A Double-Blind, Randomized, Parallel Group, Placebo-Controlled Multi-Centre Study to Evaluate the Effect of Benralizumab on Allergen-Induced Inflammation in Mild, Atopic Asthmatics
Phase: PHASE3
Conditions: Asthma
Sponsor: AstraZeneca

1 (113)
Clinical Study Protocol 
Drug Substance
MEDI-563
Study Code
D3250C00040
Version
4.0
Date
26-March-2018
A Double-Blind, Randomized, Parallel Group, Placebo-Controlled Multi-
Centre Study to Evaluate the Effect of Benralizumab on Allergen-Induced 
Inflammation in Mild, Atopic Asthmatics
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden

Clinical Study Protocol Synopsis
Drug Substance MEDI-563
Study Code D3250C00040
Version 4.0
Date 26-Mar-2018
2 (113)
VERSION HISTORY
Version 4.0, 26 March 2018 
Changes to the protocol are summarized below.
Protocol Synopsis (Objectives – Secondary Objectives): Section was updated to clarify that 
objectives related to bone marrow and bronchoscopy are done in only a sub-set of subjects.
Protocol Synopsis (Statistical methods): Stratification text was clarified to show that 
stratification is done based on types of measurements.
Section 2.2 (Secondary Objectives): Section was updated to clarify that objectives related to 
bone marrow and bronchoscopy are done in only a sub-set of subjects. 
Section 3.5 (Methods for assigning treatment groups): Stratification text was clarified to show 
that stratification is done based on types of measurements.
Section 4 (Table 2 Study Plan – Treatment Period): Footnote (e) was updated to clarify that 
only a sub-set of subjects in a designated study centre will provide bone marrow.
Section 4 (Table 2 Study Plan - Treatment Period): Footnote (t) was added to clarify which 
preceding Visit dictates the time to the FU Visit (in line with Section 4.3).
Section 4.1 (Enrolment/screening period): Text updated to clarify that only a sub-set of up to 
22 subjects recruited at one of the study centres will be required to provide consent to supply a 
sample of their bone marrow.
Section 5.1.7 (Bone marrow aspiration, processing and culture): Text updated to clarify that 
bone marrow aspirates will only be collected from a sub-set of up to 22 subjects enrolled at 
one study site.
Section 8.2 (Sample size estimate): The section was modified to add clarity to the number of 
subjects that are part of the sub-set participating in the bone marrow aspirate collection.
Version 3.0, 14 February 2017 
Changes to the protocol are summarized below.
Protocol Synopsis (Study site(s) and number of subjects planned): The section was modified 
to clarify that study subjects will be recruited at 6 centres
 
Protocol Synopsis (Secondary Objectives): Objective #1 was added to clarify that the percent
of eosinophils in sputum will be measured 24-hr post allergen challenge and evaluated as 
described in section 8.4.1.1. 

Clinical Study Protocol Synopsis
Drug Substance MEDI-563
Study Code D3250C00040
Version 4.0
Date 26-Mar-2018
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Protocol Synopsis (Secondary Objectives – Objective #7 (Outcome Measure): The section 
was modified to correct a typo in the word “cytospins”. 
Section 2.2 (Secondary Objectives): Objective #1 was added to clarify that the percent of 
eosinophils in sputum will be measured 24-hr post allergen challenge and evaluated as 
described in section 8.4.1.1. 
Section 2.2 (Secondary Objectives – Objective #7 (Outcome Measure): The section was 
modified to correct a typo in the word “cytospins”. 
Section 3.2 (Exclusion Criteria): For consistency, the restricted use of inhaled or intranasal 
corticosteroids throughout the study (previously mentioned in exclusion criterion #11) was 
moved to section 3.8 (restriction #6). Exclusion criterion #12 was revised to clarify that use of 
orally or systemically administered corticosteroids is prohibited within the 12 weeks prior to 
enrolment into this study. Exclusion criterion #30 was revised to clarify that allergen 
immunotherapy is prohibited within 4 months prior to the date informed consent is obtained. 
For consistency, the prohibited use of allergen immunotherapy throughout the study was 
moved to section 3.8 (restriction #18).  Exclusion criterion #32 was modified to correct a typo 
in the word “non-biologic”.
Section 3.8 (Restrictions): Restriction #2 was modified to be in line with Table 5. The section 
was also modified to clarify the prohibited use of the following medication/therapy should 
also be throughout the study: a) chronic use of antiplatelet agents (restriction #15), b) 
immunosuppressive medication (restriction #16), c) immunoglobulin and blood products 
(restriction #17), any marketed (eg omalizumab) or investigational biologic (restriction #18), 
d) live attenuated vaccines (restriction #20) and any investigational non-biologic (restriction 
#21). Last, the section was modified to clarify use of allergen immunotherapy in line with 
section 3.2 (restriction #19). 
Section 3.9 (Discontinuation of Investigational Product): The section was modified to clarify 
that IP unblinding will be a reason for discontinuation.   
Section 4 (Table 1 Study Plan – Enrollment, screening/run-in period): The table was revised to 
correct the section numbers referring to “Demographics” and “Medical and asthma history”
and to add a footnote “d”. 
Section 4 (Table 2 Study Plan - Treatment Period):  Visit windows were modified for Visit 6, 
Visit 9, Visit 10 and Visit 13. Footnote (i) was revised to clarify that basophil counts will be 
redacted from the lab report sent to the investigative sites for these sample collections. 
Footnote (i) was also revised to clarify that at visit 7 where Full Hematology and Hematology 
for leukocyte PD markers will be performed, only one blood sample will be required. 
Footnotes (j) to (u) were added to clarify the time between visits, the windows around visits 
and also which preceding Visit dictates the time to the next Visit.

Clinical Study Protocol Synopsis
Drug Substance MEDI-563
Study Code D3250C00040
Version 4.0
Date 26-Mar-2018
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Section 4.2.2.2 (Effect of Benralizumab on allergen-induced inflammation – Allergen 
Challenge Period 2): This section was revised to clarify the timing for the two allergen 
challenge triads.   
Section 5.1.6 (Spirometry): The section was revised to clarify that Visit 4 is performed at Day-
3.  
Section 5.1.9 (Blood for cell assessments and serum protein markers): The section was revised 
to clarify that basophil counts will be recorded from each collection and redacted from the lab 
report sent to the investigative sites.
Section 5.3.2 (Blood Coagulation): The section was modified to remove sample collection 
specifications for the coagulation testing. 
Section 5.4.1(Storage, re-use and destruction of biological samples): The section was 
modified to clarify sample storage conditions and sample use. 
Section 5.4.3 (Chain of Custody of Biological Samples): The section was modified to the 
principal investigator will keep documentation of all shipments.  
Section 7.8 (Table 5 and Table 6): Tables were modified to align the prohibited use of the 
medication/therapy with the revisions outlined in section 3.8 (restrictions). 
Section 8.4.1 (Calculation or Deviation of Efficacy Variables): The section was modified to 
remove the confusing statement that the two primary endpoints will be collected in the second 
analysis part of the study. 
Section 8.5.3 (Analyses methods for safety variables): The section was revised to clarify that 
ECG data will be summarized by presenting incidence of clinically notable ECG 
abnormalities. 
Appendix D (Anaphylaxis: signs and symptoms, management – Clinical Criteria for Defining 
Anaphylaxis and Immune Disease Anaphylaxis): The section was modified to remove 
“Immune Disease Anaphylaxis” from the heading and the description of immune complex 
disease.  
Version 2.0, 14 June 2016 
Changes to the protocol are summarized below.
Table of Contents: headings 2. Clinical Criteria for Defining Anaphylaxis and Immune 
Disease, 3. Signs and Symptoms and Management of Acute Anaphylaxis and 4. Management 

Clinical Study Protocol Synopsis
Drug Substance MEDI-563
Study Code D3250C00040
Version 4.0
Date 26-Mar-2018
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of Acute Anaphylaxis below the List of References were removed (formatting error)
List of abbreviations and definition of terms: The list was modified to add the abbreviation 
“PD” and its definition. 
Section 1.1 (Background and Rationale for Conducting this Study): Hyperlink inserted for 
reference Blanchard and Rothenberg 2009.
Section 1.4 (Study Design): The section was revised to clarify the approximate number of 
subjects that will be recruited to complete the study. 
Section 2.2 (Secondary Objectives): 
 
Section 3.1 (Inclusion Criteria): Inclusion criterion #4 was modified to revise “B2” to beta 
symbol (i.e. β2).
Section 3.1 (Inclusion Criteria): The section was modified to separate inclusion criterion 13 
from inclusion criterion 12 (formatting error).  
Section 3.6 (Methods for Ensuring Blinding): The section was modified to clarify the 
hematology findings (for full hematology and leukocyte PD markers) that will be reported 
back to the investigative site as well as those to be redacted from the lab reports. Additionally, 
the section was revised to clarify that procedures to mitigate unblinding should be followed 
from visit 4 on. 
Section 3.8 (Restrictions): restriction #11 was reworded to align with the opening statement. 
Section 3.9 (Discontinuation of Investigational Product): The section was revised to clarify the 
time when subjects who prematurely discontinue IP should return to the study centre and 
complete the procedures described for the IPD visit.  
Section 3.10.2 (Withdrawal of the informed consent): The section was modified to clarify the 
visits that subjects who withdraw from the study will be asked to complete. 
Section 4 (Table 1 Study Plan – Enrollment, screening/run-in period): Table 1 was modified to 
revise section numbering for cotinine testing and serology. Table 1 was modified to clarify 
that spirometry (FEV1) is being assessed at V1b as part of the already specified MCh PC20 
test.
Section 4 (Table 2 Study Plan - Treatment Period):  Table 2 was modified to revise visit 
window for V7 and V8, to remove the ADA/nAb testing (and the parallel footnote) and the 
height, weight and BMI assessments from EOT and IPD visits, to revise physical examination 
from “brief” to “complete” at IPD visit, to add full hematology, serum chemistry and 
urinalysis to V7 and full hematology to UNS. In addition, Table 2 was revised to change 
wording of “hematology for blood eosinophil count” to “hematology for leukocyte PD 

Clinical Study Protocol Synopsis
Drug Substance MEDI-563
Study Code D3250C00040
Version 4.0
Date 26-Mar-2018
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markers” will be performed at V4, V7 and V9 to V15 to clarify the type of analysis to be 
performed. Furthermore, footnotes were either revised or created to clarify the hematology 
(full hematology or for hematology for leukocyte PD markers) findings that will be reported 
back (and redacted) to the investigate site for these samples collections. Furthermore, 
footnotes were revised to clarify that subjects will be contacted prior to EOT visit (V16). 
Lastly, the footnote nomenclature was adjusted to reflect the modifications mentioned above.
Section 4.1 (Enrolment/screening Period (Visit 1 – Visit 3)): The number of study centres 
from which subjects will be required to provide consent for endobronchial biopsies was 
revised.
Section 4.1 (Enrolment/screening Period (Visit 1 – Visit 3)/Repeat of screening assessments 
versus Rescreening/Repeat assessments): The text “new section” was removed from 
“Methacholine PC20 (new section)”.  An unnecessary added “period” was also removed from 
the section on assessments performed at visit 4 (typo). Spirometry assessment was added to 
Visit 1b in line with the addition in Table 2.
Section 4.1 (Enrolment/screening Period (Visit 1 – Visit 3)/Repeat of screening assessments 
versus Rescreening/Rescreen assessments): The text was modified to clarify that if a subject 
requires rescreening, all procedures from screening/run-in period should be repeated with the 
exception of the skin prick testing. 
Section 4.2.1 (Baseline Inflammation Assessments): ADA/nAb testing was removed from the 
assessments to be conducted at visit 4. The section was revised to change wording of 
“hematology (for blood eosinophils)” to “for leukocyte PD markers” to clarify the blood 
sample analysis to be performed at V4.
Section 4.2.2 (Randomised Treatment Period): Timing for vital signs collection was clarified. 
Section 4.2.2.1 (Effect of Benralizumab on Baseline Inflammation): Timing for vital signs 
collection was clarified. The section was revised to change wording of “hematology (for blood 
eosinophils)” to “for leukocyte PD markers” to clarify the blood sample analysis to be 
performed at V7. Lastly, the section was modified to clarify that a predose blood sample will 
be collected for full hematology at V7. 
Section 4.2.2.2 (Effect of Benralizumab on Allergen-induced Inflammation/Allergen 
challenge period 1): The section was revised to change wording of “hematology (for blood 
eosinophils)” to “for leukocyte PD markers” to clarify the blood sample analysis to be 
performed at V10, V11 (7 hours post allergen challenge) and V12 (24 hours (±2 hours) post 
allergen challenge).
Section 4.2.2.2 (Effect of Benralizumab on Allergen-induced Inflammation/Allergen 
challenge period 2): The section was revised to change wording of “hematology (for blood 
eosinophils)” to “for leukocyte PD markers” to clarify the blood sample analysis to be 
performed at V13, V14 (7 hours post allergen challenge) and V15. In addition, the section was 
revised to clarify that subjects will be contacted prior to EOT visit (V16). Lastly, the text was 

Clinical Study Protocol Synopsis
Drug Substance MEDI-563
Study Code D3250C00040
Version 4.0
Date 26-Mar-2018
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revised to clarify the time when subjects who prematurely discontinue IP should return to the 
study centre and complete the procedures described for the IPD visit.  
Section 5.1.8 (Bronchoscopy and processing of samples): The section was modified to remove 
the assessment of eosinophil progenitor cells in endobronchial biopsies. 
Section 5.1.9 (Blood for cell assessments and serum protein markers): The section was 
reworded to clarify the different leukocytes recorded from each collection and to clarify which 
data should be reported back to the sites.
Section 5.2.1 (Laboratory Safety Assessments): Table 3 was modified to include assessment 
of RBC morphology. In addition, footnote to table was reworded to clarify data that is 
reported back to sites.
Section 5.3.3 (Immunogenicity): The section was removed. Immunogenicity (ADA/nAb) of 
benralizumab will not be assessed in this trial. 
Section 7.1 (Identity of Investigational Product(s)): Table 4 was modified to revise IP 
manufacturer. 
Section 7.3 (Management of IP related reactions): ADA testing was removed and lung 
function testing prior to IP administration was removed.  
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 Synopsis
Drug Substance MEDI-563
Study Code D3250C00040
Version 4.0
Date 26-Mar-2018
8 (113)
PROTOCOL SYNOPSIS
A Double-Blind, Randomized, Parallel Group, Placebo-Controlled Multi-
Centre Study to Evaluate the Effect of Benralizumab on Allergen-Induced 
Inflammation in Mild, Atopic Asthmatics
National Co-ordinating Investigator
 
Study site(s) and number of subjects planned
The study will include approximately 38 randomised patients, recruited at 6 centres 
 
 in Canada.
Study period
Phase of development
Estimated date of first subject enrolled
Q3 2016
3
Estimated date of last subject completed
Q4 2018
3
Study design
This randomized, double-blind, parallel group, placebo-controlled study will evaluate the 
effect of a fixed 30 mg dose of benralizumab administered subcutaneously every 4 weeks on 
allergen-induced inflammation in subjects with mild atopic asthma challenged with an inhaled 
allergen. 
Subjects who meet the eligibility criteria will be randomized to receive 3 subcutaneous (SC) 
doses of benralizumab 30 mg or placebo (1:1). 
Following the third dose of study treatment subjects will return to the clinic for the two 
allergen challenge periods. The first allergen challenge will assess effects of benralizumab on 
allergen–induced eosinophils in induced sputum and the late asthmatic response (LAR).  The 
second allergen challenge will assess effects of benralizumab on allergen–induced eosinophils 
and basophils in lung tissue.  Only clinical sites participating in bronchial biopsy collections 

Clinical Study Protocol Synopsis
Drug Substance MEDI-563
Study Code D3250C00040
Version 4.0
Date 26-Mar-2018
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will participate in the second allergen challenge. Subjects will return to the clinic 8 weeks and 
12 weeks following the last dose of benralizumab for End-of-Treatment (EOT) and follow-up 
assessments, respectively.
Objectives
(a)
Primary Objectives
Objective
Outcome Measure
To evaluate  the effect of benralizumab on 
allergen-induced increases in eosinophils in 
induced sputum 
Change in percent of eosinophils in sputum 7 hours 
post allergen challenge 
To evaluate the effect of benralizumab on the 
allergen-induced late (3 – 7 hrs post challenge) 
asthmatic response (LAR) 
Primary measure: Maximal percentage decrease in 
Forced Expiratory Volume in 1 Second (FEV1) 3-7 
hours post allergen challenge (LAR3-7 hr)
Supportive measure: AUC of time adjusted percent 
decrease in FEV1  curve in late asthmatic response 
(LAR3-7 hr)
(b)
Secondary Objectives
Objective
Outcome Measure
To assess the effect of benralizumab on 
allergen-induced increases in number of 
eosinophils in induced sputum
Change in percent of eosinophils in sputum 24 hours 
post allergen challenge
To assess the effect of benralizumab on 
allergen-induced increases in number of 
basophils in induced sputum
Change in percent of basophil numbers by toluidine 
blue staining 
To assess the effect of benralizumab on 
allergen-induced early (within 2 hrs post 
allergen challenge) asthmatic response (EAR)
Maximal percentage decrease in FEV1 0 – 2 hours 
post allergen challenge (EAR0-2 hr)
AUC of time adjusted percent decrease in FEV1  
curve in early asthmatic response (EAR0-2 hr)
To assess the effect of benralizumab on 
allergen-induced increases in number of 
eosinophils and basophils in lung tissue 
biopsies
Change in eosinophil and basophil numbers in 
endobronchial biopsies from prechallenge to 24 hours 
post allergen challenge (in a sub-set of subjects)
To assess the effect of benralizumab on 
allergen-induced increases in eosinophils, 
eosinophil progenitor cells and basophils in 
bone marrow aspirates
Change in eosinophils by smears, eosinophil 
progenitor cells and basophils by flow cytometry in 
bone marrow aspirates, from prechallenge to 24 hours 
post allergen challenge (in a sub-set of subjects)

Clinical Study Protocol Synopsis
Drug Substance MEDI-563
Study Code D3250C00040
Version 4.0
Date 26-Mar-2018
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To assess the effect of benralizumab on 
allergen-induced increases in eosinophils and 
basophils in blood
Change in eosinophil counts (by central lab count) 
and basophil counts (by flow cytometry) in blood  
from prechallenge to 24 hours post allergen challenge
To assess the effect of benralizumab on 
baseline levels of eosinophil and basophil 
inflammation in sputum, blood, bone marrow 
aspirates and lung tissue prior to allergen 
challenge
Change in percent of eosinophils in cytospins and 
basophils by toluidine blue staining from baseline to 
Visit 10 in induced sputum.
Change in eosinophil counts (by central lab count) 
and basophil counts (by flow cytometry) from 
baseline to Visit 10 in blood
Change in eosinophils by smears, eosinophil 
progenitor cells and basophils measured by flow 
cytometry from baseline to Visit 10 in bone marrow 
aspirates (in a sub-set of subjects)
Change in eosinophil and basophil numbers from 
baseline to Visit 8 in endobronchial biopsies (in a 
sub-set of subjects)
To evaluate the effect of benralizumab on 
airway hyper-responsiveness post allergen 
challenge
Methacholine PC20 (concentration of inhaled 
methacholine that produces a 20% fall in FEV1)
(c)
Safety Objective
Objective:
Outcome Measure :
To assess the safety and tolerability of 
benralizumab in subjects with mild atopic 
asthma
Adverse Events (AEs) and Serious adverse 
events ( SAEs)
Vital signs
Electrocardiogram (ECG)
Clinical chemistry/haemotology/urinalysis
Physical examination 

Clinical Study Protocol Synopsis
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Study Code D3250C00040
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(d)
Exploratory Objectives
Exploratory Objective:
Outcome Measure :
 
 
 
 
 
 
 
 
 
Target subject population
Men and women, 18 to 65 years of age, with mild allergic asthma, not using regular asthma 
controller medication and with confirmed dual (early and late) asthmatic response to inhaled 
allergen challenge.
Duration of treatment
Total length of the study is up to 37 weeks
!
Up to 16 weeks screening/run-in period
!
13 weeks treatment period
!
Follow-up period:
o
11 weeks for subjects doing allergen challenge 1
o
8 weeks for subjects doing allergen challenges 1 and 2
Investigational product, dosage and mode of administration
Benralizumab 30 mg/mL, or placebo, solution for injection in an accessorized pre-filled 
syringe (PFS) will be administered at the study centre SC every 4 weeks for 3 doses. 
Statistical methods
Approximately 38 subjects in total and 19 subjects in each treatment group are needed for this 
study based on the choice of two primary endpoints; the change in percentage of eosinophils 
in induced sputum at 7-hr post allergen challenge and the maximum percent decrease in FEV1  
in late asthmatic response (LAR3-7 hr) both measured after the first allergen challenge. These 
endpoints will be tested using a hierarchical fixed-sequence approach, the first assessment 
being the effect on percentage of eosinophils in sputum.
Subjects will be randomized in a 1:1 ratio to benralizumab or placebo. In order to have 
balanced number of subjects for the outcomes from induced sputum, blood, bone marrow and 
bronchoscopy measures, randomization will be stratified by the following types of 

Clinical Study Protocol Synopsis
Drug Substance MEDI-563
Study Code D3250C00040
Version 4.0
Date 26-Mar-2018
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measurements: 1) bone marrow plus bronchoscopy measurements, 2) bronchoscopy measures 
only, and 3) neither bone marrow nor bronchoscopy measurements.
The primary analysis method for the allergen induced change in percentage of eosinophils in 
induced sputum at 7-hr and 24-hr post challenge 1 will be compared between Benralizumab 
and Placebo using a repeated measures analysis. Treatment group will be fitted as an 
explanatory variable, pre-dose allergen induced change at Screening will be fitted as a 
covariate and visit will be fitted as a categorical variable.
The maximum percent decrease in FEV1 at LAR3-7 hr will be compared between Benralizumab 
and Placebo using an ANCOVA. Treatment group will be fitted as an explanatory variable 
and the corresponding pre-dose FEV1 value at Screening will be fitted as a covariate. 
Efficacy analysis will be performed using the full analysis set, which consists of all 
randomized subjects who received at least one dose of investigational product. 
All safety variables will be summarised descriptively.  Safety analysis will be performed in 
safety analysis set which is the same as full analysis set.

Clinical Study Protocol
Drug Substance MEDI-563
Study Code D3250C00040
Version 4.0
Date 26-March-2018
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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
PROTOCOL SYNOPSIS.....................................................................................8
TABLE OF CONTENTS................................................................................... 13
1.
INTRODUCTION ............................................................................................. 20
1.1
Background and rationale for conducting this study ........................................... 20
1.2
Rationale for study design, doses and control groups.......................................... 21
1.3
Benefit/risk and ethical assessment .................................................................... 22
1.4
Study Design...................................................................................................... 24
2.
STUDY OBJECTIVES...................................................................................... 27
2.1
Primary objective............................................................................................... 27
2.2
Secondary objectives.......................................................................................... 27
2.3
Safety objectives................................................................................................28
2.4
Exploratory objectives .......................................................................................29
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 29
3.1
Inclusion criteria ................................................................................................29
3.2
Exclusion criteria ............................................................................................... 32
3.3
Subject enrolment and randomization................................................................. 35
3.4
Procedures for handling incorrectly enrolled or randomized subjects.................. 35
3.5
Methods for assigning treatment groups............................................................. 36
3.6
Methods for ensuring blinding ........................................................................... 36
3.7
Methods for unblinding...................................................................................... 37
3.8
Restrictions........................................................................................................ 37
3.9
Discontinuation of investigational product .........................................................39
3.9.1
Procedures for discontinuation of a subject from investigational product............ 40
3.10
Criteria for withdrawal.......................................................................................40
3.10.1
Screen failures ................................................................................................... 40
3.10.2
Withdrawal of the informed consent................................................................... 40
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 41

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Study Code D3250C00040
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4.1
Enrolment/screening period (Visit 1 – Visit 3) ................................................... 48
4.2
Treatment period................................................................................................ 51
4.2.1
Baseline Inflammation assessments.................................................................... 51
4.2.2
Randomised treatment period............................................................................. 52
4.2.2.1
Effect of Benralizumab on baseline inflammation .............................................. 52
4.2.2.2
Effect of Benralizumab on allergen-induced inflammation................................. 53
4.3
Follow-up period................................................................................................ 57
5.
STUDY ASSESSMENTS..................................................................................57
5.1
Efficacy assessments.......................................................................................... 57
5.1.1
Allergen Inhalation Challenge............................................................................ 57
5.1.2
Allergen Skin Testing ........................................................................................59
5.1.3
Allergen Skin Titration Testing.......................................................................... 59
5.1.4
Methacholine Inhalation Tests............................................................................ 59
5.1.5
Sputum Induction............................................................................................... 60
5.1.6
Spirometry.........................................................................................................60
5.1.7
Bone Marrow Aspiration, processing and culture ............................................... 61
5.1.8
Bronchoscopy and processing of samples........................................................... 62
5.1.9
Blood for cell assessments and serum protein markers ....................................... 62
5.2
Safety assessments............................................................................................. 63
5.2.1
Laboratory safety assessments............................................................................ 63
5.2.1.1
Pregnancy Test...................................................................................................64
5.2.2
Physical examination ......................................................................................... 65
5.2.3
Brief physical examination................................................................................. 65
5.2.4
ECG................................................................................................................... 65
5.2.5
Vital signs.......................................................................................................... 65
5.3
Other assessments.............................................................................................. 66
5.3.1
Weight and height.............................................................................................. 66
5.3.2
Blood coagulation..............................................................................................66
5.3.3
Other screening/run in assessments ....................................................................66
5.3.3.1
Serology ............................................................................................................ 66
5.3.3.2
Cotinine testing..................................................................................................66
5.4
Biomarker analysis............................................................................................. 67
5.4.1
Storage, re-use and destruction of biological samples......................................... 67
5.4.2
Labelling and shipment of biological samples .................................................... 67
5.4.3
Chain of custody of biological samples .............................................................. 67
5.4.4
Withdrawal of Informed Consent for donated biological samples....................... 67
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 68
6.1
Definition of adverse events............................................................................... 68
6.2
Definitions of serious adverse event ................................................................... 68
6.3
Recording of adverse events............................................................................... 69
6.3.1
Time period for collection of adverse events ...................................................... 69

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6.3.2
Follow-up of unresolved adverse events............................................................. 69
6.3.3
Variables............................................................................................................ 69
6.3.4
Causality collection............................................................................................ 70
6.3.5
Adverse events based on signs and symptoms....................................................71
6.3.6
Adverse events based on examinations and tests ................................................71
6.3.7
Symptoms of the disease under study................................................................. 73
6.4
Reporting of serious adverse events ................................................................... 74
6.5
Overdose............................................................................................................ 74
6.6
Pregnancy .......................................................................................................... 75
6.6.1
Maternal exposure.............................................................................................. 75
6.6.2
Paternal exposure............................................................................................... 75
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 76
7.1
Identity of investigational product(s)..................................................................76
7.2
Dose and treatment regimens ............................................................................. 76
7.3
Management of IP related reactions.................................................................... 77
7.4
Labelling............................................................................................................ 78
7.5
Storage............................................................................................................... 79
7.6
Compliance........................................................................................................ 79
7.7
Accountability.................................................................................................... 79
7.8
Concomitant and other treatments...................................................................... 79
7.8.1
Other concomitant treatment .............................................................................. 81
8.
STATISTICAL ANALYSES BY ASTRAZENECA.......................................... 81
8.1
Statistical considerations.................................................................................... 81
8.2
Sample size estimate .......................................................................................... 82
8.3
Definitions of analysis sets................................................................................. 82
8.3.1
All subjects analysis set......................................................................................82
8.3.2
Full analysis set..................................................................................................82
8.3.3
Safety analysis set..............................................................................................83
8.4
Outcome measures for analyses.......................................................................... 83
8.4.1
Calculation or derivation of efficacy variables.................................................... 83
8.4.1.1
Allergen induced change in percentage of eosinophils in induced sputum 
post allergen challenge during allergen challenge 1............................................ 83
8.4.1.2
Maximum percent decrease in FEV1 in late asthmatic response (LAR)3-7 hr
during allergen challenge ................................................................................... 84
8.4.1.3
AUC of time adjusted percent decrease in FEV1 curve in late asthmatic 
response (LAR)3-7 hr during allergen challenge ................................................... 84
8.4.1.4
Percentage of eosinophils in induced sputum for the effect on baseline 
inflammation...................................................................................................... 84

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8.4.1.5
Basophil count in induced sputum for both allergen challenge and baseline 
inflammation...................................................................................................... 85
8.4.1.6
Maximum percent decrease in FEV1 in early asthmatic response 0-2 hr 
(EAR0-2hr)........................................................................................................... 85
8.4.1.7
AUC of time adjusted percent decrease in FEV1 curve in early asthmatic 
response (EAR0-2 hr)............................................................................................85
8.4.1.8
Number of eosinophils and basophils in lung tissue biopsies for both 
allergen challenge and baseline inflammation..................................................... 86
8.4.1.9
Eosinophil, eosinophil progenitor cells and basophils in bone marrow 
aspirates for both allergen challenge and baseline inflammation......................... 86
8.4.1.10
Eosinophils and basophils counts in the blood.................................................... 86
8.4.1.11
Methacholine PC20 (concentration of inhaled methacholine that produces 
a 20% fall in FEV1)............................................................................................ 87
8.4.1.12
Soluble inflammatory markers associated with pathology of asthma or the 
pharmacology of Benralizumab.......................................................................... 87
8.4.2
Calculation or derivation of safety variables.......................................................87
8.4.2.1
Safety variables..................................................................................................87
8.5
Methods for statistical analyses.......................................................................... 87
8.5.1
Analysis of the primary variable (s).................................................................... 88
8.5.1.1
Allergen induced change in percentage of eosinophils in induced sputum 
7-hr post allergen challenge during Allergen Challenge 1................................... 88
8.5.1.2
Maximum percent decrease in FEV1 in late asthmatic response (LAR3-7 hr) 
on Visit 11 during Allergen Challenge 1 ............................................................ 89
8.5.2
Analysis of the secondary variable(s) ................................................................. 89
8.5.3
Analyses methods for safety variables................................................................ 92
8.5.4
Exploratory analysis...........................................................................................92
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA......................... 93
9.1
Training of study site personnel ......................................................................... 93
9.2
Monitoring of the study...................................................................................... 93
9.2.1
Source data ........................................................................................................ 94
9.2.2
Study agreements............................................................................................... 94
9.2.3
Archiving of study documents............................................................................ 94
9.2.4
Deviation from the clinical study protocol.......................................................... 94
9.3
Study timetable and end of study........................................................................ 95
9.4
Data management by AstraZeneca ..................................................................... 95
10.
ETHICAL AND REGULATORY REQUIREMENTS....................................... 96
10.1
Ethical conduct of the study ............................................................................... 96
10.2
Subject data protection.......................................................................................96
10.3
Ethics and regulatory review ..............................................................................97
10.4
Informed consent ...............................................................................................97

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10.5
Changes to the protocol and informed consent form........................................... 98
10.6
Audits and inspections .......................................................................................98
11.
LIST OF REFERENCES ...................................................................................99
LIST OF TABLES
Table 1
Study Plan - Enrollment, screening/run-in period ..................................42
Table 2
Study Plan - Treatment period...............................................................44
Table 3
List of Safety Laboratory Tests .............................................................64
Table 4
Identity of investigational product.........................................................76
Table 5
Restricted Medications..........................................................................80
Table 6
Non-allowed medication .......................................................................80
LIST OF FIGURES
Figure 1
Study flow chart....................................................................................26
Figure 2
Injection sites and rotation scheme ........................................................77
LIST OF APPENDICES
Appendix A
Additional Safety Information............................................................. 102
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document............................................................................104
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ......................................................................105
Appendix D
Anaphylaxis: signs and symptoms, management ................................. 110

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ADA
Anti-drug Antibodies
AE
Adverse Event
AHR
Airway Hyperresponsiveness
CRF
Case Report Form (electronic/paper)
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Event
DAE
Discontinuation of Investigational Product due to Adverse Event
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
EAR
Early Allergic Response
FEV1  
Forced Expiratory Volume in 1 Second
GCP
Good Clinical Practice
ICH
International Conference on Harmonisation
ILC2
Type 2 Innate Lymphoid Cell 
IP
Investigational Product 
IPD
Investigational Product Discontinuation
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LAR
Late Allergic Response 
LSLV
Last Subject Last Visit
LIMS
Laboratory information management system
MCH
Methacholine
OAE
Other Significant Adverse Event
PI
Principal Investigator 
PD
Pharmacodynamics
SAE
Serious adverse event 

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Abbreviation or 
special term
Explanation
WBDC
Web Based Data Capture

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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Asthma is recognised by the presence of reversible bronchoconstriction, airway hyper-
responsiveness (AHR) and airway inflammation.  Environmental allergens are an important 
cause of asthma and can be studied in the laboratory by allergen inhalation challenge studies.
Allergen inhalation in sensitised subjects, induces an immediate bronchoconstriction (the early 
response), which is usually maximal within 30 minutes after allergen challenge and resolves 
between 1 to 3 hours.  A proportion of these subjects will also proceed to develop a second, 
delayed bronchoconstrictor response (the late asthmatic response) which is associated with 
prolonged AHR and a pronounced airway eosinophilia (Weersink et al 1994, Gauvreau et al 
1999).  These subjects who show both an early and late response are referred to as dual 
responders. 
Both the early response and the late response, after inhaled allergen challenge, are associated 
with inflammatory changes within the airways.  These inflammatory events have been 
investigated in airway tissue biopsy material, bronchoalveolar lavage fluid (BALF) and 
induced sputum.  Through the use of the allergen challenge model it is now recognised that 
mast cells are probably the predominant inflammatory cell involved in the early response 
whereas eosinophils, T lymphocytes (of the Th2 phenotype) and basophils are the major 
inflammatory cells contributing to the late response.  Indeed recent data suggests that 
basophils may be key important immune function cells for the induction of the late asthmatic 
response observed in the inhaled allergen model in atopic asthmatic subjects (Watson et al 
2015).
As well as inflammatory changes in the airways themselves, it is also recognised that there is a 
contribution to the inflammatory response to allergen provocation from the blood and the bone 
marrow, to selectively recruit and drive an eosinophilic response towards the airway (Gibson
et al 1991, Sehmi et al 1997).
As such the inhaled allergen challenge model in allergic asthmatic subjects has proved to be a 
useful model to understand some of the mechanisms involved in the inflammatory condition 
of allergic asthma and also for examining the effect of anti-inflammatory and 
immunomodulatory agents on allergen-induced inflammatory mechanisms and inflammation 
that can be used to help understand the mechanism of action of these agents as reviewed by 
Gauvreau et al 2015.  
Interleukin-5 (IL-5) is a key cytokine involved in the differentiation and maturation of 
eosinophils from hematopoietic stem cells in the bone marrow, their mobilization and 
migration from the bone marrow to the blood, and their activation and survival in tissue 
(Blanchard and Rothenberg 2009).  The receptor for IL-5 (IL-5Rα) is exclusively expressed 
on eosinophils and basophils.  

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Benralizumab (MEDI-563) is a humanized, afucosylated monoclonal antibody (IgG1k), which 
binds with high affinity to IL-5Rα and induces apoptosis of eosinophils and basophils through 
enhanced antibody dependant cellular cytotoxicity (ADCC) (Kolbeck et al 2010). Through 
this mechanism a clinical study with benralizumab in mild to moderate asthmatics showed a 
96% median reduction in eosinophils in the lung tissue, 90% median reduction in sputum 
eosinophils, 100% reduction in eosinophils in blood and 100% reduction in eosinophils and 
eosinophil precursors in bone marrow (Laviolette et al 2013). In this study benralizumab also 
reduced blood basophils by a median of 74%.
Furthermore, benralizumab has demonstrated efficacy in a Ph2b clinical trial in uncontrolled 
moderate to severe asthma subjects with eosinophilic inflammation reducing exacerbations, 
improving lung function and symptoms (Castro et al 2014) and is currently in Phase 3 trials 
(NCT01928771, NCT01914757).
We hypothesize that benralizumab may be effective in attenuating an allergen-induced late 
asthmatic response since benralizumab shows effective depletion of both eosinophils and 
basophils in blood and lung tissue of subjects with asthma.
1.2
Rationale for study design, doses and control groups
This will be a multi-centre, randomized, double-blind, parallel group, placebo controlled 
study.  The primary endpoints of the study are effect of treatment on percentage of eosinophils 
in sputum following allergen challenge and effect on the late asthmatic response in mild 
allergic asthmatics.  
Mild allergic asthmatics are the choice of study population in order to observe a mild 
respiratory physiological response and inflammatory response to inhaled allergen provocation. 
Both the proportion of sputum eosinophils and the LAR are primary endpoints in the study 
given the eosinophil and basophil depleting properties of benralizumab.  
Key secondary endpoints include the effect of treatment on the number of basophils in sputum 
and the number of eosinophils and basophils in the blood, bone marrow and lung tissue 
following allergen challenge. Sample collections for evaluating effects in the lung tissue and 
bone marrow have been reduced to a minimum of:
!
A collection prior to treatment to establish the number of eosinophils and 
basophils in these tissues prior to treatment (baseline), 
!
At the end of the treatment period but prior to allergen challenge to 
evaluate the effect of treatment on baseline eosinophils and basophils
!
After allergen challenge to evaluate the effect on allergen-induced 
increases in eosinophils and basophils
One of the aims of the study is to evaluate the effect of benralizumab on eosinophils and 
basophils in each of the tissue compartments where these cells are produced or migrate to 

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contributing to the pathology of asthma and to evaluate these effects on baseline inflammation 
and in response to allergen-induced inflammation.
Endobronchial biopsies are being collected to evaluate the effect of benralizumab on 
eosinophils and basophils in the lung tissue.  It has been shown that the anti-IL-5 antibodies 
(e.g. mepolizumab) can significantly deplete eosinophils in sputum (median 86% reduction) 
but only reduced tissue eosinophils by 55% (Flood-Page et al 2003).  Benralizumab has been 
shown to deplete eosinophils in lung tissue by median of 96% (Laviolette et al 2013) but is not 
known how effective benralizumab is at depleting basophils in lung tissue and whether it will 
reduce eosinophils and basophils in response to a provocating agent that results in enhanced 
eosinophilic and basophilic inflammation in the airway.
The bone marrow is the site where leukocytes are produced from progenitor cells.  
Mepolizumab and benralizumab (Flood-Page et al 2003; Laviolette et al 2013) have been 
shown to reduce eosinophils in the bone marrow but again there is little information on the 
effect on basophils and the effect on both eosinophils and basophils in response to allergen 
challenge.
In order to protect against any potential bias to the results, the study will be randomized and 
double-blind. The study is a parallel design, because benralizumab is a monoclonal antibody 
and has a long half-life and therefore precludes the possibility of a cross-over design which 
would prolong the washout period and have risk of carry over effects of drug between 
treatments. 
The benralizumab dose (30 mg SC) is based on all available safety, efficacy and 
immunogenicity data. 
The effects of treatment after 3 doses of benralizumab are being evaluated as previous data 
suggests that three SC doses every 4 weeks of benralizumab may be required to achieve 
optimal depletion of eosinophils in the lung tissue (Laviolette et al 2013).  A similar dosing 
regimen in the current study may optimize the pharmacological effects on the late asthmatic 
response. The first allergen challenge is timed to be conducted when PK concentration is 
expected to peak in serum and lung following the third dose of benralizumab. The second 
allergen challenge period is timed to be conducted when benralizumab PK exposure is at 
steady-state trough level.
A placebo treatment group is included to evaluate the effect of treatment relative to effects in 
a control group.
1.3
Benefit/risk and ethical assessment
It is not expected that asthma subjects in this study will receive any clinical benefit from 
participation in this study.  As the study population are proposed to be mild asthmatics that 
only use short-acting bronchodilators for treatment of symptoms, it is not expected that 
benralizumab will have clinical benefit in this population.

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Eosinophils are a prominent feature of the inflammatory response to helminthic parasitic 
infections, and the presence of infiltrating eosinophils has been circumstantially associated 
with a positive prognosis in certain solid tumors. Therefore, there is a theoretical risk that 
prolonged eosinophil depletion may diminish the ability to defend against helminthic 
parasites, or negatively impact the natural history of certain malignant tumors. Risk 
minimization measures include exclusion of subjects with untreated parasitic infection and 
active or recent malignancy, in conjunction with the performance of routine 
pharmacovigilance activities.
Anti-Drug Antibodies
Development of ADA to benralizumab has been documented. Theoretical risks of developing 
ADA include decreased drug efficacy and hypersensitivity reactions (eg, anaphylaxis or 
immune complex disease).
A detailed assessment of the overall risk/benefit of benralizumab in subjects with asthma is 
given in the Investigator’s Brochure.
Methacholine Challenge Test
Methacholine elicits airway narrowing in all individuals, but asthma subjects are 
hyperresponsive, in that it requires lower methacholine concentrations to achieve a response 
compared to non-asthmatic subjects. Severe bronchoconstriction, hyperinflation, or severe 
coughing are extremely rare events. In general, the methacholine challenge test is well 
tolerated, and respiratory symptoms in those who react to methacholine typically reverse 
promptly following bronchodilator administration. This test will be performed in a research 
laboratory with available personnel trained to treat acute bronchospasm and to use 
resuscitation equipment if needed.
Allergen Inhalation Challenge
Allergen inhalation challenges have been performed for over 20 years without safety 
concerns. Between 2003 and 2008, 965 individual research allergen inhalation challenges 
have been conducted across a number of centres in Canada
 
Allergen challenges are not 
without risk.  When conducted by experienced laboratories however, provoked models of 
asthma are extremely safe (O’Byrne 2009). 
Sputum Induction
The procedures for sputum induction have shown to be simple and safe, and the risks in 
subjects with stable asthma are acceptable (Pizzichini et al 2002). A multicenter study 
examining the safety of sputum induction in subjects with moderate to severe asthma 
concluded that sputum induction has acceptable risks, and sputum induction has a predictable 
risk of bronchoconstriction. Perceived risks are minimized in that our study population will be 
individuals with mild asthma.  Additionally, sputum induction will be undertaken in carefully 

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monitored conditions with rigorous safeguards to identify and treat bronchoconstriction (Fahy 
et al 2001). 
Bone Marrow Aspirates
Bone marrow aspirates will be performed using the
 standard operating procedures. 
Aspirates are obtained from the iliac crest using a bone marrow aspiration needle. The surface 
of the skin is disinfected then anaesthetized with lidocaine down to the level of the bone and 
surrounding periosteum. Subjects may experience some local tenderness once the local 
anesthetic wears off. The risk of infection is very low. Subjects will be instructed to contact 
the study physician if they experience excessive or prolonged (>24-36 hrs) pain or bleeding at 
the site of insertion, or if they develop fevers, sweats, chills or any other unexpected 
symptoms. 
Endobronchial Biopsies
Bronchoscopies will be performed using 
 standard operating procedures, and 
according to the recommendations of the U.S. National Institutes of Health. Facilities for the 
management of medical emergencies and cardiopulmonary resuscitation will be available.
Biopsies will be performed by qualified pulmonologists experienced in research 
bronchoscopies, and all due precautions will be taken to minimize the risk to subjects. 
Subjects will receive a sedative and local anaesthetic to reduce any discomfort. Subjects will 
be informed of the risks associated with bronchoscopy and bronchial biopsy procedure before 
participating in the study.
1.4
Study Design 
This randomized, double-blind, parallel group, placebo-controlled study will evaluate the 
effect of a fixed 30 mg dose of benralizumab administered SC every 4 weeks for 3 doses on 
allergen-induced inflammation in subjects with mild atopic asthma challenged with an inhaled 
allergen. 
Approximately 38 non-smoking men and women (18 – 65 years of age) corticosteroid-free 
(oral and inhaled) mild, atopic asthmatics who have demonstrated a dual (early and late) 
asthmatic response to inhaled allergen challenge at screening will be recruited to complete the 
study. 
This study will include 6 centres in 
 
 Canada. All centres will participate in the characterization of the early and late 
asthmatic response and induced sputum collections. A subset of 5 centres will conduct the 
endobronchial biopsy collections, and bone marrow aspirates will be conducted at one centre 
only.
After enrolment and confirmation of entry criteria, subjects will enter a 4 week run-in period 
during which their suitability for randomization will be confirmed and to allow resolution of 
airway inflammation induced from the allergen challenge screening assessments. Subjects 

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who meet all the eligibility criteria will return to the clinic for collection of tissue samples 
according to the participation of the study site (sputum, bone marrow aspirates, lung biopsies 
and blood) for assessment of baseline inflammation.  This will be conducted at 2 visits over a 
3 day period.  
Subjects will then be randomized to receive either benralizumab 30 mg SC or matching 
placebo (1:1). Subjects will receive 2 additional doses of study treatment every 4 weeks for a 
total of 3 doses. 
Twenty eight days following the first dose, subjects will return to the clinic for assessment of 
dosing effects on airway hyperresponsiveness (MCh PC20) and collection of a blood sample 
for eosinophil and serum biomarkers measurements and a sputum sample for eosinophil and 
biomarker measurements.
Twenty eight days following the second dose, subjects will return to the clinic for assessment 
of dosing effects on baseline inflammation in the lung biopsies (only sites participating in the 
bronchial biopsy collections) and collection of a blood sample (all sites) for blood eosinophil 
measurements. Subjects will then receive a third dose of study treatment and return to the 
clinic no less than 7 days later for the first allergen challenge period. 
The first allergen challenge will assess effects of benralizumab on the primary endpoint of 
allergen–induced eosinophils in induced sputum and the LAR.  The first allergen challenge 
and associated assessments will take place over 3 consecutive days. At least twenty one days 
and no more than 28 days following the first allergen challenge, subjects will return to the 
clinic for a second allergen challenge.  The second allergen challenge will assess effects of 
benralizumab on the secondary endpoint of allergen–induced eosinophils and basophils in 
lung tissue.  Subjects will return to the clinic 8 weeks and 12 weeks following the last dose of 
benralizumab for EOT and follow-up assessments, respectively.

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Figure 1
Study flow chart
Treatment period
Randomization 
1:1
Enrollment, 
Screening/run-in
Week -6 day 5 to 
Week -4 day 3
Day 0
Placebo, SC every 4 weeks
Days -3 to -1
Visits 1 - 3
Visits 4 - 5
Benralizumab 30mg, SC 
every 4 weeks
Visit 6
Visits 7-9
Week 4 to Week 8 day 1
Visits 10 - 12
Week 9 day 1 to Week 9 day 3
Allergen 
Challenge #1
Visits 13 - 15
Week 12 day 1 to Week 12 
day 3
Allergen 
Challenge #2
Week 16 day 1
Visit 16
End of 
treatment
End of 
treatment
Follow up
Follow up
Week 20 day 1
Visits 17
Allergen 
Challenge #1
Allergen 
Challenge #2

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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To evaluate  the effect of benralizumab on 
allergen-induced increases in eosinophils in 
induced sputum 
Change in percent of eosinophils in sputum 7 
hours post allergen challenge 
To evaluate the effect of benralizumab on the 
allergen-induced late (3 – 7 hrs post challenge) 
asthmatic response (LAR) 
Primary measure: Maximal percentage decrease 
in Forced Expiratory Volume in 1 Second 
(FEV1) 3-7 hours post allergen challenge (LAR3-
7 hr)
Supportive measure: AUC of time adjusted 
percent decrease in FEV1  curve in late 
asthmatic response (LAR3-7 hr)
2.2
Secondary objectives
Secondary Objective:
Outcome Measure :
To assess the effect of benralizumab on 
allergen-induced increases in number of 
eosinophils in induced sputum
Change in percent of eosinophils in sputum 24 hours 
post allergen challenge
To assess the effect of benralizumab on 
allergen-induced increases in number of 
basophils in induced sputum
Change in percent of basophil numbers by 
toluidine blue staining 
To assess the effect of benralizumab on 
allergen-induced early (within 2 hrs post 
allergen challenge) asthmatic response 
(EAR)
Maximal percentage decrease in FEV1  0 – 2 
hours post allergen challenge (EAR0-2 hr)
AUC of time adjusted percent decrease in FEV1  
curve in early asthmatic response (EAR0-2 hr)
To assess the effect of benralizumab on 
allergen-induced increases in number of 
eosinophils and basophils in lung tissue 
biopsies
Change in eosinophil and basophil numbers in 
endobronchial biopsies from prechallenge to 24 
hours post allergen challenge (in a sub-set of 
subjects)

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To assess the effect of benralizumab on 
allergen-induced increases in eosinophils, 
eosinophil progenitor cells and basophils in 
bone marrow aspirates
Change in eosinophils by smears, eosinophil 
progenitor cells and basophils by flow cytometry 
in bone marrow aspirates, from prechallenge to 
24 hours post allergen challenge (in a sub-set of 
subjects)
To assess the effect of benralizumab on 
allergen-induced increases in eosinophils and 
basophils in blood
Change in eosinophil counts (by central lab 
count) and basophil counts (by flow cytometry) 
in blood  from prechallenge to 24 hours post 
allergen challenge
To assess the effect of benralizumab on 
baseline levels of eosinophil and basophil 
inflammation in sputum, blood, bone marrow 
aspirates and lung tissue prior to allergen 
challenge
Change in percent of eosinophils in cytospins 
and basophils by toluidine blue staining from 
baseline to Visit 10 in induced sputum.
Change in eosinophil counts (by central lab 
count) and basophil counts (by flow cytometry) 
from baseline to Visit 10 in blood
Change in eosinophils by smears, eosinophil 
progenitor cells and basophils measured by flow 
cytometry from baseline to Visit 10 in bone 
marrow aspirates (in a sub-set of subjects)
Change in eosinophil and basophil numbers from 
baseline to Visit 8 in endobronchial biopsies (in 
a sub-set of subjects)
To evaluate the effect of benralizumab on 
airway hyper-responsiveness post allergen 
challenge
Methacholine PC20 (concentration of inhaled 
methacholine that produces a 20% fall in FEV1)
2.3
Safety objectives
Safety Objective:
Outcome Measure :

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To assess the safety and tolerability of 
benralizumab in subjects with mild atopic 
asthma
Adverse Events (AEs) and Serious adverse 
events ( SAEs)
Vital signs
Electrocardiogram (ECG)
Clinical chemistry/haemotology/urinalysis
Physical examination 
2.4
Exploratory objectives  
Exploratory Objective:
Outcome Measure :
 
 
 
 
 
 
 
 
 
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study subjects should fulfil the following criteria:
1.
Written informed consent for study participants must be obtained prior to any study 
related procedures being performed and according to local guidelines.
2.
Female or male aged 18 to 65 years, inclusively, at the time of enrolment. 

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3.
General good health as declared by the investigator
4.
Mild, stable, allergic asthma and asthma therapy limited to inhaled, short-acting β2 
agonists (should not be used in more than 2 occasions in a week). If the subject uses 
the short-acting β2 agonist for prophylactic treatment this should not be included in the 
number of times that it is used in a 1 week-period
5.
Ability to produce a sputum sample and viable cytospin for assessment of the cell 
differential count at screening pre, 7 and 24 hours post- challenge 
6.
History of episodic wheeze and shortness of breath; Pre-bronchodilator FEV1 at 
screening of at least 70% of the predicted value 

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7. 
No current exposure to allergens to which a subject experiences asthmatic responses 
(with the exception of the house dust mite).
8.
Positive methacholine challenge (PC20 ≤16 mg/mL) at screening
9.
Positive skin-prick test to at least one common aeroallergen (including but not limited 
to cat, dust mite, grass/tree pollen) at screening
10.
Positive early and late airway responses during the screening allergen challenge.  The 
early response will be a fall in FEV1 of ≥20% during the two hours after allergen 
challenge.  The late response will be defined as a fall in FEV1 of ≥15% during the 3-7 
hours after allergen inhalation.
11.
Demonstrate an increase in sputum eosinophils at 7 hrs post allergen challenge relative 
to the pre allergen challenge sputum sample at screening.
12.
Women of childbearing potential (WOCBP) must use an effective form of birth 
control (confirmed by the Investigator). Effective forms of birth control include: true 
sexual abstinence, a vasectomized sexual partner, Implanon, female sterilization by 
tubal occlusion, any effective IUD intrauterine device/IUS levonorgestrel Intrauterine 
system, Depo-Provera™ injections, oral contraceptive, and Evra Patch™ or 
Nuvaring™. WOCBP must agree to use effective method of birth control, as defined 
above, from enrolment, throughout the study duration and within 16 weeks after last 
dose of IP, and 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 randomization without an alternative medical cause.  The following age-
specific requirements apply:
∀
Women <50 years old would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatment and follicle stimulating hormone (FSH) levels in the postmenopausal 
range.

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∀
Women ≥50 years old would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatment.
13.
All male subjects who are sexually active must agree to use an acceptable method of 
contraception (condom with or without spermicide, vasectomy) from the first dose of 
IP until 16 weeks after their last dose.
3.2
Exclusion criteria
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
1.
A worsening of asthma or a respiratory tract infection within 6 weeks preceding 
enrolment
2.
Current lung disease other than mild allergic asthma
3.
History of clinically significant hypotensive episodes or symptoms of fainting, 
dizziness, or light headedness, as judged by the investigator
4.
Any history or symptoms of cardiovascular disease, particularly coronary artery 
disease, arrhythmias, hypertension, or congestive heart failure
5.
Any history or symptoms of significant neurologic disease, including transient 
ischemic attack (TIA), stroke, seizure disorder, or behavioral disturbances
6.
Any history or symptoms of clinically significant autoimmune disease
7.
Any history of clinically significant haematologic abnormality, including coagulopathy 
or any history of chronic treatment with anticoagulants (e.g. warfarin, etc) or 
antiplatelet agent (e.g, aspirin, etc)
8.
Clinically significant abnormalities in laboratory test results at enrolment and during 
the screening period (including complete blood count, coagulation, chemistry panel 
and urinalysis) unless judged not significant by the investigator
9.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.5 times 
the upper limit of normal (ULN) confirmed during screening period
10.
Being pregnant or lactating or have positive serum pregnancy test at enrolment or 
positive urine pregnancy test during the study
11.
Use of regular treatment with inhaled or intranasal corticosteroids within the 4 weeks 
prior to enrolment (Visit 1) into the study 
12.
Use of orally or systemically administered corticosteroids within the 12 weeks prior to 
enrolment into this study

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13.
Use of nonsteroidal anti-inflammatory drugs (NSAIDs) 72 hours before or aspirin prn 
within 7 days of enrolment (Visit 1), as judged by the investigator
14.
Use of long-acting bronchodilators such as tiotropium and salmeterol in the 2 weeks 
prior to enrolment (Visit 1) into the study
15.
Have chronic use of any other medication for treatment of allergic lung disease other 
than short- acting β2-agonists
16. 
Blood draws of 100 mL or more within 45 days prior to enrolment (Visit 1) into the 
study
17.
Current smokers.  Ex-smokers must not have smoked for a minimum of 6 months, and 
should not have a smoking history ≥10 pack years.  Subjects who administer nicotine 
in other forms (patches, chew tobacco, e-cigarette, etc) will also be excluded from the 
study. Cotinine testing must be conducted at screening (Visit 1) to support 
confirmation of non-smoking status. 
18.
Concomitant disease or condition which could interfere with the conduct of the study, 
or for which the treatment might interfere with the conduct of the study, or which 
would, in the opinion of the investigator, pose an unacceptable risk to the subject in 
this study, including, but not limited to, cancer, alcoholism, drug dependency or abuse, 
or psychiatric disease
19.
History of cancer:
-
Subjects 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 subject is in remission and curative therapy was completed at least 12 
months prior to the date informed consent, and assent when applicable was 
obtained,
-
Subjects who have had other malignancies are eligible provided that the subject 
is in remission and curative therapy was completed at least 5 years prior to the 
date informed consent, and assent when applicable, was obtained.
20.
Alcohol or drug abuse (past or present) or any conditions suggesting the potential for 
poor study compliance
21.
Subject who has a scheduled in-patient surgery or hospitalization during the study.
22.
History of anaphylaxis to any biologic therapy or vaccine
23.
History of Guillain-Barré syndrome

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24.
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
25.
Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a 
positive medical history for hepatitis B or C. Subjects with a history of hepatitis B 
vaccination without history of hepatitis B are allowed to enrol
26.
A history of known immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test
27.
Use of immunosuppressive medication (including but not limited to: methotrexate, 
troleandomycin, cyclosporine, azathioprine, intramuscular long-acting depot 
corticosteroid, oral corticosteroid, or any experimental anti-inflammatory therapy) 
within 3 months prior to the date informed consent is obtained 
28.
Receipt of immunoglobulin or blood products within 30 days prior to the date 
informed consent is obtained 
29.
Receipt of any marketed (eg omalizumab) or investigational biologic within 4 months 
or 5 half-lives prior to randomization is obtained, whichever is longer
30. 
Any allergen immunotherapy within 4 months prior to the date informed consent is 
obtained.
31.
Receipt of live attenuated vaccines 30 days prior to the date of randomization 
-
Receipt of inactive/killed vaccinations (eg, inactive influenza) are allowed 
provided they are not administered within 1 week before/after any IP 
administration.
32. 
Receipt of any investigational non-biologic within 30 days or 5 half-lives prior to the 
date informed consent is obtained, whichever is longer
33.
Previously received benralizumab (MEDI-563)
34.
AstraZeneca staff involved in the planning and/or conduct of the study
35.
Employees of the study centre or any other individuals involved with the conduct of 
the study, or immediate family members of such individuals
Procedures for withdrawal of incorrectly enrolled subjects see Section 3.4

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3.3
Subject enrolment and randomization
Investigator(s) should keep a record of subjects 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 or designee will:
1.
Obtain signed informed consent, and assent when applicable, from the potential 
subject before any study specific procedures are performed.
2.
Assign each potential subject a unique enrollment number, beginning with ‘E1001001 
via interactive web/voice response system (IWRS/IVRS).
3.
Determine subject’s eligibility. See sections 3.1 and 3.2
∀
During the screening period, subjects will be screened with medical history,
physical examination, spirometry and routine laboratory tests. These 
assessments may be carried out over two test days in order to minimize tests 
while entry criteria are being established
If subjects continue to meet entry criteria their allergic status will be 
documented by skin testing against a panel of common airborne allergens.
Note: If subjects meet entry criteria to progress to the screening allergen 
challenge triad then the visits for the screening allergen challenge must be 
conducted over three consecutive days.
∀
An allergen challenge will be performed to confirm the presence of an early
and late phase response. Only subjects with a documented early (≥20% fall in
FEV1 ) and late (≥15% fall in FEV1 ) asthmatic response to inhaled incremental
allergen challenge will be eligible for randomisation. The screening allergen
challenge can be repeated at the discretion of the Investigator, as per
 
 SOPs.
4.
Assign eligible subject unique randomization code via IWRS/IVRS. Randomisation 
codes will be assigned strictly sequentially per site, ie, lowest available randomisation 
number will be assigned.
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.
3.4
Procedures for handling incorrectly enrolled or randomized 
subjects
Subjects 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.  Subjects who 

Clinical Study Protocol
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Study Code D3250C00040
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are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment, and must be withdrawn from the study.
Where a subject does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and the subject should be discontinued from the study
3.5
Methods for assigning treatment groups
Subjects will be randomized in a 1:1 ratio to benralizumab or placebo. 
In order to have balanced number of subjects for the outcomes from induced sputum, blood, 
bone marrow and bronchoscopy measures, randomization will be stratified by the following 
types of measurements: 1) bone marrow plus bronchoscopy measurements, 2) bronchoscopy 
measures only, and 3) neither bone marrow nor bronchoscopy measurements. 
Randomization codes will be assigned strictly sequentially as subjects become eligible for 
randomization.
Specific information concerning the use of the IWRS/IVRS will be provided in the separate 
manual.  
Subjects who fail to meet the inclusion/exclusion criteria should not, under any circumstances, 
be randomized or receive study medication. There can be no exceptions to this rule.
3.6
Methods for ensuring blinding
The study will be conducted in double-blind fashion.  AstraZeneca staff involved in the study, 
the subjects, and the investigators involved in the treatment of the subjects or in their clinical 
evaluation will not be aware of the treatment allocation.
Placebo solution will be visually matched with benralizumab solution. Both benralizumab and 
placebo will be provided in an accessorized pre-filled syringe (APFS).
Maintaining the blind to the subject’s blood, sputum and bone marrow eosinophil and
basophil counts
While not entirely specific, subjects on active benralizumab treatment are expected to have 
lower eosinophil and basophil counts than subjects on placebo.  Procedures to mitigate 
unblinding on this basis include:
!
From Visit 4 on, eosinophil, basophil and monocyte counts will be 
redacted from the full hematology and leukocyte PD markers reports
!
From Visit 4 on, eosinophil and basophil assessments conducted in 
induced sputum, endobronchial biopsies, blood and bone marrow at 
McMaster University Laboratory will be conducted by separate 

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laboratory staff who do not have communication with the subjects and 
are not involved in any other data collection in the study (i.e. adverse 
event reporting, clinical testing procedures conducted at the study site, 
laboratory procedures conducted at the study site). To further maintain 
blinding of personnel at the McMaster clinical site the following 
procedure will be followed by the McMaster central laboratory staff:
!
Samples at the time of collection by study site staff will be labelled with 
subject identification, study, test and date. 
!
An individual not involved with the study will prepare an additional layer of 
blinding so that each sample cannot be traced back to the subject 
identification number. This will require a separate coded number.
!
The results will be collected and maintained on a password protected 
computer that is regularly backed up.  Results will not be shared with others 
who collect data.
!
Once all procedures have been completed for a subject, the separate code can 
be broken and subject data entered into the database
3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomisation for each randomised 
subject, will be available to the Investigator(s) or pharmacists from the IVRS/IWRS. Routines 
for this will be described in the IVRS/IWRS user manual that will be provided to each centre.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomisation. The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to subject to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities. Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
subject have been made and documented.
3.8
Restrictions
Subjects will be required to: 
1.
Withhold the use of short acting β2-agonist for at least 8 hours before each visit.
2.
Withhold the intake of xanthines and caffeine-containing products or medications for 4 
hours before each visit where spirometry will be conducted.

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3.
Limit the use of alcohol. The use of alcohol by adults will be limited to no more than 1 
drink per day (1 drink being equivalent to 12 ounces of regular beer, 5 ounces of wine, 
or 1.5 ounces of 80 proof distilled spirits). Subjects must withhold the intake of 
alcohol for 48 hours prior to each visit.
4.
Withhold the use of aspirin products for 7 days before each visit and nonsteroidal anti-
inflammatory drugs (NSAIDs) for 3 days before each visit. 
5.
Abstain from vigorous physical activity (such as long distance running) on the days of 
laboratory visits and during the 24 hours following allergen challenges and bronchial 
biopsy.
6.
Withhold the use of corticosteroids (oral, systemic, nasal or inhaled) in line with the 
exclusion criteria (Section 3.2) and throughout the study.
Withhold the use of long-
acting bronchodilators including anticholinergics (e.g. tiotropium) for two weeks prior 
to enrolment and throughout the study.
8.
Withhold the use of anti-leukotriene therapies for two weeks prior to enrolment and
throughout the study.
9. 
Withhold the use of cromoglycate or nedocromil for 4 weeks prior to enrolment and 
throughout the study.
10. 
Withhold the use of short-acting antihistamines for 3 days, intermediate anti-
histamines for 7 days and long acting-antihistamines for 9 days prior to skin prick 
testing and inhaled allergen testing (refer to
 SOPs for further guidance).
11. 
Abstain from the use of nicotine or tobacco containing products (including but not 
limited to: snuff, chewing tobacco, cigars, cigarettes, pipes, or nicotine patches).
12. 
Abstain from donating blood, plasma from the time of informed consent, and assent 
when applicable, and for 16 weeks (5 half-lives) after last dose of IP.
13. 
Withhold the use of theophylline for four weeks prior to enrolment and throughout the 
study. 
14. 
Withhold the use of herbal remedies for the treatment of allergic, inflammatory, or 
respiratory diseases for 30 days prior to enrolment and throughout the study.
15.
Withhold the chronic use of anticoagulant and antiplatelet agents in line with section 
3.2 (exclusion criterion #7) and throughout the study. Note PRN use of aspirin is 
allowed in line with restriction #4. 
16.
Withhold the use of immunosuppressive medication in line with Section 3.2 (exclusion 
criterion #27), during treatment period and 3 months or 5 half-lives (whichever is 

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Study Code D3250C00040
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longer) after last dose of the IP. Topical administration may be allowed at the 
discretion of the Investigator after discussion with the AstraZeneca physician.
17.
Withhold the receipt of immunoglobulin or blood products in line with Section 3.2
(exclusion criterion #28) and throughout the study. 
18.
Withhold the use of any marketed (eg omalizumab) or investigational biologic in line 
with Section 3.2 (exclusion criterion # 29), during treatment period and 4 months or 5 
half-lives (whichever is longer) after the last dose of the IP.
19. 
Withhold the use of any allergen immunotherapy in line with Section 3.2 (exclusion 
criterion # 30) and throughout the study.
20.
Abstain from the use of live attenuated vaccines in line with Section 3.2 (exclusion 
criterion #31), during treatment period and 4 months (5 half-lives) after the last dose of 
the IP. 
21.
Withhold the use of any investigational non-biologic in line with Section 3.2
(exclusion criterion # 32) and throughout the study.
3.9
Discontinuation of investigational product
Subjects will be discontinued from investigational product (IP) in the following situations:
!
Subject decision.  The subject is at any time free to discontinue 
treatment, without prejudice to further treatment (see Section 3.1)
!
Adverse event (AE) that, in the opinion of the investigator, 
contraindicates further dosing
!
Risk to subject as judged by the investigator or AstraZeneca 
!
Severe non-compliance to study protocol
!
Eligibility requirement found not to be fulfilled (see section 3.4)
!
Pregnancy
!
Lost to follow-up1
!
IP unblinding 
                                               
1 Subject is considered lost to follow up when the following two attempts of contact are failed: 3 attempts of 
either phone calls, faxes or emails and having sent 1 registered letter/certified mail. 
2 Oral corticosteroids may be used to rescue after allergen challenge if needed.  If the subject has to use inhaled 
or oral corticosteroids, the remaining secondary and exploratory outcomes of the allergen challenge triad should 
be aborted. Subjects will report for safety assessments, including spirometry. 

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Study Code D3250C00040
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!
Development of any study specific criteria for discontinuation:
(a) Anaphylactic reaction to the investigational product requiring administration of 
epinephrine.
(b) Development of helminth parasitic infestations requiring hospitalization.
(c) If one dose of IP is missed during course of the study.
(d)  An asthma-related event requiring an ER visits or use of oral corticosteroids2
(e) Worsening of asthma, as judged by the investigator
All subjects who prematurely discontinue IP should return to the study centre and complete 
the procedures described for the IPD (Premature IP Discontinuation) visit and Follow-up visit 
within 4 weeks (+7 days) and 12 weeks (±7 days) after the last dose of IP, respectively. 
Reasons for premature discontinuation of IP should be recorded in the eCRF.
3.9.1
Procedures for discontinuation of a subject from investigational product 
A subject that discontinues will always be asked about the reason(s) for discontinuation and 
the presence of any adverse events. The Principal Investigator/Investigator will perform the 
best possible observation(s), test(s) and evaluation(s) as well as give appropriate medication 
and all possible measures for the safety of the subject. They will also immediately inform 
AstraZeneca of the withdrawal. Adverse events will be followed up (See Section 6). 
If a subject is withdrawn from study, see Section 3.1.
3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screening failures are subjects who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomized.  These subjects should have the reason for study 
withdrawal recorded in eCRF.
3.10.2
Withdrawal of the informed consent
Subjects are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further health treatment.
A subject who withdraws consent, and assent when applicable will always be asked about the 
reason(s) and the presence of any adverse events (AE). The investigator will follow up AEs 
outside of the clinical study. 
Subjects who withdraw from the study before Visit 9 will be asked to return to the study 
centre and complete procedures described for the IPD (Premature IP Discontinuation) visit 

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and Follow-up visit within 4 weeks (+7 days) and 12 weeks (±7 days) after the last dose of IP, 
respectively.
Subjects who withdraw from the study after Visit 9 will be asked to return to the study centre 
and complete procedures described for the End-of-Treatment (EOT) visit and Follow-up visit 
within 8 weeks (+7 days) and 12 weeks (±7 days) after the last dose of IP, respectively. 
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn subjects may be replaced.
4.
STUDY PLAN AND TIMING OF PROCEDURES 

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Table 1
Study Plan - Enrollment, screening/run-in period
Assessment/activity
Refer to 
Enrollment
Screening/run-in
V1aa
V1b
V2 d
V3 d
W-6 d5
W-4 d5
W-4 d4
W-4 d3
Written informed consent 
10.4
X
Inclusion/exclusion criteria
3.1/3.2
X
Demographics 
4.1
X
Complete Physical examination
5.2.2
X
Weight, Height, BMI
5.3.1
X
Medical and asthma history
4.1
X
12-lead ECG
5.2.4
X
Vital signs
5.2.5
X
Serum chemistry
5.2.1
X
Cotinine testing
5.3.3.2
X
Full Hematology
5.2.1
X
Urinalysis
5.2.1
X
Blood coagulation
5.3.2
X
FSH 
5.2.1.1
X
Urine pregnancy test
5.2.1.1
X
Serum pregnancy test 
5.2.1.1
X
Skin prick test
5.1.2
X
Skin titration test b
5.1.3
X
Serology (HIV-1; HIV-2; Hep 
B,C)
5.3.3.1
X
Spirometry
5.1.6
X
X
Xc
X
MCh AHR
5.1.4
X 
X
Induced sputum for cell 
differential count
5.1.5
X 
X
X
Allergen Challenge  
5.1.1
X
Concomitant medication
7.8
X
X
X
Adverse event review (AEs and 
SAEs)
6.1
X
X
X

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a
The window between Visit 1a and Visit 1b would be dictated by the time taken to receive blood safety 
results to allow entry criteria to be met before proceeding with V2.
b
May be conducted at Visit 1a or Visit 1b 
c
Serial FEV1  measurements will be performed
d
Visit is timed from when V1b occurs

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Table 2
Study Plan - Treatment period
Assessment/
activity
Refer 
to 
Treatment 
EOT
FU
IPDg
UNS
Dosing & effect on baseline inflammation
Ag challenge #1
Ag challenge #2 f, s
V4 j
V5 k
V6 l
V7 m
V8 n
V9 o
V10 p 
V11
V12
V13 q
V14
V15
V16 r
V17 t
N/A
N/A
d-3
d-1
d0
W4 
W8
W8 
d1
W9
d1
W9 
d2
W9 
d3
W12
d1
W12 
d2
W12 
d3
W16
d1
W20
d1
Visit window (days)
+ 14 
days 
+ 1 
day
+ 6 
day
-3/+7 
days
-3/+7 
days
+3 
days
+7 
days
+7
days
+/- 3 
days
+/- 3 
days
Inclusion/exclusi
on criteria
3.1/3.2
X
  X
X
Complete 
Physical 
examination
5.2.2
X
X
Brief Physical 
examination
5.2.3
X
X
12-lead ECG
5.2.4
X
X
Vital signs
5.2.5
X
X
X
X
X
X
Serum chemistry
5.2.1
X
X
X
X
X
Full hematology 
5.2.1
X h
Xh
X h
X h
X h
Hematology for 
leukocyte PD 
markers
5.1.9
X i
X i
X i
Xi
X i
Xi
X i
X i 
Xi
Urinalysis
5.2.1
X
X
X
X
Urine Pregnancy 
Test
5.2.1.1
X
X a
Xa
X b
X a
X
X
X
X
X

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Assessment/
activity
Refer 
to 
Treatment 
EOT
FU
IPDg
UNS
Dosing & effect on baseline inflammation
Ag challenge #1
Ag challenge #2 f, s
V4 j
V5 k
V6 l
V7 m
V8 n
V9 o
V10 p 
V11
V12
V13 q
V14
V15
V16 r
V17 t
N/A
N/A
d-3
d-1
d0
W4 
W8
W8 
d1
W9
d1
W9 
d2
W9 
d3
W12
d1
W12 
d2
W12 
d3
W16
d1
W20
d1
Visit window (days)
+ 14 
days 
+ 1 
day
+ 6 
day
-3/+7 
days
-3/+7 
days
+3 
days
+7 
days
+7
days
+/- 3 
days
+/- 3 
days
Spirometry
5.1.6
X
X
X
X
X
X c
X
X
X c
X
X
X
MCh AHR
5.1.4
X
X
X
X
X
Induced sputum:
differential count
flow cytometry
biomarkers
5.1.5
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for serum 
protein 
biomarkers
5.1.9
X
X
X
X
X
Blood for flow 
cytometry 
assessments
5.1.9
X
X
X
Bronchoscopy d
5.1.8
X
X
X

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Assessment/
activity
Refer 
to 
Treatment 
EOT
FU
IPDg
UNS
Dosing & effect on baseline inflammation
Ag challenge #1
Ag challenge #2 f, s
V4 j
V5 k
V6 l
V7 m
V8 n
V9 o
V10 p 
V11
V12
V13 q
V14
V15
V16 r
V17 t
N/A
N/A
d-3
d-1
d0
W4 
W8
W8 
d1
W9
d1
W9 
d2
W9 
d3
W12
d1
W12 
d2
W12 
d3
W16
d1
W20
d1
Visit window (days)
+ 14 
days 
+ 1 
day
+ 6 
day
-3/+7 
days
-3/+7 
days
+3 
days
+7 
days
+7
days
+/- 3 
days
+/- 3 
days
Bone marrow 
aspirate for cell 
count, flow 
cytometry, 
protein 
biomarkers and 
functional 
activity e
5.1.7
X
X
X
Allergen 
Challenge  
5.1.1
X
X
Concomitant 
medication
7.8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse event 
review (AEs and 
SAEs)
6.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
4.2.2
X
Administration of 
investigational 
product
7
X
X
X
a
For all females except those NOT of child bearing potential as defined in inclusion criterion 12, urine HCG test to be done at centre on each treatment 
visit before IP administration

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b
Urine HCG test to be performed before bronchoscopy
c
Serial FEV1  will be performed 
d
Designated study centres only.
e
Sub-set of subjects at designated study centre only.
f
Subjects not participating in the bronchial biopsy collection will not participate in Allergen Challenge #2 and will continue to V16 according to the study 
schedule. Subjects will be contacted by telephone 4 weeks after last dose of study medication, prior to the EOT visit (V16). Please see section 4.2.2.2
g
Subjects will be contacted by telephone 4 weeks after last dose of study medication, prior to the EOT visit (V16). Please section 3.9
h
After visit 1a, lymphocyte, neutrophil and total white cell count will be reported to sites.  Eosinophil, basophil and monocyte counts will be redacted 
from the lab report, please refer to 5.1.9, 5.2.1 and 3.6 for further details.
i
Lymphocyte, neutrophil and total white cell count will be reported to investigative sites.  Eosinophil, basophil, and monocyte counts will be redacted 
from the lab report, please refer to 5.1.9, 5.2.1 and 3.6 for further details. At Visit 7 where Full Hematology is also performed, only one blood sample 
collection will be required for all assessments.   
j
Must take place at least 28 days after Visit 3 without exceeding 42 days. 
k
Must take place 48 hours after Visit 4 without exceeding 3 days. 
l
Can take place between 1 and 7 days after V5. 
m
Must take place 28 days after V6 with a window of -3/+7 days.
n
Must take place 56 days after V6 with a window of -3/+7 days.
o
For Subjects participating in the bronchial biopsy collection, Visit 9 should take place 1 day after V8 with a window of +3 days. For Subjects not 
participating in the bronchial biopsy collection, Visit 9 should take place 57 days after V6 with a window of +/-3 days.
p
Must take place 7 to 14 days after V9 
q
Must take place 20 to 27 days after V11
r
Visit is timed from time of Visit 9 (Please refer to section 4.3)
s
Please see section 4.2.2.2 (Allergen Challenge period 2) for details on the required timing between the two allergen challenge triads. 
t
Visit is timed from time of Visit 9 (Please refer to section 4.3)
D  Days; EOT  End-of-Treatment; FU  Follow-up; R  Randomization; V  Visit; UNS  Unscheduled; W  Week.

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4.1
Enrolment/screening period (Visit 1 – Visit 3)
Each potential subject must provide written informed consent prior to any study specific 
procedures and undergo assessments applicable for the visit (see Table 1).
Subjects must sign the Informed Consent Form (ICF) prior Visit 1 procedures. 
A sub-set of up to 22 subjects recruited at one of the study centres will be required to provide 
consent to supply a sample of their bone marrow. Subjects recruited at 5 of the 6 study centres 
will be required to provide consent for endobronchial biopsies.  These consents are included in 
the main subject informed consent form.  
At Visit 1a the following assessments will be conducted:
!
Collection of demographics and evaluation of the health and asthma 
status of the subject including height and weight, physical examination, 
vital signs, ECG, clinical chemistry and hematology, urinalysis, 
spirometry, medical and asthma history, pregnancy test 
Other study assessments and procedures to be performed at enrolment Visit 1 are mentioned 
in Table 1. It is preferred that Visit 1a is conducted over two days, however, Visit 1a may be 
conducted over a period of up to two weeks to allow any repeat assessments that may need to 
be made. 
Subjects who do not meet the Visit 1a assessment criteria must not be enrolled in the study.
Subjects who meet eligibility criteria from V1a will return for the allergen challenge screening 
assessments at Visit 1b, Visit 2 and Visit 3.  Visit 1b, Visit 2 and Visit 3 must be conducted 
over 3 consecutive days.   
At Visit 1b the following assessments will be conducted:
!
Spirometry
!
Methacholine PC20 test to determine that a subject has hyper-responsive 
airways for inclusion criteria and to calculate the concentration of 
allergen to be used on each subject for the inhaled allergen challenge test 
at Visit 2 (Cockcroft et al 1987). The calculated MCh PC20 at the site 
will be recorded in the CRF.
!
Induced sputum procedure to determine ability of subject to provide a 
viable sputum sample and to determine the pre-allergen challenge 
eosinophil count.
Note that the skin prick test to confirm atopy and identify the specific allergen and allergen 
sensitivity for inhalation challenge testing may be conducted at Visit 1a or Visit 1b at the 
preference of the study site investigator.

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At Visit 2 assessment the following assessments will be conducted:
!
Spirometry (this will include serial measurements to at least 7 hours post 
allergen challenge)  
!
Inhaled allergen challenge
!
Induced sputum collection 7 hours post allergen challenge
At Visit 3 subjects will return to the clinic for the following assessments 24 hours post 
allergen challenge:
!
Spirometry
!
Methacholine PC20 test to assess airway responsiveness post allergen 
challenge
!
Induced sputum for assessment of sputum eosinophils 24 hours post 
allergen challenge.   
Methacholine PC20 and induced sputum will be performed 24 hrs (± 2) after allergen 
challenge (Visit 3).   
To be eligible for continuation in the study subjects must meet the following criteria:
!
A positive skin prick test to at least one aeroallergen
!
A MCh PC20 test result of ≤16 mg/mL at Visit 1b
!
Produce a viable and evaluable sputum cytospin at Visit 1b, at 7 hours 
post allergen challenge at Visit 2  and at 24 hrs post allergen challenge at 
Visit 3
!
Demonstrate a fall in FEV1  of ≥20% from baseline during the period of 
early reaction (within 2hrs post challenge) and a fall in FEV1  of ≥15% 
from baseline during the period of late reaction (3 – 7 hrs post challenge) 
to inhaled allergen challenge at Visit 2
!
Demonstrate an increase in sputum eosinophils in the 7 hrs post 
challenge sputum sample when compared with pre-allergen challenge.
Repeat of screening assessments versus Rescreening 
Repeat assessments
Some assessments conducted at Visit 1a may be repeated at the discretion of the investigator.  
These include:

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!
Pre-bonchodilator FEV1  if <70% predicted 
!
Clinical chemistry and/or hematology 
These assessments may be repeated on one occasion, unless they are for follow-up safety, and 
should be conducted within the 2 week time frame between Visit 1a and Visit 1b.
At Visit 1b the following assessments may be repeated:
!
Induced sputum assessment
The induced sputum assessment may only be repeated on one occasion and should be repeated 
within 2 weeks of the initial assessment.  If a subject returns for a repeat induced sputum the 
methacholine PC20 assessment must also be repeated.    
Note that if a subject fails an initial induced sputum assessment and this must be repeated, the 
Visit 2 and Visit 3 assessments must be delayed and run on consecutive days after the induced 
sputum assessment.
!
Methacholine PC20 
The methacholine PC20 can be repeated on one occasion within 2 weeks at the discretion of 
the investigator.
Rescreen assessments
Re-screening is allowed only once for the subject. Subjects should keep the same Ecode.  The 
following assessments may allow for a re-screening:
!
If the reason for screen failure was transient (including but not limited to 
study-supplied equipment failure, unforeseen personal events that 
mandate missed screening visits), which would mean that the subject 
would fall outside of the enrolment/screening window. 
!
If a subject fails to achieve a late asthmatic response the allergen 
inhalation challenge triad may be repeated as per Investigator discretion.
The rescreen as a result of needing to repeat the allergen challenge triad should be conducted 
as early as 2 but not later than 6 weeks after the first allergen challenge.  
If a subject requires rescreening then subjects should re-sign informed consent before the re-
screening procedures.  All procedures from screening/run-in period should be repeated with 
the exception of the skin prick testing. 
Subjects may not be re-screened if:

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!
They fail to show an skin prick response after confirmation of 
antihistamine washout
!
They fail to show an increase in sputum eosinophils at 7 hours post 
allergen challenge
4.2
Treatment period
4.2.1
Baseline Inflammation assessments 
No less than 4 and no greater than 6 weeks following screening and allergen challenge (to 
allow inflammation to return to baseline), subjects will return to the clinic for assessment of 
baseline inflammation prior to dosing with study treatment.  These assessments will take place 
during two visits over three days (Visit 4 and 5).
At Visit 4 subjects who have met screening eligibility criteria will undergo the following 
assessments:
!
Urine pregnancy test
!
Spirometry. FEV1 should be ≥70% predicted. 
If FEV1 is <70%, procedures may continue at the discretion of the 
investigator, 
 If it is not possible to continue 
with procedures then the Visit should be postponed and rescheduled.
!
MCh PC20 test. The MCh concentration to induce a 20% fall in FEV1
should not be more than one doubling concentration lower than the value 
at enrolment (Visit 1). If the MCh PC20 is more than one doubling dose 
lower, the remainder of the visit should be postponed and the visit
rescheduled. 
!
A blood sample collection for leukocyte PD markers, flow cytometry 
assessments (basophils, eosinophil progenitor cells, ILC2s) and serum 
protein biomarkers.
!
An induced sputum sample for cell differential count, flow cytometry 
assessments (basophils, eosinophil progenitor cells, ILC2s) and protein 
biomarkers
!
A bone marrow aspirate (in a sub-group of subjects at one site only) will 
be collected for eosinophil count, flow cytometry assessments (basophils, 
eosinophil progenitor cells, ILC2s) and protein biomarkers. 
At least forty eight hours after Visit 4 subjects participating in endo-bronchial biopsy sub-
group assessments will attend Visit 5. The endobronchial biopsy is collected at least 48 hours 

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after the induced sputum assessment to allow transient neutrophilic inflammation from the 
isotonic saline inhalation to resolve. At Visit 5 this sub-group of subjects will undergo:
!
Spirometry.  FEV1 should be ≥70% predicted. 
If FEV1 is <70%, procedures may continue at the discretion of the 
. If it is not possible to continue 
with procedures then the Visit should be postponed and rescheduled 
according to the visit window in the schedule of assessments. 
!
Endobronchial biopsy procedure
4.2.2
Randomised treatment period 
Subjects confirmed to be eligible will be randomized at Visit 6 in a 1:1 ratio to benralizumab 
or placebo. 
A 30 mg dose of benralizumab or matching placebo will be administered subcutaneously (SC) 
every 4 weeks for 8 weeks (Day 0 (Visit 6), Week 4 (Visit 7) and Week 8 D1 (Visit 9)).
At Visit 6 subjects will undergo the following procedures:
!
Urine pregnancy test (females)
!
Randomization
!
Dose with study medication. Vital signs will be obtained prior to dosing 
(see section 5.2.5).
4.2.2.1
Effect of Benralizumab on baseline inflammation
Twenty eight days after the first dose subjects will return to the clinic for Visit 7 assessments.  
Visit 7 will assess the effect of treatment on baseline inflammatory markers one month after 
dosing.  At Visit 7 subjects will undergo:
!
Spirometry. FEV1 should be ≥70% predicted. 
If FEV1 is <70%, procedures may continue at the discretion of the 
investigator, as 
. If it is not possible to continue 
with procedures then the Visit should be postponed and rescheduled up to 
1 week later.
!
Pregnancy test (females) 
!
Collection of a predose blood sample for full hematology 
!
Blood sample for leukocyte PD markers and serum protein biomarkers

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!
MCh PC20 test 
!
An induced sputum sample for cell differential count and protein biomarkers
!
Administration of the second dose of study medication.  Vital signs will be 
obtained prior to dosing (see section 5.2.5).
Twenty eight days after the second dose the sub-group of subjects participating in the 
endobronchial biopsy assessments will return to the clinic for collection of an endobronchial 
biopsy (at those sites conducting this assessment) (Visit 8). This lung biopsy will provide data 
for the effect of treatment on baseline inflammation prior to allergen challenge testing. 
Subjects not participating in collection of endobronchial biopsies will not attend Visit 8.
The sub-group of subjects participating in the endobronchial biopsy assessments at Visit 8 will 
undergo the following procedures:
!
Spirometry. FEV1 must be ≥ 70% predicted. 
If FEV1 is <70%, procedures may continue at the discretion of the 
investigator
. If it is not possible to continue with 
procedures then the Visit should be postponed and rescheduled up to 1 week 
later.
!
Urine pregnancy test (females)
!
Endobronchial biopsy procedure to evaluate the effect of treatment on 
eosinophilic inflammation prior to allergen challenge
All subjects will attend Visit 9 for administration of the third dose of study medication.  At 
this visit subjects will undergo the following procedures:
!
Urine pregnancy test (females)
!
Blood sample for leukocyte PD markers and serum protein biomarkers
!
Administration of the third dose of study medication.  Vital signs will be 
obtained prior to dosing (see section 5.2.5).
4.2.2.2
Effect of Benralizumab on allergen-induced inflammation
Allergen challenge period 1
A minimum of 7 days after receiving the third dose of study medication all subjects will return 
to the clinic (Visit 10) for allergen challenge and related assessments. The first allergen 
challenge period will take place over 3 consecutive days (Visits 10, 11 and 12).  
At Visit 10 all subjects will undergo the following procedures:

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!
Spirometry. FEV1 should be ≥70% predicted.  
If FEV1 is <70%, procedures may continue at the discretion of the 
investigator,
. If it is not possible to continue with 
procedures then the Visit may be postponed and rescheduled up to one week 
later. If the visit cannot be rescheduled in the 7 day window, then subjects 
who are participating in the endobronchial biopsy assessments will skip visits 
10, 11 and 12 and return to the clinic according to the protocol schedule for 
Visit 13 for the second allergen challenge. Subjects who are not participating 
in the endobronchial biopsy assessments will be withdrawn. 
!
Urine pregnancy test (females)
!
Blood sample collection for leukocyte PD markers, for flow cytometry 
assessments (basophils, eosinophil progenitor cells, ILC2s) and serum protein 
biomarkers  
!
MCh PC20 test to evaluate effect of treatment on airway hyperresponsiveness
!
An induced sputum sample for cell differential count, flow cytometry 
assessments (basophils, eosinophil progenitor cells, ILC2s) and protein 
biomarkers
!
A bone marrow aspirate (in a sub-group of subjects at one site only) will be 
collected for eosinophil count, flow cytometry assessments (basophils, 
eosinophil progenitor cells, ILC2s) and protein biomarkers
These assessments conducted prior to allergen challenge will provide the data for effect of 
study treatment on baseline inflammation in each of the tissue compartments. 
Twenty four hours after Visit 10, subjects will return to the clinic for Visit 11 to undergo 
allergen challenge procedure. At Visit 11 the following procedures will be conducted:
!
Prior to allergen exposure a pre-challenge FEV1 will be determined. FEV1
should be ≥70% predicted. If FEV1 is <70%, procedures may continue at the 
discretion of the investigator,
. If it is not possible 
to continue with procedures then the visit will be postponed and it may be 
possible to reschedule the complete allergen triad visits again, repeating the 
pre-allergen challenge assessments from Visit 10. If Visit 10 has not already 
been extended by 1 week, the allergen challenge triad may be repeated 1 week 
later, repeating the Visit 10 prechallenge assessments followed by Visit 11 
and Visit 12. If the Visit 10 assessment has already been extended by 1 week 
then the allergen challenge triad may not be repeated. Subjects who are 
participating in the endobronchial biopsy assessments should skip allergen 
challenge period 1 and return to the clinic according to the protocol schedule 
for Visit 13 and the start of allergen challenge triad 2. Subjects who are not 

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participating in the endobronchial biopsy assessments should be withdrawn 
from the study.
!
Inhaled allergen challenge using the same allergen and concentration as 
determined at screening
!
An induced sputum sample collection 7 hours post allergen challenge for cell 
differential count and protein biomarkers
!
A blood sample collection 7 hours post allergen challenge for leukocyte PD 
biomarkers and serum protein biomarkers
Subjects will then return to the clinic 24 hours following the allergen challenge procedure 
(Visit 12) for collection of assessments 24 hours (+/- 2 hours) post allergen challenge.  At 
Visit 12 subjects will undergo the following procedures:
!
Spirometry
!
Blood sample collection for leukocyte PD markers, for flow cytometry 
assessments (basophils, eosinophil progenitor cells, ILC2s) and serum protein 
biomarkers.  
!
MCh PC20 test to evaluate effect of treatment on airway hyperresponsiveness
!
An induced sputum sample for cell differential count, flow cytometry 
assessments (basophils, eosinophil progenitor cells, ILC2s) and protein 
biomarkers
!
A bone marrow aspirate (in a sub-group of subjects at one site only) will be 
collected for eosinophil count, flow cytometry assessments (basophils, 
eosinophil progenitor cells, ILC2s) and protein biomarkers
Allergen challenge period 2
The sub-group of subjects who participate in the endobronchial biopsy assessments will return 
to the clinic for a second allergen challenge triad. Subjects should return for the start of the 
second allergen triad (Visit 13) no earlier than 20 days after the first allergen challenge (Visit 
11). 
At Visit 13 subjects will undergo the following pre-allergen challenge procedures:
!
Spirometry. FEV1 should be ≥70% predicted.  
If FEV1 is <70%, procedures may continue at the discretion of the 
investigator,
. If it is not possible to continue with 
procedures then the Visit should be postponed and rescheduled up to 1 week 
later.

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!
Urine pregnancy test (females)
!
Blood sample collection for leukocyte PD markers
!
MCh PC20 test  
Twenty four hours after Visit 13, subjects will return to the clinic for Visit 14 to undergo the 
allergen challenge procedure.  At Visit 14, subjects will undergo the following procedures:
!
Prior to allergen exposure a pre-challenge FEV1 will be determined. FEV1
should be ≥70% predicted. If FEV1 is <70%, procedures may continue at the 
discretion of the investigator
. If it is not possible 
to continue with procedures then the visit will be postponed and it may be 
possible to reschedule the complete allergen triad visits again, repeating the 
pre-allergen challenge assessments from Visit 13. If Visit 13 has not already 
been extended by 1 week, the study allergen challenge triad may be repeated 
1 week later, repeating the Visit 13 prechallenge assessments followed by 
Visit 14 and Visit 15. If the subjects Visit 13 assessment has already been 
extended by 1 week then the allergen challenge triad may not be repeated and 
the subject should be withdrawn.
!
Spirometry will be performed throughout the procedure at regular intervals up 
to 7 hrs post challenge. 
!
Inhaled allergen challenge using the same allergen and concentration as 
determined at screening
!
A blood sample collection 7 hours post allergen challenge for leukocyte PD 
markers
Twenty four hours after the allergen challenge procedures subjects will return to the clinic for 
Visit 15. At Visit 15 the endobronchial biopsy subject sub-group will undergo the following 
procedures:
!
Spirometry.
!
Blood sample collection for leukocyte PD markers
!
Endobronchial biopsy procedure to evaluate the effect of treatment on 
eosinophilic inflammation following allergen challenge
Subjects not participating in the bronchial biopsy collection will not participate in allergen 
challenge 2 and will continue to V16 according to the study schedule. Subjects will be 
contacted by telephone 4 weeks after last dose of study medication to collect information on 
AEs and concomitant medication as well as to remind them to return for the EOT visits (V16). 

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Subjects who prematurely discontinued IP (see Section 3.9) should return to the study centre 
and complete procedures described for the IPD visit (Premature IP Discontinuation) and 
Follow-up visit within 4 weeks (+7 days) and 12 weeks (±7 days) after the last dose of IP, 
respectively. Study assessments and procedures to be performed at IPD and Follow-up visits 
are mentioned in Table 1.
Reasons for premature discontinuation of IP should be recorded in the eCRF.
4.3
Follow-up period
Subjects will return to the clinic 8 and 12 weeks after the last dose of study medication for 
EOT and follow-up assessments as indicated in the table of assessments (Table 2), 
respectively.
5.
STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The investigator will ensure that data are recorded on the eCRFs as specified 
in the study protocol and in accordance with the instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be archived 
at the study site upon study completion. .
The Principal Investigator/Investigator will record data on the observations, tests and 
assessments specified in the protocol on the eCRFs provided by AstraZeneca. The CRF will 
be accompanied with ‘Instructions for the Investigator’, which should be followed. These 
instructions provide guidance for the recording of study data in the CRF including how to 
change data incorrectly recorded.
5.1
Efficacy assessments
5.1.1
Allergen Inhalation Challenge
Allergen inhalation challenge is performed as described by O’Byrne and colleagues (O’Byrne 
et al 1987) in accordance with 
 SOPs.  
Inhalation with specific allergen agent (as determined from skin prick tests (see Section 5.1.2) 
will be performed on Day 2 (Visit 2) of Screening (to determine whether the subject 
demonstrates a dual response), at Visit 11 and at Visit 14 (only for subjects participating in the 
endobronchial biopsy procedures).  Allergen inhalation periods will be separated by a 
minimum of 3 weeks between challenges.
Prior to beginning each inhaled allergen challenge, baseline FEV1 will be measured with 3 
technically satisfactory readings.  The highest value will be entered into the CRF and be used 
for calculation of the percentage fall in FEV1 (see section 5.1.6 for spirometry assessments).

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The allergen challenge should be performed in a designated area, with emergency equipment 
and medical facilities readily available. Emergency drugs should be available, including 
salbutamol (and ipratopium if applicable) MDI and nebules: steroids (injectable and inhaled); 
injectable antihistamine (eg, Diphenhydramine) epinephrine, and atropine. A resuscitation bag 
and wheelchair should also be available. The test will be carried out by qualified study 
personnel under physician supervision defined as the investigator or delegate being aware of 
the procedure, and being present in the laboratory or available immediately by phone/pager.
Screening Allergen Challenge
The FEV1 will be required to be within 10% of Visit 1a FEV1 to proceed with the challenge 
and should be >70% predicted. The concentration of allergen extract for inhalation will be 2-4 
doubling concentrations below predicted to result in a 20% decrease in FEV1 as determined 
from a formula described by Cockcroft et al (Cockcroft et al 2005). 
Allergen will be inhaled by 2 minutes of tidal breathing and FEV1 will be measured at 10 
minutes post-inhalation.  Inhalations will therefore occur at 12 minute intervals.
!
If FEV1 falls 10-15%, the next concentration of allergen should be 
inhaled after waiting an additional 10 minutes and measuring another 
FEV1.  
!
If FEV1 falls between 15-20% the next concentration may be inhaled for 
1.5 minutes or 2 minutes (as determined by the investigator or delegate).  
Allergen will be inhaled until the FEV1 falls by a minimum of 20%.
Maximum decreases in FEV1 will be chosen to quantify the early and late response 
magnitudes.  
The FEV1 will then be measured at regular intervals until 7 hours post allergen inhalation: 10, 
20, 30, 45, 60, 90, 120, 180, 240, 300, 360 and 420 minutes post allergen inhalation.
The early bronchoconstrictor response (i.e., EAR) is taken to be the largest percentage fall in 
FEV1  within 2 hours post allergen inhalation, and the late response (i.e., LAR) is taken to be 
the largest percentage fall in FEV1  between 3 hours and 7 hours post allergen inhalation. The 
area under the curve (AUC) is determined during the early (0-2 h) and late (3-7 h) responses. 
Only subjects who achieve a fall in FEV1 of ≥20% during the period of early response and a 
fall in FEV1 of ≥15% during the period of late response at screening V2 will be randomised.
Post treatment Allergen Challenge Triads
The same doses of allergen as used at screening are administered during each subsequent 
challenge unless it is unsafe to do so.  If this happens the procedure will proceed with the 
highest allergen dose that can be administered as outlined in 
 SOPs.

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Note: If the subject has to use inhaled or oral corticosteroids, the remaining secondary and 
exploratory outcomes of the allergen challenge triad should be aborted. Subjects will report 
for safety assessments, including spirometry.  
5.1.2
Allergen Skin Testing
An allergy skin test, also called a skin prick test, will be used to determine the allergen that is 
given to each subject in the inhalation allergen challenge in accordance with 
 SOPs. 
It is performed by applying extract of an allergen to the skin of the volar aspect of the forearm, 
scratching or pricking the skin to allow exposure, and then evaluating the local reaction in the 
skin. Allergen extracts will include, but are not limited to: ragweed, tree mix, grass mix, dog, 
cat, horse, feathers, dust mites (Dermatophagoides farinae and D. pteronyssinus), Alternaria, 
and Aspergillus. A positive control (1 mg/mL histamine) and a negative control (diluent) are 
applied to the skin. If an allergen provokes an allergic reaction, a raised itchy bump (wheal) 
develops. The size of the wheal (the raised area, not the redness) will be measured and 
recorded with a ruler in millimeters in the horizontal and vertical directions, perpendicular to 
each other after approximately 15 minutes. The size of the wheal for each antigen will be 
recorded on the Skin Test Form, along with any observed adverse reaction or event and any 
actions taken. A reaction greater than 2 x 2 mm will be regarded as positive, provided that the 
positive and negative controls are appropriately positive (histamine) and negative (diluent),
respectively. The investigator is to choose an allergen for inhalation on the basis of the largest 
skin response. This procedure will be completed in accordance with the allergen skin testing 
using the epicutaneous method SOP 
. 
5.1.3
Allergen Skin Titration Testing
The allergen skin titration test will be performed in accordance with
 SOPs.  An 
allergy skin titration test, is used to identify the lowest titration of allergen which causes a skin 
wheal at least 2 x 2 mm in size. It is performed by applying serial dilutions of a selected 
allergen extract to the volar aspect of the forearm skin (opposite to arm used for determination 
of the appropriate allergen), scratching or pricking the skin to allow exposure, and then 
measuring the skin's reaction with a ruler. The diameter of each wheal is measured in two 
perpendicular directions after 10 minutes. The average wheal diameter for each dilution in the 
horizontal and vertical directions is recorded on the worksheet (i.e 4 x 3 mm). The weakest 
dilution of allergen which produces an average wheal of at least 2 x 2 mm is the ``skin test 
endpoint``. This is used to calculate the starting allergen dose for inhalation.
5.1.4
Methacholine Inhalation Tests
Methacholine inhalation challenge will be performed as described by Cockcroft (Cockcroft 
DW 1985) and in accordance with the 
 SOPs using tidal breathing, from a Wright 
nebulizer (Roxon Meditech, Montreal, PQ, Canada).  Subjects inhale normal saline, then 
doubling concentration of methacholine for 2 minutes using a nebulizer with a mouthpiece on 
a one-way Hans-Rudolph valve.  Spirometry is measured at regular intervals after each 
inhalation.  The test will be terminated when a fall in FEV1 of at least 20% of the baseline 
value occurs, and the methacholine PC20 has been calculated. The methacholine PC20 
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screening period (24 hours before and 24 hours following allergen challenge), at the start of 
the treatment period pre-dose, and at the end of the treatment period (24 hours before and 24 
hours following allergen challenge). The methacholine PC20 measured at the start of the 
treatment period (Visit 4) must not be  more than 1 doubling dose lower than that measured 
during screening pre-allergen (Visit 1) to proceed with treatment.  The methacholine 
inhalation challenge will be performed before any induced sputum procedures.
5.1.5
Sputum Induction
Sputum will be induced and processed using modified methods adapted from the method 
described by Pizzichini (Pizzichini et al 1996) and in accordance with the 
 SOPs. In 
brief, subjects will inhale 3%, 5% and 7% saline for 7 minutes at each concentration 
 
SOPs. 
The sputum samples collected will be used in the following ways:
!
The total cell count will be determined using a Neubauer hemocytometer 
chamber (Hausser Scientific, Blue Bell, PA) and expressed as the number 
of cells per milliliter of sputum. 
!
Cells will be prepared on glass slides for differential counts and stained 
with DiffQuik (American Scientific Products, McGaw Park, IL). Using 
sputum cytospins, the differential cell count and the number of 
eosinophils will be counted (Visits 1b, 2, 3, 4, 7, 10, 11 and 12).
!
Separate cytospin slides will be prepared and stained with toluidine blue 
to determine basophil counts (Visits 1b, 2, 3, 4, 7, 10, 11 and 12)
!
Remaining cells from the sputum processing will be used to determine 
the presence of basophils, eosinophil progenitor cells and ILC2s by flow 
cytometry (Visits 4, 10 and 12). 
!
The sputum supernatant will also be analyzed for cytokines and protein 
biomarkers (Visits 4, 7, 10, 11 and 12). 
The cell differential counts will be performed at a central
 sputum laboratory. The sputum 
processing procedure and procedures for cytospin staining, counting and flow cytometry 
analysis and supernatant assessments will be defined in a lab manual separate to the study 
protocol.
5.1.6
Spirometry
Spirometry (FVC, FEV1, FEV1 /FVC ratio, FVC % predicted, FEV1 % predicted) will be 
measured in accordance with the 
 SOPs.  Prior to administration of study medication 
and at baseline, pre allergen challenge, pre MCh PC20 or pre induced sputum FEV1
measurements will be measured from 3 technically satisfactory readings.  The highest FEV1
value will be entered into the CRF and used for analysis. 

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The spirometry procedure will be conducted according to American Thoracic Society (ATS) 
European Respiratory Society (ERS) Guidelines 2005 (Miller et al 2005).  In general:
!
The centre will be responsible for calibrating and recording the 
calibration of the spirometer according to the recommendations of the 
manufacturer.  Unless otherwise advised, this should be on a daily basis 
and where there is a significant fluctuation in temperature or barometric 
pressure.
!
The subject should rest for 15 minutes before lung function tests are 
performed.
!
The subject should be sitting with the head level and tight clothing 
should be loosened.
!
The subject should perform the manoeuvre with a nose clip.
All subjects must have a Day -3 (Visit 4) FEV1 within 10% of that measured pre-screening 
allergen challenge to demonstrate asthma stability.
5.1.7
Bone Marrow Aspiration, processing and culture
Bone marrow aspirates will only be collected from a sub-set of up to 22 subjects enrolled at 
one study site (McMaster University). Bone marrow aspirates will be collected at Visits 4, 10 
and 12.
Following local freezing, a bone marrow aspirate will be obtained from the iliac crest using a 
bone marrow aspiration needle. 10 ml of bone marrow will be collected into a syringe pre-
filled with heparin. Total cell count will be performed as per Cell Counting SOP, and slides 
for differential counts will be prepared.
Bone marrow aspirates will be used for the following assessments:
!
Slides for differential cell counts and measurement of mature eosinophils
!
Basophils, eosinophil progenitor cells and ILC2s by flow cytometry
!
Plasma for measurement of cytokines and protein biomarkers
!
Evaluation of functional activity of eosinophil progenitor cells by an in 
vitro methylcellulose method evaluating IL-5 induced growth.
The cell counts, flow cytometry assessments and in vitro cell growth assays will be performed 
at a central
 sputum laboratory. The bone marrow aspirate processing procedure and 
procedures for cytospin staining, counting and flow cytometry analysis, plasma assessments 
and in vitro assay will be defined in a lab manual separate to the study protocol.

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5.1.8
Bronchoscopy and processing of samples
Endobronchial biopsy will be performed at 5 of the 6 participating clinical study sites in 
accordance with the 
SOPs. Subjects who participate in the endobronchial biopsy 
assessments will have endobronchial biopsies collected at Visits 5, 8 and 15.
Spirometry is measured on fasted subjects, and pulse oximetry is monitored throughout the 
procedure. Subjects are pre-medicated as per McMaster Bronchoscopy SOP (if required 
midazolam IV and/or Fentanyl IV is used for sedation and titrated to response by physician). 
Nasopharyngeal anaesthetic is administered to vocal cords and the trachea. Bronchoscopy is 
conducted using a fibreoptic bronchoscope, which is passed through the vocal cords and 
introduced into the airways and wedged into a segmental or sub segmental bronchus. Five 
endobronchial biopsies are taken from the carini at the take-off of the bronchi of the lower and 
upper lobes, using Radial Jaw single use forceps from Boston Scientific M00515181. The 
sampling time of the last biopsy will be recorded in the CRF. Throughout the procedure, 
100% oxygen is delivered via a nasal cannula at a rate of 2 L/min whilst oxygen saturation is 
monitored continuously using an oximeter with the probe placed on a finger.
Subjects will be allowed to recover in hospital and will be released when a study physician 
deems it is safe to do so. If the patient has received sedation they will be kept under 
observation for 1-4h or according to the bronchoscopist. They will be allowed to eat and drink 
2-4 hours after the procedure or according to the bronchoscopist. Release time will be noted in 
the patient’s charts. Patients will be reminded of contact information of study physician 
should complications due to the procedure arise. Subjects should be instructed to return if they 
experience bleeding; if they develop fevers, sweats, chills or any other unexpected symptoms. 
Endobronchial biopsies will be used for the following assessments:
!
Number of eosinophils and basophils
!
Eosinophil activation markers
!
Other cell assessments associated with asthma and the pharmacology of 
benralizumab
The processing and evaluation of the endobronchial biopsy tissue will be performed at a 
central
 sputum laboratory. The endobronchial biopsy tissue processing procedures and 
procedures for staining, counting and analysis will be defined in a lab manual separate to the 
study protocol.
5.1.9
Blood for cell assessments and serum protein markers
Blood will be collected from all participating subjects for the following pharmacodynamics 
assessments:
!
Samples for full hematology will be collected at Visit 1a, Visit 7, Visit 
16 and Visit 17 (see section 5.2.1).  In regards to WBC count and 

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differentials the following will be recorded: total cell count, neutrophils, 
lymphocytes, monocytes, basophils and eosinophils as percent and 
absolute counts.  After Visit 1a, the total white cell count as well as 
neutrophil and lymphocyte counts will be reported to the investigative 
site. Note the eosinophil, basophil and monocyte counts will be redacted 
from the report. 
!
Samples for leukocyte PD markers will be collected at Visits 4, 7 and 9 
to 15.  In regards to WBC count and differentials the following will be 
recorded: total cell count, neutrophils, lymphocytes, monocytes, 
basophils and eosinophils as percent and absolute counts.   These 
hematology results will be reported back to the sites redacting eosinophil, 
basophil and monocyte counts. 
!
Basophils, eosinophil progenitor cells and ILC2s by flow cytometry 
(collected at Visits 4, 10, 12).
!
Serum protein biomarkers (collected at Visits 4, 7, 10, 11, 12)
The blood eosinophil counts will be performed by the central lab. If possible collection of 
blood should be at same time each day (+/- 2 hrs). Flow cytometry assessments and in vitro 
cell growth assays will be performed at a central
 sputum laboratory. Serum protein 
biomarkers will be sent to a 3rd party vendor for analysis. Blood processing procedure and 
procedures for collection, counting and flow cytometry analysis, serum assessments and in 
vitro cell growth assays will be defined in a lab manual separate to the study protocol.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Safety laboratory tests (list provided in Table 3) will be performed in a central laboratory. For 
information on methods of collection, assessment, labelling, storage and shipment of samples 
please refer to the separate Laboratory Manual.  Safety samples will be collected in 
accordance with the schedules provided in Table 1 and Table 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 6.3.
In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer to 
Appendix C ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions.

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Table 3
List of Safety Laboratory Tests
Serum Chemistry
Haematology
Urinalysis
Alkaline phosphatase
Gamma-GT (gamma-
glutamyl 
transpeptidase)
Hematocrit
Appearance
ALT (alanine 
aminotransferase)
Glucose
Hemoglobin
Blood
AST (aspartate 
aminotransferase)
Phosphorus
Mean corpuscular 
volume (MCV)
Colour
BUN (blood urea 
nitrogen)
Potassium
Platelet count
Glucose
C-reactive protein
Sodium
Red blood cell (RBC) 
count
Ketones
Calcium
Total bilirubin
RBC morphology
Chloride
Total cholesterol
WBC count with 
differentials a
CO2 (carbon dioxide)
Uric acid
Creatinine
a
After Visit 1a, the total white cell count as well as neutrophil and lymphocyte counts will be reported to the 
investigative site. Note the eosinophil, basophil and monocyte counts will be redacted from the report 
5.2.1.1
Pregnancy Test 
The following tests are applicable to female subjects only and will be conducted in accordance 
with the schedules provided in Table 1.
!
Serum beta-HCG : To be done in all females at screening Visit 1a except 
for those who are NOT of child bearing potential as defined in inclusion 
criterion 3.  This test is to be sent to and analyzed at the central 
laboratory.
!
FSH: To be done at screening Visit 1a only, for female subjects to 
confirm postmenopausal status in women <50 years who have been 
amenorrheic for >12 month 
!
Urine HCG: To be performed at the study centre for all females at each 
treatment visit before IP administration using a dipstick except for those 
females who are NOT of child bearing potential as defined in inclusion 
criterion 3. A positive urine test result must be confirmed with serum 
beta HCG.

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5.2.2
Physical examination
Complete physical examination will be performed in accordance with schedule provided in 
Table 1 and Table 2.
The 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.
Baseline data will be collected at Visit 1a. Any new finding(s) or aggravated existing 
finding(s), judged as clinically significant by the investigator, will be reported as an AE as 
described in Section 6.1.
5.2.3
Brief physical examination
The brief physical examination will include an assessment of the general appearance, 
abdomen, cardiovascular and respiratory system.  For the brief physical examination only 
information on whether the assessment was performed or not is to be recorded.
5.2.4
ECG
ECG will be performed in accordance with schedule provided in Table 1.
In all subjects, the printouts of the ECG will be collected and signed, dated and stored at the 
study centre along with a signed and dated copy (if the printouts are not on archive-quality 
paper).
A 12-lead ECG will be taken in supine position, after the subject has been resting for at least 5 
minutes
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 investigators interpretation take precedence and should be noted on the printout and 
recorded in the eCRF.  Two identical copies of the ECG will be produced and quality checked 
and kept in case of further need for re-evaluation.
It is highly recommended that the same machine is used for assessment throughout the 
subject’s participation in the study.
ECG data and evaluation will be recorded in the eCRF.
5.2.5
Vital signs
Pre-dose vital signs (pulse, blood pressure, respiration rate and body temperature) will be 
obtained in accordance with schedule provided in Table 1.

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The vital signs will be taken prior to IP administration, and, if possible, blood draw. If it is not 
logistically possible, 10 minutes should be allotted between phlebotomy and vital signs 
assessment. Vital signs should also be taken prior to per protocol bronchodilator 
administration if applicable for that visit.
Pulse rate and blood pressure should be measured after the subject has been resting for at least 
5 minutes. The measurement will be taken in sitting position. Pulse rate will be obtained 
before blood pressure. 
Respiration rate will be obtained after subject has been resting for at least 5 minutes, by 
counting number of breaths (how many times the chest rises) for 1 minute.
Body temperature will be measured in Celsius before IP administration in accordance with 
local standards.
5.3
Other assessments
5.3.1
Weight and height 
Weight and height will be measured in accordance with the schedules provided in Table 1. 
The subject’s weight will be recorded in kilograms; height will be recorded in centimetres.
Weight and height measurements will be performed in light clothing and with shoes off.
5.3.2
Blood coagulation 
The blood coagulation test will be performed at Visit 1a screening.  
Samples will be tested for APTT using standard techniques.
5.3.3
Other screening/run in assessments
5.3.3.1
Serology
Hepatitis B surface antigen, hepatitis C antibody: To be done only at 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 a 
separate laboratory manual provided to the centres.
5.3.3.2
Cotinine testing
Cotinine testing should be done only at screening; test to be performed at central laboratory.
Instructions for sample collection, processing, storage, and shipment can be found in a 
separate laboratory manual provided to the centres.

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5.4
Biomarker analysis 
The subject’s consent to the use of donated biological samples (i.e. blood, sputum, 
endobronchial biopsies and bone marrow aspirates) is mandatory.  
5.4.1
Storage, re-use and destruction of biological samples
Samples may be stored for a maximum of 15 years from the date of the Last Subject’s Last 
Visit, after which they will be destroyed. If a subject withdraws consent to allow samples for 
future use they may continue with their samples being used for the main study. The results of 
this biomarker research will be reported either in the Clinical Study Report itself or as an 
addendum, or separately in a scientific report or publication. The results of this biomarker 
research may be pooled with biomarker data from other studies with the study drug to 
generate hypotheses to be tested in future research. Any residual samples may be used for
future biomarker research. 
5.4.2
Labelling and shipment of biological samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix B ‘IATA 6.2 Guidance Document’.
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the subject unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved.
5.4.3
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator keeps full traceability of all collected samples from subjects 
(including blood, sputum, bronchial biopsies and bone marrow aspirates) during storage at the 
centre until shipment or disposal (where appropriate) and keeps documentation of all 
shipments. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used/disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca Biobank during the entire 
life cycle.
5.4.4
Withdrawal of Informed Consent for donated biological samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.

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The Principal Investigator:
!
Ensures subjects’ withdrawal of informed consent to the use of donated 
samples is notified immediately to AstraZeneca
!
Ensures that biological samples from that subject, if stored at the study 
site, are immediately identified, disposed of /destroyed, and the action 
documented
!
Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed 
of/destroyed, the action documented and the signed document returned to 
the study site
!
Ensures that the subject and AstraZeneca are informed about the sample 
disposal.
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product.  An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory 
findings, electrocardiogram).  In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A serious adverse event (SAE) is an AE occurring during any study phase (i.e., run-in, 
treatment, washout, follow-up), that fulfils one or more of the following criteria:
!
Results in death

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!
Is immediately life-threatening
!
Requires in-subject hospitalisation or prolongation of existing 
hospitalisation 
!
Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the subject or may 
require medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
All AEs, including SAEs, will be collected from the time the subject signs the informed 
consent throughout the treatment period and including the follow-up period.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at follow-up in the study will be followed up by the 
investigator for as long as medically indicated, but without further recording in 
the CRF.  AstraZeneca retains the right to request additional information for any 
subject with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
The requirement to follow-up AEs is not intended to delay database lock or 
production of the Clinical Study Report (CSR).  These activities should proceed 
as planned with ongoing AEs if necessary.
Any follow-up information of ongoing SAEs after database lock will be reported 
to AstraZeneca.
6.3.3
Variables 
The following variables will be collect for each AE;
!
AE (verbatim)
!
The date and when the AE started and stopped
!
Maximum intensity of the AE
!
Whether the AE is serious or not

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!
Investigator causality rating against the IP (yes or no)
!
Action taken with regard to IP
!
AE caused subject’s withdrawal from study (yes or no)
!
Outcome.
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE
!
Date Investigator became aware of serious AE
!
AE is serious due to
!
Date of hospitalisation
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
Description of AE.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE . 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.
6.3.4
Causality collection
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.

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A guide to the interpretation of the causality question is found in Appendix A to the CSP.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the CRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report.  Deterioration as compared to baseline in protocol-mandated laboratory 
values and vital signs should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the IP.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
will use the clinical, rather than the laboratory term (e.g., 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. Cases in which a patient 
shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN may need to be reported as SAEs 
(please refer to Appendix C ‘Actions required in cases of combined increase of 
Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions).
An adverse event will also include any untoward or unfavorable medical occurrence 
associated with the following study mandated procedures and/or occurring within 48 hours 
after: 
!
Allergy Skin Test
!
Sputum Induction
!
Bronchoscopy 
!
Whole Lung Allergen Challenge 
!
Methacholine Challenge 
!
Whole blood collection 

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!
Bone Marrow Aspirate 
The following clinical situations, when associated with study procedures will be considered to 
be outside of the normal range of findings and will be recorded as Adverse Events.  These 
situations do not limit the principal investigator from reporting any other events, associated or 
not with these procedures, from being recorded and reported as AEs.   
Blood Draws
!
Fainting /Vasovagal events
!
Bruising at puncture site larger than 2 cm diameter
!
Bleeding from puncture site lasting more than 5 minutes
!
Swelling at puncture site larger than 2 cm
Allergen Skin Testing
!
Prolonged (>24 hours) itching at test site
!
Swelling (> 10 cm ) at site of test lasting more than 24 hours
!
Nasal allergic symptoms within 30 minutes from the procedure
!
Fainting /Vasovagal event within 30 minutes from the procedure
!
Systemic reaction
Pulmonary Function Testing 
!
Wheezing or bronchoconstriction requiring treatment with 
bronchodilators within 30 minutes from the procedure
!
Coughing requiring treatment with bronchodilators within 30 minutes 
from the procedure 
Methacholine Challenge 
!
FEV1  has not returned to at least 90% of the baseline (pre-diluent) value 
with 4 puffs of salbutamol
!
FEV1   drops by more than 50% during the procedure
Allergen Inhalation challenge
!
Systemic Reaction

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!
Asthma exacerbation requiring prednisone therapy
!
Significant decrease in lung function 
a).  FEV1  decreases by >60% from baseline (defined at the highest pre-test FEV1
on the day of the allergen challenge Visit)
or
b) FEV1 decreases by 40-59% from baseline AND does not begin to recover 
spontaneously during the first 60 minutes post immediate decline in FEV1, OR does 
not respond to salbutamol therapy employed to reverse bronchoconstriction
or
c) Failure to recover to within 80% of baseline FEV1 at discharge. Salbutamol 
therapy may be used to assist in recovery.
Bronchoscopy
!
Asthma exacerbation requiring prednisone in response to bronchoscopy
!
Significant decrease in lung function 
a)  FEV1 decreases by >60% from baseline
or
b) FEV1 decreases by 40-59% from baseline AND does not begin to recover 
spontaneously during the first 60 minutes post immediate decline in FEV1, OR does 
not respond to salbutamol therapy employed to reverse bronchoconstriction
or
c) Failure to recover to within 80% of baseline FEV1 at discharge. Salbutamol 
therapy may be used to assist in recovery.
!
Significant hypoxemia during bronchoscopy
!
The bronchoscopy procedure results in hypoxemia of <85% oxygen 
saturation for greater than 30 seconds despite supplemental O2.
6.3.7
Symptoms of the disease under study
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. Asthma symptoms or signs, such as wheeze, cough, chest 
tightness, dyspnoea, breathlessness and phlegm, will be recorded as AEs only when:

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The sign or symptom is serious according to definitions, see Section 6.2.
The patient discontinues the study due to the sign or symptom 
The sign or symptom is new to the patient or not consistent with the patient’s pre-existing 
asthma history (defined as within 1 year of Visit 1a) as judged by the investigator.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel will 
inform the appropriate AstraZeneca representatives within 1 day, i.e., immediately but no 
later than 24 hours from when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
the necessary information is provided to the AstraZeneca Subject Safety data entry site within 
1 calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately.  Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day, i.e., immediately but no later than 24 hours from 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 will be sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel is to 
report 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 IB for the AstraZeneca 
drug.
6.5
Overdose
!
An overdose with associated AEs will be recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the CRF and on the 
Overdose CRF module.
!
An overdose without associated symptoms will be reported on the 
Overdose CRF module only.

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If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel will inform appropriate AstraZeneca representatives 
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 Subject Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
If a subject becomes pregnant during the course of the study IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the subject 
was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
will inform the appropriate AstraZeneca representatives within 1 day, i.e., immediately but no 
later than 24 hours from 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 Subject Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The pregnancy (PREGREP) module in the CRF will be used to report the pregnancy and the 
pregnancy outcome (PREGOUT) module will be used to report the outcome of the pregnancy.
6.6.2
Paternal exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
16 weeks (5 half-lives) following the last dose.
Pregnancy of the subject’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 

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occurring from the date of the first administration of IP until 16 weeks (5 half-lives) after the 
last administration of IP.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
All investigational products will be manufactured in accordance with Good Manufacturing 
Practice (GMP).
Benralizumab and placebo administered in the study will be a clear to opalescent, colourless 
to yellow solution.
Table 4
Identity of investigational product
Investigational product
Dosage form and strength
Manufacturer
Benralizumab
30 mg/mL solution for injection 
in accessorized pre-filled 
syringe, 1mL fill volume
MedImmune
Placebo
Matching placebo solution for 
injection in accessorized pre-
filled syringe, 1mL fill volume
MedImmune
7.2
Dose and treatment regimens
The IP will be administered at the study centre on treatment visits and within visit windows as 
specified in Table 2.
Before IP administration
Prior to each IP administration:
Investigator/authorized delegate will assess injection site as per standards of medical care
For WOCBP urine pregnancy test will be done; IP will be administered only when the result 
of the test is negative (see Section 5.2.1)
IP administration
The IP will be administered by the Investigator/authorized delegate.  It is suggested that the 
site of injection of the IP is rotated such that the patient receives IP at a different anatomical 
site (see Figure 2) at each treatment visit. The injection site must be recorded in the source 
documents and the eCRF at each treatment visit.

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Figure 2
Injection sites and rotation scheme
Further details on IP administration are provided in the IP Handling Instruction.  IP 
administration must be carried out in line with the Instruction. 
After IP administration
After IP administration the subject should be observed for a minimum of 2 hours for the 
appearance of any acute drug reactions.
Conditions requiring IP administration rescheduling 
If any of the following should occur, the investigator should reschedule the visit and the IP 
should not be administered until the rescheduled visit:
!
The subject has an intercurrent illness, that in the opinion of the 
investigator may compromise the safety of the subject in the study (eg, 
viral illnesses)
!
The subject is febrile (≥38°C; ≥100.4°F) within 72 hours prior to IP 
administration
7.3
Management of IP related reactions
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, and corticosteroids, as 
well as medical equipment to treat acute anaphylactic reactions must be immediately 
available.  Study personnel must be trained to recognize and treat anaphylaxis (Lieberman et 
al 2010).  Details on anaphylaxis management are provided in Appendix D.
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Simpson et al 2006).  Anaphylaxis typically manifests as 1 of 3 clinical scenarios:
1.
The acute onset of a reaction (minutes to hours) with involvement of the skin, 
mucosal tissue, or both, and at least one of the following: a) respiratory 
compromise; or b) reduced blood pressure or symptoms of end-organ dysfunction

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2.
Two or more of the following that occur rapidly after exposure: involvement of the 
skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated 
symptoms, and/or persistent gastrointestinal symptoms
3.
Reduced blood pressure after exposure
Subjects will have had a pre-assessment (ie, vital signs) prior to IP administration and should 
be observed after IP administration for a minimum of 2 hours for the appearance of any acute 
drug reactions. 
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.
7.4
Labelling
Labelling of the IP will be carried out by AstraZeneca or designee in accordance with current 
Good Manufacturing Practice (GMP) and regulatory requirements of each country 
participating in the study.  The labels will be translated into local languages where applicable.
The labels will include the following information:
!
Study code
!
Investigational product/study drug dosage form, route of administration, 
and quantity of dosage units
!
Kit ID
!
P Lot ID
!
Expiry date
!
Investigator name (to be written on the label)
!
E-code (to be written on the label)
!
Sponsor name
!
Directions for use
!
Storage conditions
!
Standard statements required by Regulatory Authorities
!
Sponsor name and contact details

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7.5
Storage
Benralizumab/placebo is to be stored at the study centre in a secured facility with limited 
access and controlled temperature. The temperature should be monitored on a daily basis and 
documented in the temperature monitoring log.
The IP must be kept in the original outer container and under conditions specified on the label 
(between 2–8°C (36–46°F), protected from the light).
In the following cases:
!
Temperature excursion upon receipt or during storage at the study
!
Damaged kit upon receipt
!
Damaged syringe/cartridge
The centre staff should not use affected IP and should immediately contact an AstraZeneca 
representative for further guidance.  Damaged IP should be documented via IWRS/IVRS 
(please refer to IWRS/IVRS manual for further details).
7.6
Compliance
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the eCRF.
The IP will be administered at the study centre on treatment visits and within visit windows as 
specified in Table 2. If 1 dose of the IP is missed during course of the study the subject should 
be discontinued; please refer to Section 3.9.
7.7
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 centre, unused study drugs, and 
for appropriate destruction.  Certificates of delivery, destruction, and/or return should be 
signed.
In the case of a malfunctioning accessorized prefilled syringe (APFS), the centre should 
contact the study monitor to initiate a product complaint process according to applicable 
guidelines.
7.8
Concomitant and other treatments 
The Informed Consent form must be signed before conducting any study-related procedures, 
e.g. discontinuation of pre-study treatment.

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During the study, all subjects should have access to a SABA. 
Salbutamol pMDI, inhaled corticosteroid, and prednisolone will be provided in connection 
with study assessments, when/if applicable as per the
 SOPs.
Restricted medication during the study is shown in Table 5.
Table 5
Restricted Medications
Restricted Medication prior to Visits 1a-17
Time limits prior to Visits 1a-17
Aspirin prn (all doses)
7 days
NSAIDs
72 hours
Ephedrine-containing drugs
24 hours
Inhaled/oral short-acting β2-agonists (SABA)
8 hours
Short-acting anti-histamines a
3 days
Intermediate anti-histamines a
7 days
Long-acting anti-histamines a
9 days
Xanthine (tea, coffee, chocolate) b
4 hours
a
Prior to skin prick test and inhaled allergen testing only.  Please refer to 
 SOPs for further guidance.
b
Applicable only to visits where spirometry will be conducted. 
Medication not allowed during the study, from Visit 1a to end of Visit 17 are shown in Table 
6.
Table 6
Non-allowed medication
Non-allowed medication during the study
(Visits 1a-17)
Time limit prior to Visit 1a
Inhaled a and nasal b steroids
4 weeks
Oral, rectal, parenteral (including periarticular 
injections) steroids c
3 months
Topical GCS for dermal use, group II – IV d
from Visit 2
Chronic use of anticoagulants and antiplatelet 
medication
4 weeks
Herbal remedies for the treatment of allergic, 
inflammatory, or respiratory diseases 
30 days
Inhaled disodium cromoglycate and inhaled
nedocromil sodium
4 weeks
Inhaled/oral long-acting β2-agonists (LABA)
14 days
Leukotriene antagonists and 5-Lipoxygenase
Inhibitors
14 days

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Non-allowed medication during the study
(Visits 1a-17)
Time limit prior to Visit 1a
Inhaled short-acting anticholinergics 
8 hours
Inhaled long-acting anticholinergics
14 days
Theophyline
4 weeks 
Betablockers including eyedrops
from Visit 2
Macrolide antibiotics
from Visit 2
Immunosuppresives e
3 months
Immunoglobulins and blood products
30 days 
Allergen immunotherapy
4 months
Any marketed or investigational biologic e
4 months or 5 half-lives (whichever is longer)  
Live attenuated vaccines e
30 days 
Any investigational non-biologic
30 days or 5 half-lives (whichever is longer)
a
Use of inhaled steroids is prohibited during the study (please see section 3.8 for further details). Inhaled ICS 
may be used acutely after allergen challenge or to stabilize asthma during the study if needed, provided 
dosing is acute (3-5 days maximum) and washout (1 week) is applied before study visits.
b
Use of nasal steroids is prohibited during the study (please see section 3.8 for further details). If there is a 
need for acute use of nasal steroids a 12 hour washout period is required prior to any study related 
procedures. 
c
Use of systemic steroids is prohibited during the study (please see section 3.8 for further details). Systemic 
steroids may be used acutely after allergen challenge or to stabilize asthma during the study if needed, 
provided a washout (1 week) is applied before study visits.
d
Topical GCS group I are allowed on areas up to the size of the subject's palm.
e
Please refer to section 3.8 for further details.
7.8.1
Other concomitant treatment
Medications other than those described above which are considered necessary for the safety 
and well-being of the subject, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the Case Report Form.
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
!
All personnel involved with the analysis of the study will remain blinded 
until database lock and protocol violators identified.
!
Analyses will be performed by AstraZeneca or its representatives.   
!
Full details of the analyses for this study will be detailed in the Statistical 
Analysis Plan (SAP) which will be completed prior to unblinding of the 
data.

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8.2
Sample size estimate
It is expected that approximately 38 subjects in total and 19 subjects in each treatment group 
are needed for this study. This is based on two primary endpoints the allergen induced change 
in percentage of eosinophils in induced sputum at 7-hr post allergen challenge during Allergen 
Challenge 1, and the maximum percent decrease in FEV1  in late asthmatic response (LAR3-7 
hr), also during Allergen Challenge 1. These endpoints will be tested using step down 
approach (first assessing the effect on percentage of eosinophils in sputum) as described in 
section 8.5.
For the percent eosinophils in induced sputum, it is assumed the mean of Placebo group and 
the standard deviation [SD] are similar to sputum eosinophil data from a previously conducted 
study (mean of 20.8, and a SD of 17.3 at 7-hr post challenge in Placebo group). A sample size 
of approximately 19 subjects per treatment group (38 total) will be needed to achieve 80% 
power of detecting an 80% reduction in the Benralizumab group versus Placebo, assuming 
mean of 20.8 in Placebo group, and a SD of 17.3. This calculation assumed a two-sided 5% 
alpha level. 
For the maximum percent decrease in FEV1  LAR3-7hr , a sample size of approximately 19 
subjects per treatment group (38 total) will be needed to achieve 80% power of detecting a 
11% absolute difference between Benralizumab group and Placebo, assuming a SD of 12% 
(similar to the variability estimated in Gauvreau et al 2014). This calculation assumed a two-
sided 5% alpha level.
Based on previous studies with bone marrow aspirate collections, it is estimated that 
approximately 22 subjects are required to be able to detect meaningful differences between 
placebo and active treatment. 
Although formal powering has been used to estimate the sample size required it is expected to 
be sufficient for all endpoints using an estimation type approach which has been used for most 
studies of this type.
8.3
Definitions of analysis sets
All efficacy analyses will be performed using an Intent-to-Treat (ITT) approach based on the 
full analysis set. For consistency, demographic, baseline characteristics and safety objectives 
will be presented using the full analysis set. 
8.3.1
All subjects analysis set
This analysis set will comprise all subjects screened for the study and will be used for 
reporting of disposition and screening failures.
8.3.2
Full analysis set
The full analysis analysis set consists of all randomized subjects who received at least one 
dose of investigational product irrespective of their protocol adherence and continued 
participation in the study. Subjects will be analyzed according to the randomized treatment 

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assignment, irrespective of whether or not they have prematurely discontinued, according to 
the ITT principle. Subjects who withdraw consent, and assent when applicable to participate 
in the study will be included up to the date of their study termination. Subjects with data 
available for baseline and at least one post baseline assessment will be included in the 
corresponding analysis.
8.3.3
Safety analysis set
The safety analysis set will be the same as the full analysis set.  Any major deviations from the 
randomized treatment assignment will be listed and considered when interpreting the safety 
data.  All safety summaries will be based on this analysis set.
8.4
Outcome measures for analyses
8.4.1
Calculation or derivation of efficacy variables
This study has two main analysis parts for efficacy evaluations as described below: 
1.
Visit 4 up to Visit 10 to evaluate the effect on baseline inflammation
2.
Screening Allergen Challenge, post-dose Allergen Challenge 1 and Allergen 
Challenge 2 to evaluate response to allergen challenge
The study also has two primary endpoints:
1.
Allergen induced change in percentage of eosinophils in induced sputum at 7-hr 
post allergen challenge during Allergen Challenge 1,
2.
Maximum percent decrease in FEV1  in late asthmatic response (LAR)3-7 hr during 
Allergen Challenge 1
8.4.1.1
Allergen induced change in percentage of eosinophils in induced sputum post 
allergen challenge during allergen challenge 1
There are 2 triads where percentages of eosinophils post allergen challenge are collected in the 
study – at Screening and at Allergen Challenge 1. At each triad, a pre-challenge, 7-hr and 24-
hr post challenge samples will be taken (refer to table below for visit associated with 
measurements). The 7-hr post allergen challenge measure during allergen challenge 1 will be 
considered as primary.
Triad
Pre-challenge  
7-hr post challenge
24-hr post challenge
Screening  (pre-dose)
Visit 1 
Visit 2 
Visit 3 
Allergen Challenge 1 
(post-dose)
Visit 10 
Visit 11 
Visit 12 

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The allergen induced change at 7-hr and 24-hr post challenge will be derived by percentages 
of eosinophils post-challenge minus the percentages of eosinophils pre-challenge within each 
triad: 
Allergen Induced Change screening = post-challenge screening – pre-challenge screening
Allergen Induced Change Allergen Challenge 1= post-challenge Allergen Challenge 1 – pre-challenge Allergen 
Challenge 1
8.4.1.2
Maximum percent decrease in FEV1 in late asthmatic response (LAR)3-7 hr
during allergen challenge
FEV1 measurements will be taken for up to 7 hrs post-allergen challenge at the following 3 
visits: Screening, Visit 11 (Allergen Challenge 1), and Visit 14 (Allergen Challenge 2).
Triad
Pre-challenge 
Post-challenge LAR3-7 hr
Screening  (pre-dose)
Visit 2 pre-challenge
Visit 2  post challenge
Allergen Challenge 1 
(post-dose)
Visit 11  pre-challenge
Visit 11  post-challenge
Allergen Challenge 2 
(post-dose)
Visit 14  pre-challenge
Visit 14  post-challenge
Maximum percent decrease in FEV1 in LAR3-7 hr in each triad will be defined as 100* 
(Minimum value of FEV1 between 3 – 7 hours post allergen challenge – pre-challenge 
value)/(pre-challenge value). The FEV1 in LAR3-7 hr on Visit 11 is considered as the primary 
endpoint.
8.4.1.3
AUC of time adjusted percent decrease in FEV1 curve in late asthmatic 
response (LAR)3-7 hr during allergen challenge
The total AUC for percent decrease FEV1  in LAR3-7 hr will be estimated using the linear 
trapezoidal rule (LxHour) using all available FEV1  data between and inclusive of the 3 to 7 
hours.  The time adjusted total AUC FEV1 in LAR3-7 hr is calculated as total AUC/ (the length 
of time (hr) the total AUC is calculated).
8.4.1.4
Percentage of eosinophils in induced sputum for the effect on baseline 
inflammation
Eosinophils in induced sputum are collected on Visit 4 (pre-dose, will be defined as baseline 
for the summary of effect on baseline inflammation), and on Visit 7 and Visit 10. The change 
from baseline (Visit 4) of percent eosinophils to each post-baseline visit will be used in the 
analyses. 

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8.4.1.5
Basophil count in induced sputum for both allergen challenge and baseline
inflammation
Similar to change from baseline of percent eosinophils in induced sputum, there are 2 types of 
measurements for basophil count in induced sputum: allergen induced change at 7-hr and 24-
hr post allergen challenge to evaluate allergen response at Screening and Allergen Challenge 
1, and measurements for effect on baseline inflammation at Visit 4, Visit 7 and Visit 10. 
Basophil count in sputum will be obtained by two types of readings: flow cytometry and 
cytospins with toluidine blue staining, refer to tables below for the scheduling of each type of 
reading.
Allergen Challenge related:
Pre-challenge
7-hr post
24-hr post
Screening
cytospins with 
toluidine blue staining
cytospins with 
toluidine blue staining
cytospins with 
toluidine blue staining
Allergen 
Challenge 1
flow cytometry;
cytospins with 
toluidine blue staining
cytospins with 
toluidine blue staining
flow cytometry;
cytospins with 
toluidine blue staining
Baseline Inflammation related:
Visit 4 (baseline)
Visit 7 
Visit 10
flow cytometry ; 
cytospins with 
toluidine blue staining
cytospins with toluidine blue 
staining
flow cytometry ; 
cytospins with toluidine blue 
staining
8.4.1.6
Maximum percent decrease in FEV1 in early asthmatic response 0-2 hr (EAR0-
2hr)
Maximum percent decrease in FEV1 in EAR0-2 hr at each visit will be defined as 100* 
(Minimum value of FEV1 between 0 – 2 hours post allergen challenge – pre-challenge 
value)/(pre-challenge value).
8.4.1.7
AUC of time adjusted percent decrease in FEV1 curve in early asthmatic 
response (EAR0-2 hr)
The total AUC for FEV1 in EAR0-2 hr will be estimated using the linear trapezoidal rule 
(LxHour) using all available FEV1 data between and inclusive of the 0 to 2 hours.  The time 

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adjusted total AUC FEV1 in EAR0-2 hr is calculated as total AUC/ (the length of time (hours) 
the total AUC is calculated).
8.4.1.8
Number of eosinophils and basophils in lung tissue biopsies for both allergen 
challenge and baseline inflammation
Biopsy samples are collected at Visit 5 (baseline), Visit 8 (pre allergen challenge), and Visit 
15 (24-hr post challenge). Effect on baseline inflammation will be evaluated by change from 
baseline (Visit 5) to Visit 8.  Effect on allergen response will be evaluated by change from 
pre-challenge (Visit 8) to post-challenge (Visit 15). 
8.4.1.9
Eosinophil, eosinophil progenitor cells and basophils in bone marrow aspirates 
for both allergen challenge and baseline inflammation
Eosinophils, Eosinophil progenitor cells and basophils in bone marrow aspirates are collected 
in the bone marrow aspirate sub-group of subjects on Visit 4 (baseline), Visit 10 (pre-
challenge) and Visit 12 (post-challenge).
Effect on baseline inflammation will be evaluated by change from Visit 4 to Visit 10.  Effect 
on allergen response will be evaluated by change from pre-challenge (Visit 10) to post-
challenge (Visit 12).
8.4.1.10
Eosinophils and basophils counts in the blood
Similar to percentage of eosinophils in induced sputum, there are 2 types of measurements for 
eosinophils: 1) allergen induced change to evaluate allergen response, and 2) measurements 
for effect on baseline inflammation at Visit 4, 7, 9 and 10. For basophil counts in blood only 
allergen challenge 1 is assessed for allergen induced change and Visit 4 and Visit 10 for 
baseline inflammation. For allergen induced change, see table below for corresponding visit:
For Eosinophils:
Triad
Pre-challenge 
Post-challenge
Allergen Challenge 1 
(post-dose)
Visit 10 
Visit 11 and Visit 12 
Allergen Challenge 2 
(post-dose)
Visit 13 
Visit 14 and Visit 15 
For Basophils:
Triad
Pre-challenge
Post-challenge
Allergen Challenge 1 
(post-dose)
Visit 10 
Visit 12 

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8.4.1.11
Methacholine PC20 (concentration of inhaled methacholine that produces a 
20% fall in FEV1)
Similar to percentage of eosinophils in induced sputum, there are 2 types of measurements for 
Methacholine PC20: 1) allergen induced change to evaluate allergen response, and 2) 
measurements for effect on baseline inflammation at Visit 4, 7 and 10. For allergen induced 
change, see table below for corresponding visit:
Triad
Pre-challenge
Post-challenge
Screening  (pre-dose)
Visit 1 
Visit 3 
Allergen Challenge 1 
(post-dose)
Visit 10 
Visit 12 
8.4.1.12
Soluble inflammatory markers associated with pathology of asthma or the 
pharmacology of Benralizumab
Details of the analyses will be specified in a separate analyses plan.
8.4.2
Calculation or derivation of safety variables
8.4.2.1
Safety variables
The following safety data will be collected: vital signs, physical examination and ECG, 
haematology, clinical chemistry, urinalysis, reported AEs and SAEs.
8.5
Methods for statistical analyses
Demographics and subject characteristics will be summarized by treatment group using 
frequency and percentages (for categorical variables) and descriptive statistics of mean, 
standard deviation, minimum, median and maximum (for continuous variables) using the full 
analysis set.
The prior medications, categorized according to the WHO Drug Reference List dictionary 
which employs the Anatomical Therapeutic Chemical (ATC) classification system, will be 
summarized by treatment group as frequency and percentage of subjects reporting usage.
The concomitant medication will be categorized according to the WHO Drug Reference List 
dictionary which employs the Anatomical Therapeutic Chemical (ATC) classification system. 
The frequency and percentage of subjects taking concomitant medications and non-drug 
therapies during the treatment period will be summarized by drug class and drug name using 
ATC code.
The analysis of the primary, secondary and exploratory endpoints will include all data 
captured during the study, unless the subject withdraws consent, and assent when applicable to 

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study participation, regardless of whether study treatment was prematurely discontinued, or 
delayed, and/or irrespective of protocol adherence.
Descriptive statistics will also be provided for safety and efficacy data. Unless otherwise 
stated, the data analysis include subjects in the full analysis set. Descriptive statistics on 
continuous variables will be summarized by treatment group using mean, standard deviation, 
minimum, median and maximum, while categorical data were summarized using frequency 
counts and percentages. When data are summarized by time, the values recorded against the 
scheduled time points listed in the protocol were used. When assessing minimum/maximum 
increases or decreases during the study, all assessments, including unscheduled assessments 
will be used. For analysis assessing change from baseline, only subjects with both baseline 
and at least 1 evaluable post-baseline measure will be included. Nominal visit will be used for 
all summary and analysis, no analysis window will be applied.
Testing strategy to account for multiplicity considerations
There are two primary endpoints, the allergen induced change in percentage of eosinophils in 
sputum 7-hr post allergen challenge and maximum percent decrease in FEV1 in the late 
asthmatic response on Visit 11. These endpoints will be tested using the following hierarchical 
fixed-sequence approach in order to control the overall type I error rate at the 0.05 level:
Step 1 first perform the test on allergen induced change in percentage of eosinophils in 
sputum 7-hr post allergen challenge. If the p-value is <= 0.05, then proceed with Step 2. 
Otherwise, neither of the two hypothesis will be rejected.
Step 2 perform the test on maximum percent decrease in FEV1 in the late asthmatic response 
on Visit 11, at alpha level of 0.05.
8.5.1
Analysis of the primary variable (s)
8.5.1.1
Allergen induced change in percentage of eosinophils in induced sputum 7-hr 
post allergen challenge during Allergen Challenge 1
The null hypothesis is that the allergen induced change in percentage of eosinophils in 
induced sputum 7-hr post allergen challenge during Allergen Challenge 1 in the Benralizumab 
group is equal to the allergen induced change in percentage of eosinophils in induced sputum 
7-hr post allergen challenge during Allergen Challenge 1 in the Placebo group. The alternative 
hypothesis is that the allergen induced change in percentage of eosinophils in induced sputum 
7-hr post allergen challenge during Allergen Challenge 1 in the Benralizumab group is not 
equal to that in Placebo group, ie,:
H0: Allergen Induced Change 7-hr post challenge at Allergen Challenge 1 (Benralizumab) = Allergen 
Induced Change 7-hr post challenge at Allergen Challenge 1 (Placebo)
Ha: Allergen Induced Change 7-hr post challenge at Allergen Challenge 1 (Benralizumab) ≠ Allergen 
Induced Change 7-hr post challenge at Allergen Challenge 1 (Placebo)

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The primary analysis method for the allergen induced change on Visit 11 (7-hr post challenge) 
and 12 (24-hr post challenge) will be compared between Benralizumab and Placebo using a 
repeated measures analysis. The dependent variable will be the allergen induced change in 
percentage of eosinophils in induced sputum at 7-hr and 24-hr post allergen. Treatment group 
will be fitted as an explanatory variable pre-dose allergen induced change at Screening will be 
fitted as a covariate. Visit will be fitted as a categorical variable, and the variance-covariance 
matrix will be assumed to be unstructured. If the procedure does not converge the compound 
symmetric variance-covariance matrix will be used instead. The least squares mean for the 
difference in treatment groups using the interaction between visit and treatment group its 95% 
CI, and the 2-sided p-values will be reported for each visit.
8.5.1.2
Maximum percent decrease in FEV1 in late asthmatic response (LAR3-7 hr) on 
Visit 11 during Allergen Challenge 1
The null hypothesis is that the maximum percent decrease in FEV1 in late asthmatic response 
(LAR3-7 hr) on Visit 11 in Benralizumab group is equal to the maximum percent decrease in 
FEV1 in late asthmatic response (LAR3-7 hr) on Visit 11 in Placebo group. The alternative 
hypothesis is that the maximum percent decrease in FEV1  in late asthmatic response (LAR3-7 
hr ) on Visit 11 in Benralizumab group is not equal to that in Placebo group, ie,:
H0: Maximum percent decrease in FEV1 in LAR3-7 hr visit 11(Benralizumab) = Maximum 
percent decrease in FEV1 in LAR3-7 hr Visit 11 (Placebo)
Ha: Maximum percent decrease in FEV1 in LAR3-7 hr visit 11 (Benralizumab) ≠ Maximum 
percent decrease in FEV1 in LAR3-7 hr Visit 11 (Placebo)
Maximum percent decrease in FEV1 at LAR3-7 hr on Visit 11 will be compared between 
Benralizumab and Placebo using an ANCOVA.  The dependent variable will be maximum 
percent decrease in FEV1  at LAR3-7 hr. Treatment group will be fitted as an explanatory 
variable and the corresponding pre-dose FEV1  value at Screening will be fitted as a covariate. 
The least squares mean for the difference in treatment groups and its 95% CI, and the 2-sided 
p-values will be provided.
As a supportive analysis to the primary analyses the time adjusted AUC of FEV1 at LAR3-7 hr 
will be analyzed and summarized descriptively as for maximum percent decrease in FEV1.
The above analyses will be repeated at allergen challenge 2 triad.
FEV1 at both pre- and post-challenge timepoints and minimum FEV1 post-challenge for 
LAR3-7 hr will also be summarized descriptively by visit (Visit 2, 11 and 14).
8.5.2
Analysis of the secondary variable(s)
Endpoints for secondary objectives to evaluate the response to allergen challenge in this study 
are:

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!
Maximum percent decrease in FEV1  in early asthmatic response 0-2 hr 
(EAR0-2 hr)
!
AUC of time adjusted percent decrease in FEV1  curve in EAR0-2 hr 
!
Eosinophil, eosinophil progenitor cells and basophils in bone marrow 
aspirates after allergen challenge 
!
Eosinophil and basophil counts in blood
!
Number of eosinophils and basophils in lung tissue biopsies
!
Basophil count in induced sputum
The maximum percent decrease in FEV1 in EAR0-2 hr will be analysed as for the maximum 
percent decrease and AUC in FEV1 in LAR3-7 hr.
The change from pre-allergen challenge in basophil count in induced sputum from cytospins 
with toluidine blue staining will be analysed as for the allergen induced change in percentage 
of eosinophils in induced sputum. 
The change from pre-allergen challenge eosinophil, eosinophil progenitor cells and basophils 
in bone marrow aspirates after allergen challenge will be analysed using an ANCOVA.  The 
dependent variable will be the change in the number of eosinophils and absolute eosinophil 
progenitor cells and basophils in bone marrow aspirates all on Visit 12 from Visit 10. 
Treatment group will be fitted as an explanatory variable and baseline (Visit 4) will be fitted 
as a covariate. 
The change from pre-allergen challenge in basophils counts in blood after allergen challenge 
will be analysed using an ANCOVA at Allergen Challenge 1. The dependent variable will be 
the allergen induced change in absolute basophils counts in blood after allergen challenge on 
Visit 12. Treatment group will be fitted as an explanatory variable and baseline (Visit 4) will 
be fitted as a covariate. 
The change from pre-allergen challenge eosinophils counts in blood after allergen challenge 
will be analysed using a repeated measures approach separately for the Allergen Challenge 1 
and 2 triads. The dependent variable will be the allergen induced change in absolute 
eosinophil counts at 7-hr and 24-hr post challenge. Treatment group will be fitted as an 
explanatory variable and baseline (Visit 4) will be fitted as a covariate. Visit (7-hr, 24-hr) will 
be fitted as a categorical variable, and the variance-covariance matrix will be assumed to be 
unstructured. If the procedure does not converge the compound symmetric variance-
covariance matrix will be used instead. The least squares mean for the difference in treatment 
groups using the interaction between visit and treatment group its 95% CI, and the 2-sided p-
values will be reported for each visit. 

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The change from pre-allergen challenge in the number of eosinophils and basophils in lung 
tissue biopsies will be analysed using an ANCOVA. The dependent variable will be the 
change in the number of eosinophils and absolute basophils in lung tissue biopsies from Visit 
8 to Visit 15. Treatment group will be fitted as an explanatory variable and baseline (Visit 5) 
will be fitted as a covariate. 
Allergen induced change in methacholine PC20 at Allergen Challenge 1 will be analysed 
using ANCOVA with treatment as explanatory variable and allergen induced change at 
Screening fitted as a covariate.
Endpoints for secondary objectives to evaluate the effect on baseline inflammation in this 
study are:
!
Percentage of eosinophils in induced sputum for the effect on baseline 
inflammation
!
Eosinophils and basophils counts in blood
!
Number of eosinophils and basophils in lung tissue biopsies
!
Basophil count in induced sputum from cytospins with toluidine blue 
staining
The primary timepoint for this evaluations will be Visit 10 (except Visit 8 for bronchoscopy 
measures).
The change from baseline of percent eosinophils in induced sputum will be compared between 
Benralizumab and Placebo using a repeated measures analysis.  The dependent variable will 
be change from baseline in percent eosinophils in induced sputum.  Treatment group will be 
fitted as an explanatory variable and baseline (Visit 4) will be fitted as a covariate.  Visit will 
be fitted as a categorical variable, and the variance-covariance matrix will be assumed to be 
unstructured.  If the procedure does not converge the compound symmetric variance-
covariance matrix will be used instead.  The least squares mean for the difference in treatment 
groups using the interaction between visit and treatment group its 95% CI, and the 2-sided p-
values will be reported for each visit (Visit 7 and 10).
Change from baseline for basophil counts in induced sputum from cytospins with toluidine 
blue staining (Visit 7 and 10) will be analyzed as for the percentage of eosinophils in inducted 
sputum. Eosinophils count (Visit 7, 9 and 10) in blood will also be analysed in this way. 
Change from baseline in the number of basophils counts in the blood will be analysed using 
an ANCOVA.  The dependent variable will be the change from baseline in number of 
basophils on Visit 10.  Treatment group will be fitted as an explanatory variable and baseline 
(Visit 4) will be fitted as a covariate. 

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Change from baseline in the number of eosinophils and basophils in lung tissue biopsies will 
be analysed using an ANCOVA. The dependent variable will be change from baseline in 
number of eosinophils and basophils in lung tissue biopsies on Visit 8. Treatment group will 
be fitted as an explanatory variable and baseline (Visit 5) will be fitted as a covariate.
Change from baseline in methacholine PC20 at visit 7 and 10 will be analyzed after log 
transformation using repeated measures analysis with treatment as explanatory variable, and 
baseline (visit 4) fitted as a covariate.
8.5.3
Analyses methods for safety variables
Adverse events will be coded using the MedDRA dictionary. Number of subjects with events 
and percentages will be tabulated by preferred term and system organ class. An event that 
occurred once or more times during the study treatment period will contribute one observation 
to the numerator of the proportion. The denominator of the proportion will comprise all 
subjects in the Safety set. Adverse events will also be summarized by intensity/severity and 
separately, by causality/relatedness (as determined by the investigator). Should a subject 
report the same preferred term/system organ class within multiple intensity/severity or 
causality/relatedness categories, the subject’s worst occurrence (most severe/most related) will 
be tabulated. Serious AEs, AEs leading to discontinuation, and commonly occurring AEs will 
be summarized in a generally similar manner. Adverse events, SAEs, AEs leading to death, 
and AEs leading to study discontinuation will be summarized for each treatment group as 
applicable
Laboratory data will be summarized by presenting shift tables using normal ranges (baseline 
to most extreme post-baseline value) and by presenting summary statistics of observed and 
change from baseline values (means, medians, quartiles, ranges). The incidence of clinically 
notable lab abnormalities will be summarized. 
Vital sign data will be summarized by presenting summary statistics of observed and change 
from baseline values. The incidence of clinically notable vital sign abnormalities will be 
summarized.
The incidence of clinically notable ECG abnormalities will be summarized.
8.5.4
Exploratory analysis
 
 
 
 
 
  
 

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9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and WBDC, 
IWRS/IVRS and other systems to be utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:
!
Provide information and support to the Investigator(s)
!
Confirm that facilities remain acceptable
!
Confirm that the investigational team is adhering to the protocol, that 
data are being accurately and timely recorded in the CRFs, that biological 
samples are handled in accordance with the Laboratory Manual and that 
study drug accountability checks are being performed
!
Perform source data verification (a comparison of the data in the CRFs 
with the subject’s medical records at the hospital or practice, and other 
records relevant to the study) including verification of informed consent 
of participating subjects. This will require direct access to all original 
records for each subject (e.g., clinic charts)
!
Ensure withdrawal of informed consent to the use of the subject’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the subject.

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The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Please refer to the Clinical Study Agreement (CSA) for location of source data.
9.2.2
Study agreements
The Principal Investigator at each centre should comply with all the terms, conditions, and 
obligations of the Study Agreement with the Principal Investigator, or equivalent, for this 
study. In the event of any inconsistency between this CSP and the Study Agreement with 
Principal Investigator, the terms of CSP shall prevail with respect to the conduct of the study 
and the treatment of subjects and in all other respects, not relating to study conduct or 
treatment of subjects, the terms of the Study Agreement with Principal Investigator shall 
prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or any subjects are enrolled.
9.2.3
Archiving of study documents
Study files.  AstraZeneca will provide the Principal Investigator with a file in which to 
organise and retain all study-related documents.  All study documents (including letters from 
AstraZeneca) should be retained in this file by the Principal Investigator.  The monitor will 
regularly check the file to ensure that all relevant documents are retained.  The contents of the 
file may be audited/inspected by AstraZeneca’s auditor, regulatory authorities, or IRB.
Period of record retention.  The study site (and the Principal Investigator) will retain the 
essential documents specified in the ICH GCP (e.g., source document such as medical records, 
contract, signed consent form).  Essential documents should be retained at the study site for at 
least 15 years following completion of the study, or per regulatory obligations if longer, and 
thereafter destroyed only after agreement with AstraZeneca.  However this is not always 
applied to those that are not preservable such as blood samples. In the event of any 
inconsistency between the above-mentioned contents and the contract with the study site, the 
contract shall prevail.  These documents should be retained for a longer period however if 
needed by AstraZeneca, and the specific period and method of retention will be separately 
discussed between the study site and AstraZeneca.  AstraZeneca should notify the head of the 
study site in writing when the study related records are no longer needed.  The records should 
be managed by a responsible person appointed by the head of the study site
9.2.4
Deviation from the clinical study protocol
The Investigator(s) must not deviate from or make any changes to the protocol without 
documented agreement between the Principal Investigator and AstraZeneca or the IRB 
approval based on its deliberations. However, this shall not apply to cases where the deviation 
or change is necessary to avoid an immediate hazard to the subjects or for other compelling 
medical reasons, or where the changes involve only logistical or administrative aspects of the 

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clinical study (e.g., changes to the organisation/structure of the AstraZeneca, the 
name/department name of the study site, the address or phone number of the study site or 
AstraZeneca, the job title of the Investigator, and monitors).
The Investigator(s) should document any deviation from the protocol regardless of their 
reasons. Only when the protocol was not followed in order to avoid an immediate hazard to 
the subjects or for other medically compelling reason, the Investigator should prepare and 
submit the records explaining the reasons thereof to AstraZeneca and the head of study site, 
and retain a copy of the records.
The Investigator(s) may deviate from or make a change to the protocol without documented 
agreement between the Principal Investigator and AstraZeneca or the IRB approval, only in 
the event of a medical emergency, e.g., it is only way to avoid an immediate hazard to the 
subjects. In such case, the Principal Investigator must notify details of the deviation or 
change, the reason, and a proposed revision in the protocol if required, to AstraZeneca and the 
head of the study site and IRB via the head of the study site as soon as possible, in order to 
obtain their approval. A certificate of approval by the head of the study site as well as 
AstraZeneca should be obtained via the head of the study site.
9.3
Study timetable and end of study
Planned duration of the study: 3 years
Study period: July 2016 – December 2018
Discontinuation or suspension of the whole study programme
If AstraZeneca decides to prematurely terminate or suspend the study, the Principal 
Investigator/Investigator, the head of the study site, and regulatory authorities should receive 
written notification of the reasons for the premature termination or suspension.
The Principal Investigator/Investigator will immediately notify the decision to the subjects, 
give appropriate medical treatment; take necessary measures, and record treatment or 
measures provided on the source documents.
Completion of the study
Upon terminating the study, the Principal Investigator/Investigator will report in writing the 
completion of the study as well as the summary of the results to the head of the study site in 
accordance with the study site’s rules.  The head of the study site, who is informed of the 
termination by the Investigator, will provide a written notification of the results to the IRB and 
AstraZeneca. 
9.4
Data management by AstraZeneca 
Data management will be performed by AstraZeneca Data Management Centre staff, 
according to the Data Management Plan.

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AEs and medical/surgical history will be classified according to the terminology of the latest 
version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications will be 
classified according to the AstraZeneca Drug Dictionary.  All coding will be performed by the 
Medical Coding Team at the AstraZeneca Data Management Centre.
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The Investigator will ensure that data are recorded on the electronic Case 
Report Forms as specified in the study protocol and in accordance with the instructions 
provided.
The investigator will ensure the accuracy, completeness, and timeliness of the data recorded 
and of the provision of answers to data queries according to the Clinical Study Agreement.  
The investigator will sign the completed electronic Case Report Forms.  A copy of the 
completed electronic Case Report Forms will be archived at the study centre.
Data associated with biological samples will be transferred from laboratories internal or 
external to AstraZeneca.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Subject Safety database 
and/or the investigational site.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Subject data protection
The Master Informed Consent Form will explain that:
!
Study data will be stored in a computer database, maintaining 
confidentiality in accordance with national data legislation
!
Subject data will be maintaining confidentiality in accordance with 
national data legislation
!
For data verification purposes, authorised representatives of 
AstraZeneca, a regulatory authority, an IRB may require direct access to 
parts of the hospital or practice source records relevant to the study, 
including subjects’ medical history

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!
All data computer processed by AstraZeneca will be identified by study 
code and enrolment code (E-code)
10.3
Ethics and regulatory review
An IRB should approve the final study protocol, including the final version of the Informed 
Consent Form and any other written information and/or materials to be provided to the 
subjects. The head of the study site will ensure the distribution of these documents to the 
applicable IRB, and the Principal Investigator to the Investigator and study site staff.
The opinion of the IRB should be given in writing. The head of the study site should submit a 
notification of direction/determination as well as a copy of the IRB written approval to 
AstraZeneca and the Principal Investigator before enrolment of any subject should into the 
study.
The IRB should approve all advertising used to recruit subjects for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
A valid contract between the study site and AstraZeneca should be signed before the 
Investigator can enrol any subject into the study. The protocol should be re-approved by the 
IRB annually.
The head of the study site should seek the opinion of the IRB with respect to the 
appropriateness of continuing the study at the study site at least once a year when the duration 
of the study exceeds one year. The Principal Investigator should submit progress reports to the 
IRB via the head of the study site at the time of the protocol re-approval.
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the ICF, should be approved by the national regulatory authority with notification 
provided, according to local regulations.  AstraZeneca will handle the distribution of any of 
these documents to the national regulatory authorities.
AstraZeneca will provide Regulatory Authorities, IRB, the head of the study site and the 
Principal Investigator with safety updates/reports according to local requirements.
The head of the study site should submit a written report to the IRB providing the details of all 
safety relative information reported by AstraZeneca.
10.4
Informed consent
The Principal Investigator(s) at each study centre will:
!
Ensure each subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the 

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study (before any study procedures are performed) as per local 
requirements. 
!
Ensure each subject is notified that they are free to discontinue from the 
study at any time
!
Ensure that each subject is given the opportunity to ask questions and 
allowed time to consider the information provided
!
Ensure each subject provides signed and dated Informed Consent before 
conducting any procedure specifically for the study
!
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File and kept for a period that is complaint with 
GCP/local regulatory requirements, whichever is longer
!
Ensure a copy of the signed Informed Consent Form is given to the 
subject
!
Ensure that any incentives for subjects who participate in the study as 
well as any provisions for subjects harmed as a consequence of study 
participation are described in the Informed Consent Form that is 
approved by an Ethics Committee EC.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.  If it is necessary for the study protocol to be amended, the 
amendment should be submitted to the Head of the Study Site and be approved by its IRB.  If 
applicable, AstraZeneca should submit a notification to the regulatory authority before it is 
implemented.  If a protocol amendment requires a change to a particular centre's Informed 
Consent Form, then AstraZeneca and the centre's IRB should be notified.  Approval of the 
revised Informed Consent Form by AstraZeneca and by the IRB is required before the revised 
form is used.  If an administrative change is required, such a change should be notified to or 
approved by each IRB according to local requirements.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements.  The Investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency or other body about an inspection or an audit at the study 
centre.

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All study data may undergo a reliability review and onsite-GCP inspection by the regulatory 
authorities. 
11.
LIST OF REFERENCES
Blanchard and Rothenberg 2009
Blanchard C, Rothenberg ME. Biology of the Eosinophil. In Adv Immunol. 2009; 101: 81–
121.
Castro et al 2014
Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, Busse WW, Gossage DL, Ward 
CK, Wu Y, Wang B, Khatry DB, van der Merwe R, Kolbeck R, Molfino NA, Raible DG. 
Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for 
uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir 
Med 2014; 2: 878–90.
Cockcroft DW 1985
Cockcroft DW. Airway responsiveness: measurement and interpretation. Mississauga (ON): 
Astra Pharmaceuticals Canada Ltd. c1985. Measure of airway responsiveness to inhaled 
histamine or methacholine; method of continuous aerosol generation and tidal breathing 
inhalation. p. 22-28.
Cockcroft et al 1987
Cockcroft DW, Murdock KY, Kirby J, Hargreave F. Prediction of airway responsiveness to 
allergen from skin sensitivity to allergen and airway responsiveness to histamine. Am Rev 
Respir Dis. 1987;135:264-67.
Cockcroft et al 2005
Cockcroft DW, Davis BE, Boulet LP, et al. The links between allergen skin test sensitivity, 
airway responsiveness and airway response to allergen. Allergy. 2005; 60: 56-59.
Fahy et al 2001
Fahy JV, Boushey HA, Lazarus SC, Mauger EA, Cherniack RM, Chinchilli VM, Craig TJ, 
Drazen JM, Ford JG, Fish JE, Israel E, Kraft M, Lemanske RF, Martin RJ, McLean D, Peters 
SP, Sorkness C, Szefler SJ.  Safety and reproducibility of sputum induction in asthmatic 
subjects in a multicenter study.  Am J Respir Crit Care Med. 2001 May; 163(6):1470-5.
Flood-Page et al 2003
Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil’s Role Remains 
Uncertain as Anti–Interleukin-5 only Partially Depletes Numbers in Asthmatic Airway. Am J 
Respir Crit Care Med Vol 167. pp 199–204, 2003.
Gauvreau et al 2015
Gauvreau GM, El-Gammal AI, O’Byrne PM. Allergen-induced airway responses. Eur Respir 
J 2015; 46: 819-831

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Gauvreau et al 2014
Gauvreau GM, O’Byrne PM, Boulet L-P, et al. Effects of an anti-TSLP antibody on allergen-
induced asthmatic responses. N Engl J Med 2014; 370:2102-10.
Gauvreau et al 1999
Gauvreau GM, Watson RM, O’Byrne PM.  Kinetics of allergen-induced airway eosinophilic 
cytokine production and airway inflammation.  Am J Respir Crit Care Med 1999;160: 640-
647.
Gibson et al 1991
Gibson PG, Manning PJ, O’Byrne PM, Girgis-Girbado A, Dolovich J, Denburg JA, Hargreave 
FE.  Allergen-induced asthmatic responses: relationship between increases in airway 
responsiveness and increases in circulating eosinophils, basophils and their progenitors.  Am 
Rev Respir Dis 1991;143: 331-335.
Kolbeck et al 2010
Kolbeck R et al., MEDI-563, a humanized anti–IL-5 receptor a mAb with enhanced antibody-
dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010;125: 1344-53.
Laviolette et al 2013
Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, Busse WW, 
Wenzel S, Wu Y, Datta V, Kolbeck R, Molfino NA. J Allergy Clin Immunol. 2013 
November; 132(5): 1086–1096.
Lieberman et al 2010
Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM,Bernstein DI, et al. The 
diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin 
Immunol . 2010 Sep;126(3):477-80.e1-42.
Miller et al 2005
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, 
van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas 
D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. Eur Respir J. 2005 
Aug;26(2):319-38.
O’Byrne et al 1987
O'Byrne PM, Dolovich J, Hargreave FE. Late asthmatic responses. Am Rev Respir Dis 
1987;136:740-51.
O’Byrne 2009
O’Byrne P. Allergen-induced airway inflammation and its therapeutic intervention.  Allergy 
Asthma Immunol Res. 2009 October; 1(1): 3–9.
Pizzichini et al 2002
Pizzichini E1, Pizzichini MM, Leigh R, Djukanović R, Sterk PJ. Safety of sputum induction. 
Eur Respir J Suppl. 2002 Sep;37:9s-18s.

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Pizzichini et al 1996
Pizzichini E, Pizzichini MM, Efthimiadis A, et al. Indices of airway inflammation in induced 
sputum: reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit 
Care Med 1996;154: 308-17.
Watson et al 2015
Watson BM, Oliveria JP, Tworek D, Scime T, Watson RM, Gauvreau GM. Allergen 
Inhalation Increases Circulating Basophil Activation in Early and Dual Responding Mild 
Allergic Asthmatics. American Journal of Respiratory and Critical Care Medicine, Vol. 191, 
Meeting Abstracts, 2015. A4146.
Sehmi et al 1997
Sehmi R., Wood LJ, Watson RM, Foley R., Hamid Q, O’Byrne PM, Denburg JA.  Allergen-
induced increases in IL-5 receptor -subunit expression on bone marrow derived CD34+ cells 
from asthmatic subjects: a novel marker of progenitor cell commitment towards eosinophilic.  
J Clin Invest 1997;100: 2466-2475
Simpson et al 2006 
Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment 
and identification using induced sputum. Respirology 2006;11(1):54-61.
Weersink et al 1994
Weersink EJM, Postma DS., Aalbers R., de Monchy JGR.  Early and late asthmatic reaction 
after allergen challenge.  Respir Med 1994;88:103-114.

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Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outsubject treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation
Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

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

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Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations
!
Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging 
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable
!
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.

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

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!
AST ≥ 3xULN
!
TBL ≥ 2xULN
When a subject meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:
!
Notify the AstraZeneca representative
!
Request a repeat of the test (new blood draw) by the central laboratory
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
!
Determine whether the subject meets PHL criteria (see Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results)
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative
!
Determine whether the subject meets PHL criteria (see Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory CRF
Follow-up
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the subject has not met PHL criteria.
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.

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Potential Hy’s Law Criteria met
If the subject does meet PHL criteria the Investigator will:
!
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Actions Required When Potential Hy’s Law Criteria are Met Before 
and After Starting Study Treatment)
!
Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:
!
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 
!
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician 
!
Complete the three Liver CRF Modules as information becomes available 
!
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
!
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes

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If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
!
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes. 
∀
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
∀
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:
!
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above
!
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment 
This section is applicable to subjects who meet PHL criteria on study treatment having 
previously met PHL criteria at a study visit prior to starting study treatment.
At the first on study treatment occurrence of PHL criteria being met the Investigator will:
!
Determine if there has been a significant change in the subjects’ condition# compared 
with the last visit where PHL criteria were met#
∀
If there is no significant change no action is required
∀
If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Potential Hy’s Law Criteria met of this Appendix
# A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.

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Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a subject meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
!
Was the alternative cause for the previous occurrence of PHL criteria being met 
chronic or progressing malignant disease or did the subject meet PHL criteria prior to 
starting study treatment and at their first on study treatment visit as described in 
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment? 
If No: follow the process described in Potential Hy’s Law Criteria met of this Appendix
If Yes:
Determine if there has been a significant change in the subject’s condition# compared with 
when PHL criteria were previously met
!
If there is no significant change no action is required
!
If there is a significant change follow the process described in Potential Hy’s Law 
Criteria met
# A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf

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

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3.
Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that patient’s baseline.
3.
Signs and Symptoms and Management of Acute Anaphylaxis 
Anaphylaxis is an acute and potentially lethal multi-system allergic reaction in which some or 
all of the following signs and symptoms occur: 
!
Diffuse erythema
!
Pruritus
!
Urticaria and/or angioedema
!
Bronchospasm
!
Laryngeal edema
!
Hypotension
!
Cardiac arrhythmias
!
Feeling of impending doom
!
Unconsciousness
!
Shock
Other earlier or concomitant signs and symptoms can include:
!
Itchy nose, eyes, pharynx, genitalia, palms, and soles
!
Rhinorrhea
!
Change in voice
!
Metallic taste
!
Nausea, vomiting, diarrhea, abdominal cramps and bloating
!
Lightheadedness
!
Headache
!
Uterine cramps

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!
Generalized warmth
4.
Management of Acute Anaphylaxis
4.1
Immediate intervention
1.
Assessment of airway, breathing, circulation, and adequacy of mentation
2.
Administer epinephrine intramuscularly every 5-15 minutes, in appropriate doses, as 
necessary, depending on the presenting signs and symptoms of anaphylaxis, to control 
signs and symptoms and prevent progression to more severe symptoms such as 
respiratory distress, hypotension, shock and unconsciousness.
4.2
Possibly appropriate, subsequent measures depending on response to epinephrine
(a)
Place patient in recumbent position and elevate lower extremities.
(b)
Establish and maintain airway.
(c)
Administer oxygen.
(d)
Establish venous access.
(e)
Normal saline IV for fluid replacement.
4.3
Specific measures to consider after epinephrine injections, where appropriate
(a)
Consider epinephrine infusion.
(b)
Consider H1 and H2 antihistamines.
(c)
Consider nebulized β2 agonist [eg, albuterol (salbutamol)] for bronchospasm resistant 
to epinephrine.
(d)
Consider systemic corticosteroids.
(e)
Consider vasopressor (e.g. dopamine).
(f)
Consider glucagon for patient taking b-blocker.
(g)
Consider atropine for symptomatic bradycardia.
(h)
Consider transportation to an emergency department or an intensive care facility.
(i)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged 
resuscitation efforts are encouraged, if necessary.

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Adapted from: Kemp SF, Lockey RF, Simons FE; World Allergy Organization ad hoc 
Committee on Epinephrine in Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. 
A statement of the World Allergy Organization. Allergy. 2008; 63(8):1061-70.

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