A Multicenter, Open-Label, Functionality, Reliability and Performance Study of a Single-Use Auto-Injector With Home-administered Subcutaneous Benralizumab in Adult Patients With Severe Asthma (GRECO)
Phase: PHASE3
Conditions: Asthma
Sponsor: AstraZeneca

 
  
 
 
 
 
 
 
 
 
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 
 
Clinical Study Protocol  
 
Drug Substance 
Benralizumab (Medi-563) 
 
Study Code 
D3250C00031 
 
Version 
1.0 
 
Date 
23 August 2016 
 
A Multicenter, Open-label, Functionality, Reliability and Performance Study 
of a Single-use Auto-injector with Home-administered Subcutaneous 
Benralizumab in Adult Patients with Severe Asthma (GRECO) 
 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden 
 

Clinical Study Protocol 
Drug Substance Benralizumab (Medi-563)  
Study Code D3250C00031 
Version 1.0 
Date 23 August 2016 
 
 
2(83) 
VERSION HISTORY 
Version 1.0, 23 August 2016 
Initial creation 
 
 
 
 

Clinical Study Protocol 
Drug Substance Benralizumab (Medi-563)  
Study Code D3250C00031 
Version 1.0 
Date 23 August 2016 
 
 
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PROTOCOL SYNOPSIS 
 
A Multicenter, Open-label, Functionality, Reliability and Performance Study 
of a Single-use Auto-injector with Home-administered Subcutaneous 
Benralizumab in Adult Patients with Severe Asthma (GRECO) 
 
 
 
International Coordinating Investigator: 
 
 
 
  
 
 
 
Study sites(s) and number of subjects planned: 
This study will be conducted in North America in approximately 30 study centers.  
Approximately 120 patients will enter the treatment phase of the study. 
Study period 
 
Phase of development 
Estimated date of first subject enrolled 
Q4 2016 
Phase 3b 
Estimated date of last subject completed 
Q4 2017 
 
 
 
 
 
 
Redacted

Clinical Study Protocol 
Drug Substance Benralizumab (Medi-563)  
Study Code D3250C00031 
Version 1.0 
Date 23 August 2016 
 
 
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Study design 
This is a multicenter, open-label study designed to assess patient- or caregiver-reported 
functionality, performance, and reliability of a single-use auto-injector (AI) with a fixed 30 
mg dose of benralizumab administered subcutaneously (SC) in an at-home setting.   
Approximately 120 adult patients with severe asthma will enter the treatment period to receive 
5 subcutaneous doses (Week 0, Week 4, Week 8, Week 12, and Week 16) of benralizumab.  
Following a 2 week screening period, eligible patients will receive 3 SC doses of 30 mg of 
benralizumab at the study site (Week 0, Week 4, and Week 8). At Week 0, the Principal 
Investigator or his/her designee will administer the study drug. At Week 4, the patient or 
caregiver will have the option of administering the study drug under study site supervision to 
ensure they understand the procedure and are capable of doing so.  At Week 8, the patient or 
caregiver will have to perform the injection, again under site staff supervision.  Patients or 
caregivers unable or unwilling to administer investigational product (IP) at this visit will be 
discontinued from the study.  
The patient or caregiver will be given the Instructions for Use (IFU) to refer to for home 
administrations.  The final 2 doses of benralizumab (Week 12 and Week 16) will be self-
administered by the patient or administered by the caregiver at home.  After each of these 
administrations, the patient will return for a scheduled on-site visit within 48 hours. 
For the at-home administrations, whether the patient is self-administering or the caregiver is 
administering to a patient, the person administering the dose will fill out an administration 
questionnaire designed to indicate whether the device functioned correctly and the dose was 
successfully administered.  Both the completed questionnaire and the used device are to be 
returned to the site during each of the clinic visits (Visit 5 and Visit 6).  The site is to 
subsequently return the used devices and completed questionnaires to the Sponsor for 
evaluation.   
An end-of-treatment (EOT) visit will be performed at Week 20 and a follow-up visit at Week 
28 (12 weeks after last IP administration). 

Clinical Study Protocol 
Drug Substance Benralizumab (Medi-563)  
Study Code D3250C00031 
Version 1.0 
Date 23 August 2016 
 
 
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Objectives 
Primary objective 
Outcome measure 
To assess patient- or caregiver-reported 
functionality and reliability of the 
benralizumab single-use auto-injector (AI) 
in an at-home setting and performance of 
the AI device after use. 
 
x 
Proportion of patients/caregivers who 
successfully administered benralizumab 
30 mg subcutaneously (SC) by injection 
with an AI device at home 
x 
Proportion of returned AI devices used to 
administer benralizumab at home that 
have been evaluated as functional 
x 
Proportion of AI devices used to 
administer benralizumab at home or in 
the clinic and have been reported as 
malfunctioning (Product Complaints)  
 
Secondary objectives 
Outcome measure 
To monitor metrics of asthma control  
x 
Change from baseline in mean Asthma 
Control Questionnaire-6 (ACQ-6) score  
To evaluate the pharmacokinetics, 
pharmacodynamics, and immunogenicity of 
benralizumab 
x 
Pharmacokinetic parameters 
x 
Peripheral blood eosinophil levels 
x 
Anti-drug antibodies (ADA)  
 
Safety objectives 
Outcome measure 
To assess the safety and tolerability of 
benralizumab  
x 
Adverse events (AEs) and serious 
adverse events (SAEs) 
x 
Laboratory variables 
x 
Physical examination 
 

Clinical Study Protocol 
Drug Substance Benralizumab (Medi-563)  
Study Code D3250C00031 
Version 1.0 
Date 23 August 2016 
 
 
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Target subject population 
Male and female adult patients 18 to 75 years of age with severe asthma will be enrolled. 
Investigational product, dosage and mode of administration 
Benralizumab 30 mg/mL solution for injection in a single-use auto-injector (AI) will be 
administered at the study center subcutaneously every 4 weeks for 3 doses (Week 0, Week 4, 
and Week 8) and then at-home every 4 weeks for 2 doses (Week 12 and Week 16). 
Duration of treatment 
Following enrollment, the patient will enter a 2-week screening period, followed by a 20 week 
treatment period.  A follow-up visit will be conducted at Week 28. 
The total planned study duration is a maximum of 30 weeks. 
Statistical methods 
The primary endpoints are the proportion of patients/caregivers who successfully administered 
benralizumab with an AI at home, the proportion of returned AIs used to administer 
benralizumab at home that have been evaluated as functional, and the proportion of AIs used 
to administer benralizumab at home or at the clinic and have been reported as malfunctioning 
(Product Complaints). Additional variables include the proportion of patient/caregivers who 
successfully administered benralizumab with an AI at both home administrations and the 
proportion of patients/caregivers who have returned AIs used to administer benralizumab at 
home that have been evaluated as functional at both times. All these endpoints will be 
presented using descriptive statistics and exact 95% confidence interval (CI) estimates. 
The estimated sample size recruitment of 120 patients is based upon a targeted recruitment 
and successful enrollment of 100 patients plus an adjustment to account for an assumed 
patient dropout rate of approximately 17% (20 patients); therefore, no hypotheses will be 
tested statistically and the endpoints and safety results will be summarized descriptively and 
all data will be listed.

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Drug Substance Benralizumab (Medi-563)  
Study Code D3250C00031 
Edition Number 1.0 
Date 23 August 2016 
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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ............................................................................................................................ 1 
VERSION HISTORY .............................................................................................................. 2 
PROTOCOL SYNOPSIS ......................................................................................................... 3 
TABLE OF CONTENTS ......................................................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................... 11 
1. 
INTRODUCTION ................................................................................................. 13 
1.1 
Background ............................................................................................................ 13 
1.2 
Rationale for study design, doses, and control groups ........................................... 14 
1.3 
Benefit/risk and ethical assessment........................................................................ 14 
1.4 
Study design ........................................................................................................... 15 
2. 
STUDY OBJECTIVES .......................................................................................... 17 
2.1 
Primary objective ................................................................................................... 17 
2.2 
Secondary objectives ............................................................................................. 17 
2.3 
Safety objective ...................................................................................................... 17 
3. 
SUBJECT SELECTION, ENROLMENT, TREATMENT, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL ..................... 18 
3.1 
Inclusion criteria .................................................................................................... 18 
3.2 
Exclusion criteria ................................................................................................... 19 
3.3 
Subject enrolment and treatment ........................................................................... 22 
3.4 
Procedures for handling incorrectly enrolled patients ........................................... 22 
3.5 
Concomitant medications, restrictions during and after the study ......................... 23 
3.5.1 
Concomitant medication ........................................................................................ 23 
3.5.2 
Restrictions ............................................................................................................ 23 
3.6 
Discontinuation of investigational product ............................................................ 25 
3.7 
Criteria for withdrawal ........................................................................................... 26 
3.7.1 
Screen failures ........................................................................................................ 26 
3.7.2 
Withdrawal of the informed consent ...................................................................... 26 
3.7.3 
Discontinuation of the study .................................................................................. 26 
4. 
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 27 
4.1 
Enrollment and screening period ........................................................................... 30 
4.1.1 
Enrollment (Visit 1) ............................................................................................... 30 

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Study Code D3250C00031 
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4.1.2 
Re-screening .......................................................................................................... 30 
4.2 
Treatment period .................................................................................................... 30 
4.3 
Follow-up period .................................................................................................... 31 
5. 
STUDY ASSESSMENTS ..................................................................................... 31 
5.1 
Efficacy assessments .............................................................................................. 32 
5.1.1 
Spirometry .............................................................................................................. 32 
5.1.2 
Assessment of self and caregiver administration with the single-use auto-
injector ................................................................................................................... 34 
5.1.3 
Assessment of returned single-use auto-injector device through in vitro 
evaluation ............................................................................................................... 34 
5.2 
Safety assessments ................................................................................................. 34 
5.2.1 
Physical examination ............................................................................................. 34 
5.2.2 
Vital signs .............................................................................................................. 35 
5.2.3 
Electrocardiograms ................................................................................................ 35 
5.2.4 
Laboratory safety assessments ............................................................................... 35 
5.3 
Other assessments and procedures ......................................................................... 37 
5.3.1 
Weight and height .................................................................................................. 37 
5.3.2 
Patient-reported outcomes ..................................................................................... 37 
5.3.3 
Other screening assessments .................................................................................. 37 
5.3.4 
Pharmacokinetics ................................................................................................... 38 
5.3.5 
Pharmacodynamics ................................................................................................ 38 
5.3.6 
Immunogenicity ..................................................................................................... 38 
5.3.7 
Pharmacogenetics .................................................................................................. 38 
5.3.8 
Biomarker analysis ................................................................................................. 39 
5.3.9 
Handling of biological samples ............................................................................. 39 
6. 
MANAGEMENT OF INVESTIGATIONAL PRODUCT .................................... 39 
6.1 
Identity of investigational product(s) ..................................................................... 39 
6.2 
Labeling ................................................................................................................. 40 
6.3 
Storage ................................................................................................................... 40 
6.4 
Accountability ........................................................................................................ 41 
6.5 
Methods for return of used single-use auto-injector devices ................................. 41 
6.5.1 
Reporting product complaints ................................................................................ 41 
6.6 
Investigational product administration and treatment compliance ........................ 42 
6.7 
Management of investigational product-related reactions ..................................... 44 
7. 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 45 
7.1 
Definition of adverse events .................................................................................. 45 
7.2 
Definitions of serious adverse event ...................................................................... 45 
7.3 
Recording of adverse events .................................................................................. 46 

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7.3.1 
Time period for collection of adverse events ......................................................... 46 
7.3.2 
Follow-up of unresolved adverse events ................................................................ 46 
7.3.3 
Variables ................................................................................................................ 46 
7.3.4 
Causality collection ................................................................................................ 47 
7.3.5 
Adverse events based on signs and symptoms....................................................... 47 
7.3.6 
Adverse events based on examinations and tests ................................................... 48 
7.3.7 
Disease progression ............................................................................................... 48 
7.3.8 
Hy’s Law ................................................................................................................ 48 
7.4 
Reporting of serious adverse events....................................................................... 48 
7.5 
Overdose ................................................................................................................ 49 
7.6 
Pregnancy ............................................................................................................... 50 
7.6.1 
Maternal exposure .................................................................................................. 50 
7.6.2 
Paternal exposure ................................................................................................... 50 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA ............................................ 50 
8.1 
Statistical considerations ........................................................................................ 50 
8.2 
Sample size estimate .............................................................................................. 51 
8.3 
Definitions of analysis sets .................................................................................... 51 
8.3.1 
All patients analysis set .......................................................................................... 51 
8.3.2 
Full analysis set ...................................................................................................... 51 
8.3.3 
Pharmacokinetic analysis set ................................................................................. 51 
8.4 
Variables for analyses ............................................................................................ 51 
8.4.1 
Calculation or derivation of primary endpoints ..................................................... 51 
8.4.2 
Calculation or derivation of efficacy variable(s) ................................................... 52 
8.4.3 
Calculation or derivation of safety variable(s) ....................................................... 53 
8.4.4 
Calculation or derivation of pharmacokinetic variables ........................................ 53 
8.4.5 
Calculation or derivation of immunogenicity variables ......................................... 53 
8.5 
Methods for statistical analyses ............................................................................. 53 
8.5.1 
Primary and secondary analysis method(s) ............................................................ 54 
8.5.2 
Analysis methods for safety variables ................................................................... 54 
8.5.3 
Subgroup analysis .................................................................................................. 55 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA .......................... 55 
9.1 
Training of study center personnel ........................................................................ 55 
9.2 
Monitoring of the study ......................................................................................... 55 
9.2.1 
Source data ............................................................................................................. 56 
9.2.2 
Recording of data ................................................................................................... 56 
9.2.3 
Study agreements ................................................................................................... 56 
9.2.4 
Archiving of study documents ............................................................................... 56 
9.3 
Study timetable and end of study ........................................................................... 56 
9.4 
Data management by AstraZeneca ........................................................................ 57 

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Study Code D3250C00031 
Edition Number 1.0 
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10. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 57 
10.1 
Ethical conduct of the study ................................................................................... 57 
10.2 
Subject data protection ........................................................................................... 58 
10.3 
Ethics and regulatory review.................................................................................. 58 
10.4 
Informed consent ................................................................................................... 58 
10.5 
Changes to the protocol and informed consent form ............................................. 59 
10.6 
Audits and inspections ........................................................................................... 59 
11. 
LIST OF REFERENCES ....................................................................................... 61 
 
LIST OF TABLES 
Table 1 
Study Plan – Enrollment, screening period .............................................. 27 
Table 2 
Study Plan – Treatment period and follow-up.......................................... 28 
Table 3 
List of safety laboratory tests.................................................................... 36 
Table 4 
Identity of investigational product ............................................................ 39 
 
LIST OF FIGURES 
Figure 1 
Study flow chart ....................................................................................... 16 
Figure 2 
Reversibility testing algorithm ................................................................. 33 
Figure 3 
Injection sites and rotation scheme ........................................................... 44 
 
LIST OF APPENDICES 
Appendix A 
ADDITIONAL SAFETY INFORMATION ............................................ 66 
Appendix B 
INTERNATIONAL AIRLINE TRANSPORTATION 
ASSOCIATION: 6.2 GUIDANCE DOCUMENT ................................... 68 
Appendix C 
ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY'S LAW ...................... 69 
Appendix D 
ANAPHYLAXIS: SIGNS AND SYMPTOMS, MANAGEMENT......... 74 
Appendix E 
PROHIBITED AND RESTRICTED MEDICATIONS ........................... 78 
Appendix F 
BACKGROUND THERAPY EQUIVALENCE TABLE ....................... 80 
Appendix G 
AUTO-INJECTOR ADMINISTRATION QUESTIONNAIRE .............. 81 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ACQ-6 
Asthma Control Questionnaire 6 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AI 
Auto-Injector 
AST 
Aspartate aminotransferase 
ATS/ERS 
American Thoracic Society/European Respiratory Society 
Beta-hCG 
Beta- human chorionic gonadotropin 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CO2 
Carbon dioxide 
COPD 
Chronic obstructive pulmonary disease 
CSA 
Clinical Study Agreement 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ED 
Emergency department 
EOT 
End of treatment 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
FVC 
Forced vital capacity 
Gamma-GT 
Gamma-glutamyl transpeptidase 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 
GMP 
Good Manufacturing Practice 
HCP 
Health care provider 
HIV 
Human immunodeficiency virus 

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Edition Number 1.0 
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Abbreviation or 
special term 
Explanation 
IATA 
International Air Transport Association 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICS 
Inhaled corticosteroids 
Ig 
Immunoglobulin 
IL 
Interleukin 
IL-5 
Interleukin-5 
IL-5R 
Interleukin-5 receptor 
IL-5Rα 
Interleukin-5 receptor alpha subunit 
IP 
Investigational product 
IPD 
Premature IP Discontinuation 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LABA 
Long-acting β2 agonists 
LTRA 
Leukotriene receptor antagonists 
MedDRA 
Medical Dictionary for Regulatory Activities 
nAb 
OAE 
Neutralizing antibody 
Other significant adverse event 
PK 
Pharmacokinetic(s) 
PRO 
Patient reported outcome 
RBC 
Red blood cell 
SABA 
Short-acting β2 agonists 
SAE 
Serious adverse event  
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous  
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
ULN 
Upper limit of normal 
UNS 
Unscheduled 
WBC 
White blood cell 
WBDC 
Web-based Data Capture 
WOCBP 
Women of childbearing potential 

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1. 
INTRODUCTION 
1.1 
Background  
Asthma is a syndrome characterized by airway inflammation, reversible airway obstruction, 
and airway hyperresponsiveness.  Patients present clinically with recurrent wheezing, 
shortness of breath, cough, and chest tightness.  Asthma is a leading cause of morbidity with a 
global prevalence of approximately 300 million; it is estimated that the number of people with 
asthma may increase to 400-450 million people worldwide by 2025 (Masoli et al 2004). 
The current approach to anti-inflammatory controller therapy in asthma is based on a 
step-wise intensification of a daily maintenance regimen primarily centered around inhaled 
corticosteroids (ICS) and leukotriene receptor antagonists (LTRA), with the addition of long-
acting β2 agonists (LABA) in patients with more severe asthma (GINA 2016, NAEPP 2007).  
Despite treatment per management guidelines, up to 50% of patients have asthma that is not 
well-controlled (Bateman et al 2010).  This results in considerable impact on quality of life, 
disproportionate use of healthcare resources, and adverse reactions from regular systemic 
steroid use.  Therefore, there remains an unmet medical need for patients whose asthma is not 
controlled by existing therapies. 
The observed variability in clinical response to currently available asthma therapies appears to 
be related, in part, to distinctive inflammatory phenotypes (Wenzel 2012).  In particular, 
asthma associated with eosinophilic inflammation in the airway (often referred to as 
eosinophilic asthma) is common (approximately 40% to 60% of asthmatics) with the degree of 
eosinophilia associated with clinical severity including the risk of asthma exacerbations 
(Bousquet et al 1990; Louis et al 2000; Di Franco et al 2003; Scott and Wardlaw 2006, 
Simpson et al 2006; Zhang and Wenzel 2007).  
Interleukin-5 (IL-5) is a key cytokine essential for eosinophil trafficking and survival 
(Molfino et al 2011). Benralizumab (MEDI-563) is a humanized, afucosylated, monoclonal 
antibody that binds specifically to the human IL-5 receptor alpha subunit (IL-5Rα) on the 
target cell.  The IL-5 receptor (IL-5R) is expressed almost exclusively on the surface of 
eosinophils and basophils (Takatsu et al 1994; Toba et al 1999).  Afucosylation confers 
enhanced antibody-dependent cellular cytotoxicity (ADCC) which results in highly efficient 
eosinophil depletion by apoptosis (Kolbeck et al 2012).  Single and repeated doses of 
benralizumab in mild to severe asthma patients has resulted in depletion of blood and airway 
eosinophils (Busse et al 2010, Gossage et al 2012, Molfino et al 2012).  Also, a recent dose 
finding trial in severe asthma proved benralizumab to have benefit across a range of asthma 
outcomes including reductions in asthma exacerbations, improvements in lung function, and 
reduction in symptoms (Castro et al 2014). 
The efficacy and safety of benralizumab has been confirmed in two large phase 3 trials, in 
severe asthmatics with a history of exacerbations, still symptomatic despite using medium-to-
high dose ICS/LABAs with or without oral corticosteroids or additional controller 

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Study Code D3250C00031 
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medications. (Bleecker et al 2016, FitzGerald et al 2016). The dose studied in these trials was 
30 mg, a dose derived from pharmacokinetic/pharmacodynamic (PK/PD) modelling of the 
Phase 2 dose finding study, administered in 2 dosing regimens – either 30 mg every 4 weeks 
(Q4W) or 30 mg every 4 weeks (Q4W) for the first 3 doses followed by dosing every 8 weeks 
(Q8W) thereafter. The primary endpoint in each study was the annual rate of asthma-related 
exacerbations with key secondary endpoints being FEV1 and asthma symptoms as defined by 
a daily patient diary.  
The purpose of this study is to assess patient-or caregiver-reported functionality, performance, 
and reliability of a single-use auto-injector device used to administer a fixed 30 mg dose of 
benralizumab subcutaneously (SC) in an at-home setting.  
1.2 
Rationale for study design, doses, and control groups 
This is a multicenter open-label functionality, reliability and performance study of a single-use 
auto-injector with benralizumab. The primary endpoints will be the proportion of 
patients/caregivers who successfully administered benralizumab SC with an AI, the proportion 
of returned AI device used to administer benralizumab at home that have been evaluated as 
functional, and the proportion of AI device used to administer benralizumab at home or at the 
clinic and have been reported as malfunctioning (Product Complaints). 
The benralizumab dose (30 mg SC, fixed) is based on population exposure-response 
modeling, and stochastic trial simulations from earlier benralizumab trials. The dosing 
regimen chosen, every 4 weeks (Q4W), is used in the pivotal Phase 3 efficacy and safety 
studies. Other stable asthma therapies on top of inhaled corticosteroids/long-acting β2 agonists 
(ICS/LABA) that are within expert guidance and that are not restricted per protocol (see 
Section 3.5.2) are allowed in order to accommodate local standards of care. 
1.3 
Benefit/risk and ethical assessment 
Benralizumab is primarily being studied in severe asthma where there are few treatment 
options for patients whose asthma remains uncontrolled on high dose ICS/LABA and oral 
corticosteroids (GINA 2016).  In adult patients whose asthma was poorly controlled on 
medium-to-high dose ICS/LABA therapy, benralizumab at doses of ≥20 mg produced 
improvements in multiple metrics of asthma control including the annual rate of asthma 
exacerbations, lung function, ACQ-6 scores, and symptoms (Castro et al 2014). These 
findings have subsequently been confirmed in two large Phase 3 studies (Bleecker et al 2016, 
FitzGerald et al 2016) where a fixed dose of 30 mg was given either Q4W or Q8W. 
 
Development of anti-drug antibodies (ADA) to benralizumab has been documented. 
Theoretical risks of developing ADA include decreased drug efficacy and hypersensitivity 
reactions (eg, anaphylaxis or immune complex disease). Eosinophils are a prominent feature 
of the inflammatory response to helminthic parasitic infections and the presence of infiltrating 
eosinophils has been circumstantially associated with a positive prognosis in certain solid 
tumors. Therefore, there is a theoretical risk that prolonged eosinophil depletion may diminish 
the ability to defend against helminthic parasites, or negatively impact the natural history of 
certain malignant tumors. Risk minimization measures herein include exclusion of patients 

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with untreated parasitic infection and active or recent malignancy, in conjunction with the 
performance of routine pharmacovigilance activities. 
 
The efficacy and safety data obtained to date support the continued clinical development of 
benralizumab in patients with asthma.  
 
The purpose of this trial is to confirm the successful use of benralizumab in an AI in an at-
home setting by the patient or caregiver. A detailed assessment of injection site reactions and 
the overall risk/benefit of benralizumab in patients with asthma is given in the Investigator’s 
Brochure (IB). 
1.4 
Study design 
This is a multicenter, open-label study designed to assess patient- or caregiver-reported 
functionality, performance, and reliability of a single-use auto-injector (AI) with a fixed 30 
mg dose of benralizumab administered subcutaneously (SC) in an at-home setting.   
Approximately 120 adult patients with severe asthma will enter the treatment period to receive 
5 subcutaneous doses (Week 0, Week 4, Week 8, Week 12, and Week 16) of benralizumab.  
Following a 2 week screening period, eligible patients will receive 3 SC doses of 30 mg of 
benralizumab at the study site (Week 0, Week 4, and Week 8) (Figure 1). At Week 0, the 
Principal Investigator or his/her designee will administer the study drug. At Week 4, the 
patient or caregiver will have the option of administering the study drug under study site 
supervision to ensure they understand the procedure and are capable of doing so.  At Week 8, 
the patient or caregiver will have to perform the injection, again under site staff supervision.  
Patients or caregivers unable or unwilling to administer investigational product (IP) at this 
visit will be discontinued from the study.  
The patient or caregiver will be given the Instructions for Use (IFU) to refer to for home 
administrations.  The final 2 doses of benralizumab (Week 12 and Week 16) will be self-
administered by the patient or administered by the caregiver at home.  After each of these 
administrations, the patient will return for a scheduled on-site visit within 48 hours. 
For the at-home administrations, whether the patient is self-administering or the caregiver is 
administering to a patient, the person administering the dose will fill out an administration 
questionnaire designed to indicate whether the device functioned correctly and the dose was 
successfully administered.  Both the completed questionnaire and the used device are to be 
returned to the site during each of the clinic visits (Visit 5 and Visit 6).  The site is to 
subsequently return the used devices and completed questionnaires to the Sponsor for 
evaluation.   
An end-of-treatment (EOT) visit will be performed at Week 20 and a follow-up visit at Week 
28 (12 weeks after last IP administration). 
 

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Study Code D3250C00031 
Edition Number 1.0 
Date 23 August 2016 
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Figure 1 
Study flow chart 
 

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Study Code D3250C00031 
Edition Number 1.0 
Date 23 August 2016 
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2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary objective 
Outcome measure 
To assess patient- or caregiver-reported 
functionality and reliability of the 
benralizumab single-use auto-injector (AI) 
device in an at-home setting and 
performance of the AI device after use. 
 
x 
Proportion of patients/caregivers who 
successfully administered benralizumab 
30 mg subcutaneously (SC) by injection 
with an AI device at home 
x 
Proportion of returned AI devices used to 
administer benralizumab at home that 
have been evaluated as functional 
x 
Proportion of AI device used to 
administer benralizumab at home or in 
the clinic and have been reported as 
malfunctioning (Product Complaints)  
 
2.2 
Secondary objectives 
Secondary objectives 
Outcome measure 
To monitor metrics of asthma control 
x 
Change from baseline in mean Asthma 
Control Questionnaire-6 (ACQ-6) score  
To evaluate the pharmacokinetics, 
pharmacodynamics, and immunogenicity of 
benralizumab 
x 
Pharmacokinetic parameters 
x 
Peripheral blood eosinophil levels 
x 
Anti-drug antibodies (ADA)  
 
2.3 
Safety objective  
Safety objectives 
Outcome measure 
To assess the safety and tolerability of 
benralizumab  
x 
Adverse events (AEs) and serious 
adverse events (SAEs) 
x 
Laboratory variables 
x 
Physical examination 
 
 

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3. 
SUBJECT SELECTION, ENROLMENT, TREATMENT, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL  
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study. Each caregiver should meet the applicable inclusion criteria for this study. Under no 
circumstances can there be exceptions to this rule. 
  
3.1 
Inclusion criteria 
For inclusion in the study subjects should meet the following criteria: 
1. 
Written informed consent for study participation must be obtained prior to any study 
related procedures being performed and according to international guidelines and/or 
applicable European Union (EU) guidelines.  
2. 
Male and female patients aged 18 to 75 years of age at the time of Visit 1. 
3. 
Patient or caregiver must be willing and able to administer the IP. Caregiver must be age 
of consent or older at the time of Visit 1, if applicable. 
4. 
Women of childbearing potential (WOCBP) must use an effective form of birth control 
(confirmed by the Investigator). Effective forms of birth control includes: true sexual 
abstinence, a 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 birth control, as defined above, from enrollment, throughout the 
study duration and until 16 weeks after last dose of investigational product (IP). WOCBP 
must also have negative serum pregnancy test result on Visit 1.  
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 Visit 2 without an alternative 
medical cause. The following age-specific requirements apply: 
 
Women <50 years old are considered postmenopausal if they have been amenorrheic 
for 12 months or more following cessation of exogenous hormonal treatment and 
follicle stimulating hormone (FSH) levels in the postmenopausal range 
 
Women ≥50 years old are considered postmenopausal if they have been amenorrheic 
for 12 months or more following cessation of all exogenous hormonal treatment 
5. 
All male patients who are sexually active must agree to use a double barrier method of 
contraception (condom with spermicide) from the first dose of IP until 16 weeks after 
their last dose 

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Study Code D3250C00031 
Edition Number 1.0 
Date 23 August 2016 
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6. 
Weight of ≥40 kg 
7. 
Evidence of asthma as documented by airway reversibility (FEV1 >12% and 200 ml) 
demonstrated at Visit 1 or 1A or Visit 2 
If patients do not demonstrate airway reversibility at either Visit 1 or 1A or Visit 2 the 
patient must not enter the treatment period and must be rescreened, if appropriate. If re-
screened, the study center should reiterate the need to withhold short- and long-acting 
bronchodilators as required in Section 5.1.1 prior to spirometry visits in an effort to meet 
this inclusion criterion. Visit 1A is optional for additional measurements if patient is on 
bronchodilators at the time of Visit 1. 
8. 
Documented history of current treatment with ICS and LABA.  The ICS and LABA can 
be parts of a combination product or given by separate inhalers.  The ICS dose must be 
greater than or equal to 500 μg/day fluticasone propionate dry powder formulation or 
equivalent daily.  Equivalents for fluticasone dry powder can be found in Appendix F. 
 
For ICS/LABA combination preparations, both the mid- and high-strength 
maintenance doses approved in the local country will meet this ICS criterion. 
 
Additional asthma controller medications (e.g., LTRAs, tiotropium, theophylline, 
oral corticosteroids) are allowed (see Section 3.5.2.1 for restricted therapies)  
9. 
Pre-bronchodilator (pre-BD) FEV1 of >50% predicted normal at Visit 1 or 1A or Visit 2 
10. 
Not well-controlled asthma as documented by either  
– 
An ACQ6  >1.5 OR 
– 
A peak expiratory flow of 60-80% predicted normal OR 
– 
One or more exacerbation that required oral or systemic corticosteroids in the 
previous year 
Inclusion criteria at start of Treatment Period  
11. 
For WOCBP only: Have a negative urine pregnancy test prior to administration of the IP 
at day of Visit 2 (Week 0) 
3.2 
Exclusion criteria 
Patients must not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Clinically important pulmonary disease other than asthma (eg, active lung infection, 
chronic obstructive pulmonary disease (COPD), bronchiectasis, pulmonary fibrosis, 
cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 
anti-trypsin deficiency, and primary ciliary dyskinesia) or ever been diagnosed with 
pulmonary or systemic disease, other than asthma, that are associated with elevated 

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Study Code D3250C00031 
Edition Number 1.0 
Date 23 August 2016 
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peripheral eosinophil counts (eg, allergic bronchopulmonary aspergillosis/mycosis, 
Churg-Strauss syndrome, hypereosinophilic syndrome) 
2. 
Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, 
psychiatric, or major physical impairment that is not stable in the opinion of the 
Investigator and could: 
 
Affect the safety of the patient throughout the study 
 
Influence the findings of the studies or their interpretations 
 
Impede the patient’s ability to complete the entire duration of study 
3. 
Known history of allergy or reaction to the IP formulation 
4. 
History of anaphylaxis to any biologic therapy 
5. 
History of Guillain-Barré syndrome 
6. 
A helminth parasitic infection diagnosed within 24 weeks prior to the date informed 
consent is obtained that has not been treated with, or has failed to respond to standard of 
care therapy 
7. 
Acute upper or lower respiratory infections requiring antibiotics or antiviral medication 
within 30 days prior to the date informed consent is obtained or during the screening 
8. 
Any clinically significant abnormal findings in physical examination, vital signs, 
hematology, clinical chemistry, or urinalysis during screening period, which in the 
opinion of the Investigator, may put the patient at risk because of his/her participation in 
the study, or may influence the results of the study, or the patient’s ability to complete 
entire duration of the study 
9. 
Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality 
obtained during the screening/run-in period, which in the opinion of the Investigator may 
put the patient at risk or interfere with study assessments 
10. 
History of alcohol or drug abuse within 12 months prior to the date informed consent is 
obtained 
11. 
Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive 
medical history for hepatitis B or C.  Patients with a history of hepatitis B vaccination 
without history of hepatitis B are allowed to enroll 
12. 
A history of known immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test 

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Edition Number 1.0 
Date 23 August 2016 
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13. 
Current smokers or former smokers with a smoking history of ≥10 pack years. A former 
smoker is defined as a patient who quit smoking at least 6 months prior to Visit 1. 
14. 
History of cancer: 
 
Patients who have had basal cell carcinoma, localized squamous cell carcinoma of 
the skin or in situ carcinoma of the cervix are eligible provided that the patient is in 
remission and curative therapy was completed at least 12 months prior to the date 
informed consent was obtained 
 
Patients who have had other malignancies are eligible provided that the patient is in 
remission and curative therapy was completed at least 5 years prior to the date 
informed consent was obtained 
15. 
Use of immunosuppressive medication (including but not limited to: oral corticosteroid 
[for reasons other than asthma], methotrexate, troleandomycin, cyclosporine, 
azathioprine, intramuscular long-acting depot corticosteroid [for reasons other than 
asthma], or any experimental anti-inflammatory therapy) within 3 months prior to the 
date informed consent. 
16. 
Current use of an oral or ophthalmic non-selective β-adrenergic antagonist (eg, 
propranolol) 
17. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥1.5 times 
the upper limit of normal (ULN) confirmed during screening period. 
18. 
Five- lipoxygenase inhibitors (eg, Zileuton) and roflumilast are prohibited. 
19. 
Receipt of immunoglobulin or blood products within 30 days prior to the date informed 
consent is obtained. 
20. 
Receipt of any marketed (eg, omalizumab, mepolizumab etc) or investigational biologic 
within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever 
is longer 
21. 
Receipt of live attenuated vaccines 30 days prior to the date of Visit 2 (Week 0) 
 
Receipt of inactive/killed vaccinations (eg, inactive influenza) is allowed provided 
they are not administered within 1 week before/after any investigational product 
administration. 
22. 
Receipt of any investigational non-biologic within 30 days or 5 half-lives prior to Visit 2 
whichever is longer 
23. 
Previously received benralizumab (MEDI-563)  
24. 
Initiation of new allergen immunotherapy is not allowed within 30 days prior to the date 
of informed consent. Immunotherapy initiated prior to this period or as a routine part of 

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Study Code D3250C00031 
Edition Number 1.0 
Date 23 August 2016 
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the patient’s seasonal treatment is allowed.  If the immunotherapy is delivered as an 
injection, there should be a gap of 7 days between the immunotherapy and IP 
administration.  
25. 
Planned surgical procedures during the conduct of the study 
26. 
Currently breastfeeding or lactating women 
27. 
Concurrent enrollment in another drug-related interventional clinical trial or post-
authorization safety study (PASS) 
28. 
AstraZeneca staff involved in the planning and/or conduct of the study 
29. 
Employees of the study center or any other individuals involved with the conduct of the 
study, or immediate family members of such individuals 
3.3 
Subject enrolment and treatment  
Investigator(s) should keep a record of patients considered for and included in the study.  This pre-
screening/screening log will be evaluated periodically by AstraZeneca or its delegates during 
routine monitoring visits. 
The Investigator will: 
1. 
Obtain signed informed consent from the potential patient and caregiver if applicable, 
before any study specific procedures are performed. 
2. 
Assign each potential patient a unique enrollment number, beginning with E# via 
interactive web/voice response system (IWRS/IVRS) 
3. 
Determine patient eligibility 
If a patient withdraws from participation in the study, then his/her enrolment code cannot be reused. 
Specific information concerning the use of the IWRS/IVRS will be provided in the separate 
manual.  
3.4 
Procedures for handling incorrectly enrolled patients 
Patients who fail to meet the eligibility criteria should not, under any circumstances, be enrolled or 
receive study medication.  There can be no exceptions to this rule.  Patients who are enrolled, but 
subsequently found not to meet all the eligibility criteria must not be initiated on treatment, and 
must be withdrawn from the study. 
Where a patient does not meet all the eligibility criteria, but is incorrectly started on treatment, the 
Investigator should inform the AstraZeneca Study Physician immediately, and a discussion should 
occur between the AstraZeneca Study Physician and the Investigator regarding whether to continue 
or discontinue the patient from treatment.  The AstraZeneca Study Physician must ensure all 
decisions are appropriately documented. 

Draft Clinical Study Protocol 
Drug Substance Benralizumab (Medi-563)  
Study Code D3250C00031 
Edition Number 1.0 
Date 23 August 2016 
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3.5 
Concomitant medications, restrictions during and after the study 
3.5.1 Concomitant medication 
Information about any treatment in the 3 months prior to the date of the informed consent and all 
the concomitant treatments given during the study with reason for the treatment will be collected by 
the Investigator/authorized delegate at each visit (as shown in Table 1 and Table 2) and recorded in 
the electronic Case Report Form (eCRF). 
Note: To satisfy inclusion criterion 8 (Section 3.1), the history of treatment with asthma therapies at 
the protocol designated doses prior to Visit 1 should be documented in source and recorded in the 
eCRF (see Section 4.1.1). 
3.5.1.1 
Background medication  
Background asthma medications may be increased from Visit 2 through 8 at the discretion of the 
Investigator to improve the patient’s asthma control, if needed. If the addition of a new asthma 
controller therapy or a change in dose of any asthma medication(s) is judged by the Investigator as 
necessary, the justification should be documented in the source and in the eCRF.   
A step down in therapy is discouraged and must be discussed beforehand with the AstraZeneca 
Study Physician. 
3.5.1.2 
Rescue medication  
Short-acting bronchodilators (SABAs) may be used as rescue medication during the study. 
The patient is to be prescribed an epinephrine-containing device (eg, EpiPen®) for use in the event 
of an allergic reaction and trained by the study center on its use (see Table 2).  If a caregiver is 
administering the IP, the caregiver must also be trained on its use. 
3.5.2 Restrictions 
3.5.2.1 
Asthma medication restrictions 
(a) 
Use of long-acting beta-agonists as a reliever (eg, Symbicort Maintenance and Reliever 
Treatment) is not allowed from enrollment and throughout the study duration 
(b) 
Use of short-acting anticholinergics (eg, ipratropium) as a rescue treatment for 
worsening asthma symptoms is not allowed from enrolment and throughout the study 
duration. 
(c) 
Use of short-acting beta-agonists 
Regularly scheduled or prophylactic SABA use is discouraged from enrolment and 
throughout the study duration.   
(d) 
Maintenance of asthma controller medications 
Any and all changes to the patient’s background medication should be recorded in an 
eCRF and documented in source records along with a rationale for the change.   

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Study Code D3250C00031 
Edition Number 1.0 
Date 23 August 2016 
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Asthma exacerbations should be treated with oral or other systemic corticosteroids 
according to standard practice. 
(e) 
Asthma medication restrictions on the days of scheduled spirometry visit 
Pre- and/or post-BD spirometry assessments will be performed at the study center at 
scheduled visits (see Table 1 and Table 2): restrictions to patient’s background 
medication are required prior to the spirometry as described below: 
Visit 1 or 1A or 2: Patients should withhold their usual ICS-LABA medications on the 
day(s) when reversibility testing is being performed.  
Twice daily ICS and LABA therapies should be withheld for 12-24 hours; once daily therapies 
containing ICS, LABA, or LAMA therapies should be withheld for ≥24 hours for eligibility 
assessment. In addition, SABA should not be used within 6 hours of these spirometry assessments. 
The patient’s usual asthma medications may be administered following completion of the lung 
function procedures.  
3.5.2.2 
Other medication restrictions  
(a) 
Use of immunosuppressive medication or administration of live/attenuated vaccines is 
not allowed.  Topical administration of immunosuppressive medication may be allowed 
at the discretion of the Investigator after discussion with the AstraZeneca Study 
Physician.  Please see Section 3.2 exclusion criterion 15 for examples and further details. 
(b) 
Receipt of live attenuated vaccines within 30 days prior to Visit 2, during the treatment 
period, and for 16 weeks (5 half-lives) after the last dose of the IP is not allowed 
(c) 
Patient should not receive allergen immunotherapy injection on the same day as the IP 
administration 
(d) 
When enrolling a patient who is on theophylline, digoxin, or other drugs with a narrow 
therapeutic range, the Investigator should ensure the levels of each of these medications 
must not exceed the upper limit of therapeutic range.  The Investigator will also be 
responsible for ensuring that these levels are regularly checked and documented as per 
local practice (see Table 1) 
(e) 
Patients should not take any other excluded medications: 
 
Five-lipoxygenase inhibitors (eg, Zileuton) 
 
Roflumilast 
 
Oral or ophthalmic non-selective β-adrenergic antagonist (eg, propranolol). 
A table with medication-related restrictions presented in the Appendix E. 

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Drug Substance Benralizumab (Medi-563)  
Study Code D3250C00031 
Edition Number 1.0 
Date 23 August 2016 
25(83) 
3.5.2.3 
Other restrictions 
(a) 
Fertile and sexually active patients or their partners should use highly effective 
contraceptive methods throughout the study and at least for 16 weeks (5 half-lives) after 
last administration of the IP.  Male patients should refrain from fathering child or 
donating sperm from the time of informed consent, and for 16 weeks (5 half-lives) after 
last dose of IP (see Section 3.1, inclusion criteria 4 and 5; and Section 7.6) 
(b) 
Patients must abstain from donating blood or plasma from the time of informed consent 
and for 16 weeks (5 half-lives) after the last dose of IP. 
3.6 
Discontinuation of investigational product  
Patients will be discontinued from IP in the following situations: 
1. 
Patient decision.  The patient is free to discontinue treatment at any time without 
prejudice to further treatment. 
2. 
Adverse event (AE) that, in the opinion of the Investigator, contraindicates further dosing 
3. 
Risk to patient as judged by the Investigator or AstraZeneca 
4. 
Severe non-compliance to study protocol 
5. 
Eligibility requirement found not to be fulfilled (see Section 3.4) 
6. 
Pregnancy 
7. 
Lost to follow-up1 
8. 
Development of any study specific criteria for discontinuation: 
1. Anaphylactic reaction to the IP requiring administration of epinephrine 
2. Development of helminth parasitic infestations requiring hospitalization 
3. An asthma-related event requiring mechanical ventilation. 
9. 
A patient who is self-administering IP who becomes unwilling or unable to continue to 
self-administer must be discontinued.  Similarly, if a caregiver is giving the IP and 
becomes unwilling or unable to continue to administer IP to a patient, then that patient 
must be discontinued.   
All patients who prematurely discontinue IP should return to the study center and complete the 
procedures described for the Premature IP Discontinuation (IPD) visit after 4 weeks (±3 days) and 
                                                 
1 Patient is considered lost to follow up when any of the following attempts of contact are failed: -3 attempts of either 
phone calls, faxes or emails; - having sent 1 registered letter/certified mail; 1 unsuccessful effort to check the vital 
status of the patient using publicly available sources, if allowed by local regulations. 

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Study Code D3250C00031 
Edition Number 1.0 
Date 23 August 2016 
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the procedures for the Follow-up visit after 12 weeks (±3days) of the last IP administration.  The 
reason(s) for premature discontinuation of IP should be recorded in the eCRF. 
3.7 
Criteria for withdrawal 
3.7.1 Screen failures  
Screen failures are patients who do not fulfill the eligibility criteria for the study and therefore must 
not enter the treatment part of the study.  These patients should have the reason for study 
withdrawal recorded as ‘Incorrect Enrollment’ (ie, patient does not meet the required 
inclusion/exclusion criteria).  This reason for study withdrawal is only valid for screen failures (not 
patients in the treatment phase). 
3.7.2 Withdrawal of the informed consent 
Patients or caregivers, if applicable, are free to withdraw from the study at any time (IP and 
assessments) without prejudice to further treatment. 
A patient who withdraws consent will always be asked about the reason(s) and the presence of any 
AE.  The Investigator will follow up with AEs outside of the clinical study.   
The enrollment code of the withdrawn patient cannot be reused. Withdrawn subjects will not be 
replaced. 
3.7.3 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: 
x meet individual stopping criteria or are otherwise considered significant 
x are assessed as causally related to study drug, 
x 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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Study Code D3250C00031 
Edition Number 1.0 
Date 23 August 2016 
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4. 
STUDY PLAN AND TIMING OF PROCEDURES 
Table 1 
Study Plan – Enrollment, screening period 
Assessment/ activity 
Refer to 
Screening 
V1 (W –2) 
V1Ad (V1 + max. 3 days) 
Informed consent 
10.4 
X 
 
Inclusion/exclusion criteria 
3.1/3.2 
X 
 
Medical and asthma history 
4.1.1 
X 
 
Complete physical examination 
5.2.1.1 
X 
 
Weight, Height, BMI 
5.3.1 
X 
 
Vital Signs 
5.2.2 
X 
 
Local ECG 
5.2.3 
X 
 
Serum chemistry  
5.2.4 
X 
 
Hematology  
5.2.4 
X 
 
Urinalysis 
5.2.4 
X 
 
Blood concentration (digoxin, 
theophylline) a 
3.5.2.2 
X 
 
Serology  
(hepatitis B,C; HIV-1; HIV-2) 
5.3.3.1 
X 
 
Serum pregnancy test 
5.2.4.1 
X 
 
FSH b 
5.2.4.1 
X 
 
Adverse events 
7.1 
X 
 
Concomitant medication 
3.5 
X 
 
ACQ-6 at Study Center 
5.3.2.1 
X 
 
Pre- and post-bronchodilator 
spirometryc  
5.1.1 
X 
Xd 
Review of the AI IFU and the 
Administration Questionnaire 
6.6 
X 
 
Training on epinephrine-containing 
device 
3.5.1.2 
X 
 
a 
If and when appropriate prior to treatment period; for patients who are on theophylline or digoxin, (see Section 
3.5.2.2) 
b 
FSH test done only for female patients to confirm postmenopausal status in women <50 years who have been 
amenorrheic for >12 month 
c 
Pre- and post-bronchodilator spirometry can be done at Visit 1 ( or optional Visit 1Ad) OR Visit 2 
d  
Visit 1A is optional for spirometry measurement only 

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Study Code D3250C00031 
Edition Number 1.0 
Date 23 August 2016 
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Table 2 
Study Plan – Treatment period and follow-up 
Assessment/ activity 
Refer to 
Treatment 
 
EOT 
IPD 
FU 
Unsch 
V2 
V3 
V4 
V5 
V6 
V7 
 
V8 
 
W0 
W4 
W8 
W12 
W16 
W20 
 
W28 
 
Visit window (days) a 
±3 
±3 
±3 
±3h 
±3h 
±3 
±3 
±3 
N/A 
Inclusion/exclusion criteria 
3.1/3.2 
X 
 
 
 
 
 
 
 
 
Review of the AI IFU and 
Questionnaire 
6.6 
X 
X 
X 
Xb 
Xb 
 
 
 
Xb 
Training on epinephrine-containing 
device 
3.5.1.2 
X 
X 
X 
X 
 
 
 
 
Xb 
Complete physical examination 
5.2.1.1 
X 
 
 
 
 
X 
X 
X 
 
Brief physical examination 
5.2.1.2 
 
X 
X 
X 
X 
 
 
 
X 
Vital Signs 
5.2.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry  
5.2.4 
X 
 
 
 
 
X 
X 
X 
 
Hematology  
5.2.4 
X 
 
 
 
 
X 
X 
X 
 
Urinalysis 
5.2.4 
X 
 
 
 
 
X 
X 
X 
 
Urine pregnancy test (dipstick) c 
5.2.4.1 
X 
X 
X 
X 
X 
X 
X 
X 
 
At-home urine pregnancy test before IP 
administrationc 
5.2.4.1 
 
 
 
X 
X 
 
 
 
 
PK 
5.3.4 
X* 
 
X* 
 
 
X 
X 
X 
 
ADA/nAbj 
5.3.6 
X* 
 
X* 
 
 
X 
X 
X 
 
ACQ-6 at Study Center 
5.3.2.1 
X 
X 
X 
X 
X 
X 
X 
 
 
Pre- and post-bronchodilator spirometryi  5.1.1 
X 
 
 
 
 
 
 
 
 

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Study Code D3250C00031 
Edition Number 1.0 
Date 23 August 2016 
29(83) 
Table 2 
Study Plan – Treatment period and follow-up 
Assessment/ activity 
Refer to 
Treatment 
 
EOT 
IPD 
FU 
Unsch 
V2 
V3 
V4 
V5 
V6 
V7 
 
V8 
 
W0 
W4 
W8 
W12 
W16 
W20 
 
W28 
 
Visit window (days) a 
±3 
±3 
±3 
±3h 
±3h 
±3 
±3 
±3 
N/A 
Adverse events 
7.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
3.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IP Administration at site g 
6.6 
Xd 
Xe 
Xe 
 
 
 
 
 
 
IP Administration at home g 
6.6 
 
 
 
Xe 
Xe 
 
 
 
 
Visit Reminder Call f 
6.6 
 
 
 
X 
X 
 
 
 
 
Return of AI and admin. questionnaire 
6.5 
 
 
 
X 
X 
 
 
 
 
a 
All visits are to be scheduled from the date of Visit 2 but not from the date of previous visit except in the case of early discontinuation from IP (see 
Section 3.6 for details). 
b 
At those Visits training/review with the patient is optional.  
c 
For WOCBP only, a urine HCG test must be done prior to IP administration at Visits 2 (Week 0), 3 (Week 4), and 4 (Week 8) at the study center.  
At-home urine pregnancy tests are to be done by WOCBP prior to IP administration at Weeks 12 and 16 and repeated by the center staff at Visits 5 
and 6.  In the case of a positive test, the patient is NOT to administer IP and is to call the study center.  Urine pregnancy tests will be done at the 
study center at the EOT visit (Visit 7, Week 20) and the Follow-up visit (Visit 8, Week 28).   
d 
Study drug will be administered on site by HCP in either the arm, thigh, or abdomen 
e 
At Visit 3, the patient/caregiver has the option to administer the study drug.  At Visits 4, 5, and 6, the patient/caregiver must administer the study 
drug.  If self-administered by the patient, the study drug can be given in the thigh or abdomen.  If administered by the caregiver, the sites of injection 
are in the upper arm, thigh, or abdomen  
f 
Study center to perform visit reminder call to the patient within 48 prior scheduled home administration date for V5 & V6 
g 
In case of anaphylaxis, additional samples to be taken (see Section 6.7 and Appendix D) 
h 
The ±3 day window is related to the IP administration at home and not the clinic visit, which should occur no later than 48h after IP administration 
i 
Pre- and post-bronchodilator spirometry can be done at Visit 1 (optional Visit 1A) OR Visit 2.   
j 
 
Neutralizing antibody (nAb) testing will occur for all samples that are ADA positive. Samples that are ADA negative will not be tested for nAb. 
* pre-dose sample 
EOT  End-of-treatment; FU  Follow-up; HCG  Human chorionic gonadotropin; HCP  Healthcare provider; IFU  Instructions for Use; V  Visit; W  Week

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4.1 
Enrollment and screening period 
4.1.1 Enrollment (Visit 1) 
Each patient and caregiver, if applicable, will provide written informed consent prior to any study 
specific procedures and undergo assessments applicable for the visit (see Table 1). 
Patients (and caregiver, if applicable) must sign the Informed Consent Form (ICF) prior to any Visit 
1 procedures.  Registration of the patient’s enrollment via IWRS/IVRS should occur on day when 
other Visit 1 procedures are done. The auto-injector IFU, epinephrine containing device and 
administration questionnaire will be reviewed as part of the informed consenting process. 
Visit 1 assessments are primarily concerned with confirmation of the asthma disease state and the 
requisite level of severity based on background medications. 
A record of physician-diagnosed asthma is required in source documentation.  A patient’s verbal 
history suggestive of asthma symptoms, but without supporting documentation, is not sufficient to 
satisfy these inclusion criteria. 
Current regular use of ICS prior to enrollment must be documented in the source.  This 
documentation may be in the form of a recent active medication list as per an HCP note or filled 
prescriptions based on a pharmacy record. 
4.1.2 Re-screening 
Re-screening is allowed only once for any patient. 
Re-screened patients should re-sign the informed consent on the re-screening Visit 1.  All Visit 1 
procedures should be repeated. 
4.1.2.1 
Procedures for patients who experience an exacerbation during screening 
Patients who experience an asthma exacerbation during screening should be treated according to 
local medical practice. 
4.2 
Treatment period 
Inclusion criteria will be confirmed at Visit 2 (Week 0).  Eligible patients will receive 5 doses of 
benralizumab 30 mg every 4 weeks (Q4W). 
Following a 2 week screening period, eligible patients will receive 3 SC doses of benralizumab at 
the study center (Week 0, Week 4, and Week 8). The first injection of IP will be done at the study 
center by the HCP at Visit 2 (Week 0). At the Visit 3 (Week 4) and Visit 4 (Week 8) 
administrations, the patient or caregiver will be asked to administer the study drug themselves 
under study center supervision to ensure they understand the procedure and are capable of doing so. 
If the patient is not willing/able to self-administer (or the caregiver is not willing/able to administer) 
at Visit 4 (Week 8), the patient will be discontinued from IP. At Visit 4 (Week 8) after completion 
of a self-administration, the patient will be given: epinephrine containing device, IP along with the 

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Instructions for Use (IFU) and Administration Questionnaire to complete after home 
administration. The final 2 doses of benralizumab (Week 12 and Week 16) will then be 
administered by the patient or a caregiver at home. After each of these administrations, the patient 
will return for a scheduled on-site visit within 48 hours. 
The AI Administration Questionnaire (please see Appendix G) is to be filled out by the patient (if 
self-administering) or by the caregiver (if they administered the IP to the patient).  That person will 
fill out a questionnaire designed to indicate whether the device functioned correctly and the dose 
was successfully administered.  Both the administration questionnaire and the used device are to be 
returned to the study center during each of the clinic visits after at-home administration.  Study 
Center Staff will instruct the patient or caregiver, if applicable, on how to complete the 
questionnaire and properly return the device. 
For Visit 2 through Visit 4, all study procedures must be done on the scheduled day of IP injection.  
Urine pregnancy tests must be done prior to IP administration at Visits 2 (Week 0), 3 (Week 4), and 
4 (Week 8).  At-home urine pregnancy tests are to be done by WOCBP prior to IP administration at 
Weeks 12 and 16 and repeated by the study center staff at Visits 5 and 6.  In the case of a positive 
test, the patient is NOT to administer IP and is to call the study center.  Urine pregnancy tests will 
be done at the study center at the EOT visit (Week 20) and the Follow-up visit (Week 28).  
The same person must administer the IP during the entire study, whether it is the patient or 
caregiver. 
Restrictions as set out in Section 3.5.2 will continue to apply throughout the treatment period.  In 
case of asthma worsening/exacerbation (see Section 7.3.7), patients should be evaluated at the study 
center when feasible. 
Patients will return to the study center at Week 20 for the EOT visit and at Week 28 for a Follow-
up visit.  If the IP was administered by a caregiver, the caregiver must accompany the patient to 
these visits. 
For premature discontinuation please refer to Section 3.6. 
Completion or early termination of the treatment will be registered via IWRS/IVRS for each 
patient. 
4.3 
Follow-up period 
Patients who complete the treatment period will be followed for 12 weeks after the last dose of IP 
for the Follow Up visit (Week 28). 
5. 
STUDY ASSESSMENTS 
Medidata Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling. The investigator will ensure that data are recorded on the electronic Case Report 
Forms as specified in the study protocol and in accordance with the instructions provided. 

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The investigator ensures the accuracy, completeness and timeliness of the data recorded and of the 
provision of answers to data queries according to the Clinical Study Agreement. The investigator 
will sign the completed electronic Case Report Forms. A copy of the completed electronic Case 
Report Forms will be archived at the study site. 
5.1 
Efficacy assessments 
5.1.1 Spirometry 
General requirements 
Lung function (reversibility, FEV1 and FVC) at the study center will be measured by spirometry 
using the study centers own equipment.  Spirometry will be performed by the Investigator or 
authorized delegate according to American Thoracic Society/European Respiratory Society 
(ATS/ERS) guidelines (Miller et al 2005). 
The Principal Investigator or authorized delegate is responsible for assuring that the spirometer is in 
a good working condition, calibrated and meets ATS/ERS recommendations and that the study 
center personnel who will be performing the testing are properly certified.   
Patients should withhold their SABA medication(s) for at least 6 hours prior to spirometry (see 
Section 3.5.2.1).  LABA therapy (with or without ICS) should be withheld for 12-24 depending on 
whether the patient is using twice or once daily LABA-containing therapy, respectively. 
Time for scheduled centre visit spirometry 
Spirometry testing should be done according to the schedule provided in Table 1 and Table 2. 
Spirometry technique 
Patients should avoid engaging in strenuous exertion for at least 30 minutes prior to spirometry 
measurements.  Patients should avoid eating a large meal for at least 2 hours prior to spirometry 
measurements at the center.  Forced expiratory maneuvers should be performed with the patient 
seated in an upright position.  If this is not comfortable for the patient, standing is permitted.  The 
same position should be used by the patient for each forced expiratory maneuver. The head must 
not be tilted during maneuvers and the thorax should be able to move freely; hence tight clothing 
should be loosened.  A nose-clip should be used for the maneuver.  
The forced expiratory maneuvers (FEV1 and FVC) should start with a maximal inspiration and then 
followed by a fast and forceful expiration that should last for at least 6 seconds.  It is important to 
encourage the patient to continue the expiration to be fast and forceful throughout the maneuver.  
Ensure that none of the following has occurred: coughing during the first second, glottis closure, or 
leak or obstruction of the mouthpiece (by the tongue). 
Multiple forced expiratory efforts (at least 3 but no more than 8) will be performed for each center 
spirometry session and the 1 best effort (highest FEV1) that meet the ATS/ERS acceptability and 
reproducibility criteria will be recorded in the eCRF. The absolute measurement (for FEV1 and 
FVC), and the percentage of predicted normal value will be recorded. The best effort values will be 
based on the one with highest FEV1.  

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5.1.1.1 
Reversibility test and post-BD FEV1 assessment 
The procedure described in this section refers to the reversibility testing at Visit 1 or optional 1A or 
Visit 2. Bronchodilatation can be induced using albuterol (90 μg metered dose), salbutamol (100 μg 
metered dose) or levalbuterol (45 μg metered dose) up to a maximum of 4 inhalations. It is highly 
recommended to use a spacer device for this procedure. The algorithm for reversibility testing is 
outlined in Figure 2.  
Figure 2 
Reversibility testing algorithm 
 
1 
Verify with the patient that the medication restrictions to allow the reversibility assessment have 
been met (Section 3.5.2)  
 
2 
After a gentle and complete expiration, albuterol, salbutamol or levalbuterol is inhaled in one breath 
to TLC from a spacer device.  The breath is then held for 5–10 seconds before the patient exhales. 
Four separate inhalations are delivered at 
approximately 30- second intervals.  Post-BD 
spirometry should be performed 30-60 minutes 
later. 
 
3 
If the patient still has not met reversibility 
criteria at Visit 1 further attempts to demonstrate 
reversibility criteria are allowed at optional Visit 
1A or Visit 2 
 
 
 
A lower total dose, eg, 2 inhalations instead of 4 
puffs, can be used if there is a concern about any 
effect on the patient’s heart rate, tremor, or safety. 
Reversibility should be calculated as follows: 
% Reversibility=(post-BD FEV1- pre BD 
FEV1)×100 
 
 
 
 
 
pre-BD FEV1 
Record keeping 
A signed and dated copy of the spirometry printout must be kept at study center for source data 
verification.  The printout must be marked with the study code, enrollment code, date and time of 
measurement, visit number.  Recorded data will be entered into the eCRF. 

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5.1.2 Assessment of self and caregiver administration with the single-use auto-injector 
One of the primary endpoints of interest is the proportion of patients/caregivers who successfully 
administered benralizumab with the AI device at home.  A successful administration is defined as 
an injection completed and an answer of “Yes” to all 5 questions in the administration 
questionnaire (please see Appendix G) and satisfactory in vitro evaluation of the returned devices. 
5.1.3 Assessment of returned single-use auto-injector device through in vitro evaluation 
In addition to the administration questionnaire filled out and returned with each at-home 
administered dose, the used AI device will be returned to the Sponsor for in vitro evaluation.  The 
data collected in the in vitro evaluation of the AI devices falls into 2 categories: 1) Visual 
inspection, and 2) Functional evaluation.  The visual inspection will assess the returned devices for 
any visible damage or disassembly, full plunger travel indicating a complete dose was expelled, and 
needle guard deployment.  The functional evaluation will challenge the needle safety guard to 
assess whether it deployed correctly and continued to provide protection against accidental needle 
stick injuries.  As mentioned in Section 5.1.2, a satisfactory in vitro evaluation of the returned 
devices and a completed administration questionnaire with an answer of “Yes” to all 5 questions in 
the questionnaire will constitute a successful administration. Any device defects reported during the 
in vitro evaluation will result in a full product complaint investigation. In the event that the answers 
to one or more of the questions on the questionnaire indicate that the user was unable to complete a 
successful administration, an evaluation will be performed on the returned device. The evaluation 
will take into account information provided on the administration questionnaire.  If the in vitro 
evaluation of the device shows no observable device defect, then the unsuccessful administration 
may be classified as a use error and not a device malfunction (e.g. user removes Autoinjector from 
the injection site before the injection is complete). 
5.2 
Safety assessments 
5.2.1 Physical examination  
Physical examination will be done in accordance with schedule provided in Table 1and Table 2. 
Baseline data will be collected at Visit 1.  Any new finding(s) or aggravated existing finding(s), 
judged as clinically significant by the Investigator, will be reported as an AE as described in 
Section 7.1 
5.2.1.1 
Complete physical examination  
The complete physical examination will include an assessment of the following: general 
appearance, skin, head and neck (including eyes, ears, nose, mouth, and throat), lymph nodes, 
abdomen, musculoskeletal (including spine and extremities), cardiovascular, respiratory, and 
neurological systems.  
5.2.1.2 
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.  

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5.2.2 Vital signs  
Vital signs (pulse, blood pressure, respiration rate, and body temperature) are to be obtained in 
accordance with schedule provided in Table 1 and Table 2. 
Body temperature will be measured in Celsius. 
5.2.3 Electrocardiograms  
Electrocardiograms (ECGs) are to be performed in accordance with the schedule provided in Table 
1.  Measurements will be performed on local study center based equipment. 
A 12-lead ECG will be taken in supine position after the patient has been resting for at least 5 
minutes.   
A standard ECG with a recommended paper speed of 50 mm/second covering at least 6 sequential 
beats should be used.  The Investigator or authorized delegate will be responsible for the overall 
interpretation and determination of clinical significance of any potential ECG findings.  In case of 
discrepancy between the Investigators interpretation and that provided by the ECG machine (if 
applicable), the Investigator’s interpretation takes precedence and should be noted on the printout 
and recorded in the eCRF.  Two identical copies of the ECG will be produced, quality checked, and 
kept in case of further need for re-evaluation.   
Record keeping 
A signed and dated copy of the ECG printout must be kept at study center for source data 
verification.  The printout must be marked with the study code, enrollment code, date and time of 
measurement, visit number. ECG data and evaluation will be recorded in the eCRF. 
5.2.4 Laboratory safety assessments 
Safety laboratory tests (list provided in Table 3 below) will be performed in a central laboratory. 
For information on methods of collection, assessment, labeling, storage, and shipment of samples 
please refer to the separate Laboratory Manual. Safety samples will be collected in accordance with 
the schedules provided in Table 1 and Table 2 
Hematology and urinalysis will be assessed in line with the schedules provided in the Table 1 and 
Table 2. 
 

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Table 3 
List of safety laboratory tests 
Clinical chemistry  
(serum or plasma) 
Haematology/Haemostasis 
(whole blood) 
Urinalysis 
ALP (Alkaline phosphatase) 
Hematocrit 
Appearance 
ALT (alanine aminotransferase) 
Hemoglobin 
Blood 
AST (aspartate aminotransferase) 
Mean corpuscular volume 
(MCV) 
Color 
Bilirubin, total 
BUN (blood urea nitrogen) 
Platelet count 
Glucose 
Calcium 
Red blood cell (RBC) count 
Ketones 
Chloride 
Cholesterol, total 
WBC count with differential 
Microscopy including 
WBC/high power field 
(HPF), RBC/HPF 
CO2 (carbon dioxide) 
 
pH 
Creatinine 
 
Specific gravity 
Gamma-GT (gamma-glutamyl 
transpeptidase) 
 
 
Glucose 
 
 
Phosphorus 
 
 
Potassium 
 
 
Sodium 
 
 
Uric acid 
 
 
Serum concentration a 
 
 
a 
For patients on theophylline or digoxin (see Section  3.5.2.2) 
 
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at centre as 
source data for laboratory variables. For information on how AEs based on laboratory tests should 
be recorded and reported, see Section 7.3 
NB. In case a subject shows an AST or ALT ≥3xULN and total bilirubin ≥2xULN please 
refer to Appendix C ‘Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law’, for further instructions.  
 
5.2.4.1 
Pregnancy test  
The following tests are applicable to female patients only and will be conducted in accordance with 
the schedules provided in Table 1 and Table 2: 

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x 
Serum beta-HCG: To be done at screening Visit 1 only for WOCBP (analyzed at central 
laboratory)   
x 
FSH: To be done at screening Visit 1 only for female patients to confirm postmenopausal 
status in women <50 years who have been amenorrheic for ≥12 months  
x 
Urine HCG: To be performed at the study center for WOCBP at Visits 2, 3, and 4 before IP 
administration using a dipstick.  The test will be performed at home prior to the 2 at-home 
IP administrations, and again at the study center at Visits 5, 6, 7, 8.  A positive urine test 
result must be confirmed with serum beta HCG. 
5.3 
Other assessments and procedures 
5.3.1 Weight and height 
Weight and height will be measured, and the BMI will be calculated, in accordance with schedules 
provided in Table 1. 
The patient’s weight will be recorded in kilograms and height in centimeters. 
Weight and height measurements will be performed in light clothing and with shoes off. 
5.3.2 Patient-reported outcomes 
5.3.2.1 
Asthma Control Questionnaire (ACQ-6) 
The ACQ-6 is a shortened version of the ACQ that assesses asthma symptoms (night-time waking, 
symptoms on waking, activity limitation, shortness of breath, wheezing, and short-acting β2 agonist 
use) omitting the FEV1 measurement from the original ACQ score. 
Patients are asked to recall how their asthma has been during the previous week by responding to 1 
bronchodilator use question and 5 symptom questions. 
Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled).  
The mean ACQ-6 score is the mean of the responses.  Mean scores of ≤0.75 indicate well-
controlled asthma, scores between 0.75 and ≤1.5 indicate partly controlled asthma, and a score >1.5 
indicates not well controlled asthma (Juniper et al 2006).  Individual changes of at least 0.5 are 
considered to be clinically meaningful.  The questionnaire will be completed at the study center in 
accordance with schedule provided in Table 1and Table 2. 
5.3.3 Other screening assessments 
5.3.3.1 
Serology 
Hepatitis B surface antigen, hepatitis C antibody: To be done only at screening; test to be 
performed at central laboratory. 
HIV-1 and HIV-2 antibodies: To be done only at screening; test to be performed at central 
laboratory. 
Instructions for sample collection, processing, storage, and shipment can be found in the separate 
Laboratory Manual provided to the study centers. 

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5.3.4 Pharmacokinetics 
For the PK analysis, it is important that the date and time of each SC injection is recorded for each 
patient. Instructions for sample collection, processing, storage, and shipment can be found in the 
separate Laboratory Manual provided to the centers.  Samples will be collected according to the 
schedule of study procedures. 
Samples for determination of benralizumab concentration in serum will be analyzed by a central 
laboratory on behalf of AstraZeneca, using a validated bioanalytical method. Full details of the 
analytical method used will be described in bioanalytical report.  
 
The PK samples will be retained at AstraZeneca or designee for a maximum of 3 years following 
publication of the CSR to properly address potential questions from regulatory authorities (RAs). 
 
A summary of PK analysis results will be reported in the Clinical Study Report (CSR). 
5.3.5 Pharmacodynamics  
Samples for the analysis of peripheral blood eosinophils will be performed in a central laboratory as 
part of the routine hematology assessment (complete blood count [CBC]).  
5.3.6 Immunogenicity  
Instructions for immunogenicity (ADA and nAb) sample collection, processing, storage, and 
shipment can be found in the separate Laboratory Manual provided to the centers. 
The immunogenicity samples will be retained at AstraZeneca or designee for a maximum of 3 years 
following publication of the CSR to properly address potential questions from RAs. 
A summary of the analysis will be presented in the CSR. Details of the analytical method used will 
be described in a bioanalytical report. 
Anti-drug antibodies   
Serum samples for analysis of anti-drug antibodies (ADA) will be collected pre-dose at selected 
visits according to the study plan (see Table 2). 
The presence or absence of ADA will be determined in the serum samples using validated 
bioanalytical methods. 
Neutralizing antibodies 
Neutralizing antibodies (nAb) testing will occur on all samples that are ADA positive. Samples that 
are ADA-negative will not be tested for nAb.  
 
The presence or absence of neutralizing antibodies will be determined using a validated 
bioanalytical method. 
5.3.7 Pharmacogenetics 
Pharmacogenetic samples will not be taken during the study. 

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5.3.8 Biomarker analysis 
Samples for biomarker analysis will not be collected during the study. 
5.3.9 Handling of biological samples 
5.3.9.1 
Labeling and shipment of biological samples 
The Principal Investigator is to ensure that samples are labeled and shipped in accordance with the 
Laboratory Manual and the Biological Substance, Category B Regulations (materials containing or 
suspected to contain infectious substances that do not meet Category A criteria), see Appendix B 
‘IATA 6.2 Guidance Document’. 
Any samples identified as Infectious Category A materials are not to be shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate labeling, 
shipment, and containment provisions are approved. 
5.3.9.2 
Chain of custody of biological samples  
A full chain of custody will be maintained for all samples throughout their lifecycle. 
The Principal Investigator at each study center is to keep full traceability of collected biological 
samples from the patients while in storage at the study center until shipment or disposal (where 
appropriate) and is to keep documentation of receipt of arrival (where applicable). 
The sample receiver is to keep full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and is to keep documentation of receipt of arrival. 
AstraZeneca will maintain oversight of the entire life cycle through internal procedures, monitoring 
of study centers and auditing of external laboratory providers. 
Samples retained for further use will be registered in the AstraZeneca biobank system during the 
entire life cycle. 
6. 
MANAGEMENT OF INVESTIGATIONAL PRODUCT 
6.1 
Identity of investigational product(s) 
All IP will be manufactured in accordance with Good Manufacturing Practice (GMP). 
Benralizumab administered in the study will be a clear to opalescent, colorless to yellow solution. 
Table 4 
Identity of investigational product 
Investigational product 
Dosage form and strength 
Manufacturer 
Benralizumab 
30 mg/mL solution for injection 
in the single-use auto-injector 
device, 1mL fill volume 
MedImmune 
 

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6.2 
Labeling 
Labelling of the IP will be carried out by AstraZeneca or desingee in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines of each country participating in the 
study. The labels will fulfil GMP Annex 13 requirements for labelling. Label text will be translated 
into local language.  
The label will include the following information: 
x 
study code 
x 
Investigational product/study drug dosage form, route of administration and quantity of 
dosage units 
x 
kit ID 
x 
P Lot ID 
x 
Expiry date 
x 
Investigator Name (to be written on the label) 
x 
E-code (to be written in the label) 
x 
Sponsor name and contact details 
x 
Directions for use 
x 
Storage condition 
x 
Standard statements required by regulatory authorities 
6.3 
Storage 
Benralizumab is to be stored at the study center in a secured facility with limited access and 
controlled temperature.  The temperature should be monitored on a daily basis and documented in 
the temperature monitoring log while IP stored at study center. 
The IP must be kept in the original outer container and under conditions specified on the label 
(between 2-8°C [36-46°F], protected from the light).   
Patients can transport the IP in uncontrolled temperature conditions but should return it to a 
refrigerator as soon as possible.  The temperature is not monitored during storage by the patient; 
standard refrigeration is sufficient to maintain appropriate temperatures while the IP is in the 
patient’s possession. 
In the following cases neither the center staff nor the patient or caregiver should use the affected IP 
and should immediately contact an AstraZeneca representative for further guidance: 

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x 
Temperature excursion upon receipt or during storage at the study center 
x 
Damaged kit upon receipt 
x 
Damaged AI device 
Damaged IP should be documented via IWRS/IVRS (please refer to IWRS/IVRS manual for 
further details). 
6.4 
Accountability 
The study drug provided for this study will be used only as directed in the study protocol. 
The study personnel will account for all study drugs dispensed to the patient. 
The monitor will account for all study drugs received at the center, unused study drugs, and for 
appropriate destruction or return of materials to the Sponsor.  Certificates of delivery, destruction, 
and/or return should be signed. 
The patient will be responsible for refrigerating the product at home.  The patient will be 
responsible for returning used AI devices and completed administration questionnaires to the study 
center. 
Patients who fail to meet the inclusion/exclusion criteria should not, under any circumstances, 
be enrolled or receive study medication.  There can be no exceptions to this rule. 
6.5 
Methods for return of used single-use auto-injector devices 
Study sites will be shipped an appropriate number of Bio-bottles (hard plastic, wide-mouth bottles 
approved for containing and shipping biohazardous and/or sharps materials).  Patients who are 
given IP to administer at home will also be given one Bio-bottle for each of the two doses to be 
administered at home.  The Bio-bottle will be given at the time the IP is provided to the patient.   
Instruction for Use (IFU) provided to the patient with each IP kit will include instructions on how 
to properly package the used AI device in the Bio-bottle.  Patients will be instructed to bring the 
used AI device packaged in the Bio-bottle along with the completed administration questionnaire to 
the clinic during next center visit.  
The completed administration questionnaire and the Bio-bottle containing the used AI will be 
returned to the Sponsor by the clinical site following the Auto-injector Return Working Instruction 
document provided to the study sites.  All site coordinators of clinical centers participating in the 
study will receive training prior to study start. 
6.5.1 Reporting product complaints 
Any defects with the IP must be reported immediately to the Site Monitor.  All defects will be 
communicated to the Sponsor and investigated further with the AstraZeneca Supply Chain Group.  
During the investigation of the product complaint, all IP must be stored at labeled conditions 2°C to 
8°C (36°F to 46°F), separated from other IP kits, unless otherwise instructed. 

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6.5.1.1 
Reporting defects 
Product defects may be related to component, product, or packaging and labeling issues prior to or 
during use.  Product defects should be reported to the Study Monitor.  The list below includes, but 
is not limited to, descriptions of product complaints in these 3 categories should be reported as 
defects: 
x 
Component Issue: Defect in container or dosing mechanism of the IP.  The component 
defect may be damaged, missing, or broken.  Component examples include the Autoinjector 
and the prefilled syringe housed within the Autoinjector. 
x 
Product Issue: Defect in the product itself. The product appearance has visual 
imperfections such as foreign particles, crystallization, discoloration, turbidity, insufficient 
volume, or anything that does not apply to the product description in the IFU. 
x 
Packaging/Labeling Issue: Defect in the packaging or labeling of the product.  The 
packaging (carton, thermo-fitted tray, or tamper-evident seal) or labeling defects may be 
damaged or unreadable, or the label may be missing. 
6.5.1.2 
Single Use Auto-Injector malfunction 
An AI device malfunction is when the AI device appears normal during verification of shipment 
and then does not work during administration, e.g., the autoinjector activated prematurely, the 
autoinjector stalled or did not expel the full volume, needle guard safety feature did not deploy or 
remain locked, glass syringe breakage, needle bent or broke upon use. Device malfunctions should 
be reported using the Device Malfunction Return Instruction and the Study Monitor should be 
notified. 
Site staff will be asked to send back malfunctioning devices to the depot or local sponsor company 
according to local procedures.  Address and attention for malfunctioning device is available in the 
Device Malfunction Return Instruction. 
6.6 
Investigational product administration and treatment compliance 
The administration of all study drugs (including IPs) should be recorded in the appropriate sections 
of the Case Report Form (CRF). 
The IP will be administered at the study center for first 3 doses and at home for following 2 doses.  
IP administration should be done within visit windows as specified in 

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.  All information regarding IP administration will be provided in the Instruction for Use 
(IFU). 
Before investigational product administration 
Prior to each IP administration at study center: 
x 
Investigator/authorized delegate will assess injection site as per standards of medical 
care  
x 
For WOCBP, urine pregnancy test will be done; IP will be administered only when the 
result of the test is negative (see Section 5.2.4.1) 
Prior to each IP administration in at-home setting: 
x 
Investigator/authorized delegate will perform visit reminder call within 48h prior 
scheduled IP administration.  The conversation should include only basic information 
and serve as a reminder to the patient about the next scheduled visit to occur within 48 
hours after home administration. 
x 
For WOCBP, urine pregnancy test will be done; IP will be administered only when the 
result of the test is negative (see Section 5.2.4.1) 
Investigational product administration 
The IP will be administered by the Investigator/authorized delegate/patient/caregiver as 
specified in Table 2.  If patient is not willing or not able to self-administer (or caregiver is not 
willing/able to administer) at Visit 4 patient will be discontinued from the IP.  
It is suggested that the site of injection of the IP be rotated such that the patient receives IP at 
a different anatomical site each time.  Suggested injection site rotation sequence is presented 
below (see Figure 3).  In the case when rotation of the injection site is not favorable for the 
patient and/or Investigator, the reason should be recorded in the source documents.  The 
injection site must be recorded in the source documents and the eCRF at each treatment visit.  
If IP is self-administered by the patient, the injection should be done in the abdomen or thigh; 
when the injection is performed by the healthcare provider (HCP) or caregiver: in the 
abdomen, or thigh or upper arm (site reserved only for injections performed by HCP or 
caregiver - see Figure 3). The same person must administer the IP throughout the study, 
whether it is the patient or caregiver. 
Further details on IP administration are provided in the Instruction for Use (IFU).  
Investigational product administration must be carried out in line with the instructions 
provided. 

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Figure 3 
Injection sites and rotation scheme 
 
After investigational product administration 
After IP administration the patient should be observed for a minimum of 2 hours by the HCP 
(or responsible adult if injection was done at home) for the appearance of any acute drug 
reactions. Patient/caregiver will be trained by the study site on the use of epinephrine 
containing device that will be provided. If IP administration was performed at home, the 
patient should visit the study centre for the previously scheduled center visit within 48 hours 
after IP administration. 
Conditions requiring investigational product administration rescheduling  
If any of the following occur, the Investigator should reschedule the visit and the IP should not 
be administered until the rescheduled visit: 
x 
The patient has an intercurrent illness that, in the opinion of the Investigator, may 
compromise the safety of the patient in the study (eg, viral illnesses) 
The patient and caregiver, if applicable, should be informed about these conditions and 
reminded prior to at-home administration. In case of any doubts before at-home 
administration, patient should contact study center. 
6.7 
Management of investigational product-related reactions 
Prior to the first 3 administrations, which will be performed in the clinic, patients will have 
had a pre-assessment (ie, vital signs) prior to IP administration, and will be observed after IP 
administration for a minimum of 2 hours for the appearance of any acute drug reactions. 
 Study personnel should inform patients that, for subsequent administrations, they should be 
observed for 2 hours after IP administration for the appearance of any acute drug reactions. As 
with any medication, in case of an anaphylactic reaction at home, the patient or caregiver 
should immediately contact an emergency care unit or emergency transportation as per 
standard medical practice, and contact study site personnel.   
Appropriate drugs (eg, epinephrine, H1 and H2 antihistamines, and corticosteroids), and 
medical equipment to treat acute anaphylactic reactions must be immediately available.  Study 
personnel must be trained to recognize and treat anaphylaxis (Lieberman et al 2010).  Details 
on anaphylaxis management are provided in Appendix D. 

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Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Simpson et al 2006).  Anaphylaxis typically manifests as 1 of 3 clinical scenarios: 
10. 
The acute onset of a reaction (minutes to hours) with involvement of the skin, 
mucosal tissue, or both, and at least 1 of the following: a) respiratory compromise 
or b) reduced blood pressure or symptoms of end-organ dysfunction 
11. 
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 
12. 
Reduced blood pressure after exposure 
In order to help understand the potential drug-relatedness of any acute reaction, a blood 
sample should be drawn during the event for additional ADA testing (if not already scheduled 
for this visit).  Serum tryptase or other blood or urine testing relevant to the diagnosis of 
anaphylaxis may be obtained at a local lab at the discretion of the Investigator. 
7. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
7.1 
Definition of adverse events 
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product.  An 
undesirable medical condition can be symptoms (eg, nausea, chest pain), signs (eg, 
tachycardia, enlarged liver) or the abnormal results of an investigation (eg, laboratory 
findings, ECG).  In clinical studies, an AE can include an undesirable medical condition 
occurring at any time, including run-in or washout periods, even if no study treatment has 
been administered. 
The term AE is used to include both serious and non-serious AEs. 
7.2 
Definitions of serious adverse event 
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, 
treatment, washout, follow-up), that fulfills 1 or more of the following criteria: 
x 
Results in death 
x 
Is immediately life-threatening 
x 
Requires in-patient hospitalization or prolongation of existing hospitalization  

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x 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
x 
Is a congenital abnormality or birth defect 
x 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent 1 of the outcomes listed above. 
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol 
7.3 
Recording of adverse events 
7.3.1 Time period for collection of adverse events 
Adverse events will be collected from the time the patient signs the informed consent, 
throughout the treatment period and including the follow-up period (through Week 28). 
Serious adverse events will be recorded from the time of informed consent. 
7.3.2 Follow-up of unresolved adverse events 
Any AEs that are unresolved at follow-up in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in 
the case report form (CRF). AstraZeneca retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary. 
7.3.3 Variables  
The following variables will be collect for each AE; 
x 
AE (verbatim) 
x 
The date when the AE started and stopped 
x 
Maximum intensity of the AE 
x 
Whether the AE is serious or not 
x 
Investigator causality rating against the Investigational Product (yes or no) 
x 
Action taken with regard to investigational product 
x 
AE caused subject’s withdrawal from study (yes or no) 
x 
Outcome. 
In addition, the following variables will be collected for SAEs: 

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x 
Date AE met criteria for serious AE 
x 
Date Investigator became aware of serious AE 
x 
AE is serious due to 
x 
Date of hospitalization 
x 
Date of discharge 
x 
Probable cause of death 
x 
Date of death 
x 
Autopsy performed 
x 
Causality assessment in relation to Study procedure(s) 
x 
Description of AE 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 7.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 7.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 7.2. 
7.3.4 Causality collection 
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’ 
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol. 
7.3.5 Adverse events based on signs and symptoms 
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the CRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 

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symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 
7.3.6 Adverse events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarized in the 
clinical study report.  Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
7.3.7 
Disease progression 
When collecting AEs, the recording of diagnoses is preferred when possible to the recording 
of signs or symptoms. Asthma signs or symptoms such as wheeze, cough, chest tightness, 
breathlessness etc. will be recorded as AEs only when: 
x The sign or symptom is serious according to definition, see Section 7.2 
x The patient discontinues the study due to the sign or symptom. 
x The sign or symptom is new to the patient or is not consistent with the patient’s pre-
existing asthma history as judged by the Investigator. 
Asthma exacerbation should be recorded as an AE or SAE only if it fulfills any of the above 
criteria. 
7.3.8 Hy’s Law 
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3xULN together with total bilirubin ≥2xULN may need to 
be reported as SAEs.  Please refer to Appendix C for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law. 
7.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the CRF. 

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If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours  of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1 
calendar day of initial receipt for fatal and life threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day ie, immediately but no later than 24 hours of when he or she becomes 
aware of it. 
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative. 
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed.  
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure (IB) for the AstraZeneca drug. 
7.5 
Overdose 
x 
An overdose with associated AEs will be recorded as the AE diagnosis/symptoms on 
the relevant AE modules in the CRF and on the Overdose CRF module 
x 
An overdose without associated symptoms will be reported on the Overdose CRF 
module only 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
Investigators or other center personnel will inform appropriate AstraZeneca representatives 
within 1 day, ie, immediately but no later than 24 hours from when he or she becomes aware 
of it. 
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with a SAE, standard reporting timelines apply, see Section 7.4 For 
other overdoses, reporting should be done within 30 days. 

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7.6 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. 
7.6.1 Maternal exposure 
If a subject becomes pregnant during the course of the study investigational product should be 
discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the subject was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day ie, immediately but no later 
than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section7.4) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy. 
7.6.2 Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the study and for 
16 weeks (5 half-lives) following the last dose. 
Pregnancy of the patient’s partners will not be considered an AE.  However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should be followed up and documented for conceptions 
occurring from the date of the first administration of IP until 16 weeks (5 half-lives) after the 
last administration of IP. 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA 
8.1 
Statistical considerations 
Analyses will be performed by AstraZeneca or its representatives. 

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The SAP will be prepared prior to first patient enter treatment period and any subsequent 
amendments will be documented, with final amendments completed prior to data base lock  
8.2 
Sample size estimate  
No hypotheses will be tested statistically. Approximately 120 patients will receive the 
treatment to allow approximately 100 patients to complete the study. It is based upon a 
targeted recruitment with an adjustment to account for a 17% patient’s drop-out rate.  
8.3 
Definitions of analysis sets 
Three patient populations are defined below: All patients’ analysis set, Full analysis set (FAS), 
and Pharmacokinetics analysis set. 
 
Patients must have provided their informed consent. If no signed informed consent is collected 
(major protocol deviation (PD)), then the patient will be excluded from all analysis sets 
defined below. 
 
8.3.1 All patients analysis set 
The all patients analysis set will comprise all patients screened for the study and will be used 
for the reporting of disposition and screening failures. 
8.3.2 Full analysis set 
All patients receiving at least one IP will be included in the full analysis set (FAS), 
irrespective of their protocol adherence and continued participation in the study.  Patients who 
withdraw consent to participate in the study will be included up to the date of their study 
termination.  
All analyses, except for PK analysis, will be performed using the FAS. 
8.3.3 Pharmacokinetic analysis set 
All patients who received benralizumab and from whom PK blood samples were collected are 
assumed not to be affected by factors such as protocol violations will be included in the PK 
analysis dataset.  Those patients who had at least 1 quantifiable serum PK observation post 
first dose will be included in the PK analysis dataset. All PK summaries will be based on this 
analysis set. 
8.4 
Variables for analyses 
8.4.1 Calculation or derivation of primary endpoints  
8.4.1.1 
Primary endpoints 
The primary endpoints are as follows:  
x 
Proportion of patients/caregivers who successfully administered benralizumab with an 
AI device at home among those who have been deemed by the Principal Investigator to 
be suitable for at-home administration and are still in the study at Week 12 or Week 
16.  A successful administration is defined as an injection completed, an answer of 

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“Yes” to all 5 questions in the administration questionnaire (see Appendix G), and the 
autoinjector adequately passed the visual inspection and functional tests.  
Patients/caregivers who are unwilling to self-administer at Week 8 will not be 
considered as failures, but will be counted as unsuitable for at-home administration and 
follow the premature IP Discontinuation (IPD) procedure.  
x 
Proportion of returned AI devices used to administer benralizumab at home that have 
been evaluated as functional among all returned AI devices used to administer 
benralizumab at home.  A functional AI device is defined as an answer of “Yes” to all 
the questions in the visual inspection and function tests. Devices that are not returned 
for evaluation will be excluded from analysis. 
x 
Proportion of returned AI devices used to administer benralizumab at home and in the 
clinic that have been reported as malfunctioning (Product Complaints). 
The first 2 endpoints above will be calculated at Weeks 12 and 16, while the third endpoint 
will be obtained at each of the post-treatment periods (Weeks 0, 4, 8, 12, and 16). 
In addition, the following variables will be calculated among all patients/caregivers who have 
been deemed by the Investigator to be suitable for at-home administration at Week 8 and are 
still in the study at Week16:  
x 
Proportion of patients/caregivers who successfully administered benralizumab with an 
AI device at both Weeks 12 and 16, and 
x 
Proportion of patients/caregivers who returned an AI device used to administer 
benralizumab at home and evaluated as functional at both Weeks 12 and 16. 
8.4.2 Calculation or derivation of efficacy variable(s) 
8.4.2.1 
Asthma Control Questionnaire (ACQ-6) 
The outcome variable for ACQ-6 will be the change in mean score from baseline (Week 0) to 
each of the post-treatment periods. 
Patients will be categorized according to their asthma control responder status using the 
following limits (Juniper et al 2005) at the end of treatment (EOT) visit: 
x 
ACQ-6  EOT – baseline) ≤ -0.5 → Improvement 
x 
-0.5< ACQ-6 (EOT – baseline) < 0.5 → No change 
x 
ACQ-6 (EOT – baseline) ≥ 0.5 → Deterioration 
An ACQ-6 responder will be defined as a patient who had improvement on ACQ-6, ie, an 
ACQ-6 responder variable takes value 1 if change from baseline to end of treatment in 
ACQ-6 ≤ -0.5 and 0 otherwise. 

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Furthermore, patients will also be categorized according to their ACQ-6-defined asthma 
control status at the end of treatment using the following score thresholds (Juniper et al 2006) 
at the EOT visit: 
x 
ACQ-6 (EOT ) ≤ 0.75 → Well controlled 
x 
0.75< ACQ-6 (EOT) < 1.5 → Partly controlled 
x 
ACQ-6 (EOT) ≥ 1.5 → not well controlled 
8.4.3 Calculation or derivation of safety variable(s) 
8.4.3.1 
Safety variables 
The following safety data will be collected: AEs, vital signs, physical examination, 
hematology, clinical chemistry, urinalysis. 
Change from baseline (Week 0) to each post-treatment time point where scheduled 
assessments were made will be calculated for relevant measurements.   
8.4.3.2 
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 hematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction, 
or significant additional treatment. 
8.4.4 Calculation or derivation of pharmacokinetic variables 
No formal PK data analysis is planned due to the limited sampling schedule and variations in 
sampling time post self-administration.  Benralizumab serum concentrations will be 
summarized at each visit using descriptive statistics.  The PK results will be provided in the 
CSR. 
8.4.5 Calculation or derivation of immunogenicity variables 
ADA assessments will be conducted utilizing a tiered approach (screen, confirm, titer).  
8.5 
Methods for statistical analyses 
The analysis of the primary endpoints will include all data captured during Weeks 12 and 16 
(for Product Complaints with addition of Weeks 0, 4 and 8) while secondary endpoints will 
include all data captured during the 20-week treatment period, and up to follow-up (where 
applicable), unless the patient withdraws consent to study participation, regardless of whether 
study treatment was prematurely discontinued, or delayed, and/or irrespective of protocol 

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adherence. All efficacy analyses will be performed using an Intent-to-Treat (ITT) approach 
based on the FAS. For consistency, demographic and baseline characteristics will be presented 
using FAS. Safety objectives will also be analyzed using the FAS. 
8.5.1 Primary and secondary analysis method(s) 
No formal statistical analyses will be performed.  Primary and secondary endpoints will be 
summarized descriptively and all data will be listed.  Exact 95% confidence interval estimates 
will also be presented for the primary endpoints.   
8.5.1.1 
Analysis methods for pharmacokinetic variables 
The PK analyses will be performed at or under the guidance of AstraZeneca Research and 
Development. 
Benralizumab serum concentrations will be summarized using descriptive statistics at each 
visit.  No formal PK data analysis is planned due to sparse sampling and variations of 
sampling time following benralizumab self-administrations.  Observed serum concentrations 
of benralizumab for each individual will be listed by visit to confirm benralizumab 
administration.  Serum concentrations of benralizumab will be provided in the CSR. 
8.5.1.2 
Analysis methods for blood eosinophil levels 
Blood eosinophil levels will be summarized using standard summary statistics and plots at 
each visit. 
8.5.1.3 
Analysis method for immunogenicity variables 
The potential association of ADA with safety will be evaluated.  The association of ADA titer 
with benralizumab concentration and blood eosinophil levels will be evaluated for ADA-
positive patients only.  
8.5.2 Analysis methods for safety variables 
AEs will be summarized by means of counts by study period (treatment period and follow-up 
period). AEs will be listed for each patient and summarized by System Organ Class (SOC) 
and Preferred Term (PT) assigned to the event by MedDRA.   
Laboratory 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. Similar summaries will be 
performed for vital signs.  Shifts from normal to abnormal between baseline and follow-up 
will be evaluated for the physical examination. 

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8.5.3 Subgroup analysis 
To explore the uniformity of the estimates, the primary endpoints will also be summarized 
separately for patients self-administering and caregivers who are administering to the patient 
for the first 2 endpoints.  
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA 
9.1 
Training of study center personnel 
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and WBDC, 
IWRS/IVRS, PROs, and other systems to be utilized. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, study patient and caregiver if applicable, and that any new information 
relevant to the performance of this study is forwarded to the staff involved.  
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
9.2 
Monitoring of the study 
During the study, an AstraZeneca representative will have regular contacts with the study 
center, including visits to: 
x 
Provide information and support to the Investigator(s) 
x 
Confirm that facilities remain acceptable 
x 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed 
x 
Perform source data verification (a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating patients.  This will 
require direct access to all original records for each patient (eg, clinic charts) 
x 
Ensure withdrawal of informed consent to the use of the patient’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, 
and the action is documented, and reported to the patient. 
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the center needs information and advice about the study conduct. 

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9.2.1 Source data 
Please refer to the Clinical Study Agreement (CSA) for location of source data. 
9.2.2 Recording of data  
A Web-based Data Capture (WBDC) system will be used for data collection and query 
handling. Trained study center personnel will be responsible for entering data on the 
observations, tests, and assessments specified in the CSP into the WBDC system and 
according to eCRF instructions.  The eCRF instructions will also guide the study center in 
performing data entry. 
Data entered in the WBDC system will be immediately saved to a central database and 
changes tracked to provide an audit trail.  The data will then be source data verified, 
reviewed/queried and updated as needed.  The data will be validated as defined in the Data 
Management Plan.  The Investigator will ensure that data are recorded on the eCRFs as 
specified in the CSP and in accordance with the instructions provided.  
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the CSA. The Investigator will sign 
the completed eCRFs. A copy of the completed eCRFs will be archived at the study center. 
9.2.3 Study agreements 
The Principal Investigator at each/the study center should comply with all the terms, 
conditions, and obligations of the Clinical Study Agreement (CSA), or equivalent, for this 
study.  In the event of any inconsistency between this CSP and the CSA, the terms of CSP 
shall prevail with respect to the conduct of the study and the treatment of patients and in all 
other respects, not relating to study conduct or treatment of patients, the terms of the CSA 
shall prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled. 
9.2.4 Archiving of study documents 
The Investigator follows the principles outlined in the CSA. 
9.3 
Study timetable and end of study 
The end of the study is defined as ‘the last visit of the last patient undergoing the study. 
The study is expected to start in Q4 2016 and to end by Q4 2017 
The study may be terminated at individual study centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow. AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with benralizumab. 

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9.4 
Data management by AstraZeneca 
Data management will be performed by AstraZeneca Data Management Centre staff 
according to the Data Management Plan. Adverse events and medical/surgical history will be 
classified according to the terminology of the latest version the Medical Dictionary for 
Regulatory Activities (MedDRA). Medications will be classified according to the AstraZeneca 
Drug Dictionary. Classification coding will be performed by the Medical Coding Team at the 
AstraZeneca Data Management Centre. 
 
The data collected through third party sources will be obtained and reconciled against study 
data.  
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version MedDRA. Medications will be classified according to the AstraZeneca Drug 
Dictionary. All coding will be performed by the Medical Coding Team at the AstraZeneca 
Data Management Centre. 
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trail. 
The data will be validated as defined in the data management plan (DMP). Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. The DMP will also clarify the roles and responsibilities of 
the various functions and personnel involved in the data management process. 
When all data have been coded, validated, signed and locked, clean file will be declared. Any 
treatment revealing data may thereafter be added and the final database will be locked. 
Serious adverse event reconciliation 
Serious adverse event reconciliation reports are produced and reconciled with the Patient 
Safety database and/or the investigational site. 
Data associated with human biological samples 
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca. 
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on 

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Harmonisation/Good Clinical Practice, applicable regulatory requirements and the 
AstraZeneca policy on Bioethics and Human Biological Samples. 
10.2 
Subject data protection 
The Informed Consent Form (ICF), will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
10.3 
Ethics and regulatory review 
An Ethics Committee (EC) should approve the final study protocol, including the final version 
of the ICF, and any other written information and/or materials to be provided to the patients.  
The Investigator will ensure the distribution of these documents to the applicable EC, and to 
the study center staff. 
The opinion of the EC should be given in writing.  The Investigator should submit the written 
approval to AstraZeneca before enrollment of any patient into the study.  
The EC should approve all advertising used to recruit patients for the study. 
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements. 
If required by local regulations, the protocol should be re-approved by the EC annually. 
Before enrollment of any patient into the study, the final study protocol, including the final 
version of the ICF 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, ECs, and Principal Investigators with safety 
updates/reports according to local requirements, including SUSARs (Suspected Unexpected 
Serious Adverse Reactions), where relevant. 
Each Principal Investigator is responsible for providing the ECs/Institutional Review Board 
(IRB) with reports of any serious and unexpected adverse drug reactions from any other study 
conducted with the IP.  AstraZeneca will provide this information to the Principal Investigator 
so that he/she can meet these reporting requirements. 
10.4 
Informed consent 
The Principal Investigator(s) at each study center will: 
x 
Ensure each patient or legal guardian is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study (before 

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

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analysed, and accurately reported according to the protocol, GCP guidelines of the 
International Conference on Harmonisation (ICH), and any applicable regulatory 
requirements.  The Investigator will contact AstraZeneca immediately if contacted by a 
regulatory agency or other body about an inspection or an audit at the study center. 

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