controlled study designed to 
evaluate the onset of effect and safety of a fixed 30 mg dose of benralizumab administered 
subcutaneously (SC) to patients with severe, uncontrolled asthma. Approximately 230 
patients with peripheral blood eosinophil counts ≥300 cells/μL will be randomized globally to 
receive SC benralizumab 30 mg or placebo. 
After enrolment, eligible patients will enter a 5-week screening/run-in period. Patients who 
meet eligibility criteria will enter a 12-week treatment period and receive 30 mg benralizumab 
or placebo at Day 0, Day 28 (+/- 3 days), and Day 56 (+/- 3 days). An End-of-Treatment 
(EOT) visit will be conducted at Day 84 (Week 12) and a follow-up (FU) visit will be 
conducted at Day 112 (Week 16). 
See the clinical study protocol (CSP) Section 4, Tables 2 and 3 for a detailed list of visits and 
assessments.
1.3
Number of subjects
The study will recruit approximately 230 patients in total and 115 patients in each treatment 
group based on the primary objective of the study to determine the effect of benralizumab on 
the time course of change (onset and maintenance of effect) of pre-bronchodilator (BD) FEV1. 
Patients will be randomized in a 1:1 ratio to benralizumab or placebo.  In order to have a 
balanced number of patients for each region and the body plethysmography sub-study, the 
randomization will be stratified by these variables.
The study is powered for the primary objective of the study to determine the effect of 
benralizumab on the time course of change (onset and maintenance of effect) of pre-BD FEV1. 


Statistical Analysis Plan 
Study Code D3250C00038
Edition Number 2.0
Date 13 Aug 2018
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The first post-baseline timepoint where the p-value for the mean difference between 
benralizumab and placebo is ≤0.05 will be used to determine time to onset of effect. The 
average over the mean differences between benralizumab and placebo based on the change 
from baseline (Visit 4) to Days 28 (Visit 8), 56 (Visit 9), and 84 (Visit 10) in pre-BD FEV1
will be used to determine if the study is positive and to determine maintenance of effect. 
The results of the Phase 2b study, MI-CP220 (Castro et al 2014) and the Phase 3 asthma 
exacerbation studies, SIROCCO (Bleeker et al 2016) and CALIMA (Fitzgerald et al 2016)
were used as a basis for the sample sizing.  From these studies, it is expected that around 115 
patients per treatment arm (230 in total) will provide approximately 90% power for the 
primary endpoint pre-BD FEV1 with type I error controlled at a two-sided alpha level of 0.05 
if the true average over the mean treatment differences (benralizumab – placebo) across Days 
28 (Visit 8), 56 (Visit 9), and 84 (Visit 10) is 138 mL. The sample size will also be sufficient 
to have approximately 80% power for an average over the mean treatment difference of 
120 mL.  The assumed variability has a within-group standard deviation of 375 mL and 
within-patient correlation of 0.6.  If the within-patient variability is reduced to 350 mL, the 
sample size would be sufficient 80% power for an average of 110 mL.  In addition, it is 
expected that around 115 patients per treatment arm will have 80% power to detect a true 
treatment difference (benralizumab – placebo) of 130 mL, assuming a within-group standard 
deviation of 350 mL or a true treatment difference of 140 mL, assuming a standard deviation 
of 375 mL.  Based on these assumptions, the minimum difference that would be statistically 
significant at the 5% level ranges from approximately 85 to 100 mL. The sample size was 
estimated using nQuery + nTerim version 3.0 using methodology by Liu et al (Liu et al 2005).
2.
ANALYSIS SETS
2.1
Definition of analysis sets
Five analysis sets are defined below: 
!
All patient analysis set
!
Full analysis set (FAS)
!
Sub-study analysis set
!
Safety analysis set
!
Pharmacokinetics (PK) analysis set
Patients must have provided their informed consent. If no signed informed consent is 
collected (major protocol deviation), the patient will be excluded from all analysis sets defined 
below.


Statistical Analysis Plan 
Study Code D3250C00038
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All efficacy will be performed according to the Intent-to-Treat (ITT) principle based on the 
FAS. For consistency, demographic and baseline characteristics will be presented using the
FAS. Safety objectives will be analyzed based on the safety analysis set.
2.1.1
All patients analysis set
This analysis set comprises all patients screened for the study and will be used for reporting of 
disposition and screening failures.
2.1.2
Full analysis set
All patients randomized and receiving at least 1 dose of investigational product (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, and assent when applicable, to participate in the study will be included 
up to the date of their study termination. All efficacy and patient-reported outcome (PRO)
data will be based on this analysis set. 
2.1.3
Body plethysmography sub-study analysis set
The subset of patients who are randomized as part of the body plethysmography sub-study and 
receive any IP will be analyzed as described for the FAS.
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 1 or several occasions received active treatment will be classified as active. All safety 
summaries and anti-drug antibodies (ADA) analyses will be based on this analysis set.
2.1.5
Pharmacokinetic analysis set
All patients who received benralizumab and from whom PK blood samples are assumed not to 
be affected by factors such as protocol violations and who had at least 1 evaluable serum PK 
observation post first dose will be included in the PK analysis set. All PK summaries will be 
based on this analysis set.
2.2
Violations and deviations
Patients who do not meet eligibility criteria but are still randomized will be analyzed
according to the analysis sets described in Section 2.1. There is no intention to perform a 
per-protocol analysis in this study.
2.2.1
Important protocol deviations
Important deviations will be those which are considered to potentially impact upon the 
interpretation of the primary endpoint in the study. Only important protocol deviations will be 
listed and tabulated in the CSR.


Statistical Analysis Plan 
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Edition Number 2.0
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The following categories of protocol deviations will be reviewed by medical advisors and 
statisticians prior to database lock to determine those which are considered important 
deviations as outlined below, with additional details provided in Appendix 8.3:    
!
Patients who do not meet key inclusion criteria (patients incorrectly randomised)
!
Patients who meet any of the key exclusion criteria (patients incorrectly 
randomised)
!
Patients who developed IP discontinuation criteria during the study but were not 
discontinued
!
Patients who received prohibited/restricted concomitant medication(s)
!
Deviations from study procedures
Patients for whom significant protocol deviations were recorded that impact the interpretation 
of the study safety outcomes will have a footnote added to applicable output to describe the 
deviation and its potential impact. Such patients will be identified as part of the protocol 
deviation review process prior to database lock.
Patients who received incorrect study treatment will be identified after database lock and 
unblinding. Patients will be classified according to the treatment they actually received for the 
safety analysis set according to the following rules, based on the unblinded data from the
Interactive Voice Response System (IVRS) system:
!
Patients assigned to benralizumab treatment regimen who receive only placebo will 
be assigned to the placebo group.
!
Patients assigned to the placebo group who received 1 or more doses of 
benralizumab will be assigned to the benralizumab group.
2.2.2
Visit window definitions
No visit windows will be defined for screening visits. For local laboratory and all vital signs, 
safety labs other than white blood cell (WBC) cell count and differentials, and 
ADA/neutralizing antibodies (nAb), the visit recorded in web-based data capture (WBDC) 
will be used. For endpoints that present visit-based data including WBC cell count and 
differentials (including eosinophil count data), spirometry, FeNO, body plethysmography
(sub-study), and patient reported outcomes (PROs), the variables will be summarized based on 
the scheduled days with adjusted analysis-defined visit windows. The adjusted analysis-
defined visit windows will be based on the collection schedule listed in the protocol and 
variables will be windowed to the closest scheduled visit for that variable. 
The adjusted analysis-defined visit windows for assessments conducted are summarized in 
Table 1.


Statistical Analysis Plan 
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Edition Number 2.0
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Table 1
Visit windows for assessments
Adjusted defined windows visit 
Scheduled study day
Maximum windows
Week 0 (Day 0)
1
Study Day=1 
Day 3
4
2 ≤Study Days≤5
Day 7
8
6 ≤Study Days≤11
Day 14 (Week 2)
15
12 ≤Study Days≤22
Day 28 (Week 4)
29
23 ≤Study Days≤42 
Day 56 (Week 8)
57
43 ≤Study Days≤70 
Day 84 (Week 12/EOT)
85
71 ≤Study Days≤98 
Day 112 (Week 16/Follow-up)
113
99 ≤Study Days
For assignment of data to adjusted analysis-defined visit windows, study day will be defined
as follows: (Date of assessment – date of randomization) +1
For example, by this definition, the day of randomization will be Study Day 1 and the planned 
date of Week 4 will be Study Day 29 (=28+1).  
If multiple assessments are recorded within a single visit window, please refer to the rules 
below:
!
If there are 2 or more observations within the same visit window, then the 
non-missing one closest to the scheduled visit will be used in the analysis. 
!
If 2 observations are equidistant from the scheduled visit, then the non-missing 
observation with the earlier collection date will be used in the analysis. 
!
If 2 observations are collected on the same day, then the non-missing one with the 
earlier collection time will be included in the analysis. 
If a visit window does not contain any observations, then the data will remain missing. 
For pre-BD FEV1 (L) and body plethysmography data, the non-missing value with acceptable 
quality (acceptable or borderline quality grade) which is closest to the scheduled visit will be 
included in the analysis.  For post-BD FEV1, the highest value with acceptable quality from 
the same date as the pre-BD FEV1 result will be used.
2.2.3
The definition of baseline
In general, the last recorded value on or prior to the date of randomization will serve as the 
baseline measurement for efficacy endpoints, while the last recorded value prior to first dose 
of study treatment will serve as the baseline measurement for safety endpoints. If there is no 
value prior to randomization (or the first dose of study treatment, depending on the endpoint), 
then the baseline value will not be imputed and will be set to missing. No data known to be 


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collected post first dose will be used in determining the baseline value, unless otherwise 
specified.
For categorical (yes/no) baseline respiratory disease characteristics, if ‘yes’ is indicated in any 
visit during enrollment (scheduled or unscheduled), ‘yes’ will be used.  
There are 2 pre-BD spirometry assessments – 30 and 60-mins prior to IP administration on 
Day 0 of randomization visit. Day 0 pre-BD FEV1 value will be set to:
-
The average of the two if both have acceptable quality, or 
-
the value of the one with acceptable quality if only 1 has acceptable quality, or
-
missing, if none of the two has acceptable quality
Day 0 pre-BD value of FVC, FEF 25-75% and ratio of FEV1/FVC will be calculated using the 
same logic as for Day 0 pre-BD FEV1.
For pre-BD FEV1 (L) and sub-study assessments from whole body plethysmography, the last 
non-missing value with acceptable quality (acceptable or borderline quality grade) on or prior 
to the date of randomization will be used as baseline. The first dose of study treatment is 
scheduled to be administered on the date of randomization (Visit 4); however, if the first dose 
of study treatment is delayed until after the date of randomization, the last recorded value with 
acceptable quality prior to the first dose of study treatment will be used as baseline 
measurement for spirometry parameters. Baseline of pre-BD FVC will be assigned in the 
same way as for pre-BD FEV1.
For FeNO, the mean of repeated assessments at Week 0 (Visit 4) prior to randomization will 
be used as baseline values. If the first dose of study treatment is delayed until after the date of 
randomization, the mean of last recorded values prior to the first dose of study treatment will 
be used as baseline. If the assessments prior to randomization/first dose are missing, the mean 
value from Day -21 (Visit 2) will be used for baseline.
ACQ-6, SGRQ, and PGI-S assessments at Week 0 (Visit 4) prior to randomization will be 
used for calculating the respective baselines. For ACQ-6, if the value at Week 0 (Visit 4) is 
missing, the non-missing value from Day -35 (Visit 1) will be used for baseline.
For summaries of vital signs and laboratory results by visit and in the calculation of change 
from baseline, the last non-missing assessment prior to first dose of study treatment will be 
used as baseline.
2.2.4
Prior/concomitant medications
All patients are required to be treated with stable dose inhaled corticosteroids (ICS)/ Long-
acting β2 agonists (LABA) for at least 30 days prior to Visit 1 and during the course of the 
study.  
The background asthma controller medications should be maintained at a stable dose from 
Visit 1 until the end of the study. No changes are allowed to background medications 
throughout the duration of the study except during the treatment of an asthma exacerbation.


Statistical Analysis Plan 
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Short-acting β2 agonists (SABAs) may be used as rescue medication during the study in the 
event of a worsening of asthma symptoms.
A medication will be regarded as ‘prior’ if it was stopped on or before the date of 
randomization (medication stop date ≤ date of randomization).
A medication will be regarded as ‘concomitant’ if the start date is after the date of 
randomization, or if it started on or prior to the date of randomization and was ongoing after 
the date of randomization.
3.
EFFICACY AND SAFETY VARIABLES
3.1
Primary efficacy outcome variable 
The primary efficacy variable is the change from baseline in pre-BD FEV1. Details regarding 
the definition of baseline for pre-BD FEV1 are provided in Section 2.2.3.
3.2
Secondary efficacy outcome variables
3.2.1
FEV1 responder
A FEV1 responder at each post-baseline visit will be defined as a patient who had 
improvement on FEV1 by the following cut-offs: 50, 100, 150, 200, 250 and 300 mL, ie, a 
subject with a change from baseline in FEV1 greater than or equal to the cut-off at a visit will 
be categorized as a responder at that visit.  A patient with missing value of change from 
baseline at a visit will be excluded from the calculation of proportion of responders at that 
visit.
3.2.2
Eosinophil counts in the blood
Absolute and percentage changes from baseline Week 0 (Visit 4) in blood eosinophil counts
(from hematology) at each post-baseline visit are the secondary efficacy variables.
These variables will also be used to assess the treatment effect over time of eosinophils in the 
blood.
3.2.3
Pre-bronchodilator forced vital capacity
The change from baseline (Visit 4) in FVC to each of the post-baseline visits will be a 
secondary efficacy variable for this study.
3.2.4
Asthma Control Questionnaire-6 
The Asthma Control Questionnaire-6 (ACQ-6) is a shortened version of the ACQ that assesses 
asthma symptoms (nighttime waking, symptoms on waking, activity limitation, shortness of 


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breath, wheezing, and short-acting β2 agonist use) omitting the FEV1 measurement from the 
original ACQ-7 score.  
Patients are asked to recall how their asthma has been during the previous week by responding 
to 1 bronchodilator use question and 5 symptom questions. Questions are weighted equally 
and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ-6 score is 
the mean of the responses. Mean scores of ≤0.75 indicate well-controlled asthma, scores 
between 0.75 and <1.5 indicate partly controlled asthma, and a score ≥1.5 indicates not well 
controlled asthma. Individual changes of at least 0.5 are considered to be clinically 
meaningful.
The questionnaire will be completed at the study center via provided site tablet (ePRO) in 
accordance with schedule provided in CSP Section 4, Tables 2 and 3.
The outcome variable for ACQ-6 will be the change in mean score from baseline to each of 
the post-randomization periods. There will be no imputation for missing values. 
Patients will be categorized according to the following limits (Juniper et al 2005):
!
ACQ-6 (post-baseline visit – baseline) ≤-0.5 → Improvement
!
-0.5 < ACQ-6 (post-baseline visit – baseline) <0.5 → No change
!
ACQ-6 (post-baseline visit – baseline) ≥0.5 → Deterioration
An ACQ-6 responder will be defined as a patient who had improvement on ACQ-6, ie, an 
ACQ-6 responder variable takes value 1 if change from baseline to post-baseline visit in 
ACQ-6 ≤-0.5 and 0 otherwise.
Furthermore, patients will be categorized according to their ACQ-6-defined asthma control 
status at the baseline and at each post-baseline visit using the following score thresholds 
(Juniper et al 2006):
!
ACQ-6 ≤0.75 → Well-controlled
!
0.75< ACQ-6 <1.5 → Partly controlled
!
ACQ-6 ≥1.5 → Not well-controlled
In addition to ACQ-6, the ACQ-5 score will be calculated by omitting the question related to 
rescue medication use. The change in mean score from baseline to each of the 
post-randomization periods will be calculated and the asthma control responder status will be 
derived as defined above for ACQ-6. Patients will not be categorized as well-controlled, 
partly controlled, and not well-controlled based on ACQ-5.


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3.2.5
St. George’s Respiratory Questionnaire
The St. George’s Respiratory Questionnaire (SGRQ) is a 50-item PRO instrument developed 
to measure the health status of patients with airway obstruction diseases (Jones et al 1991). 
The questionnaire is divided into 2 parts: 
!
Part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the 
preceding 4 weeks; 
!
Part 2 consists of 42 items related to the daily activity and psychosocial impacts of 
the individual’s respiratory condition. 
The SGRQ yields a total score and 3 domain scores (symptoms, activity, and impacts). The 
total score indicates the impact of disease on overall health status. This total score is 
expressed as a percentage of overall impairment, in which 100 represents the worst possible 
health status and 0 indicates the best possible health status. Likewise, the domain scores range 
from 0 to 100, with higher scores indicative of greater impairment. Specific details on the 
scoring algorithms are provided by the developer in a user manual (Jones et al 2009).
The change in mean total score in SGRQ from baseline (Visit 4) to each of the 
post-randomization periods in total score will be a secondary efficacy variable for this study.
For the responder analysis of SGRQ, a responder will be defined as an individual with a 
≥4-point decrease (improvement) in SGRQ total score from baseline to each post-baseline 
visit.
3.2.6
Fractional exhaled nitric oxide measurement 
The mean change from baseline of fractional exhaled nitric oxide (FeNO) to EOT visit will be 
a secondary efficacy variable.
Airway inflammation will be evaluated using a standardized single-breath FeNO (ATS 2005) 
test. 
Since spirometry can potentially impact the nitric oxide measurement, the FeNO test needs be 
completed prior to spirometry. In addition, patients should not eat or drink 1 hour prior to 
having the FeNO, as this may affect the results. 
While sitting, patients are to inhale to total lung capacity through the NIOX MINO® Airway 
Inflammation Monitor (Aerocrine, New Providence, New Jersey) and then exhale for 
10 seconds at 50 mL/sec (assisted by visual and auditory cues). The value obtained will be 
recorded and the process will be repeated multiple times. Average of valid replicates provided 
by the ERT lab will be used in the analysis of the FeNO (ppb) data. 


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3.3
Exploratory efficacy outcome variables
3.3.1
Patient Global Impression of Severity 
Patient Global Impression of Severity (PGI-S) is a single question asking the patient to rate 
the severity of their symptoms using a 6-point categorical response scale (0=no symptoms, 
6=Very severe symptoms).  Improvement from baseline using the PGI-S will include changes 
from moderate, severe, and very severe to no symptoms, very mild, and mild.
3.3.2
Clinician Global Impression of Change and Patient Global Impression of 
Change 
Clinician Global Impression of Change (CGI-C) and Patient Global Impression of Change 
(PGI-C) instruments are used for an overall evaluation of response to treatment. The 
Investigator (clinician) and the patient will be asked to rate the degree of change in the overall 
asthma status compared to the start of treatment, ie, randomization visit. A 7-point rating 
scale will be used: 1=Very Much Improved, 2=Much Improved, 3=Minimally Improved, 
4=No Changes, 5=Minimally Worse, 6=Much Worse, and 7=Very Much Worse.
The Investigator and the patient will be asked to rate the degree of change in the overall status 
compared with the randomization visit. There will be no imputation for missing values.
Patients will also be categorized according to the following responses post-baseline, 
separately for CGI-C and PGI-C:
!
Very much improved, much improved, minimally improved → ‘Improved’
!
Very much improved, much improved → ‘Much improved’
!
Very much improved → ‘Very much improved’
Agreement between CGI-C and PGI-C will be assessed at each visit, where agreement is 
achieved when both the Investigator and the patient provide the same response (eg, if both the 
Investigator and the patient indicate a response of 1 (very much improved) at a particular visit, 
agreement is achieved for that visit). Agreement will also be assessed for categorized 
responses at each visit.
A responder will be defined for CGI-C and PGI-C separately as anyone with a response of 
Improved, Much improved, or Very much improved at the EOT visit.
3.4
Sub-study efficacy outcome variables
Additional assessments will be performed for a subset of patients at designated sites, 
approximately 50 patients in the study, to determine the effect of benralizumab on the time 
course of change in lung function as assessed through body plethysmography.
The mean change from baseline (Visit 4) to each of the post-randomization visits up to and 
including the end of treatment visit (Visit 10) will be used as efficacy variables within the 


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body plethysmography sub-study analysis set. Baseline is defined as the last non-missing 
value prior to randomization.
3.4.1
Primary efficacy variable 
The primary variable for the sub-study is the change from baseline in residual volume (RV).  
3.4.2
Secondary efficacy variables
The secondary efficacy variables for the sub-study include the change from baseline in total 
lung capacity (TLC), ratio of RV/TLC, inspiratory capacity (IC), and functional residual 
capacity (FRC), vital capacity (VC).
3.4.3
Exploratory efficacy variables 
The exploratory variables for the sub-study are change from baseline in Specific airway 
conductance (SGaw) and Airway resistance (Raw).
3.5
Safety outcome variables 
The following safety data will be collected: reported AEs and SAEs, clinical chemistry, 
hematology, urinalysis, 12-lead electrocardiogram (ECG), physical examination, and vital 
signs. 
All safety measurements will use all available data for analyses, including data from 
unscheduled visits and repeated measurements.
Change from baseline to each post-treatment timepoint where scheduled assessments were 
made will be calculated for relevant measurements. AEs will be summarized by means of 
using descriptive statistics and qualitative summaries.
No safety data will be imputed. The handling of partial/missing dates for AEs and 
prior/concomitant medications is detailed in Appendix 8.2.
3.5.1
Adverse events
Adverse events 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. 
Adverse event data will be categorized according to their onset date into the following study 
period:
!
Adverse events in the on-study period are defined as those with onset date on or 
after the day of first dose of study treatment.
If an AE has a missing onset date, then unless the stop date of the AE indicates otherwise, this 
will be considered an ongoing AE. Similarly, if an AE has a partial onset date, then unless the 
partial onset date or the stop date indicates otherwise, this will be considered an ongoing AE.


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3.5.2
Laboratory variables
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
parameters will be taken at the times detailed in the CSP and will be assessed in a central 
laboratory. The parameters outlined in Section 5.2.1, Table 4 of the CSP will be collected. 
In summaries, figures, and listings, lab results and normal ranges will be presented in System 
International (SI) units. Eosinophil data will be presented in both SI and conventional units 
(cells/μL) in summaries. 
For the purposes of clinical chemistry, hematology, and urinalysis shift tables, baseline will be 
defined as the last available non-missing assessment prior to first dose of randomized 
treatment, and maximum or minimum value post-baseline will be calculated over the entire 
post-baseline period, including the post-treatment period.
Changes in hematology and clinical chemistry variables between baseline and each 
post-baseline assessment will be calculated.  The change from baseline is defined as the 
post-baseline visit value minus the baseline visit value. There will be no imputation for 
missing values.  For 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.
Absolute 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 reference 
ranges will be used for laboratory variables. All values (absolute and change) falling outside 
the reference ranges will be flagged.
Urinalysis data will be categorized as negative (0), positive (+), or strongly positive (++, +++, 
or >+++) at each timepoint.
For the liver function tests: aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase (ALP), gamma-GT (GGT), and total bilirubin (TBL), the 
multiple of the central laboratory upper limit of the normal (ULN) range will be calculated for 
each data point.
Multiple=Value/ULN
That is, if the ALT value was 72 IU/L (ULN=36) then the multiple would be 2.
Patients who meet any of the following criteria at any point during the study will be flagged:
!
AST ≥3x ULN 
!
ALT ≥3x ULN 
!
TBL ≥2xULN


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3.5.3
Local electrocardiogram
Electrocardiogram (ECG) measurements will be performed at Visit 1 and the FU visit. The 
outcome of the overall evaluation is to be recorded as normal/abnormal in the electronic case 
report form (eCRF) by the Investigator/authorized delegate, with any abnormalities being 
recorded as not clinically significant or clinically significant.
3.5.4
Physical examination
Complete and brief physical examinations will be performed at timepoint specified in Tables 2
and 3 of the CSP. 
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 6.3 of the CSP.
3.5.5
Vital signs
Pre-dose vital signs (pulse, systolic blood pressure, diastolic blood pressure, respiration rate,
and body temperature) will be obtained in accordance with the visit schedule provided in the 
CSP.
Changes in vital signs variables between baseline and each subsequent scheduled assessment 
will be calculated. Baseline is defined as the last value prior to the first dose of randomized
treatment. The change from baseline is defined as the post-baseline visit value minus the 
baseline visit value. There will be no imputation for missing values.
Absolute values will be compared with the reference ranges in Table 2 and classified as low 
(below range), normal (within range or on limits), or high (above range). All values (absolute 
and change) falling outside the reference ranges will be flagged.
Table 2
Vital signs reference ranges
Parameter
Standard units
Lower limit
Upper limit
Diastolic Blood Pressure (DBP)
mmHg
60
120
Systolic Blood Pressure (SBP)
mmHg
100
160
Pulse Rate
Beats/min
40
120
Respiratory Rate
Breaths/min
8
28
Body Temperature
Celsius
36.5
38
Weight
kg
40
200
Body mass index (BMI) will be calculated from the height and weight as follows:
BMI (kg/m2)=weight (kg)/(height [m])2


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3.6
Pharmacokinetic variables
Pharmacokinetic trough concentration will be assayed for each visit where serum samples are 
collected. 
In addition, estimation of PK parameters, ie, Cmax, tmax, and AUC[0,28d] will be computed for 
the first dosing cycle using a noncompartmental estimation method.  Cmax and Tmax are direct 
measurements of the maximum observed concentration and the time to reach the Cmax,
respectively, during the first dosing cycle.
3.7
Immunogenicity variables
Anti-drug antibodies assessments will be conducted utilizing a tiered approach (screen, 
confirm, titer). The presence of nAb will be tested in all ADA-positive samples using a ligand 
binding assay.
For each patient, the following response variables will be evaluated. Samples taken post dose 
on the day of IP administrations are excluded from analysis.
!
ADA positive at any visit (including baseline and unscheduled visits)
!
ADA positive at both post-baseline and baseline
!
ADA positive at post-baseline only
!
ADA positive at baseline only
!
nAb positive at any visit
Safety outcomes by ADA status (if the number of occurrences ADA responses is sufficient)
will also be evaluated.
4.
ANALYSIS METHODS
4.1
General principles
The analysis of the primary and secondary efficacy endpoints will include all data captured 
during the 12-week double-blind treatment period, defined as the period after administration 
of randomized IP at Visit 4 (Week 0) and the conclusion of Visit 10 (Week 12), inclusive. 
This includes data regardless of whether study treatment was prematurely discontinued or 
delayed, and/or irrespective of protocol adherence, unless the patient withdraws consent to 
study participation. The statistical analyses will compare benralizumab with placebo. The 
analysis of safety endpoints will include all data captured during the on-study period, defined 
as the period after first administration of randomized IP at Visit 4 (Week 0) and the 
conclusion of the scheduled post-treatment FU visit (Week 11), inclusive.


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The data analyses will be conducted using the SAS® System 9.2 (SAS Institute Inc., Cary, 
NC) or higher version. Pharmacokinetic analyses will be performed using WinNonlin 
(version 6.3, or higher, Certara, L.P., St. Louis, MO).
Summary data will be presented in tabular format by treatment group. Descriptive statistics 
on continuous variables will be summarized by treatment group using mean, standard 
deviation, median, quartile, and range as applicable, while categorical data will be
summarized using frequency counts and percentages. When data are summarized by time, the 
values recorded against the scheduled timepoints listed in the protocol will be used. When 
assessing minimum/maximum increases or decreases during the study, all assessments, 
including unscheduled assessments will be used. For analysis assessing change from baseline, 
only patients with both baseline and at least 1 evaluable post-baseline measure will be 
included. 
Given there is a single primary endpoint and treatment comparison, no formal testing strategy
will be used for the analysis in this study.
All hypothesis testing will be reported using 2-sided tests. All p-values apart from the 
primary analyses of the primary endpoint will be nominal. All p-values will be rounded to 4 
decimal places. 
The absolute change from baseline is computed as (visit value – baseline value). Percent 
change from baseline is computed as ([visit value – baseline value]/baseline value)×100%. If 
either a visit value or the baseline visit value is missing, the absolute change from baseline 
value and the percent change from baseline will also be set to missing.
The prior medications, categorized according to the WHO Drug Reference List dictionary 
which employs the Anatomical Therapeutic Chemical (ATC) classification system, will be 
summarized by treatment group as frequency and percentage of patients reporting usage.
The concomitant medication will be categorized according to the WHO Drug Reference List 
dictionary which employs the Anatomical Therapeutic Chemical (ATC) classification system. 
The frequency and percentage of patients taking concomitant medications and non-drug 
therapies during the treatment period will be summarized by drug class and drug name using 
the ATC codes.
4.2
Analysis methods
4.2.1
Patient disposition
Patient disposition will be summarized using the all patients analysis set. 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 will be presented by the following categories: randomized, received treatment with 
study drug, did not receive treatment with study drug (and reason), completed treatment with 
study drug, discontinued treatment with study drug (and reason), discontinued treatment with 


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study drug 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 of patients randomized by country and center will also be summarized by 
treatment group in the FAS.
4.2.2
Demography data and patient characteristics
Demography data such as age, gender, race, and ethnicity will be summarized by treatment 
group for all patients in the FAS. Age will be derived from the date of informed consent 
date-of-birth, rounded down to the nearest integer. For patients in country where date of birth 
is not recorded, the age as recorded in the eCRF will be used.
Various baseline characteristics will also be summarized by treatment for the FAS. These 
include maintenance asthma medications, maintenance ICS medications, medical and surgical 
histories, FEV1 (pre- and post-BD) at baseline, and respiratory disease characteristics 
including age at onset of asthma, number of exacerbations in the previous 12 months, and  
number of exacerbations requiring hospitalizations in the previous 12 months. 
The following will be summarized for patients in the FAS and repeated by region and for the 
body plethysmography sub-study set:
!
Patient characteristics (weight, height, BMI, baseline eosinophil count)
!
Baseline lung function data (FEV1 [L], FEV1 [% PN], FVC [L], FVC [% PN], 
FEV1/FVC, FEF 25-75% [L/S], reversibility (%)
!
ACQ-6 score
!
Respiratory disease characteristics
Medical and surgical histories will be summarized by MedDRA Preferred Term (PT) within a 
MedDRA System Organ Class (SOC).
The number of patients remaining on treatment, patients discontinued IP but still in study 
follow-up, and patients who withdraw from the study will be presented by treatment group 
and scheduled visit. 
4.2.3
Prior and concomitant medications
The number and percentage of patients taking maintenance asthma medications, including 
ICS/LABA fixed dose combinations, at baseline will be summarized.
The number and percentage of patients who take prior medications, those who take allowed 
concomitant medications, and those who take disallowed concomitant medications during the 
study will be presented by treatment group. Concomitant medications will be classified 


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according to the WHO Drug Dictionary (WHODD). The summary tables will present data by 
generic term within the ATC code.
4.2.4
Study Treatments
4.2.4.1
Exposure
Exposure to IP will be calculated in days as:
Last dose date of IP-first dose date of IP+1, 
and will be summarized by treatment group for the safety analysis set.
4.2.4.2
Study treatment compliance
Study treatment compliance will be summarized by treatment group for the FAS and 
calculated as: 
Study treatment compliance=(total doses administered/total doses expected)x100.
Patients who received no study treatment will have zero compliance. Total number of doses 
expected includes all visits with protocol scheduled IP administration on or before a subject's 
IP discontinuation or treatment complete date.
4.2.5
Primary outcome variable
4.2.5.1
Primary analysis
The change from baseline in pre-BD FEV1 up until the EOT at Visit 10 will be compared 
between the 30 mg benralizumab group and placebo using a mixed-effect model for repeated 
measures (MMRM) analysis on patients with a baseline pre-BD FEV1 and at least 1 
post-randomization pre-BD FEV1 in the FAS. 
The dependent variable will be the change from baseline in pre-BD FEV1 at post-baseline 
protocol specific visits (up to and including the EOT Visit). Treatment group will be fitted as 
the explanatory variable, region, visit and treatment*visit interaction as fixed effects, and
baseline pre-BD FEV1 will be fitted as a covariate. The variance-covariance matrix will be 
assumed to be unstructured. If the procedure does not converge, then a compound symmetric 
variance-covariance matrix will be used instead. The model is:
Change in FEV1=treatment+baseline pre-BD FEV1+region+visit+treatment*visit
The primary objective of the study is to determine the effect of benralizumab on the time 
course of change (onset and maintenance of effect) of pre-BD FEV1 using the model 
described above. The first post-baseline timepoint where the p-value for the mean difference 
between benralizumab and placebo is ≤0.05 will be used to determine time to onset of effect. 
The average over the mean differences between benralizumab and placebo based on the 
change from baseline (Visit 4) to Days 28 (Visit 8), 56 (Visit 9), and 84 (Visit 10) in 
pre-BD FEV1 will be used to determine if the study is positive as well as to determine the 


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maintenance of effect. Contrasts will be used to obtain estimates of the treatment differences 
over Days 28, 56, and 84, as well as at each timepoint separately.  
Results will be presented in terms of least square means (LSMEANS), treatment differences 
in LSMEANS, 95% confidence intervals (CI) of treatment differences, and p-values at each 
planned timepoint. 
4.2.5.2
Sensitivity analysis
A sensitivity analysis of pre-BD FEV1 may be performed as applicable by excluding patients
who meet at least one of situations below: 
!
Who do not withhold their regular asthmas medication prior to spirometry 
assessment
!
Who do not withhold their SABA for more than 6 hours prior to spirometry 
assessment
4.2.5.3
Subgroup analysis
To explore the uniformity of the detected overall treatment effect on the primary efficacy 
variable, subgroup analyses, including statistical modelling where the interaction between 
treatment and covariates to estimate the treatment effect within each subgroup, may be 
performed for the following factors for maintenance of effect: OCS use at baseline (yes/no),
gender, race, age group categories (<65, ≥65 years), geographic region, BMI (≤35, >35 
kg/m2), the number of exacerbations during the previous year (2, ≥3 exacerbations), nasal 
polyps (yes/no), baseline immunoglobulin E (IgE) concentration (<150kU/L, ≥150kU/L),
baseline EOS and FeNO. In addition, an overall standardized effects plot and forest plot 
across all subgroups will be produced for maintenance of effect. ANCOVA will be utilized in 
the overall standardized effects plot to assure convergence and avoid run-time issue. Average 
value from Day 28, 56 and 84 will be the response variable. Treatment group and baseline 
pre-BD FEV1 will be included in the model for overall effect model.  Treatment group, 
subgroup being evaluated, interaction of treatment group and subgroup being evaluated, and 
baseline pre-BD FEV1 will be included in the subgroup effect model. Missing data will be 
imputed by last observation carried forward (LOCF) prior to the average of Day 28, 56 and 84 
is derived.
Additionally, subgroup analysis of pre-BD FEV1 will be performed to explore the relationship 
with baseline blood eosinophil counts using the categories ≥300-449/μL and ≥450/μL, and 
with baseline FeNO using the categories of ≤50 and >50 ppb. Blood eosinophil data collected 
at Screening visit will be used for this categorization to ensure that all subjects can be 
classified and included in the summary.
It is important to note that the study has not been designed or powered to assess efficacy 
within any of these pre-defined subgroups, and as such, these analyses are considered
exploratory.


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4.2.5.4
Supportive analyses
The modelled treatment response as well as differences between benralizumab and placebo 
using the mean change from baseline in pre-BD FEV1 endpoint using an exponential model 
over time will be estimated. The model will be used to determine the modelled time to onset 
of effect.
Onset of effect will be defined as: (i) the time taken for benralizumab and placebo to reach a 
pre-defined change from baseline value, (ii) the time taken for the difference between 
benralizumab and placebo [change from baseline values to reach a pre-defined value.  
As detailed in the study protocol, the main focus is to estimate onset of effect using the 
primary variable, pre-BD FEV1.  Onset of effect will be estimated using change from baseline 
measurements which were scheduled on days 3, 7, 14, 28, 56, and 84, actual day that data is 
collected in study is utilized. An exponential relationship will be assumed over time (Gelman, 
et al 2013), using Bayesian methodology (Marostica, et al 2013) to fit a nonlinear mixed 
effects model to the observed data. The fitted model will then be used to estimate onset of 
effect for the set of change from baseline values 50, 100, 150, 200, 250, and 300 mL and the 
set of differences 50, 100, 150, 200, 250, and 300 mL. In addition, an average change from 
baseline will be estimated for days 1, 3, 7, 14, 21 and 28, 56, 84, and the proportion of 
subjects with a change from baseline value greater than or equal to {50, 100, 150, 200 and 250 
and 300 mL} will be estimated for days 1, 3, 7, 14, 21, 28, 56, 84.  Differences between 
proportions and odds ratios will also be estimated.
It is anticipated that an exponential model will adequately describe pre-BD FEV1 change from 
baseline over time, based on (Gelman, et al 2013) and modelling similar data taken from the 
Phase III SIROCCO and CALIMA trials.  However, if the data show that an exponential 
model is a poor choice, an alternative model will be investigated following the same principles 
outlined below.
In addition to pre-BD FEV1, one or more secondary variables may also be investigated.
As described in the protocol, measurements for pre-BD FEV1 will be recorded on day 0, 3, 7, 
14, 28, 56, 84. For every subject, pre-BD FEV1 change from baseline values will be 
calculated for day 3, 7, 14, 28, 56, 84.  If a baseline value or post-baseline measurement is 
missing, the corresponding change from baseline value will be set to missing.  Onset of effect 
will be estimated for subjects in the full analysis set (FAS) with a baseline value and at least 
one pre-BD FEV1 measurement recorded after the first dose of study drug.
Model
For each treatment separately, Bayesian methodology will be used to fit the following 
nonlinear mixed effects model to the observed pre-BD FEV1 change from baseline data 


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where 
denotes the change from baseline value for the 
subject at the 
time point 
(
)
ԑij ~ t (0, σ2, df)
Note that 
is an asymptote, representing the maximum (or minimum) change from baseline 
over time and 
is a rate, constrained to be greater than zero, representing how quickly the 
change from baseline values increase or decrease over time.  This model takes into account 
the inherent structure that is present in the observed data and gives an estimate of C and 
for 
a specific treatment group, and allows these parameters to vary between subjects.
Prior distributions for the model parameters will be:
σ2 ~igamma (shape=0.01, scale=0.01)
σc2 ~igamma (shape=0.01, scale=0.01)
σlogƟ2 ~igamma (shape=0.01, scale=0.01)
df ~ uniform (2, 50)
Note that igamma refers to inverse gamma distribution.
For each parameter, a chain of 200,000 samples will be drawn from the posterior distribution, 
after discarding the first 100000 burn-in samples. The 200,000 samples will be thinned every 
200th observation to ensure there is little correlation in the remaining 1,000 posterior samples.  
Following the same process, a further two chains will be run, whereby the seed and set of 
starting values will be changed for each of these additional chains. Seed numbers of 3598, 
2917 and 6301 will be utilized for benralizumab, and seed numbers of 1256, 8734 and 7376  
for placebo group. Starting values for both treatment groups will be 25, 50 and 75 mL for C, 
and -1 for log . Sensitivity analysis may be carried out for different starting values from those
specified to assess the robustness of model fitting.
Note that when modelling the pre-BD FEV1 measurements, data collected beyond Day 98
(upper visit window of Day 84) will be excluded in the analysis.


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Model checks
The convergence of the model will be investigated by assessing stationarity and mixing across 
chains.  If convergence is not met, it may be deemed necessary to consider alternatives for (i) 
the set of priors, (ii) the distributions associated with the model parameters describing the 
data, (iii) the exponential model.  Any deviation from the planned analysis will be 
documented as a change to the statistical analysis plan.
!
Stationarity
For each parameter, the 1000 posterior samples will be plotted against iteration number for 
each chain separately.  Posterior summary will be provided for C and log
from each 
chain, the efficiency associated with the effective sample size will also be checked for 
each parameter to ensure that this statistic is high (e.g. greater than 0.9) across chains.  If 
an obvious pattern exists in the posterior samples or the efficiency < 0.9 for a specific 
chain, auto-correlation exists and stationarity has not been reached.  Consequently, a larger 
number of samples will be discarded as burn-in, and the number of samples per chain will 
be increased with a greater amount of thinning.
!
Mixing
For each parameter, the 1000 posterior samples from each chain will be plotted together 
against iteration number, with a different coloured line used for each chain.  If the chains 
overlap, they are deemed to mix well and they will be combined to give 3000 posterior 
samples for each model parameter.  If the chains do not mix well, the proposed model will 
be reviewed and refined if deemed necessary.
Estimating the change from baseline at time points of interest in a treatment group, and 
difference in change from baseline at time points of interest between treatment groups
For a specific treatment group, let {
denote the set of estimated model parameters 
for the 
subject from the 
posterior sample, where 
and 
(assuming the 3 chains are stationary and mix well). Let denote a time point of interest, 
where t=1, 3, 7, 14, 21, 28, 58, 84. The change from baseline at each time point of interest will 
be estimated for benralizumab and placebo by following the steps below:
i.
For the 
posterior sample 
, the fitted change from baseline value at 
time point for the 
subject 
in a specific treatment group is
where 
.
ii.
The mean change from baseline value at time for the 
posterior sample 
will be calculated as


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iii.
The 50th and (2.5th, 97.5th) percentiles of {
will be derived, giving the 
median and corresponding 95% credible interval for the average change from baseline 
value at time point 
iv.
Steps (i) through to (iii) will be carried out for each treatment and all values of .
Note that it is anticipated that some subjects may withdraw from the study early.  For these 
subjects, their fitted response will be extrapolated beyond their last visit.  Consequently, 
inferences will be based on all subjects in the analysis set.
Estimates and credible intervals for the change from baseline from the modelling above will 
be tabulated by treatment and time point. A figure will be provided for the change from 
baseline values over time.
To estimate the difference between treatment groups in change from baseline at time points of 
interest, assuming the 3 chains are stationary and mix well, by independence the 
posterior 
sample for benralizumab will be associated with the 
posterior sample for placebo 
  
v.
The difference between treatment groups in mean change from baseline value at time 
for the 
posterior sample will be calculated as (mean change from baseline value in 
benralizumab) – (mean change from baseline value in placebo), where mean within 
treatment group is derived as per step ii above.
vi.
The 50th and (2.5th, 97.5th) percentiles of the differences {d1, …, d3000} at time t will 
be derived, giving the median and corresponding 95% credible interval for the 
difference between benralizumab and placebo in change from baseline at time t.  If 
either the 50th, 2.5th or 97.5th percentile is greater than T=84, such values will be 
reported as “>84”.
Estimating the time taken for a treatment to reach a pre-defined change from baseline 
value
For a specific treatment group, let {
denote the set of estimated model parameters 
for the 
subject from the 
posterior sample, where 
and 
(assuming the 3 chains are stationary and mix well).  Let 
denote a pre-defined change from 
baseline value, where 
= 50, 100, 150. 200, 250, and 300 mL. Let 
be the planned duration 
of the study in days, where T=84 is divided into 1000 time points to give 
.  The 
time taken to reach a pre-defined change from baseline value will be estimated for 
benralizumab and placebo by following the steps below:


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i.
For the 
posterior sample 
, the fitted change from baseline at time 
point 
for the 
subject 
in a specific treatment group 
is
where 
.
ii.
The mean change from baseline value at time 
for the 
posterior sample 
will be calculated as
iii.
For pre-BD FEV1, an improvement is associated with 
  Thus, from the set of 
values 
, all values greater than or equal to a specific value of 
will be retained.  The earliest time point will be selected and labelled 
(which gives 
the earliest time point at which 
is closest to ).   If there are no values that are 
greater than or equal to , the time 
will be set to a large value greater than 
(e.g. 
).  Consequently, all posterior samples will be included in the summary of 
.  
iv.
The 50th and (2.5th, 97.5th) percentiles of 
will be derived, giving the 
median and corresponding 95% credible interval for the average time taken for the 
change from baseline to reach . If either the 50th, 2.5th or 97.5th percentile is greater 
than T=84, such values will be reported as “>84”.
v.
Steps (i) through to (iv) will be carried out for each treatment and all values of 
Note that it is anticipated that some subjects may withdraw from the study early.  For these 
subjects, their fitted response will be extrapolated beyond their last visit.  Consequently, 
inferences will be based on all subjects in the analysis set.
Estimates and credible intervals for the time taken for a treatment to reach a pre-defined 
change from baseline value from the modelling above will be tabulated by treatment and pre-
defined change from baseline value.
Estimating the time taken for the difference between benralizumab and placebo [change
from baseline values] to reach a pre-defined value
Assuming the 3 chains are stationary and mix well, by independence the 
posterior sample 
for benralizumab will be associated with the 
posterior sample for placebo 
   For the 
posterior sample, let 
denote the set of estimated 
model parameters for the 
subject in the benralizumab group (
) and let 
denote the set of estimated model parameters for the 
subject in the placebo 
group (
).  Let denote a pre-defined difference between benralizumab and 


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placebo change from baseline values, where
= 50, 100, 150, 200, 250, and 300 mL.  Let 
be the planned duration of the study in days, where T=84 is divided into 1000 time points to 
give 
.  The time taken for the difference between benralizumab and placebo to 
reach a pre-define value will be calculated as follows:
i.
For the 
posterior sample 
, the fitted change from baseline at time 
point 
for the 
subject (
) in the placebo group is 
where 
and the mean change from baseline value at time 
for the 
posterior sample will be calculated as
ii.
For the 
posterior sample 
, the fitted change from baseline at time 
point 
for the 
subject (
) in the benralizumab group is
where 
and the mean change from baseline value at time 
for the 
posterior sample will be calculated as
iii.
For the 
posterior sample 
the average difference between 
benralizumab and placebo at time point 
will be calculated as
iv.
For pre-BD FEV1, an improvement is associated with 
Thus, from the set of 
values 
all values greater than or equal to a specific value of 
will be retained.  The earliest time point will be selected and labelled 
(which gives 
the earliest time point at which 
is closest to ).   If there are no values that are 
greater than or equal to , the time 
will be set to a large value greater than 
(e.g. 
).  Consequently, all posterior samples will be included in the summary of 
.
Note that for a secondary variable an improvement could be associated with 
Thus, from the set of values 
all values less than or equal to a 
specific value of will be retained.  The earliest time point will be selected and 
labelled 
(which gives the earliest time point at which 
is closest to ).   If there 


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are no values that are less than or equal to , the time 
will be set to a large value 
greater than 
(e.g. 
).  Consequently, all posterior samples will be included 
in the summary of 
.
v.
The 50th and (2.5th, 97.5th) percentiles of 
will be derived, giving the 
median and corresponding 95% credible interval for the average time taken for the 
average difference between benralizumab and placebo to reach .  If either the 50th, 
2.5th or 97.5th percentile is greater than T=84, such values will be reported as “>84”.
vi.
Steps (i) through to (v) will be carried out for all values of 
Estimates and credible intervals for the time taken for the difference between benralizumab 
and placebo [change from baseline values] from the modelling above will be tabulated by 
treatment and pre-defined difference value.
Estimating the proportion of subjects ≥ pre-defined thresholds at time points of interest
For a specific treatment group, let {
denote the set of estimated model parameters 
for the 
subject from the 
posterior sample, where 
and 
(assuming the 3 chains are stationary and mix well).  Let denote a time point of interest, 
where t=1, 3, 7, 14, 21, 28, 58, 84.  Let 
denote a pre-defined change from baseline value, 
where
= 50, 100, 150, 200, 250, and 300 mL.  At a specific time point, the proportion of 
subjects 
will be estimated for benralizumab and placebo by following the steps below:
i.
For the 
posterior sample 
, the fitted change from baseline at time 
point for the 
subject 
in a specific treatment group is
where 
.
!
If, at time point :
!
The proportion of subjects will be calculated as
iv.
The 50th and (2.5th, 97.5th) percentiles of 
will be derived, giving the 
median and corresponding 95% credible interval for the proportion of subjects greater 
than or equal to a specific value of 
at time point .
v.
Steps (i) through to (iv) will be carried out for each treatment and all values of and 


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Estimates and credible intervals for the proportion of responders ≥ pre-defined thresholds at 
time points of interest from the modelling above will be tabulated by treatment, pre-defined 
thresholds and timepoints of interest.
Estimating the difference between proportions 
Following the steps outlined in Section 5.4, let 
denote the set of proportions for 
benralizumab and let 
denote the set of proportions for placebo for a specific 
value of and .
i.
For the 
posterior sample 
, calculate the difference
ii.
The 50th and (2.5th, 97.5th) percentiles of 
will be derived, giving the 
median and corresponding 95% credible interval for the difference between 
proportions
iii.
Steps (i) through to (ii) will be carried out for all values of and 
Difference of proportions between treatment groups over time will be tabulated for each pre-
defined threshold. Figures will be provided.
Estimating the odds ratio
Following the steps outlined in Section 5.4, let 
denote the set of proportions for 
benralizumab and let 
denote the set of proportions for placebo for a specific 
value of and .
i.
For the 
posterior sample (
), calculate the odds ratio
ii.
The 50th and (2.5th, 97.5th) percentiles of 
will be derived, giving the 
median and corresponding 95% credible interval for the odds ratio
iii.
Steps (i) through to (ii) will be carried out for all values of and 
In the cases when proportions of responders or non-responders in either treatment group is 
zero, odds ratio would be estimated using the following approach:
i) calculation of odds ratio on iteration level: when proportion of responders or non-responders 
is 0 in a treatment group, make adjustment by adding 0.5 to all cell counts, eg out of N=100 in 
a treatment arm, if there is 0 responder, and 100 non-responders observed in an iteration, 
replace the count of responder with 0.5, and non-responder with 100.5 in that treatment arm.
And add 0.5 to cell counts in the other treatment arm. Then calculate odds ratio for that 


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iteration. This applies to cases when 0 count occurs in either or both Benra and Placebo 
groups.
ii) summary statistics across 3000 iterations: if more than 5% odds ratios are estimated as 
outlined in step i) due to 0 count, then set the estimates (median, 95% credible intervals) to 
NC; otherwise, median, and 95% credible intervals are based on 3000 iteration results with 
estimated odds ratios (as outlined in step i) included.
Odds ratio over time will be tabulated for each pre-defined threshold. Figures will be 
provided.
Alternative models
Convergence issues may arise when carrying out the planned analysis and it may be deemed 
necessary to consider alternatives for (i) the set of priors, (ii) the distributions associated with 
the model parameters describing the data and (iii) the exponential model.  
However, if such changes still lead to convergence issues, a simplified analysis will be carried 
out whereby an exponential model (or alternative) will be fitted through the mean change 
from baseline values for each treatment.  Consequently, focus will be based on point estimates 
only, without any measures of precision, given that between-subject and 
within-subject components could not be incorporated in the model successfully.  In this case, 
we will estimate
i.
the change from baseline at t=3,7,14,28,56,84
ii.
the time taken for benralizumab and placebo to reach
= 50, 100, 150, 200, 250, and 
300 mL
iii.
the time taken for the difference between benralizumab and placebo change from 
baseline values to reach
= 50, 100, 150, 200, 250, and 300 mL
Note that all deviations from the planned analysis will be documented as a change in the 
statistical analysis plan
4.2.6
Secondary efficacy outcome variables
4.2.6.1
Secondary analyses 
For each secondary efficacy variable described in Section 3.2, the objective is to determine the 
effect of benralizumab on the time course of change (onset and maintenance of effect).
FEV1 responder at each post-baseline visit will be defined as a subject with change from 
baseline ≥prespecified cutoffs as in Section 3.1, and analysed using a logistic regression 
model with repeated measures using generalized equation estimate method. The model will 
include treatment, region, visit and treatment group by visit interaction as fixed factors, and 
baseline FEV1 scores as a covariate. The variance-covariance matrix will be assumed to be 
unstructured.  


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The percent change from baseline at each timepoint for the eosinophils counts, change from 
baseline at each timepoint for Pre-BD FVC, ACQ-6 score, SGRQ score, and FeNO will be 
compared between benralizumab and placebo using an MMRM analysis described in the 
primary analysis above. The least squares mean for the difference in treatment groups using 
the interaction between visit and treatment group, its 95% CI, and the 2-sided p-values will be 
reported for each post-baseline visit. 
As for the primary endpoint, the first post-baseline timepoint where the p-value for the mean 
difference between benralizumab and placebo is less than or equal to 0.05 from the repeated 
measures analysis will be used to determine time to onset of effect for each secondary 
parameter. The average over the mean differences between benralizumab and placebo based 
on the change from baseline (Visit 4) to Days 28 (Visit 8), 56 (Visit 9), and 84 (Visit 10) will 
be used to determine maintenance of effect. Contrasts will be used to obtain estimates of the 
average treatment differences over Days 28, 56, and 84.
Results will be presented in terms of LSMEANS, treatment differences in LSMEANS, 95% 
CIs of treatment differences, and p-values at each planned timepoint. To explore correlations 
between changes in eosinophil depletion and lung function, and correlations between changes 
in FeNO and lung function, the following analyses will be conducted, blood eosinophil data 
collected at Screening visit will be used in the analyses below to be consistent with the 
subgroup analysis of pre-BD FEV1 by baseline EOS categories:
!
Analyses will be conducted on change from baseline versus baseline eosinophil 
count at Day 28 and Day 84 in pre-BD FEV1 using a moving average and MMRM
approach. In this analysis, patients will be ordered by baseline eosinophil count and 
grouped by percentile into overlapping subgroups (0 – 40th, 10th – 50th, 20th – 60th, 
30th – 70th, 40th – 80th, 50th - 90th, 60th –100th). The MMRM model will be then
applied to each subgroup to estimate the treatment difference at Day 28 and Day 84 
separately and associated 95% CI for each percentile grouping. 
!
A scatterplot of observed change in pre-BD FEV1 at Day 28 and 84 versus baseline 
eosinophils at Day 28 and Day 84 will be prepared separately with locally weighted 
scatter plot smoothing curves (LOESS) and corresponding 95% CIs superimposed. 
!
Same kinds of MMRM and LOESS analyses will be performed using baseline 
FeNO data.
!
If significant treatment effect is detected at timepoints earlier than Day 28, the same 
kinds of MMRM and LOESS analyses will also be performed at the earliest
timepoint where significant treatment effect is detected.
A scatter plot with correlation coefficient will be provided for baseline FeNO and EOS count 
data to evaluate the association between baseline FeNO and EOS.


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4.2.6.2
Proportion of responders by PRO measures
Responder at the post-baseline visit from the selected secondary endpoints below will be 
analyzed using a logistic regression model with repeated measures using generalized equation 
estimate method. The model will include treatment, region, visit and treatment group by visit
interaction as fixed factors, and baseline scores as a covariate. The variance-covariance matrix 
will be assumed to be unstructured.  
ACQ-6 responder at each post-baseline visit: Will be based on change from baseline to each 
post-baseline visit as defined in Section 3.3.2.  Patients with missing or non-evaluable score at 
a post-baseline visit will be considered non-responders.
SGRQ responder at each post-baseline will be defined for each post-baseline visit as an 
individual with a ≥4-point decrease (improvement) from baseline in SGRQ total score.
Patients with missing or non-evaluable score at any post-baseline visit will be considered non-
responders.
4.2.7
Exploratory efficacy outcome variable
4.2.7.1
Exploratory analysis of PGI-S
The same analysis approach described in the primary analysis will be performed on the
change from baseline in PGI-S at each post-baseline visit.  A summary table will be produced 
showing the number and percentage of patients with improvement from baseline at each 
post-baseline visit.  
Patients with a PGI-S improvement at the EOT visit will be analyzed using a logistic
regression model with covariates of treatment and region. 
4.2.7.2
Exploratory analysis of CGI-C and PGI-C
The CGI-C and PGI-C responses will be summarized by treatment group and visit. The 
number and percentage of patients will be presented for CGI-C, PGI-C, and for agreement in 
CGIC and PGIC responses as described in Section 3.3.2.
The number and percentage of patients defined as responders based on categorized responses
for CGI-C and PGI-C (improved, much improved, very much improved) will also be 
presented by treatment group and visit. 
Responders at the EOT visit will be analyzed using a logistic regression model with covariates 
of treatment and region. 
4.2.8
Sub-study body plethysmography outcome variable
The objective of the sub-study is to determine the effect of benralizumab on the time course of 
change (onset and maintenance of effect) of body plethysmography outcome variables. Only 
the outcome values with acceptable quality (acceptable or borderline quality grade) will be 
used for analyses. All the observed and change from baseline of sub-study variables will be 
summarized by treatment and visit. 


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4.2.8.1
Sub-study primary analysis
The change from baseline in RV at each timepoint will be compared between benralizumab 
and placebo using an MMRM analysis in the sub-study population if sufficient acceptable 
quality data warrants.
The dependent variable will be the change from baseline in RV at post-baseline protocol 
specific visits (up to and including the EOT Visit). Treatment group will be fitted as the 
explanatory variable, visit and treatment*visit interaction as fixed effects, and baseline RV 
will be fitted as a covariate. Region may be fitted as a fixed effect. The variance-covariance 
matrix will be assumed to be unstructured. If the procedure does not converge, then a 
compound symmetric variance-covariance matrix will be used instead.
As for the primary efficacy analysis, contrasts will be used to obtain estimates of the treatment 
differences over Days 28, 56, and 84 as well as at each timepoint separately.  Results will be 
presented in terms of LSMEANS, treatment differences in LSMEANS, 95% CIs of treatment 
differences, and p-values at each planned timepoint. 
4.2.8.2
Sub-study secondary analysis
The change from baseline at each timepoint for TLC, ratio TLC/RV, VC, IC and FRC may be 
compared between benralizumab and placebo using an MMRM analysis in the sub-study 
population as for the primary efficacy analysis of sub-study as described above.
4.2.8.3
Sub-study explorative analysis
Only descriptive statistics for SGaw and Raw and change from baseline will be provided at 
each scheduled visit at which assessments are performed.
Subgroup analyses of RV and ratio TLC/RV may be performed for the age group categories 
(18-30 years, 31-65 years). 
4.2.9
Safety outcome variables
All safety variables will be summarized using the safety analysis set and data presented 
according to actual treatment received. 
4.2.9.1
Adverse events 
Adverse events (AEs) will be summarized for the on-study period, as defined in Section 3.5.1.
All summaries will be presented by treatment group.
An overall summary table will be produced showing the number and percentage of patients 
with at least 1 AE in any of the following categories: AEs, serious adverse events (SAEs), 
AEs with outcome of death, and AEs leading to discontinuation of IP (DAEs). The total 
number of AEs in the different AE categories in terms of AE counts will also be presented (ie,
accounting for multiple occurrences of the same event in a patient). 


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Adverse events, AEs with outcome of death, and SAEs will be summarized by SOC and PT
assigned to the event by MedDRA. For each PT, the number and percentage of patients 
reporting at least 1 occurrence will be presented (ie, multiple occurrences of an AE for a 
patient will only be counted once). Adverse events causing discontinuation of the study 
treatment and SAEs causing discontinuation from the study will also be summarized. 
The rate of AEs per person-years at risk, calculated as (number of patients reporting AE)/(total 
period with patients at risk for AE), will also be reported. The total period at risk for each 
patient will be defined as the period from first dose of study treatment to the follow-up visit 
(Week 16). Rates will be expressed in terms of events per 100 patient-years.
A summary of the most common (frequency of ≥5%) AEs will be presented by PT. Adverse
events will be summarized by PT and Investigator’s causality assessment (related versus not 
related) and maximum intensity. 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). Adverse events of injection 
site reactions (high-level term of administration and injection site) and hypersensitivity 
(standardized MedDRA query of hypersensitivity) will be summarized by PT. The summary 
of injection site reactions will be summarized by injection site location and number of IP 
administrations.  
Adverse events related to device malfunction will be listed.  All adverse events will be listed.
4.2.9.2
Laboratory data 
All continuous laboratory parameters will be summarized descriptively by absolute value at 
each visit by treatment group, together with the corresponding changes from baseline. All 
parameters will be summarized in SI units, with the exception of blood eosinophil counts 
which will be summarized in both SI and conventional units. Results which are reported from 
the central laboratory in conventional units will be converted to SI units for reporting. 
Central laboratory reference ranges will be used for the identification of abnormalities, and a 
shift table will be produced for each laboratory parameter to display low, normal, high values, 
and missing values. The shift tables will present baseline and post-baseline 
maximum/minimum value, as applicable, for each parameter and will include patients with 
both baseline and post-baseline data.
Shift plots showing each individual patient’s laboratory value at baseline and at 
maximum/minimum post-baseline will be produced for each continuous laboratory variable.
If any laboratory variables show any unusual features (high or low values or a general shift in 
the data points) at other timepoints, then shift plots of these data may be produced. 
Data for patients who have treatment-emergent changes outside central laboratory reference 
ranges will be presented. This data presentation will include all visits for this subset of 
patients. 


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Maximum post-baseline bilirubin elevations by maximum post-baseline ALT and AST will be 
presented, expressed as multiples of ULN.  Bilirubin will be presented in multiples of the 
following ULN: ≤1.5, >1.5-2, and >2. Alanine aminotransferase and AST will be presented in
multiples of the following ULN: ≤1, >1-3, >3-5, >5-10, and >10.
Maximum post-baseline total bilirubin (TBL) will be presented (<2 and ≥2xULN) and plotted 
against maximum post-baseline ALT (<3, ≥3-<5, ≥5-<10, and ≥10 x ULN), expressed as 
multiples of ULN.  This will be repeated to show maximum post-baseline TBL against 
maximum post-baseline AST. 
Data for patients with ALT or AST ≥3xULN, and TBL≥2xULN will be presented, which will
include all visits for this subset of patients.  A line plot of liver biochemistry test results 
(including ALP, ALT, AST, TBL, and GGT) over time will also be presented for this subset 
of patients.
For urinalysis data, a shift table will be generated to present changes from baseline to 
maximum post-baseline value for each parameter and will include patients with both baseline 
and post-baseline data.  
Descriptive statistics will be presented for IgE baseline value by treatment group.
Any data outside the central laboratory reference ranges will be explicitly noted on the listings 
that are produced.
4.2.9.3
Electrocardiograms
A shift table will be produced for each ECG parameter to display normal, abnormal – not 
clinically significant, abnormal – clinically significant, and not done. The shift tables will 
present baseline and last observation post-baseline value, as applicable for each parameter.
4.2.9.4
Physical examination
Any new finding(s) or aggravated existing finding(s), judged as clinically significant by the 
Investigator will be reported as AEs.
4.2.9.5
Vital signs 
Descriptive statistics and change from baseline for vital signs data will be presented for each 
treatment group by visit.  Baseline to maximum post-baseline and baseline to minimum 
post-baseline value shift tables may be generated as applicable for each parameter and will 
include patients with both baseline and post-baseline data.
The normal reference ranges listed on Table 2 will be used for the identification of low, 
normal, and high values.
4.2.10
Pharmacokinetic analyses 
The PK analyses will be performed at or under the guidance of AstraZeneca Research and 
Development. 


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Benralizumab serum concentrations and derived PK parameters will be summarized using 
descriptive statistics at each visit. In addition to the standard statistics, geometric mean and 
coefficient of variation (CV%) based on log-transformation will be presented for PK data. For the 
computation of geometric means, arithmetic means and medians, the BLQ data are set to 
LLOQ/2 before computation.
For non-compartment analysis (NCA), only patients with at least three evaluable serum PK 
observations post first dose (collected on day 3, day 7 and either day 14 or pre-dose on day 
28) will be included.
When PK concentration data is missing on scheduled visit, data from unscheduled visits will 
be included based on the adjusted analysis defined visit window in Section 2.2.2; on dosing 
visits (ie, Baseline, Days 28 and 56), pre-dose values only are included. For subjects who 
prematurely discontinued study drug, PK data collected after the last dose date + 28 days (one 
dosing cycle) +3 days (visit window) will be excluded from PK analysis.
4.2.11
Immunogenicity analyses 
Anti-drug antibody assessments will be conducted and analyzed as per the details in Section 3
of the “Statistical Analysis Plan for Benralizumab Anti-Drug Antibody data” with the 
following exceptions:
!
Demographics/patient characteristics summary by ADA status and further by 
positive subgroup will not be produced.
!
Summaries will not be produced by baseline blood eosinophils count cut off (≥300 
or <300 cells/μL) due to all patients enrolled in this study having baseline blood 
eosinophils count ≥300 cells/μL.
!
Summary of first positive post-baseline ADA response during the study will not be 
produced.
!
Listing of patients who had ADA titres increased by >4-fold from onset to 
maximum titre will not be produced.
!
Eosinophil levels will be summarized by visit for ADA positive and negative 
patients only. 
!
Summary of nAb will not be provided by subgroup of ADA positive.
!
Relationship between ADA and efficacy will not be explored. 
!
Relative risk tables for select safety outcomes will be omitted due to low frequency 
of events.
!
Listing of ADA titre by visit for ADA-positive patients will be produced.


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5.
INTERIM ANALYSES
No interim analysis is planned for this study.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
Protocol Section 8.5.2.3 mentions that ECG intervals will be summarized by presenting 
summary statistics of observed and change from baseline values. The (uncorrected) QT 
interval will be corrected according to the Fridericia’s formula. However, this study collects 
only ECG outcome of the overall evaluation recorded as normal and abnormal; therefore, the 
summaries of observed and change from baseline values will not be performed. 
7.
REFERENCES
ATS 2005
American Thoracic Society/European Respiratory Society. ATS/ERS recommendations for 
standardized procedures for the online and offline measurement of exhaled lower respiratory 
nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005; 171:912–930.
Bleeker et al 2016
Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, Sproule S, Gilmartin 
G, Aurivillius M, Werkström V, Goldman M; SIROCCO study investigators. Efficacy and 
safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled 
corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo 
controlled phase 3 trial. Lancet. 2016;388:2115–27.
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; 2:878-90.
Fitzgerald et al 2016
FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, Ferguson GT, Busse 
WW, Barker P, Sproule S, Gilmartin G, Werkström V, Aurivillius M, Goldman M; CALIMA 
study investigators. Benralizumab, an anti–interleukin-5 receptor α monoclonal antibody, as 
add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a 
randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016; 388:2128–41.
Jones et al 1991
Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir 
Med. 1991; 85 Suppl B:25-31.


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Jones et al 2009 
Jones PW, Harding G, Berry P, Wiklund I, Chen W-H, Leidy NK. Development and
firstvalidation of the COPD Assessment Test. Eur Respir J 2009, 34: 648–654.
Juniper et al 2005
Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respir Med. 2005 99:553–58.
Juniper et al 2006
Juniper EF, Bateman ED. The GOAL Committee. Identifying ‘well-controlled’ and ‘not well-
controlled’ asthma using the Asthma Control Questionnaire. Respir Med. 2006 100:616–21.
Liu et al 2005
Liu, H, Wu T. Sample size calculation and power analysis of time-averaged difference. J Mod 
Appl Stat Methods. 2005 4(2): 434-45.
Gelman et al 2013
Gelman, A., Carlin, J.B., Stern, H.S., Dunson, D.B., Vehtari, A., Rubin, D.B. (2013). 
Bayesian Data Analysis (Third Edition). Florida: CRC Press
Marostica et al 2013
Marostica, E., Yang, S.,Russu, A., De Nicolao, G., Zamuner, S., Beerahee, M. (2013). First-
order longitudinal population model of FEV1 data: single-trial modeling and meta-analysis. 
Abstracts of the 22nd Annual Meeting of the Population Approach Group in Europe (PAGE)
8.
APPENDIX
8.1
Accounting for missing data for pre-bronchodilator FEV1
Patients dropping out of this study may lead to unobserved data.  It is hoped the amount of 
missing data is minimized in this study as patients are encouraged to complete visits until they 
withdraw from the study.
This section summarizes how we will describe the pattern of and reasons for missing data 
from the study.  It will also describe how we plan to account for missing data, including both 
the primary and sensitivity analyses to assess the robustness of the treatment effect under 
different underlying assumptions to account for missing data.
Missing data descriptions
Tabular summaries for the percentage of patients by the reason for discontinuation of 
randomized treatment as well as for withdrawal from the study will be presented by treatment 
to describe why patients discontinue from randomized treatment or withdraw from the study.  
The time to discontinuation of randomized treatment and withdrawal from the study will be 
presented using Kaplan Meier plots (overall and split by treatment related/not treatment 


Statistical Analysis Plan 
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related reason for discontinuation, as defined in Tables 1 and 2).  Dependent on these outputs 
additional exploratory analyses may be produced as deemed necessary to further understand 
the pattern of missing data.
Primary analysis under the Treatment Policy Estimand using the Missing at Random
assumption
The primary analysis of the pre-BD FEV1 is under the treatment policy estimand which allows 
for differences in outcomes over the entire study treatment period to reflect the effect of 
initially assigned randomized treatment as well as if subsequent treatments are taken. This 
primary analysis includes all data until patients withdraw from the study regardless of if they 
discontinue from randomised treatment. The Mixed Model Repeated Measures model 
(MMRM) used is a direct likelihood approach (DL) which is valid under the Missing at 
Random (MAR) assumption.
Sensitivity analysis under the Treatment Policy Estimand using both MAR and MNAR 
assumptions
To examine the sensitivity of the results of the primary analysis to departures from the 
underlying assumptions, sensitivity analyses of the repeated measures analyses will be 
performed for the pre-BD FEV1 using controlled sequential multiple imputation methods 
based on pattern mixture models, as described in the European Medicines Agency Guideline 
on Missing Data in Confirmatory Clinical Trials (EMA 2010). As with the primary analysis, 
the sensitivity analyses include all data unitl patients withdrew from the study regardless of if 
patients discontinue from randomised treatment.
The imputation process consists of a sequence of multiple imputation (MI) steps, where each 
step is intended to impute missing values at 1 timepoint only. This model will assume that 
some pre-specified subset of patients who withdraw from the study have correlations with 
future (unobserved) visits similar to patients in the placebo arm. This allows us to assess 
various deviations from the MAR assumption.
The assumptions that will be used to impute the missing data who withdraw early are as 
follows:
(a)
MAR: Assumes that the trajectory for patients who dropped out in each arm is 
similar to those observed in their own treatment arm
(b)
DRMI: Assumes that the trajectory for patients in the benralizumab arms who 
dropped out for a treatment related reasons (according to the classification for
DRMI) is similar to that of the placebo patients, whereas the remaining patients 
who has dropped out are imputed assuming MAR.
Approach b) can be considered more conservative than the approach for the primary analysis 
because the assumptions mean that as soon as patients withdraw for a treatment related reason, 
they begin to worsen immediately. 


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The MNAR imputation is achieved by using only appropriate data at each stage of the 
imputation. Imputation will be done in 2 steps, the non-monotone (intermediate) missing 
FEV1 values will be imputed first (Markov chain Monte Carlo [MCMC] method is used to 
partially impute the data using SAS PROC MI) and then the missing value at each visit will be 
imputed using a sequential regression method (using MONOTONE REG option of SAS 
PROC MI). 
For example, to impute missing values at time t for patients in the benralizumab arms who
dropped out due to an AE, include only placebo observations up to and including time t, plus 
observations from patients in the benralizumab arms, that dropped out due to an AE, up to and 
including time t-1. This is carried out for each visit, 1 at a time using observed data, and 
missing values imputed up until that visit. Placebo missing observations and benralizumab 
observations that are not missing due to AEs are imputed assuming missing at random (MAR) 
and follow the pattern of observed placebo observations in each treatment arm, respectively. 
One-hundred imputations will be carried out.  A seed of 784088 will be used for the monotone 
imputation step and a seed of 409345 will be used for the sequential regression imputation 
step. The analysis of each imputed dataset will be as described for the primary analysis in 
Section 4.2.5.1 and these will be combined using SAS procedure PROC MIANALYZE.
To avoid possible convergence issues when fitting MMRM models to 100 imputed datasets, 
the estimated unstructured covariance parameters from the first imputation where the model 
converges will be used as the starting values to fit the models for all imputed datasets.
A summary of reasons for patients withdrawing from the benralizumab treatment arm and the 
corresponding treatment arm used to calculate the imputation under MAR, and DRMI is given 
in Table 1.
Reason for withdrawal
MAR
DRMI
Adverse Event
Benralizumab
Placebo
Development of study-specific 
discontinuation criteria*
Benralizumab
Placebo
Death
Benralizumab
Placebo
Severe non-compliance to protocol
Benralizumab
Placebo
Eligibility criteria not fulfilled
Benralizumab
Benralizumab
Patient lost to follow up
Benralizumab
Benralizumab
Patient decision 
Benralizumab
Based on review prior to study 
unblinding
Other
Benralizumab
Based on review prior to study 
unblinding
*Development of study-specific discontinuation criteria are based on the following:  anaphylactic reaction to the 
IP requiring administration of epinephrine, development of helminth parasitic infestations requiring 
hospitalization, 2 consecutive doses of IP missed or more than 2 scheduled doses of IP are missed during course 
of the study, an asthma-related event requiring mechanical ventilation.


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Together with the primary analysis, the sensitivity analyses are considered to cover the range 
from realistic to plausible worst case assumptions about missing data.  The MAR multiple 
imputation approach is expected to correspond closely to the primary analysis, and is included 
to allow for comparisons with MNAR assumptions (specifically methods b) using the same 
multiple imputation methodology.
The dropout reason-based multiple imputation (DRMI) approach was selected as the most 
conservative approach based on the fact that placebo patients are receiving standard of care 
and are not expected to change to a substantially more effective treatment after withdrawing 
from study or study treatment. For patients receiving benralizumab who withdraw from the 
study due to treatment related reasons, it is assumed that, at worst, they would be on the 
standard of care treatment, ie, the placebo arm.  For patients receiving benralizumab who 
withdraw from the study due to non-treatment related reasons, it seems reasonable to assume 
they would be similar to those patients who complete treatment.
Overall summary of analyses to account for missing data
A summary of the different analyses to be carried out under different estimands and
assumptions are described in Table 3.


50
Treatment Policy Estimand
DL
MAR
DRMI
Population
On-treatment + post-discontinuation of randomized treatment
Estimand
Treatment policy 
(MAR)
Treatment policy 
(MNAR)
Imputation of
pre-BD FEV1 in 
Benra arm
No explicit 
imputation*
Benra rate assumed for 
all reasons for 
withdrawal 
Placebo rate assumed for AEs, Death, development of study specified reasons to 
stop active treatments and Severe non-compliance to protocol, otherwise Benra 
or based on review prior to study unblinding.
* Implicitly assumes unobserved data the same as observed 


51
Forest plots will be used to show the primary and sensitivity analysis under the different 
estimands.
It is noted that if the primary analysis is statistically significant, it is not necessarily expected 
that all sensitivity analyses will also give statistically significant results. If the results of the 
sensitivity analyses provide reasonably similar estimates of the treatment effect to the primary 
analysis, this will be interpreted as providing assurance that neither the lost information nor 
the mechanisms which cause the data to be missing have an important effect on primary 
analysis conclusions. Based on these outputs and the drug’s mechanism of action, the 
plausibility of the assumptions made about missing data in the different analyses will be 
considered and described in the clinical study report.
References
EMA 2010
European Medicines Agency. Committee for Proprietary Medicinal Products (CPMP). 
Guideline on Missing Data in Confirmatory Clinical Trials 2 July 2010
EMA/CPMP/EWP/1776/99 Rev. 1.


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Edition Number 2.0
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8.2
Partial dates for adverse events and prior/concomitant medication
and medical history
Dates missing the day or both the day and month of the year will adhere to the following 
conventions in order to classify treatment-emergent AEs and to classify prior/concomitant 
medications:
Adverse events
!
The missing day of onset of an 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.
!
The missing day of resolution of an 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 onset date of an AE is missing both the day and month, the onset date 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 the resolution date of an AE or end date of a IP is missing both the day and 
month, the date 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.
Prior/concomitant medication, medical history


Statistical Analysis Plan 
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!
The missing day of start date of a therapy (or symptom, diagnosis)will be set to the 
first day of the month that the event occurred.
!
The missing day of end date of a therapy will be set to the last day of the month of 
the occurrence.
!
If the start date of a therapy (or symptom, diagnosis) is missing both the day and 
month, the onset date will be set to January 1 of the year of onset.
!
If the end date of a therapy is missing both the day and month, the date will be set to 
December 31 of the year of occurrence.
!
If the start date of a therapy is null and the end date is not a complete date then the 
start date will be set to the date of the first study visit.
!
If the start date of a therapy is null and the end date is a complete date
∀
and the end date is after the date of the first study visit then the start date will 
be set to the date of the first study visit.
∀
otherwise the start date will be set to the end date of the therapy.
!
If the end date of a therapy is null and the start date is not a complete date then the 
end date will be set to the date of the study end date from the termination page If the 
end date of a therapy is null and the start date is a complete date
∀
and the start date is prior to the date of the last study visit then the end date will 
be set to the date of the last study visit.
∀
otherwise, the end date will be set to the start date of the therapy.


Statistical Analysis Plan 
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8.3
Important protocol deviations
As specified in Section 2.2.1, Important deviations will be those which are considered to 
potentially impact upon the interpretation of the primary endpoint in the study. The following 
IPDs will be summarized and listed in the CSR.
A. Eligibility deviations (patients incorrectly randomised and received IP)
1. No proof ICS/LABA used ≥30 days prior to Visit 1
or daily ICS dose < 500 μg powdered fluticasone propionate (or equivalent), or combined 
ICS/LABA use below locally approved maintenance dose.
2. Fewer than 2 documented asthma exacerbations in the 12 months prior to informed consent 
that required use of a systemic corticosteroid or temporary increase from the usual 
maintenance dose; re-screened patients based on physician’s review
3. Pre-bronchodilator (pre-BD) FEV1 of ≥80% predicted at Visit 2 or Visit 3
4. Lack of evidence of asthma as documented by airway reversibility (FEV1 ≥12% and 200 
mL) demonstrated at Visit 1, Visit 2 or Visit 3. For patients entering the body 
plethysmography sub-study, reversibility must be demonstrated at Visit 1 or at Visit 2 only.
5. Peripheral blood eosinophil count of < 300 cells/μL assessed by central lab at Visit 1
6. (substudy only) Residual volume < 125% of predicted at Visit 3
7. During the 7 days before randomization: < 2 days with a daytime or nighttime asthma 
symptoms; < 2 days of rescue SABA use; and no nights with awakenings due to asthma 
8. Clinically important pulmonary disease (other than asthma), or diagnosed pulmonary or 
systemic disease (other than asthma) associated with elevated peripheral eosinophils.
9. Acute upper or lower respiratory infections requiring antibiotics or antiviral medication 
screening/run-in period, prior to randomization Visit 4
10. Upper respiratory tract infection or an asthma exacerbation that required treatment with 
systemic corticosteroids or an increase in regular maintenance dose of OCS during the 
screening/run-in period, prior to randomization Visit 4
11. Subject is a current smoker or former smoker with a smoking history of ≥10 pack-years
12. Subject previously randomised and dosed in the present study
13. Subject had greater than/equal to 20% change (or missing data for this assessment) in 
mean Pre BD FEV1 value (mean of the Pre-BD FEV1 taken 30 min (+/- 10 min) and 60 min 


Statistical Analysis Plan 
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(+/- 10 min) prior to dosing) at randomization Visit 4 (Day 0) from the mean pre BD FEV1 
calculated from the pre BD FEV1 recorded at Visit 2 and Visit 3.
B. Restricted and prohibited medications
1. Medium to high-dose systemic corticosteroids for non-asthma diagnosis as judged by 
Sponsor’s medical review
C. Study treatment deviations
1
Patient received incorrect IP kit (active IP instead of placebo or placebo instead of active 
IP)
D. Study conduct
1. Changes in dose and regimen of asthma controller medications (ICS-LABA) or in dose 
and regimen of additional maintenance controllers done without medical need as judged 
by the Investigator
2. Regular LAMA- or LABA- containing maintenance therapy not withheld for 12-24h 
(twice daily scheme) or for >24h (once daily scheme) prior to scheduled lung function 
assessments based on physician's review
3. Administration of SABA within 6 hours prior to scheduled lung function assessments 
based on physician's review
4.  Spirometry data missing for 2 or more visits between Visit 4 to Visit 7
E. Discontinuation and withdrawal
1. Subject met IP discontinuation criteria but was not discontinued from IP