Clinical trial NCT02155660
Conditions: Moderate to Very Severe Chronic Obstructive Pulmonary Disease
Keywords: Obstructive Lung Diseases Chronic Obstructive Pulmonary Disease Lung Disease Bronchial Diseases COPD Exacerbation Respiratory Tract Diseases
Sponsor: AstraZeneca
Start date: 2014-06-25; Completion date: 2018-04-09
Enrollment: 2255 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to determine if benralizumab reduces COPD exacerbation rate in symptomatic patients with moderate to very severe COPD who are receiving standard of care therapies.

Detailed description:

Arms: arm 1: Benralizumab administered subcutaneously arm 2: Benralizumab administered subcutaneously arm 3: Benralizumab administered subcutaneously arm 4: Placebo administered subcutaneously
Interventions: intervention 1: Benralizumab Arm A intervention 2: Benralizumab Arm B intervention 3: Benralizumab Arm C intervention 4: Placebo
Intervention descriptions: intervention 1: Benralizumab subcutaneously on study week 0 until study week 48 inclusive intervention 2: Benralizumab subcutaneously on study week 0 until study week 48 inclusive intervention 3: Benralizumab subcutaneously on study week 0 until study week 48 inclusive intervention 4: Benralizumab subcutaneously on study week 0 until study week 48 inclusive

Protocol documents:
Prot_000.pdf: 
5HGDFWHG
5HGDFWHG


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
2 (111)
PROTOCOL SYNOPSIS
A Randomised, Double-blind, Double Dummy, Chronic Dosing (56 week) 
Placebo-controlled, Parallel Group, Multicentre, Phase III Study to 
Evaluate the Efficacy and Safety of 3 Doses of Benralizumab (MEDI-563) in 
Patients with Moderate to Very Severe Chronic Obstructive Pulmonary 
Disease (COPD) with a History of COPD Exacerbations (TERRANOVA)
International Co-ordinating Investigator 
Study centre(s) and number of subjects planned
Approximately 380 study centres worldwide in 24 countries will randomise a total of 2168
subjects.
Study period
Phase of development
Estimated date of first subject enrolled
Q2 2014
Phase III
Estimated date of last subject completed
Q4 2017
5HGDFWHG


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
3 (111)
Objectives
(a)
Primary Objective
Primary Objective:
Outcome Measure:
To evaluate the effect of three doses of 
benralizumab on COPD exacerbations in subjects 
with moderate to very severe COPD 
Annual COPD exacerbation rate, where a COPD 
exacerbation is defined by symptomatic 
worsening of COPD requiring:
!
Use of systemic corticosteroids for at least 3 
days; a single depot injectable dose of 
corticosteroids will be considered equivalent 
to a 3-day course of systemic corticosteroids; 
and/or
!
Use of antibiotics; and/or
!
An inpatient hospitalization or death due to 
COPD
(b)
Secondary Objectives
Secondary Objective:
Outcome Measure:
To evaluate the effect of three doses of
benralizumab on health status/health-related 
quality of life
!
St. George’s Respiratory 
Questionnaire (SGRQ)*
!
COPD assessment tool (CAT)
To evaluate the effect of three doses of 
benralizumab on pulmonary function
Pre-dose/pre-bronchodilator Forced expiratory 
volume in one second (FEV1)* at the study centre
To evaluate the effect of three doses of 
benralizumab on respiratory symptoms
!
Baseline/Transitional Dyspnea Index 
(BDI/TDI)
!
Exacerbations of Chronic Pulmonary 
Disease Tool – Respiratory Symptoms 
(E-RS)
To evaluate the effect of three doses of 
benralizumab on nocturnal awakenings
Number of nights with awakening due to COPD


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
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Secondary Objective:
Outcome Measure:
To evaluate the effect of three doses of 
benralizumab on rescue medication use
Total rescue medication use (average puffs/day)
To evaluate the effect of three doses of 
benralizumab on the severity, frequency and 
duration of EXACT-PRO defined events.
Exacerbations of Chronic Pulmonary Disease 
Tool – Patient-reported Outcome (EXACT-PRO)
To evaluate the effect of three doses of 
benralizumab on other parameters associated with 
COPD exacerbations
Time to first COPD exacerbation and proportion 
of subjects with K1 COPD exacerbation
To evaluate the effect of three doses of 
benralizumab on COPD exacerbations involving 
emergency room visits and hospitalizations 
Annual rate of COPD exacerbations that are 
associated with an emergency room visit or a 
hospitalization
To evaluate the effect of three doses of 
benralizumab on health care resource utilization 
due to COPD
Annual rate of hospitalizations due to COPD; 
annual rate of hospitalizations and emergency 
department visits combined due to COPD; annual 
rate of unscheduled outpatient visits including 
unscheduled visits to study centres due to COPD; 
and annual rate of unscheduled healthcare 
encounters due to COPD 
To evaluate the pharmacokinetics and 
immunogenicity of three doses of benralizumab
!
PK parameters
!
Anti-drug antibodies (ADA)
* Key secondary efficacy endpoint
(c)
Safety Objective
Safety Objective:
Outcome Measure:
To evaluate the safety and tolerability of three 
doses of benralizumab
!
Adverse events/Serious adverse events 
(AE/SAE)
!
Laboratory variables
!
12 lead Electrocardiogram (ECG)
!
Physical Examination
!
Vital Signs


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
5 (111)
(d)
Exploratory Objectives
Exploratory Objective:
Outcome Measure:
To evaluate the effect of three doses of
benralizumab on general health status
European Quality of Life-5 Dimensions (EQ-5D-
5L)
To evaluate the impact of three doses of 
benralizumab on blood eosinophil levels
Blood eosinophils
To evaluate the effect of three doses of 
benralizumab on blood biomarkers
Serum biomarkers
To evaluate the effect of three doses of 
benralizumab on patient and physician global 
assessments
PGIC and CGIC
To understand the dose response relationship 
across a broad range of doses
Primary and key secondary endpoints across 3 
benralizumab dose levels (10mg, 30mg, and 
100mg).
To evaluate the effect of three doses of 
benralizumab on all cause and respiratory related 
mortality
Mortality rate
Study design
This is a randomised, double-blind, double dummy, placebo-controlled, parallel group, 
multicentre, phase III study to evaluate the efficacy and safety of benralizumab (MEDI-563), 
10mg, 30mg and 100mg dose administered by subcutaneous (SC) injection every 4 weeks for 
the first 3 doses and then every 8 weeks thereafter with the last dose of IP administered at 
week 48 and last treatment evaluation performed at week 56, in subjects with moderate to 
very severe COPD receiving standard maintenance therapy (inhaled corticosteroid/long-acting 
N2 agonist (ICS/LABA), long-acting N2 agonist /long acting muscarinic antagonist 
(LABA/LAMA) or ICS/LABA/LAMA) with a history of COPD exacerbation(s) in the year 
prior to enrolment (Visit 1).
The study will recruit approximately 2168 subjects randomised 1:1:1:1 to the treatment arms, 
stratified by country and blood eosinophil count (K300/OL and <300/OL strata). The subject 
recruitment will be capped at the study level for the cohorts with baseline eosinophil counts 
<220/OL, 220-299/OL, and K300/OL in order to keep predefined cohort sample size and 
approximately 2:1 ratio of subjects above and below the boundary of 220/QL. Details of the 
estimated numbers of recruited subjects/arm in each cohort (<220/OL, 220-299/OL, K300/OL) 
are described in the SAP.


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
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The investigational product (IP) will be administered at the study centre every 4 weeks for the 
first 3 doses, and then every 8 weeks thereafter, the last dose will be given at week 48 and the 
last treatment evaluation will be performed at week 56. 
After the initial enrolment period and confirmation of the entry criteria, subjects will proceed 
to the screening/run-in period for 3 weeks to allow adequate time for all of the eligibility 
criteria to be evaluated. Subjects who meet all the eligibility criteria will be randomised to a 
56-week treatment period, with the last dose of benralizumab/placebo administered at week 
48. The end of treatment (EOT) visit will occur at week 56. Subjects will be maintained on 
their currently prescribed maintenance therapies, from enrolment throughout the run-in and 
treatment period.
Final follow-up visit will be conducted at week 60. For discontinuation procedures refer to 
section 3.6.1.
Target subject population
Male and female subjects between 40 to 85 years of age inclusive, with a diagnosis of COPD, 
post-bronchodilator FEV1>20% and T65% of predicted normal value, Modified Medical 
Research Council (mMRC) score K1, and history of K2 moderate COPD exacerbations (i.e. 
treated with systemic steroids and/or antibiotics) or K1 severe exacerbation (i.e. requiring
COPD related hospitalization) in the previous year, willing to provide informed consent and 
requiring maintenance treatment with double (ICS/LABA, LABA/LAMA) or triple 
(ICS/LABA/LAMA) therapy. 
Investigational product, dosage and mode of administration
Benralizumab 20mg/mL, 30mg/mL or 100mg/mL solution for injection in two accessorized 
pre-filled syringes (APFS) corresponding to 10mg, 30 mg and 100 mg will be administered at 
the study centre by a subcutaneous (SC) injection every 4 weeks for the first 3 doses and then 
every 8 weeks thereafter with the last dose of IP administered at week 48.  
Comparator, dosage and mode of administration
Matching placebo solution for injection in an accessorized pre-filled syringes (APFS) will be 
administered at study centre by a subcutaneous (SC) injection in the same schedule as 
investigational product. Each study subject will receive two syringes with a fill volume of 1 
ml and 0.5 ml respectively to achieve blinding in a double dummy fashion.
Duration of treatment
Following the initial enrolment at Week -4 the subject will enter a 3-week screening/run-in 
period which is followed by a 56-week double-blind, randomised treatment period, with the 
last dose of benralizumab/placebo administered at week 48 and end the of treatment (EOT)
visit at week 56. Visit 1 (enrolment visit) and Visit 2 (start of screening/run-in) can occur on 
the same day if there are no restrictions to medications for spirometry. Visit 2 may take place 
as soon as the medication restrictions prior to spirometry are met, and should occur no later 
than one week after Visit 1.


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
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Final follow-up visit will be conducted at week 60. For discontinuation procedures refer to 
section 3.6.1.
The total planned study duration for each subject is approximately 64 weeks.
Statistical methods
The primary efficacy variable is the annual COPD exacerbation rate and the two key 
secondary endpoints are change from baseline in pre-dose/pre-bronchodilator FEV1 at Week 
56 and also change from baseline in St. George’s Respiratory Questionnaire (SGRQ) at Week 
56. The exacerbation rate in each of the three benralizumab dose groups will be compared to 
the exacerbation rate in the placebo group using a negative binomial model including 
covariates of treatment group, eosinophil cohort (220-299/OL or K300/OL), country, 
background therapy (ICS/LABA, LABA/LAMA, or ICS/LABA/LAMA), and the number of 
exacerbations in the year before the study. The logarithm of the follow-up time will be used as 
an offset variable in the model. Change from baseline in pre-dose/pre-bronchodilator FEV1 at 
Week 56 will be compared between each of the three benralizumab dose groups and placebo 
using a repeated measures analysis. Treatment group will be fitted as the explanatory variable. 
Eosinophil cohort (220-299/OL or K300/OL), country, background therapy (ICS/LABA, 
LABA/LAMA, or ICS/LABA/LAMA), and baseline pre-bronchodilator FEV1 will be fitted as 
covariates. Visit will be fitted as a categorical variable. 
Change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score at Week 
56 will be analyzed using a similar model as the model for change from baseline in pre-
dose/pre-bronchodilator FEV1. 
The primary endpoint and the two key secondary endpoints will be analyzed primarily using 
the subjects with baseline blood eosinophil counts K220/OL in the full analysis set. The full 
analysis set includes all randomised subjects who received any dose of investigational 
product. In addition, the exacerbation rate and the two key secondary endpoints will also be 
summarized in subjects with baseline blood eosinophil counts <220/OL, <150/OL, 150-
219/OL, 220-299/OL, 300-449/OL, and K450/OL separately for descriptive purpose only. 
Multiplicity will be adjusted for the primary endpoint and the two key secondary endpoints on 
the analysis of subjects with baseline blood eosinophils K220/OL for the comparisons of 30mg 
vs. placebo and 100mg vs. placebo according to a gatekeeping procedure (see section 8.5). 
Multiplicity will also be adjusted for the primary endpoint and the two key secondary 
endpoints on the analysis of subjects with baseline blood eosinophils K220/OL for the 
comparisons of 10mg vs. placebo according to a serial gatekeeping procedure (see section 
8.5).
The study will recruit subjects with blood eosinophil counts K220/OL and <220/OL at a ratio 
of approximately 2:1 and the study is powered for the primary efficacy analysis of the subjects 
with blood eosinophils K220/OL. For the primary endpoint annual COPD exacerbation rate, 
348 subjects with baseline blood eosinophil counts K220/OL per treatment arm (1392 total) 
will need to be randomised to achieve 90% power of detecting a 30% reduction in both the 


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
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30mg and 100mg benralizumab dose groups versus placebo after multiplicity adjustment. This 
calculation has assumed two-sided 4% alpha level test, an annual placebo rate of 0.93 
events/subject (1.0 events/subject/56 weeks), a negative binomial shape parameter of 0.4, and 
a dropout rate of 10%. The sample size calculation is based on simulations and has accounted 
for the power loss from a proposed futility analysis. According to the approximately 2:1 ratio, 
the study will also enrol 174 subjects/arm (696 total) with baseline blood eosinophil counts 
<220/OL. An additional 20 subjects/arm will also be recruited to the 220-299/OL cohort to 
better characterize patients within this cohort. This addition results in 368 subjects/arm in the 
K220/OL cohort (1472 total). A total of 2168 subjects are expected to be randomised in the 
study. Details of the estimated numbers of recruited subjects/arm in each cohort (<220/OL, 
220-299/OL, K300/OL) are described in the SAP.
An unblinded futility analysis based on the primary endpoint will be conducted in this study. 
The futility analysis will be carried out using pre-defined rules by an external Independent 
Data Monitoring Committee in order to ensure the integrity of the blinded nature of the study. 
Furthermore, an internal blinded estimate of the overall exacerbation rate and shape parameter 
will be conducted before the last subject with eosinophil counts K220/OL is randomised. The 
review may result in an adjustment to the sample size.
All safety parameters will be analyzed descriptively. Safety analyses will be based on the 
safety analysis set, defined as all subjects who received at least 1 dose of investigational 
product.


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
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TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
PROTOCOL SYNOPSIS.........................................................................................2
TABLE OF CONTENTS.........................................................................................9
1.
INTRODUCTION .................................................................................................18
1.1
Background and rationale for conducting this study .............................................18
1.2
Rationale for study design, doses and control groups............................................19
1.3
Benefit/risk and ethical assessment........................................................................21
1.4
Overall Study Design.............................................................................................22
2.
STUDY OBJECTIVES..........................................................................................25
2.1
Primary objective...................................................................................................25
2.2
Secondary objectives .............................................................................................25
2.3
Safety objective......................................................................................................26
2.4
Exploratory objectives ...........................................................................................27
3.
SUBJECT SELECTION CRITERIA, ENROLMENT AND 
WITHDRAWAL CRITERIA ................................................................................28
3.1
Inclusion criteria ....................................................................................................28
3.2
Exclusion criteria ...................................................................................................30
3.3
Subject Enrollment and Randomisation.................................................................33
3.4
Procedures for handling incorrectly enrolled or randomised subjects...................34
3.5
Concomitant medications, restrictions during and after the study.........................34
3.5.1
Concomitant medication ........................................................................................34
3.5.2
Restrictions ............................................................................................................35
3.6
Discontinuation from investigational product .......................................................41
3.6.1
Procedures for discontinuation of a subject from IP..............................................42
3.7
Withdrawal from the study ....................................................................................44
3.7.1
Screen failures........................................................................................................44
3.7.2
Withdrawal due to recruitment completion in a randomisation stratum................44
3.7.3
Withdrawal of the Informed Consent.....................................................................44
3.8
Withdrawal of Informed Consent for donated biological samples ........................44
3.9
Discontinuation of the study..................................................................................45
4.
STUDY PLAN AND PROCEDURES ..................................................................46


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
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4.1
Enrolment and screening/run-in period .................................................................53
4.1.1
Enrolment (from Visit 1 to Visit 2)........................................................................53
4.1.2
Screening/Run-in (from Visits 2 to Visit 3)...........................................................54
4.1.3
Rescreening............................................................................................................55
4.2
Randomised treatment period ................................................................................55
4.2.1
Randomisation and treatment period .....................................................................55
4.3
Follow-up period....................................................................................................56
5.
STUDY ASSESSMENTS AND PROCEDURES.................................................56
5.1
Efficacy assessments..............................................................................................56
5.1.1
Assessment of COPD exacerbations......................................................................56
5.1.2
Spirometry (Pre and Post Bronchodilator Assessments at Clinic Visits) ..............59
5.1.3
Patient Reported Outcomes....................................................................................61
5.1.3.1
St. George’s Respiratory Questionnaire (SGRQ) ..................................................63
5.1.3.2
Baseline/Transitional Dyspnea Index (BDI/TDI)..................................................63
5.1.3.3
The Modified Medical Research Council (mMRC) dyspnea scale .......................63
5.1.3.4
COPD Assessment Test (CAT) .............................................................................64
5.1.3.5
Exacerbations of Chronic Pulmonary Disease Tool – Patient-reported 
Outcome (EXACT-PRO) and EXACT-Respiratory Symptoms (E-RS) ...............64
5.1.3.6
EQ-5D-5L ..............................................................................................................64
5.1.3.7
Major/minor symptom worsening assessment and alert system............................65
5.1.3.8
Rescue Medication Use..........................................................................................65
5.1.3.9
Nocturnal Awakenings...........................................................................................65
5.1.3.10
Maintenance Medication Use ................................................................................65
5.1.4
Healthcare Resource Utilization ............................................................................66
5.1.5
Clinician Global Impression of Change (CGIC) and Patient Global 
Impression of Change (PGIC) ...............................................................................66
5.2
Safety assessments.................................................................................................66
5.2.1
Physical examination .............................................................................................66
5.2.1.1
Complete physical examination.............................................................................66
5.2.1.2
Brief physical examination ....................................................................................67
5.2.2
Smoking status.......................................................................................................67
5.2.3
Weight and height..................................................................................................67
5.2.4
Vital signs ..............................................................................................................67
5.2.5
ECG........................................................................................................................67
5.2.6
Laboratory Safety Assessments .............................................................................68
5.2.7
Pregnancy Test.......................................................................................................70
5.3
Other Study Assessments.......................................................................................70
5.3.1
Central Laboratory Eosinophil Testing..................................................................70
5.3.2
Serology .................................................................................................................70
5.3.3
Total IgE and IgE FEIA.........................................................................................71
5.3.4
Pharmacokinetics ...................................................................................................71
5.3.5
Pharmacodynamics ................................................................................................71
5.3.5.1
Serum Biomarkers .................................................................................................71


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
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5.3.5.2
Immunogenicity.....................................................................................................72
5.3.6
Handling of Biological Samples ............................................................................72
5.3.6.1
Labelling and Shipment of Biological Samples.....................................................72
5.3.6.2
Chain of Custody of Biological Samples...............................................................73
5.3.7
Supplemental Oxygen (O2)....................................................................................73
5.3.8
Oxygen saturation (SpO2) .....................................................................................73
5.3.9
Chest X-ray ............................................................................................................73
5.3.10
Pneumococcal and Annual Influenza Vaccination ................................................73
6.
MANAGEMENT OF INVESTIGATIONAL PRODUCTS .................................74
6.1
Identity of investigational product(s).....................................................................74
6.2
Labelling ................................................................................................................74
6.3
Storage ...................................................................................................................75
6.4
Accountability........................................................................................................75
6.5
Methods for assigning treatment groups................................................................75
6.6
Methods for ensuring blinding...............................................................................76
6.7
Methods for unblinding..........................................................................................77
6.8
IP administration and treatment compliance..........................................................77
6.9
Management of IP related reactions.......................................................................79
7.
SAFETY REPORTING.........................................................................................80
7.1
Adverse events.......................................................................................................80
7.1.1
Definition of adverse events ..................................................................................80
7.1.2
Definitions of serious adverse event......................................................................80
7.1.3
Recording of adverse events ..................................................................................81
7.1.4
Variables ................................................................................................................81
7.1.5
Causality collection................................................................................................82
7.1.6
Adverse Events based on signs and symptoms......................................................82
7.1.7
Adverse Events based on examinations and tests..................................................82
7.1.7.1
Adverse events of Pneumonia requiring a confirmed diagnosis............................83
7.1.8
Drug Induced Liver Injury (DILI) .........................................................................83
7.1.9
Reporting of serious adverse events.......................................................................83
7.1.10
Reporting of COPD exacerbations.........................................................................84
7.2
Overdose ................................................................................................................84
7.3
Pregnancy...............................................................................................................84
7.3.1
Maternal exposure..................................................................................................84
7.3.2
Paternal exposure...................................................................................................85
7.4
Independent Adjudication Committee ...................................................................85
7.5
Independent Data Monitoring Committee .............................................................85
8.
STATISTICAL ANALYSES BY ASTRAZENECA............................................86


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
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8.1
Statistical considerations........................................................................................86
8.2
Sample size estimate..............................................................................................86
8.3
Definitions of analysis sets ....................................................................................87
8.3.1
All patients analysis set..........................................................................................87
8.3.2
Full analysis set......................................................................................................87
8.3.3
Safety analysis set..................................................................................................87
8.3.4
Pharmacokinetic analysis set .................................................................................87
8.4
Variables for analyses............................................................................................88
8.4.1
Calculation or derivation of efficacy variables......................................................88
8.4.1.1
Exacerbation rate....................................................................................................88
8.4.1.2
Proportion of subjects with K1 COPD exacerbation during 56 weeks of 
treatment ................................................................................................................89
8.4.1.3
Time to first exacerbation ......................................................................................89
8.4.1.4
Forced expiratory volume in 1 second...................................................................89
8.4.1.5
Annual rate of COPD exacerbations that are associated with an emergency 
room visit or a hospitalization................................................................................89
8.4.1.6
Annual rate of healthcare encounters due to COPD ..............................................90
8.4.2
Calculation or derivation of safety variable(s).......................................................90
8.4.2.1
Safety variables......................................................................................................90
8.4.2.2
Other significant adverse events ............................................................................90
8.4.3
Calculation or derivation of patient reported outcome variables...........................90
8.4.4
Calculation or derivation of pharmacokinetic variables ........................................91
8.4.5
Calculation or derivation of immunogenicity variables.........................................92
8.5
Methods for statistical analyses .............................................................................92
8.5.1
Primary analysis method(s)....................................................................................95
8.5.2
Secondary analysis methods ..................................................................................95
8.5.2.1
Analysis methods for secondary efficacy variables...............................................95
8.5.2.2
Analysis methods for safety variables ...................................................................98
8.5.2.3
Analysis Methods for PK Variables ......................................................................98
8.5.2.4
Analysis Method for Immunogenicity Variables...................................................98
8.5.3
Exploratory analysis...............................................................................................99
8.5.4
Sensitivity analysis.................................................................................................99
8.5.5
Subgroup analysis ..................................................................................................99
8.5.6
Interim Analysis.....................................................................................................99
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ........................100
9.1
Training of study centre personnel ......................................................................100
9.2
Monitoring of the study .......................................................................................100
9.2.1
Source data...........................................................................................................101
9.2.2
Recording of data.................................................................................................101
9.2.3
Study agreements.................................................................................................101
9.2.4
Archiving of study documents.............................................................................101
9.3
Study timetable and end of study.........................................................................101


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Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
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9.4
Data management by AstraZeneca ......................................................................102
10.
ETHICAL AND REGULATORY REQUIREMENTS.......................................102
10.1
Ethical conduct of the study.................................................................................102
10.2
Subject data protection.........................................................................................103
10.3
Ethics and regulatory review................................................................................103
10.4
Informed consent .................................................................................................104
10.5
Changes to the protocol and informed consent form...........................................104
10.6
Audits and inspections .........................................................................................105
11.
LIST OF REFERENCES.....................................................................................106
LIST OF TABLES
Table 1
Allowed, restricted and prohibited concomitant medication...................35
Table 2
Study Plan – Enrolment, screening/run-in period ...................................46
Table 3
Study Plan – Randomisation, treatment period and follow-up................49
Table 4 
List of Laboratory Safety Tests ................................................................69
Table 5 
Clinical Chemistry Test Schedule ............................................................69
LIST OF FIGURES
Figure 1
Study Flow Chart......................................................................................24
Figure 2
Premature IP discontinuation ...................................................................43
Figure 3
Injection sites and rotation scheme...........................................................78
Figure 4 
Gatekeeping Procedure.............................................................................94
LIST OF APPENDICES
Appendix A
Not applicable
Appendix B
Additional Safety Information 
Appendix C
IATA 6.2 Guidance document
Appendix D
Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law
Appendix E
Anaphylaxis: definition, signs, symptoms and management


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ADA
Anti-drug-antibodies
AE
Adverse event (see definition in section 7.1.1)
AECOPD
Acute Exacerbations of COPD
ALP
Alkaline phophatase
ALT
Alanine aminotransferase
APFS
Accessorised pre-filled syringes
AST
Aspartate aminotransferase
ATS
American Thoracic Society
AUC
Area under the curve
BAL
Bronchoalveolar lavage
BD
Bronchodilator
BDI/TDI
Baseline/Transitional Dyspnea Index
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CAT
COPD assessment tool
CGIC
Clinician Global Impression of Change
CO2
Carbon dioxide
COPD
Chronic obstructive pulmonary disease
CRF
Case Report Form (electronic/paper)
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CT
Computed Tomography
Ctrough
Pre-dose (trough) concentration
CXR
Chest X-ray
D
Day
DAE
Discontinuation of Investigational Product due to Adverse Event
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid


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Drug Substance Benralizumab (MEDI-563)
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Edition Number 4.0
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Abbreviation or 
special term
Explanation
DUS
Disease under Study
ECG
Electrocardiogram
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECP
Eosinophil Cationic Protein
ED90
Benralizumab dose corresponding to 90% of maximum efficacy
eCRF
Electronic case report form
EOT
End of Treatment
EQ-5D
European Quality of Life-5 Dimensions
ePRO
Electronic patient reported outcome
ERS
European Respiratory Society
E-RS
Exacerbations of Chronic Pulmonary Disease Tool – Respiratory 
Symptoms
EXACT-PRO
Exacerbations of Chronic Pulmonary Disease Tool – Patient-reported
Outcome
FEV1
Forced expiratory volume in one second
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
FWER
Family-wise error rate
GCP
Good Clinical Practice
GOLD
Global Initiative for Chronic Obstructive Pulmonary Disease
GINA
Global Initiative for Asthma
GLI
Global Lung Function Initiative
GMP
Good Manufacturing Practice
KHK
Kyowa Hakko Kirin Group
HCG
Human chorionic gonadotropin
HCP
Healthcare practitioner
HIV-1/2
Human immunodeficiency virus-1/2
HPF
High power field
IAC
Independent Adjudication Committee 
IATA
International Air transport Association
IC
Inspiratory Capacity
ICF
Informed consent form


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Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
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Abbreviation or 
special term
Explanation
ICH
International Conference on Harmonisation
ICS
Inhaled corticosteroids
IDMC
Independent data monitoring committee
IL-5
Interleukin-5
IL-5R
Interleukin-5 receptor
IL-5RV
Interleukin-5 receptor alpha subunit
IM
Intramuscular
IND
Investigation New Drug (application)
International 
Co-ordinating 
investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally.
IP
Investigational Product 
IUD
Intrauterine device
IUS
Intrauterine system
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LABA
Long-acting beta agonist
LAMA
Long-acting muscarinic antagonist
LIMS
Laboratory Information Management System
LLOQ
Lower Limit of Quantification
LSLV
Last Subject Last Visit
LTOT
Long term oxygen therapy
mAb
Monoclonal antibody
MCV
Mean corpuscular volume
mMRC
Modified Medical Research Council
nAb
Neutralizing antibodies
NOAEL
No-observed-adverse-effect level
O2
Oxygen
OAE
Other Significant Adverse Event
PGIC
Patient Global Impression of Change 
PI
Principal Investigator 


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Drug Substance Benralizumab (MEDI-563)
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Edition Number 4.0
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Abbreviation or 
special term
Explanation
PK
Pharmacokinetics
PN
Predicted Normal
PRN
Pro Re Nata (as needed)
PRO
Patient reported Outcome
Q4W
Every 4 weeks
Q8W
Every 8 weeks
Q12W
Every 12 weeks
R
Randomisation
RBC
Red blood cell
SABA
Short acting beta-agonist
SAE
Serious adverse event (see definition in section 7.1.2)
SAMA
Short acting muscarinic antagonists
SAP
Statistical Analysis Plan
SC
Subcutaneous
SGRQ
St. George’s Respiratory Questionnaire
SpO2
Oxygen saturation via pulse oximetry
TB
Tuberculosis
TEAEs
Treatment emergent adverse events
TESAES
Treatment emergent serious adverse events
ULN
Upper limit of normal
UNS
Unscheduled
V
Visit
W
Week
WBC
White blood cell
WBDC
Web Based Data Capture
WOCBP
Women of childbearing potential


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Drug Substance Benralizumab (MEDI-563)
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Edition Number 4.0
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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and 
mortality worldwide. In contrast to other chronic diseases, COPD is increasing in prevalence 
and is projected to be the third-leading cause of death and disability worldwide by 2020 
(Global Initiative for Chronic Obstructive Lung Disease (GOLD 2013)).
Acute exacerbations of COPD (AECOPD) are responsible for a large portion of the economic 
burden of COPD. An AECOPD is defined as a sustained worsening of the patient’s condition, 
from the stable state and beyond normal day-to-day variations, that is acute in onset and 
necessitates a change in regular medication in a patient with underlying COPD (Rodriquez-
Roisin R 2000). In addition to a substantial economic burden, AECOPD is also responsible for 
much of the morbidity and mortality from COPD. Patients with frequent AECOPD show 
associated increased inflammation and accelerated decline in lung function as compared to 
patients with infrequent exacerbations (Donaldson et al 2002).
While airway inflammation in COPD has been traditionally described as being predominately
neutrophilic, elevated blood and sputum eosinophils have been reported in a subset of COPD 
patients (Saha and Brightling 2006; Bafadhel et al 2011). Approximately 30-40% of patients 
with COPD have elevated levels of eosinophils in the airway as measured by sputum 
induction or bronchoalveolar lavage (BAL; Brightling et al 2000; Brightling et al 2005;
Pizzichini et al 1998; Leigh et al 2006; Saha and Brightling 2006). The prevalence of elevated 
blood eosinophils in COPD has been less well characterized; however, blood eosinophils have 
been reported to be an accurate predictor of >3% sputum eosinophils in COPD (Bafadhel et al 
2011).
In some patients with COPD, the response to oral and inhaled corticosteroids may be related 
to the degree of airway eosinophilic inflammation (Brightling et al 2000; Brightling et al 
2005). In several studies, a sputum eosinophilia K3% has been demonstrated to be a good 
predictor of response to steroids in COPD (Pizzichini et al 1998; Leigh et al 2006; Siva et al 
2007). Befadhel et al (Bafadhel et al 2009) showed that a management strategy that aims to 
minimize eosinophilic airway inflammation and symptoms is associated with a significant 
reduction in the frequency of COPD exacerbations requiring hospital admission. Evidence 
also indicates that COPD patients with increased sputum eosinophil counts had significant 
improvements in forced expiratory volume in 1 second (FEV1) and quality of life-scores that 
were associated with decreased sputum eosinophil counts, eosinophil cationic protein (ECP), 
and IL-5 levels (Pizzichini et al 1998;Bafadhel et al 2009). There are some reports indicating 
that steroids were not able to reduce eosinophilic airway inflammation in COPD (Brightling et 
al 2005). Furthermore, a recent report suggested that patients with elevated eosinophils in 
blood may have an inappropriate response to systemic steroids with worsening in several 
biomarkers (Bafadhel et al 2011)


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Edition Number 4.0
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These data suggest that therapies specifically targeting eosinophils in COPD patients with 
elevated eosinophils in the blood or airways may have beneficial effects and that not all 
patients with eosinophilic inflammation associated with COPD will respond adequately to 
steroids, particularly inhaled steroids. Treatment options are limited in severe exacerbations of 
COPD and by depleting eosinophils in the periphery and sputum; benralizumab may be an 
alternative treatment option for this high unmet need in COPD associated with elevated blood 
and/or sputum eosinophils.
Interleukin-5 is a cytokine secreted predominantly by T-lymphocytes, mast cells, and 
eosinophils and is involved in regulating the differentiation, proliferation, and activation of 
eosinophils via the human IL-5 receptor (IL-5R; Kouro and Takatsu 2009). The human IL-5R 
is a heterodimer consisting of an V-chain and a N-chain. Monomeric IL-5RV is a low affinity 
receptor, while dimerization of IL-5RV with the N-chain produces a high affinity receptor 
(Tavernier et al 1991). In the absence of IL-5 interaction with the V-chain, binding to the N 
chain alone by the ligand does not occur (Takatsu 1995). Expression of the IL-5RV chain is 
restricted largely to eosinophils, basophils, and some mast cells in humans (Toba et al 1999; 
Dahl et al 2004). The V-chain exclusively binds IL-5 and the intracellular portion of IL-5RV is 
associated with Janus kinase 2, a protein tyrosine-kinase essential in IL-5 signal transduction 
(Ogata et al 1998; Takaki et al 1994). Interleukin-5 is the key growth/survival factor for 
eosinophils; therefore, suppression of eosinophils by targeting IL-5RV should have a 
beneficial effect in COPD.
Benralizumab (MEDI-563) is a humanized, afucosylated, monoclonal antibody that binds 
specifically to the human IL-5 receptor alpha subunit (IL-5RV) on the target cell. 
Benralizumab is being developed for the treatment of both chronic obstructive pulmonary 
disease (COPD) and persistent (i.e., nonseasonal) asthma associated with elevated eosinophils. 
The IND for benralizumab was originally submitted by BioWa, Inc, a member of the Kyowa 
Hakko Kirin (KHK) Group, on 29 Jun2006. MedImmune accepted transfer of IND 100237 on 
07Mar2007 and assumed responsibility for the clinical development program outside of 
specific Asian countries. The monoclonal antibody (mAb) is also being developed by KHK in 
Asia under the product name “KHK4563” in parallel with our development program for the 
asthma indication.
1.2
Rationale for study design, doses and control groups
The final results of study MI-CP196 support conducting this Phase 3 study in patients with 
COPD with severe and very severe disease, treated with double (ICS/LABA, LABA/LAMA) 
and triple therapy (ICS/LABA/LAMA), who have elevated peripheral eosinophils. The 
greatest improvements in the annual exacerbation rate were observed in patients with
increasing blood eosinophils (specifically K200 and K300/OL) based on a pre-specified 
subgroup analysis (predose FEV1 and health-related quality of life as measured by SGRQ-C). 
In patients with low eosinophil counts (<300/QL), the exacerbation signal was not 
commensurate with what was observed in the high eosinophil group, and the exacerbation rate 
was not favourable for benralizumab, although the changes in FEV1 and SGRQ-C were 
directionally similar to the high eosinophil group.


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Study Code D3251C00004
Edition Number 4.0
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The clinical development program for benralizumab is designed to evaluate benralizumab’s 
ability to reduce the COPD exacerbation rate in patients with moderate to very severe COPD.
The proposed Phase 3 subject populations are patients with moderate to very severe COPD, as 
evidenced by a post-bronchodilator FEV1 >20% and T65% of predicted normal (GOLD 2013).
It was not considered appropriate to include patients with mild to moderate disease without 
exacerbations, or those being treated with single therapy. This is similar to the population 
explored in recent trials such as SPARK (Wedzicha et al 2013), which essentially evaluated 
the effect of triple versus double therapy in a severe to very severe patient population. Patients 
on monotherapy have several therapeutic options available before a biologic becomes part of 
their therapeutic options.
The proposed benralizumab Phase 3 study will evaluate the efficacy and safety of 
benralizumab in patients who are uncontrolled despite standard of care therapies (double such 
as ICS/LABA, LABA/LAMA or triple such as ICS/LABA/LAMA) as evidenced by 2 or more 
moderate exacerbations or 1 or more severe exacerbation(s) in the previous year. Moderate 
exacerbations are defined as those requiring treatment with systemic steroids and/or 
antibiotics. Severe exacerbations are defined as those requiring a COPD related 
hospitalization or result in death. Hospitalization will be further defined as an inpatient 
admission K24 hours in the hospital, in an observation area, the emergency department or 
other equivalent healthcare facility depending on the country and healthcare system.
Subjects in this Phase 3 study will be stratified by country and blood eosinophil levels 
(K300/QL or <300/QL) with a blood eosinophils boundary of K220/QL used for the primary 
and secondary efficacy analyses. Randomization will be capped at the study level for the 
baseline eosinophil cohorts (<220/OL, 220-299/OL, K300/OL) in order to keep predefined 
cohort sample size and approximately 2:1 ratio of subjects above and below the boundary of 
220/QL.
Based on the efficacy observed in CP196 and recent data in the literature (Pascoe S et al 
2015), the primary endpoint will be powered and conducted in subjects with blood eosinophil 
count K220/OL. Subjects with lower blood eosinophils levels (<220/QL) will be included to 
assess the benefit:risk relationship of benralizumab in COPD patients with a broad range of 
blood eosinophil levels. Descriptive statistics will be used to assess efficacy in COPD subjects 
across a broad spectrum of eosinophil levels as detailed in the SAP in order to better identify 
patients who are likely to benefit from benralizumab and also to evaluate inflection points for 
efficacy and safety to better define which patients need to be treated with this compound.
Three dose levels 10, 30 and 100 mg Q8W benralizumab will be evaluated in this Phase 3 
study in COPD subjects, based on PK and eosinophil modelling, observed incidence of ADA, 
clinical efficacy, and safety. 
Since only one dose level was investigated in Study MI-CP196, the dose-efficacy relationship 
of benralizumab in COPD has not been fully evaluated. Simulations indicate that the Q12W 
regimen is associated with a broader distribution of peripheral blood eosinophil counts. This 


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Edition Number 4.0
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implies inadequate depletion of eosinophils in many COPD patients following Q12W 
treatment. Considering that a potentially higher ADA incidence may be associated with 
infrequent dosing, low and variable PK level, and likely loss of treatment effect in a small 
subset of ADA-positive subjects, there is no rationale to pursue the Q12W regimen for Phase 
3 in COPD. On the other hand, given the low ADA incidence in COPD subjects, in terms of 
peripheral blood eosinophil depletion, the Q4W dosing does not appear to convey much 
apparent improvement over the Q8W regimen.
While a 2 mg dose is expected to reduce the blood eosinophil count by half, it is likely 
associated with a higher risk of immunogenicity response and inadequate eosinophil depletion 
in tissues. In asthma subjects (Study MI-CP220), no apparent therapeutic efficacy on 
exacerbation reduction was observed at this dose level. Doses T10 mg are likely suboptimal in 
terms of tissue eosinophil depletion and therapeutic effect (drug level in lung will be much 
lower than in blood).
For the asthma program, a dose regimen of 30 mg Q8W (ED90 of AER, ACQ, and FEV1) was 
selected for Phase 3 studies. This dose is anticipated to maintain steady-state PK exposure in 
the majority of subjects to potentially reduce the impact of PK variability (body weight, ADA, 
delayed visits) on therapeutic effect of benralizumab. This was supported through eosinophil 
and efficacy modelling and simulations. Since the PK of benralizumab and eosinophil 
response were similar in asthma and COPD subjects, the 30 mg Q8W dose is expected to 
maintain substantial depletion of blood eosinophils in COPD as well. A 30 mg dose is also 
convenient for drug product and injection device development, as the same dose will be used 
for both the asthma and COPD indications. The 100 mg Q8W top dose investigated in Studies 
MI-CP196 and MI-CP220, and a NOAEL Q2W dose of 30 mg/kg in nonhuman primates 
provided wide safety margin coverage.
1.3
Benefit/risk and ethical assessment
COPD is a progressive disease which is characterized by exacerbations and health related 
quality of life loss (GOLD 2013). Despite being adequately treated with double and triple 
therapy, many patients continue to have COPD exacerbations (Wedzicha et al 2013).  
Benralizumab is aimed at decreasing the number of exacerbations in patients with moderate to
very severe COPD who continue to have exacerbations while on standard double or triple 
therapy.
In a previous study patients who had an eosinophil count K300 appeared to have the greatest 
benefit from the drug and remained the main target of the study. The exacerbation rate 
reduction was not evident in the <300 eosinophil group although the sample size was small.  
In order to better identify the eosinophil threshold for predicted response to Benralizumab, 
and based on recent data in the literature (Pascoe S et al 2015) to support a boundary of 220/
OL for the primary analysis, additional patients will be recruited to a K220/OL in addition to 
the K300/OL blood eosinophil cohort in this study. This will result in including patients above 
and below the 220 eosinophil cutoff in an approximately 2:1 ratio, allowing for exploration of
the benefit risk profile in the broader population.


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Edition Number 4.0
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Development of anti-drug antibodies (ADA) to benralizumab has been documented. 
Theoretical risks of developing ADA include decreased drug efficacy and hypersensitivity 
reactions (e.g. 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 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 COPD.
A detailed assessment of the overall risk/benefit of benralizumab in patients with asthma and 
COPD is given in the Investigator’s Brochure.
1.4
Overall Study Design
This is a randomised, double-blind, double dummy, placebo-controlled, parallel group, 
multicentre, phase III study to evaluate the efficacy and safety of benralizumab (MEDI-563), 
10mg, 30mg and 100mg dose administered by subcutaneous (SC) injection every 4 weeks for 
the first 3 doses and then every 8 weeks thereafter with the last dose of IP administered at 
week 48 and last treatment evaluation performed at week 56, in subjects with moderate to 
very severe COPD receiving standard maintenance therapy (inhaled corticosteroid/long-acting 
N2 agonist (ICS/LABA), long-acting N2 agonist /long acting muscarinic antagonist 
(LABA/LAMA) or ICS/LABA/LAMA) with a history of COPD exacerbation(s) in the year 
prior to enrolment (Visit 1).
The study will recruit approximately 2168 subjects randomised 1:1:1:1 to the treatment arms, 
stratified by country and blood eosinophil count (K300/OL and <300/OL strata).The subject 
recruitment will be capped at the study level for the cohorts with baseline eosinophil counts 
<220/OL, 220-299/OL, and K300/OL in order to keep predefined cohort sample size and 
approximately 2:1 ratio of subjects above and below the boundary of 220/QL. Details of the 
estimated numbers of recruited subjects/arm in each cohort (<220/OL, 220-299/OL, K300/OL) 
are described in the SAP.
The investigational product (IP) will be administered at the study centre every 4 weeks for the 
first 3 doses, and then every 8 weeks thereafter, the last dose will be given at week 48 and the 
last treatment evaluation will be performed at week 56.
After the initial enrolment period and confirmation of the entry criteria, subjects will proceed 
to the screening/run-in period for 3 weeks to allow adequate time for all of the eligibility 
criteria to be evaluated. Subjects who meet the eligibility criteria will be randomised to a 56-


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Study Code D3251C00004
Edition Number 4.0
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week treatment period, with last dose of benralizumab/placebo administrated at week 48 and 
the end of treatment (EOT) visit at week 56. Subjects will be maintained on their currently 
prescribed maintenance therapy (ICS/LABA, LABA/LAMA or ICS/LABA/LAMA), from 
enrolment throughout the run-in and treatment period.
Final follow-up visit will be conducted at Week 60.
For discontinuation procedures refer to Section 3.6.1.


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Study Code D3251C00004
Edition Number 4.0
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Figure 1
Study Flow Chart
        
                         
Double blind randomised treatment period                                     EOT
   Visit 4 (w0)
       Visit 4-Visit 7
   Visit 8-Visit 18
               Visit19
Run-
in
Randomization
1:1:1:1
End of 
treatment
End of 
treatment
Enrolment
End of 
treatment
Benralizumab 10mg, 
SC every 8 weeks
Benralizumab 30mg, 
SC every 8 weeks 
Matching placebo, SC every 
8 weeks
Benralizumab 10mg, 
SC every 4 weeks
Benralizumab 30mg,
SC every 4 weeks
Matching placebo, 
SC every 4 weeks
   Run-in from V2 until V4 
   Visit 1          Visit 2   Visit 3
      Final FU
      Visit 20
Final 
Follow up
Final 
Follow up
Final 
Follow up
Benralizumab 
100mg,
SC every 4 weeks
End of 
treatment
Final 
Follow up
Benralizumab 100mg, 
SC every 8 weeks 


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Edition Number 4.0
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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To evaluate the effect of three doses of 
benralizumab on COPD exacerbations in subjects 
with moderate to very severe COPD 
Annual COPD exacerbation rate, where a COPD 
exacerbation is defined by symptomatic 
worsening of COPD requiring:
!
Use of systemic corticosteroids for at 
least 3 days; a single depot injectable 
dose of corticosteroids will be 
considered equivalent to a 3-day 
course of systemic corticosteroids; 
and/or
!
Use of antibiotics; and/or
!
An inpatient hospitalization or death
due to COPD
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To evaluate the effect of three doses of
benralizumab on health status/health-related 
quality of life
!
SGRQ*
!
CAT
To evaluate the effect of three doses of 
benralizumab on pulmonary function
Pre-dose/pre-bronchodilator FEV1* at the study 
centre
To evaluate the effect of three doses of 
benralizumab on respiratory symptoms
!
BDI/TDI
!
E-RS
To evaluate the effect of three doses of 
benralizumab on rescue medication use
Total rescue medication use (average puffs/day)
To evaluate the effect of three doses of 
benralizumab on nocturnal awakenings
Number of nights with awakening due to COPD


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Edition Number 4.0
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Secondary Objective:
Outcome Measure:
To evaluate the effect of three doses of 
benralizumab on the severity, frequency and 
duration of EXACT-PRO defined events
EXACT-PRO
To evaluate the effect of three doses of 
benralizumab on other parameters associated with 
COPD exacerbations
Time to first COPD exacerbation and proportion 
of subjects with K1 COPD exacerbation
To evaluate the effect of three doses of 
benralizumab on COPD exacerbations involving 
emergency room visits and hospitalizations 
Annual rate of COPD exacerbations that are 
associated with an emergency room visit or a 
hospitalization
To evaluate the effect of three doses of 
benralizumab on health care resource utilization 
due to COPD
Annual rate of hospitalizations due to COPD; 
annual rate of hospitalizations and emergency 
department visits combined due to COPD; annual 
rate of unscheduled outpatient visits including 
unscheduled visits to study centres due to COPD; 
and annual rate of unscheduled healthcare 
encounters due to COPD 
To evaluate the pharmacokinetics and 
immunogenicity of three doses of benralizumab
!
PK parameters
!
Anti-drug antibodies (ADA)
* Key secondary efficacy endpoints
2.3
Safety objective
Safety Objective:
Outcome Measure:
To evaluate the safety and tolerability of three 
doses of benralizumab
!
AE/SAE
!
Laboratory variables
!
12 lead ECG
!
Physical Examination
!
Vital Signs


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Edition Number 4.0
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2.4
Exploratory objectives
Exploratory Objective:
Outcome Measure:
To evaluate the effect of three doses of
benralizumab on general health status
EQ-5D-5L
To evaluate the impact of three doses of 
benralizumab on blood eosinophil levels
Blood eosinophils
To evaluate the effect of three doses of 
benralizumab on blood biomarkers
Serum biomarkers
To evaluate the effect of three doses of 
benralizumab on patient and physician global 
assessments
PGIC and CGIC
To understand the dose response relationship 
across a broad range of doses
Primary and key secondary endpoints across 3 
benralizumab dose levels (10mg, 30mg, and 
100mg).
To evaluate the effect of three doses of 
benralizumab on all cause and respiratory related 
mortality
Mortality rate
The exploratory analysis will be reported separately.


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Edition Number 4.0
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3.
SUBJECT SELECTION CRITERIA, ENROLMENT AND 
WITHDRAWAL CRITERIA
Each subject enrolled 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 fulfil the following criteria:
1.
Provision of informed consent prior to any study specific procedures.
2.
Female or male subjects aged 40-85 years inclusive at the time of enrolment (Visit 
1).
3.
History of moderate to very severe COPD with a post-bronchodilator 
FEV1/FVC<0.70 and a post-bronchodilator FEV1>20% and T65% of predicted 
normal value at screening (central spirometry will be used for this criteria 
assessment).
4.
History of 2 or more moderate COPD exacerbations that required treatment with 
systemic corticosteroids and/or antibiotics, or 1 or more severe COPD 
exacerbation(s) that required hospitalization (defined as an inpatient admission K24 
hours in the hospital, in an observation area, the emergency department or other 
equivalent healthcare facility depending on the country and healthcare system) 
within 2 to 52 weeks prior to enrolment. Prior use of antibiotics alone does not 
qualify as a moderate exacerbation unless the antibiotic was specifically prescribed
for the treatment of worsening COPD symptoms.
5.
mMRC score K1 at Visit 1
6.
Subjects should have evidence of having been treated with double (ICS/LABA or 
LABA/LAMA) or triple (ICS/LABA/LAMA) therapy for COPD throughout the 
year prior to enrolment (Visit 1). It is acceptable for subjects to have stepped up or 
stepped down during that period of time (from double to triple therapy and vice 
versa), but they have to be consistently treated with locally approved COPD 
medications and on approved doses for at least 2 weeks prior to enrolment (Visit 1). 
Subjects currently receiving background therapy that is not approved for COPD are 
not eligible for the study 
7.
Current smoker or ex-smoker with a tobacco history of K10 pack-years (1 pack year 
= 20 cigarettes smoked per day for 1 year).
8.
Women of childbearing potential (WOCBP) must use a highly effective form of 
birth control (confirmed by the Investigator). Highly effective forms of birth control 


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Edition Number 4.0
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includes: true sexual abstinence, a vasectomised 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 highly effective 
method of birth control, as defined above, from enrolment, throughout the study 
duration and within 16 weeks after last dose of IP, and must 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 
postemenopausal if they have been amenorrheic for 12 months prior to the planned 
date of randomisation without an alternative medical cause. The following age-
specific requirements apply:

Women <50 years old would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatment and follicle stimulating hormone (FSH) levels in the postmenopausal 
range.

Women K50 years old would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatment
9.
Male subjects who are sexually active must be surgically sterile at least one year 
prior to Visit 1 or must use an adequate method of contraception (condom or 
condom with spermicide depending on local regulations) from the first dose of IP 
until 16 weeks after their last dose. Men with a partner or partners who is (are) not 
of childbearing potential are exempt of these requirements. 
10.
Ability to read, write and use electronic devices.
Additional criteria to be checked prior to randomisation:
11.
Blood eosinophils due to a subject’s stratification and cap for blood eosinophil 
levels. When any eosinophil cohort (<220/OL, 220-299/OL, or K300/OL) is full, 
subjects in the completed cohort will not be randomised and will be withdrawn 
from the study. 
12.
Compliance with the eDiary defined as completing at least 8 EXACT-PRO/E-RS 
assessments in the 14 day period prior to Visit 4 (i.e. Study days -15 to -1).
13.
At least 70% compliance with the subject’s maintenance therapy (defined as taking 
all maintenance medication as scheduled for the day) during the run-in period (from 
Visit 2 to Visit 4) based on the eDiary. 


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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 COPD (e.g. active lung infection, 
clinically significant bronchiectasis, pulmonary fibrosis, cystic fibrosis, 
hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin 
deficiency and primary ciliary dyskinesia) or another diagnosed pulmonary or 
systemic disease that is associated with elevated peripheral eosinophil counts (e.g. 
allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, 
hypereosinophilic syndrome) and/ or radiological findings suggestive of a 
respiratory disease other than COPD that is contributing to the subject’s respiratory 
symptoms. 
2.
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/or could:

Affect the safety of the subject throughout the study

Influence the findings of the study or their interpretation

Impede the subject’s ability to complete the entire duration of study
Subjects who have epilepsy must be on a stable dose of medication for 30 days 
prior to Visit 4.
3.
Unstable ischemic heart disease, arrhythmia, cardiomyopathy, heart failure, renal 
failure, uncontrolled hypertension as defined by the Investigator, or any other 
relevant cardiovascular disorder as judged by the Investigator or any ECG 
abnormality obtained during the screening/run-in period that in Investigator’s 
judgement may put the patient at risk or negatively affect the outcome of the study.
4.
Treatment with systemic corticosteroids and/or antibiotics, and/or hospitalization 
for a COPD exacerbation within 2 weeks prior to enrolment (Visit 1) or during the 
enrolment and screening/run-in period, based on last dose of steroids or last date of 
hospitalization whatever occurred later. 
5.
Acute upper or lower respiratory infection within 2 weeks prior to enrolment (Visit 
1) or during the enrolment and screening/run-in period. 
6.
Pneumonia within 8 weeks prior to enrolment (Visit 1), based on the last day of 
antibiotic treatment or hospitalization date, whatever occurred later or during the 
enrolment and screening/run-in period. 


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Edition Number 4.0
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7.
Pregnant, breastfeeding, or lactating women.
8.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level K1.5 
times the upper limit of normal (ULN) confirmed by repeated testing during 
screening period
9.
Risk factors for pneumonia (including, but not limited to: immunosuppression, 
neurological disorder with increased risk of aspiration).
10.
Known history of allergy or reaction to any component of the investigational 
product formulation.
11.
History of anaphylaxis to any other biologic therapy.
12.
Donation of blood, plasma or platelets within the past 90 days prior to Visit 1. 
13.
Long term oxygen therapy (LTOT) with signs and/or symptoms of cor pulmonale 
and/or right ventricular failure. Subjects receiving long term treatment with oxygen 
>4.0 liters/minute (L/min). While breathing supplemental oxygen, subjects should 
demonstrate an oxyhemoglobin saturation K89%. In order to be admitted to the trial 
subjects on LTOT have to be ambulatory and be able to attend clinic visits. 
14.
Use of any non-invasive positive pressure ventilation device (NIPPV). Note: 
Subjects using continuous positive airway pressure (CPAP) or bilevel positive 
airway pressure (BiPAP) for Sleep Apnea Syndrome are allowed in the study.
15.
Any clinically significant abnormal findings in physical examination, vital signs, 
haematology, clinical chemistry, or urinalysis during screening/run-in period, which 
in the opinion of the Investigator, may put the subject at risk because of his/her 
participation in the study, or may influence the results of the study, or the subject’s 
ability to complete entire duration of the study.
16.
Fever >37.8°C (100°F) measured using the tympanic temperature (or equivalent 
oral/rectal/axillary temperature) at Visit 4.
17.
Use of immunosuppressive medication, including rectal corticosteroids and 
systemic steroids within 2 weeks prior to enrolment (Visit 1) and/or during the 
enrolment and screening/run-in period.
18.
Receipt blood products within 30 days prior to enrolment (Visit 1).
19.
Receipt of any investigational non-biologic product within 30 days or 5 half-lives 
prior to Visit 1.
20.
Receipt of any marketed (e.g. omalizumab) or any other monoclonal or polyclonal 
antibody therapy (e.g. gamma globulin) taken for any reason within 6 months or 5 
half-lives prior to Visit 1, whichever is longer.


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Edition Number 4.0
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21.
Receipt of live attenuated vaccines 30 days prior to Visit 4.
22.
Subjects are excluded if they have any of the following: 
-
A history of known immunodeficiency disorder including a positive test 
for human immunodeficiency virus, HIV-1 or HIV-2
-
Positive hepatitis B surface antigen, or positive 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
23.
A helminth parasitic infection diagnosed within 24 weeks prior to Visit 1 that has 
not been treated with, or has failed to respond to standard of care therapy.
24.
History of alcohol or drug abuse within the past year, which may compromise the 
study data interpretation as judged by Investigator or Study Physician. 
25.
Malignancy, current or within the past 5 years, except for adequately treated 
noninvasive basal cell and squamous cell carcinoma of the skin and cervical 
carcinoma-in-situ treated with apparent success more than 1 year prior to Visit 1.
26.
Subjects who in the opinion of the investigator or qualified designee have evidence 
of active tuberculosis (TB). Subjects with a recent (within 2 years) first-time or 
newly positive purified protein derivative (PPD) test or Quantiferon test need to 
complete an appropriate course of treatment before being considered for enrolment.
Evaluation will be according to the local standard of care and may consist of history 
and physical examinations, chest x-ray, and/or TB test as determined by local 
guidelines.
27.
Scheduled in-patient hospitalization or surgical procedure during the course of the 
study. Elective hospitalisations that cannot be delayed until after the end of the 
study need to be discussed with AstraZeneca Study Physician.
28.
Subjects participating in, or scheduled for, an intensive (active) COPD 
rehabilitation program (subjects who are in the maintenance phase of a 
rehabilitation program are eligible to take part).
29.
Subjects with lung volume reduction surgery within the 6 months prior to Visit 1. 
Subjects with history of partial or total lung resection (single lobe or 
segmentectomy is acceptable).
30.
Employees of the clinical study centre or family members (first-degree relatives) of 
such individuals or anyone involved in the planning and/or conduct of the study.
31.
Asthma as a primary or main diagnosis according to the Global Initiative for 
Asthma (GINA) guidelines (GINA 2011) or other accepted guidelines. Subjects 


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with a past medical history of asthma (e.g. childhood or adolescence) may be 
included.
32.
Treatment with allergy immunotherapy, active or within 90 days prior to Visit 1.
33.
Previous treatment with benralizumab (MEDI-563).
3.3
Subject Enrollment and Randomisation
Procedures for withdrawal of incorrectly enrolled or randomised subjects are described in 
section 3.4.
Investigator(s) should keep a record of subjects considered for and included in the study on 
the subject screening log.
The Investigator will:
1.
Obtain signed informed consent from the potential subject before any study specific 
procedures are performed.
2.
Assign each potential subject a unique enrolment number, beginning with ‘E# via 
interactive web/voice response system (IWRS/IVRS)
3.
Determine subject eligibility.
4.
Assign eligible subject unique randomisation code via IWRS/IVRS
Subjects will be allocated to the four treatment arms in a 1:1:1:1 ratio. The randomisation 
numbers will be grouped in blocks. The study will recruit approximately 2168 subjects, 
randomised 1:1:1:1 to the treatment arms, stratified by country and blood eosinophil count 
(K300/OL and <300/OL strata). Subject recruitment will be capped at the study level for the 
cohorts with baseline eosinophil counts <220/OL, 220-299/OL, and K300/OL in order to keep 
predefined cohort sample size and approximately 2:1 ratio of subjects above and below the 
boundary of 220/QL. Details of the estimated numbers of recruited subjects/arm in each cohort 
(<220/OL, 220-299/OL, K300/OL) are described in the SAP. It is expected that the <220/OL 
cohort will fill first based on prevalence. Instructions for screen failing these subjects from the 
study after a stratum is closed are noted in the protocol (Section 3.7.2).
Specific information concerning the use of the IWRS/IVRS will be provided in a separate 
manual. If a subject withdraws from participation in the study, then his/her 
enrolment/randomisation code cannot be reused. Withdrawn subjects will not be replaced. 


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Edition Number 4.0
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3.4
Procedures for handling incorrectly enrolled or randomised 
subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
randomised or receive study medication. There can be no exceptions to this rule.  Subjects 
who are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomised or initiated on treatment, and must be withdrawn from the study.
Where a subject does not meet all the eligibility criteria but is randomised 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 subject from 
treatment. The AstraZeneca Study Physician must ensure all decisions are appropriately 
documented.
3.5
Concomitant medications, restrictions during and after the study 
3.5.1
Concomitant medication
Information about any treatment in the 3 months prior to Visit 1 (and 1 year prior to Visit 1 for 
background (maintenance) COPD medications) 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.
The subject’s usual pre-study double (ICS/LABA or LABA/LAMA) or triple 
(ICS/LABA/LAMA) therapy formulation, dose and regimen, and any other additional allowed 
COPD medications that may have been taken prior to enrolment, should be continued 
throughout the enrolment, screening/run-in and treatment period as outlined below.
Background (maintenance) medication 
All subjects are required to be treated with maintenance double (ICS/LABA or 
LABA/LAMA) or triple (ICS/LABA/LAMA) therapy for COPD throughout the year prior to 
enrolment (Visit 1) and have to be consistently treated with locally approved COPD 
medications on approved doses for at least 2 weeks prior to Visit 1 and during the course of 
the study (see inclusion criteria 6).
The aim of this study is to establish the treatment effect of benralizumab as add-on therapy. 
Therefore the background medications should be maintained at the same dose and schedule 
from Visit 1 until the end of the study. 
During the study, background medications that are given once daily, should be administered in 
the morning to conform with spirometric measurement requirements. Changes to the subject’s 
maintenance therapy are discouraged during the treatment period, unless judged medically 
necessary by the Investigator; such changes should be discussed with the AstraZeneca Study 
Physician, the justification for treatment changes should be documented in the source notes 
along with the rationale for the change and recorded in the eCRF.


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Edition Number 4.0
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Background (maintenance) medication is not regarded as an investigational product, but will 
be provided by AstraZeneca locally according to local regulations, in order to maintain 
appropriate oversight and access to these concomitant therapies from enrolment and up to 
Week 60 unless the patient withdraws informed consent.
Rescue medication 
SABA (short-acting N2-agonists, e.g. salbutamol, albuterol, terbutaline) will be used as rescue 
medication during the study in the event of a worsening of COPD symptoms. In the rare cases 
where a subject has an adverse or allergic reaction to salbutamol/albuterol, levalbuterol can be 
used. The rescue medication is not regarded as an investigational product, but will be provided 
by AstraZeneca locally according to local regulations, in order to ensure access for this 
therapy from enrolment and up to Week 60 unless the patient withdraws informed consent.
Allowed Medications to treat a COPD exacerbation
Medications to treat an exacerbation should not be used for more than 14 days. Recent data 
have suggested that treatment with systemic steroids for shorter periods of time results in 
similar outcomes with less systemic steroid exposure. Therefore, it is recommended that 
subjects are treated with a 5 day course of steroids (Leuppi et al 2013) and no longer than 14 
days (see section 3.5.2 and Table 1).
3.5.2
Restrictions
The restrictions that apply during the study are summarized in Table 1.
If at discretion of the Investigator a subject needs treatment with any disallowed medication, 
“step up” or treatment for an exacerbation for greater than 14 days, the Investigator must 
contact the AstraZeneca Study Physician to discuss justification for disallowed medication use 
and/or prolonged steroid treatment.
Table 1
Allowed, restricted and prohibited concomitant medication
Unless specifically indicated, all conditions apply from enrolment and throughout the study 
duration.
Medication
Allowed/ Restricted/ 
Prohibited
Details
Background (maintenance) 
COPD medication 
double (ICS/LABA or 
LABA/LAMA) 
or triple 
(ICS/LABA/LAMA) 
Allowed 
Subjects should have evidence of having 
been treated with double (ICS/LABA or 
LABA/LAMA) or triple (ICS/LABA/
LAMA) therapy for COPD throughout the 
year prior to Visit 1 and have to be 
consistently treated with locally COPD 
approved medications on approved doses for 
at least 2 weeks prior to Visit 1 and 


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Edition Number 4.0
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throughout the study.
ICS in a separate, single device is permitted 
if all of the following criteria are met:
- ICS is approved as part of a fixed dose 
combination product for COPD; 
- it is administered at the same dose and 
schedule as in the fixed dose combination 
product; 
- it is not given in combination with a LAMA 
alone. 
If an Investigator decides to switch a subject 
who is on an ICS in a separate single device 
to a fixed-dose combination device therapy, 
this should be done at Visit 1 and the ICS 
component has to remain at the same dose 
and schedule as used in the 2 weeks prior to 
Visit 1 (provided dose and regimen are 
locally approved for COPD).
Nebulized budesonide is accepted as part of 
maintenance therapy if the dosing regimen is 
equivalent to that of budesonide approved as 
part of a combination product for COPD (e.g. 
for budosonide/formoterol combination 
320mcg/9mcg BID equivalent dose of 
nebulized budesonide is 0.5mg BID).
Nebulized LABA is accepted as part of 
maintenence therapy.
ICS in addition to COPD 
ICS maintenance 
medication
Restricted
Can only be given concomitantly with
systemic steroids during hopitalisation/ER 
COPD exacerbation treatment (additional use 
of ICS outside of this is not allowed).
Systemic corticosteroids 
(tablets, suspension or 
injections)
Restricted
Prohibited within 2 weeks prior to Visit 1 and 
throughout the study.
Allowed only to treat a COPD exacerbation 
and should not be used for more than 14 
days.  If treatment duration is expected to 
exceed 14 days the AstraZeneca study 
physician must be contacted.


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Edition Number 4.0
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SABA (short-acting N2-
agonists, e.g., salbutamol, 
albuterol, terbuataline 
levalbuterol) 
Allowed as rescue 
medication and for 
treatment of acute 
COPD exacerbation. 
Prohibited if 
administered as 
maintenance medication 
or in a scheduled dose.
Prophylactic use of SABA in the absence of 
symptoms is discouraged. However, if 
deemed necessary by the subject and 
Investigator (e.g. prior to planned exercise), 
it can be used, but prophylactic inhalations 
should not be recorded in the daily eDiary, 
such use should be documented in the 
medical notes and recorded in the eCRF.
SABA (nebulized)
Restricted as rescue 
medication.
Prohibited  if 
administered as 
maintenance medication 
or in a scheduled dose 
from enrolment and 
throughout the study 
duration
Routine use for rescue is discouraged unless 
it is used for managing an acute COPD 
exacerbation event OR if the Investigator 
deems access to nebulized SABA as rescue 
medication is essential for a specific subject.
Occasions (# of times used) where SABA 
was administered via nebulisation will be 
recorded separately from metered dose 
inhaler (MDI) inhalations in the eDiary.
SAMA (short acting 
muscarinic antagonists =
short acting 
anticholinergics; e.g.
Ipratropium bromide, MDI 
or nebulized)
Allowed if administered 
as part of double/triple
maintenance therapy in 
a scheduled dose.
Restricted as rescue 
medication and if used 
as a component of 
combination products  
(e.g., combivent)
Subject on maintenance treatment should be 
on a stable dose, not exceeding 2 puffs q 6-8
hours, and not on a concomitant LAMA 
(long-acting anti-muscarinic agent, e.g. 
tiotropium).
Taken at regularly scheduled intervals (every 
6-8 hours) will be considered equivalent to 
maintenance treatment with LAMA. 
Rescue use is not allowed unless used 
concomitantly with systemic CS for 
managing an acute COPD exacerbation 
event. Use on their own, or for step-up or 
step-down are not allowed.
When used for managing an acute COPD 
exacerbation, should not be used for more 
than 14 days. If treatment duration is 
expected to exceed 14 days the AstraZeneca 
study physician must be contacted.
Antitussives prn 
Allowed
Allowed if not containing ephedrine and/or 
opiates and/or other bronchodilators.


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Edition Number 4.0
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Mucolytics 
Allowed
Allowed if not containing ephedrine.
Dermal topical steroids, 
nasal steroids, topical 
ophthalmic and otic 
corticosteroids
Allowed
Use of high potency topical steroids for K4 
weeks prior to enrolment (V1) and during the 
study is not allowed.
Antihistamines prn not 
containing ephedrine or 
bronchodilators
Allowed
Xanthines
Restricted
Allowed in a dose equivalent to theophylline 
T400mg q day. For doses greater than 400 
mg, the dose has to be stable and blood levels 
should be confirmed to be equal to or below 
12 mg/dl, within 8 weeks prior to Visit 1 or 
during screening/run-in period.
Blood levels greater than 12 mg/dl should be 
managed according to local standards of care 
and the Investigator’s judgment and 
discussed with AZ study physician. It is 
recommended that additional increments in 
dose are evaluated with blood levels.
Inhaled disodium 
cromoglycate or 
nedocromil sodium
Restricted
Can only be given concomitantly with 
systemic steroids during a COPD
exacerbation, use on their own or “step-up” is 
not allowed.
Should not be used for more than 14 days. If 
treatment duration is expected to exceed 14 
days the AstraZeneca study physician must 
be contacted.
If leukotriene antagonist is discontinued at 
Visit 1, approximately 72 hours have to 
elapse before performing spirometry testing 
at Visit 2.
Leukotriene antagonists 
and 5-lipoxygenase 
inhibitors
Restricted
Antibiotics
Restricted
Antibiotics to treat a COPD exacerbation 
should not be used for more than 14 days. If 
treatment duration is expected to exceed 14 
days the AstraZeneca study physician must 
be contacted.


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Edition Number 4.0
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Antibiotics taken for the prevention of a 
COPD exacerbation (e.g. macrolides, 
quinolones) are disallowed.
Omalizumab, denosumab 
or any other monoclonal or 
polyclonal antibody 
therapy (e.g. gamma 
globulin)
Prohibited
Disallowed if taken for any reason within 6 
months prior to Visit 1 and during the study.
Allergen immunotherapy
Prohibited
Disallowed within 90 days prior to Visit 1 
and during the study.
Live attenuated vaccines 
Prohibited
Disallowed within 30 days prior to 
randomisation, during the treatment period 
and for 16 weeks (5 half lives) after the last 
dose of IP.
Ephedrine-containing 
medication
Prohibited
Systemic treatment with 
potent Cytochrome P 
(CYP) 3A4 inhibitors (e.g., 
ketoconazole)
Prohibited
Roflumilast (Daxas®, 
Daliresp®)
Prohibited
If Roflumilast is discontinued at Visit 1, 
approximately 7 days have to elapse before 
performing spirometry testing at Visit 2.
(a)
COPD medication restrictions on the days of scheduled spirometry visits 
Spirometry assessments will be performed at the study centre at scheduled visits (see Table 2
and Table 3). There are restrictions regarding the subject’s COPD medications prior to the 
spirometry assessments.
Screening Visit 2: Subjects will be asked to withhold their usual double (ICS/LABA or 
LABA/LAMA) or triple (ICS/LABA/LAMA) medications on the morning of the screening 
pre and post BD spirometry (preferably should be at least 12 hours prior to the assessment/24 
hours prior to the assessment for once daily medications) for the eligibility assessment (see 
section 3.1, inclusion criterion 3). In addition, SABA and SAMA should not be used within 6 
hours of this spirometry assessment. The subject’s usual COPD medications may be 
administered following completion of the screening lung function procedures.


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Edition Number 4.0
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Treatment Visits 4-19: Subjects will be asked to withhold their usual double (ICS/LABA or 
LABA/LAMA) or triple (ICS/LABA/LAMA) medications on the mornings of the scheduled 
spirometry visits and preferably for at least 12 hours prior to the spirometry assessment/24 
hours prior to the assessment for once daily medications). This is especially important prior to 
scheduled spirometry assessments (see Table 3) in order to maintain the integrity of planned 
efficacy analyses around lung function improvement. In addition, SABA and SAMA should 
not be used within 6 hours prior to the spirometry assessments. The subject’s usual COPD 
medications may be administered following completion of the pre-BD spirograms. The 
subject’s usual COPD medications may be administered following completion of the lung 
volume assessments. The IP will be administered at a scheduled visit after the lung volume 
and/or spirometry assessments.
If the subject has taken their usual double (ICS/LABA or LABA/LAMA) or triple 
(ICS/LABA/LAMA) medications on the morning of the scheduled spirometry visit, the 
Investigator/authorized delegate should remind the subject of the importance of withholding 
their usual morning maintenance therapy, and reschedule the visit for another day, within the 
allowed window. If rescheduling is absolutely not feasible for the subject, spirometry may be 
performed with a notation indicating that the lung volume measurements and/or spirometry 
were performed after the usual double (ICS/LABA or LABA/LAMA) or triple 
(ICS/LABA/LAMA) medications administered.
If the subject has taken the rescue SABA within 6 hours of the planned centre visit spirometry 
they should ideally remain at the centre until such time that the 6 hours withholding time has 
been reached if it does not exceed the 1.5 hour spirometry window or return on another day, 
within the visit window. If neither of options is feasible for the subject, spirometry may be 
performed with a notation indicating that the lung volume measurements and/or spirometry 
were conducted within 6 hours of SABA use.
(b)
COPD medication restrictions at unscheduled visits
COPD medication restrictions at an unscheduled visit may not be feasible, and may be applied 
at the discretion of the Investigator. Timing of the double (ICS/LABA or LABA/LAMA) or 
triple (ICS/LABA/LAMA) medications and rescue SABA use relative to the unscheduled 
spirometry should be recorded.
(c)
COPD medication restrictions at centre visits with scheduled ECG assessment
The subjects should be instructed not to take their usual double (ICS/LABA or 
LABA/LAMA) or triple (ICS/LABA/LAMA) medications (i.e. LABA) prior to the scheduled 
ECG assessment. The use of a SABA should be avoided within 6 hours before the ECG 
assessments.
Medications do not have to be withheld for the Visit 1 and Visit 3 ECG.


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Edition Number 4.0
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Other restrictions

Fertile and sexually active subjects or their partners should use highly effective 
contraceptive methods throughout the study and at least for 16 weeks (5 half-
lives) after last administration of the IP. Male subjects should refrain from 
fathering a child or donating sperm from the time of informed consent and for 
16 weeks (5 half-lives) after last dose of IP.

Subjects must abstain from donating blood, plasma from the time of informed 
consent and for 16 weeks (5 half-lives) after last dose of IP.
3.6
Discontinuation from investigational product
Subjects will be discontinued from investigational product (IP) in the following situations:
1.
Subject decision. The subject is at any time free to discontinue treatment, without 
prejudice to further treatment
2.
Adverse Event that, in the opinion of the Investigator, contraindicates further dosing
3.
Risk to subject as judged by the Investigator or AstraZeneca
4.
Severe non-compliance to study protocol
5.
Eligibility requirement found not to be fulfilled
6.
Pregnancy
7.
Lost to follow-up 
8.
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

If the time between IP administrations is greater than 10 weeks due to a delay 
in IP dosing

Intensive care unit admission (prolonged intubation and mechanical ventilation) 
for a COPD-related event
Before a decision to discontinue a subject from IP is instituted, the AstraZeneca Study 
Physician should be consulted regardless of the reason for discontinuation.
The reason for premature discontinuation of investigational product should be documented in 
the source documentation and recorded in the eCRF.


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Edition Number 4.0
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Subjects who prematurely discontinued treatment of the IP should return to the study centre 
and complete procedures described for the EOT 12 weeks (±7 days) after the last dose of IP, 
see section 3.6.1.
3.6.1
Procedures for discontinuation of a subject from IP
Subjects who prematurely discontinue treatment should return to the study centre and 
complete the procedures described for the EOT 12 weeks (±7 days) after the last dose of IP. 
It is highly recommended that all study procedures, including any scheduled visits and ePRO 
completion, are continued till EOT visit, if possible. The subject will bring the ePRO device to 
the EOT visit. 
At EOT visit the subject will be given two options on how to be followed up: 
!
The subject should be encouraged to return for all regular clinic and phone call 
visits until he/she completes a total of 56 weeks in the study. At week 56 all the 
procedures described for Visit 19 are to be conducted 
!
If the subject cannot comply or does not wish to comply with the option above, 
he/she will be offered to be followed up on a monthly basis via phone calls while
continuing eDiary completion, until the subject completes 56 weeks in the study. 
No further procedures will be performed. The subject’s decision needs to be 
documented and the specific section in the ICF addendum needs to be signed. 
The key elements to be collected are AEs/SAEs, changes in concomitant medications, 
smoking status and COPD exacerbation information.
The Investigator will be instructed to force data transfer from the ePRO device on the day of 
EOT visit and then to redispense the device to subject. ePRO alerts will still be in place to 
notify both the subject and the study center of a potential symptom worsening event (see 
section 5.1.3.7). The subject will be asked to return the ePRO device to the study centre after 
the subject completes participation in the study (week 56).
!
If the subject refuses the two previous options, he/she will need to sign the specific 
withdrawal of consent portion of the ICF addendum and return all study materials to 
the study centre.
AstraZeneca will continue to provide maintenance and rescue medications up to 56 weeks 
from the time of randomisation (see section 3.5.1) unless the patient withdraws consent. It is 
the Investigator’s responsibility to fully evaluate the patient upon discontinuation or 
withdrawal to ensure that the patient receives appropriate treatment according to his/her 
clinical status/ condition.


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Figure 2
Premature IP discontinuation
EOT 
Discontinuation 
visit
Scheduled visits 
and procedures 
continue
Option 1: Attend all further 
scheduled clinic and phone 
visits (w/o IP) 
Visit 19
procedures, 
study completion
Last Phone FU 
call, study 
completion
Last 
dose of 
IP
Option 2: Phone Follow-up
calls every 4 weeks and 
eDiary completion.
ICF addendum to be signed.
12 weeks after the last
dose of IP
Procedures described 
for EOT visit in the 
Protocol
12 weeks after IP Last dose
V19 (week 56)
Follow up for discontinued subjects
Decision on IP 
Discontinuation 
<- - -Treatment period - - - > 


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3.7
Withdrawal from the study
3.7.1
Screen failures 
Screening failures are subjects who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised. These subjects should have the reason for study withdrawal 
recorded as ‘Incorrect Enrolment’ (i.e. subject does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screen failures (not randomised 
subjects).
3.7.2
Withdrawal due to recruitment completion in a randomisation stratum
When any eosinophil cohort (<220/OL, 220-299/OL, or K300/OL) is full, subjects in the 
completed cohort will not be randomised and will be withdrawn from the study. The reason of 
the withdrawal should be documented in the source and eCRF as a development of study
specific criteria for discontinuation. As with screen failures, no further study related follow-up 
of these subjects is required.
3.7.3
Withdrawal of the Informed Consent
Subjects are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE). The Investigator will follow up AEs outside of the clinical study. 
The subject will return all study related materials to the study centre. 
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn subjects will not be replaced.
3.8
Withdrawal of Informed Consent for donated biological samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analysed, 
AstraZeneca is not obliged to destroy the results of this research.
The collection of the biological samples is an integral part of the study. 

A subject who does not allow for further collection or analysis of biologic 
samples will need to be discontinued.

In the case a subject allows for collection and analysis of biological samples 
but specifically withdraws his/her consent for the retention of samples for 
exploratory research after the end of the study, the subject does not need to be 
discontinued and will be allowed to continue participation in the study.
The Principal Investigator or designee:


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!
Ensures subjects’ withdrawal of informed consent for the use of donated samples is 
notified immediately to AstraZeneca.
!
Ensures that biological samples from that subject, if stored at the study centre, are 
immediately identified, disposed of /destroyed, and the action documented.
!
Ensures the local laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destroyed, the action 
documented and the signed document returned to the study centre.
!
Ensures that the subject and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study centre.
3.9
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 eCRF. 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 PROCEDURES
Table 2
Study Plan – Enrolment, screening/run-in period
Assessment/Activity
Refer to section
Enrolment
Screening/run-in
V1 (w –4)a
V2 (w –3)a
V3 (w –1)
Visit window (refer to section 4.1)
0-7 days prior to V2
Day –21 (±3 d)
Day –7 (±3d) 
Informed consent
10.4
X
Inclusion/exclusion criteria
3.1/3.2
X
X
X
Medical and COPD history
4.1.1
X b
Concomitant medication
.3.5.1
X
X
X
Adverse events
7.1
X
X
X
Acute exacerbation of COPD
5.1.1
X
X
X
Smoking status
4.1.1/5.2.2
X b
X
X
mMRC
5.1.3.3
X b
CAT
5.1.3.4
X b
Site assigns ePRO device and trains 
subject per the training guidelines
5.1.3
X
Site to check ePRO compliance at each 
visit
5.1.3
X
Subject uses ePRO device daily at home 
to complete the following: 
! Daily Morning
 Nocturnal awakening
5.1.3.5/5.1.3.6
X
X


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Assessment/Activity
Refer to section
Enrolment
Screening/run-in
V1 (w –4)a
V2 (w –3)a
V3 (w –1)
Visit window (refer to section 4.1)
0-7 days prior to V2
Day –21 (±3 d)
Day –7 (±3d) 
 Rescue medication
 Major/minor symptoms
! Daily Evening
 EXACT-PRO/E-RS
 Rescue medication
Maintenance Medication
Complete physical examination
5.2.1.1
X b
Weight, Height
5.2.3
X b
Vital Signs
5.2.4
X b
X
Supplemental oxygen (O2) status
5.3.7
X b
Oxygen saturation (SpO2)
5.3.8
X b
Chest x-ray (if applicable)
5.3.9
X b
ECG 
5.2.5
X b
X
Pre and Post BD spirometry
5.1.2
X
Clinical chemistry
5.2.6
X
X
Haematology 
5.2.6
X
X
Urinalysis
5.2.6
X
X
Serology (hepatitis B,C; HIV-1; HIV-2)
5.3.2
X
Serum pregnancy test
5.2.7
X
FSH c
5.2.7
X


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Assessment/Activity
Refer to section
Enrolment
Screening/run-in
V1 (w –4)a
V2 (w –3)a
V3 (w –1)
Visit window (refer to section 4.1)
0-7 days prior to V2
Day –21 (±3 d)
Day –7 (±3d) 
TB test (if applicable)
4.1.1
X b
Pneumococcal and annual influenza 
vaccination, if applicable.
5.3.10
X d
a
Visit 1 and Visit 2 can occur on the same day if there are no restrictions to medications for spirometry. Visit 2 may take place as soon as the medication 
restrictions prior to spirometry are met (see section 5.1.2), and should occur no later than one week after Visit 1.
b
These V1 procedures can be performed at any time between Visit 1and Visit 2 inclusive.
c
FSH test done only for female subjects to confirm postmenopausal status in women <50 years who have been amenorrheic for >12 month
d
Pneumococcal and annual influenza vaccination can be done at V1 or at any other visit throughout the study (except for within ±7 days of IP 
administration) at the discretion of investigator.


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Table 3
Study Plan – Randomisation, treatment period and follow-up
Assessment/
Activity
Refer 
to 
section
R
Treatment
EOT
Final 
FU
Phone 
FUg
UNSh
V4
V5
phone
V6
V7
V8
phone
V9
V10
phone
V11
V12
phone
V13
V14
phone
V15
V16
phone
V17
V18
phone
V19
V20
phone 
w0
w0
d6
w4
w8
w12
w16
w20
w24
w28
w32
w36
w40
w44
w48
w52
w56
w60
Visit window (days) a
+0
+2
+3
+3
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
N/A
N/A
Inclusion/exclusion criteria
3.1/3.2
X
Randomisation
4.2
X
Concomitant medication
3.5.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
7.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Acute exacerbation of 
COPD evaluation
5.1.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Smoking status
5.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Healthcare resource 
utilization
5.1.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CGIC and PGIC
3.5.1
X
X
X
X
SGRQ
5.1.3.1
X
X
X
X
X
X
X
X
X
BDI
5.1.3.2
X


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Assessment/
Activity
Refer 
to 
section
R
Treatment
EOT
Final 
FU
Phone 
FUg
UNSh
V4
V5
phone
V6
V7
V8
phone
V9
V10
phone
V11
V12
phone
V13
V14
phone
V15
V16
phone
V17
V18
phone
V19
V20
phone 
w0
w0
d6
w4
w8
w12
w16
w20
w24
w28
w32
w36
w40
w44
w48
w52
w56
w60
Visit window (days) a
+0
+2
+3
+3
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
N/A
N/A
TDI
5.1.3.2
X
X
X
X
X
X
X
X
mMRC
5.1.3.3
X
CAT
5.1.3.4
X
X
X
X
X
X
X
X
X
Site to check eDiary 
compliance at each visit
5.1.3.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject uses ePRO device 
daily at home to complete 
the following:
!Daily Morning
Nocturnal awakening
Rescue medication
Major/minor symptoms
!Daily Evening
EXACT-PRO/E-RS
Rescue medication
Maintenance Medication
!Weekly (7±2 days)
EQ-5D-5L
5.1.3.5/
5.1.3.6/
5.1.3.7/
5.1.3.8/
5.1.3.9/
5.1.3.10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Assessment/
Activity
Refer 
to 
section
R
Treatment
EOT
Final 
FU
Phone 
FUg
UNSh
V4
V5
phone
V6
V7
V8
phone
V9
V10
phone
V11
V12
phone
V13
V14
phone
V15
V16
phone
V17
V18
phone
V19
V20
phone 
w0
w0
d6
w4
w8
w12
w16
w20
w24
w28
w32
w36
w40
w44
w48
w52
w56
w60
Visit window (days) a
+0
+2
+3
+3
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
N/A
N/A
Complete physical 
examination
5.2.1.1
X
X
X
Brief physical examination
5.2.1.2
X
X
X
X
X
X
X
Weight
5.2.3
X
X
X
Vital Signs
5.2.4
X
X
X
X
X
X
X
X
X
X
Supplemental O2 status
5.3.7
X
X
X
X
X
X
X
X
X
Oxygen saturation (SpO2)
5.3.8
X
X
X
X
X
X
X
X
X
ECG 
5.2.5
X
X
Pre-BD spirometry
5.1.2
X
X
X
X
X
X
X
X
X
Clinical chemistryb
5.2.6
X
X
X
X
X
Haematology 
5.2.6
X
X
X
X
X
Xc
Urinalysis
5.2.6
X
X
X
X
X
Urine pregnancy test 
(dipstick)d
5.2.7
X
X
X
X
X
X
X
X
X
PK
5.3.4
X
X
X
X
X
X
X
X
X
X


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Assessment/
Activity
Refer 
to 
section
R
Treatment
EOT
Final 
FU
Phone 
FUg
UNSh
V4
V5
phone
V6
V7
V8
phone
V9
V10
phone
V11
V12
phone
V13
V14
phone
V15
V16
phone
V17
V18
phone
V19
V20
phone 
w0
w0
d6
w4
w8
w12
w16
w20
w24
w28
w32
w36
w40
w44
w48
w52
w56
w60
Visit window (days) a
+0
+2
+3
+3
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
N/A
N/A
ADA/nAbe
5.3.5.2
X
X
X
X
X
X
X
X
X
Serum for total IgE and IgE 
FEIA
5.3.3
X
X
X
Serum/Plasma Biomarkers
5.3.5
X
X
X
X
ImmunoCAP ECP
5.3.5.1
X
X
X
X
Plasma fibrinogen
5.3.5.1
X
X
X
X
Administration of IPf
6.8
X
X
X
X
X
X
X
X
a
All visits are to be scheduled from the date of randomisation and not from the date of previous visit. Randomisation visit should occur 21 (±3) days after 
Visit 2. If there is a need to postpone Randomisation visit, screening/run-in period can be extended by another 7 days as described in section 4.1.2.
b
Detailed schedule for clinical chemistry tests is provided in section 5.2.6.
c
Eosinophil count to be measured only
d
For WOCBP only, urine HCG test to be done at centre at each treatment visit before the IP administration.
e
nAb will be assessed on all ADA positive samples. Samples that are ADA negative will not be tested for nAb.
f
In case of anaphylaxis additional samples will be taken (see section 6.9)
g
Phone follow-up applicable for subjects that discontinue from IP. Every 4 weeks (± 7 days) after the EOT visit up to week 56 as per the study plan.
h
Unscheduled visits may be initiated as needed, and additional assessments performed at these visits, at the discretion of the Investigator


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4.1
Enrolment and screening/run-in period
4.1.1
Enrolment (from Visit 1 to Visit 2)
Each potential subject will provide written informed consent prior to any study specific 
procedures and undergo assessments applicable for the visit (see Table 2).
In cases where subject signs the informed consent form (ICF) prior to Visit 1, Visit 1 
procedures must be initiated within 3 working days from the date of ICF. Registration of the 
subject’s enrolment via IWRS/IVRS should occur on the day of Visit 1.
The Visit 1 assessments are primarily concerned with past medical history, past surgical 
history, comorbidities and confirmation of the COPD disease state, smoking history, the 
requisite level of severity based on background medications, spirometry measurements and
exacerbation history. It is important to record whether the patient meets criteria for chronic 
bronchitis (chronic cough and mucus production for at least three months in two successive 
years) and if the patient has historical or current radiographic evidence (chest radiograph or 
CT scan) of emphysema.
A historical value of blood eosinophils (highest absolute value of eosinophils in the year prior 
to V1) is an important part of medical history and needs to be recorded in the pertinent CRF 
module (if available).
A record of a physician-diagnosed COPD, ICS/LABA, LABA/LAMA or ICS/LABA/LAMA 
use (Section 3.1, criteria 3 and 6) and COPD exacerbation(s) in the previous year (Section 3.1, 
criterion 4) is suggested source documentation.  A subject’s verbal history suggestive of 
COPD symptoms and/or prior COPD exacerbation(s), but without supporting documentation, 
is not sufficient to satisfy these inclusion criteria.
Examples of acceptable documentation of the COPD disease state and prior COPD 
exacerbation(s) include clinic visit (primary or specialist HCP), emergency room or hospital 
records listing COPD as a current problem, plus documentation of at least two moderate or 
one severe exacerbation during the 12 months prior to Visit 1. A qualifying historical COPD 
exacerbation is:

Use of systemic corticosteroids(a single depot injectable dose of corticosteroids 
is acceptable), and/or

Use of antibiotics, and/or

An inpatient hospitalization due to COPD
Current, regular use of ICS/LABA, LABA/LAMA or ICS/LABA/LAMA for at least 2 weeks 
prior to enrolment should be documented in the source notes. This documentation may be in 


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the form of a recent, active medication list as per a HCP note, or filled prescriptions based on 
a pharmacy record. 
Following the registration of a subject at the enrolment visit, the screening procedures will be 
initiated to assess the study eligibility (inclusion/exclusion) criteria (see Table 2). At Visit 1 
central laboratory test for absolute blood eosinophils and for safety will be drawn.
If applicable a TB test should be performed according to the local standard of care as 
determined by local guidelines.
Duration of enrolment period (from Visit 1 to Visit 2) is up to 7 days. Visit 1 and Visit 2 can 
occur on the same day if there are no restrictions to medications for spirometry (and no 
washout period is needed). Visit 2 may take place as soon as the medication restrictions prior 
to spirometry are met (see section 5.1.2) and should occur no later than one week after Visit 1.
Visit 2 is primarily concerned with evaluating whether lung function meets the study 
eligibility criteria. Subjects who are unable to produce acceptable post-bronchodilator 
spirometry data at V2 to evaluate inclusion criteria may be retested at an unscheduled visit.
At Visit 2 a subject is dispensed with an ePRO device (eDiary) (see section 5.1.3).
Enrolment procedures when any of the eosinophil cohorts is closed 
As soon as any of the eosinophil cohorts is closed, it is recommended to split enrolment 
procedures between Visit1 and Visit 2 (as described in Table 2) and to allow sufficient time 
between Visit 1 and Visit 2 (up to 7 days) to obtain central eosinophil blood count results. The 
subjects in the completed cohort will be withdrawn from the study (screen failure), no further 
study related procedures are required for those subjects (see section 3.7.2).
4.1.2
Screening/Run-in (from Visits 2 to Visit 3)
The run-in period should be 3 weeks (±3 days) in duration (from Visit 2 to Visit 4). Visit 3 
should occur 2 weeks (±3 days) after Visit 2. The subjects should remain on their current 
COPD treatment with no changes throughout screening/run-in period. Assessments applicable 
for the period are listed in Table 2.
If there is a need to postpone Randomisation visit, run-in period can be extended by another 7 
days after consultation and in agreement with Study Physician.
Visit 3 (week -1): Safety assessments and other procedures will be performed at this visit as 
listed in Table 2. 
The subject’s eligibility should be evaluated at each visit during the screening/run-in period 
with the relevant documentation entered in the source and eCRF.


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4.1.3
Rescreening
Subjects who experience a COPD exacerbation within 2 weeks prior to Visit 1 or during the 
enrolment and screening/run-in period should be screen failed. They may be re-screened no 
sooner than 2 weeks after their last dose of systemic steroids.
Subjects with respiratory infections, excluding pneumonia, within 2 weeks prior to Visit 1 or 
during the enrolment and screening/run-in period, should also be screen failed and may be re-
screened but no sooner than 2 weeks after their last dose of antibiotics.
The subjects who experience pneumonia during the enrolment and screening/run-in period 
should be screen failed. They may be re-screened but no sooner than 12 weeks after the last 
day of antibiotic treatment or the last date of hospitalisation, whatever occurred later.
Other instances where rescreening is being considered should be discussed with the AZ Study
Physician.
Re-screening only allowed once per subject. 
One additional re-screening may be allowed for patients who have been screen failed due to 
eosinophil stratum/ cohort closure; those instances need to be discussed with the AZ Study 
Physician.  
If a subject is re-screened, a new informed consent form is to be signed, and re-screening Visit 
1 procedures must be initiated within 3 working days from the date of the new ICF. Re-
screened subject keeps an originally assigned enrolment number.
4.2
Randomised treatment period
4.2.1
Randomisation and treatment period
The inclusion/exclusion criteria at the randomisation visit (Visit 4) will be confirmed. Before 
randomisation the subject’s compliance with his/her maintenance medications and ePRO 
completion must be confirmed.
Subjects confirmed to be eligible will be randomised at Visit 4 in a 1:1:1:1 ratio to receive 
benralizumab 10 mg, 30 mg or 100 mg or placebo every 4 weeks for the first 3 doses and then 
every 8 weeks thereafter with the last dose of IP administered at week 48 and last treatment 
evaluation performed at week 56. 
The first dose of the IP will be administered at Visit 4 after the subject’s randomisation via the 
IWRS/IVRS.
Following randomisation, the subject will enter the 56-week double-blind treatment period 
with the last dose of benralizumab/placebo administered at Visit 17 (week 48).
Subjects will have scheduled clinic visits at 4-week intervals up to Visit 7 and then at 8 week 
intervals up to Visit 19 to complete protocol-specific assessments and IP administration, as 


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listed in Table 3. Telephone visits will also occur as per the study plan, listed in Table 3. The 
restrictions noted in section 3.5 will continue to apply throughout the treatment period. In case 
of a COPD worsening/exacerbation (see section 5.1.1), subjects should be evaluated at the 
study centre, when feasible, at an unscheduled visit, or a scheduled visit if the worsening 
happens to fall within a scheduled visit window.
Subjects will continue to record their COPD symptoms and responses to the questionnaires 
using the ePRO device throughout the 56-week treatment period (see section 5.1.3 for details).
At week 56 subjects will come to the centre for the End of Treatment (EOT) visit.
Subjects who prematurely discontinue from IP (see section 3.6) should return to the study 
centre and complete procedures described for the EOT visit 12 weeks (±7 days) after the last 
dose of IP.
Subjects will return the ePRO device and all background/rescue medications at the EOT visit.
Subjects will return the ePRO device  at week 56.
Subjects who prematurely discontinue from IP should follow the procedures and visit 
schedule described in section 3.6.
Completion, or early termination of the treatment will be registered via IWRS/IVRS for each 
subject.
4.3
Follow-up period
Subjects who complete Visit 19 (week 56) will return at week 60 for a final follow-up visit.
5.
STUDY ASSESSMENTS AND PROCEDURES
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling. The investigator will ensure that data are recorded on the electronic Case 
Report Forms as (eCRF) 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 centre.
5.1
Efficacy assessments
5.1.1
Assessment of COPD exacerbations 
For the purpose of the protocol, a COPD exacerbation will be defined as a change in the 
subject’s usual COPD symptoms that lasts 2 or more days, is beyond normal day-to-day 


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variation, is acute in onset and may warrant a change in regular medication and leads to any of 
the following:

Use of systemic corticosteroids for at least 3 days; a single depot injectable 
dose of corticosteroids will be considered equivalent to a 3-day course of 
systemic corticosteroids and/or

Use of antibiotics

An inpatient hospitalization due to COPD (defined as an inpatient admission 
K24 hours in the hospital, in an observation area, the emergency department or 
other equivalent healthcare facility depending on the country and healthcare 
system). 

Exacerbations will be considered moderate if they require treatment with 
systemic steroids and/or antibiotics, and do not result in hospitalization or 
death. Exacerbations will be considered severe if they result in hospitalization 
or death.
Symptoms will be assessed by the subject each morning using an ePRO device (eDiary) for 
the purposes of a symptom worsening alert. The purpose of this alert is to notify both the 
subject and the study center of a potential symptom worsening event that warrants contact 
between the subject and the center for further evaluation.
Each morning the subject will complete 3 questions pertaining to the major symptoms of a 
worsening event (dyspnea, sputum volume, and sputum color). Subject reported worsening of 
1 or more of these symptoms will trigger assessment of the minor symptoms of a worsening 
event (sore throat, cold, fever without other cause, cough, and wheeze). All questions will 
have a 24 hour recall period. Questions pertaining to the severity of symptoms vs. their usual 
state will have 3 response options (e.g. How breathless have you been in the last 24 hours? 
Less breathlessness than usual, Usual level of breathlessness, More breathless than usual) 
whereas questions related to the presence or absence of a symptom will have a dichotomous 
response (e.g. Have you had a sore throat in the last 24 hours? No, Yes, I had a sore throat).
If athere is worsening of at least 2 major symptoms or 1 major and 1 minor symptom for 2 
consecutive days an alert directed to the subject and site will be generated by ePRO system.
If an event is not associated with ePRO symptom worsening alert as described above (e.g. 
technical issue, subject self-reports symptom worsening/exacerbation event, the exacerbation 
is identified during a visit or phone contact, the exacerbation is evaluated and treated at non-
study centre, or an acute/severe symptom deterioration which is not captured in the ePRO
system occurs), the Investigator should interview the subject and evaluate potential worsening 
and duration of the following symptoms: 

Shortness of breath 


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
Mucus Volume 

Mucus purulence
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Cough

Wheezing

Sore throat 

Cold symptoms such as a runny nose or nasal congestion

Fever

Chest Tightness
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Other findings
The Investigator should record all pertinent findings  (symptom worsening) associated with 
the exacerbation event and their duration in source documents and in the eCRF exacerbation 
module.
If an exacerbation is not associated with worsening of COPD symptoms or it was not possible 
to capture the symptoms (e.g. patient intubated upon arrival to the emergency department), the 
investigator must document the justification for diagnosing and treating the event as an 
exacerbation and record it in the eCRF.
The start of an exacerbation is defined as the start date of systemic corticosteroids or antibiotic 
treatment or hospital admission, whichever occurs earlier, and the end date is defined as the 
last day of systemic corticosteroids or antibiotic treatment or hospital discharge, whichever 
occurs later.
For the list of allowed medications to treat a COPD exacerbation please refer to section 3.5.1. 
Based on recent literature it is recommended that treatment with systemic steroids is done for 
a total of 5 days, but this remains at the discretion of the treating physician. Treatment with 
systemic steroids should not exceed 14 days unless discussed with Study Physician.
A COPD exacerbation that occurs T7 days of the last dose of systemic steroids (oral, IM, IV) 
or antibiotics or the last day of hospitalisation will be counted as the same exacerbation event.
The subject may remain in the study after an exacerbation and continue to receive 
investigational product if the Investigator judges that it is medically appropriate for the subject 
to do so.
Study centre evaluations for a COPD worsening may occur as a part of an ordinary centre 
visit, or as an unscheduled visit, if deemed necessary by Investigator. A copy of the medical 
record should be obtained for exacerbations evaluated and treated at non-study centres (e.g. by 


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the primary care HCP or at an emergency department/hospital) and details entered into the 
exacerbation module in eCRF in a timely fashion. Changes in concomitant medication due to 
an exacerbation must be recorded in the appropriate module of the eCRF.
5.1.2
Spirometry (Pre and Post Bronchodilator Assessments at Clinic Visits)
General requirements
Lung function (FEV1 and FVC) at the study centre will be measured by spirometry using 
equipment provided by a 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 centre personnel who will be performing the testing are 
properly certified. Spirometry calibration will be detailed in a separate spirometry procedures 
manual.
In case spirometry assessment results at Visit 2 and/or Visit 4 are not of acceptable quality, 
they should be discussed with AstraZeneca Study Physician to decide on patient eligibility and 
the need for additional assessments.
Important! Subjects should be instructed not to use their ICS/LABA, LABA or LAMA 
medication within 12 hours (24 hours for once daily medications) of scheduled centre visit 
spirometry as this will affect the pre/post BD FEV1 value; they may be taken subsequently, at 
the centre.  For the same reason subjects should not use their rescue SABA medication 
(albuterol/salbutamol) within 6 hours of a scheduled centre visit spirometry. This restriction is 
particularly critical for efficacy measures taken during the treatment period, but should also 
facilitate meeting the screening FEV1 criteria.
Options for handling subjects who have inadvertently taken their COPD medication within the 
restricted window are described in section 3.5.2.
Time of day for scheduled centre visit spirometry
Spirometry testing should be done according to the schedule provided in Table 2 and Table 3. 
It is recommended that spirometry testing will be initiated in the morning between 6:00 AM 
and 11:00 AM and all post-randomisation spirometry assessments are performed within ± 1.5 
hours of the time that the randomisation spirometry was performed. For example, if the 
randomisation spirometry was started at 8:00 AM, then all subsequent spirometry testing 
should be initiated between 6:30 AM and 9:30 AM.
Spirometry technique
Subjects should avoid engaging in strenuous exertion for at least 30 minutes prior to 
spirometry measurements. Subjects should avoid eating a large meal for at least 2 hours prior 
to spirometry measurements at the centre. Forced expiratory manoeuvres should be performed 
with the subject seated in an upright position. If this is not comfortable for the subject, 


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standing is permitted. The same position should be used by the subject for each forced 
expiratory manoeuvre from enrolment throughout the study. The head must not be tilted 
during manoeuvres and the thorax should be able to move freely; hence tight clothing should 
be loosened. A nose-clip should be used for the manoeuvre. The subject from enrolment 
throughout the study should use mouthpieces of the same dimension and shape.
The forced expiratory manoeuvre (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 subject to continue the expiration to be fast and forceful 
throughout the manoeuvre. 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 
centre spirometry session and the 2 best efforts that meet the ATS/ERS acceptability and 
reproducibility criteria will be recorded. The best efforts will be based on the highest FEV1. 
The absolute measurement (for FEV1 and FVC), and the percentage of predicted normal value 
(Quanjer et al 2012) will be recorded. The highest FVC will also be reported regardless of the 
effort in which it occurred (even if the effort did not result in the highest FEV1).
Post-bronchodilator spirometry
Post-BD spirometry will be performed at V2 for all subjects (to evaluate inclusion criterion 3, 
see section 3.1).
Maximal bronchodilation will be induced using 4 inhalations of albuterol (90 Og metered 
dose) or salbutamol (100 Og metered dose) with or without a spacer device within 30 minutes 
± 15 minutes of the final pre-BD spirometry measurement. Post-BD spirometry will be 
performed 20-30 minutes later. If a subject cannot tolerate 4 puffs of beta agonist, a lower 
number of inhalations may be considered at the investigator’s clinical judgment.
Order of administration for the COPD maintenance medication and IP relative to the 
scheduled pre- and post-bronchodilator spirograms
The subject’s usual COPD morning maintenance therapy must not be given until after the 
initial pre-medication, pre/post bronchodilator spirograms are complete for the reasons 
discussed above. IP dosing should also be withheld until pre-bronchodilator/post 
bronchodilator spirometry is complete.
Record keeping
A signed and dated copy of the pre- and post- BD printout must be kept at study centre for 
source data verification. The printout must be marked with the study code, enrolment code, 
date and time of measurement, visit number.


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Spirometry references
The Global Lung Function Initiative (GLI) equations will be used to determine the subjects 
predicted normal (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
5.1.3
Patient Reported Outcomes
Subjects will complete PRO assessments at the study center on paper and at home using a 
handheld electronic device (ePRO). PRO assessments must be collected in a systematic way 
to ensure data integrity. The following best practice guidelines should be followed when 
collecting PRO data at the site or via an ePRO device:
For PRO instruments administered during site visits
!
Administer before other procedures

Always administer PRO instruments before other study procedures
!
Provide the right environment

Provide a quiet and private location to complete the instrument
!
No right or wrong answers

Remind subjects that there are no right or wrong answers and that we are 
asking them to complete these questionnaires because we’re interested in 
hearing directly from them on how they feel.
!
Help with procedural questions

Make sure the subject understands how to complete the instrument. Instrument 
instructions are usually self-explanatory but staff may answer questions about 
procedural issues like what it means to “tick a box”. 
!
Avoid bias: do not clarify the meaning of questions or responses

Sometimes subjects will ask center staff to clarify the meaning of a question or 
response. To avoid introducing any bias, politely tell the subject that you 
cannot clarify items. Remind them that there are no right or wrong answers. 
Tell them that they should select the response that best answers the question as 
they understand it. 
!
No time limits


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
Although most instruments require only a few minutes to complete the subject 
should be given as much time as is needed
!
Review for completeness 

Prompt review of the questionnaire for completeness will minimize missing 
data and data queries. If an item is left blank ask the subject if they intended to 
leave the item blank. Provide an opportunity for the subject to answer if they 
wish.
!
Enter PRO data in appropriate modules of eCRF
For PRO instruments captured at home using an ePRO device
!
Guidelines similar to paper

Many of the same principles apply for ePRO as paper. Remind subjects that 
there are no right or wrong answers, avoid bias by not clarifying items, remind 
subjects that they should complete the ePRO questions in a quiet and private 
location without help from others.
!
Train the subject on ePRO device usage

Train the subject on how to use the ePRO device using the materials and 
training provided by the ePRO vendor

Provide guidance on whom the subject should call if they have problems
!
Monitor compliance

Minimizing missing data is a key aspect of study success. Compliance must be 
checked at each study visit and should be checked more frequently to identify 
problems early. If compliance drops below 80% a check-in call from the site to 
ask the subject if they are having difficulties is highly recommended.

Recommended background medication compliance during the study is higher 
than 80%. It is recommended that compliance levels below 70% prompt the 
site/investigator to evaluate the reasons for low compliance and to provide re-
education to the patient in regards to the importance of compliance. It is 
strongly recommended that when compliance level falls below 50% the site 
contacts the Study Physician in order to discuss the potential safety 
implications for the patient and future decisions.
Additional and more specific details concerning PRO instrument administration are provided 
in subsequent sections where each instrument is described.


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5.1.3.1
St. George’s Respiratory Questionnaire (SGRQ)
The 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 two 
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 three 
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, 2009).
5.1.3.2
Baseline/Transitional Dyspnea Index (BDI/TDI)
The BDI/TDI is an instrument developed to provide a multidimensional measure of dyspnea 
in relation to activities of daily living (Mahler et al 1984). The Baseline Dyspnea Index (BDI) 
provides a measure of dyspnea at a single state, the baseline, and the Transitional Dyspnea 
Index (TDI) evaluates changes in dyspnea from the baseline state. The instrument consists of 
three components: functional impairment, magnitude of task, and magnitude of effort. For the 
BDI, each of these three components are rated in five grades from 0 (severe) to 4 
(unimpaired), and are summed to form a baseline total score from 0 to 12. For the TDI, 
changes in dyspnea are rated for each component by seven grades from -3 (major 
deterioration) to +3 (major improvement), and are added to form a total TDI score from -9 to 
+9. Positive scores indicate an improvement, and a change from the BDI or a difference 
between treatments of 1 point has been estimated to constitute the minimum clinically 
important difference (MCID) (Mahler et al 2005).
The BDI should be captured at Visit 4. The Visit 4 BDI assessment will serve as a baseline 
and reference for subsequent TDI assessments.
TDI at post-randomization Visits will be completed using the Visit 4 BDI as a baseline 
reference point.
The BDI/TDI assessments should be completed according to the instructions and before other 
study procedures. The BDI/TDI is completed by a trained interviewer, who asks the 
respondent various questions as part of a medical history, and selects a grade (score) using 
specific criteria for each of the three components. The same interviewer will complete the BDI 
and the TDI for an individual subject.
5.1.3.3
The Modified Medical Research Council (mMRC) dyspnea scale
The Modified Medical Research Council (mMRC) dyspnea scale uses a simple grading 
system to assess a subject’s level of dyspnea that consists of five statements about perceived 
breathlessness. It is an interviewer-administered ordinal scale on which subjects provide their 


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dyspnea according to five grades of increasing severity (scores ranges from 0 (none) to 4 (very 
severe))
5.1.3.4
COPD Assessment Test (CAT)
The CAT is an 8-item PRO developed to measure the impact of COPD on health status (Jones 
et al 2009).  The instrument uses semantic differential six-point response scales which are 
defined by contrasting adjectives to capture the impact of COPD. Content includes items 
related to cough, phlegm, chest tightness, breathlessness going up hills/stairs, activity 
limitation at home, confidence leaving home, sleep and energy. A CAT total score is the sum 
of item responses. Scores range from 0-40 with higher scores indicative of greater COPD 
impact on health status.
5.1.3.5
Exacerbations of Chronic Pulmonary Disease Tool – Patient-reported 
Outcome (EXACT-PRO) and EXACT-Respiratory Symptoms (E-RS)
The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity 
and duration of COPD exacerbations (Jones et al 2011, Leidy et al 2011). The instrument was 
developed for daily, at home, administration using a handheld electronic device. Respondents 
are instructed to complete the diary each evening just prior to bedtime and to answer the 
questions while considering their experiences “today”.  The daily EXACT-PRO total score 
has a range of 0-100 with higher scores indicative of greater severity. Total score changes are 
used to identify the onset and recovery from an EXACT-PRO defined exacerbation event. In 
identifying event onset and recovery the EXACT-PRO can provide information on event 
frequency and duration as well as event severity. 
The E-RS is an 11-item PRO developed to evaluate the severity of respiratory symptoms of 
COPD (Sexton et al 2010, Sexton et al 2011). The E-RS is a subset of items from the 
EXACT-PRO. The E-RS was designed to be captured as part of the daily EXACT-PRO 
assessment. Summation of E-RS item responses produces a total score ranging from 0 to 40, 
with higher scores indicating greater severity. In addition to the total score, symptom domain 
scores can be calculated for breathlessness (5 items; score range: 0–17), cough and sputum (3 
items; score range: 0–11) and chest symptoms (3 items; score range: 0–11) by summing the 
responses of items within a respective domain. As with the total score, higher domain scores 
indicate greater severity.
5.1.3.6
EQ-5D-5L
The questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, 
moderate problems, severe problems, and extreme problems) that reflect increasing levels of 
difficulty.
The subject will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions. The questionnaire also includes a visual 
analogue scale, where the subject will be asked to rate current health status on a scale of 0-
100, with 0 being the worst imaginable health state.


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The EQ-5D-5L will be completed weekly (7±2 days) starting from visit 4 (week 0) throughout 
week 56 (visit 19) using the ePRO device.
5.1.3.7
Major/minor symptom worsening assessment and alert system
Symptoms will be assessed each morning for the purposes of a symptom worsening alert. The 
purpose of this alert is to notify both the subject and the study center of a potential symptom 
worsening event that warrants contact between the subject and center for further evaluation.
Each morning the subject will complete 3 questions pertaining to the major symptoms of a 
worsening event (dyspnea, sputum volume, and sputum color). Subject reported worsening of 
1 or more of these symptoms will trigger assessment of the minor symptoms of a worsening 
event (sore throat, cold, fever without other cause, cough, and wheeze).  All questions will 
have a 24 hour recall period. Questions pertaining to the severity of symptoms vs. their usual 
state will have 3 response options (e.g. How breathless have you been in the last 24 hours? 
Less breathlessness than usual, Usual level of breathlessness, More breathless than usual) 
whereas questions related to the presence or absence of a symptom will have a dichotomous 
response (e.g. Have you had a sore throat in the last 24 hours? No, Yes, I had a sore throat).
An alert will be triggered if two or more major symptoms (dyspnea, sputum volume, and 
sputum color) worsen for two consecutive days or if one major symptom and one minor 
symptom (sore throat, cold, fever without other cause, cough, and wheeze) worsen for at least 
two consecutive days. When either of these criteria is met the subject will be alerted via the 
ePRO device to contact the study center as soon as possible for further evaluation. Likewise 
the study center will be alerted to contact the subject within approximately 24-72 hours if he 
or she has not yet contacted the center for further evaluation.
5.1.3.8
Rescue Medication Use
Rescue medication usage including reliever inhaler and nebulizer use will be captured twice 
daily. Inhaler usage will be reported as the number of puffs in a given period whereas 
nebulizer use will be reported as the number of times. Rescue medication usage at night will 
be assessed in the morning and rescue medication used during the day will be assessed in the 
evening.
5.1.3.9
Nocturnal Awakenings
Subjects will be asked to report the occurrence of nocturnal awakenings due to COPD 
symptoms each morning using the ePRO device. A single question with yes/no response 
options will be used.
5.1.3.10
Maintenance Medication Use
Maintenance medication adherence will be assessed each evening via a single yes/no question. 
The subject will be asked if they took their regularly scheduled inhaler (yes/no) and instructed 
not to consider instances of rescue inhaler usage when answering this question.


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5.1.4
Healthcare Resource Utilization
Broad-based COPD related health care utilization event information will be collected by the 
Investigator/authorized delegate in accordance with the schedule provided in Table 3 and 
recorded in the appropriate eCRF module.
At Visit 4 (week 0) COPD related Healthcare Resource Utilization information will be 
collected with a one year recall period. All the subsequent visits will collect COPD related 
Healthcare Resource Utilization information with a recall period of ‘since last scheduled 
visit’. 
Note: cases of hospitalization also must be reported as an SAE (see section 7.1.2 and 7.1.9).
5.1.5
Clinician Global Impression of Change (CGIC) and Patient Global Impression 
of Change (PGIC)
The Clinician Global Impression of Change (CGIC) and Patient Global Impression of Change 
(PGIC) instruments are used to evaluate overall response to treatment (change from baseline). 
The assessments are independent of each other. The subject completes the assessment without 
reference to the clinician’s rating and the clinician completes the assessment without reference 
to the subject's rating. Both assessments use a 7-point rating scale: 1 = Very Much Improved; 
2 = Much Improved; 3 = Minimally Improved; 4 = No Change; 5 = Minimally Worse; 6 = 
Much Worse; and 7 = Very Much Worse.
The investigator (clinician) and the subject will be asked to rate the degree to which overall 
COPD status may have changed when compared to baseline (i.e. randomization visit/initiation 
of study drug). The CGIC and PGIC will be completed at the site visits as indicated in Table 
3. It is recommended that the same clinician completes the CGIC for an individual subject.
5.2
Safety assessments
5.2.1
Physical examination 
Physical examination will be done in accordance with the schedule 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 7.1.
5.2.1.1
Complete physical examination 
The complete physical examination will include an assessment of the following: general 
appearance, skin, head and neck (including eyes, ears, nose, mouth, and throat), lymph nodes, 
abdomen, musculoskeletal (including spine and extremities), cardiovascular, respiratory, and 
neurological systems. 


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5.2.1.2
Brief physical examination
The brief physical examination will include an assessment of the general appearance, 
abdomen, cardiovascular and respiratory system. For the brief physical examination only 
information on whether the assessment was performed or not is to be recorded. 
5.2.2
Smoking status
Smoking status will be assessed at each visit starting from enrolment (Visit 1) throughout 
week 56 (Visit 19) by collecting the subject’s response to a single yes/no question from study 
personnel: ‘What is your smoking status as of today, do you currently smoke?
5.2.3
Weight and height
The subject’s height will be measured at the screening Visit 1 only. Weight will be measured 
in accordance with the schedule provided in Table 2 and Table 3.
The subject’s weight will be recorded in kilograms and height will be recorded in centimetres.
Weight and height measurements will be performed in light clothing and without shoes.
5.2.4
Vital signs 
Pre-dose vital signs (pulse, blood pressure, respiration rate and body temperature) will be 
obtained in accordance with the schedule provided in Table 2 and Table 3. The vital signs will 
be taken prior to the blood draw, IP administration, and, if possible, the COPD maintenance 
therapy. Vital signs should also be taken prior to the per protocol bronchodilator 
administration if applicable for that visit.
The pulse rate and blood pressure should be measured after the subject has been resting for at 
least 5 minutes. The measurement will be taken in a sitting position. The pulse rate will be 
obtained before blood pressure. 
The respiration rate will be obtained after the subject has been resting for at least 5 minutes, 
by counting the number of breaths (how many times the chest rises) for one minute.
Body temperature will be measured in Celsius before IP administration in accordance with 
local standards.
5.2.5
ECG 
ECG will be performed in accordance with the schedule provided in Table 2 and Table 3. The 
equipment will be provided by a central vendor, and only this equipment should be used for 
assessment throughout the subject’s participation in the study. 
A 12-lead ECG will be taken in the supine position, after the subject has been resting for at 
least 5 minutes. The assessment should be performed before interventions with the subject 
(e.g. spirometry and administration of the COPD related medications and IP).


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The Investigator or authorized delegate will be responsible for the overall interpretation and 
determination of clinical significance of any potential ECG findings. The ECG printouts will 
be signed and dated by the investigator and stored at the study centre. The ECG will be 
transmitted to a central reader.
5.2.6
Laboratory Safety Assessments
The safety laboratory tests will be performed at a central laboratory. For information on 
methods of collection, assessment, labelling, storage and shipment of samples please refer to 
the Laboratory Manual. The safety laboratory samples will be collected in accordance with the 
schedule provided in Table 2 and Table 3.
Haematology and urinalysis will be assessed in line with the schedule provided in Table 2 and
Table 3.
Absolute blood eosinophil count required for subject stratification will be assessed by a 
central laboratory as a part of safety haematology testing at Visit 1 (Table 2).
Laboratory results should be reviewed by the Investigator/authorized delegate and evaluated 
for abnormalities. Any laboratory abnormalities considered to be significant in the 
Investigator’s/authorized delegate’s judgement should be reported as described in section 
7.1.3.
The copy of laboratory result report should be signed and dated by the Investigator and 
retained at the study centre.


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Table 4
List of Laboratory Safety Tests
Clinical chemistry
Haematology
Urinalysis
Alkaline phosphatase
Gamma-GT (gamma-
glutamyl 
transpeptidase)
Hematocrit
Appearance
ALT (alanine 
aminotransferase)
Glucose
Hemoglobin
Blood
AST (aspartate 
aminotransferase)
Phosphorus
Mean corpuscular 
volume (MCV)
Colour
BUN (blood urea 
nitrogen)
Potassium
Platelet count
Glucose
Calcium
Sodium
Red blood cell (RBC) 
count
Ketones
Chloride
Total bilirubin
WBC count with 
differential*
Microscopy including 
WBC/high power field 
(HPF), RBC/HPF
CO2 (carbon dioxide)
Total cholesterol
pH
Creatinine
Uric acid
Specific gravity
*
eosinophil, basophil and monocyte counts will be redacted from the central laboratory reports, except Visit 
1 laboratory report (see section 6.6)
Table 5
Clinical Chemistry Test Schedule
VISIT
V1
V3
V6
V7
V11
V15
V19
Alkaline phosphatase
X
X
X
X
X
X
X
ALT
X
X
X
X
X
X
X
AST
X
X
X
X
X
X
X
BUN
X
X
X
X
X
X
X
Calcium
X
X
Chloride
X
X
CO2 (carbon dioxide)
X
X
Creatinine
X
X
X
X
X
X
X
Gamma-GT
X
X
X
X
X
X
X
Glucose
X
X


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VISIT
V1
V3
V6
V7
V11
V15
V19
Phosphorus
X
X
Potassium
X
X
Sodium
X
X
Total bilirubin
X
X
X
X
X
X
X
Total cholesterol
X
X
Uric acid
X
X
5.2.7
Pregnancy Test 
The following tests are applicable to female subjects only and will be conducted in accordance 
with the schedule provided in Table 2 and Table 3.
!
Serum beta-HCG – the test will be performed at the screening Visit 1 only, for 
WOCBP (analysed at the central laboratory) 
!
FSH – the test will be performed at Visit 1 only, for female subjects to confirm 
postmenopausal status in women <50 years who have been amenorrheic for K12 
months 
!
Urine HCG – the test will be performed at the study centre for WOCBP at each 
treatment visit before IP administration using a urine dipstick. A positive urine test 
result must be confirmed with a serum beta HCG.
5.3
Other Study Assessments
5.3.1
Central Laboratory Eosinophil Testing
Subjects will be stratified by the absolute blood eosinophil count as assessed by a central 
laboratory (haematology sample taken at Visit 1, see section 5.2.6), and randomization will be 
capped at the study level for the baseline eosinophil cohorts (<220/OL, 220-299/OL, K300/OL) 
in order to keep predefined cohort sample size and approximately 2:1 ratio of subjects above 
and below the boundary of 220/QL. Once any of the eosinophil cohorts is filled, subjects 
allocated to that particular cohort based on the Visit 1 eosinophil count, will be screen failed 
(see section 3.7.2). 
5.3.2
Serology
Blood samples for the hepatitis B surface antigen and hepatitis C antibody will be taken at 
Visit 1 and the analysis will be performed at the central laboratory.


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Blood samples for the HIV-1 and HIV-2 antibodies will also be taken at Visit 1 and as above 
the analysis will be performed at the central laboratory.
Instructions for sample collection, processing, storage, and shipment will be found in the 
central laboratory manual.
5.3.3
Total IgE and IgE FEIA
The test will be performed at Visits 4, 11 and 19, see Table 3. The analysis will be performed 
at the central laboratory.
Instructions for sample collection, processing, storage, and shipment will be found in the 
central laboratory manual.
5.3.4
Pharmacokinetics
It is important that date and time of PK sample collection and date and time of IP 
administration is recorded for each subject.
Serum will be collected pre-dose according to the schedule of study procedures, Table 3.
Samples will be collected, labelled, stored and shipped as detailed in the laboratory manual.
Samples for determination of benralizumab concentration in serum will be analyzed at the 
central laboratory on behalf of AstraZeneca, using a validated bioanalytical method. Details of 
the analytical method used will be described in the bioanalytical report.
A summary of PK analysis results will be reported either in the Clinical Study Report (CSR) 
itself or as an addendum to the CSR.
The PK samples will be retained at AstraZeneca or designee for a maximum of 15 years 
following Last Patient Last Visit to properly address potential questions from Regulatory 
Authorities.
5.3.5
Pharmacodynamics
5.3.5.1
Serum Biomarkers
Serum samples will be collected according to the schedule in Table 3 to analyze predictive 
biomarkers to further evaluate subject populations responsive to benralizumab, and 
pharmacodynamic biomarkers to further evaluate the pharmacology of benralizumab. These 
biomarkers will include pharmacodynamic markers of benralizumab, markers of eosinophil 
and basophil recruitment, activation and survival, as well as biomarkers of inflammation 
including cytokines, chemokines, acute phase response proteins, ECP, fibrinogen, serum-
amyloid A, procalcitonin, IL-8, vitamin D, and other inflammatory mediators.
Instructions for sample collection, processing, storage, and shipment can be found in a 
separate laboratory manual provided to the centers.


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Samples will be stored for a maximum of 15 years from the date of the Last Subject’s Last 
Visit, after which they will be destroyed.  The results of any investigation will be reported 
either in the Clinical Study Report itself or as an addendum, or separately in a scientific report 
or publication.
5.3.5.2
Immunogenicity
Instructions for immunogenicity (ADA and nAb) sample collection, processing, storage, and 
shipment can be found in a separate laboratory manual provided to the centers.
The immunogenicity samples will be retained at AstraZeneca or designee for a maximum of 
15 years following the Last Patient’s Last Visit.
The analysis time points will be determined by the cumulative information obtained from the 
Asthma and COPD programs and will be described in SAP.
Summary of the analysis will be presented in the CSR.
Anti-benralizumab antibodies 
The pre-dose serum samples to measure presence of ADA will be collected according to the 
schedule of study procedures (see Table 3).
The presence or absence of ADA will be determined in the serum samples using validated 
bioanalytical method. The method will be summarized in the CSR and fully described in the
validation report.
Neutralizing antibodies (nAb)
Neutralizing antibodies (nAb) will be assessed on all ADA positive samples. ADA negative 
samples will not be tested for nAb.
The presence or absence of neutralizing ADA will be determined using a validated 
bioanalytical method. The method details will be described in a separate bioanalytical report.
5.3.6
Handling of Biological Samples
5.3.6.1
Labelling and Shipment of Biological Samples
The Principal Investigator or designee 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 Appendix C ‘IATA 6.2 Guidance Document’.
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.


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5.3.6.2
Chain of Custody of Biological Samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator or designee at each study centre keeps full traceability of collected 
biological samples from the subjects while in storage at the study centre until shipment or 
disposal (where appropriate) and keeps documentation of receipt of arrival.
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 centres and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca biobank system during the 
entire life cycle.
For the process of Withdrawal of Informed Consent for donated biological samples refer to 
section 3.8.
5.3.7
Supplemental Oxygen (O2)
Oxygen use will be assessed according to the schedule in Table 2 and Table 3.
5.3.8
Oxygen saturation (SpO2)
Pulse oximetry will be used to measure the subject’s oxygen saturation according to the 
schedule in Table 2 and Table 3.
5.3.9
Chest X-ray
A historical (previously done) chest X-ray (posterior/anterior and lateral) or Computed 
Tomography (CT) dated within 8 weeks prior to enrolment is required to ensure that there are 
no abnormal radiological findings that would exclude the subject from study participation as 
per exclusion criterion 1. If a historical (previously done) chest X-ray (or CT) is not available, 
it should be done at Visit 1, or at any time prior to randomisation. 
5.3.10
Pneumococcal and Annual Influenza Vaccination
Subjects should have a pneumococcal vaccination unless contraindicated if they have not had 
one before. In the event that they have previously received a vaccination, the Investigator 
must ensure that the subject does not require a booster (generally after 5-6 years according to 
current guidelines, e.g. CDC guidelines 2010). If a booster is required, it should be given. 
Subjects should receive an annual influenza vaccination in the autumn or winter period unless 
the subject has received it prior to study start (CDC guidelines 2013-2014). If the subject has 
previously received the influenza vaccination within the last 12 months prior to study start, the 
vaccination should be given at the next autumn or winter period. If a subject has an egg 
intolerance or refuses to be vaccinated, the vaccination may be omitted. If the Investigator 


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makes a decision to not vaccinate with either vaccine, the rationale should be clearly 
specified.
Pneumococcal and/ annual influenza vaccination can be given at V1 or at any other visit 
throughout the study (except for ±7 days of IP administration) at the discretion of investigator.
6.
MANAGEMENT OF INVESTIGATIONAL PRODUCTS
6.1
Identity of investigational product(s)
All investigational products will be manufactured at Cook Pharmica LLC, 1300 South 
Patterson Drive, Bloomington, IN, 47403, USA on behalf of MedImmune in accordance with 
Good Manufacturing Practice (GMP).
Benralizumab and placebo administered in the study will be a clear to opalescent, colourless 
to yellow solution.  Each study subject will receive two injections from two syringes with a 
fill volume of 1 ml and 0.5 ml respectively to achieve blinding in a double dummy fashion.
Investigational product
Dosage form and strength
Manufacturer
Benralizumab
20mg/mL solution for injection 
in accessorized pre-filled 
syringe, 0.5 mL fill volume
Cook Pharmica LLC on behalf of 
MedImmune
Benralizumab
30mg/mL solution for injection 
in accessorized pre-filled 
syringe, 1mL fill volume
Cook Pharmica LLC on behalf of 
MedImmune
Benralizumab
100mg/mL solution for 
injection in accessorized pre-
filled syringe, 1mL fill volume
Cook Pharmica LLC on behalf of 
MedImmune
Placebo
Matching placebo solution for 
injection in accessorized pre-
filled syringe, 1mL fill volume
Cook Pharmica LLC on behalf of 
MedImmune
Placebo
Matching placebo solution for 
injection in accessorized pre-
filled syringe, 0.5 mL fill 
volume
Cook Pharmica LLC on behalf of 
MedImmune
6.2
Labelling
Labelling of the Investigational Product will be carried out by AstraZeneca or designee in 
accordance with Annex 13 and current Good Manufacturing Practice (GMP) and regulatory 
requirements of each country participating in the study. The labels will be translated into local 
languages where applicable and required by local regulations.


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6.3
Storage
Benralizumab/placebo is to be stored at the study centre in a secured facility with limited 
access and controlled temperature. The temperature should be monitored on daily basis and 
documented in the temperature monitoring log according to the IP Handling instruction.
The IP must be kept in the original outer container and under conditions specified on the label.
In the following cases the centre staff should not use affected IP and should immediately 
contact AstraZeneca representative for further guidance:

Temperature excursion upon receipt or during storage at the study

Damaged kit upon receipt

Damaged syringe/cartridge
Damaged IP should be documented using the IWRS/IVRS (please refer to IWRS/IVRS 
manual for further details).
6.4
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The study personnel will account for all study drugs dispensed to the subject.
The monitor will account for all study drugs received at the centre, unused study drugs and for 
appropriate destruction (according to local procedures). Certificates of delivery, destruction 
and/or return should be signed. 
In any case of malfunctioning accessorized pre-filled syringe (APFS), the centre should 
contact the study monitor to initiate a product complaint process according to applicable 
guidelines.
About 10 pre-selected sites in US will participate in APFS return program. These sites will
collect in total approximately 100 APFSs presumed to have functioned properly during 
dosing, and then contact study monitor to initiate return process according to applicable 
guidelines; the users of the devices will be asked to complete questionnaire to evaluate the 
device performance. The results of the investigation will be reported either in an addendum to 
CSR, or separately in a scientific report or publication.
6.5
Methods for assigning treatment groups
Randomisation codes will be assigned strictly sequentially in each stratum as subjects become 
eligible for randomisation.
Subjects who fail to meet the inclusion/exclusion criteria should not, under any circumstances, 
be randomised or receive study medication. There can be no exceptions to this rule.


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6.6
Methods for ensuring blinding
The study will be conducted in double blind, double dummy fashion. All packaging and 
labeling will be done in such way as to ensure blinding. The following personnel will have 
access to the randomisation list:

the personnel carrying out the packaging and labelling of IP

the personnel generating the randomisation list
The information in the randomisation list will be kept from other personnel involved in the 
conduct of the study, and in a secure location until the end of the study.
AstraZeneca staff involved in the study, the subjects, and the investigators involved in the 
treatment of the subjects 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 accessorized pre-filled syringes.
Maintaining the blind to the subject’s blood eosinophil counts
While not entirely specific, subjects on active benralizumab treatment are expected to have 
lower blood eosinophil counts than subjects on placebo. Procedures to mitigate unblinding on 
this basis include:
!
Per protocol haematology will be run by the central laboratory. Except for the Visit 1 
screening eosinophil count, eosinophil and basophil counts will be redacted from the 
laboratory reports. Because complete knowledge of the remaining cell types could 
permit deduction of the ‘eosinophil+ basophil’ compartment, monocyte counts will 
also be redacted from the reports. 
!
If the Investigator orders any local safety laboratory assessments, the requested tests 
should be restricted to the question at hand. For example, if haemoglobin is desired, 
the Investigator should avoid ordering a complete blood cell count with a differential 
count.
!
Handling of laboratory results obtained during the treatment period but ordered 
outside of the clinical trial. Centre staff who are directly involved in the subject’s 
management should remain blinded to any eosinophil, basophil and monocyte results 
included as part of an outside lab reports. To help ensure this, each investigational 
centre will designate an individual (e.g. administrator or another ancillary person) not 
directly involved in subject management, to receive and blind any eosinophil, 
basophil and monocyte results prior to the report being handed over to the centre staff 
involved in subject’s management and prior to filing as a source document. Similarly, 
eosinophil and basophil results must be redacted from all communications with the 
Sponsor.


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!
In cases where the Investigator requires an eosinophil, basophil or monocyte count for 
managing safety issues he/she may order these tests. AstraZeneca should be notified 
of all such cases.
6.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomisation for each randomised 
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 randomisation. 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.
6.8
IP administration and treatment compliance
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the eCRF.
The IP will be administered subcutaneously at the study centre on treatment visits and within 
visit windows as specified in Table 3. 
IP should be administered after all other visit procedures are completed.
In cases where a treatment visit needs to bere-scheduled, the IP must be administered within 
10 weeks of the previous IP dose. If the time between doses is greater than 10 weeks the 
subject should be discontinued from IP, please refer to section 3.6.1. Minimum interval 
between IP doses should not be less than 3 weeks.
If the dose for Visit 6 is significantly delayed (>1 week) this is the only time at which the dose 
can be skipped, the next dosing should be done at Visit 7 as per Study plan (Table 3).
If IP dosing needs to be delayed, all study procedures for that visit should be postponed until 
the day of dosing. However if any of treatment visit procedures have been already performed, 
there is no need to repeat them provided IP is administered within the next 7 days.
Before IP administration
Prior to each IP administration:


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
Investigator/authorized delegate will assess the injection site as per standards of 
medical care

For WOCBP the urine pregnancy test will be done; IP will be administered 
only when the result of the test is negative (see section 5.2.7)
IP administration
The IP will be administered by the Investigator/authorized delegate IP is administered 
subcutaneously. Two injections are required. The two injections will be administered at the 
same anatomical site with a distance of at least 3 cm between the two injections. It is advised 
that the site of injection of IP is rotated such that the subject receives IP at a different 
anatomical site at each treatment visit. Suggested injection site rotation sequence is presented 
below (see Figure 3). The injection site must be documented in the source at each treatment 
visit and recorded in the eCRF.
Figure 3
Injection sites and rotation scheme
In cases when rotation of the injection site is not favourable for the subject and/or 
Investigator, the reason for this should be documented in the source as well as injection site at 
each treatment visit.
The specific details for IP administration are provided in the IP Handling Instruction. The IP 
administration must be carried out in line with these instructions.
After IP administration
After IP administration the subject should be observed for a minimum of 2 hours for the 
appearance of any acute drug reactions.
Conditions requiring IP administration rescheduling 
If a subject presents with a condition that prohibits administration of IP or other events that in 
the opinion of the Investigator contraindicate dosing, administration of IP will be withheld 
until the condition resolves, up to a maximum of 10 weeks between IP dosing. 


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Unscheduled visit procedures may be performed at the discretion of the Investigator.
If there is a delay in the administration of Benralizumab such that it will not be administered 
within the specified timeframe, the study monitor must be notified immediately. If the time 
between IP doses is greater than 10 weeks the subject should be discontinued, please refer to 
section 3.6.
If any of the following occurs, the Investigator should reschedule the visit and investigational 
product should not be administered until the rescheduled visit:
!
The subject has an intercurrent illness, that in the opinion of the Investigator may 
compromise the safety of the subject in the study (e.g. viral illnesses)
!
The subject shows signs of a clinically significant infection during the treatment 
period. Benralizumab should not be administered to a subject with a clinically 
significant active infection treated with oral or IV antimicrobials, antivirals, or 
antifungals until it is confirmed by the investigator that the infection has resolved
!
The subject, in the opinion of the Investigator, is experiencing an acute or emerging 
COPD exacerbation. Benralizumab should not be administered until it is confirmed 
by the investigator that the exacerbation has resolved
!
The subject is febrile (K38°C; K100.4°F) within 72 hours prior to investigational 
product administration
!
The subject has LFTs (ALT and/or AST) of > 3×ULN and concurrent elevated 
bilirubin > 2×ULN
!
Any event that in the opinion of the investigator or the sponsor contraindicates 
further dosing or could result in complications
6.9
Management of IP related reactions
Appropriate drugs, such as epinephrine and H1 and H2 antihistamines, corticosteroids, etc, 
and medical equipment to treat acute anaphylactic reactions must be immediately available, 
and study personnel must be trained to recognize and treat anaphylaxis (Lieberman et al 
2010). Details on anaphylaxis management are provided in Appendix E.
Anaphylaxis will be defined as serious reaction that is rapid in onset and may cause death 
(Sampson et al 2006). Anaphylaxis typically manifest as one of three clinical scenarios:
1.
The acute onset of a reaction (minutes to hours) with involvement of the skin, 
mucosal tissue or both and at least one of the following: a) respiratory compromise; 
b) or reduced blood pressure or symptoms of end-organ dysfunction; or


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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; or
3.
Reduced blood pressure after exposure.
Subjects will have had a pre-assessment (i.e. 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.
SAFETY REPORTING
7.1
Adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section.
7.1.1
Definition of adverse events
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product.  An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory 
findings, electrocardiogram). In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
7.1.2
Definitions of serious adverse event
A serious adverse event (SAE) is an AE occurring during any study phase (i.e., run-in, 
treatment, washout, follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalisation or prolongation of existing hospitalisation 


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!
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 jeopardise the subject or may require 
medical intervention to prevent one of the outcomes listed above
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol.
7.1.3
Recording of adverse events
Time period for collection of adverse events
All AEs, including SAEs, will be collected from the time the subject signs the informed 
consent throughout the treatment period up to the final follow-up visit (Visit 20, week 60).
For the patients prematurely discontinued from IP all AEs, including SAEs, will be collected 
up to Visit 19, week 56.
Follow-up of unresolved adverse events
Any AEs that are unresolved at the end of the study are followed up by the Investigator for as 
long as medically indicated, but without further recording in the eCRF. AstraZeneca retains 
the right to request additional information for any subject with ongoing AE(s)/SAE(s) at the 
end of the study, if judged necessary.
The requirement to follow-up AEs is not intended to delay database lock or production of the 
Clinical Study Report (CSR). These activities should proceed as planned with ongoing AEs if 
necessary.
Any follow-up information of ongoing SAEs after database lock will be reported to 
AstraZeneca.
7.1.4
Variables 
The following variables will be collected for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum intensity of the AE
!
Whether the AE is serious or not
!
Investigator causality rating against the Investigational Product (yes or no)


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!
Action taken with regard to investigational product
!
AE caused subject’s withdrawal from study (yes or no)
!
Outcome
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in section 7.1.2. An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE.
7.1.5
Causality collection
The Investigator will assess causal relationship between Investigational Product and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
7.1.6
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 eCRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
7.1.7
Adverse Events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report. Deterioration as compared to baseline in protocol-mandated laboratory 
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 (e.g., anaemia versus low haemoglobin 


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value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
7.1.7.1
Adverse events of Pneumonia requiring a confirmed diagnosis
Events of suspected pneumonia should be confirmed by the presence of a new infiltrate on x-
ray within approximately 48 hours, as well as at least 2 of the following signs and symptoms: 
increased cough, increased sputum purulence or production, consistent auscultatory findings, 
dyspnea or tachypnea, fever, leukocytosis, or hypoxemia.
Events of confirmed diagnoses of pneumonia must be recorded as the adverse event 
“Pneumonia (confirmed)” in the eCRF.
7.1.8
Drug Induced Liver Injury (DILI)
Cases where a subject shows an AST or ALT K3xULN or total bilirubin K2xULN may need to 
be reported as SAEs. Please refer to Appendix D for further instructions in cases of combined 
increase of aminotransferase and total bilirubin.
7.1.9
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 eCRF.
If any SAE occurs in the course of the study, then the Investigators or other centre personnel 
will inform the appropriate AstraZeneca representatives within one day i.e., immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within one 
calendar day of initial receipt for fatal and life threatening events and within five calendar 
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other centre personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other centre 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 centre personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone.


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The AstraZeneca representative will advise the Investigator/study centre personnel how to 
proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug.
7.1.10
Reporting of COPD exacerbations
COPD exacerbations should be captured on a specific eCRF module (COPDEX).
COPD exacerbations should not be reported as Adverse Events unless they meet Serious 
Adverse Event definition (see 7.1.2). In such case, COPD exacerbation should be reported 
both as an exacerbation and as a SAE.
7.2
Overdose
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
Investigators or other centre personnel inform appropriate AstraZeneca representatives within 
one day i.e., 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.
For overdoses associated with SAE, standard reporting timelines apply, see section 7.1.9. For 
other overdoses, reporting should be done within 30 days.
7.3
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
7.3.1
Maternal exposure
If a subject becomes pregnant during the course of the study, the investigational product 
should be discontinued immediately.
Pregnancy itself is not regarded as an AE 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.


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If any pregnancy occurs in the course of the study, then Investigators or other centre personnel 
inform appropriate AstraZeneca representatives within one day i.e., 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 
days for SAEs, see section 7.1.9 and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The pregnancy (PREGREP) module in the eCRF is used to report the pregnancy and the 
pregnancy outcome (PREGOUT) module is used to report the outcome of the pregnancy.
7.3.2
Paternal exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
16 weeks (5 half-lives) following the last dose of IP.
Pregnancy of the subject’s partner is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should, if possible, be followed up and documented.
Information on the pregnancy of a male subject’s partner must be obtained directly from the 
subject’s partner; the male subject should not be asked to provide this information. Prior to 
obtaining information related to the pregnancy and outcome of the pregnancy, the Investigator 
must obtain the subject’s partner consent. A consent form specific to this situation must be 
used. The outcome of any conception occurring from the date of the first dose until 16 weeks 
(5 half-lives) after the last administration of IP should be followed up and documented.
7.4
Independent Adjudication Committee
An Independent Adjudication Committee will be constituted to provide an independent, 
external, systematic and unbiased assessment of  blinded data to confirm the diagnosis of: 1) 
investigator reported non-fatal  myocardial infarction, non-fatal stroke (hemorrhagic, 
ischemic, embolic), as well as cardiovascular deaths and 2) investigator reported malignancies 
during the Phase III trials. The committee will operate in accordance with an Adjudication 
Committee Charter/Manual of Operations, which will also provide detail on what specific 
information the committee requires to enable a thorough adjudication.
7.5
Independent Data Monitoring Committee
The Independent Data Monitoring Committee will be responsible for monitoring the safety of 
the study participants, ensuring that the studies are being conducted with the highest scientific 
and ethical standards and making appropriate recommendations based on the available data.  
The IDMC will function independently of all other individuals associated with the conduct of 
the studies, including the study sponsor AstraZeneca.  The committee will operate in 
accordance with an Independent Data Monitoring Committee Charter (also refer to section 


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8.5.6). The IDMC will evaluate general safety output including but not limited to wound 
healing and host defense (infections and infestations).  It will also evaluate the output of the 
independent adjudication committee (major adverse cardiovascular events and malignancies). 
This will be done in addition to usual pharmacovigilance programs.
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
Refer to the SAP for additional details.
8.2
Sample size estimate
The study will recruit subjects with blood eosinophil counts <220/OL, 220-299/OL, and 
K300/OL. The approximately 2:1 ratio between K220/OL and <220/OL allows analysis of the 
primary population for subjects most likely to respond to benralizumab (i.e. K220/OL), while 
still including subjects below this threshold in order to help understand efficacy and safety in 
this group. The study is powered for the exacerbation rate comparisons of the subjects with 
blood eosinophils K220/OL (primary efficacy analysis).
For the primary endpoint annual COPD exacerbation rate, 348 subjects with baseline blood 
eosinophil counts K220/OL per treatment arm (1392 total) will need to be randomised to 
achieve 90% power of detecting a 30% reduction in both the 30mg and 100mg benralizumab 
dose groups versus placebo based on a Hochberg Procedure (Hochberg 1988). This 
calculation has assumed two-sided 4% alpha level tests, an annual placebo rate of 0.93 
events/subject (1.0 events/subject/56 weeks), a negative binomial shape parameter of 0.4, and 
a dropout rate of 10%. The sample size calculation is based on simulations and has accounted 
for the power loss from a proposed futility analysis (Section 8.5.6).
As stated previously an approximately 2:1 ratio will be used for subjects with blood 
eosinophil counts K220/OL and <220/OL. Therefore this study will randomise 174
subjects/arm (696 total) with baseline blood eosinophil counts <220/OL. An additional 20 
subjects/arm will also be recruited to the 220-299/OL cohort to better characterize patients 
within this cohort. This addition results in 368 subjects/arm in the K220/OL cohort (1472 
total). A total of 2168 subjects are expected to be randomised in this study. Details of the 
estimated numbers of recruited subjects/arm in each cohort (<220/OL, 220-299/OL, K300/OL) 
are described in the SAP.
The sample size necessary to achieve a stated power (90% in our case) in this study is 
calculated based on the estimate of overall exacerbation rate and shape parameter from the 
negative binomial model (Section 8.5.1). In order to better estimate the overall exacerbation 


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rate and shape parameter, we plan to conduct a single blinded sample size re-estimation in 
both studies D3251C0003 and D3251C0004. Blinded estimates of the overall exacerbation 
rate as well as the shape parameter from data pooled across placebo and all benralizumab 
doses (for patients with eosinophil counts K220/OL) will be used in the sample size re-
estimation and strictly no treatment information will be used in the review. The pooled study 
summaries will not contain any information that would potentially reveal the treatment 
assignments (e.g., post-randomization eosinophil levels). The review will be conducted before 
the last patient with eosinophil counts K220/OL is randomized and after the futility analysis 
(Section 8.5.6). The exacerbation rate and shape parameter will be estimated using the 
maximum likelihood approach as proposed by Friede and Schmidli 2010. This review may 
result in an adjustment of sample size. Since this review will be performed in a blinded 
fashion, no adjustment for the type I error is needed. The blinded data review will be 
performed by AstraZeneca internal personnel or its designees and the full details of the review 
will be specified in a blinded data review plan.
8.3
Definitions of analysis sets
8.3.1
All patients analysis set
This analysis set comprises all subjects screened for the study and will be used for reporting of 
disposition and screening failures.
8.3.2
Full analysis set
All subjects randomized and receiving at least 1 dose of investigational product will be 
included in the full analysis set, irrespective of their protocol adherence and continued 
participation in the study. Subjects will be analyzed according to their randomized treatment, 
irrespective of whether or not they have prematurely discontinued, according to the ITT 
principle. Subjects who withdraw consent or assent to participate in the study will be included 
up to the date of their study termination. All efficacy analyses will be analyzed using the full 
analysis set.
8.3.3
Safety analysis set
All subjects who received at least 1 dose of investigational product will be included in the 
safety analysis set. Subjects will be classified according to the treatment they actually 
received. A subject who has on one or several occasions received active treatment will be 
classified as active. If a subject has received both active doses, then the subject will be 
classified as the higher active dose. All safety summaries and ADA data will be based on this 
analysis set.
8.3.4
Pharmacokinetic analysis set
All subjects who received benralizumab and from whom PK blood samples are assumed not 
to be affected by factors such as protocol violations (e.g., disallowed medication) will be 
included in the PK analysis set. All PK summaries will be based on this analysis set.


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8.4
Variables for analyses
8.4.1
Calculation or derivation of efficacy variables
All efficacy objectives will be evaluated for the 56-week double-blind treatment period, 
defined as the period after administration of randomised investigational product at Visit 4 and 
the EOT at Visit 19, inclusive.
8.4.1.1
Exacerbation rate
The annual COPD exacerbation rate will be used as the primary efficacy variable.
A COPD exacerbation is defined in section 5.1.1.
In order to calculate the number of exacerbations experienced by a subject during the 56-week 
treatment period, the following rule will be applied.
The start of an exacerbation is defined as the start date of systemic corticosteroids or antibiotic 
treatment or hospital admission, whichever occurs earlier, and the end date is defined as the 
last day of systemic corticosteroids or antibiotic treatment or hospital discharge, whichever 
occurs later. In the primary analysis, the number of exacerbations observed for a subject 
during the 56-week double-blind treatment period will be used as response variable.
Additional systemic corticosteroid treatments, emergency room visits requiring use of 
systemic corticosteroids, or inpatient hospitalization due to COPD occurring during an 
exacerbation should not be regarded as a new exacerbation. In order to be counted for as a 
new exacerbation it must be preceded by at least 7 days in which neither criterion is fulfilled.
Maximum follow-up time for exacerbations for a subject is approximately 56 weeks; defined 
as the time from randomisation to the date of Visit 19. For a subject lost to follow-up, this will 
be defined as the time from randomisation to the time point after which an exacerbation could 
not be assessed.
In the statistical analysis, the number of COPD exacerbations experienced by a subject during 
the 56-week double-blind treatment period will be used as response variable, and the 
logarithm of the subject’s corresponding follow-up time will be used as an offset in the 
analysis to adjust for subjects having different exposure times during which the events occur.
For the production of summary statistics, the annual exacerbation rate per subject is 
calculated, and standardized per 56-week period according to the formula described below. 
Annual Exacerbation Rate = Number of Exacerbations*365.25 / (Last follow-up date – Visit 4 
date + 1).
For subjects who prematurely discontinue treatment, efforts will be made to continue 
collecting the exacerbation data until the scheduled Visit 19/ EOT at Week 56 after 
randomisation (refer to section 3.6.1). In the statistical analysis of exacerbation rate, the data 
collected up to Visit 19/ EOT at Week 56 will be included for the patients who prematurely 


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discontinue treatment according to the intent-to-treat principle. For the patients who died 
during the treatment period the exacerbation data collected up to the date of death will be 
included in the statistical analysis.
If the cause of death is related to COPD or a COPD exacerbation, the event will also be 
included in the rate calculation.
8.4.1.2
Proportion of subjects with M1 COPD exacerbation during 56 weeks of 
treatment
The proportion of subjects with K1 COPD exacerbation during the 56 weeks of treatment will 
be a supportive variable to the primary objective.
8.4.1.3
Time to first exacerbation 
Time from randomisation to the first COPD exacerbation will also be used as a supportive 
variable to the primary objective, and is calculated as follows:
Start Date of first COPD exacerbation d Date of Randomisation + 1.
The time to first COPD exacerbation for subjects who do not experience an COPD 
exacerbation during the treatment period will be censored at the date of their last visit for the 
56-week double-blind treatment period, or at the time point after which an exacerbation could 
not be assessed (for lost-to-follow-up subjects).
8.4.1.4
Forced expiratory volume in 1 second 
The change from baseline to each of the post-randomisation visits (post Visit 4) up to and 
including the end of 56-week double-blind treatment visit (Visit 19) will be used as secondary 
efficacy variables. The pre-bronchodilator measurement recorded at Visit 4 will be used as 
baseline FEV1. If the Visit 4 pre-bronchodilator measurement is missing, the last non-missing 
pre-bronchodilator value before Visit 4 will be used as baseline instead.
8.4.1.5
Annual rate of COPD exacerbations that are associated with an emergency 
room visit or a hospitalization
The annual rate of COPD exacerbations that are associated with an emergency room visit or a 
hospitalization will be a secondary efficacy variable.
In the statistical analysis, the number of COPD exacerbations that are associated with an 
emergency room visit or a hospitalization experienced by a subject during the 56-week 
double-blind treatment period will be used as response variable, and the logarithm of the 
subject’s corresponding follow-up time will be used as an offset in the analysis to adjust for 
subjects having different exposure times during which the events occur.
Maximum follow-up time is approximately 56 weeks, and the follow-up time is derived as 
described in section 8.4.1.1.


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8.4.1.6
Annual rate of healthcare encounters due to COPD
The annual rate of hospitalizations due to COPD, the annual rate of hospitalizations and 
emergency room visits combined due to COPD, the annual rate of unscheduled outpatient 
visits including unscheduled visits to study centres due to COPD and all unscheduled 
healthcare encounters combined due to COPD (hospitalizations, emergency room visits, 
unscheduled outpatient visits including unscheduled visits to study centres) will be secondary 
variables.
In the statistical analysis, the number of hospitalizations due to COPD, the number of 
emergency room visits and hospitalizations combined due to COPD, the number of 
unscheduled outpatient visits due to COPD and the number of all unscheduled healthcare 
encounters due to COPD experienced by a subject during the 56-week double-blind treatment 
period will be used as response variables in four different statistical models with the logarithm 
of the subject’s corresponding follow-up time used as an offset in the analysis to adjust for 
subjects having different exposure times similar to COPD exacerbations as described in 
section 8.4.1.5. If multiple healthcare encounters are associated with one COPD exacerbation 
all the encounters will be counted for this endpoint.
8.4.2
Calculation or derivation of safety variable(s)
8.4.2.1
Safety variables
The following safety data will be collected: vital signs, physical examination, 12-lead ECG, 
haematology, clinical chemistry, urinalysis, and reported AEs.
Change from baseline (Visit 4) to each post-treatment time point where scheduled assessments 
were made will be calculated for relevant measurements. AEs will be summarized by means 
of descriptive statistics and qualitative summaries.
8.4.2.2
Other significant adverse events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and discontinuations due to AEs.
Based on the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant AEs 
(OAEs) and reported as such in the CSR.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction, 
or significant additional treatment.
8.4.3
Calculation or derivation of patient reported outcome variables
SGRQ
Potential health status treatment benefits of benralizumab will be evaluated by comparing the 
change from baseline at Week 56 in SGRQ Total scores. For the responder analysis of SGRQ 


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a responder will be defined as an individual with a K4-point decrease (improvement) in SGRQ 
total score at Week 56.
E-RS
Respiratory symptoms will be evaluated using the E-RS.  Individual daily E-RS total and 
subscale scores will be calculated and summarized as a biweekly (14 day) mean. Data 
collected in the two-week period prior to randomisation will be used to calculate the 
individual E-RS total and subscale baseline means.
EXACT-PRO
The number, average duration, and severity of EXACT-PRO defined events will be evaluated. 
EXACT-PRO daily total scores as well as domain scores will be calculated according to the 
developer approved scoring algorithm. The total score will be used to identify event onset and 
recovery as well as the magnitude (severity) of the event. The baseline total score will be the 
mean within subject score over the 7 days prior to randomisation. A minimum of 4 days of 
data is required for calculating the baseline total score. To allow for improvement or 
deterioration in disease state over the course of the trial, the baseline total score should be 
reset every 4 weeks in the absence of an EXACT-PRO defined event. Event frequency is 
calculated by comparing the baseline with daily total scores. Calculating event duration 
requires identification of the following five parameters: 1) onset; 2) three-day rolling average; 
3) maximum observed value; 4) threshold for improvement; and 5) recovery. The severity of 
an event is indicated by the worst (highest) EXACT-PRO total score during an event. 
Complete details concerning variable calculation are provided in the scoring manual and will 
be provided in the study Statistical analysis plan (SAP).
BDI/TDI
The instrument consists of three components: functional impairment, magnitude of task, and 
magnitude of effort. For the BDI, each of these three components are rated in five grades from 
0 (severe) to 4 (unimpaired), and are summed to form a baseline total score from 0 to 12. The 
BDI will be captured at baseline only. For the TDI, changes in dyspnea are rated for each 
component by seven grades from -3 (major deterioration) to +3 (major improvement), and are 
added to form a total TDI score from -9 to +9.
8.4.4
Calculation or derivation of pharmacokinetic variables
Due to the limited sampling schedule, the PK assessment will be primarily based on the 
observed steady-state serum trough (predose) concentrations, Ctrough. Empirical evaluation 
of potential impact of demographic covariates and ADA on Ctrough will be conducted.   
The PK data will be merged with those from other clinical studies for a population-based 
meta-analysis. Results of the meta-analysis will be presented in a separate pharmacometrics 
report outside of the CSR.


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8.4.5
Calculation or derivation of immunogenicity variables
ADA assessments will be conducted utilizing a tiered approach (screen, confirm, titer).  The 
presence of anti-benralizumab antibodies is determined relative to a cutoff value that is 
calculated for each plate as the mean response of the negative control wells multiplied by a cut 
point factor.  The cut point factor was statistically determined during assay validation.  
Samples that measure at or above the cut point value are considered as potential positives for 
ADA and are retested in a confirmatory (specificity) assay, both in the absence and presence 
of excess benralizumab.  Samples are confirmed to be positive for ADA if the percent 
inhibition of response in the presence of benralizumab is greater than or equal to the 
confirmatory cut point established during assay validation.  Confirmed positive samples are 
then measured in a titer assay.  Titers are performed by serially diluting samples with negative 
control serum and are reported as the reciprocal of the highest dilution (over the 1:50 
minimum required sample dilution) that measure positive in the assay, before returning a 
negative response.
Neutralizing antibody (nAb) evaluations will be conducted on those serum samples that test 
positive for ADA at end of treatment and also during the study follow up period.  ADA-
positive samples will retested in a competitive ligand-binding assay to determine if the ADA 
present is capable of inhibiting (neutralizing) the binding of benralizumab to soluble 
recombinant human interleukin 5 receptor (IL-5R). The test sample is deemed positive or 
negative for the presence of neutralizing antibodies (nAb) to benralizumab relative to a pre-
determined (in assay validation), statistically derived cut point. Samples positive for nAb to 
benralizumab are then titered to determine relative amounts of nAb present in each test 
sample.
8.5
Methods for statistical analyses
The primary analysis of the primary and key secondary endpoints will include all data 
captured during the 56-week treatment period, regardless of whether study treatment was 
prematurely discontinued, or delayed, and/or irrespective of protocol adherence.
Demography and baseline characteristics will be summarized by treatment group for the full 
analysis set. In the event that there are major differences between the full analysis set and 
safety analysis set, these summaries will also be repeated for the safety analysis set.
Testing strategy to account for multiplicity considerations
To account for multiplicity to test the primary (exacerbation) and two key secondary 
endpoints (FEV1 and SGRQ) for each of the 30mg and 100mg dose groups (for subjects with 
baseline blood eosinophils K220/OL) a testing strategy will be followed to control the overall 
type I error rate at level 0.05. The testing strategy will be according to the following gate 
keeping procedure:
Step 1: Perform the two tests of annual COPD exacerbation rate (one test for each dose vs. 
placebo) at the family wise error rate (FWER) of 0.04 using a Hochberg Procedure (Hochberg 


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1988). If both p-values are less than 0.04, then proceed to Step 2; else if the smaller p-value is 
less than 0.02 then proceed to Step 2a; otherwise no null hypothesis is rejected
Step 2: Test the two key secondary endpoints for both doses as one family at the FWER of 
0.05 using a Holm Procedure (Holm 1979).
Step 2a: Test the two secondary endpoints for the smaller-p-value dose at the FWER of 0.01 
using a Holm Procedure.


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The gatekeeping procedure is also shown in the diagram below:
Figure 4
Gatekeeping Procedure
Since the correlation of the two test statistics for COPD exacerbation rate in the Step 1 is 
positive, the FWER of the Hochberg Procedure is strongly controlled at 0.04. The overall 
FWER of the gatekeeping procedure is strongly controlled at 0.05.
For the comparison of the 10mg dose group and placebo in subjects with baseline blood 
eosinophils K300/OL, multiplicity will be adjusted for the testing of the primary and two key 
secondary endpoints using a serial gatekeeping procedure (Dmitrienko and Tamhane 2007). In 
the procedure the primary endpoint will be tested at 0.05 level for the comparison of the 10mg 
dose group and placebo. The two secondary endpoints will be tested using a Holm procedure 
at the 0.05 level for the comparison of the 10mg dose group and placebo only if the test for the 
primary endpoint is significant at 0.05 level.
In summary the FWER will be strongly controlled for the comparison of 30mg and 100mg vs. 
placebo at 0.05 on testing of the primary endpoint and two key secondary endpoints. The 
FWER will also be strongly controlled for the comparison of 10mg vs. placebo at 0.05 on 
Test exacerbationrate 
of the two doses at 
0.04 using Hochberg
Test the 2 secondary 
for the smaller p-value 
dose at 0.01 using 
Holm Procedure
no
yes
Max(P1, P2)<0.04?
Test the 4 secondary 
endpoints at 0.05 using 
Holm Procedure
Stop and no null 
hypothesis is rejected
Min(P1, P2)<0.02?
no
yes


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testing of the primary endpoint and two key secondary endpoints. The FWER will not be 
strongly controlled at 0.05 for the testing of the primary endpoint and two key secondary 
endpoints across all three doses.
8.5.1
Primary analysis method(s)
The primary efficacy variable is the annual COPD exacerbation rate and the primary analysis 
is to compare the annual COPD exacerbation rate of each benralizumab dose group with 
placebo in subjects with baseline blood eosinophil counts K220/OL.
For each of the three benralizumab dose groups, the null hypothesis is that the exacerbation 
rate on benralizumab is equal to the exacerbation rate on placebo. The alternative hypothesis 
is that the exacerbation rate on benralizumab is not equal to the exacerbation rate on placebo, 
i.e.:
H0: Rate ratio (benralizumab vs. Placebo) = 1
Ha: Rate ratio (benralizumab vs. Placebo) e 1
Exacerbation rate in each of the three benralizumab dose groups will be compared to 
exacerbation rate in the placebo group using a negative binomial model. The response variable 
in the model will be the number of COPD exacerbations over the 56-week treatment period. 
The model will include covariates of treatment group, eosinophil cohort (220-299/OL or 
K300/OL), country, background therapy (ICS/LABA, LABA/LAMA, or ICS/LABA/LAMA), 
and the number of exacerbations in the year before the study. The logarithm of the follow-up 
time will be used as an offset variable in the model.
The estimated treatment effect (i.e., the rate ratio of benralizumab versus placebo), 
corresponding 95% confidence interval (CI), and two-sided p-value for the rate ratio will be
presented. In addition, the exacerbation rate and the corresponding 95% CI within each 
treatment group will be presented.
In addition, the exacerbation rate will also be summarized in subjects with baseline blood 
eosinophil counts <220/OL, <150/OL, 150-219/OL, 220-299/OL, 300-449/OL, and K450/OL 
separately for descriptive purpose only. 
8.5.2
Secondary analysis methods
8.5.2.1
Analysis methods for secondary efficacy variables
Key secondary efficacy endpoints in this study are:

Change from baseline in pre-dose/pre-bronchodilator FEV1 at Week 56

Change from baseline in SGRQ total score at Week 56
Other secondary efficacy endpoints include 

Proportion of subjects with K1 COPD exacerbation


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
Time to the first COPD exacerbation 

Proportion of subjects with K4-point decrease (improvement) in SGRQ total 
score at Week 56

Annual rate of COPD exacerbations that are associated with an emergency 
room visit or a hospitalization

Annual rate of hospitalizations, annual rate of hospitalizations and emergency 
room visits combined, annual rate of unscheduled outpatient visits including 
unscheduled visits to study centres and all unscheduled healthcare encounters 
due to COPD

Rescue medication use (average puffs/day)

Number of nights with awakening due to COPD and requiring rescue 
medication

Change from baseline in E-RS total score and domain scores at Week 56

Area under the curve (AUC) of E-RS total score 

BDI/TDI

CAT

EXACT-PRO
All the secondary efficacy endpoints will be analyzed in subjects with baseline blood 
eosinophil counts K220/OL. In addition, the two key secondary endpoints will also be 
summarized in subjects with baseline blood eosinophil counts <220/OL, <150/OL, 150-
219/OL, 220-299/OL, 300-449/OL, and K450/OL separately for descriptive purpose only. 
Change from baseline in pre-dose/pre-bronchodilator FEV1 at Week 56 will be compared 
between each of the three benralizumab dose groups and placebo using a repeated measures 
analysis on subjects with a baseline pre-dose/pre-bronchodilator FEV1 and at least one post-
randomisation pre-dose/pre-bronchodilator FEV1 in the full analysis set. The dependent 
variable will be the change from baseline in pre-bronchodilator FEV1 at post-baseline 
protocol-specified visits (up to the EOT visit). Treatment group will be fitted as the 
explanatory variable, and eosinophil cohort (220-299/OL or K300/OL), country, background 
therapy (ICS/LABA, LABA/LAMA, or ICS/LABA/LAMA), visit, the interaction between 
visit and treatment and baseline pre-bronchodilator FEV1 will be fitted as covariates. Visit will 
be fitted as a categorical variable, and 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:


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Change in FEV1 = Treatment group+ eosinophil cohort (220-299//L or 1300//L) + baseline 
FEV1+ country + background therapy (ICS/LABA, LABA/LAMA, or ICS/LABA/LAMA) + visit 
+ treatment*visit
Change from baseline in SGRQ total score and three domain scores (symptoms, activity, and 
impacts) at Week 56 will be analyzed separately using a similar model as the above model for 
change from baseline in pre-dose/pre-bronchodilator FEV1.
Proportion of subjects with K4-point decrease (improvement) in SGRQ total score at Week 56 
in each of the three benralizumab dose groups will be compared with the proportion in the 
placebo group using a Cochran–Mantel–Haenszel test controlling for eosinophil cohort (220-
299/OL or K300/OL), country, and background therapy (ICS/LABA, LABA/LAMA, or 
ICS/LABA/LAMA). Cumulative distribution function of absolute changes in SGRQ total 
score at week 56 will be plotted in a figure.
The proportion of subjects with K1 COPD exacerbation during the 56 weeks of treatment will 
be addressed as a supportive variable to the primary objective. The proportion in each of the 
three benralizumab dose groups will be compared with the proportion in the placebo group 
using a logistic regression model with eosinophil cohort (220-299/OL or K300/OL), country, 
background therapy (ICS/LABA, LABA/LAMA, or ICS/LABA/LAMA), and number of 
exacerbations in the year before the study as covariates.
Time to first COPD exacerbation will be analyzed as another supportive efficacy variable to 
the primary objective to explore the extent to which treatment with benralizumab delays the 
time to first exacerbation compared with placebo. A Cox proportional hazard model will be 
fitted to data with the covariates of treatment, eosinophil cohort (220-299/OL or K300/OL), 
country, background therapy (ICS/LABA, LABA/LAMA, or ICS/LABA/LAMA), and 
number of exacerbations in the year before the study.
Annual rate of COPD exacerbations that are associated with an emergency room visit or a 
hospitalization will be analyzed using a similar Negative binomial model as outlined for the 
primary efficacy variable in section 8.5.1.
Annual rates of hospitalizations, hospitalizations and emergency room visits combined, 
unscheduled outpatient visits including unscheduled visits to study centres as well as all 
unscheduled healthcare encounters due to COPD (hospitalizations, emergency room visits, 
and unscheduled outpatient visits including unscheduled visits to study centres) will be 
analyzed using Negative Binomial Models as outlined for the primary efficacy variable in
section 8.5.1.
The number of nights with awakening due to COPD and requiring rescue medication will be 
analyzed as the response variable by fitting a repeated measures model to data. Treatment 
group will be fitted as the explanatory variable, and eosinophil cohort (220-299/OL or 
K300/OL), country, baseline value and background therapy (ICS/LABA, LABA/LAMA, or 
ICS/LABA/LAMA) will be fitted as covariates. Rescue medication use (average puffs/day) 
will be analyzed using a similar model.


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Change from baseline in E-RS total score and domain scores at Week 56 will be analyzed 
separately using a similar model as the model for change from baseline in pre-dose/pre-
bronchodilator FEV1. AUC of E-RS total score will be analyzed by fitting an ANCOVA 
model with treatment, eosinophil cohort (220-299/OL or K300/OL), country, baseline value, 
and background therapy (ICS/LABA, LABA/LAMA, or ICS/LABA/LAMA) as covariates.
The BDI/TDI, EXACT-PRO, and CAT will be summarized by treatment and visit.
8.5.2.2
Analysis methods for safety variables
AEs will be summarized by means of counts summaries by study period (treatment period and 
follow-up period). AEs will be listed for each subject and summarized by System Organ Class 
(SOC) and Preferred Term (PT) assigned to the event by MedDRA. Laboratory safety 
variables will be summarized using standard summary statistics and plots as appropriate. 
Other safety variables will be summarized as appropriate. Further details will be provided in 
the SAP.
Laboratory data for hematology and clinical chemistry will be summarized. The frequency of 
changes with respect to normal ranges between baseline and each post-treatment time point 
will be tabulated. Frequencies of clinically noteworthy values (defined in the SAP) occurring 
during the clinical study will also be given. Shifts from normal to abnormal between baseline 
and each post-baseline time point will be evaluated for urinalysis. Changes in vital signs and 
ECGs will be examined at each visit and at endpoint. Frequencies of clinically noteworthy 
values (defined in the SAP) occurring during the clinical study will be presented. Shifts from 
normal to abnormal between baseline and follow-up will be evaluated for the physical 
examination.
8.5.2.3
Analysis Methods for PK Variables
The PK analyses will be performed at or under the guidance of AstraZeneca Research and 
Development.
Benralizumab serum concentrations will be summarized using descriptive statistics at each 
visit by treatment group. Serum concentration-time profiles of benralizumab by treatment 
group will be generated. The potential influence of demographic covariates such as body 
weight, race, gender and age will be evaluated. Impact of ADA on PK will also be assessed. 
Serum concentrations of benralizumab, summary statistics, empirical covariate analysis results 
and PK profiles will be provided in a clinical PK report (an addendum to the CSR).
To further characterize the pharmacokinetic properties of benralizumab, the PK data will be 
merged with those from other clinical studies for a population-based meta-analysis.  The 
population modelling results will be presented in a separate pharmacometrics report outside of 
the CSR.
8.5.2.4
Analysis Method for Immunogenicity Variables
Anti-drug antibodies (ADA) to benralizumab will be summarized using descriptive statistics 
at each visit by treatment group.  ADA titers-time profiles of benralizumab by treatment group 


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will be generated. The impact of ADA on PK and eosinophil level will be assessed.  The 
potential association of ADA with safety and efficacy will be evaluated.  The association of 
the nAb titer with the ADA titer, benralizumab concentration, blood eosinophil levels, and 
asthma exacerbation rate will be evaluated for ADA positive subjects only.
8.5.3
Exploratory analysis
An exploratory objective of this study is to understand the dose-response relationship. This 
will be explored through modelling the dose response for the primary and key secondary 
endpoints across all 3 benralizumab dose levels (10mg, 30mg, and 100mg).
Analysis for the other exploratory objectives will be specified in the SAP.
8.5.4
Sensitivity analysis
Sensitivity analyses for the primary endpoint and the key secondary endpoints based on 
different missing data mechanism assumptions including those expected to be more 
conservative such as missing not at random will be used to explore the robustness of any 
treatment effect, including multiple imputation approaches. Full details of the sensitivity 
analyses will be pre-specified in the SAP and documented prior to database lock of the 
studies. 
8.5.5
Subgroup analysis
Details of all subgroup analyses and statistical modeling including possible testing of 
interaction between treatment group and covariates will be described in the SAP.
8.5.6
Interim Analysis 
The futility analysis will be based on the pooled data of study D3251C00003 and study 
D3251C00004 when approximately 15% patients with baseline blood eosinophil counts
K220/OL have completed the studies. The percentage of patients is based on the total number 
of patients with eosinophil counts K220/OL expected to be recruited in the studies. In the 
futility analysis, decision will be based on the comparison of the futility boundary and the 
estimated exacerbation rate reductions of benralizumab doses vs. placebo in patients with 
eosinophil counts K220/OL from the negative binomial model as documented for the final 
analysis in section 8.5.1. Futility will be declared if the higher exacerbation rate reduction of 
benralizumab 30mg vs. placebo and benralizumab 100mg vs. placebo is less than 8%. A 
futility boundary of 8% was chosen based on the operating characteristics of ~55% chance of 
stopping the study for futility under the null hypothesis of equal exacerbation rates across all 
treatments and ~2% chance of stopping the study for futility assuming an exacerbation rate 
reduction of 30% for both benralizumab doses vs. placebo.  Full details about the futility 
analysis decision rules and procedures will be specified in an IDMC charter and the charter 
will also specify the roles and responsibilities of the IDMC members. A firewall will be 
established to ensure the maintenance of the study blind for the sponsor, the investigational 
site staff and patients. Further the IDMC charter will specify the timing of analysis and the 
expected extent of data available at the time of interim analysis. Conducting a futility analysis 


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results in power loss. The sample size calculation in section 8.2 has accounted for this loss and 
the study has 90% of power under the powering assumptions and the futility boundary of 8%.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study centre 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 the WBDC and 
ePROs system(s) utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study 
centre, 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 eCRFs, 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 eCRFs 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 (e.g., 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 centre needs information and advice about the study conduct.


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9.2.1
Source data
Refer to the Clinical Study Agreement 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 centre 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 centre 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 Clinical Study Agreement (CSA). 
The Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be 
archived at the study centre.
9.2.3
Study agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol 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 Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator 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 Clinical Study Agreement (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 Q2 2014 and to end by Q4 2017.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with benralizumab.


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9.4
Data management by AstraZeneca
Data management will be performed by AstraZeneca Data Management Centre staff or other 
party, according to the Data Management Plan.
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 the Medical Dictionary for Regulatory Activities (MedDRA). Medications 
will be classified according to the AstraZeneca Drug Dictionary. All coding will be performed 
by the Medical Coding Team at the AstraZeneca Data Management 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. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. The study Data Management Plan 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 (SAE) Reconciliation
SAE 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 laboratories 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 ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.


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10.2
Subject data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law.
Precautions are taken to preserve confidentiality and prevent genetic data being linked to the 
identity of the subject. In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, an AstraZeneca Study Physician or an investigator might know a 
subject’s identity and also have access to his or her genetic data. Also Regulatory authorities 
may require access to the relevant files, though the subject’s medical information and the 
genetic files would remain physically separate.
10.3
Ethics and regulatory review
An Ethics Committee should approve the final study protocol, including the final version of 
the Informed Consent Form and 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 Ethics Committee, and to the study centre staff.
The opinion of the Ethics Committee should be given in writing. The investigator should 
submit the written approval to AstraZeneca before enrolment of any subject into the study.
The Ethics Committee should approve all advertising used to recruit subjects for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the Informed Consent Form, 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 Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements, including SUSARs 
(Suspected Unexpected Serious Adverse Reactions), where relevant.


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For the US and Canada, may also be applicable to other countries, Each Principal Investigator 
is responsible for providing the Ethics Committees/IRB with reports of any serious and 
unexpected adverse drug reactions from any other study conducted with the investigational 
product.  AstraZeneca will provide this information to the Principal Investigator so that he/she 
can meet these reporting requirements.
10.4
Informed consent
The Principal Investigator(s) or designee 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 Informed Consent Form(s) is/are stored in the 
Investigator’s Study File

Ensure a copy of the signed Informed Consent Form 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 Ethics Committee.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator, the Principal Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to Ethics Committee see section 10.3.


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If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, 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, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements.  The investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the centre.


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11.
LIST OF REFERENCES
Bafadhel et al 2011
Bafadhel M, McKenna S, Terry S, Mistry V, Reid C, Haldar P, et al. Acute exacerbations of 
chronic obstructive pulmonary disease. Identification of biologic cluster and their biomarkers. 
Am J Respir Crit Care Med. 2011;184:662–671.
Bafadhel et al 2009
Bafadhel M, Saha S, Siva R, McCormick M, Monteiro W, Rugman P, et al. Sputum IL-5 
concentration is associated with a sputum eosinophilia and attenuated by corticosteroid 
therapy in COPD. Respiration. 2009;78(3):256–262.  
Brightling et al 2000
Brightling CE, Monterio W, Ward R, Parker D, Morgan MDL, Wardlaw AJ, Pavord ID. 
Sputum eosinophilia and the short term response to prednisolone in chronic obstructive 
pulmonary disease: a randomised controlled trial. Lancet 2000. 28; 356 (9240): 1480-5.
Brightling et al 2005
Brightling CE, McKenna S, Hargadon B, Birring SS, Green RH, Siva R, Berry M, Parker D, 
Monteiro W, Pavord ID, Bradding P. Sputum eosinophilia and short-term response to inhaled 
mometasone in chronic obstructive pulmonary disease Thorax 2005; 60: 193-8.
CDC guidelines 2013-2014
Summary Recommendations: Prevention and Control of Influenza with Vaccines: 
Recommendations of the Advisory Committee on Immunization Practices—(ACIP)—United 
States, 2013-2014. Centers for Disease Control and Prevention (CDC). Available from: URL: 
http://www.cdc.gov/flu/professionals/acip/2013-summary-recommendations.htm
CDC guidelines 2010
Updated Recommendations for Prevention of Invasive Pneumococcal Disease Among Adults 
Using the 23-Valent Pneumococcal Polysaccharide Vaccine (PPSV23). Centers for Disease 
Control and Prevention (CDC). Morbidity and Mortality Weekly Report .2010 / 59(34);1102-
1106. Available from: URL: http://www.cdc.gov/vaccines/hcp/acip-recs/vacc-
specific/pneumo.html


Revised Clinical Study Protocol
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Dahl et al 2004
Dahl C, Hoffman HJ, Saito H, Shiotz PO. Human mast cells express receptors for IL-3, IL-5 
and GM-CSF; a partial map of receptors on human mast cells cultured in vitro. Allergy. 
2004;59(10):1087–96.
Donaldson et al 2002
Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between 
exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. 
Thorax. 2002; 57(10):847-52.
Dmitrienko and Tamhane 2007
Dmitrienko A, Tamhane AC. Gatekeeping procedures with clinical trial applications. 
Pharmaceutical Statistics. 2007; 6:171-180.
Friede and Schmidli 2010
Friede T, Schmidli H. Blinded Sample Size Reestimation with Negative Binomial Counts in 
Superiority and Non-inferiority Trials. Methods of Information in Medicine. 2010; 49(6): 618-
624.  
GINA 2011
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma 
(GINA) December 2011. Available from: URL: http://www.ginasthma.org/guidelines-
ginareport-global-strategy-for-asthma.html
GOLD 2013
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative 
for Chronic Obstructive Lung Disease (GOLD) 2013. Available from: 
http://www.goldcopd.org.
Hochberg 1988
Hochberg, Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988. 75; 800-2


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
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108 (111)
Holm 1979
Holm, S. A simple sequentially rejective multiple test procedure. Scand.J. Statist.1979. 6, 65-
70.
Jones, 2009
Jones PW. The St George’s Respiratory Questionnaire  Manual. Version 2.3; St George’s, 
University of London, London, UK: June 2009.
Jones et al 2011
Jones PW, Chen WH, Wilcox TK, Sethi S, Leidy NK. Characterizing and quantifying the 
symptomatic features of COPD exacerbations. Chest 2011;139(6):1388–1394.
Jones et al 1991
Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir 
Med. 1991;85 Suppl B:25-31.
Jones et al 2009
Jones PW, Harding G, Berry P,  Wiklund I, Chen W-H,  Leidy NK. Development and first 
validation of the COPD Assessment Test. Eur Respir J 2009, 34: 648–654
Kouro and Takatsu 2009
Kouro T, Takatsu K. IL-5- and eosinophil-mediated inflammation: from discovery to therapy. 
Int Immunol. 2009 Dec;21(12):1303-9
Lieberman et al 2010
Lieberman P, Nicklas RA, Oppenheimer J,  Kemp SF, Lang DM,Bernstein DI, Bernstein JA, 
Burks AW, Feldweg AM, Fink JN, Greenberger PA, Golden DB, James JM, Kemp SF, 
Ledford DK, Lieberman P, Sheffer AL, Bernstein DI, Blessing-Moore J, Cox L, Khan 
DA,Lang D,Nicklas RA,Oppenheimer J,Portnoy JM,Randolph C,Schuller DE, Spector SL, 
Tilles S, Wallace D . The diagnosis and management of anaphylaxis practice parameter: 2010 
update. J Allergy Clin Immunol . 2010 Sep;126(3):477-80.e1-42.
Leidy et al 2011
Leidy NK, Wilcox TK, Jones PW, et al. Standardizing measurement of chronic obstructive 
pulmonary disease exacerbations. Reliability and validity of a patient-reported diary. Am J 
Respir Crit Care Med 2011;183(3):323–329.


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Leigh et al 2006
Leigh R, Pizzichini MM, Morris MM, Maltais F, Hargreave FE, Pizzichini E. Stable COPD: 
predicting benefit from high-dose inhaled corticosteroid treatment. Eur Respir J. 2006; 
27(5):964-71.
Leuppi et al 2013
Short-term vs Conventional Glucocorticoid Therapy in Acute Exacerbations of Chronic 
Obstructive Pulmonary Disease. JAMA. 2013; 309(21):2223-2231.
Mahler et al 1984
Mahler DA, Weinberg DH, Wells CK, Feinstein AR.; The measurement of dyspnea: contents, 
inter-observer agreement, and physiologic correlates of two new clinical indexes., Chest 1984; 
85:751–758.
Mahler et al 2005
Mahler DA, Witek Jr TJ.; The MCID of the transition dyspnea index is a total score of one 
unit., COPD, 2005; 2: 99-103.
Miller et al 2005
Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, et al. General 
considerations for lung function Testing. Eur Respir J 2005;26(1):153-61
Ogata et al 1998
Ogata N, Kouro T, Yamada A, Koike M, Hanai N, Ishikawa T, et al. JAK2 and JAK1 
constitutively associate with an interleukin-5 (IL-5) receptor alpha and beta subunit, 
respectively, and are activated upon IL-5 stimulation. Blood. 1998;91(7):2264-71.
Pascoe S et al 2015
Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord I, Blood eosinophil counts, 
exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in 
patients with chronic obstructive pulmonary disease: a secondary analysis of data from two 
parallel randomised controlled trials.  Lancet Resp. Med. 2015; 3: 435-442.  
Pizzichini et al 1998
Pizzichini E, Pizzichini MM, Gibson P, Parameswaran K, Gleich GJ, Berman L, Dolovich J, 
Hargreave FE. Sputum eosinophilia predicts benefit from prednisone in smokers with chronic 
obstructive bronchitis. Am J Respir Crit Care Med. 1998; 158(5 Pt 1): 1511-7.


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
110 (111)
Quanjer et al 2012
Quanjer PH, Stanojevic S, Cole TJ, Baur X, L Hall GL, Culver B, Enright PL, Hankinson JL, 
Zheng J, Stocks J and the ERS Global Lung Function Initiative. Multi ethnic reference values 
for spirometry for the 3-95 year age range: the global lung function 2012 equations.. Report of 
the Global Lung Function Initiative (GLI), ERS Task Force to establish improved Lung 
Function Reference Values. 2012 Jun, as doi: 10.1183/09031936.00080312.
Rodriquez-Roisin R 2000
Rodriquez-Roisin R. Toward a consensus definition for COPD exacerbations. Chest. 
2000;117:398S-401S
Saha and Brightling 2006
Saha S, Brightling CE. Eosinophilic airway inflammation in COPD. International Journal of 
COPD 2006; 1: 39-47.
Sampson et al 2006
Sampson H, Muñoz-Furlong A, Campbell R, Adkinson F, Bock A, Branum A, Brown S, 
Camargo C, Cydulka R, Galli S, Gidudu J, Gruchalla R, Harlor A, Hepner D, Lewis L, 
Lieberman P, Metcalfe D, O’Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons 
E, Thomas S, Wood J, Decker W. Second symposium on the definition and management of 
anaphylaxis: Summary report—Second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium. The Journal of Allergy and 
Clinical Immunology 117.2 (2006): 391-397.
Sexton et al 2010
Sexton C, Notte S, Murray L, Leidy NK. PRO evidence dossier to support the use of the E-RS 
to evaluate respiratory symptoms in patients with COPD. United BioSource Corporation; 
Bethesda, MD: May 2010.
Sexton et al 2011
Sexton C, Leidy NK, Notte SM, et al. Quantifying the severity of respiratory symptoms of 
COPD: reliability and validity of a patient diary. Poster presented at the American Thoracic 
Society International Meeting; May 2011: Denver, CO.


Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3251C00004
Edition Number 4.0
Date 06 July 2015
111 (111)
Siva et al 2007
Siva R, Green RH, Brightling CE, Shelley M, Hargadon B, McKenna S, Monteiro W, Berry 
M, Parker D, Wardlaw AJ, Pavord ID. Eosinophilic airway inflammation and exacerbations of 
COPD: a randomised controlled trial. Eur Respir J. 2007; 29(5):906-13.
Takaki et al 1994
Takaki S, Kanazawa H, Shiiba M, Takatsu K. A critical cytoplasmic domain of the 
interleukin-5 (IL-5) receptor alpha chain and its function in IL-5-mediated growth signal 
transduction. Mol Cell Biol. 1994;14(11):7404-13.
Takatsu 1995
Takatsu K. Structure and Function of IL-5 Receptor. Yakugaku 1995; 115(8): 570-583
Tavernier et al 1991
Tavernier J, Devos R, Cornelis S, Tuypens T, Van der Heyden J, Fiers W, et al. A human high 
affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific alpha chain and a beta 
chain shared with the receptor for GM-CSF. Cell. 1991;66(6):1175-84.
Toba et al 1999
Toba K, Koike T, Shibata A, Hashimoto S, Takahashi M, Masuko M, et al. Novel technique 
for the direct flow cytofluorometric analysis of human basophils in unseparated blood and 
bone marrow, and the characterization of phenotype and peroxidase of human basophils. 
Cytometry. 1999;35(3):249-59.
Wedzicha et al 2013
Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, Sandström T, Taylor AF, et al. 
Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator 
QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-
blind, parallel-group study. The Lancet. 2013;1(3):199-209.


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75 5
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SAP_001.pdf: 
1
Statistical Analysis Plan
Study Code
D3251C00004
Edition Number
4.0
Date
11 May 2018
A randomised, double-blind, double dummy, chronic dosing (56 week)
placebo-controlled, parallel group, multicentre, phase III study to evaluate
the efficacy and safety of 3 doses of benralizumab (MEDI-563) in patients 
with moderate to very severe Chronic Obstructive Pulmonary Disease 
(COPD) with a history of COPD exacerbations (TERRANOVA)






Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 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................................................................................10
1.
STUDY DETAILS............................................................................................. 14
1.1
Study objectives................................................................................................. 14
1.1.1
Primary Objective .............................................................................................. 14
1.1.2
Secondary Objectives......................................................................................... 14
1.1.3
Safety Objective................................................................................................. 15
1.1.4
Exploratory Objectives....................................................................................... 16
1.2
Study design ...................................................................................................... 16
1.3
Number of subjects ............................................................................................17
2.
ANALYSIS SETS ............................................................................................. 18
2.1
Definition of analysis sets .................................................................................. 18
2.1.1
All patients analysis set...................................................................................... 18
2.1.2
Full analysis set..................................................................................................18
2.1.3
Safety analysis set..............................................................................................18
2.1.4
Pharmacokinetic analysis set.............................................................................. 19
2.2
Violations and deviations ................................................................................... 19
2.2.1
Important protocol deviations............................................................................. 19
2.2.2
Visit window definitions .................................................................................... 20
2.2.3
The definition of baseline................................................................................... 22
2.2.4
Prior/concomitant medications ...........................................................................24
3.
PRIMARY AND SECONDARY VARIABLES................................................. 24
3.1
Primary outcome variable .................................................................................. 24
3.2
Secondary efficacy outcome variables................................................................ 26
3.2.1
Time to first COPD exacerbation (days)............................................................. 26
3.2.2
Proportion of patients with ≥1 COPD exacerbation during 56 weeks of 
treatment............................................................................................................ 26
3.2.3
Annual rate of COPD exacerbations that are associated with an emergency 
room visit or a hospitalization ............................................................................26
3.2.4
FEV1 (L) pre-bronchodilator measured at the study center .................................26
3.2.5
Healthcare resource utilization due to COPD...................................................... 27


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
5
3.3
Patient reported outcome variables..................................................................... 27
3.3.1
St. George’s Respiratory Questionnaire (SGRQ)................................................28
3.3.2
COPD Assessment Test (CAT) ..........................................................................29
3.3.3
Baseline/Transitional Dyspnea Index (BDI/TDI)................................................ 29
3.3.4
Exacerbations of Chronic Pulmonary Disease Tool – Patient-reported 
Outcome (EXACT-PRO) ...................................................................................29
3.3.5
Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary 
Disease (E-RS: COPD) ......................................................................................30
3.3.6
Total rescue medication use ...............................................................................31
3.3.7
Nights with awakening due to respiratory symptoms..........................................31
3.3.8
European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L)........................... 31
3.3.9
Clinician Global Impression of Change (CGIC) and Patient Global 
Impression of Change (PGIC)............................................................................32
3.4
Safety outcome variables.................................................................................... 33
3.4.1
Adverse events...................................................................................................33
3.4.2
Laboratory variables .......................................................................................... 33
3.4.3
Twelve-lead electrocardiogram ..........................................................................35
3.4.4
Physical examination ......................................................................................... 35
3.4.5
Vital signs.......................................................................................................... 35
3.5
Pharmacokinetic variables.................................................................................. 36
3.6
Immunogenicity variables .................................................................................. 36
4.
ANALYSIS METHODS....................................................................................36
4.1
General principles.............................................................................................. 36
4.1.1
Testing strategy to account for multiplicity considerations ................................. 37
4.2
Analysis methods............................................................................................... 38
4.2.1
Patient disposition..............................................................................................38
4.2.2
Demography data and patient characteristics ...................................................... 38
4.2.3
Prior and concomitant medications..................................................................... 39
4.2.4
Study treatment administration........................................................................... 39
4.2.5
Primary outcome variable ..................................................................................39
4.2.5.1
Primary analysis................................................................................................. 39
4.2.5.2
Subgroup analysis for the primary outcome variable .......................................... 41
4.2.5.3
Supportive analysis for the primary outcome variable ........................................ 42
4.2.6
Secondary efficacy outcome variables................................................................ 42
4.2.6.1
Proportion of subjects with ≥1 COPD exacerbation............................................ 43
4.2.6.2
Time to first COPD exacerbation ....................................................................... 43
4.2.6.3
FEV1 (L) pre-bronchodilator measured at the study centre..................................43
4.2.6.4
St. George’s Respiratory Questionnaire (SGRQ)................................................45
4.2.6.5
COPD assessment tool (CAT)............................................................................ 46
4.2.6.6
Baseline/Transitional Dyspnea Index (BDI/TDI)................................................ 46
4.2.6.7
Exacerbations of Chronic Pulmonary Disease Tool – Patient-reported 
Outcome (EXACT-PRO) ...................................................................................46


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
6
4.2.6.8
Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary 
Disease (E-RS: COPD) ......................................................................................47
4.2.6.9
Medication Use.................................................................................................. 47
4.2.6.10
Nights with awakening due to respiratory symptoms.......................................... 47
4.2.6.11
Healthcare resource utilization ........................................................................... 48
4.2.7
Additional modelling for primary and key secondary endpoints ......................... 48
4.2.8
Exploratory Objectives.......................................................................................48
4.2.8.1
European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L)........................... 48
4.2.8.2
Clinician Global Impression of Change (CGIC) and Patient Global 
Impression of Change (PGIC)............................................................................48
4.2.8.3
Blood eosinophils...............................................................................................49
4.2.8.4
Serum biomarkers .............................................................................................. 49
4.2.8.5
Benralizumab dose response relationship ........................................................... 50
4.2.8.6
Mortality rate ..................................................................................................... 50
4.2.9
Safety outcome variables....................................................................................50
4.2.9.1
Adverse events (AEs)......................................................................................... 50
4.2.9.2
Laboratory data.................................................................................................. 51
4.2.9.3
ECGs ................................................................................................................. 52
4.2.9.4
Physical examination ......................................................................................... 52
4.2.9.5
Vital signs.......................................................................................................... 52
4.2.10
Pharmacokinetic analyses................................................................................... 53
4.2.11
Immunogenicity analyses................................................................................... 53
5.
INTERIM ANALYSES ..................................................................................... 53
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 54
7.
REFERENCES ..................................................................................................54
8.
APPENDIX ....................................................................................................... 57
8.1
Accounting for missing data............................................................................... 57
8.2
Partial dates for adverse events and prior/concomitant medication ..................... 66
8.3
Analysis plan for immunogenicity data .............................................................. 68
8.4
Important protocol deviations............................................................................. 71
LIST OF TABLES
Table 1 General analysis-defined visit windows for assessments........................................20
Table 2 Biweekly windows for daily diary assessments......................................................21
Table 3 Vital signs reference ranges...................................................................................35


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
7
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ADA
Anti-drug antibodies
AE
Adverse event 
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AZDD
AstraZeneca drug dictionary
BD
Bronchodilator
BDI/TDI
Baseline/transitional dyspnea index
BMI
Body Mass Index
CAT
COPD assessment tool
CGIC
Clinical global impression of change
CI
Confidence interval
CMH
Cochran–Mantel–Haenszel
COPD
Chronic obstructive pulmonary disease
COTE
COPD specific comorbidity test
CSP
Clinical study protocol
CSR
Clinical study report
DAE
Discontinuation of investigational product due to adverse event
DBP
Diastolic blood pressure
ECG
Electrocardiogram
ECL
Electrochemiluminescent 
eCRF
Electronic case report form
eDiary
Electronic diary
EOT
End of treatment
EQ-5D-5L
European quality of life-5 dimensions-5 levels
ePRO
Electronic patient reported outcome
ER
Emergency room
E-RS: COPD
Evaluating respiratory symptoms in chronic obstructive pulmonary disease
EXACT-PRO
Exacerbations of chronic pulmonary disease tool – Patient-reported 
outcome


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
8
Abbreviation or 
special term
Explanation
FAS
Full analysis set 
FEV1
Forced expiratory volume in 1 second
FU
Follow-up (visit)
FWER
Family-wise error rate
GCP
Good clinical practice
GGT
Gamma-glutamyltransferase
GOLD
Global Initiative for Chronic Obstructive Lung Disease
ICS
Inhaled corticosteroids
IDMC
Independent data monitoring committee
IL-5
Interleukin-5
IL-5R
Interleukin-5 receptor
IM
Intramuscular
IP
Investigational product
IPD
Investigational product discontinuation
ITT
Intent-to-treat
IV
Intravenous
LABA
Long-acting beta agonist
LAMA
Long-acting muscarinic antagonist
LSMEANS
Least squares means
LOCF
Last observation carried forward
MACE
Major adverse cardiac events
MCID
Minimum clinically important difference
MedDRA
Medical dictionary for regulatory activities
MMRM
Mixed-effect model for repeated measures
N/A
Not applicable
nAb
Neutralizing antibodies
PGIC
Patient global impression of change
PK
Pharmacokinetics
PN
Percent normal
PRO
Patient reported outcome
PT
Preferred term
SAE
Serious adverse event


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
9
Abbreviation or 
special term
Explanation
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SC
Subcutaneous
SCE
Summary of clinical efficacy
SD
Standard deviation
SGRQ
St. George’s respiratory questionnaire
SI
System international (units)
SOC
System organ class
TBL
Total bilirubin
ULN
Upper limit of normal
WBDC
Web based data capture


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
10
AMENDMENT HISTORY
Date
Brief description of change
21 January 2016
(v2.0)
!
SAP text amendment due to CSP amendment 4.0: lowering baseline 
eosinophil cutoff from ≥300/μL to ≥220/μL, corresponding sample size 
changes, and additional covariate of baseline eosinophil cohort (220-299/μL 
or ≥300/μL) for ≥220/μL inferential analyses.
!
Updated definition of exacerbations to include death due to COPD.
!
Clarification around the process for identifying and summarizing important 
protocol deviations.
!
Updates to visit window definitions, taking into account the way in which 
daily diary metrics are recorded (daytime assessments recorded in the 
evening and night-time assessments recorded the morning of following 
calendar day) and ensuring that there are no gaps in visit windows.  Update 
to definition of study day; relative to randomization to align with the way in 
which study visits are scheduled.
!
Clarification provided on the definition of baseline for efficacy versus safety 
endpoints.
!
Clarification on the definition of prior and concomitant medications.
!
Clarification provided on summaries of baseline demographic data and
patient characteristics by baseline eosinophil groups (<220/μL, 220/μL).
!
Updated the method for primary endpoint from patient-based approach to 
time-based approach.
!
Additional details added for the definition of maximum follow-up time for 
exacerbations and added sensitivity analysis for on-treatment analysis, 
multiple imputation method details, and additional statistical modelling 
(primary and key secondary endpoints).
!
Updated the method for subgroup analyses (primary and key secondary 
endpoints) to a single model per subgroup factor with inclusion of subgroup 
main effect and treatment*subgroup interaction, to align with methods 
described in the protocol.
!
Updates to expand the list of endpoints to be analysed in patients with 
baseline blood eosinophil count <220/μL; and also by baseline blood 
eosinophil count categories (<150/μL, 150-219/μL, 220-299/μL, 300-
449/μL, ≥450/ μL), and cumulative baseline blood eosinophil count 
categories (≥150/μL, ≥200/μL, ≥250/μL, ≥300/μL, ≥350/μL, ≥400/μL, 
≥450/μL).
!
Clarification provided on SGRQ total score response status and analysis 
method.
!
Analysis of SGRQ and TDI responders updated to evaluate patients with 
missing data at Week 56 as non-responders.
!
Clarification on the definition of an EXACT-PRO event, and rescue 
medication (incorporating morning/evening assessments).


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
11
Date
Brief description of change
!
Removal of ANCOVA analysis for E-RS: COPD total score.
!
Updated analysis of healthcare utilization from annual rates to summary 
statistics.
!
Added descriptions and statistical summary analyses on exploratory 
endpoints for subset analysis. 
!
Updated categorization of adverse events into study periods (on-study, on-
treatment, and post-treatment) and clarification of adverse event summaries 
above/below 220/μL. 
!
Updates to incorporate protocol amendments, including: addition of CGIC 
and PGIC endpoints, removal of ADA analysis set (as analyses of ADA will 
be conducted in the safety set), removal of analysis of potential risks 
(included as part of adverse events).
!
Clarifications on dose response relationship analysis to be analysed and 
reported in the SCE.
!
Added immunogenicity analyses and reference to the separate Statistical   
Analysis Plan for Benralizumab Anti-Drug Antibody data.


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
12
Date
Brief description of change
25 April 2018 
(v3.0)
!
Removed text on 10% drop out rate in sample size calculation erroneously 
included in the CSP. Actual sample sizes in CSP and SAP are correct and do 
not account for a 10% drop out rate. 
!
Clarified ePRO data will be analyzed up to completion or discontinuation 
date and exclude data after ICF withdrawal
!
Updated baseline definition for EQ-5D-5L
!
Clarified baseline eosinophil levels for stratification are taken from central 
laboratory. Only if lab data is missing will IVRS stratification be used. 
!
Added imputation rules for partially missing systemic corticosteroid or 
antibiotic exacerbation start/end dates
!
Added summary of healthcare resource utilization annual rates
!
Adding missing data rules for SGRQ and CAT scores
!
Changed nights with awakenings due to COPD to due to respiratory 
symptoms, and removed analysis of nights with awakenings requiring 
rescue medication to align with actual ePRO setup
!
Updated AE definitions for on-study, on-treatment, and post-treatment 
periods
!
Added imputation rules for inferential analyses in case of missing 
background therapy 
!
Added details of disposition summary
!
Added marginal standardization method for analyzing negative binomial 
models
!
Added weights will be used for analysis by baseline cumulative eosinophil 
categories
!
Added supportive/sensitivity analyses to the primary endpoint: 
exacerbations associated with hospitalization or death, exacerbations with 
data truncated at the point when subjects switched background therapies, 
exacerbations 
!
Added subgroup analyses to the primary endpoint: by prior exacerbations, 
smoking status
!
Added subgroup analyses for pre-BD FEV1: baseline eosinophil categories, 
cumulative eosinophil categories, and prior exacerbations
!
Added rules for MMRM covariance structures when convergence issues 
arise
!
Added subgroup analyses for SGRQ: baseline eosinophil categories and  
cumulative eosinophil categories
!
Added sensitivity analysis for SGRQ responder analysis using LOCF
!
Added summaries for switches in background therapy during the study
!
Added sensitivity analyses for primary and key secondary endpoints 
excluding potential data anomalies
!
Added plot comparing historical versus baseline eosinophil levels


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
13
Date
Brief description of change
!
Changed cutoff for most common AEs from ≥5% to ≥3%
!
Added summaries of injection site reaction AEs
!
Added summaries of hypersensitivity AEs causally related with IP
!
Added SAE narratives will be provided
!
Added final list of important protocol deviations in appendix
!
Added all ADA analyses in appendix
!
Removed pDRMI from all MI analyses and MAR from on-treatment MI 
analyses
11 May 2018
(v4.0)
!
Revision to the multiple testing procedure following the readout of study 
D3251C00003 (GALATHEA) for the primary and key secondary endpoints


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
14
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 evaluate the effect of three doses of
benralizumab on COPD exacerbations in 
subjects with moderate to very severe COPD
Annual COPD exacerbation rate, where a COPD 
exacerbation is defined by symptomatic worsening 
of COPD requiring:
!
Use of systemic corticosteroids for at least 3 
days; a single depot injectable dose of 
corticosteroids will be considered equivalent to a 
3-day course of systemic corticosteroids; and/or
!
Use of antibiotics; and/or
!
An inpatient hospitalization or death due to 
COPD
1.1.2
Secondary Objectives
Secondary Objective:
Outcome Measure:
To evaluate the effect of three doses of 
benralizumab on health status/ health-related 
quality of life
!
St. George’s Respiratory Questionnaire 
(SGRQ)*
!
COPD assessment tool (CAT)
To evaluate the effect of three doses of 
benralizumab on pulmonary function
Pre-dose/pre-bronchodilator Forced expiratory 
volume in one second (FEV1) * at the study center
To evaluate the effect of three doses of 
benralizumab on respiratory symptoms
!
Baseline/Transitional Dyspnea Index 
(BDI/TDI)
!
Evaluating respiratory symptoms in chronic 
obstructive pulmonary disease (E-RS: COPD)
To evaluate the effect of three doses of
benralizumab on nocturnal awakenings
Number of nights with awakening due to COPD


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
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Secondary Objective:
Outcome Measure:
To evaluate the effect of three doses of 
benralizumab on rescue medication use
Total rescue medication use (average puffs/day)
To evaluate the effect of three doses of 
benralizumab on the severity, frequency and 
duration of EXACT-PRO defined events.
Exacerbations of Chronic Pulmonary Disease 
Tool – Patient-reported Outcome (EXACT-PRO)
To evaluate the effect of three doses of 
benralizumab on other parameters associated with 
COPD exacerbations
Time to first COPD exacerbation and proportion 
of subjects with ≥1 COPD exacerbation
To evaluate the effect of three doses of 
benralizumab on COPD exacerbations involving 
emergency room visits and hospitalizations
Annual rate of COPD exacerbations that are 
associated with an emergency room visit or a 
hospitalization
To evaluate the effect of three doses of 
benralizumab on healthcare resource utilization 
due to COPD
Annual rate of hospitalizations due to COPD; 
annual rate of hospitalizations and emergency 
department visits combined due to COPD; annual 
rate of unscheduled outpatient visits including 
unscheduled visits to study centers due to COPD; 
and annual rate of unscheduled healthcare 
encounters due to COPD
To evaluate the pharmacokinetics and 
immunogenicity of three doses of benralizumab
!
Pharmacokinetic (PK) parameters
!
Anti-drug antibodies (ADA)
* Key secondary efficacy endpoints
A summary of PK analysis results will be reported either in the Clinical Study Report (CSR) 
itself or as an addendum to the CSR.
1.1.3
Safety Objective
Safety Objective:
Outcome Measure:
To evaluate the safety and tolerability of three
doses of benralizumab
!
Adverse events/ Serious adverse events 
(AE/SAE)
!
Laboratory variables
!
12 lead Electrocardiogram (ECG)
!
Physical Examination
!
Vital Signs


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
16
1.1.4
Exploratory Objectives
Exploratory Objective:
Outcome Measure:
To evaluate the effect of three doses of 
benralizumab on general health status
European Quality of Life-5 Dimensions-5 Levels
(EQ-5D-5L)
To evaluate the impact of three doses of 
benralizumab on blood eosinophil levels
Blood eosinophils
To evaluate the effect of three doses of 
benralizumab on blood biomarkers
Serum biomarkers
To evaluate the effect of three doses of 
benralizumab on patient and physician global 
assessments
Patient Global Impression of Change (PGIC) and 
Clinical Global Impression of Change (CGIC)
To understand the dose response relationship
across a broad range of doses
Primary and key secondary endpoints across 3
benralizumab dose levels (10mg, 30mg, and
100mg).
To evaluate the effect of three doses of 
benralizumab on all cause and respiratory related 
mortality
Mortality rate
The results of the exploratory objectives may be reported outside of the CSR.
1.2
Study design
This is a randomised, double-blind, double dummy, placebo-controlled, parallel group, 
multicentre, phase III study to evaluate the efficacy and safety of benralizumab (MEDI-563), 
10mg, 30mg, and 100mg doses administered by subcutaneous (SC) injection every 4 weeks 
for the first 3 doses and then every 8 weeks thereafter with the last dose of IP administered at 
Week 48 and last treatment evaluation performed at Week 56, in subjects with moderate to 
very severe COPD receiving standard maintenance therapy (inhaled corticosteroid/long-acting 
β2 agonist (ICS/LABA), long-acting β2 agonist /long acting muscarinic antagonist 
(LABA/LAMA) or ICS/LABA/LAMA) with a history of COPD exacerbation(s) in the year 
prior to enrolment (Visit 1).
The study will recruit approximately 2168 subjects randomised 1:1:1:1 to the treatment arms 
(10mg, 30mg, 100mg, placebo) stratified by country and blood eosinophil count (≥300/μL or
<300/μL). Subjects will be recruited based on baseline blood eosinophil counts <220/μL, 
220-299/μL, and ≥300/μL. The approximately 2:1 ratio between ≥220/μL and <220/μL allows 
analysis of the primary population for subjects most likely to respond to benralizumab (i.e.,
≥220/μL), while still including subjects below this threshold in order to help understand 
efficacy and safety in this group. The subject recruitment will also be capped at the study level 
for the cohorts with baseline eosinophil count (<220/μL, 220-299/μL, or ≥300/μL) in order to 
keep predefined cohort sample size and approximately 2:1 ratio of subjects above and below 
the boundary of 220/μL.  Instructions for screen failing these subjects from the study after a 
stratum is closed are noted in the protocol (Section 4.1.3 of the protocol). The estimated 


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
17
number of recruited subjects per arm in each of these cohorts (<220/μL, 220-299/μL, 
≥300/μL) will be 174, 90, and 278, respectively.
The investigational product (IP) will be administered at the study centre every 4 weeks for the 
first 3 doses, and then every 8 weeks thereafter. The last dose will be given at Week 48 and 
the last treatment evaluation will be performed at Week 56.
After the initial enrolment and confirmation of the entry criteria, subjects will proceed to the 
screening/run-in period for 3 weeks to allow adequate time for all of the eligibility criteria to 
be evaluated. Subjects who meet the eligibility criteria will be randomised to the 56-week 
treatment period, with the last dose of benralizumab/placebo administered at Week 48. The 
end of treatment (EOT) visit will occur at Week 56. Subjects will be maintained on their 
currently prescribed maintenance therapies, from enrolment throughout the run-in and 
treatment period.
Final follow-up visit will be conducted at Week 60. 
See CSP Section 4, Tables 2 and 3 for a detailed list of visits and assessments.
1.3
Number of subjects
The study will recruit subjects with blood eosinophil counts ≥220/μL and <220/μL at a ratio of 
approximately 2:1 and the study is powered for the primary efficacy analysis of the subjects 
with baseline blood eosinophils ≥220/μL. For the primary endpoint annual COPD 
exacerbation rate, 348 subjects with baseline blood eosinophil counts ≥220/μL per treatment 
arm (1392 total) will need to be randomised to achieve 90% power of detecting a 30% 
reduction in both the 30mg and 100mg benralizumab dose groups versus placebo after 
multiplicity adjustment. This calculation has assumed 2-sided 4% alpha level test, an annual 
placebo rate of 0.93 events/subject (1.0 events/subject/56 weeks), and a negative binomial 
shape parameter of 0.4. The sample size calculation is based on simulations and has 
accounted for the power loss from a proposed futility analysis. According to the
approximately 2:1 ratio, the study will also enrol 174 subjects/arm (696 total) with baseline 
blood eosinophil counts <220/μL. An additional 20 subjects/arm will also be recruited to the 
220-299/μL cohort to better characterize patients within this cohort. This addition results in 
an overall 368 subjects/arm in the ≥220/μL cohort (1472 total). Therefore, a total of 2168 
subjects are expected to be randomised in the study.
A futility analysis based on the primary endpoint will be conducted in this study. The futility 
analysis will be carried out using pre-defined rules by an external Independent Data 
Monitoring Committee (IDMC) in order to ensure the integrity of the blinded nature of the 
study.  An IDMC charter and analysis plan will be created to detail the data to be reviewed, 
along with the roles and responsibilities of the IDMC members.  
The sample size necessary to achieve a stated power (90% in our case) in this study is 
calculated based on the estimate of overall exacerbation rate and shape parameter from the 
negative binomial model. In order to better estimate the overall exacerbation rate and shape 


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
18
parameter, a blinded sample size re-estimation will be conducted before the last subject with 
baseline eosinophil counts ≥220/μL is randomised. The sample size re-estimation will use 
blinded estimates of the overall exacerbation rate as well as the shape parameter from data 
pooled across all benralizumab doses and placebo for subjects with eosinophil counts ≥220/μL 
and the potential for >180 days of follow-up time, including prematurely withdrawn subjects.  
Strictly no treatment information will be used in the review. The exacerbation rate and shape 
parameter will be estimated using the maximum likelihood approach as proposed by Friede 
and Schmidli 2010.  Since this review will be performed in a blinded fashion, no adjustment 
for the type I error is needed. Additional blinded review(s) will be conducted if deemed 
necessary by the sponsor. The blinding will be strictly maintained and not be affected by the 
review(s) in any measure. Details of the sample size re-estimation is included in a separate 
blinded data review plan.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
Four patient populations are defined below: all patient analysis set, full analysis set (FAS; 
effectively the ITT population), safety analysis set, and pharmacokinetics (PK) analysis set. 
Subjects must have provided their informed consent. If no signed informed consent is 
collected (major protocol deviation), then the subject will be excluded from all analysis sets 
defined below.  
2.1.1
All patients analysis set
This analysis set comprises all subjects screened for the study and will be used for reporting of 
disposition and screening failures.
2.1.2
Full analysis set
All subjects randomised and who received at least 1 dose of investigational product will be 
included in the full analysis set, irrespective of their protocol adherence and continued 
participation in the study. Subjects will be analysed according to their randomised treatment, 
irrespective of whether or not they have prematurely discontinued, according to the ITT 
principle. Subjects 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 analyses will be performed using an ITT approach based on the FAS. For 
consistency, demographic and baseline characteristics will be presented using the FAS.
2.1.3
Safety analysis set
All subjects who received at least 1 dose of investigational product will be included in the 
safety analysis set. Subjects will be classified according to the treatment they actually 
received. A subject who has on one or several occasions received active treatment will be 
classified as active. If a subject has incorrectly received more than one active dose, then the 


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
19
subject will be classified as the highest active dose.  All safety summaries and anti-drug 
antibodies (ADA) analyses will be based on this analysis set.
2.1.4
Pharmacokinetic analysis set
All subjects 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 one quantifiable 
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
Subjects who do not meet eligibility criteria but are still randomised will be analysed 
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 protocol deviations are a subset of protocol deviations that may significantly impact
the completeness, accuracy, and/or reliability of the study data or that may significantly affect 
a subject’s rights, safety, or well-being.
The final list of important protocol deviations will be documented prior to unblinding the 
study data, and will include but is not limited to:
!
Eligibility criteria not met (patients incorrectly randomised) – deviations from 
inclusion criteria
!
Eligibility criteria not met (patients incorrectly randomised) – deviations from 
exclusion criteria
!
Deviations from IP discontinuation procedures
!
Received prohibited/restricted concomitant medication
!
Deviations from requirements on background double/triple COPD therapy
!
Deviations from visit schedule and study procedures
!
IP management and treatment unblinding
!
Other (such deviations will be clearly described in the CSR) 
Only important protocol deviations will be summarised and listed in the CSR. Important 
protocol deviations will be reviewed and documented by the medical advisors and statisticians 
prior to unblinding. Additional details are provided in Appendix 8.4.


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
20
Subjects 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 subjects will be identified as part of the protocol 
deviation review process prior to database lock.
2.2.2
Visit window definitions
For the exacerbation-related analyses, no windows will be applied. For local laboratory and 
all vital signs, the visit recorded in web based data capture (WBDC) will be used. For 
endpoints that present visit-based data, the variables will be summarised 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. 
Visit windows have been constructed so that every observation collected can be allocated to a 
particular visit. No visit windows will be defined for screening visits.
The general adjusted analysis-defined visit windows for assessments are summarised in Table 
1.
Table 1 General analysis-defined visit windows for assessments
Analysis-Defined Windows Visit 
Scheduled Study Day
Maximum Windows
Week 0 Day 1 
1 
Study Day=1 
Week X 
X*7+1=a 
2≤ Study Days≤ ((b-a)/2+a)-1 
Week Y 
Y*7+1=b 
((b-a)/2+a) ≤Study Days≤((c-b)/2+b)-1 
Week Z (Follow-up)
Z*7+1=c 
((c-b)/2+b) ≤Study Days 
Study day will be defined as follows:
(Date of assessment – date of randomization) +1
For each analysis parameter, the windowing will be based on the protocol-specified schedule 
of events as defined in Section 4 of the protocol.
If multiple readings 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. 


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
21
For patient reported outcomes collected twice daily (i.e., rescue medication use), if 2
observations are collected on the same day during the same period (i.e., AM or PM) then the 
non-missing observation with the earlier collection time during the period will be included in 
the analysis.
If a visit window does not contain any observations, then the data will remain missing. 
For endpoints which are not collected every 4 weeks, such as EQ-5D-5L which is assessed 
every week, the above rules will be applied to derive adjusted analysis defined visit windows 
based on the protocol-defined visit schedule for that endpoint.
For pre-bronchodilator FEV1 (L), 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-bronchodilator FEV1 assessed in the subset of subjects, the highest value 
with acceptable quality from the same date as the pre-bronchodilator FEV1 result will be used.
For the patient-report questionnaires collected by electronic patient reported outcomes 
(ePRO), the following rules will be applied:
Data for all ePRO assessments will be analysed up to the study completion or study 
discontinuation date. In the event that data is captured in the ePRO device after the patient has 
withdrawn consent, all results collected on or after the evening of the date of consent 
withdrawal will be excluded from analysis.
For daily diary assessments, biweekly means will be calculated using daily diary entries 
between the scheduled study days contained in Table 2. For daily assessments of rescue 
medication use, the daytime measurement is captured in the evening and the night-time 
measurement is captured in the following morning. Therefore, the total rescue medication use 
span across 2 calendar days. Night-time awakenings are also captured the following morning. 
All the measurements from the daily metrics must fall within specified AM/PM windows. 
Any observation recorded after the morning of Study Day 393 will not be included in the 
analysis but will be listed.
Table 2 Biweekly windows for daily diary assessments
Adjusted defined 
windows visit
Scheduled 
study day
Maximum windows
Baseline
1
The last 14 days from evening of Study Day -14 to the 
morning of Study Day 1
Week 2
15
Evening of Study Day 1 to the morning of Study Day 15
Week 4
29
Evening of Study Day 15 to the morning of Study Day 29
Week 6
43
Evening of Study Day 29 to the morning of Study Day 43
Week 8
57
Evening of Study Day 43 to the morning of Study Day 57
Week 10
71
Evening of Study Day 57 to the morning of Study Day 71


Statistical Analysis Plan 
Study Code D3251C00004
Edition Number 4.0
Date 11 May 2018
22
Table 2 Biweekly windows for daily diary assessments
Adjusted defined 
windows visit
Scheduled 
study day
Maximum windows
Week 12
85
Evening of Study Day 71 to the morning of Study Day 85
Week 14
99
Evening of Study Day 85 to the morning of Study Day 99
Week 16
113
Evening of Study Day 99 to the morning of Study Day 113
Week 18
127
Evening of Study Day 113 to the morning of Study Day 127
Week 20
141
Evening of Study Day 127 to the morning of Study Day 141
Week 22
155
Evening of Study Day 141 to the morning of Study Day 155
Week 24
169
Evening of Study Day 155 to the morning of Study Day 169
Week 26
183
Evening of Study Day 169 to the morning of Study Day 183
Week 28
197
Evening of Study Day 183 to the morning of Study Day 197
Week 30
211
Evening of Study Day 197 to the morning of Study Day 211
Week 32
225
Evening of Study Day 211 to the morning of Study Day 225
Week 34
239
Evening of Study Day 225 to the morning of Study Day 239
Week 36
253
Evening of Study Day 239 to the morning of Study Day 253
Week 38
267
Evening of Study Day 253 to the morning of Study Day 267
Week 40
281
Evening of Study Day 267 to the morning of Study Day 281
Week 42
295
Evening of Study Day 281 to the morning of Study Day 295
Week 44
309
Evening of Study Day 295 to the morning of Study Day 309
Week 46
323
Evening of Study Day 309 to the morning of Study Day 323
Week 48
337
Evening of Study Day 323 to the morning of Study Day 337
Week 50
351
Evening of Study Day 337 to the morning of Study Day 351
Week 52
365
Evening of Study Day 351 to the morning of Study Day 365
Week 54
379
Evening of Study Day 365 to the morning of Study Day 379
Week 56
393
Evening of Study Day 379 to the morning of Study Day 393
For overall analyses not based on any particular study visit, all data will be listed and/or 
analysed, including any repeat or unscheduled visits, unless otherwise specified. For safety 
endpoints, all post-baseline results will be included in the overall analysis up to and including 
the follow-up visit. For efficacy endpoints, the post-baseline treatment period will be included 
up to and including the end of treatment (EOT) visit (Visit 19, Week 56).
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 


Statistical Analysis Plan 
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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 
collected post first dose will be used in determining the baseline value, unless otherwise 
specified.
For baseline respiratory and cardiovascular disease characteristics, the latest screening 
assessment will be used.
For pre-bronchodilator FEV1 (L), 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 first dose of 
study treatment will be used as baseline measurement for spirometry parameters.
Baseline EQ-5D-5L will be the Visit 4 assessment if available; Visit 3 assessment if Visit 4 
assessment is missing; or set to missing if both Visit 3 and Visit 4 assessments are missing.
For EXACT-PRO, the baseline total score will be the mean score for each subject over the 7 
days prior to randomization.  A minimum of 4 days of data (>50%) is required for calculating 
the baseline total score.  To allow for improvement or deterioration in disease state over the 
course of the trial, the baseline total score will be reset every 4 weeks in the absence of an 
EXACT-PRO defined event.
For E-RS: COPD, data collected in the last 14 days prior to randomization will be used to 
calculate the individual E-RS: COPD total and subscale baseline means. If more than 7 daily 
measures/scores (>50%) are missing, then baseline is set to missing.
For rescue medication use and nights with awakenings due to respiratory symptoms, baseline 
is defined as the mean from the last 14 days prior to the date of randomisation and will be 
derived from data collected on the evening of Study Day -14 to the morning of Study Day 1.
The biweekly mean is calculated as the sum of all non-missing daily measures/scores over 14 
sequential days divided by the number of non-missing daily measures/scores. If more than 7 
daily measures/scores (>50%) within the baseline period are missing, then baseline is set to 
missing. 
For summaries of 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. 
For ECG, the last non-missing measurement at Week -1 (Visit 3) will be the baseline value.
For all data summaries and analyses by baseline blood eosinophil count strata (<220/μL vs. 
≥220/μL), baseline blood eosinophil count category (<150/μL, 150-219/μL, 220-299/ μL, 300-
399/μL, ≥400/μL), baseline blood eosinophil count cumulative categories (<150/μL, ≥150/μL, 
<220/μL, ≥220/μL, <300/μL, ≥300/μL, <400/μL, ≥400/μL) or continuous baseline blood 
eosinophil count (i.e., modeling activities), the blood eosinophil count result from the central 


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Date 11 May 2018
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laboratory will be used. If no data is available, then the stratum recorded in the IVRS system 
will be used to classify subjects into baseline blood eosinophil count strata (<220/μL vs. 
≥220/μL), while for patients in the ≥220/μL stratum, the IVRS data will be used to further 
classify subjects (220-299/μL vs. ≥300/μL) for inferential analyses where this is included as a 
covariate in the model. The other baseline blood eosinophil count categories will be set to 
missing.
2.2.4
Prior/concomitant medications
Background COPD medication (i.e., double/triple therapy) will be classified as a ‘COPD 
medication at baseline’ if it started on or prior to randomization and was ongoing after 
randomization.
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.
PRIMARY AND SECONDARY VARIABLES
3.1
Primary outcome variable 
The annual COPD exacerbation rate will be used as the primary efficacy variable.  A COPD 
exacerbation will be defined as a change in the subject’s baseline COPD symptoms that lasts 2 
or more days, is beyond normal day-to-day variation, is acute in onset and may warrant a 
change in regular medication, and leads to any of the following:
!
Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of 
corticosteroids will be considered equivalent to a 3-day course of systemic 
corticosteroids 
!
Use of antibiotics
!
An inpatient hospitalization or death due to COPD
Exacerbations will be considered moderate if they require treatment with systemic steroids 
and/or antibiotics, and do not result in hospitalization or death. Exacerbations will be 
considered severe if they result in hospitalization or death.
In order to calculate the number of exacerbations experienced by a patient during the 56-week 
treatment period, the following rule will be applied:
The start of an exacerbation is defined as the start date of systemic corticosteroids or 
antibiotic treatment or hospital admission, whichever occurs earlier, and the end date is 


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defined as the last day of systemic corticosteroids or antibiotic treatment or hospital 
discharge, whichever occurs later.  The last date of depot corticosteroid injection will be 
calculated as the day of injection plus 2 days.
In the event of partial or missing start or stop dates recorded in the eCRF for systemic 
corticosteroids, antibiotic treatment, or hospital admission, the partial or missing start or stop 
dates will be imputed based on the overall exacerbation start and end dates as specified above.
In the primary analysis, the number of exacerbations observed for a patient during the 56-
week double-blind treatment period will be used as the response variable.
A COPD exacerbation that occurs ≤7 days of the last dose of systemic steroids (oral, 
intramuscular (IM), intravenous (IV)), last dose of antibiotics or hospital discharge will be 
counted as the same exacerbation event.  Inpatient hospitalization due to COPD occurring 
during an exacerbation should not be regarded as a new exacerbation. In order to be counted 
as a new exacerbation it must be preceded by at least 7 days in which none of the exacerbation 
criterion is fulfilled.
Maximum follow-up time for calculation of the annual exacerbation rate is approximately 56 
weeks, defined as the time from randomization up to and including the date of Visit 19 (EOT 
visit at Week 56). For patients who discontinue study treatment and remain in the study after 
the IPD visit, exacerbations will be counted from the time of randomization up to and 
including the date of Visit 19 (Week 56). For a patient lost to follow-up before Visit 19 (Week 
56), the follow-up time will be defined as the time from randomization to the time point after 
which an exacerbation could not be assessed. Exacerbations that start after Visit 19 (Week 56) 
will not be included in the efficacy assessments but will be listed. If a subject misses Visit 19 
(Week 56), then any exacerbations that start after the scheduled Visit 19 (Week 56) date (i.e.,
Study Day 393) will be excluded from efficacy assessments. If an exacerbation is ongoing at 
Visit 19 (Week 56), the exacerbation will be counted in the calculation of annual exacerbation 
rate, however the maximum follow-up time will be truncated at the date of Visit 19 (Week 
56), as will the duration of the exacerbation.
For the production of summary statistics, the annual exacerbation rate in each treatment group 
will be calculated using the time-based approach below: 
Annual Exacerbation Rate =365.25*Total Number of Exacerbations / Total duration of 
follow-up within the treatment group (days)
The on-treatment annual exacerbation rate will be calculated similarly, as a sensitivity 
analysis, using only exacerbations and follow-up occurring during the on-treatment period as 
defined in Section 3.4.1.
An additional sensitivity analysis will be performed to evaluate the impact of out-of-window 
EOT visits on the annual exacerbation rate. For this analysis, the exacerbation follow up 
period will be truncated at Day 406 (according to the analysis visit windowing described in 


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Section 2.2.2 for the EOT visit at Week 56). Exacerbations recorded with start date after Day 
406 will be excluded from this sensitivity analysis.
3.2
Secondary efficacy outcome variables
3.2.1
Time to first COPD exacerbation (days)
Time from randomization to the first COPD exacerbation will be used as a supportive variable 
to the primary outcome variable, and is calculated as follows:
Start Date of first COPD exacerbation −Date of Randomization +1.
An exacerbation event will be defined in the same way as outlined in Section 3.1.  The time to 
first COPD exacerbation for patients who do not experience a COPD exacerbation during the
treatment period will be censored at the date of their last visit for the 56-week double-blind 
treatment period, and for lost-to-follow-up patients, at the time point after which an 
exacerbation could not be assessed or at 56 weeks, whichever occurs first.
Time to first COPD exacerbation associated with a hospitalization or ER visit will be derived 
using the same approach.
3.2.2
Proportion of patients with ≥1 COPD exacerbation during 56 weeks of 
treatment
The proportion of patients with ≥1 COPD exacerbation during the 56 weeks of treatment will 
also be a supportive variable to the primary outcome variable.
An exacerbation event will be defined in the same way as outlined in Section 3.1.  In the 
statistical analysis, a binary variable taking on the value 1 if a patient has experienced 1 or 
more exacerbations during the 56-week double-blind treatment period and 0 otherwise, will be 
used as response variable.
3.2.3
Annual rate of COPD exacerbations that are associated with an emergency 
room visit or a hospitalization
The annual rate of COPD exacerbations that are associated with an emergency room (ER) 
visit or a hospitalization will be a secondary efficacy variable, based on data recorded in the 
eCRF.  
The number of COPD exacerbations associated with a hospitalization or ER visit experienced 
by a patient during the 56-week treatment period and maximum follow-up time used in the 
calculation of this annual exacerbation rate will be derived according to the rule for the 
primary outcome variable in Section 3.1.
3.2.4
FEV1 (L) pre-bronchodilator measured at the study center
FEV1 (L) pre-bronchodilator is a key secondary efficacy endpoint of this study.  


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The change from baseline to each of the post-randomization visits (post Week 0, Visit 4) up to 
and including the end of the 56-week double-blind treatment visit (Week 56, Visit 19) will be 
used as the key secondary efficacy variable. Details regarding the definition of baseline for 
FEV1 pre-bronchodilator is provided in Section 2.2.3.
3.2.5
Healthcare resource utilization due to COPD
COPD related healthcare utilization information will be collected by the 
Investigator/authorized delegate at each visit as specified in the protocol and recorded in the 
appropriate eCRF module.  
The number of days/times the following resources were utilized and corresponding annual 
rates will be presented for each subject:
!
Ambulance transport
!
Hospitalization, intensive care (days in intensive care)
!
Hospitalization, general care (days in general care)
!
Emergency room visit
!
Visit to specialist
!
Visit to primary health care physician
!
Other health care visit
!
Home visit, physician
!
Home visit, other health care
!
Telephone call to physician
!
Telephone call to nurse
!
Telephone contact with other physician/health care provider
If multiple healthcare encounters are associated with 1 COPD exacerbation all the encounters 
will be counted for this endpoint.
3.3
Patient reported outcome variables 
COPD patient reported outcomes (PROs) are captured during site visits or using an electronic 
patient diary (i.e., ePRO). PROs at site visits include SGRQ, CAT, BDI/TDI, and PGIC. 
ePROs include EXACT-PRO, E-RS: COPD, daily diary metrics (rescue medication use and 


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night-time awakenings), and EQ-5D-5L. Daily diary metrics will be recorded each day from 
the evening of Visit 2 to the morning of Visit 19.
The EQ-5D-5L will be completed weekly (7±2 days) starting from Week 0 (Visit 4) 
throughout Week 56 (Visit 19).
Baseline is defined as the last non-missing value before randomization for the COPD PROs 
and as the average of the last 14 days before randomization for the daily metrics, as defined in 
Section 2.2.3. Post-randomization periods for the daily metrics will be defined for the 
calculation of biweekly means using the analysis-defined visit windows described in Section 
2.2.2 and listed in Table 2. 
The post-randomization biweekly means for daily metrics are calculated as the sum of all non-
missing daily measures/scores over the 14 day window divided by the number of non-missing 
daily measures/scores. If more than 7 daily measures/scores (>50%) within that window are 
missing, then the mean daily measure/score for that period is set to missing. The change from 
baseline to each post-randomization period will be used as secondary efficacy variables. No 
imputations will be made for missing values in the endpoint derivation although a multiple 
imputation sensitivity analysis is planned for SGRQ total score (see Section 4.2.6.4).
3.3.1
St. George’s Respiratory Questionnaire (SGRQ)
The change from baseline in SGRQ is a key secondary efficacy endpoint of this study.
The 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; and 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 three 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 symptoms domain score will be set to missing if there are >2 missing items; activity 
domain score will be set to missing if there are >4 missing items; impacts domain score will 
be set to missing if there are >6 missing items; and total score will be set to missing if one of 
the 3 domain scores is missing.
Potential health status treatment benefits of benralizumab will be evaluated by comparing the 
change from baseline at Week 56 in SGRQ total score. A 4-point threshold will be used to 
define the response. If SGRQ total score at Week 56 has a ≥4-point decrease from baseline, it 
is defined as “improvement”; if it has a ≥4-point increase, it is defined as “worsening”. If the 
SGRQ total score change at Week 56 is not more than 4-points, it will be defined as “no 


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change”. Missing SGRQ total score change at Week 56 will be considered as “not evaluable”.
For the responder analysis of SGRQ, a responder will be defined as an individual who had 
“improvement” at Week 56 (ie, ≥4-point decrease in SGRQ total score at Week 56). Patients 
who had SGRQ total score change defined as “no change” or “worsening” will be considered 
as non-responders. If SGRQ total score change at Week 56 is not evaluable due to missing 
data, then the patient will also be treated as non-responder.
3.3.2
COPD Assessment Test (CAT)
The CAT is an 8-item PRO developed to measure the impact of COPD on health status (Jones 
et al. 2009).  The instrument uses semantic differential six-point response scales, which are 
defined by contrasting objectives to capture the impact of COPD. Content includes items 
related to cough, phlegm, chest tightness, breathlessness going up hills/stairs, activity 
limitation at home, confidence leaving home, sleep and energy. The CAT total score is the 
sum of all item responses. Scores range from 0-40 with higher scores indicative of greater 
COPD impact on health status. A score cannot be calculated if >2 responses are missing; 
when one or two items are missing, their scores can be set to the average of the non-missing 
item scores.
3.3.3
Baseline/Transitional Dyspnea Index (BDI/TDI)
The BDI/TDI is an instrument developed to provide a multidimensional measure of dyspnea 
in relation to activities of daily living (Mahler et al. 1984). The Baseline Dyspnea Index 
(BDI) provides a measure of dyspnea at a single state, the baseline, and the Transitional 
Dyspnea Index (TDI) evaluates changes in dyspnea from the baseline state. The instrument 
consists of three components: functional impairment, magnitude of task, and magnitude of 
effort. For the BDI, each of these three components are rated in five grades from 0 (severe) to 
4 (unimpaired), and are summed to form a baseline focal (total) score from 0 to 12.  The BDI 
will be captured at Week -4 and Week 0 only.  For the TDI, changes in dyspnea are rated for 
each component by seven grades from -3 (major deterioration) to +3 (major improvement), 
and are added to form a focal (total) TDI score from -9 to +9. Positive scores indicate an 
improvement, and a change from the BDI or a difference between treatments of 1 point has 
been estimated to constitute the minimum clinically important difference (MCID) (Mahler et 
al. 2005).
A TDI responder will be defined as a patient who had a change from the BDI of at least one
positive point at Week 56. For a patient who had a change of less than one positive point or 
non-evaluable change due to missing measurement at Week 56, the patient will be considered 
as a non-responder.
3.3.4
Exacerbations of Chronic Pulmonary Disease Tool – Patient-reported 
Outcome (EXACT-PRO)
The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity 
and duration of COPD exacerbations (Jones et al. 2011, Leidy et al. 2011).  The instrument 
was developed for daily, at home, administration using a handheld electronic device. 
Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to 


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bedtime and to answer the questions while considering their experiences “today”. The daily 
EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater 
severity. Total score changes are used to identify the onset and recovery from an EXACT-
PRO defined exacerbation event. In identifying event onset and recovery, the EXACT-PRO 
can provide information on event frequency and duration as well as event severity.
The number, average duration, and severity of EXACT-PRO defined events will be evaluated.  
EXACT-PRO daily total scores will be calculated according to the developer approved 
scoring algorithm.  The total score will be used to identify event onset and recovery as well as 
the magnitude (severity) of the event.  The baseline total score will be the mean score within 
subject over the 7 days prior to randomization.  A minimum of 4 days of data is required for 
calculating the baseline total score.  To allow for improvement or deterioration in disease state 
over the course of the trial, the baseline total score will be reset every 4 weeks in the absence 
of an EXACT-PRO defined event.  Event frequency is calculated by comparing the baseline 
with daily total scores.  An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 
days indicate an event has occurred.  Calculating event duration requires identification of the 
following five parameters: 1) onset; 2) three-day rolling average; 3) maximum observed 
value; 4) threshold for improvement; and 5) recovery.  The severity of an event is indicated by 
the worst (highest) EXACT-PRO total score during an event.  Complete details concerning 
variable calculation are provided in the scoring manual (Evidera, Inc. 2013).
For the production of summary statistics, the annual EXACT-PRO defined exacerbation rate 
in each treatment group will be calculated using the same time-based approach as specified in 
Section 3.1.
3.3.5
Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease 
(E-RS: COPD)
The E-RS: COPD is an 11-item PRO developed to evaluate the severity of respiratory 
symptoms of COPD (Sexton et al. 2010, Sexton et al. 2011). The E-RS: COPD is a subset of 
items from the EXACT-PRO. The E-RS: COPD was designed to be captured as part of the 
daily EXACT-PRO assessment. Summation of E-RS: COPD item responses produces a total 
score ranging from 0 to 40, with higher scores indicating greater severity. In addition to the 
total score, symptom domain scores can be calculated for breathlessness (5 items; score range: 
0–17), cough and sputum (3 items; score range: 0–11) and chest symptoms (3 items; score 
range: 0–12) by summing the responses of items within a respective domain. As with the total 
score, higher domain scores indicate greater severity.
Individual daily E-RS: COPD total and subscale scores will be calculated and summarised as 
a biweekly (14 day) mean. 
The biweekly mean is calculated as the sum of all non-missing daily measures/scores over 14 
sequential days divided by the number of non-missing daily measures/scores. If more than 7 
daily measures/scores (>50%) within that period are missing, then the mean daily 
measure/score for that period is set to missing.


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3.3.6
Total rescue medication use 
The number of rescue medication inhalations and nebulizer treatments taken will be recorded 
by the patient in the eDiary twice daily.  Daytime use is recorded in the evening, and night-
time use is recorded in the morning of the next calendar day. Total rescue medication use is 
the sum of daytime and night-time use. If either daytime or night-time use is missing, then 
total rescue medication use for that day is set to missing. 
Rescue medication usage will be summarised as the number of puffs with one instance of 
nebulizer use converted to 2 puffs. Inhaler usage will be reported as the number of puffs in a 
given period whereas nebulizer use will be reported as the number of times. The number of 
rescue medication inhalations and nebulizer treatments captured in the eDiary each day will be 
calculated per patient.
Total rescue medication use (inhaler and/or nebulizer), defined as the number of puffs per day 
will be calculated as follows:
Number of daytime inhaler puffs (recorded in the evening) +2 x [number of daytime nebulizer 
times (recorded in the evening)] + number of night-time inhaler puffs (recorded the next 
morning) +2 x [number of night-time nebulizer times (recorded the next morning)]
Total reliever inhaler puffs per day will be calculated as:
Number of daytime inhaler puffs (recorded in the evening) + number of night-time inhaler 
puffs (recorded the next morning)
Total nebulizer use (number of times) per day will be calculated as:
Number of daytime nebulizer times (recorded in the evening) + number of night-time 
nebulizer times (recorded in the next morning)
Biweekly mean rescue medication use (average puffs/day in total use) and change from 
baseline in the biweekly mean rescue medication use will be calculated. 
3.3.7
Nights with awakening due to respiratory symptoms
Nocturnal awakenings due to respiratory symptoms will be recorded by the patient in the 
eDiary each morning by answering a question about whether he/she woke up during the night 
due to respiratory symptoms by a “yes” or “no” response. 
The biweekly proportion of nights with nocturnal awakenings due to respiratory symptoms 
with non-missing night-time awakening data, and the corresponding change from baseline for 
each post-randomization period will be calculated.
3.3.8
European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L)
The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 response options (no 


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problems, slight problems, moderate problems, severe problems, and extreme problems) that 
reflect increasing levels of difficulty.
The subject will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions. The questionnaire also includes a visual 
analogue scale, where the subject will be asked to rate current health status on a scale of 0 to 
100, with 0 being the worst imaginable health state.
The questionnaire will be completed by the patients using the ePRO device every week 
throughout the 56-week treatment period.
3.3.9
Clinician Global Impression of Change (CGIC) and Patient Global Impression 
of Change (PGIC)
Clinician Global Impression of Change (CGIC) and Patient Global Impression of Change 
(PGIC) instruments are used for an overall evaluation of response to treatment, conducted 
separately by the Investigator and by the patient using a 7-point scale: 1=Very Much 
Improved; 2=Much Improved; 3=Minimally Improved; 4=No Change; 5=Minimally Worse; 
6=Much Worse; and 7=Very Much Worse.
The Investigator (clinician) and the patient will be asked to rate the degree of change in the 
overall COPD status compared to the randomization visit. The CGIC and PGIC assessments 
were added through a protocol amendment, therefore not all subjects in the full analysis set 
will have these assessments. 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.
The questionnaire will be completed by the patients and clinicians at Weeks 16, 24, 32, and 
EOT.
Patients will also be categorized according to the following responses post-baseline, 
separately for CGIC and PGIC:
!
Very much improved, much improved, minimally improved → ‘Improved’
!
Very much improved, much improved → ‘Much improved’
!
Very much improved → ‘Very much improved’
Agreement between CGIC and PGIC will be assessed at each visit, where agreement is 
achieved when both the patient and clinician provide the same response (e.g., if both the 
patient and clinician 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.


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3.4
Safety outcome variables 
The following safety data will be collected: reported AEs (including SAEs), clinical 
chemistry, haematology, 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 time point where scheduled assessments were 
made will be calculated for relevant measurements. AEs will be summarised 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.
3.4.1
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 
periods:
!
AEs in the on-treatment period are defined as those with onset date between day of 
first dose of study treatment and the day of the scheduled end of treatment (EOT) 
visit (defined by the CSP as Week 56 +/- 7 days) for patients who complete study 
treatment. For instances where a patient does not attend EOT visit within the 
protocol defined window or prematurely discontinues IP, AEs occurring on or 
before the last dose of study medication +56 days will be assigned to the on-
treatment period, while AEs with onset date after this date will be assigned to the 
post-treatment period.
!
AEs in the on-study period are defined as those with onset date on or after the day 
of first dose of study treatment.
!
AEs in the post-treatment period are defined as those with onset date after the on-
treatment period defined above.
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.
3.4.2
Laboratory variables
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis 
parameters will be taken at the times detailed in the CSP, and will be assessed in a central 


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laboratory.  The parameters outlined in Section 5.2.6, Tables 4 and 5 of the CSP will be 
collected.  
In summaries, figures, and listings, lab results and normal ranges will be presented in System
International (SI) units. Eosinophils data will be presented in both SI and conventional units 
(cells/μL) in summaries. 
For the purposes of clinical chemistry, haematology, and urinalysis shift tables, baseline will 
be defined as the last available non-missing assessment prior to first dose of randomised
treatment, and maximum or minimum value post-baseline will be calculated over the entire 
post-baseline period, including the post-treatment period.
Changes in haematology 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 
analysed 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 categorized as negative (0), positive (+), or strongly positive (++, +++, or 
>+++) or equivalent categories as reported by the central lab.
For the liver function tests: aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (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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3.4.3
Twelve-lead electrocardiogram
Twelve-lead electrocardiogram (ECG) measurements will be recorded in accordance with the 
protocol, with the baseline visit being defined as the last available non-missing measurement 
prior to first dose of randomised treatment.
The outcome of the overall evaluation is to be recorded as normal/abnormal in the eCRF by 
the Investigator/authorized delegate, with any abnormalities being recorded as not clinically 
significant or clinically significant.
The ECG will also be transferred to a central reader.
3.4.4
Physical examination
Complete and brief physical examinations will be performed at time points specified in Tables 
2 and 3 of the CSP. Assessments will be dependent on whether the examination is complete 
or brief, as described in Section 5.2 of the CSP.  For the brief physical examination, only 
information on whether the assessment was performed or not is to be recorded.
Each component of the baseline complete physical examination will be recorded as normal or 
abnormal.  Each component of the follow-up complete physical examinations will be recorded 
as normal, same as baseline, or new/aggravated.   
Any new finding(s) or aggravated existing finding(s), judged as clinically significant by the 
Investigator, will be reported as an AE.
3.4.5
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 randomised 
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 to the reference ranges in Table 3and 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 3 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


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Table 3 Vital signs reference ranges
Parameter
Standard Units
Lower Limit
Upper Limit
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
3.5
Pharmacokinetic variables
Blood samples (processed to serum) for pharmacokinetic assessments will be collected from 
all subjects at baseline prior to first benralizumab administration at Week 0 Day 1, at Weeks 
4, 8, 16, 24, 32, 40, 48, and 56 before benralizumab administrations during the treatment 
period, and at the Week 60 follow-up visit.  Serum concentrations of benralizumab will be 
determined using a validated electrochemiluminescent (ECL) immunoassay. Results below 
the lower limit of quantification (BLQ) will be set to LLOQ/2 for analysis and will be listed as 
<LLOQ.
3.6
Immunogenicity variables
Anti-drug antibodies (ADA) variables, such as ADA responses, will be generated and 
analysed as per the details in Appendix 8.3.
4.
ANALYSIS METHODS
4.1
General principles
The analysis of the primary and secondary efficacy endpoints will include all data captured 
during the 56-week double-blind treatment period, defined as the period after administration 
of randomised investigational product at Visit 4 (Week 0) and the conclusion of Visit 19 
(Week 56), 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 each 
dosing regimen of benralizumab to placebo.  The analysis of secondary safety endpoints will 
include all data captured during the on-study period, defined as the period after first 
administration of randomised investigational product at Visit 4 (Week 0) and the conclusion 
of the scheduled post-treatment follow-up visit (Week 60), inclusive.
The data analyses will be conducted using the SAS® System (SAS Institute Inc., Cary, NC).
All SAS® programs used to generate analytical results will be developed and validated 
according to AstraZeneca SAS® programming standards and validation procedures.  
Pharmacokinetic analyses will be performed using NONMEM or other appropriate software. 


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Summary data will be presented in tabular format by treatment group. Categorical data will 
be summarised by the number and percentage of subjects in each category. Continuous 
variables for parametric data will be summarised by descriptive statistics including N, mean, 
SD, median, and range.  All clinical data will be listed.  Data listings will be sorted by 
treatment and patient number.
Following ongoing review of protocol deviations during the trial conduct, a small number of 
randomised subjects were identified as not on protocol-specified double (ICS/LABA, 
LABA/LAMA) or triple (ICS/LABA/LAMA) therapy at baseline.  As such, these subjects 
have missing values for the background therapy covariate used in the statistical analyses. In 
order to ensure all patients in the full analysis set contribute to the primary and secondary 
endpoint inferential analyses, the following imputation rules will be applied. Each of these 
patients will be documented as having an important protocol deviation and summarised as 
described in Section 2.2.1. 
!
Subjects on ICS alone will be categorized as ICS/LABA
!
Subjects on LABA alone will be categorized as LABA/LAMA
!
Subjects on LAMA alone will be categorized as LABA/LAMA
!
Subjects on ICS/LAMA alone will be categorized as ICS/LABA
All hypothesis testing will be reported using 2-sided tests. All p-values will be nominal and 
will be displayed in SAS pvalue6.4 format.
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. If baseline value is 
zero, the percent change will be set to missing. 
4.1.1
Testing strategy to account for multiplicity considerations 
Following the high-level results of study D3251C00003 (GALATHEA), the multiple-testing 
strategy outlined in Section 8.5 of the clinical study protocol was revised as outlined below.  
To account for multiplicity to test the primary outcome variable (annual COPD exacerbation 
rate) for both the benralizumab 30 mg and 100 mg dose levels compared to placebo, a fixed-
sequence testing strategy at the family-wise error rate of 0.05 will be applied. No multiple 
testing procedure will be applied to any of the secondary endpoints.  
The testing strategy will be according to the following procedure: 
Step 1: Perform the test of the primary endpoint, annual COPD exacerbation rate, for the 
benralizumab 100 mg group versus placebo at the 2-sided 5% significance level.  If the p-


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value is less than 0.05 and the treatment effect favors benralizumab, reject H0 and accept H1.  
Continue to step 2; else stop and fail to reject H0 for both benralizumab dose groups. 
Step 2: Perform the test of the primary endpoint, annual COPD exacerbation rate, for the 
benralizumab 30 mg group versus placebo at the 2-sided 5% significance level.  If the p-value 
is less than 0.05 and the treatment effect favors benralizumab, H1 is accepted for the 30 mg 
group; else fail to reject H0 for the benralizumab 30 mg group.   
4.2
Analysis methods
4.2.1
Patient disposition
Patient disposition will be summarised using the all patients analysis set and separately for 
patients in the full analysis set with baseline eosinophil count ≥220/μL and <220/μL.  The 
total number of patients will be summarised for the following groups: those who enrolled and 
those who were not randomised (and reason). The number and percentage of patients within 
each treatment group will be presented by the following categories; randomised, did not 
receive treatment with study drug, received treatment with study drug, completed treatment
with study drug, completed treatment but discontinued study, discontinued treatment with 
study drug (and reason), discontinued treatment with study drug but completed study, 
completed study, and withdrawn from study (and reason).
Screen failure information will be listed for the all patients analysis set.
The number of patient randomised by country and centre will also be summarised by 
treatment group in the full analysis set.
4.2.2
Demography data and patient characteristics
Demography data such as age, gender, race, and ethnicity will be summarised by treatment 
group for all patients in the full analysis set, and for patients in the full analysis set with 
baseline blood eosinophil counts ≥220/μL and baseline blood eosinophil counts <220/μL.
Age will be derived from the date of informed consent-date of birth, rounded down to the 
nearest integer. For patients in countries where date of birth is not recorded, the age as 
recorded in the electronic case report form (eCRF) will be used.
Medical, surgical, and cardiovascular histories (including comorbidities of arrhythmia, 
ischemic or structural cardiac disease, and systemic inflammatory and peripheral vascular 
disorder) will be summarised by MedDRA PT within MedDRA SOC in the full analysis set.
The following will also be summarised for patients in the full analysis set and repeated for 
patients with baseline blood eosinophil counts <220/μL and blood eosinophil counts ≥220/μL:
!
Patient characteristics (weight, height, BMI, baseline eosinophil count as used for 
stratification for randomization, and historic eosinophil count)


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!
Baseline lung function data (pre- and post-BD FEV1 (L), FEV1 (% PN), FVC (L), 
FVC (% PN), FEV1/FVC, and reversibility)
!
Respiratory disease characteristics
!
Nicotine use and consumption
4.2.3
Prior and concomitant medications
The number and percentage of patients taking maintenance COPD medications (double or 
triple therapy) at baseline will be summarised based on actual medication therapy group, not 
the imputed therapy group used for the statistical analysis (Section 4.1). 
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 
according to the AstraZeneca Drug Dictionary (AZDD).  The summary tables will present 
data by generic term within ATC code.  
4.2.4
Study treatment administration
Duration of investigational product administration will be calculated in days as:
Last dose date of IP-first dose date of IP+1
and will be summarised by treatment group for the safety analysis set.  
Study treatment compliance will be summarised by treatment group for the full analysis set 
and calculated as: 
Study treatment compliance = (total doses administered/total doses expected) x 100. 
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 primary efficacy variable is the annual COPD exacerbation rate and the primary analysis 
is to compare the annual COPD exacerbation rate of each benralizumab dose regimen with 
placebo in patients with baseline blood eosinophil counts ≥220/μL. Patients will be analysed
using the full analysis set according to randomised treatment.
For each of the three benralizumab dose regimens, the null hypothesis is that the exacerbation 
rate on benralizumab is equal to the exacerbation rate on placebo. The alternative hypothesis 
is that the exacerbation rate on benralizumab is not equal to the exacerbation rate on placebo, 
ie:


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H0: Rate ratio (benralizumab vs Placebo) =1
Ha: Rate ratio (benralizumab vs Placebo) ≠1
Annual exacerbation rate in each of the three benralizumab dose regimen groups will be 
compared to annual exacerbation rate in the placebo group using a negative binomial model
for the primary analysis. The response variable in the model will be the number of COPD 
exacerbations experienced by a patient, over the 56-week double-blind treatment period. The 
model will include covariates of treatment group, eosinophil cohort (220-299/μL or ≥300/μL), 
region, background therapy (ICS/LABA, LABA/LAMA, or ICS/LABA/LAMA), and the 
number of exacerbations in the previous year.  The logarithm of the patient’s corresponding 
follow-up time will be used as an offset variable in the model to adjust for patients having 
different exposure times during which the events occur.
The COPD exacerbation rate and the corresponding 95% confidence interval (CI) within each 
treatment group will be presented. The estimated treatment difference from placebo (ie, the 
absolute difference between benralizumab and placebo, and the rate ratio of benralizumab 
versus placebo), corresponding 95% CI, and 2-sided p-values for the rate ratio will be 
presented. Marginal standardization methods will be used on the model estimates for all 
negative binomial analyses, unless otherwise specified.
The above negative binomial analysis will be repeated for the following: 
!
Baseline blood eosinophil counts <220/μL. Eosinophil cohort (220-299/μL or 
≥300/μL) will not be a covariate in this model.
!
Cumulative baseline blood eosinophil count categories (<150/μL, ≥150/μL, 
<220/μL, ≥220/μL, <300/μL, ≥300/μL, <400/μL, ≥400/μL). Eosinophil cohort (220-
299/μL or ≥300/μL) will not be a covariate in this model.  Non-marginal estimates 
will be weighted by the number of patients with baseline blood eosinophil count 
≥220/μL and <220/μL to adjust for the approximately 2:1 randomization ratio in 
cumulative baseline blood eosinophil count categories. Patients with missing 
baseline blood eosinophil values from central laboratory are excluded.
!
Cumulative historical blood eosinophil count categories (<150/μL, ≥150/μL, 
<220/μL, ≥220/μL, <300/μL, ≥300/μL, <400/μL, ≥400/μL). Eosinophil cohort (220-
299/μL or ≥300/μL) will not be a covariate in this model.  
!
On-treatment exacerbations in patients with baseline blood eosinophil counts 
≥220/μL (i.e., excluding assessments after the EOT or IPD visit).
!
Exacerbations that result in hospitalization or death due to COPD in patients with 
baseline eosinophil count ≥220/μL. In the statistical model, the continuous covariate 
number of exacerbations in the previous year will be replaced by a binary covariate: 
exacerbation associated with a hospitalization in the previous year (Yes, No).


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!
Exacerbations in patients with baseline blood eosinophil counts ≥220/μL, excluding 
exacerbations outside of the EOT visit window.
!
Exacerbations in patients with baseline blood eosinophil counts ≥220/μL, using the 
data truncated at the point when subjects switched their background therapies.
!
Exacerbations by number and/or severity of exacerbations during the previous year 
in patients with baseline blood eosinophil counts ≥220/μL
!
≤2 exacerbations
!
≥3 exacerbations
!
Only severe exacerbations
!
≥1 severe exacerbation
!
≥2 severe exacerbations
!
Only moderate exacerbations
!
≥2 moderate exacerbations only
!
≥3 moderate exacerbations only
Further subgroup analyses for the COPD exacerbation rate are outlined in Section 4.2.5.2.  
Additional analyses to assess the robustness of the primary analysis results to missing data are 
outlined in Appendix 8.1. Marginal standardization methods will not be applied to missing 
data analyses.
COPD exacerbation summary statistics will be presented based on the full analysis set by 
treatment group for patients with baseline blood eosinophil counts ≥220/μL and <220/μL. 
The individual exacerbation criteria (use of systemic corticosteroids, use of antibiotics, and 
inpatient hospitalization or death due to COPD) will also be summarised descriptively.
4.2.5.2
Subgroup analysis for the primary outcome variable
To explore the uniformity of the detected overall treatment effect on the primary efficacy 
variable, subgroup analyses and statistical modelling including testing for interaction between 
treatment and covariates will be performed in patients with baseline blood eosinophil counts 
≥220/μL for the following factors: background therapy (ICS/LABA, LABA/LAMA, or 
ICS/LABA/LAMA) including imputation, baseline ICS use (Yes, No), baseline theophylline 
use (Yes, No), gender, age group categories (<65, ≥65 years), geographic region (Asia, 
Eastern Europe, Europe, North America, and rest of world), smoking status (current, former), 
BMI (≤35, >35 kg/m2 and ≤21, >21 kg/m2), the number of exacerbations during the previous 
year (≤2, ≥3 exacerbations), race (White, Asian, or Other), baseline IgE concentration 
(<150KU/L, ≥150KU/L), atopic status (Yes, No), COTE index (<4, ≥4, Divo et al. 2012), and 


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baseline GOLD classification of severity of airflow limitation in COPD (moderate, severe, 
very severe) based on GOLD 2014. 
An additional subgroup analysis using the methodology outlined above will be conducted 
using baseline blood eosinophil count categories (<150/μL, 150-219/μL, 220-299/μL, 300-
399/μL, ≥400/μL). Eosinophil cohort (220-299/μL or ≥300/μL) will not be a covariate in these 
models. Patients with missing baseline blood eosinophil values from central laboratory are 
excluded.
For each of the subgroup factors, a separate negative binomial regression model will be fitted 
using the same model terms as used for the primary analysis (described in Section 4.2.5.1, 
with additional terms for the subgroup main effect and the treatment by subgroup interaction). 
Region is not a covariate if it is the subgroup; background therapy is not a covariate if 
background therapy or baseline ICS use is the subgroup; and number of exacerbations is a not 
a covariate if it is the subgroup.
Similar outputs will be presented for each subgroup as for the primary analysis. The p-value 
for the interaction term by each treatment group will be presented in the summary tables and 
forest plots.  
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 as 
exploratory.
4.2.5.3
Supportive analysis for the primary outcome variable
As a supportive analysis, the annual exacerbation rate will be calculated based on 
exacerbations that are associated with a hospitalization or ER visit and will be analysed using 
the same method as in Section 4.2.5.1, for patients with baseline eosinophil count ≥220/μL. In 
the statistical model, the continuous covariate number of exacerbations in the previous year 
will be replaced by a binary covariate: exacerbation associated with a hospitalization in the 
previous year (Yes, No).
4.2.6
Secondary efficacy outcome variables
All secondary efficacy endpoints will be summarised separately by baseline blood eosinophil 
counts ≥220/μL and <220/μL, with formal statistical analyses conducted in the baseline blood 
eosinophil counts ≥220/μL group.
Additional formal statistical analyses in the <220/μL group will be conducted for the key 
secondary endpoints (change from baseline in FEV1 (L) pre-bronchodilator at Week 56 and 
change from baseline in SGRQ total score at Week 56), where presentation by baseline 
eosinophil count categories and cumulative baseline eosinophil count categories will also be 
conducted.


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In addition, the key secondary endpoints will be analysed pooling together data from patients 
with baseline blood eosinophil counts <220/μL from this study and study D3251C00003. The 
pooled analysis will be elaborated in a separate SAP.
4.2.6.1
Proportion of subjects with ≥1 COPD exacerbation
The proportion of subjects with ≥1 COPD exacerbation during the 56 weeks treatment period
will be addressed as a supportive variable to the primary objective for patients with baseline 
blood eosinophil counts ≥220/μL. The proportion in each of the 3 benralizumab dose regimen 
groups will be compared with the proportion in the placebo group using a Cochran–Mantel–
Haenszel test controlling for eosinophil cohort (≥220-299/μL or 300/μL), region, and 
background therapy (ICS/LABA, LABA/LAMA, or ICS/LABA/LAMA) as covariates. 
The results of the analyses will be presented using odds ratio, together with associated 95% CI 
and 2-sided p-values for each active dose regimen versus placebo.  The number and 
percentage of patients with ≥1 COPD exacerbation will also be summarised by randomised
treatment.  
4.2.6.2
Time to first COPD exacerbation
Time to first COPD exacerbation will be analysed as another supportive efficacy variable to 
the primary objective to explore the extent to which treatment with benralizumab delays the 
time to first exacerbation compared with placebo. A Cox proportional hazard model will be 
fitted to the data with the covariates of treatment, eosinophil cohort (220-299/μL or ≥300/μL), 
region, background therapy (ICS/LABA, LABA/LAMA, or ICS/LABA/LAMA), and number 
of exacerbations in the previous year. This analysis will also be repeated for the time to first 
COPD exacerbation associated with a hospitalization or ER visit where exacerbations 
associated with a hospitalization in the previous year (Yes, No) will be included as a covariate 
instead of number of exacerbations in the previous year.
Results of these analyses will be summarised as hazard ratios, 95% CI and p-values for 
patients with baseline blood eosinophil counts ≥220/μL.
Time to first COPD exacerbation will be displayed graphically using a Kaplan-Meier plot, 
separately for patients with baseline blood eosinophil counts ≥220/μL and <220/μL.
The percentage of patients who are exacerbation free at Week 26 and Week 52 will be 
estimated for each treatment group.  These percentages will be estimated using the Kaplan-
Meier technique. 
4.2.6.3
FEV1 (L) pre-bronchodilator measured at the study centre
Change from baseline in FEV1 (L) pre-bronchodilator at Week 56 in the baseline blood 
eosinophil counts ≥220/μL group is a key secondary endpoint. 
Summary statistics of the change from baseline in FEV1 (L) pre-bronchodilator at the study 
center will be produced by treatment group and visit. 


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Change from baseline in FEV1 (L) pre-bronchodilator through Week 56 will be compared 
between each of the benralizumab treatment groups and the placebo group using a mixed-
effect model for repeated measures (MMRM) analysis on patients with a baseline FEV1 (L) 
pre-bronchodilator and at least one post-baseline FEV1 (L) pre-bronchodilator assessment.   
The dependent variable will be the change from baseline in FEV1 (L) pre-bronchodilator at 
post-baseline protocol-specified visits (up to the EOT visit). Treatment group will be fitted as 
the explanatory variable, and baseline FEV1 (L) pre-bronchodilator, region, eosinophil cohort 
(220-299/μL or ≥300/μL), background therapy (ICS/LABA, LABA/LAMA, or 
ICS/LABA/LAMA), visit, and treatment*visit interaction as fixed effects. The covariance 
matrices will be assumed in the following order, unstructured, Toeplitz, first-order 
autoregressive, compound symmetric, variance components. If the procedure doesn’t 
converge, the next covariance matrix will be used in the order. The model is:
Change from baseline in FEV1 (L) pre-bronchodilator = Treatment group + baseline FEV1 (L) 
pre-bronchodilator + region + eosinophil cohort (220-299/μL or ≥300/μL) + background 
therapy (ICS/LABA, LABA/LAMA, or ICS/LABA/LAMA) + visit + treatment*visit
Results will be presented in terms of least square means (LSMEANS), treatment differences 
in LSMEANS, 95% CI and p-values.  The results at Week 56 will be of primary interest.
The above MMRM analysis will be repeated for the following: 
!
Baseline blood eosinophil counts <220/μL. Eosinophil cohort (220-299/μL or 
≥300/μL) will not be a covariate in this model. 
!
Cumulative baseline blood eosinophil count categories (<150/μL, ≥150/μL, 
<220/μL, ≥220/μL, <300/μL, ≥300/μL, <400/μL, ≥400/μL). Eosinophil cohort (220-
299/μL or ≥300/μL) will not be a covariate in this model.  Estimates will be 
weighted by the number of patients with baseline blood eosinophil count ≥220/μL 
and <220/μL to adjust for the approximately 2:1 randomization ratio in cumulative 
baseline blood eosinophil count categories.
!
On-treatment pre-bronchodilator FEV1 in patients with baseline blood eosinophil 
counts ≥220/μL (ie, excluding assessments after the EOT or IPD visit).
!
By number of exacerbations during the previous year (≤2, ≥3) in patients with 
baseline blood eosinophil counts ≥220/μL.
Additional analyses to assess the robustness of the repeated measures analysis to missing data 
are outlined in Appendix 8.1.  
A subgroup analysis, using the same MMRM model defined above with additional terms for 
the subgroup main effect and the treatment by subgroup interaction, will be conducted for the 
following factor based on the full analysis set:


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!
Baseline blood eosinophil count categories (<150/μL, 150-219/μL, 220-299/μL, 
300-399/μL, ≥400/μL). Eosinophil cohort (220-299/μL or ≥300/μL) will not be a 
covariate in this model.
4.2.6.4
St. George’s Respiratory Questionnaire (SGRQ)
Change from baseline in SGRQ total score at Week 56 in the baseline blood eosinophil counts 
≥220/μL group is a key secondary endpoint. 
Summary statistics for change from baseline in SGRQ total score and the domain scores will 
be produced by treatment group and visit.
Change from baseline in SGRQ total score and the three domain scores (symptoms, activity, 
and impacts) over 56 weeks will be analysed separately using a similar model as the above 
model for change from baseline in FEV1 (L) pre-bronchodilator, described in Section 4.2.6.3.  
Results will be presented in terms of LSMEANS, treatment differences in LSMEANS, 95% 
CI and p-values for all visits.  The results at Week 56 will be of primary interest.
The above MMRM analysis will be repeated for the following: 
!
Baseline blood eosinophil counts <220/μL. Eosinophil cohort (220-299/μL or 
≥300/μL) will not be a covariate in this model. 
!
Cumulative baseline blood eosinophil count categories (<150/μL, ≥150/μL, 
<220/μL, ≥220/μL, <300/μL, ≥300/μL, <400/μL, ≥400/μL). Eosinophil cohort (220-
299/μL or ≥300/μL) will not be a covariate in this model.  Estimates will be 
weighted by the number of patients with baseline blood eosinophil count ≥220/μL 
and <220/μL to adjust for the approximately 2:1 randomization ratio in cumulative 
baseline blood eosinophil count categories.
!
On-treatment SGRQ total score in patients with baseline blood eosinophil counts 
≥220/μL (ie, excluding assessments after the EOT or IPD visit).
Additional analyses to assess the robustness of the repeated measures analysis for SGRQ total 
score to missing data are outlined in Appendix 8.1.  
A subgroup analysis, using the same MMRM model defined above with additional terms for 
the subgroup main effect and the treatment by subgroup interaction, will be conducted for the 
following factor based on the full analysis set:
!
Baseline blood eosinophil count categories (<150/μL, 150-219/μL, 220-299/μL, 
300-399/μL, ≥400/μL).  Eosinophil cohort (220-299/μL or ≥300/μL) will not be a 
covariate in this model.
The cumulative distribution function of absolute changes from baseline in SGRQ total score at 
Week 56 will be also plotted in a figure.


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The proportion of subjects in terms of SGRQ total score response status (improvement, 
worsening, no change, and not evaluable) at Week 56 will be summarised descriptively by 
treatment group. The proportion of subjects with ≥4-point decrease (improvement) in SGRQ 
total score at Week 56 in each of the three benralizumab dose groups will be compared with 
the proportion in the placebo group using a Cochran–Mantel–Haenszel (CMH) test controlling
for eosinophil cohort (220-299 or ≥300/μL), region, and background therapy (ICS/LABA, 
LABA/LAMA, or ICS/LABA/LAMA). The results of the analyses will be presented as odds 
ratios with associated 95% CI and 2-sided p-value for each active dose regimen versus 
placebo. A similar CMH analysis will be performed using last observation carried forward 
(LOCF) for patients with non-evaluable response status at Week 56.
4.2.6.5
COPD assessment tool (CAT)
The CAT total scores and changes from baseline will be summarised by treatment and visit.
Change from baseline in CAT score through Week 56 will be analysed using a similar model 
as for the change from baseline in FEV1 (L) pre-bronchodilator described in Section 4.2.6.3.  
Results will be presented in terms of LSMEANS, treatment differences in LSMEANS, 95% 
CI and p-values for all visits.
4.2.6.6
Baseline/Transitional Dyspnea Index (BDI/TDI)
The BDI focal (total) score and component scores will be summarised by treatment group, and 
the TDI focal (total) score and component scores will be summarised by treatment group and 
visit.  
Change from baseline in TDI focal (total) score through Week 56 will be analysed using a 
similar MMRM model as for the analysis of change from baseline in FEV1 (L) pre-
bronchodilator described in Section 4.2.6.3, with BDI focal (total) score as the baseline value 
for TDI focal (total) score. Results will be presented in terms of LSMEANS, treatment 
differences in LSMEANS, 95% CI and p-values for all visits.
TDI responder (yes/no) at Week 56 will be analysed using a logistic regression model with 
covariates of treatment group, BDI score, eosinophil cohort (220-299/μL or ≥300/μL), region, 
and background therapy (ICS/LABA, LABA/LAMA, or ICS/LABA/LAMA).
4.2.6.7
Exacerbations of Chronic Pulmonary Disease Tool – Patient-reported 
Outcome (EXACT-PRO)
Summary statistics of the EXACT-PRO event frequency, duration, and severity will be 
produced by treatment group.
Annual rate of EXACT-PRO defined exacerbation will be analysed using the method 
described for the primary analysis in Section 4.2.5.1 for patients in the full analysis set with 
baseline eosinophil count ≥220/μL.


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4.2.6.8
Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease 
(E-RS: COPD)
The E-RS: COPD total scores and domain scores as well as changes from baseline will be 
summarised by treatment and visit.
Change from baseline in E-RS: COPD total score and domain scores will be analysed
separately using a similar MMRM model as for the analysis of change from baseline in FEV1 
(L) pre-bronchodilator described in Section 4.2.6.3. Results will be presented in terms of 
LSMEANS, treatment differences in LSMEANS, 95% CI and p-values for all visits.
4.2.6.9
Medication Use
Total rescue medication use
Total rescue medication use and change from baseline will be summarised by treatment and 
visit.
Change from baseline in total rescue medication use (average puffs/day) will be analysed 
using the same MMRM method for FEV1 (L) pre-bronchodilator as described in Section
4.2.6.3, for patients with baseline blood eosinophil count ≥220/μL.
Background medication use
Descriptive statistics of patients who switched their background medication will be 
summarised for the on-treatment and post-treatment periods as defined in Section 3.4.1. A 
shift table will be produced to summarise the types of therapies at baseline and at the end of 
treatment. In addition, the number of patients who switched their background medication 
during the on-treatment period will be plotted over time by treatment group for each of the 
following switches: ICS/LABA  LABA/LAMA, LABA/LAMA  ICS/LABA, ICS/LABA 
 ICS/LABA/LAMA, LABA/LAMA  ICS/LABA/LAMA, ICS/LABA/LAMA 
ICS/LABA, and ICS/LABA/LAMA  LABA/LAMA.
Glucocorticoid use
The total number of days patients were on systemic glucocorticoid due to COPD exacerbation 
during the treatment period will be summarised by treatment group.
4.2.6.10
Nights with awakening due to respiratory symptoms
The number of nights with awakening and change from baseline will be summarised by 
treatment and visit.
Change from baseline in the proportion of nights with awakening due to respiratory symptoms
will be analysed using the same MMRM method for FEV1 (L) pre-bronchodilator as described 
in Section 4.2.6.3, for patients with baseline blood eosinophil count ≥220/μL.


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4.2.6.11
Healthcare resource utilization 
The number and rate of patients with COPD specific resource utilization during the treatment 
period will be summarised by treatment group.
4.2.7
Additional modelling for primary and key secondary endpoints
Additional modelling will be performed to assess the relationship in each treatment group 
between the primary and key secondary endpoints with baseline blood eosinophil count (as a 
continuous variable) and number of exacerbations in the previous year.  The following plots 
will be produced:
!
Annual COPD exacerbation rate based on baseline blood eosinophil counts
!
Annual COPD exacerbation rate based on number of exacerbations in the previous 
year
!
Change from baseline in FEV1 (L) pre-bronchodilator at end of treatment based on 
baseline blood eosinophil counts
!
Change from baseline in SGRQ total score at end of treatment based on baseline 
blood eosinophil counts
Additional sensitivity analyses will be conducted on the primary and key secondary endpoints 
to investigate the sensitivity of the efficacy conclusions upon removal of patient data from 
sites with data anomalies. The primary assessment of benefit-risk will be based on the full 
analysis set in patients with baseline eosinophils ≥220/μL. Data anomalies may include but are 
not restricted to: sites with multiple benralizumab PK concentration level anomalies (e.g. 
patients with PK levels persistently below LLOQ or excessive PK concentrations); sites with 
high correlations in entry time of ePRO data; sites with available ePRO data post-death; or 
sites closed due to quality issues. 
4.2.8
Exploratory Objectives
4.2.8.1
European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L)
The EQ-5D-5L responses from each dimension and the visual analog scale, and changes from 
baseline, will be summarised by treatment group and visit.
Shift tables will also be produced for each dimension. 
4.2.8.2
Clinician Global Impression of Change (CGIC) and Patient Global Impression 
of Change (PGIC)
The CGIC and PGIC responses will be summarised by treatment group and visit.  The number 
and percentage of patients will be presented for CGIC, PGIC, and for agreement in CGIC and 
PGIC. 


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The number and percentage of patients defined as responders based on categorized responses 
for CGIC and PGIC (improved, much improved, very much improved) will also be presented 
by treatment group and visit.
PGIC responses will be excluded from all analyses if only caregiver or other is the respondent.
4.2.8.3
Blood eosinophils
An important marker of the biological activity of benralizumab is the reduction in eosinophils 
in the peripheral blood.  
Absolute blood eosinophil count assessed by a central laboratory as a part of safety 
haematology testing at Week -4 (Visit 1) will be used as the baseline blood eosinophil 
measure to inform primary and secondary efficacy of benralizumab. Absolute eosinophil 
counts along with their absolute changes from baseline, and percentage changes from baseline 
will be summarised by treatment group and visit using conventional units (cells/μL). Baseline 
is defined as the last non-missing value prior to the first dose of study treatment. Percent 
change from baseline in eosinophil counts will be compared between each benralizumab 
group and the placebo group using a MMRM analysis, as defined for analysis of FEV1 pre-
bronchodilator in Section 4.2.6.3. Results will be presented separately by baseline blood 
eosinophil count (<220/μL and ≥220/μL). 
A shift table will be produced for the placebo treatment group to display change from baseline 
eosinophil count (≥220/μL and <220/μL). A scatterplot comparing historical eosinophil counts 
and baseline eosinophil counts will also be produced for patients with available historical 
eosinophil data.
4.2.8.4
Serum biomarkers
Serum biomarker samples will be collected at Week 0, 4, 24 and 56.  This will be done to 
evaluate the pharmacology of benralizumab as well as biomarkers of eosinophil recruitment, 
activation, and survival, and eosinophil- and inflammation-related biomarkers of COPD. This 
will be done in order to retrospectively analyse predictive biomarkers to further understand 
patient populations responsive to benralizumab, and pharmacodynamic biomarkers to further 
evaluate the pharmacology of benralizumab.  These biomarkers will include previously 
identified pharmacodynamic markers of benralizumab, additional markers of eosinophil and 
basophil recruitment, activation and survival, as well as biomarkers of COPD and 
inflammation. 
As collection of biological samples is an integral part of this study. No separate optional 
biomarker consent form was used, and so it is expected that all patients will have samples 
available.
The results of any investigation will be reported separately in a scientific report or publication.


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4.2.8.5
Benralizumab dose response relationship
The primary and 2 key secondary endpoints will be analysed across the range of benralizumab 
doses (10mg, 30mg, and 100mg). This analysis will be performed as part of the summary of
clinical efficacy (SCE) SAP, pooling together data from patients from this study and study 
D3251C00003.
4.2.8.6
Mortality rate
The number and percentage of patients who die from any cause will be presented by treatment 
group.  Similarly, the number and percentage of respiratory related deaths will be presented by 
treatment group.
4.2.9
Safety outcome variables
All safety variables will be summarised using the safety analysis set and data presented 
according to actual treatment received. 
4.2.9.1
Adverse events (AEs) 
Adverse events (AEs) will be summarised separately for the on-treatment, on-study, and post-
treatment periods, as defined in Section 3.4.1.  All AEs will be listed for each subject. 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 investigational product 
(DAEs). This summary will also be repeated by baseline blood eosinophil count (<220/μL, 
≥220/μL) for the on-study, on-treatment, and post-treatment periods.
AEs, AEs with outcome of death, SAEs and DAEs will be summarised by System Organ 
Class (SOC) and Preferred Term (PT) assigned to the event by MedDRA. For each PT, the 
number and percentage of patients reporting at least one occurrence will be presented (ie,
multiple occurrences of an AE for a patient will only be counted once). A summary of the 
most common (frequency of ≥3%) AEs will be presented by PT. AEs and SAEs causing 
discontinuation of the study treatment and SAEs causing discontinuation from the study will 
also be summarised. Presentations for AEs and SAEs will also be repeated for baseline blood 
eosinophil count (<220/μL, ≥220/μL) for the on-study, on-treatment, and post-treatment 
periods.
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 for the on-study and on-treatment 
periods. The total period at risk for each patient will be the duration of the on-treatment and 
on-study periods as defined in Section 3.4.1.  Rates will be expressed in terms of events per 
100 patient-years.
AEs and SAEs will be summarised by preferred term and investigator’s causality assessment 
(related vs. not related) and maximum intensity.  If a patient reports multiple occurrences of 


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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) and will be 
summarised for the on-study, on treatment, and post-treatment periods. Summaries of AEs by 
investigator’s causality assessment will also be repeated for baseline blood eosinophil count 
(<220/μL, ≥220/μL) for the on-study and on-treatment periods.
Adverse events of injection site reactions (high level term of administration and injection site) 
and hypersensitivity (standardized MedDRA query of hypersensitivity) will be summarised by 
preferred term. The summary of injection site reactions will be summarised by injection site 
location and number of IP administrations.  The summary of AEs of hypersensitivity (overall 
and causally related to IP) will be repeated for baseline blood eosinophil count (<220/μL, 
≥220/μL) for the on-study, on-treatment, and post-treatment periods.
Adjudicated events (major adverse cardiac events (MACE) and malignancies) will be 
summarised by treatment group for the on-treatment and on-study periods and listed.
4.2.9.2
Laboratory data 
All protocol-specified continuous laboratory parameters will be summarised descriptively by 
absolute value at each visit by treatment group, together with the corresponding changes from 
baseline.  All parameters will be summarised in SI units, with the exception of blood 
eosinophil counts which will be summarised 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, and high 
values.  The shift tables will present baseline and maximum/minimum on-treatment 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 time points 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.  
Maximum post-baseline TBL elevations by maximum post-baseline ALT and AST will be 
presented, expressed as multiples of ULN.  TBL will be presented in multiples of the 
following ULN: ≤1.5, >1.5-2, >2. AST and ALT will be presented in multiples of the 
following ULN: ≤1, >1-3, >3-5, >5-10, >10.
Maximum post-baseline TBL will be presented (<2 and ≥2 x ULN) and plotted against 
maximum post-baseline ALT (<3, ≥3-<5, ≥5-<10, and ≥10 x ULN), expressed as multiples of 


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ULN.  This will be repeated to show maximum post-baseline TBL against maximum post-
baseline AST. 
Data for patients with ALT or AST ≥3 x ULN, and TBL≥2 x ULN 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 all patients who meet the biochemical criteria for confirmed Hy’s law, a SAE narrative 
will be produced. 
For urinalysis data, a shift table will be generated to present changes from baseline to 
maximum post-baseline value for selected parameters and will include patients with both 
baseline and post-baseline data.  
Descriptive statistics and change from baseline at each visit will be presented for IgE in kU/L 
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
ECGs
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.
In addition, the number and percentage of patients with QTcF changes from baseline will be 
presented by QTcF value >450 ms, >480 ms and >500 ms and QTcF increase of >30 ms and 
>60 ms. A shift plot showing maximum post-dose QTcF change from baseline (with reference 
lines at 30 ms and 60 ms) will be also be produced.
4.2.9.4
Physical examination
Shift tables (normal, abnormal, not done) of baseline versus last observation post-baseline 
(normal, abnormal (same as baseline), abnormal (new or aggravated), not done) will be 
generated, presenting the assessment for each component of the complete physical 
examination separately.  
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 will be generated, as applicable for each parameter and will include 
patients with both baseline and post-baseline data.


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4.2.10
Pharmacokinetic analyses
The PK analyses will be performed at or under the guidance of AstraZeneca Research and 
Development. 
Benralizumab serum concentrations will be summarised using descriptive statistics at each 
visit by treatment group, and will be listed in the CSR.  The population modeling will be 
presented in a separate pharmacometrics report.
4.2.11
Immunogenicity analyses 
Anti-drug antibody (ADA) assessments will be conducted and analysed as per the details in 
Appendix 8.3.
5.
INTERIM ANALYSES
A futility analysis for study efficacy will be performed by an Independent Data Monitoring 
Committee (IDMC).  The futility analysis will be based on the pooled data of Study 
D3251C00003 and Study D3251C00004 when approximately 15% patients in the ≥220/μL 
eosinophil stratum have completed the studies. The percentage of patients is based on the 
total number of patients expected to be recruited in the ≥220/μL eosinophil stratum of the 
studies.
In the futility analysis, a decision will be based on the comparison of the futility boundary and 
the estimated exacerbation rate reductions of benralizumab doses vs. placebo in patients with 
eosinophil counts ≥220/μL from the negative binomial model as documented for the final 
analysis in Section 4.2.5.1. Futility will be declared if the higher exacerbation rate reduction 
of benralizumab 30mg vs. placebo and benralizumab 100mg vs. placebo is less than 8%. A 
futility boundary of 8% was chosen based on the operating characteristics of ~55% chance of 
stopping the study for futility under the null hypothesis of equal exacerbation rates across all 
treatments and ~2% chance of stopping the study for futility assuming an exacerbation rate 
reduction of 30% for both benralizumab doses vs. placebo.  
Full details about the futility analysis decision rules and procedures will be specified in an 
IDMC charter and the charter will also specify the roles and responsibilities of the IDMC 
members. A firewall will be established to ensure the maintenance of the study blind for the 
sponsor, the investigational site staff and patients. The IDMC charter will also specify the 
timing of analysis and the expected extent of data available at the time of interim analysis.
Conducting a futility analysis results in power loss thus the sample size calculation in Section 
1.3 has accounted for this loss and the study has 90% of power under the powering 
assumptions and the futility boundary of 8%.


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6.
CHANGES OF ANALYSIS FROM PROTOCOL
The multiple testing strategy defined in Section 8.5 of the clinical study protocol was revised 
following the review of high level results from GALATHEA.  The original Hochberg 
(Hochberg 1988) testing strategy was defined assuming that the treatment effect in the 
benralizumab 30 and 100 mg groups compared to placebo would be similar.  Based on the 
high level results from GALATHEA, the multiple testing procedure has been revised to 
incorporate a fixed sequential testing strategy for the primary endpoint, as outlined in Section
4.1.1.
The protocol indicated that country would be among the baseline covariates adjusted for in 
formal statistical models.  Based on small sample sizes within certain countries and 
consistency with the two Phase 3 asthma exacerbation studies where convergence issues were 
encountered for some of the statistical models, the decision was made to replace the country 
covariate effect with region in all analyses where this effect is included.
Additional sensitivity analyses on the primary and key secondary endpoints were added to 
investigate the sensitivity of the efficacy conclusions upon removal of patient data from sites 
with data anomalies. 
For MMRM analysis of repeated measures, covariance matrices will be assumed in the 
following order, unstructured, Toeplitz, first-order autoregressive, compound symmetric, 
variance components. If the procedure doesn’t converge, the next covariance matrix will be 
used in the order.
Exacerbations of Chronic Pulmonary Disease Tool – Respiratory Symptoms (E-RS) was 
renamed to Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease (E-
RS: COPD) after it was qualified as an exploratory endpoint (Evidera, 2016). The score range 
for E-RS: COPD for chest symptoms is correctly portrayed in SAP as 0-12 per the E-RS 
Manual (Evidera, 2016). 
To align with actual ePRO setup, the proportion of nights with awakenings due to respiratory 
symptoms and the change from baseline will be analysed instead of number of nights with 
awakenings due to COPD and requiring rescue medication.
Adverse events will also be summarised using the on-study period (in addition to pre-planned 
on-treatment and post-treatment periods). 
7.
REFERENCES
Burman et al. 2009
Burman C.F. et al. A recycling framework for the construction of Bonferroni-based multiple 
tests. Statist. Med. 2009; 28:739–761.


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Celli et al. 2004
Celli B.R. et al.  The Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity 
Index in Chronic Obstructive Pulmonary Disease. The New England Journal of Medicine. 
350;10.
Divo et al. 2012
Divo M, Cote C et al.  Comorbidities and Risk of Mortality in Patients with Chronic 
Obstructive Pulmonary Disease.  American Journal of Respiratory and Critical Care Medicine 
Vol 186: 2012.
Dmitrienko and Tamhane 2007
Dmitrienko A, Tamhane AC. Gatekeeping procedures with clinical trial applications.
Pharmaceutical Statistics. 2007; 6:171-180.
Evidera, Inc. 2014
Evidera, Inc. The Exacerbations of Chronic Pulmonary Disease Tool (EXACT) Patient-
Reported Outcome (PRO) USER MANUAL (Version 7.0).
Evidera, Inc. 2016
Evidera, Inc. Evaluating Respiratory Symptoms (E-RS™) in COPD (E-RS™: COPD) USER 
MANUAL (Version 5.0). Bethesda, MD: Evidera; March 2016.
Friede and Schmidli 2010
Friede T, Schmidli H. Blinded Sample Size Reestimation with Negative Binomial Counts in 
Superiority and Non-inferiority Trials. Methods of Information in Medicine. 2010; 49(6): 618-
624.
GOLD 2014
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative
for Chronic Obstructive Lung Disease (GOLD) 2014. Available from:
http://www.goldcopd.org.
Hochberg 1988
Hochberg, Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988. 75; 800-2.
Jones et al. 1991
Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir 
Med. 1991; 85 Suppl B:25-31.
Jones et al. 2009
Jones PW, Harding G, Berry P, Wiklund I, Chen W-H,  Leidy NK. Development and first 
validation of the COPD Assessment Test. Eur Respir J 2009, 34: 648–654.


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Jones et al. 2011
Jones PW, Chen WH, Wilcox TK, Sethi S, Leidy NK. Characterizing and quantifying the 
symptomatic features of COPD exacerbations. Chest 2011; 139(6):1388–1394.
Leidy et al. 2011
Leidy NK, Wilcox TK, Jones PW, et al. Standardizing measurement of chronic obstructive 
pulmonary disease exacerbations. Reliability and validity of a patient-reported diary. Am J 
Respir Crit Care Med 2011; 183(3):323–329.
Mahler et al. 1984
Mahler DA, Weinberg DH, Wells CK, Feinstein AR.; The measurement of dyspnea: contents, 
inter-observer agreement, and physiologic correlates of two new clinical indexes, Chest 1984; 
85:751–758.
Mahler et al. 2005
Mahler DA, Witek Jr TJ.; The MCID of the transition dyspnea index is a total score of one 
unit., COPD, 2005; 2: 99-103.
Sexton et al. 2010
Sexton C, Notte S, Murray L, Leidy NK. PRO evidence dossier to support the use of the E-RS 
to evaluate respiratory symptoms in patients with COPD. United BioSource Corporation; 
Bethesda, MD: May 2010.
Sexton et al. 2011
Sexton C, Leidy NK, Notte SM, et al. Quantifying the severity of respiratory symptoms of 
COPD: reliability and validity of a patient diary. Poster presented at the American Thoracic 
Society International Meeting; May 2011: Denver, CO.


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8.
APPENDIX
8.1
Accounting for missing data
Accounting for missing data for recurrent events (exacerbation rate endpoint)
In this study some patients dropping out of the study potentially leads to unobserved events.  
The amount of missing data is minimized in this study as patients are allowed in the protocol 
to switch to an alternative treatment or treatments after they discontinue from randomised 
treatment and are encouraged to complete visits until they withdraw from the study.   
This section summarises 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 
randomised treatment as well as for withdrawal from the study will be presented by treatment 
to describe why patients discontinue from randomised treatment or withdraw from the study.  
The time to discontinuation of randomised treatment and withdrawal from the study will be 
presented using Kaplan Meier plots (overall and split by treatment related/not treatment 
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 (MAR) 
assumption
The primary analysis 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 
randomised 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 primary analysis uses the negative binomial regression model with 
(logarithm of) the observation period as an offset term and assumes that missing data is 
missing at random (MAR) and is a direct likelihood approach (DL). 
Sensitivity analyses 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, additional analyses will be performed using controlled multiple 
imputation method introduced in [1] and further developed at AstraZeneca [2,3] which allows 
for different underlying assumptions to be used.  As with the primary analysis the sensitivity 


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analyses includes all data until patients withdraw from the study regardless of if they 
discontinue from randomised treatment.  
For this method an underlying negative binomial stochastic process for the rate of 
exacerbations is assumed and post study withdrawal counts will be imputed conditional upon 
the observed number of events prior to the withdrawal.  This allows various assumptions 
about the missing data to be analysed by modifying the post-withdrawal model assumption.
The method involves first fitting the primary analysis ie, negative binomial regression model 
to the observed data and then imputing post-withdrawal counts by sampling from the 
conditional negative binomial probability relating post-withdrawal counts and observed prior-
withdrawal counts based on various assumptions.
(1)
Here 
is number of counts before withdrawal from the study, 
is number of counts after 
withdrawal from the study, 
is the dispersion parameter and which is assumed to be the 
same for different treatment arms, j denotes the treatment arm and i denotes the subject 
identifier. Furthermore
(2)
where 
is the negative binomial distribution (NBD) rate parameter before withdrawal from 
the study, and 
is the rate parameter after withdrawal from the study as determined based 
on various assumptions. 
The imputed number of exacerbations that would have been seen is then combined with the 
observed exacerbations and data is analysed using the primary analysis methodology (DL).  
This analysis is repeated multiple times and the results combined using Rubin’s formulae [7, 
8].
The following default assumptions that will be used to impute the missing data who withdraw 
early from the study are as follows:
a) MAR: Missing counts in each arm are imputed assuming the expected event rate within 
that arm. 
b) Dropout Reason-based Multiple Imputation (DRMI): Missing counts will be imputed 
differently depending on the reason for dropout; counts for patients in the benralizumab 
arms who dropped out for a treatment related reason are imputed based on the expected 
event rate in the placebo arm, whereas the remaining patients who have dropped out are 
imputed assuming MAR. Treatment related reasons include (1) AEs, (2) Death, (3) 
development of study specified reasons to stop active treatments, and (4) severe non-
compliance of protocol.


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Some reasons for withdrawal are clearer to determine as treatment related (Adverse Events, 
Death, Development of study-specific discontinuation criteria) or non-treatment related 
(Subject lost to follow up, eligibility criteria not fulfilled).  Other reasons are less clear such as 
severe non-compliance of protocol, subject decision and ‘Other’; a review of each patient who 
withdraws from the study will therefore be carried out prior to unblinding the study.  The 
review will include assessment of the reason for discontinuation of randomised treatment for 
those patients who discontinued randomised treatment and then withdrew from the study and 
also free text for when the reason for withdrawal or discontinuation of randomised treatment 
is subject decision or other.  Based on this review the default assumptions for DRMI as 
described in b) and Table 1 may be changed.  A list of these patients and the assumptions 
made under DRMI will be documented prior to unblinding of the study. 
A summary of reasons for patients withdrawing from the benralizumab treatment arm and the 
corresponding treatment arm used to calculate the imputation exacerbation rate under MAR 
and DRMI is given in Table 1.
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
Subject lost to follow up
Benralizumab
Benralizumab
Subject decision 
Benralizumab
Based on review prior to 
study unblinding
Other
Benralizumab
Based on review prior to 
study unblinding
Note all patients on exacerbation rate in the placebo arm are imputed using the placebo arm rate
*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, a COPD-related event requiring mechanical ventilation.
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 and c) using the 
same multiple imputation methodology.


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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.
On-Treatment Analyses (Effectiveness estimand) 
In addition primary and sensitivity analyses described previously, an alternative estimand will 
be estimated using only the on initial randomised treatment data:
!
Effectiveness estimand with assumed loss of effect post discontinuation of 
benralizumab: This will be estimated using the DRMI controlled imputation 
approaches including only data from patients whilst on treatment.
Therefore the primary analyses and sensitivity analyses will be repeated including only data 
from patients whilst being on initial randomised treatment, ie, excluding data once patients 
discontinue from randomised treatment.    
A summary of reasons for patients withdrawing from the benralizumab treatment arm and the 
corresponding treatment arm used to calculate the imputation exacerbation rate under MAR
and DRMI are given in Table 2.  As for patients who withdraw from the study, a review of 
each patient who discontinued randomised treatment will be carried out prior to unblinding the 
study where the default assumptions for DRMI as described in Table 2 may be changed.  
Again, a list of these patients and the assumptions made under DRMI will be documented 
prior to unblinding of the study.
Table 2
Reason for discontinuation of randomised
treatment
MAR
DRMI
Adverse Event
Benralizumab
Placebo
Development of study-specific 
discontinuation criteria*
Benralizumab
Placebo
Severe non-compliance to protocol
Benralizumab
Placebo
Subject lost to follow up
Benralizumab
Benralizumab
Subject decision 
Benralizumab
Based on review prior to 
study unblinding
Other
Benralizumab
Based on review prior to 
study unblinding
Note all patients on exacerbation rate in the placebo arm are imputed using the placebo arm rate


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*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, a COPD-related event requiring mechanical ventilation.
Using on treatment data is easier to interpret as it is not impacted by any subsequent pattern of 
alternative treatments once patients discontinue from randomised treatment. Sensitivity 
analyses using the effectiveness estimand under the DRMI allow for alternative assumptions 
to be made based on reasons for discontinuation. 
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.


62
Table 3
Treatment Policy Estimand
On-Treatment Analyses 
(Effectiveness estimand)
On-treatment + post-discontinuation of randomised 
treatment
On-treatment
Population
Treatment policy 
(MAR)
Treatment policy 
(MNAR)
Treatment policy 
(MNAR)
Estimand
DL
MAR
DRMI
DRMI
Exacerbation 
rate for 
imputation 
in Benra armb
No explicit 
imputationa
Benra for all 
reasons for 
withdrawal 
assumed to be 
on Benra
Placebo rate for AEs, 
Death, development of 
study specified reasons to 
stop active treatments and 
Severe non-compliance to 
protocol assumed to be 
on, otherwise Benra or 
based on review prior to 
study unblinding
Placebo rate for AEs, 
Death, development of 
study specified reasons to 
stop active treatments and 
Severe non-compliance to 
protocol assumed to be on, 
otherwise Benra or based 
on review prior to study 
unblinding
Default 
definition  
for
and
based on 
formula (2)c.
For all 
treatment arms 
j=B and P
for reasons  
above otherwise
for reasons  
above otherwise
a
Implicitly assumes unobserved rate the same as observed 
b
All patients on exacerbation rate in the placebo arm are imputed using the placebo arm rate (ie, 
)
c
Note can be over written by review prior to study unblinding
B  Benralizumab 10mg, 30mg or 100mg; P  Placebo
Forest plots will be used to show the primary analysis results along with the missing data 
sensitivity and alternative estimand analysis results.
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 we make about missing data in the different analyses will be 
considered and described in the clinical study report. 
Accounting for missing data for continuous endpoints (FEV1 and SGRQ total score)
Missing data descriptions


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In addition to the tables and figures suggested above, plots of change from baseline vs time, 
by dropout pattern (eg, completers vs non-completers, split by reason for dropout and/or split 
by last available visit) will also be produced.
Primary analysis under the Treatment Policy Estimand using the MAR assumption
As for the primary variable, the primary analysis of the FEV1 and SGRQ total score key 
secondary endpoints includes all data captured during the trial and is therefore considered to 
be under the treatment policy estimand.  The Mixed Model Repeated Measures model 
(MMRM) used is a DL approach which is valid under the MAR assumption. 
Sensitivity analysis under the Treatment Policy Estimand using MNAR assumptions
Sensitivity analyses of the repeated measures analyses will be performed for the FEV1 and 
SGRQ total score using controlled sequential multiple imputation methods based on pattern 
mixture models, as described in [5]. 
The method is analogous to the multiple imputation of exacerbation events and the imputation 
process consists of a sequence of MI steps, where each step is intended to impute missing 
values at one time-point only.  This model will assume that some pre-specified subset of 
subjects who withdraw from the study have correlations with future (unobserved) visits 
similar to subjects in the placebo arm.  As for the exacerbation events, 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 same classification as 
for the DRMI analysis of the primary endpoint) is similar to that of the placebo 
subjects, 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 subjects withdraw for a treatment related 
reason, they begin to worsen immediately. 
The MNAR imputation is achieved by only using 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). 


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For example, to impute missing values at time t for subjects in the benralizumab arms, that 
dropped out due to an AE, include only placebo observations up to and including time t, plus 
observations from subjects in the benralizumab arms, that dropped out due to an AE, up to and 
including time t-1.  This is done for each visit, one at a time using observed data, and missings 
just imputed.  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.  100 imputations will be 
carried out, and a seed of 407016 will be used for the monotone imputation step and a seed of 
766275 will be used for the sequential regression imputation step.  The analysis of each of the 
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 MIANALYSE.
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.
On-Treatment Analyses (Efficacy and Effectiveness estimands) 
Analogously to the approach for the primary endpoint, efficacy and effectiveness estimands 
will be estimated using on-treatment data and the methods described above. 
Results for continuous endpoints will be presented as per the recurrent event sensitivity 
analyses.
References
1.
Keene ON, Roger JH, Hartley BF, Kenward MG. Missing data sensitivity analysis 
for recurrent event data using controlled imputation. Pharmaceutical Statistics 2014, 
13 258–264.
2.
Wan R, Hirsch I, Gottlow M, Hollis S, Darilay A, Weissfeld L, France L. 
Controlled imputation approach for analyzing missing data in recurrent events due 
to early discontinuations. DIA/FDA Statistics Forum 2015.
3.
Gottlow M, Hollis S, Wan R, Hirsch I, Darilay A, Weissfeld L, France L. A 
Simulation study of a controlled imputation approach for analyzing missing data in 
recurrent events due to early discontinuations. PSI Annual Conference 2015.
4.
The Panel on Handling Missing Data in Clinical Trials; National Research Council. 
The Prevention and Treatment of Missing Data in Clinical Trials. National 
Academies Press, 2010.
5.
Guideline on Missing Data in Confirmatory Clinical Trials 2 July 2010 
EMA/CPMP/EWP/1776/99 Rev. 1


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6.
AZ guidance (clinical OPI): Guidance on Minimizing the Loss of Patient Data in 
AstraZeneca Clinical Trials, ed 2.0. (LDMS_001_00102309)
7.
Fleming, TR. Addressing Missing Data in Clinical Trials. Ann. Intern. Med. 
2011;154:113-117.
8.
Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models. Pharmaceutical 
Statistics 2013; 12: 337-347.
9.
Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley 
& Sons, Inc. 1987.
10.
Barnard J, Rubin DB. Small-sample degrees of freedom with multiple imputation. 
Biometrika 1999; 86:948-955.
11.
Mallinckrodt CH, Lin Q, Lipkovich I, Molenberghs G. A structured approach to 
choosing estimands and estimators in longitudinal clinical trials. Pharmaceutical 
Statistics 2012, 11:456–461. 


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8.2
Partial dates for adverse events and prior/concomitant medication 
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.


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Prior/concomitant medication
!
The missing day of start date of a therapy 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 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 study end date.
!
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 study end date then the end date will be set to 
the study end date.
∀
otherwise, the end date will be set to the start date of the therapy.


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8.3
Analysis plan for immunogenicity data
The purpose of this appendix is to provide a general reference for the analysis of anti-drug 
antibody (ADA) data in this study.  The complete set of presentations described in this 
appendix will be conducted. 
All analyses will be conducted on the safety analysis set by treatment group unless otherwise 
specified.  These analyses will also be presented for subjects with baseline blood eosinophils 
≥220/μL in the safety analysis set.  All ADA results will be listed. 
Serum samples for ADA assessments will be conducted utilising a tiered approach (screen, 
confirm, titre) and ADA data will be collected at scheduled visits shown in the CSP.  ADA 
result from each sample will be reported as either positive or negative.  If the sample is 
positive, the ADA titre will be reported as well.  In the event that an ADA sample is collected 
post-IP dose instead of pre-dose (protocol deviation), the post-dose ADA sample will be 
included in listings however will be excluded from all derivations and summaries.  In 
addition, the presence of neutralizing antibody (nAb) will be tested in all ADA-positive 
samples using a ligand-binding assay.  The nAb results will be reported as positive or 
negative. 
For each subject, the following ADA response variables will be evaluated:
!
ADA prevalence; defined as ADA positive at any visit including baseline and/or post-
baseline (also generally referred to as ADA positive)
!
ADA incidence; defined as ADA negative at baseline and ADA positive at any post-
baseline visit, or ADA positive at baseline and a boosted ADA post-baseline titre result 
(> 4-fold increase)
!
ADA positive at baseline and at least one post-baseline positive assessment
!
ADA positive post-baseline only
!
ADA positive at baseline only
!
ADA persistently positive; defined as ADA negative at baseline and at least 2 post-
baseline ADA positive measurements with at least 16 weeks (112 days) between the 
first and last positive measurement or an ADA positive result at the last available 
assessment
!
ADA transiently positive; defined as ADA negative at baseline and at least one post-
baseline ADA positive measurement and not fulfilling the conditions for persistently 
positive
!
nAb prevalence; defined as nAb positive at any visit including baseline and/or post-
baseline (also generally referred to as nAb positive)
!
nAb incidence; defined as nAb negative at baseline (or ADA negative at baseline) and 
nAb positive at any post-baseline visit. Patients who are ADA negative at baseline are 
included to ensure that all patients who are nAb positive for the first time post-baseline 
satisfy this definition, given that patients who are ADA negative at baseline would not 
have an nAb result reported
!
ADA positive with maximum titre > median of maximum titres
!
ADA positive with maximum titre ≤ median of maximum titres


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The responses above will be summarized across the on-study period, up to and including the 
post-treatment follow up visit. The proportion of subjects with the responses above will be 
summarized by treatment group. No comparisons or formal hypothesis testing will be 
conducted.
In ADA positive subjects, the ADA titre at each visit and the maximum titre across the 
different visits will be summarised by descriptive statistics [n, minimum, quartiles (Q1, 
median and Q3) and maximum].  The maximum titre will be derived based on all ADA titre
results reported up to the time point of interest for each subject.  If a titre result is reported as 
≤50 at a specific visit, then the titre for this visit will be imputed as 50 for analysis. 
In addition, descriptive statistics of the maximum ADA titre for each subject will be 
summarised in subjects who are ADA persistently positive with titre ≤median of maximum 
titres and in the subjects who are ADA persistently positive with titre > median of maximum 
titres.  The median of maximum titres will be calculated based on the maximum titre for each 
ADA positive subject within each treatment group.
A summary of ADA positive subjects who had >4 fold increase in titre from time of first post-
baseline ADA positive result, as well as subjects with >75% decrease in titre from the 
maximum titre (excluding the post-treatment follow-up assessment) will be produced for each 
treatment group.  For a titre change from positive to negative to represent a >75% decrease, 
the maximum titre must be ≥200. Patients must have two post-baseline positive ADA results.
Demographic and patient characteristics by ADA subgroups
Demographic and patient characteristics at baseline will be presented by ADA subgroups; 
ADA positive, ADA negative, ADA persistently positive, and nAb positive.
ADA results by visit
The proportion of patients with a positive ADA result and the ADA titres will be summarised 
at baseline and at all scheduled post-baseline visits by treatment group.  To classify the ADA 
responses at each visit, the ADA result reported within the derived analysis visit window will be 
included in the analyses. The analysis visit windows are defined in Section 2.2.2. In addition, the 
ADA response will be presented cumulatively. The cumulative ADA response is positive for a 
specific time point if a positive ADA result is detected at any time point up to the time point 
of interest. If a positive ADA result is not detected at all time points up to time point of 
interest, then the cumulative ADA response is negative. The first post-baseline positive ADA 
result will also be summarised by visit and treatment group.
nAb response by visit
The proportion of patients with positive nAb response will be summarised by visit.  The 
summary will be repeated for ADA persistently positive patients.


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Efficacy by ADA subgroups
The effect of ADA on the primary endpoint (annual COPD exacerbation rate) and two key 
secondary endpoints (change from baseline in pre-BD FEV1 and change from baseline in 
SGRQ total score) will be evaluated in subgroups of ADA positive, ADA negative, ADA 
persistently positive, ADA positive with maximum titre > median of maximum titres, nAb 
positive, and ADA persistently positive and nAb positive.   Due to the expected small number 
of ADA positive subjects in the placebo group, no formal statistical analysis on efficacy 
(benralizumab vs placebo) by ADA status (positive/negative) is planned.  
For annual COPD exacerbation rates, a descriptive summary by treatment group will be 
presented instead of the rate estimated from the negative binomial model.  The maximum 
follow-up time for calculation of the annual COPD exacerbation rate will be as defined in 
Section 3.1. The 95% confidence interval for the treatment group rates will be estimated 
based on the Poisson distribution.  For FEV1 and SGRQ total scores, the last non-missing 
observation on or prior to the EOT (Week 56) or IPD visit will be used to calculate arithmetic 
means by treatment group, rather than the estimated least squares means estimated from the 
mixed model for repeated measures (MMRM).
Safety by ADA subgroups
Summaries of adverse events will be presented separately for the on-treatment and on-study 
periods by the subgroups of ADA positive, ADA negative, ADA positive with titre > median of 
maximum titre and ADA persistently positive. Summaries will include adverse events (AEs), 
serious adverse events (SAEs), causally related AEs and SAEs as assessed by the investigator, and 
adverse events of hypersensitivity.
Relative risk comparisons between ADA positive versus ADA negative patients for safety
outcomes are not planned due to the low expected frequency of the potential adverse events (AE) 
related to the potential risk (at the preferred term level).
Pharmacokinetics by ADA subgroups
Benralizumab serum concentrations will be summarised by visit and by ADA status (positive,
negative) using the following descriptive statistics: n, geometric mean, geometric mean 95% 
CI, geometric mean coefficient of variation (CV), arithmetic mean, standard deviation, 
median, minimum and maximum.
Blood eosinophils by ADA subgroups
Blood eosinophil levels will be summarised by visit and by subgroups of ADA positive, ADA 
negative, ADA positive with titre > median of maximum titres, ADA persistently positive, 
nAb positive, and both ADA persistently positive and nAb positive using the following 
descriptive statistics: n, mean, standard deviation, median, minimum and maximum. 


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8.4
Important protocol deviations
As specified in Section 2.2.1, important protocol deviations (PDs) are a subset of protocol 
deviations that may significantly impact the completeness, accuracy, and/or reliability of the 
study data or that may significantly affect a subject’s rights, safety, or well-being. The 
following important PDs will be summarised and listed in the CSR (*indicates an important 
PD which may impact the primary efficacy endpoint):
A. Eligibility criteria not met (patients incorrectly randomised) – deviation(s) from 
inclusion criteria:
1. Provision of informed consent prior to any study specific procedures.
2. History of moderate to very severe COPD with a post-bronchodilator FEV1/FVC<0.70 
and a post-bronchodilator FEV1>20% and ≤65% of predicted normal value at 
screening (central spirometry will be used for this criteria assessment).*
3. History of 2 or more moderate COPD exacerbations that required treatment with 
systemic corticosteroids and/or antibiotics, or 1 or more severe COPD exacerbation(s) 
that required hospitalization (defined as an inpatient admission ≥24 hours in the 
hospital, in an observation area, the emergency department or other equivalent 
healthcare facility depending on the country and healthcare system) within 2 to 52 
weeks prior to enrolment. Prior use of antibiotics alone does not qualify as a moderate 
exacerbation unless the antibiotic was specifically prescribed for the treatment of 
worsening COPD symptoms.*
4. mMRC score ≥1 at Visit 1.*
5. Subjects should have evidence of having been treated with double (ICS/LABA or 
LABA/LAMA) or triple (ICS/LABA/LAMA) therapy for COPD throughout the year 
prior to enrolment (Visit 1). It is acceptable for subjects to have stepped up or stepped 
down during that period of time (from double to triple therapy and vice versa), but 
they have to be consistently treated with locally approved COPD medications and on 
approved doses for at least 2 weeks prior to enrolment (Visit 1). Subjects currently 
receiving background therapy that is not approved for COPD are not eligible for the 
study.*
6. Ability to read, write and use electronic devices.*
7. Blood eosinophils due to subject’s stratification and cap for blood eosinophil levels. 
When any eosinophil cohort (<220/μL, 220-299/μL, or ≥300/μL) is full, subjects in the 
completed cohort will not be randomised and will be withdrawn from the study (see 
CSP Section 3.7.2).*
B. Eligibility criteria not met (patients incorrectly randomised) – deviation(s) from
exclusion criteria:
1. Clinically important pulmonary disease other than COPD (e.g. active lung infection, 
clinically significant bronchiectasis, pulmonary fibrosis, cystic fibrosis, 
hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin 
deficiency and primary ciliary dyskinesia) or another diagnosed pulmonary or 
systemic disease that is associated with elevated peripheral eosinophil counts (e.g. 
allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, 


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hypereosinophilic syndrome) and/ or radiological findings suggestive of a respiratory 
disease other than COPD that is contributing to the subject’s respiratory symptoms.*
2. 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/or could:
-Affect the safety of the subject throughout the study
-Influence the findings of the study or their interpretation
-Impede the subject’s ability to complete the entire duration of study
Subjects who have epilepsy must be on a stable dose of medication for 30 days prior to 
Visit 4.*
3. Unstable ischemic heart disease, arrhythmia, cardiomyopathy, heart failure, renal 
failure, uncontrolled hypertension as defined by the Investigator, or any other relevant 
cardiovascular disorder as judged by the Investigator or any ECG abnormality 
obtained during the screening/run-in period that in Investigator’s judgement may put 
the patient at risk or negatively affect the outcome of the study.*
4. Pregnant, breastfeeding, or lactating women.
5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥1.5 times 
the upper limit of normal (ULN) confirmed by repeated testing during screening 
period.
6. Risk factors for pneumonia (including, but not limited to: immunosuppression, 
neurological disorder with increased risk of aspiration).*
7. Known history of allergy or reaction to any component of the investigational product 
formulation.
8. History of anaphylaxis to any other biologic therapy.
9. Long term oxygen therapy (LTOT) with signs and/or symptoms of cor pulmonale 
and/or right ventricular failure. Subjects receiving long term treatment with oxygen > 
4.0 liters/minute (L/min). While breathing supplemental oxygen, subjects should 
demonstrate an oxyhemoglobin saturation ≥89 %. In order to be admitted to the trial 
subjects on LTOT have to be ambulatory and be able to attend clinic visits.*
10. Use of any non-invasive positive pressure ventilation device (NIPPV). Note: Subjects 
using continuous positive airway pressure (CPAP) or bilevel positive airway pressure 
(BiPAP) for Sleep Apnea Syndrome are allowed in the study.*
11. Any clinically significant abnormal findings in physical examination, vital signs, 
haematology, clinical chemistry, or urinalysis during screening/run-in period, which, 
in the opinion of the Investigator, may put the subject at risk because of his/her 
participation in the study, or may influence the results of the study, or the subject’s 
ability to complete entire duration of the study.
12. Fever > 37.8°C (100°F) measured using the tympanic temperature (or equivalent 
oral/rectal/axillary temperature) at Visit 4.
13. Use of immunosuppressive medication, including rectal corticosteroids and systemic 
steroids within 2 weeks prior to enrolment (Visit 1) and/or during the enrolment and 
screening/run-in period.*
14. Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior 
to Visit 1.


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15. Receipt of any marketed (e.g. omalizumab) or any other monoclonal or polyclonal 
antibody therapy (e.g. gamma globulin) taken for any reason within 6 months or 5 
half-lives prior to Visit 1, whichever is longer.*
16. Receipt of live attenuated vaccines 30 days prior to Visit 4.
17. Subjects are excluded if they have any of the following:
- A history of known immunodeficiency disorder including a positive test for human 
immunodeficiency virus, HIV-1 or HIV-2
- Positive hepatitis B surface antigen, or positive 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.
18. A helminth parasitic infection diagnosed within 24 weeks prior to Visit 1 that has not 
been treated with, or has failed to respond to standard of care therapy.
19. History of alcohol or drug abuse within the past year, which may compromise the 
study data interpretation as judged by Investigator or Study Physician.*
20. Malignancy, current or within the past 5 years, except for adequately treated 
noninvasive basal cell and squamous cell carcinoma of the skin and cervical 
carcinoma-in-situ treated with apparent success more than 1 year prior to Visit 1.
21. Subjects who in the opinion of the investigator or qualified designee have evidence of 
active tuberculosis (TB). Subjects with a recent (within 2 years) first-time or
newly positive purified protein derivative (PPD) test or Quantiferon test need to 
complete an appropriate course of treatment before being considered for enrolment.
Evaluation will be according to the local standard of care and may consist of history 
and physical examinations, chest x-ray, and/or TB test as determined by local 
guidelines.*
22. Subjects with lung volume reduction surgery within the 6 months prior to Visit 1.
Subjects with history of partial or total lung resection (single lobe or segmentectomy is 
acceptable).*
23. Asthma as a primary or main diagnosis according to the Global Initiative for Asthma 
(GINA) guidelines (GINA 2011) or other accepted guidelines. Subjects with a past 
medical history of asthma (e.g. childhood or adolescence) may be included.*
24. Previous treatment with benralizumab (MEDI-563).*
C. Deviations from IP discontinuation procedures:
1. Subject developed criteria for discontinuation of IP (as defined in the CSP Section 3.6) 
but continued IP treatment without consultation with AZ Study Physician.
D. Received prohibited/ restricted concomitant medication:
1. Systemic corticosteroids (tablets, suspension or injections) administered outside of 
COPD exacerbation event.*
2. Antibiotics taken for prevention of COPD exacerbation.*
3. Use of any of the following medications:*
• Roflumilast (Daxas, Daliresp) after Visit 1 and during the study.
• Any monoclonal antibody (e.g. omalizumab, denosumab) or polyclonal antibody 
(e.g. gamma globulin) within 6 months prior to Visit 1 and during the study.
• Allergen immunotherapy within 90 days prior to Visit 1 and during the study.


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• Live attenuated vaccines within 30 days prior to Visit 4, during the treatment period 
and for 16 weeks after the last dose of IP.
• Potent Cytochrome P (CYP) 3A4 inhibitors (if used for >4 weeks)
E. Deviations from requirements on background double/triple COPD therapy:
1. Patient not on double/triple COPD medications for >4 weeks during the treatment 
period (e.g. interruptions and/or step-down to mono therapy). Note: any deviations 
from Inclusion criteria #6 in regards to background therapy must be coded as deviation 
from eligibility criteria.*
F. Deviations from visit schedule and study procedures:
1. Multiple phone visits / phone follow-up visits (more than 2) missed during the 
treatment phase/ follow-up.*
2. COPD exacerbation not assessed and reported as per protocol.*
3. Central spirometry violations at Visit2/Visit4:
• assessment not performed
• unacceptable post-PD spirometry at visit 2 not consulted with Study Physicians and 
not repeated
Other important/ repeated violations in spirometry assessment (to be consulted with 
Study physicians)*
4. Central spirometry assessment not performed or other important/ repeated violations in 
spirometry assessment not followed at multiple (≥ 3) visits after randomization.*
5. Any safety assessment (ECG, physical examination, vital signs, safety lab tests) not 
performed at screening, baseline and/or at multiple (≥ 3) visits after randomization.
6. Pregnancy test not done prior to randomization and/or at ≥ 2 visits after randomization.
7. Central blood eosinophil testing not done/ results not received prior to randomization.*
8. Any other study procedures not performed or incorrectly performed at multiple (≥ 3) 
visits for the same subject.*
G. IP management and treatment blinding:
1. IP is not administered according to the protocol*
• Incorrect route of administration
• Incorrect dose 
• IP administered prior to completion of all visit procedures
2. IP administered in a presence of condition(s) contraindicating dosing.
3. Patient not observed for a minimum of 2 hours after IP administration.
4. Incorrect randomised treatment (wrong kit ID) administered.*
5. IP administered with interval between doses <3 weeks or >10 weeks.*
6. Use of expired or damaged IP kit/ syringe.*
7. Use of IP with temperature excursion without any approval from Supply Chain 
manager (not given either prior to or after IP administration to subject).*


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H. Other: Important PDs that do not fall into any above categories. Details of these 
important PDs will be described in the CSR.