PONENTE: A Multicenter, Open-label, Phase 3b Efficacy and Safety Study of Benralizumab 30 mg Administered Subcutaneously to Reduce Oral Corticosteroid Use in Adult Patients With Severe Eosinophilic Asthma on High Dose Inhaled Corticosteroid Plus Long-acting β2 Agonist and Chronic Oral Corticosteroid Therapy
Phase: PHASE3
Conditions: Asthma
Sponsor: AstraZeneca

Clinical Study Protocol 
Drug Substance
Benralizumab
Study Code
D3250C00065
Version
4
Date
17 October 2020
PONENTE: A Multicenter, Open-label, Phase 3b Efficacy and Safety Study 
of Benralizumab 30 mg Administered Subcutaneously to Reduce Oral 
Corticosteroid Use in Adult Patients with Severe Eosinophilic Asthma on 
High-Dose Inhaled Corticosteroid plus Long-acting β2 Agonist and Chronic 
Oral Corticosteroid Therapy
Sponsor:
AstraZeneca AB, S-151 85 Södertälje, Sweden
EudraCT Number: 2018-000170-30

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
2(157)
VERSION HISTORY
Version 4.0, 17 October 2020
This amendment includes the addition of a long-term follow-up visit 12 to 18 months after 
end of PONENTE treatment period where we will retrospectively collect data to understand 
changes in OCS dose and other background asthma therapy, and occurrence of asthma 
exacerbations under real-world conditions. We will also evaluate the recovery from adrenal 
insufficiency (AI) and the long-term impact of OCS reduction achieved during PONENTE 
study on the glucocorticoid toxicity. Appendix K has been created to describe all details 
related to the PONENTE Long Term Follow Up Visit substudy and consequently, the 
following sections include a reference to the newly created Appendix K:

CSP Synopsis

Section 1.1 – Background and rationale for conducting this study

Section 1.4 – Study design

Section 2 – Study Objectives

Section 3 – Patient Selections, Enrollment, Restrictions, Discontinuation, and Withdrawal

Section 5 – Study Assessments

Section 6 – Safety Reporting and Medical Management

Section 7.8 – Concomitant and other treatments

Section 8.2 – Sample size estimate

Section 8.3 – Safety analysis set

Section 8.4 – Outcome measures for analyses

Section 8.5 – Methods for statistical analyses
CSP Synopsis: Added synopsis of the Ponente long term follow up substudy.
CSP Synopsis: In the Primary objective regarding a ≥90%, ≥75%, and ≥50% reduction, added > 
0% reduction.
List of Abbreviations and Definition of Terms: Added abbreviations for coronavirus disease 
2019 (COVID-19),, and Standard Operating Procedures (SOP).
Figure 1: Updated to include the long term follow up visit 12- to 18-months after end of 
PONENTE treatment period. Removed text regarding fixed-visits only related to 
benralizumab dosing; as this may be confusing in context of the long term follow up 
substudy.
Section 2.1 Primary objective: In the Primary objective regarding a ≥90%, ≥75%, and ≥50% 
reduction, added > 0% reduction.

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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Section 4 - Study plan and timing of procedures:

Added new subsection, 4.4 PONENTE Long Term Follow Up Substudy, to describe 
the addition of an long term follow up period to the PONENTE study, high-level 
objectives, and to refer to new Appendix K for details.

Added new subsection, 4.5 Study Conduct Mitigation During Study Disruptions Due 
to Cases of Civil Crisis, Natural Disaster, or Public Health Crisis. The impact of 
COVID-19 has highlighted the risk to continuity of clinical trials during times of 
study disruption, whether by civil crisis, natural disaster or public health crisis. This 
section details the measures that may be implemented if a participant is not able to 
visit a study site to ensure that the clinical trial can continue whilst minimizing risk to 
the participant, maintaining compliance with GCP, and minimizing risks to study 
integrity. These changes will only be initiated at a time of study disruption.   
Section 6.3.1 – Hy’s Law: Added clarification that any potential Hy’s Law case should be 
reported as SAE promptly (even before all other possible causes of liver injury have been 
excluded). This was added after direct feedback from a regulatory authority/ethics committee
Section 8.1 – Statistical considerations: Added clarification that there will be a second and 
separate SAP for the PONENTE Long Term Follow Up substudy 
Section 8.5.3 – Analysis of safety outcomes: Corrected information regarding spaghetti plots 
will be for patients with Partial AI (not indeterminate results).  
Section 11 – List of References: Added new reference to GINA 2020 -this is the current 
GINA report at the start of the long term follow up substudy. Previous reference to GINA 
2018 will remain, as this was the version when the enrollment phase of the main study was 
active.
Appendix D – Actions Required in Cases of Increases in Liver Biochemistry and Evaluation 
of Hy’s Law: In Subsection 4.2 – potential Hy’s Law criteria met, added clarification that any 
potential Hy’s Law case should be reported as SAE promptly (even before all other possible 
causes of liver injury have been excluded). This was added after direct feedback from a 
regulatory authority/ethics committee
Appendix K: added new appendix – PONENTE Long Term Follow Up Visit Substudy to 
include details of the Long Term Follow Up visit. At this visit we will retrospectively collect 
changes in OCS dose and other background asthma as well as occurrence of asthma 
exacerbations since the PONENTE follow-up visit. In addition, we will assess recovery from 
AI in those patients who had partial or complete AI at the end of PONENTE study, and we 
will also assess the long term impact of the OCS dose reduction on glucocorticoid toxicity by 
means of GTI. Eligible patients who consent to have a Long Term Follow Up visit will be 

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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treated according to standard practice; any changes to the maintenance asthma regimen are 
allowed, including further reductions of OCS as recommended in the GINA report. Consent 
for PONENTE Long Term Follow Up can be obtained at any time from the EOT visit to 
before the Long Term Follow Up visit. 
Appendix L: new appendix, Changes Related to Mitigation of Study Disruptions Due to Cases 
of Civil Crisis, Natural Disaster, or Public Health Crisis. The impact of COVID-19 has 
highlighted the risk to continuity of clinical trials during times of study disruption, whether by 
civil crisis, natural disaster or public health crisis. This section details the measures that may 
be implemented if a participant is not able to visit a study site to ensure that the clinical trial 
can continue whilst minimizing risk to the participant, maintaining compliance with GCP, and 
minimizing risks to study integrity. These changes will only be initiated at a time of study 
disruption.   
Whole document:

Deleted mention of the supplemental protocol, as this mention has been replaced with the 
addition of the long term follow up substudy

Formatting, grammatical and minor editorial changes have been made throughout the 
document. In addition, changes have been made to section heading numbers and table cross 
references, where necessary, due to amendments detailed in this document.
Version 3.0, 06 November 2019
CSP Synopsis – Study Design: Clarified the differences between the morning cortisol test 
and ACTH stimulation test, both used to evaluate HPA integrity. Clarified that the morning 
cortisol test is used to identify patients with normal cortisol levels or complete AI only; for 
indeterminate results, patients must undergo more specific testing via the ACTH stimulation 
test.
CSP Synopsis – Study Design: updated terminology to clarify that for patients with cortisol 
levels below normal range and above the Complete AI range, “indeterminate results” 
replaced “Partial AI” in the case of morning cortisol tests; “Partial AI” is only used in the 
case of ACTH stimulation tests. The term “intermediate” is removed throughout.
CSP Synopsis – Study Design: Added an additional morning cortisol test (and if required, 
ACTH stimulation test for indeterminate result) at the end of the OCS Reduction phase, for 
patients who have Partial AI after the repeat morning cortisol test.
CSP Synopsis – Study Design Maintenance Phase: Added a final morning cortisol test (and 
if required, ACTH stimulation test for indeterminate result) at the end of the OCS 
Maintenance phase, for patients who have Complete AI or Partial AI at the end of the OCS 
Reduction phase.

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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CSP Synopsis: Added recommendation for patients who have Complete AI or Partial AI at 
the end of the Maintenance phase to be followed-up by an endocrinologist or other 
appropriate specialist, per Investigator discretion.
CSP Synopsis: All reference to the sputum substudy has been deleted. The sub-study was 
terminated due to low enrollment rate. Sputum samples already collected at the time of this 
amendment will not be analyzed, and will be destroyed.
CSP Synopsis – Exploratory Objective: Removed mention of sputum-related outcome 
measures from table listing exploratory objectives
CSP Synopsis –Statistical Methods: Added information that a database lock and analysis of 
all relevant data collected through end of OCS reduction phase may be performed after all 
patients have completed the OCS reduction phase Replaced “way of diagnosis,” with 
“method of diagnosis.”
Table of Contents: Updated all sections and page numbers to reflect new subsection(s)
Section 1.2 – Rationale for study design, doses, and control groups: Added mention of a 
supplemental protocol, which may be conducted to evaluate additional safety endpoints.
Section 1.4.3 – OCS Reduction phase (Week 4 onwards): Added clarifications on the 
differences between the morning cortisol test and ACTH stimulation test, both used to 
evaluate HPA integrity. Clarified that the morning cortisol test is used only to identify 
patients with normal cortisol levels or complete AI only; for indeterminate results, patients 
must undergo more specific testing via the ACTH stimulation test.
Section 1.4.3 – OCS Reduction phase (Week 4 onwards): Updated terminology to clarify 
cortisol levels from morning cortisol test vs from ACTH stimulation test: for patients with 
cortisol levels below normal range and above the Complete AI range, “indeterminate results” 
replaced “Partial AI” in the case of morning cortisol tests; “Partial AI” is only used in the 
case of ACTH stimulation tests. The term “intermediate” is removed throughout.
Section 1.4.3 – OCS Reduction phase (Week 4 onwards): Added an additional morning 
cortisol test (and if required, ACTH stimulation test for indeterminate result) at the end of 
the OCS Reduction phase, for patients who have Partial AI after the repeat morning cortisol 
test.
Section 1.4.4 – Maintenance Phase: Added a final morning cortisol test (and if required, 
ACTH stimulation test for indeterminate result) at the end of the OCS Maintenance phase, 
for patients who have Complete AI or Partial AI at the end of the OCS Reduction phase.

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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Section 1.4.5 – Premature Discontinuation and Follow-Up Contact: Added recommendation 
for patients who have Complete AI or Partial AI at the end of the Maintenance phase to be 
followed-up by an endocrinologist or other appropriate specialist.
Section 1.4.6 – Sputum Sampling for Exploratory Biomarkers: made this section not 
applicable due to protocol amendment. 
Figure 1: Added Footnote ‘7,’ to describe the additional follow-up recommended for patients 
who have Complete AI or Partial AI at the end of the Maintenance phase
Section 2.4 – Exploratory Objectives: Removed mention of sputum-related outcome 
measures from table
Section 3.1 – Inclusion criteria: For inclusion criterion #3, the text was updated to clarify 
that one method of highly effective form of birth control must be used, and trade names were 
removed, based on feedback from prior regulatory submissions.
Section 3.2 – Exclusion Criteria: - For exclusion criterion #19, the following wording: 
Influence the findings of the study or the interpretation was replaced with: Confound the 
study result; or would impact the scientific validity of the data outcome, based on feedback 
from prior regulatory submissions.
Section 4 – Study Plan and Timing of Procedures – Table 1: Sputum induction row and 
Footnote 'n' updated to note that the sputum study is no longer applicable due to protocol 
amendment.
Section 4 – Study Plan and Timing of Procedures - Table 1: Footnote ‘q’ updated to remove 
sputum collection. 
Section 4 – Study Plan and Timing of Procedures - Table 1: In the Morning cortisol testing 
row, an additional test was added to the “Maintenance Phase benralizumab visit” and “EOT 
visit” columns. Footnote ‘r’ was added.
Section 4.2.1 – Induction phase: Deleted mention of baseline sputum sample collection
Section 4.2.2 – OCS Reduction Phase: Added clarifications on the differences between the 
morning cortisol test and ACTH stimulation test, both used to evaluate HPA integrity. 
Clarified that the morning cortisol test is used to identify patients with normal cortisol levels 
or complete AI only; for indeterminate results, patients must undergo more specific testing 
via the ACTH stimulation test.
Section 4.2.2 – OCS Reduction Phase: Updated terminology to clarify cortisol levels from 
morning cortisol test vs from ACTH stimulation test: for patients with cortisol levels below
normal range and above the Complete AI range, “indeterminate results” replaced “Partial 

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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AI” in the case of morning cortisol tests; “Partial AI” is only used in the case of ACTH 
stimulation tests. The term “intermediate” is removed throughout.
Section 4.2.2 – OCS Reduction Phase: Added an additional morning cortisol test (and if 
required, ACTH stimulation test for indeterminate result) at the end of the OCS Reduction 
phase, for patients who have Partial AI after the repeat morning cortisol test.
Section 4.2.3 – Maintenance phase: Added a final morning cortisol test (and if required, 
ACTH stimulation test for indeterminate result) at the end of the OCS Maintenance phase, 
for patients who have Complete AI or Partial AI at the end of the OCS Reduction phase.
Section 4.3 – Follow-up period: Added recommendation for patients who have Complete AI 
or Partial AI at the end of the Maintenance phase to be followed-up by an endocrinologist or 
other appropriate specialist.
Section 5.1.2 – OCS dose titration: Added clarifications on the differences between the 
morning cortisol test and ACTH stimulation test, both used to evaluate HPA integrity. 
Clarified that the morning cortisol test is used to identify patients with normal cortisol levels 
or complete AI only; for indeterminate results, patients must undergo more specific testing 
via the ACTH stimulation test.
Section 5.1.2 – OCS dose titration: Updated terminology to clarify cortisol levels from 
morning cortisol test vs from ACTH stimulation test: for patients with cortisol levels below 
normal range and above the Complete AI range, “indeterminate results” replaced “Partial 
AI” in the case of morning cortisol tests; “Partial AI” is only used in the case of ACTH 
stimulation tests. The term “intermediate” is removed throughout.
Section 5.2.1 – HPA axis evaluation: Added clarifications on the differences between the 
morning cortisol test and ACTH stimulation test, both used to evaluate HPA integrity. 
Clarified that the morning cortisol test is used to identify patients with normal cortisol levels 
or complete AI only; for indeterminate results, patients must undergo more specific testing 
via the ACTH stimulation test.
Section 5.2.1 – HPA axis evaluation: Updated terminology to clarify cortisol levels from 
morning cortisol test vs from ACTH stimulation test: for patients with cortisol levels below 
normal range and above the Complete AI range, “indeterminate results” replaced “Partial 
AI” in the case of morning cortisol tests; “Partial AI” is only used in the case of ACTH 
stimulation tests. The term “intermediate” is removed throughout.
Figure 2 – HPA axis evaluation: Footnote was updated to also reflect the additional HPA-
axis assessments.

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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5.2.1.1 - Morning cortisol test (done at “OCS ≤ 5mg/day [morning cortisol]” visit): Added 
additional assessments to be conducted at the end of the OCS Reduction phase and OCS 
Maintenance phases. Added recommendation for patients with Complete AI or Partial AI at 
the end of the Maintenance phase, to be referred to an endocrinologist or other appropriate 
specialist per Investigator discretion.
5.2.1.2 – ACTH stimulation test: Added additional assessments to be conducted at the end of 
the OCS Reduction phase and OCS Maintenance phases. Added recommendation for 
patients with Complete AI or Partial at the end of the Maintenance phase, to be referred to an 
endocrinologist or other appropriate specialist per Investigator discretion.
Section 5.2.3 – Sputum collection and biomarkers: Section updated to note that the sputum 
substudy is no longer applicable due to protocol amendment.
Section 5.2.7 – Glucocorticoid toxicity index:  Added clarification that only a subset of the 
domains from the composite GTI will be assessed in the PONENTE study.
Section 6.4 – Reporting of serious adverse events: Added new subsection, 6.4.1 Regulatory 
Reporting Requirements for SAEs to reflect changes to the AstraZeneca global protocol 
template.
Section 8.4 – Outcome measures for analyses: Under the third Secondary efficacy Outcome 
variable, added “initial morning cortisol test,” as an additional timepoint for reporting ACQ-
6 scores.
Section 8.5.1 – Analysis of the primary variables: Added that patients who do not achieve 
100% reduction in their daily OCS dose, the reason for no further reduction will be listed
Section 8.5.2.2 – ACQ-6: Added clarification to timepoint at which OCS dose equals 5mg.
Section 8.5.3 – Analysis of safety outcomes: Added the following, “Spaghetti plots may be 
produced for patients with indeterminate AI throughout the OCS reduction phase, showing 
cortisol levels over time.”
Section 8.5.4 – Subgroup analysis: Updated the baseline OCS subgroups to the following 3 
categories: Patients with baseline OCS dose >10 mg/day, >5 mg/day to ≤10 mg/day, and 5 
mg/day
Section 8.5.4 – Subgroup analysis: Updated the baseline serum eosinophil count subgroups 
as in to the following 3 categories: Patients with baseline blood eosinophil count:
-
<150/µL and ≥150/µL; 
-
<300/µL and ≥300/µL; and 
-
<150, ≥150 to <300, and ≥300 cells/μL

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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Section 8.5.5 – Interim review and Analysis: updated section title, and added details on the 
additional database lock which may occur after all patients have completed the OCS 
reduction phase.
Section 8.5.7 – Exploratory analysis: added the following: Baseline blood eosinophil counts 
may be further investigated by summarizing vs. baseline OCS dose and/or by region/country.
Section 8.5.7 – Exploratory analysis: deleted mention of sputum
Section 11 – List of References: Deleted Bafadhel et all 2012, and Pizzichini et al 1996, 
which related to the sputum study
Appendix D – Actions required in cases of increases in liver biochemistry and evaluation of 
Hy’s Law: Updated text throughout the appendix to reflect changes to the AstraZeneca 
global protocol template, specifically in sections 1, 3, 4.2, 5, 6, and 7. A new reference has 
also been added in this appendix.
Version 2.0, 15 January 2019
Title Page: Added EudraCT number. 
CSP Synopsis: Added headers to tables. 
CSP Synopsis – Study design: Added clarification that serum prednisone/prednisolone 
testing is only for patients who were not already on prednisone/prednisolone prior to Visit 1
CSP Synopsis – Study Design: Deleted text ‘from 3 months before screening’ when 
referencing ICS/LABA in order to correct and align with rest of CSP. Text replaced with ‘as 
is defined in Section 3.1 (Inclusion Criteria)’.
CSP Synopsis – Induction phase: Clarified the timeframe of the induction phase 
CSP Synopsis – Cortisol levels confirm AI: Clarified that repeat cortisol testing will only 
occur on one occasion.
CSP Synopsis – Maintenance phase: added clarification that if a patient experiences an 
exacerbation during the maintenance phase, this period will not be extended.
CSP Synopsis – Primary Objectives: Removed “average” from the key supportive outcome 
measures when describing the daily OCS dose.

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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CSP Synopsis – Secondary Objective #2: Removed “timepoint at which OCS dose equals 
5mg” from the outcome measures.
CSP Synopsis – Safety Objective #2: Removed “severe” when describing asthma 
exacerbation rate.
CSP Synopsis – Duration of Treatment: Removed “Week 0 to Week 4” and clarified that the 
induction phase is 4 weeks in duration.
CSP Synopsis – Statistical Methods: Replaced “The proportion and confidence interval of 
the primary outcome measures will be estimated using the Clopper-Pearson formula for 
overall patients and for at least the following prespecified subgroup: baseline OCS dose 
level, baseline eosinophil count, and duration of chronic OCS dose.  The endpoints will be 
evaluated independently.” with “The proportion and 95% confidence interval for each of the 
primary outcome measures will be estimated for all patients in the full analysis set and for at 
least the following prespecified subgroups based on: baseline OCS dose level, baseline 
eosinophil count, and duration of chronic OCS dose.  The endpoints will be evaluated 
independently.  All confidence intervals will be estimated using the Clopper-Pearson exact 
method”. 
CSP Synopsis – Statistical Methods: Text describing the plans for conducting the interim 
review was clarified. The location of where the interim review would be detailed was 
updated from “SAP” to “separate interim review plan”.  Interim “analysis” was changed to 
interim “review” throughout CSP.
List of Abbreviations & Definition of Terms: Abbreviations for ACO, ‘COPD’, EGPA, and 
HES added in line with Exclusion 1 update.  
Section 1.1 – Background and rationale for conducting this study: The following text was 
removed as this is specific to the US label - “Benralizumab (Fasenra®) is indicated for the 
add-on maintenance treatment of patients 12 years of age and older and with severe 
eosinophilic asthma.”
Section 1.2 – Rationale for study design, doses, and control groups: Clarified the previous 
study referenced here is the ZONDA study. 
Section 1.4 – Study Design: Added sub-sections to organize this section. Added clarification 
on the duration of each study period (Enrollment Weeks -2 to Week -1, Induction phase 
Week 0 to Week 3, OCS Reduction phase Week 4 onwards). This change was also 
implemented globally throughout the document.
Section 1.4.1 – Study Design - Enrollment period: Clarified that at Visit 1 (screening visit) 
the serum prednisone/prednisolone laboratory test is only for patients switching from other 

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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OCS, and clarified when benralizumab is to be administered. Added text clarifying when the 
screening period may be extended.
Section 1.4.2 – Study Design - Induction phase: Clarified the benralizumab and OCS dosing 
during this period, and added instruction on how to proceed if an exacerbation occurs during 
this phase.
Section 1.4.3 – Study Design (OCS reduction phase): Added text to clarify benralizumab 
dosing. Added text to clarify that HPA axis integrity will be assessed at the start of the 
reduction phase (Visit 3, "4 weeks after the first dose of benralizumab and before initiation 
of the OCS reduction") for all patients on a baseline OCS dose of 5 mg/day. Also added text 
to clarify that the first OCS dose reduction can occur at Visit 3 after the dose of 
benralizumab at the site.
Section 1.4.4 – Maintenance phase: added clarifications to indicate that worsening of asthma 
control will be determined by the investigator based on the cortisol/ACTH stimulation 
results, the duration of the maintenance phase and the procedure should a subject experience 
an asthma exacerbation (if exacerbation, the length of the maintenance phase will not be 
extended and the patient will continue on 3 doses of benralizumab Q8W).
Figure 1 – Study flow chart: Updated to clarify the following: 

when benralizumab is to be administered

the OCS reduction phase will vary for a variety of factors detailed in the figure

information regarding the IPD visit for patients who discontinue treatment early
Section 1.5.1 – Scientific Committee: The charter details roles of scientific committee also. 
Section 2.1 – Primary Objective: Removed “average” from the key supportive outcome 
measures when describing the daily OCS dose.
Section 2.2 – Secondary Objective #2: Removed “timepoint at which OCS dose equals 5mg” 
from the outcome measures.
Section 2.3 – Safety objectives: Deleted “severe” from “annualized severe asthma 
exacerbation rate”
Section 3.1 – Inclusion criteria: The following text was added to inclusion 3 for clarity -
“[periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of exposure to study drug, and withdrawal are not 
acceptable methods of contraception].” The following text was updated for clarification: “a 
vasectomized sexual partner, female sterilization by tubal occlusion, any effective 
intrauterine device (e.g copper IUD, levonorgestrel intrauterine system), depot injections or 

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Study Code D3250C00065
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implanted contraception (e.g. Depo-Provera™, Implanon®), oral contraceptive, and 
contraceptive patches or vaginal rings (e.g. Evra Patch™, Xulane™, or NuvaRing®).”
Section 3.1 – Inclusion criteria: Inclusion 5 was updated to clarify that patients must have a 
smoking history of 20 pack years or less. 
Section 3.1 – Inclusion criteria: Inclusion 7 was updated to clarify definition of high-dose 
ICS includes: budesonide/formoterol HFA ≥ 640/18/ per day or equivalent , fluticasone 
propionate DPI > 500/day or equivalent, or authorized generics for these products; see 
Appendix E and GINA 2018 guidelines for more recommendations); and that for ICS 
monotherapy preparations, or ICS/LABA combination preparations not mentioned in GINA 
(e.g. newer formulations), the highest approved maintenance dose in the local label will also 
meet this ICS criterion. Additionally, in countries where the high-dose ICS is not available 
(e.g. only the medium-dose ICS is available in that country), the highest approved 
maintenance dose in the local label will also meet this ICS criterion. Inclusion 7 was also 
updated to note that ICS can also be given via nebulized solution for inhalation.
Section 3.2 – Exclusion Criteria: Abbreviations were included within exclusion 1 to enhance 
ability to search CSP for certain conditions; and asthma-COPD overlap [ACO] was added an 
as example of clinical important pulmonary disease other than asthma.
Section 3.2 – Exclusion Criteria: Clarified Exclusion 8 to indicate that a history of positive 
HIV test (not a baseline HIV test; as baseline HIV test is not a part of study procedures) is 
also exclusionary.
Section 3.2 – Exclusion Criteria: Clarified Exclusion 11 that interventional clinical trials (not 
all clinical trials) is an exclusion.
Section 3.2 – Exclusion Criteria: Updated Exclusion 15 (prior benralizumab in present 
study) to clarify that patients may not re-enter the study after completion or premature 
discontinuation.
Section 3.2 – Exclusion Criteria: Added the following new exclusion criteria to enhance 
patient safety and to better align with prior studies: 
19.
Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, 
neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or major 
physical impairment that is not stable in the opinion of the investigator and could:
-
Affect the safety of the patient throughout the study
-
Influence the findings of the study or the interpretation
-
Impede the subject’s ability to complete the entire duration of study.
20.
Any clinically significant abnormal findings in physical examination, medical history, vital 
signs, hematology, clinical chemistry, or urinalysis during the enrollment period, which in the opinion 
of the Investigator, may put the patient at risk because of his/her participation in the study, or may 
influence the results of the study, or the patient’s ability to complete entire duration of the study.

Clinical Study Protocol
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Study Code D3250C00065
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Date 17 October 2020
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21.  History of cancer. Patients who have had basal cell carcinoma, localized squamous cell carcinoma 
of the skin, or in situ carcinoma of the cervix are eligible provided that the patient is in remission and 
curative therapy was completed at least 12 months prior to the date informed consent was obtained.
-
Patients who have had other malignancies are eligible provided that the patient is in remission and 
curative therapy was completed at least 5 years prior to the date informed consent was obtained
Section 3.2 – Exclusion Criteria: Added new Exclusion (#22) to allow for an extension of 
screening period up to 3 months for other (non-asthma related) disease flare-up or AE/SAE 
which occurs during the screening period and requires temporary use of systemic 
corticosteroids. This extension is not allowed when OCS is used for related diseases, such as 
rhinitis or nasal polyposis; in this case, the OCS use is an exclusion. See Section 7.8 Table 6 
for more detail.
Section 3.2 – Exclusion Criteria: Added new Exclusion (#23) to clarify that current night-
shift workers are not allowed into the study.
Section 3.5 – Restrictions: Clarified that SABA rescue medication will be permitted 
throughout the study and that ICS (not LABA if taken separately) should be withheld prior to 
cortisol/ACTH stimulation testing.
Section 3.6 – Discontinuation of study drug and criteria for withdrawal: Update was made to 
how a lost to follow-up (LTFU) patient will be defined in order to reduce prevalence of 
LTFU patients. 
Section 4 – Study Plan and Timing of Procedures – Table 1: Table headers and Footnote ‘k’ 
updated to clarify Week numbers for the study periods, and for the PGIC timepoints.
Section 4 – Study Plan and Timing of Procedures - Table 1: The header for the "OCS </= 
5mg/day" visit was updated with text to designate this the "morning cortisol visit."  
Section 4 – Study Plan and Timing of Procedures - Table 1: Footnote ‘d’ updated to clarify 
calls/visits during OCS reduction period. 
Section 4 – Study Plan and Timing of Procedures - Table 1: Footnote ‘m’ updated to clarify 
that prednisone testing is only done for patients who switch to prednisone/prednisolone at 
V1.
Section 4 – Study Plan and Timing of Procedures - Table 1: Footnote ‘n’ updated to clarify 
the timing of sputum sample collection; and to mention that this includes spirometry
Section 4 – Study Plan and Timing of Procedures - Table 1: Footnote ‘q’ added to clarify 
additional types of visits to be classified as Unscheduled visits. 

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Study Code D3250C00065
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Date 17 October 2020
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Section 4.1 – Enrollment period (header): Text was removed as length of screening period 
was listed incorrectly.
Section 4.1.1 – Screening Visit: Clarified in the title that the screening visit is Visit 1 and 
starts Week -2. Text was added to clarify prednisone/prednisolone testing and to clarify that 
for patients switching to prednisone/prednisolone and who thus require a delay in the 
laboratory tests, Visit 2 can be done up to 2 weeks after collection of laboratory samples.
Section 4.1.1 – Screening Visit: Text added to clarify that patients experiencing acute 
upper/lower respiratory infection that requires antibiotics or antiviral medication during 
screening will be granted an extension to the screening period of up to 3 months. 
Section 4.1.1 – Screening Visit: Text was added to clarify that patients experiencing non-
asthma related events requiring temporary increase (bolus/burst) of systemic steroids may be 
granted an extension to the screening period of up to 3 months, if approved by the 
AstraZeneca Physician.
Section 4.1.2 – Rescreening: Text added to confirm that rescreening is allowed only once for 
each patient.
Section 4.2.1 – Induction phase: Added clarifications regarding timing of induction phase, 
timing of baseline sputum sample collection and that PGIC will completed weekly only 
during the induction phase. 
Section 4.2.2 – OCS reduction phase: Added text to clarify when reduction phase starts, that 
there are 8 weeks between the 3rd and 4th dose of benralizumab, and that HPA axis integrity 
will be assessed at the start of the reduction phase (Visit 3) for all patients on a baseline OCS 
dose of 5 mg/day. Text also added to clarify which ACQ-6 score should be used if baseline 
result is missing. 
Section 4.2.3 – Maintenance phase: Text added to clarify the following:  

that replacement/additional asthma treatment may be prescribed at EOT visit, per
Investigator discretion. 

the duration of the maintenance phase will vary based on when the patient enters the 
maintenance phase, relative to the dosing cycle of benralizumab

the length of the maintenance will not change due to an asthma exacerbation

the registration of completion of treatment will be captured in IWRS/IVRS
Section 4.3 – Follow-up Period: The following text was added for clarity - “The follow-up 
contact can be done either on-site or via telephone contact.”

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
15(157)
Section 5.1.2 - OCS dose titration: Added text to clarify how to start the initial OCS 
reduction if: 1. Table 2 instructs to reduce dose by 5mg increments, but the initial OCS dose 
is < 5mg to the nearest dosing level, and 2. Table 2 instructs to reduce the initial dose by 2.5 
mg increments, but the initial dose is < 2.5 to the next dosing level.
Section 5.1.2 Table 2 – OCS down-titration approaches: Table was updated to show the 
correct down-titration method, in line with the OCS down-titration table in the protocol 
Synopsis. Correction is in the column titled 7.5 mg (‘Q4W’ was corrected to ‘Q2W’). 
Corrected text is “2.5 mg Q2W until reaching a dose of 7.5 mg/day”. Footnote ‘a’ was 
updated to clarify that ‘Risk AI’ means cortisol testing confirmed with ACTH stimulation 
testing and if complete AI, no modification to the OCS dose will occur.
Section 5.2.1.1 – Asthma worsening or asthma exacerbation preventing OCS down-titration:
Text added to clarify which ACQ-6 score should be used if baseline result is missing. 
Section 5.2.1 – HPA axis evaluation: Moved the following from section 5.2.1.1 “For the 
morning cortisol test, the last OCS dose should be taken 24 hours prior to testing. 
Additionally, patients must not take ICS (or ICS/LABA if in single inhaler) treatment on the 
morning of the cortisol testing (for patients taking a once-daily ICS/LABA formulation, e.g. 
fluticasone furoate/vilanterol; patients must not take the treatment the night prior or the 
morning of the cortisol testing). If a patient requires a short course of macrolides, antivirals, 
or azoles, there must be a window of ≥1 week prior to the testing of cortisol levels (see 
Section 7.8).
Section 5.2.1 – HPA axis evaluation: Clarified that details related to values for normal, 
partial and complete AI for females using oral estrogen-containing contraceptives or oral 
estrogen-containing hormone replacement therapy are provided in the laboratory manual. 
Section 5.2.1.1 – Morning cortisol and Section 5.2.1.2 – ACTH stimulation test: Sections 
revised to add further detail and clarification to both the initial and repeat cortisol and ACTH 
stimulation testing process along with actions on OCS titration based on results. 
Section 5.2.1, Figure 2 – HPA axis evaluation: figure footnotes to clarify actions after 
retesting.
Section 5.2.1.2 – ACTH stimulation test: The following text was removed - “An injection of 
250 µg tetracosactide depot will be given intravenously”. This text was replaced by - “An 
injection of the fast-acting ACTH stimulant will be given intravenously”.
Section 5.2.1.2 – ACTH stimulation test: The following text was added for clarity: “Please 
refer to the package insert of the product used locally for further guidance on preparation and 
administration”

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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Section 5.2.1.2 – ACTH stimulation test: The following text was added: “In the event of any 
issues with availability of the product used for the ACTH stimulation test, please consult 
with AZ study physician for further guidance”.
Section 5.2.3 – Management of asthma exacerbations, Maintenance phase: Clarified that the 
length of the maintenance phase will not be extended should the patient experience an 
exacerbation
Section 5.2.4 – Laboratory safety assessments Table 4: Added glucose to the laboratory 
safety variables table as this is required for assessment of adrenal insufficiency. Clarified 
text for absolute leukocyte count is white blood cell count with differential.
Section 5.3.2 – Prednisone/prednisolone levels: Text was added to this section to clarify the 
prednisone/prednisolone testing is only done for patients who are switching to 
prednisone/prednisolone at V1.
Section 5.3.4.1 Patient-reported outcomes (Patient Global Impression of Change 
assessment): The text was corrected to reflect the new PGIC standards. Text was also added 
to clarify the timing of PGIC collection (in line with Table 1 – Study Plan).  
Section 5.7.3 – Sputum collection and biomarkers: Section updated to align timing of sputum 
collection in Treatment with text throughout CSP (after approximately 24 weeks of 
benralizumab treatment).
Section 5.7.3 - Sputum collection and biomarkers: Added new subsection, "Spirometry," to 
clarify that spirometry is included in the sputum induction procedure, is included only for 
patient safety during the procedure, and that spirometry results will neither be captured nor 
analyzed.
Section 5.7.3 Sputum collection and biomarkers: Added a new subsection, "order of 
administration of usual asthma controller medication and investigational product relative to 
scheduled spirometry," to give details on when to dose patient, and also to note that detailed 
sputum collection procedures are in a separate sputum manual.
Section 6.6 Pregnancy: Subsection 6.6.2 ‘Paternal exposure’ added along with the following 
text: “Pregnancy of the patients’ partners will not be considered an AE. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented for 
conceptions occurring from the date of the first administration of study drug until 16 weeks 
(approximately 5 half-lives) after the last administration of study drug.” 
Section 7.2 – Dose and treatment regimens (Conditions that will require rescheduling of study 
drug administration): “The patient, in the opinion of the Investigator, is experiencing an acute 

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
17(157)
or emerging asthma exacerbation” was removed as one of the conditions requiring study drug 
rescheduling. 
Section 7.2 – Dose and treatment regimens (Conditions that will require rescheduling of study 
drug administration): The following text was added to clarify action for potential out of 
window dosing - “Every possible effort should be made to bring the patient in within the 
allowed visit window and study drug should be administered at that visit. If this is not 
possible, the AZ study physician should be contacted to discuss further.”
Section 7.3 – Management of study drug-related reactions: Removed “lung function” as an 
example of a pre-assessment as lung function is not a CSP-required assessment.
Section 7.8 – Concomitant and other treatments: Text updated to clarify that information is 
collected in eCRF for treatments received 3 months prior (versus 6 months prior) and that 
information is collected through follow-up period. The following text was also added “The as-
needed use of short-acting bronchodilators for relief of acute asthma symptoms is permitted 
throughout the study” and removed table referencing short-acting bronchodilators. 
Section 7.8 – Concomitant and other treatments: Added Table 5 “Medication Restrictions” 
and Table 6 “Prohibited Medications” headers to existing tables. 
Section 7.8 Concomitant and other treatments: Deleted table summarizing Rescue usage and 
instead summarized in text at the top of this section. 
Section 7.8 Concomitant and other treatments 
Table 5: Clarification added regarding withholding of high-dose ICS for morning 
cortisol/ACTH stimulation test. 
Section 7.8 – Concomitant and other treatments Table 6: updated to define short course of 
marcolides, antivirals, and azole therapies as “≤ 2 weeks”. 
Section 7.8 – Concomitant and other treatments Table 6: Added new row with new washout 
periods for marketed respiratory biologics (as follows) and clarified pre-existing row is in 
reference to non-respiratory marketed biologics or any investigational biologics.
Any marketed respiratory biologic treatment (eg, omalizumab, mepolizumab, reslizumab, 
benralizumab) is not allowed 4 months or 5 half-lives (whichever is longer) prior to the date informed 
consent is obtained and throughout the entire treatment period.
-
For patients who have previously not tolerated or have not responded to marketed 
mepolizumab, omalizumab or reslizumab (as assessed by the treating physician), a shorter washout 
period of ≥ 30 days between the last dose of mepolizumab, omalizumab or reslizumab and the first dose 
of open label Benralizumab (Visit 2), is allowed. 
-
Patients who have previously received benralizumab still require a complete washout prior to 
date of informed consent; those who have not tolerated or have not responded to benralizumab would 
not be a candidate for this study.

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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Section 7.8 – Concomitant and other treatments Table 6: Added clarifications to 
immunosuppressive medications, to allow short course of OCS for non-asthma related disease 
flare ups; at any time during the study and to indicate that the prohibited period for any non-
respiratory marketed or any investigational biologics
Section 8.1 – Statistical considerations: Removed text referencing sputum collection as a 
subgroup.
Section 8.1 – Statistical considerations: Updated text from ‘synthetic control arm’ to ‘external 
data sources’ when referring to what will be used to assess certain changes seen in patients 
and clarified where it will be described. 
Section 8.2 – Sample size estimate: Provided further clarification regarding the sample size 
estimate in relation to the primary outcome measure and 95% confidence interval
Section 8.2 – Sample size estimate Table 7: Updated the values of expected distance between 
observed proportion and confidence limit.
Section 8.4 – Outcome Measures for Analyses: Removed “average” from the key supportive 
outcome variables to the primary efficacy outcome variables when describing the daily OCS 
dose.
Section 8.4 – Outcome Measures for Analyses: Removed “timepoint at which OCS dose 
equals 5mg” from the secondary efficacy outcome variables.
Section 8.4 – Outcome Measures for Analyses: Removed “severe” when describing asthma 
exacerbation rate in the safety outcome variables.
Section 8.5.1 – Analysis of the primary variable: Provided further clarification regarding the 
analysis of the primary variable using the Clopper-Pearson exact method
Section 8.5.2.1 – Time to 1st OCS increase; section header was renamed; updated to describe 
analysis method for measuring the time to 1st OCS increase
Section 8.5.2.2 – ACQ-6: ‘+’ signs added for clarification, to indicate that deterioration is a 
change from baseline in an ACQ-6 score of at least +0.5.
Section 8.5.2.4 – PGIC: The text was corrected to reflect the new PGIC standards, and to 
better align with Table 1.
Section 8.5.3 – Analysis of safety outcomes: Removed “severe” when describing how the 
annualized rate of asthma exacerbations will be summarized 
Section 8.5.4 – Subgroup analysis: Updated the baseline serum eosinophil count subgroups 
as ≥300/μL and <300/μL

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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Section 8.5.5 – Interim analysis: Text describing the plans for conducting the interim review 
was clarified. The location of where the interim review would be detailed was updated from 
“SAP” to “separate interim review plan”. Interim “analysis” was changed to interim 
“review” throughout.
Section 10.4: Text updated to clarify that genetic consent is a separate consent but not 
necessarily a separate form. 
Appendix C – Informed consent: Text updated to clarify that genetic consent is a separate 
consent but not necessarily a separate form.
Appendix E (Estimated daily doses for inhaled corticosteroids): Updated the “inhaled 
corticosteroid” section of the table to match the current GINA 2018 guidelines. Updated the 
“inhaled corticosteroid in ICS/LABA combination” to match highest dose per local labels of 
major markets; GINA 2018 does not specifically address ICS/LABA comparable doses.
Appendix E (Estimated daily doses for inhaled corticosteroids): Updated in footnotes to 
clarify references, and to add additional clarification from GINA 2018 on how to interpret 
data. Also added clarification that, “this protocol also allows clinically comparable doses of 
newer products, including authorized generics. High-dose ICS via nebulized solution for 
inhalation is also allowed. For products not listed in this table, the highest approved 
maintenance ICS or ICS/LABA dose in the local country label will meet the protocol-
defined criterion for ‘high-dose ICS.’”
Appendix F - Estimated OCS dose therapy equivalence: Added footnote that for other OCS 
products or doses not listed, to see local label of OCS product or online calculators.
Appendix G - Prednisone/Prednisolone Doses <5 mg in Relation to Available Tablet 
Strengths: Administered number of tablets to achieve a 3 mg daily dose with 5 mg tablets 
was corrected. Made corrections to dosing conversions throughout, added rows for 0.5mg 
and 1.5mg.
Appendix H – Glucocorticoid Toxicity Index: Added in-text headers to make it clear that 
Appendix H spans several pages.
Adjustments made throughout:

For general administrative purposes (i.e. headers, formatting) and grammatical corrections

To clarify the timeframe of screening and induction phases

To clarify that patients who are already taking prednisone/prednisolone at Visit 1 do not 
require the serum prednisone/prednisolone laboratory test

To clarify that baseline visit is Visit 2

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
20(157)

To clarify that repeat morning cortisol testing is done only once

To clarify that for patients who are on a baseline OCS dose of 5 mg/day, HPA axis integrity 
will be assessed after 4 weeks at 5mg/day, at the start of the reduction phase (Visit 3).

To clarify that the duration of the maintenance phase will depend on when the patient enters 
the maintenance phase relative to the dosing cycle of benralizumab.

Created consistency in the language for sputum (that sputum will be done for a subset of up 
to approximately 100 patients at selected clinical sites).

Added clarification that there are 8 weeks between the 3rd and 4th benralizumab doses
Version 1.0, 12 April 2018
Initial Creation

Clinical Study Protocol
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
21(157)
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 Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
23(157)

Induction phase (starting Week 0): Patients who are receiving benralizumab 
treatment should remain stable on their baseline (Visit 2) OCS dose during this 4-week 
phase. 

OCS reduction phase (Week 4 onwards): Patients will reduce their dosage of OCS 
according to the schema defined below for each baseline OCS dose until they reach 
5 mg/day.
Table A   OCS Titration Schema Until Reaching 5 mg/day 
Baseline OCS dose
OCS down-titration schema until reaching 5 mg/day (without worsening of 
asthma)
>20 mg/day
Reductions of 5 mg every 1 week until reaching a dose of 20 mg/day; followed 
by reductions of 5 mg every 2 weeks (Q2W) until a dose of 10 mg/day is reached; 
followed by reductions of 2.5 mg Q2W until reaching a dose of 7.5 mg/day; and 
then reductions of 2.5 mg Q4W until reaching a dose of 5 mg/day 
>10 to ≤20 mg/day
Reductions of 5 mg Q2W until reaching a dose of 10 mg/day; followed by 
reductions of 2.5 mg Q2W until reaching a dose of 7.5 mg/day; and then 
reductions of 2.5 mg Q4W until reaching a dose of 5 mg/day
>7.5 to ≤10 mg/day
Reductions of 2.5 mg Q2W until reaching a dose of 7.5 mg/day followed by 
reductions of 2.5 mg Q4W until reaching a dose of 5 mg/day
>5 to ≤7.5 mg/day
Reductions of 2.5 mg Q4W until reaching a dose of 5 mg/day
For all patients, hypothalamic-pituitary-adrenal (HPA) axis integrity will be evaluated after 4-
weeks on 5 mg/day and prior to tapering down the OCS dose (for patients with baseline OCS 
doses equal to 5 mg/day, this will be assessed 4 weeks after the first dose of benralizumab 
administration and before initiation of the OCS reduction phase).  
First, a screening method with morning serum cortisol is done (8-9 am morning cortisol level), 
to evaluate whether the patient has:

Normal cortisol levels 

Complete adrenal insufficiency (AI)
Cortisol levels from the morning cortisol test that are below normal range and above the 
Complete AI range are considered “Indeterminate;” and require additional testing as described 
below.
Secondly, the adrenocorticotropic hormone (ACTH) stimulation test (ie, Synacthen®, 
Cortrosyn™) is done within approximately 1 week in the subset of patients with indeterminate 
results from the morning cortisol test [see also Section 5.2.1.2 for details). The ACTH 
stimulation test is more specific than the morning cortisol test, and can determine whether the 
patient has:

Normal cortisol levels

Complete AI

Partial AI

Clinical Study Protocol Synopsis
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
24(157)
Depending on the morning cortisol level results and the presence of cortisol level values 
indicating AI, the patient will continue per the following guidance:
-
Cortisol levels within normal range:

Patient exhibits absence of signs and/or symptoms of AI:  continue 
OCS down-titration by 2.5 mg Q4W 

Patient exhibits signs and/or symptoms of AI:  continue OCS down-
titration at a slower pace (1 mg Q4W)
-
Cortisol levels are indeterminate: Patient will undergo the ACTH stimulation testing 
(Section 5.2.1.2).  Decisions regarding how to continue OCS down-titration will be
based on the results of the ACTH stimulation testing (see Table B)
Table B    ACTH Stimulation Testing
ACTH stimulation test results
Normal
Partial AI  
Complete AI
OCS down-titration 
Reduction of 2.5 mg 
Q4W
Reduction of 1 mg Q4W 
Continue on same 
OCS dose 
Repeat morning cortisol test 
for further OCS down-titration
No need
2 months later
3 months later (see 
below)

Cortisol levels confirm complete AI:  OCS dose will remain the same without further 
reduction until there is evidence of recovery from the complete AI.  The test will be 
repeated on one occasion 3 months later, and patients will be educated for symptom 
awareness of adrenal suppression and use of steroid emergency cards
If a patient experiences an exacerbation or an asthma deterioration, OCS dose 
reductions should stop.  After recovery from the first exacerbation or asthma 
deterioration, the patient will be allowed to proceed with another attempt to reduce 
OCS dose; however, this must follow a lower speed of OCS down-titration (reductions 
Q4W).  However, in case of a second exacerbation or asthma deterioration, no further 
OCS dose reduction will be allowed, and the patient will continue on the same OCS 
dose or will return to a one-step higher dose level (or more as considered necessary by 
the Investigator), and the patient will then enter the maintenance phase.  Further details 
are provided in Sections 5.2.2 and 5.2.3. 
At each clinic/phone call visit, in addition to the information provided by the patient 
on his/her asthma disease, investigators will have access to the patient’s weekly 
Asthma Control Questionnaire 6 (ACQ-6) scores and compliance with maintenance 
asthma therapy (completed by means of an electronic patient-reported outcome device 
[ePRO] to evaluate whether the patient’s condition has significantly deteriorated [ie, 
increase in ACQ-6 score of ≥0.5 from Visit 2, ie, before benralizumab administration]) 
and will make the final decision to further reduce the OCS dose until the patient 

Clinical Study Protocol Synopsis
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
25(157)
reaches an OCS dose of 0 mg/day (or lowest OCS dose possible in case no further 
OCS down-titration is allowed because of the presence of AI as measured by cortisol 
levels or in case of inadequate asthma control) without losing asthma control. 
Approximately 1-2 weeks prior to end of the OCS reduction phase, the patients who 
have Partial AI after the repeat morning cortisol test, will undergo an additional 
morning cortisol test (and if required, ACTH stimulation test for indeterminate result) 
at the end of the OCS Reduction phase.

Maintenance phase: This phase will last approximately 24 to 32 weeks from the time 
the patient reaches a complete withdrawal of OCS without worsening of asthma 
control. The maintenance phase could be initiated earlier if OCS dose reduction fails 
due to clinical deterioration or if the patient does not recover from AI. The length of 
the maintenance phase will vary depending on when the patient enters the maintenance 
phase. During this phase, patients will continue benralizumab Q8W for 3 doses, and 
then the End of Treatment (EOT) visit will be scheduled 8 weeks (± 7 days) after the 
last dose of benralizumab. Patients who have Complete AI or Partial AI at the end of 
the OCS Reduction phase, will undergo a final morning cortisol test (and if required, 
ACTH stimulation test for indeterminate result) approximately 1-2 weeks prior to end 
of the OCS Maintenance phase. If a patient experiences an exacerbation during the 
maintenance phase, this period will not be extended.
Patients should be maintained on their currently prescribed ICS plus LABAs with or without 
other asthma controller therapy, without change, as is defined in Section 3.1 (Inclusion 
Criteria) until the EOT visit.
All patients who prematurely discontinue study drug/investigational product or discontinue 
from the study should return to the study center and complete the procedures described for the 
Premature Investigational Product Discontinuation (IPD) visit within 4 weeks (± 7 days) after 
the last dose of benralizumab.  
For all patients dosed with benralizumab, a follow-up contact will be scheduled 12 weeks 
(± 7 days) after their last dose of benralizumab. Patients who have Partial AI or Complete AI 
at the end of the Maintenance phase should be followed-up by an endocrinologist or other 
appropriate specialist, if deemed necessary by the Investigator.
PONENTE Long Term Follow Up Visit Substudy
After completion of the EOT visit procedures, eligible patients may consent to a long term 
follow up visit that will occur 12- to 18-months after completion of the main PONENTE 
study. The objectives of this long term follow up visit are to retrospectively collect changes in 
OCS dose and other background asthma therapy and to further assess recovery from AI in a 
real-world setting. Between the EOT visit of the main PONENTE study and the long term 
follow up, patients will be treated according to standard practice; for example, any changes to 
maintenance asthma regimens are allowed, including further reductions of OCS as 
recommended in the GINA report (GINA 2020). 

Clinical Study Protocol Synopsis
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
26(157)
See Appendix K: for details on eligibility for and endpoints of the PONENTE Long Term 
Follow Up Visit substudy. 
Objectives and Endpoints
Primary Objective
Endpoints/Outcome Variables
To assess the ability to reduce OCS dose 
in adult patients with severe eosinophilic 
asthma treated with benralizumab 30 mg 
SC 
Primary outcome measures

Patients who achieve 100% reduction in daily OCS 
dose that is sustained over at least 4 weeks without 
worsening of asthma 

Patients who achieve 100% reduction or a daily OCS 
dose ≤5 mg, if reason for no further OCS reduction is 
AI, that is sustained over at least 4 weeks without 
worsening of asthma
Key supportive outcome measures

Patients who achieve a daily OCS dose of ≤5 mg that 
is sustained over at least 4 weeks without worsening 
of asthma

Patients who achieve a ≥90%, ≥75%, ≥50%, and >0% 
reduction in daily OCS dose, sustained over at least 
4 weeks without worsening of asthma

Change from baseline in daily OCS dose (mg) from 
start of OCS reduction to end of the OCS reduction 
phase
Secondary Objective
Outcome Measure
To assess the sustained reduction of daily 
OCS dose while not losing asthma 
control during approximately 6 months 
after the end of OCS down-titration 
(maintenance phase) in adult patients 
with severe eosinophilic asthma treated 
with benralizumab 30 mg SC
Key outcome measure

Change in daily OCS dose from the end of OCS 
reduction phase to the end of the maintenance phase 
(EOT visit)

Time to first increase in OCS dose during the 
maintenance phase, after achieving the minimum OCS 
dose during the OCS reduction phase 
To assess the effect of OCS 
down-titration protocol on asthma control 
in adult patients with severe eosinophilic 
asthma treated with benralizumab 30 mg 
SC
Key outcome measure

ACQ-6 scores at baseline (Visit 2), Visit 3, end of 
OCS reduction phase, and monthly from end of OCS 
reduction phase to end of maintenance phase (EOT 
visit)

Change from baseline in ACQ-6 to Visit 3, end of 
OCS reduction phase, and end of maintenance phase 
(EOT visit)

Responder analysis of ACQ-6 scores from Visit 2 
through end of maintenance phase

Clinical Study Protocol Synopsis
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
27(157)
Secondary Objective
Outcome Measure
To assess the effect of OCS 
down-titration protocol on quality of life 
in adult patients with severe eosinophilic 
asthma treated with benralizumab 30 mg 
SC
Key outcome measure

Change from baseline (Visit 2) in St. George's 
Respiratory Questionnaire (SGRQ) total scores to the 
end of maintenance phase (EOT visit)

Responder analysis of SGRQ total scores at the end of 
maintenance phase
Safety Objective
Outcome Measure
To evaluate the occurrence of AI when 
reducing OCS
Key outcome measure

Patients with complete AI 
To assess the effect of OCS 
down-titration protocol on asthma 
exacerbations in adult patients with 
severe asthma treated with benralizumab 
30 mg SC
Key outcome measures

Annualized asthma exacerbation rate

Annualized asthma exacerbation rate leading to 
hospitalization or emergency room visit
To assess the safety and tolerability of 
benralizumab in patients who reduce 
their chronic OCS dose

Adverse events/Serious adverse events

Laboratory parameters and vital signs
To evaluate corticosteroid toxicity after 
OCS reduction

Glucocorticoid toxicity index
Exploratory Objective
Outcome Measure
To investigate the contribution of 
genomic variants to the study outcomes

Association of common and rare genomic variants 
with patient responses
To assess early improvements in asthma 
status during the first 4 weeks of 
benralizumab treatment before initiation 
of OCS reduction

Patient Global Impression of Change 
To assess the impact of OCS 
down-titration on blood eosinophil levels
Key outcome measure

Change from baseline blood eosinophils
To investigate biomarkers for predicting 
response to benralizumab
Key biomarker parameters

Serum samples at baseline for protein biomarkers

Plasma for eosinophil-derived neurotoxin
Target patient population
Male and female patients aged ≥18 years with diagnosed asthma and requiring continuous 
treatment with high-dose ICS (high-dose ICS at the highest approved dose in a country) plus 
LABAs for ≥6 months.  Patients must be on chronic treatment with OCS (equivalent to a 
prednisone dose of ≥5 mg/day) for ≥3 months prior to study entry.  The OCS dose must be 
stable for ≥4 weeks prior to study entry.  Patients must have peripheral blood eosinophil 
counts of ≥150 cells/μL as assessed by a central laboratory at Visit 1 or documented 
eosinophil count of ≥300 cells/μL in the past 12 months. 

Clinical Study Protocol Synopsis
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
28(157)
Duration of treatment
Patients will start receiving open-label benralizumab at Visit 2 (Week 0) and will enter the 4 
week induction phase, where they will remain stable on their baseline OCS dose during this 
period.
The OCS reduction phase will start at Visit 3 (Week 4) and will be completed depending on 
the baseline OCS dose, the occurrence of asthma exacerbation or asthma worsening, and the 
integrity of the HPA axis (which will guide the speed of OCS down-titration for patients 
taking doses of <5 mg/day).  After OCS down-titration, patients will continue to receive 
treatment with benralizumab 30 mg Q8W for approximately 24 to 32 weeks (the maintenance 
phase).  The maintenance phase will end with an EOT visit conducted 8 weeks after the last 
dose of benralizumab.  A follow-up contact will be conducted 12 weeks following the last 
dose of benralizumab.
The total planned study duration is flexible and will vary for each individual patient
depending on the factors previously mentioned.  The expected duration can range from 
approximately 32 weeks (eg, a patient with a baseline OCS dose of 5 mg) to approximately 
48 weeks (eg, a patient with a baseline OCS dose of 40 mg), assuming the patient has 
completely withdrawn OCS without the occurrence of an asthma exacerbation, completes the 
study, and morning cortisol levels do not indicate risk for AI.
Study drug, dosage, and mode of administration
Benralizumab 30 mg/mL solution for injection in an accessorized prefilled syringe will be 
administered at the study center SC Q4W up until the third dose of benralizumab and then 
Q8W thereafter (8 weeks between the 3rd and 4th benralizumab doses).
Statistical methods
The study includes two primary endpoints: 1) Patients who can reduce their daily OCS dose 
by 100% and 2) Patients who can reduce their daily OCS dose by 100% or reduce to a dose 
≤5 mg if the reason for no further OCS reduction is AI; both endpoints to be sustained over at 
least 4 weeks without worsening of asthma.  The proportion and 95% confidence interval for 
each of the primary outcome measures will be estimated for all patients in the full analysis set 
and for at least the following prespecified subgroups based on: baseline OCS dose level, 
baseline eosinophil count, and duration of chronic OCS dose.  The endpoints will be evaluated 
independently.  All confidence intervals will be estimated using the Clopper-Pearson exact 
method. 
The full analysis set, which will include all patients who receive any dose of benralizumab, is 
defined based on an intention-to-treat approach.  All efficacy and safety analyses will be 
analyzed using the full analysis set.  
The changes in OCS daily dose, ACQ-6 scores, and SGRQ scores will be summarized in 
descriptive statistics. Asthma control and SGRQ responders will be summarized in count and 
percentage.

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As this study is primarily descriptive in nature, no statistical multiplicity adjustment will be 
made over different endpoints or subgroups.  
As the study does not include any predefined confirmatory tests, the sample size is based on 
the ability to provide sufficient precision in point estimates.  The primary outcome, the 
observed proportion of patients who successfully down-titrated their doses, is expected to be 
equal to or greater than 50%.  A total sample size of 600 patients is expected to provide 95% 
confidence intervals for a single proportion extending approximately 4.1% from the point 
estimate of a 50% success rate.
One interim review may be performed after approximately 90-100 patients have completed (or 
have had the opportunity to complete) their OCS down-titration; further details will be 
described in a separate interim review plan.
An additional database lock and analysis of all relevant data collected through the end of the 
OCS reduction phase, may be performed after the final patient has had the opportunity to 
complete the OCS reduction phase. The purpose of this analysis is to generate a sub-set of the 
pre-planned analysis outputs of all relevant data for all patients up to the end of the OCS 
reduction phase. Further details will be outlined in the Statistical Analysis Plan (SAP).  The 
number and percentage of patients diagnosed with AI will be tabulated overall and by the 
method of diagnosis.
The PONENTE long term follow up visit substudy is designed to understand the clinical 
management of OCS and other background asthma maintenance medications in a real-world 
setting following completion of the maintenance phase of PONENTE study.  Outcome 
measures include the proportion of patients who achieve 100% reduction (and other pre-
defined percentage reductions) in OCS use and other background asthma maintenance 
medications from the PONENTE baseline to the end of the PONENTE Long Term Follow 
Up.  Proportions will be presented with nominal 95% confidence intervals estimated using the 
Clopper-Pearson exact method.  Results will be presented for all patients who sign informed 
consent to continue into the PONENTE Long Term Follow Up and will be repeated by 
exposure to (i) any biologic and (ii) commercial Benralizumab during the PONENTE Long 
Term Follow Up.  No formal hypothesis will be tested and no multiplicity adjustment will be 
applied in the statistical analysis.

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TABLE OF CONTENTS
PAGE
TITLE PAGE....................................................................................................... 1
VERSION HISTORY.......................................................................................... 2
CLINICAL STUDY PROTOCOL SYNOPSIS .................................................. 22
TABLE OF CONTENTS................................................................................... 30
1.
INTRODUCTION ............................................................................................. 38
1.1
Background and rationale for conducting this study ........................................... 38
1.2
Rationale for study design, doses, and control groups......................................... 39
1.3
Benefit/risk and ethical assessment .................................................................... 40
1.4
Study design ...................................................................................................... 41
1.4.1
Enrollment Period (starting Week -2):................................................................ 42
1.4.2
Induction phase (starting Week 0):..................................................................... 42
1.4.3
OCS Reduction phase (Week 4 onwards):.......................................................... 42
1.4.4
Maintenance phase:............................................................................................ 43
1.4.5
Premature Discontinuation and Follow-Up Contact:........................................... 44
1.4.6
Sputum Sampling for Exploratory Biomarkers:.................................................. 44
1.5
Study governance and oversight......................................................................... 46
1.5.1
Scientific Committee.......................................................................................... 46
2.
STUDY OBJECTIVES...................................................................................... 46
2.1
Primary objective............................................................................................... 46
2.2
Secondary objectives.......................................................................................... 47
2.3
Safety objectives................................................................................................ 47
2.4
Exploratory objectives ....................................................................................... 48
3.
PATIENT SELECTION, ENROLLMENT, RESTRICTIONS, 
DISCONTINUATION, AND WITHDRAWAL................................................. 48
3.1
Inclusion criteria ................................................................................................ 48
3.2
Exclusion criteria ............................................................................................... 50
3.3
Patient enrollment .............................................................................................. 52
3.4
Procedures for handling incorrectly enrolled patients ......................................... 53
3.5
Restrictions........................................................................................................ 53
3.5.1
Other restrictions................................................................................................ 54
3.6
Discontinuation of study drug and criteria for withdrawal .................................. 54
3.6.1
Procedures for discontinuation of a patient from study drug ............................... 54
3.6.2
Screen failures ................................................................................................... 55
3.6.3
Withdrawal of informed consent ........................................................................ 55

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4.3.1.1
Withdrawal of consent for genetic research........................................................ 55
3.7
Discontinuation of the study............................................................................... 55
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 56
4.1
Enrollment period .............................................................................................. 62
4.1.1
Screening visit – Visit 1 (Week -2)..................................................................... 62
4.1.2
Rescreening ....................................................................................................... 63
4.2
Open-label treatment period............................................................................... 63
4.2.1
Induction phase.................................................................................................. 63
4.2.2
OCS Reduction phase ........................................................................................ 63
4.2.3
Maintenance phase............................................................................................. 66
4.3
Follow-up period................................................................................................ 67
4.4
PONENTE Long Term Follow Up Substudy: Study Plan and Timing of 
Procedures ......................................................................................................... 67
4.5
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................. 67
5.
STUDY ASSESSMENTS.................................................................................. 68
5.1
Efficacy assessments.......................................................................................... 68
5.1.1
Assessment of OCS dose.................................................................................... 68
5.1.2
OCS dose titration.............................................................................................. 69
5.1.2.1
Asthma worsening or asthma exacerbation preventing OCS down-titration........ 73
5.2
Safety assessments............................................................................................. 73
5.2.1
HPA axis evaluation........................................................................................... 73
5.2.1.1
Morning cortisol test (done at “OCS ≤ 5mg/day [morning cortisol]” visit) ......... 75
5.2.1.2
ACTH stimulation test ....................................................................................... 77
5.2.2
Assessment of asthma exacerbations .................................................................. 79
5.2.3
Management of asthma exacerbations during treatment period........................... 80
5.2.4
Laboratory safety assessments............................................................................ 81
5.2.4.1
Pregnancy test.................................................................................................... 81
5.2.5
Physical examination ......................................................................................... 82
5.2.5.1
Complete physical examination.......................................................................... 82
5.2.5.2
Brief physical examination................................................................................. 82
5.2.6
Vital signs.......................................................................................................... 82
5.2.7
Glucocorticoid toxicity index............................................................................. 82
5.3
Other assessments.............................................................................................. 83
5.3.1
Weight and height.............................................................................................. 83
5.3.2
Prednisone/Prednisolone levels .......................................................................... 83
5.3.3
Total IgE and Phadiatop..................................................................................... 83
5.3.4
Clinical outcome assessments ............................................................................ 83
5.3.4.1
Patient-reported outcomes.................................................................................. 83
5.4
Pharmacokinetics ............................................................................................... 85

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5.5
Pharmacodynamics ............................................................................................ 85
5.6
Genomics........................................................................................................... 85
5.7
Biomarker collections and analysis .................................................................... 86
5.7.1
Serum for biomarkers......................................................................................... 86
5.7.2
Plasma for eosinophil-derived neurotoxin .......................................................... 86
5.7.3
Sputum collection and biomarkers...................................................................... 86
5.7.4
Storage, reuse, and destruction of biomarker samples......................................... 86
5.7.5
Labelling and shipment of biological samples .................................................... 87
5.7.6
Chain of custody of biological samples .............................................................. 87
5.7.7
Withdrawal of informed consent for donated biological samples........................ 87
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 87
6.1
Definition of adverse events............................................................................... 87
6.2
Definitions of serious adverse events.................................................................. 88
6.3
Recording of adverse events............................................................................... 88
6.3.1
Time period for collection of adverse events ...................................................... 88
6.3.2
Follow-up of unresolved adverse events............................................................. 88
6.3.3
Variables............................................................................................................ 88
6.3.4
Causality collection............................................................................................ 89
6.3.5
Adverse events based on signs and symptoms.................................................... 90
6.3.6
Adverse events based on examinations and tests ................................................ 90
6.3.7
Hy’s Law ........................................................................................................... 90
6.3.8
Disease under study ........................................................................................... 91
6.4
Reporting of serious adverse events ................................................................... 91
4.3.1
Regulatory Reporting Requirements for SAEs ................................................... 92
6.5
Overdose............................................................................................................ 92
6.6
Pregnancy .......................................................................................................... 93
6.6.1
Maternal exposure.............................................................................................. 93
6.6.2
Paternal exposure............................................................................................... 93
6.7
Medication error ................................................................................................ 93
7.
STUDY DRUG AND OTHER TREATMENTS ................................................ 95
7.1
Identity of study drug(s)..................................................................................... 95
7.2
Dose and treatment regimens ............................................................................. 95
7.3
Management of study drug–related reactions...................................................... 97
7.4
Labelling............................................................................................................ 97
7.5
Storage............................................................................................................... 98
7.6
Compliance........................................................................................................ 98
7.7
Accountability.................................................................................................... 98

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7.8
Concomitant and other treatments ...................................................................... 98
7.8.1
Other concomitant treatment .............................................................................101
8.
STATISTICAL ANALYSES BY ASTRAZENECA.........................................101
8.1
Statistical considerations ...................................................................................101
8.2
Sample size estimate .........................................................................................101
8.3
Definitions of analysis sets................................................................................102
8.3.1
All patients analysis set.....................................................................................102
8.3.2
Full analysis set.................................................................................................102
8.3.3
Safety analysis set.............................................................................................103
8.4
Outcome measures for analyses.........................................................................103
8.5
Methods for statistical analyses.........................................................................104
8.5.1
Analysis of the primary variables ......................................................................105
8.5.2
Analysis of the secondary variables...................................................................105
8.5.2.1
Time to 1st OCS increase...................................................................................105
8.5.2.2
ACQ-6..............................................................................................................105
8.5.2.3
SGRQ ...............................................................................................................107
8.5.2.4
PGIC.................................................................................................................107
8.5.3
Analysis of safety outcomes..............................................................................107
8.5.4
Subgroup analysis.............................................................................................108
8.5.5
Interim review and Analysis..............................................................................108
8.5.6
Sensitivity analysis............................................................................................109
8.5.7
Exploratory analysis..........................................................................................109
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA........................109
9.1
Training of study site staff.................................................................................109
9.2
Monitoring of the study.....................................................................................110
9.2.1
Source data .......................................................................................................110
9.2.2
Study agreements..............................................................................................110
9.2.3
Archiving of study documents...........................................................................110
9.3
Study timetable and end of study.......................................................................110
9.4
Data management by AstraZeneca ....................................................................111
10.
ETHICAL AND REGULATORY REQUIREMENTS......................................112
10.1
Ethical conduct of the study ..............................................................................112
10.2
Patient data protection.......................................................................................112
10.3
Ethics and regulatory review .............................................................................112
10.4
Informed consent ..............................................................................................113
10.5
Changes to the Clinical Study Protocol and informed consent form...................113
10.6
Audits and inspections ......................................................................................114

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11.
LIST OF REFERENCES ..................................................................................114
LIST OF TABLES
Table 1
Study plan – Treatment period and follow-up*............................................ 57
Table 2
OCS down-titration approaches................................................................... 71
Table 3
“Rescue” OCS down-titration after recovery from an asthma 
exacerbation or deterioration ....................................................................... 72
Table 4
Laboratory safety variables.......................................................................... 81
Table 5
Medication Restrictions............................................................................... 99
Table 6
Prohibited Medications................................................................................ 99
Table 7
Expected distance between observed proportion and confidence limit 
(Clopper-Pearson 95% CI width)................................................................102
Table 8
PONENTE Long Term Follow Up Substudy – Study plan: Enrollment 
to End of Study ..........................................................................................149
LIST OF FIGURES
Figure 1 
Study flow chart.......................................................................................... 45
Figure 2
HPA axis evaluation.................................................................................... 75
Figure 3 
Injection sites and rotation scheme .............................................................. 96
LIST OF APPENDICES
Appendix A: Additional Safety Information....................................................................118
Appendix B : International Airline Transportation Association (IATA) 6.2 Guidance 
Document...................................................................................................120
Appendix C: Genetic Research........................................................................................121
Appendix D: Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law..............................................................................124
Appendix E:
Estimated Daily Doses for Inhaled Corticosteroids.....................................131
Appendix F:
Estimated OCS Dose Therapy Equivalence ................................................132

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Appendix G: Prednisone/Prednisolone Doses <5 mg in Relation to Available Tablet 
Strengths ....................................................................................................133
Appendix H: Glucocorticoid Toxicity Index....................................................................134
Appendix I:
Anaphylaxis: Signs, Symptoms, and Management......................................140
Appendix J:
Adrenal Crisis Guidelines...........................................................................143
Appendix K: PONENTE Long Term Follow Up Substudy..............................................145
Appendix L:    Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis.................................155

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Study Code D3250C00065
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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
ACO
ACQ-6
Asthma-COPD overlap
Asthma Control Questionnaire 6
ACTH
Adrenocorticotropic hormone
AE
Adverse event
AI
Adrenal insufficiency
ALT
Alanine aminotransferase
APFS
Accessorized prefilled syringe
AST
Aspartate aminotransferase
BP
Blood pressure
CI
COPD
Confidence interval 
Chronic obstructive pulmonary disease
COVID-19
Coronavirus disease 2019
CSR
Clinical Study Report
EC
Ethics Committee, synonymous to Institutional Review Board 
(IRB) and Independent Ethics Committee (IEC)
eCRF
Electronic case report form
EDN
EGPA
Eosinophil-derived neurotoxin
Eosinophilic granulomatous polyangiitis
ePRO
Electronic patient-reported outcome device
EOT
End of Treatment
FAS
Full analysis set
GC
Glucocorticoid
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
GMP
Good Manufacturing Practice
GTI
Glucocorticoid toxicity index
HCG
HES
Human chorionic gonadotropin
Hypereosinophilic syndrome
HL
Hy’s Law
HPA
Hypothalamic-pituitary-adrenal
ICH
International Conference on Harmonisation
ICF
Informed consent form
ICS
Inhaled corticosteroids
IgE
Immunoglobulin E

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Abbreviation or special term
Explanation
IL-5
Interleukin-5
IL-5Rα
Interleukin-5 receptor alpha subunit
IPD
Investigational product discontinuation
International Coordinating 
investigator
If a study is conducted in several countries, the International 
Coordinating Investigator is the Investigator coordinating the 
investigators and/or activities internationally. 
IVRS
Interactive voice response system
IWRS
Interactive web response system
LABA
Long-acting β2 agonist
LTRA
Leukotriene receptor antagonist
OCS
Oral corticosteroids
PGIC
Patient Global Impression of Change
PHL
Potential Hy’s Law
PRO
Patient-reported outcome
Q2W
Every 2 weeks
Q4W
Every 4 weeks
Q8W
Every 8 weeks
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SC
Subcutaneous
SGRQ
St. George’s Respiratory Questionnaire
SOP
Standard Operating Procedures
TBL
Total bilirubin
ULN
Upper limit of normal
WBDC
Web-based data capture
WOCBP
Women of childbearing potential

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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Asthma is a syndrome characterized by airway inflammation, reversible airway obstruction, 
and airway hyper-responsiveness.  Patients present clinically with recurrent wheezing, 
shortness of breath, cough, and chest tightness.  Asthma is a leading cause of morbidity with a 
global prevalence of approximately 300 million; it is estimated that the number of people with 
asthma may increase to 400 to 450 million people worldwide by 2025 (Masoli et al 2004).
The current approach to anti-inflammatory controller therapy in asthma is based on a 
step-wise intensification of a daily maintenance regimen primarily centered around inhaled 
corticosteroids (ICS) and leukotriene receptor antagonists (LTRAs), with the addition of 
long-acting β2 agonists (LABAs) in patients with more severe asthma (NAEPP 2007, 
GINA 2018).  Approximately 5% to 10% of persons with asthma have a severe form of 
disease that is usually managed with high-dose inhaled glucocorticoids (GCs) and 
bronchodilators (Bateman et al 2010, Chung et al 2014).  Within this group, 32% to 45% of 
persons rely on frequent or maintenance use of oral GC therapy (Moore et al 2007, Shaw et 
al 2015, Miloslavsky et al 2017).  Biologics targeting interleukin-5 (IL-5) and 
immunoglobulin E (IgE) are now included in international treatment guidelines as an add-on 
treatment to patients uncontrolled with LABA/ICS treatment (GINA 2018).
Although oral GC therapy can be effective at treating several inflammatory diseases, it 
adversely affects health-related quality of life (Sweeney et al 2016) and is associated with 
several side effects, including osteoporosis, hypertension, and depression (Dinsen et al 2013).  
Chronic use of oral GCs suppresses the hypothalamic-pituitary-adrenal (HPA) axis (Broersen 
et al 2015) and prevents cortisol production (Neogi et al 2010, Nicholas et al 2018).  Upon 
withdrawal of GCs, restoration of the HPA axis may take a longer time, thus leading to 
adrenal insufficiency (AI) in approximately 48.7% of patients (Dinsen et al 2013, Broersen et 
al 2015).  Symptoms of AI are nonspecific and can include fatigue and nausea and, in severe 
cases, acute adrenal crisis; however, the suppression of a cortisol-induced stress response can 
be fatal in physiologically traumatic situations such as during surgery, bodily injury, or severe 
systemic infections (Alves et al 2008, Dinsen et al 2013, Johnson et al 2014, Joseph et 
al 2016).  It is therefore important to monitor patients for AI while down-titrating their oral 
GC dose, especially once the patient has reached a physiological dose, which is defined as 
approximately 5 mg per day of oral prednisone (Alves et al 2008). 
Interleukin-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 [IL-5 receptor alpha subunit]) is 
exclusively expressed on eosinophils and basophils.
Benralizumab is a humanized, afucosylated, monoclonal antibody that binds specifically to the 
human IL-5Rα on the target cell (Takatsu et al 1994, Toba et al 1999, Tedeschi et al 2018).  

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The purpose of this global study is to assess the potential for reducing the use of maintenance
oral corticosteroids (OCS) in patients with severe eosinophilic asthma who are 
OCS-dependent.  Patients will receive benralizumab 30 mg on an open-label basis, and, 
4 weeks after the first benralizumab dose, investigators will initiate the tapering of the OCS 
dose while not losing asthma control and managing signs/symptoms of AI.  Primary 
effectiveness will be determined by the ability of patients to reduce their OCS dose to 
0 mg/day without losing asthma control or to reach the lowest OCS dose possible in case no 
further OCS down-titration is allowed because of the presence of AI as measured by cortisol 
levels or in case of inadequate asthma control. 
At the end of the PONENTE EOT visit, patients will be invited to participate in a long term 
follow up visit sub-study to further assess changes in asthma maintenance therapy in an a real-
world setting, i.e., according to the treatment prescribed by their healthcare provider. 
Additionally, there will be assessment of recovery from AI as well as assessment of 
glucocorticoid toxicity by means of GTI. See Appendix K for details on the background and 
rationale of the PONENTE Long Term Follow Up visit substudy. 
1.2
Rationale for study design, doses, and control groups
The treatment options for patients who remain uncontrolled on high-dose ICS/LABA are 
extremely limited; one of the treatment options is the addition of OCS to the current treatment 
(GINA 2018).  However, regular intake of OCS can lead to a number of adverse events (AEs) 
and, as a result, can decrease quality of life for these patients (Kwong et al 1987).
In the ZONDA study, benralizumab significantly reduced the median final oral GC doses 
from baseline by 75%, as compared with a reduction of 25% in the placebo group (Nair et 
al 2017), and 56% of patients who received benralizumab were able to have a 100% reduction 
in their OCS dose.  However, this study had some limitations, and there are medical questions 
still to be addressed.  Patients who were receiving baseline prednisone doses above 12.5 mg 
were not allowed to completely withdraw from OCS as the study duration did not allow for 
this.  Also, the adequacy of the speed of the OCS down-titration and whether it can be 
performed faster than the down-titration regimen used in the ZONDA study (Nair et al 2017) 
remains unclear.  Finally, the maintenance phase was limited to 4 weeks after last OCS dose 
reduction, so it is uncertain as to whether benralizumab benefits are maintained after OCS 
down-titration or withdrawal. 
Furthermore, patients who are receiving higher doses of OCS or who have been on prolonged 
OCS therapy at baseline may potentially experience secondary AI upon 
complete/inappropriate withdrawal of OCS due to HPA axis suppression.  Patients may also 
experience steroid withdrawal or deprivation symptoms and reactivation/relapse of underlying 
disease (Alves et al 2008).  This has not yet been evaluated in previous studies.
This study will recruit patients who are receiving chronic treatment with OCS for ≥3 months 
prior to study entry and receiving stable doses of OCS for ≥4 weeks prior to study entry.  
Additionally, patients must have peripheral blood eosinophil counts of ≥150 cells/μL, as 
assessed by the central laboratory at Visit 1, or documented eosinophil counts of 

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≥300 cells/μL in the past 12 months.  These historical eosinophil values will help to identify 
patients with eosinophilic phenotypes, as patients on OCS may have reduced eosinophils.
The purpose of this trial is to assess the potential for reducing the use of maintenance OCS in 
systemic corticosteroid–dependent asthma patients treated with benralizumab 30 mg (who 
have severe refractory eosinophilic asthma).  This study will allow patients to reduce their 
OCS dose to 0 mg/day or to the lowest OCS dose that is physiologically possible (given the 
possibility of AI in this population of patients) and will assess whether a faster OCS 
down-titration compared with what has been previously studied (Nair et al 2017) is 
appropriate.  Patients will enter the maintenance phase of approximately 24 to 32 weeks after 
their OCS dose has been reduced to 0 mg/day (or to the lowest OCS dose possible in case no 
further OCS down-titration is allowed because of the presence of AI as measured by cortisol 
levels or in case of inadequate asthma control), which will assess the ability of benralizumab 
to maintain clinical benefits after OCS withdrawal.  
Patients will receive open-label benralizumab 30 mg/mL solution for injection in an 
accessorized prefilled syringe (APFS).  It will be administered subcutaneously (SC) at the 
study site as every-4-week (Q4W) dosing up until the third dose of benralizumab (Visits 2 to 
4) and then every-8-week (Q8W) dosing thereafter.  This dose is aligned with the current 
prescribing information for benralizumab, and an open-label design allows for a real-world 
assessment of OCS down-titration as it relates specifically to benralizumab effectiveness.
1.3
Benefit/risk and ethical assessment
There are few treatment options for patients whose asthma remains uncontrolled on high-dose 
ICS/LABA (GINA 2018).  The evidence base for oral add-on therapies (ie, OCS, leukotriene 
inhibitors, and xanthenes) is extremely limited.  Tiotropium is a long-acting bronchodilator 
that has recently been shown to produce improvement in lung function and exacerbation risk 
(pooled data) in patients with severe asthma, with inconsistent effects on other measures of 
asthma control (Juniper et al 2005, Juniper et al 2006, Kerstjens et al 2012).  
Biologics targeting IL-5 and IgE are now included in international treatment guidelines as an 
add-on treatment to patients uncontrolled with ICS/LABA treatment (GINA 2018).  In adult 
patients whose asthma was poorly controlled on high dose ICS/LABA and chronic OCS (with 
or without other controller medications), benralizumab significantly reduced the median OCS 
doses from baseline by 75%, as compared with a reduction of 25% in the oral GC doses in the 
placebo group.  The odds of a reduction in the oral GC dose were 4.12 times higher with 
benralizumab than with placebo, respectively (P<0.001) (Nair et al 2017).
There is the risk of an asthma exacerbation or worsening due to withdrawal of OCS in 
OCS-dependent patients.  However, data from the ZONDA study shows benefits in 
exacerbation reduction as the rate of exacerbations in OCS-dependent asthmatics treated with 
benralizumab who are withdrawn from OCS was 70% lower than the rate in those who are not 
treated with benralizumab (placebo) (Nair et al 2017).

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Development of antidrug antibodies to benralizumab has been documented without an 
apparent clinical impact.  Theoretical risks of developing antidrug antibodies include 
hypersensitivity reactions (eg, anaphylaxis or immune complex disease) and decreased drug 
efficacy.
Blood eosinophils are a prominent feature of the inflammatory response to helminthic 
parasitic infections, and the presence of infiltrating eosinophils has been circumstantially 
associated with a positive prognosis in certain solid tumors.  Therefore, there is a theoretical 
risk that prolonged eosinophil depletion may diminish the ability to defend against helminthic 
parasites or negatively impact the natural history of certain malignant tumors.  Risk 
minimization measures include exclusion of patients with untreated parasitic infection and 
active or recent malignancy, in conjunction with the performance of routine 
pharmacovigilance activities.
The identified (injection-site reaction) and potential (hypersensitivity reactions/anaphylaxis, 
malignancies, and serious infections [especially helminthic ones]) risks of benralizumab are 
discussed in detail in the latest version of the Investigator’s Brochure.
Furthermore, there is a risk of AI when OCS is completely or inappropriately withdrawn 
(Alves et al 2008, Dinsen et al 2013, Johnson et al 2014, Joseph et al 2016) in:

Patients who are on prolonged OCS therapy.

Patients who are treated with a high dose of OCS at baseline.

During periods of stress to the body when a cortisol-induced response is critical to 
maintain homeostasis, eg, during acute intercurrent illness, following trauma, and 
during surgery and childbirth.
The symptoms of chronic AI include many nonspecific symptoms such as anorexia, nausea, 
vomiting, abdominal pain, weakness, tiredness, and depression. In severe cases, a 
life-threatening event of acute adrenal crisis may occur (Alves et al 2008).  The study will 
include close monitoring of the risk of AI by assessing HPA axis integrity in patients who 
have reached OCS doses equal to 5 mg/day and for patients who have baseline OCS doses 
equal to 5 mg/day. A detailed assessment of the overall risks/benefits of benralizumab in 
patients with asthma is given in the Investigator’s Brochure.  
1.4
Study design 
This is an open-label, multicenter study designed to evaluate the efficacy and safety of 
reducing OCS use after initiation of a 30-mg dose of SC benralizumab administered with 
Q4W dosing up until the third dose of benralizumab (Visits 2 to 4) and then Q8W thereafter in 
approximately 600 adult patients with severe eosinophilic asthma who are receiving high-dose 
ICS/LABA and OCS with or without additional asthma controller(s).  Each patient must have 
been receiving an average daily dose equivalent to ≥5 mg of prednisone for the last 3 months 
before study entry.  

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Please see Appendix K for details on the study design of the PONENTE Long Term Follow 
Up Substudy.
1.4.1
Enrollment Period (starting Week -2): 
After patients sign the informed consent form (ICF), patients will undergo a Screening visit 
(Visit 1) to assess eligibility criteria and laboratory tests. All patients who are not already 
taking prednisone/prednisolone as their OCS treatment will be switched to 
prednisone/prednisolone, and the laboratory tests (including serum prednisone/prednisolone) 
will be delayed 3 to 7 days. Patients who are already taking prednisone/prednisolone at Visit 1 
do not require the serum prednisone/prednisolone laboratory test (see Table 1). Additionally,
an extension of the screening period up to 3 months is allowed to ensure that a patient 
recovers from any asthma exacerbation or acute upper/lower respiratory infection (refer 
Section 4.1.1 for more details).  Patients still fulfilling inclusion/exclusion criteria at Visit 2 
(Week 0) will enter the study and receive open-label benralizumab.
The treatment period is divided into 3 phases: induction, reduction, and maintenance 
(Figure 1).  The duration of the benralizumab treatment period will be dependent on the 
baseline OCS dose, the occurrence of asthma exacerbation(s) or asthma worsening, and the 
integrity of the HPA axis, which will guide the speed of OCS down-titration below 5 mg/day. 
However benralizumab treatment will start at Visit 2, continue throughout the Reduction phase, 
and will end after 3 doses in the Maintenance Phase.
1.4.2
Induction phase (starting Week 0): 
Patients in the induction phase will start their first dose of benralizumab at Visit 2 and should 
remain stable on their baseline OCS dose during this 4-week phase. If an asthma exacerbation 
occurs during the induction phase, the patient will be managed per Section 5.2.3.
1.4.3
OCS Reduction phase (Week 4 onwards): 
Benralizumab dosing
Patients will receive Q4W benralizumab up until the 3rd dose (8 weeks between 
the 3rd and 4th benralizumab dose). Benralizumab will then continue Q8W 
through the end of the Reduction phase and continue to the Maintenance phase. 
OCS reduction
Patients will reduce their dosage of OCS according to the schema defined for each baseline 
OCS dose until they reach 5 mg/day (Section 5.1.2). 
For all patients, hypothalamic-pituitary-adrenal (HPA) axis integrity will be evaluated after 
4-weeks on 5 mg/day and prior to tapering down the OCS dose (for patients with baseline 
OCS doses equal to 5 mg/day, this will be assessed 4 weeks after the first dose of 
benralizumab administration and before initiation of the OCS reduction phase)

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First, a screening method with morning serum cortisol is done (8-9 am morning cortisol 
level), to evaluate whether the patient has:

Normal cortisol levels

Complete AI
Cortisol levels from the morning cortisol test that are below normal range and above the 
Complete AI range are considered “Indeterminate;” and require confirmation via additional 
testing described below.
Secondly, the adrenocorticotropic hormone (ACTH) stimulation test (ie, Synacthen®, 
Cortrosyn™) is done within approximately 1 week in the subset of patients with 
indeterminate results from the morning cortisol test [see also Section 5.2.1.2 for details). The 
ACTH stimulation test is more specific than the morning cortisol test, and can determine 
whether the patient has:

Normal cortisol levels

Complete AI

Partial AI.
The OCS reduction will continue until the patient reaches an OCS dose of 0 mg/day (or 
lowest OCS dose possible in case no further OCS down-titration is allowed because of the 
presence of AI as measured by cortisol levels or in case of inadequate asthma control) 
without losing asthma control. The first OCS dose reduction may occur at Visit 3 after the 
dose of benralizumab at the site. Investigators should monitor the occurrence of asthma 
exacerbation(s) or asthma deterioration.  After recovery from the first exacerbation or asthma 
deterioration, the patient will be allowed to proceed with another attempt to reduce OCS 
dose; however, this must follow a lower speed of OCS down-titration (reductions Q4W).  
However, in case of a second exacerbation or asthma deterioration, no further OCS dose 
reduction will be allowed, and the patient will continue on the same OCS dose or will return 
to a one-step higher dose level (or more as considered necessary by the Investigator), and the 
patient will then enter the maintenance phase. 
Approximately 1-2 weeks prior to end of the OCS reduction phase, the patients who have 
Partial AI after the repeat morning cortisol test, will undergo an additional morning cortisol 
test (and if required, ACTH stimulation test for indeterminate result) at the end of the OCS 
Reduction phase.
1.4.4
Maintenance phase: 
This phase will start from the time the patient reaches a complete withdrawal of OCS (or 
lowest possible OCS dose) without worsening of asthma control and as determined by the 
Investigator (based on the cortisol/ACTH stimulation results). The maintenance phase could 
be initiated earlier if OCS dose reduction failed due to clinical deterioration or because the 
patient did not recover from AI. 

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The length of the maintenance phase will last approximately 24 to 32 weeks. The duration of 
the maintenance treatment phase will depend on when the patient enters the maintenance 
phase relative to the dosing cycle of benralizumab. During this phase, patients will continue 
benralizumab Q8W for 3 doses, and then the End of Treatment (EOT) visit will be scheduled 
8 weeks (± 7 days) after the last dose of benralizumab. 
Patients who have Complete AI or Partial AI at the end of the OCS Reduction phase, will 
undergo a final morning cortisol test (and if required, ACTH stimulation test for indeterminate 
result) approximately 1- 2 weeks prior to end of the OCS Maintenance phase. 
If an asthma exacerbation occurs during the maintenance phase, the length of the maintenance 
phase will not be extended.
1.4.5
Premature Discontinuation and Follow-Up Contact:
All patients who prematurely discontinue study drug/investigational product or who 
discontinue from the study should return to the study center and complete the procedures 
described for the Premature Investigational Product Discontinuation (IPD) visit within 
4 weeks (± 7 days) after the last dose of benralizumab.
For all patients dosed with benralizumab, a follow-up contact will be scheduled 12 weeks 
(± 7 days) after their last dose of benralizumab. Patients who have Complete AI or Partial AI 
at the end of the Maintenance phase should be followed-up by an endocrinologist or other 
appropriate specialist, if deemed necessary by the Investigator.
1.4.6
Sputum Sampling for Exploratory Biomarkers: 
Not applicable due to protocol amendment.

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Figure 1
Study flow chart 
1.
The duration of the OCS reduction phase will vary based on asthma exacerbations, asthma worsening, HPA integrity, or other safety issues altering the OCS titration 
schedule.
2.
For patients who have reached OCS doses equal to 5 mg/day, HPA axis integrity will be assessed at the end of a 4-week period on 5 mg/day (8-9 am morning cortisol 
level), followed by a ACTH stimulation test within approximately 1 week, in case of indeterminate result.  For those patients who had a baseline OCS dose equal to 
5 mg/day, HPA axis integrity will be assessed 4 weeks after first dose of benralizumab administration and before initiation of the OCS reduction phase
3.
The maintenance phase will start from the time the patient reaches a complete withdrawal of OCS (or lowest possible OCS dose per Section 1.4.3) without worsening of 
asthma control and as determined by the Investigator (based on the cortisol/ACTH stimulation results). This period will last approximately 24 to 32 weeks from the time 
the patient reaches a complete withdrawal of OCS (0 mg) or the lowest OCS dose possible in case no further OCS down-titration is allowed because of the presence of AI 
as measured by cortisol levels or in case of inadequate asthma control.  The length of the maintenance phase may vary depending on the when the patient enters the 
maintenance phase.  During this phase, patients will continue benralizumab Q8W for 3 doses and then the EOT visit will be scheduled 8 weeks (± 7 days) after the last 
dose of benralizumab.
4.
End of the study will be different for individual patients and will depend on baseline OCS dose, occurrence of asthma exacerbation or asthma worsening, and HPA axis 
integrity.
5.
Patients who discontinue treatment early will undergo the Premature IPD visit within 4 weeks (± 7 days) after the last dose of benralizumab.
6.
A follow-up contact will occur 12 weeks (± 7 days) after the last dose of benralizumab, discontinuation of study drug, or discontinuation from the study.  All patients who 
prematurely discontinue study drug or discontinue from the study should return to the study center and complete the procedures described for the Premature IPD visit 
within 4 weeks (± 7 days) after the last dose of benralizumab.
7.
Patients who have Partial AI or Complete AI at the end of the Maintenance phase, should be followed-up by an endocrinologist or other appropriate specialist, if deemed 
necessary by the Investigator.
8.
Patients who enroll in the long term follow up substudy during the EOT visit will still undergo the final 4-week follow-up visit. ICF for the PONENTE Long Term 
Follow Up substudy must be obtained any time from EOT of the main PONENTE study and to prior to any activities of the PONENTE Long Term Follow Up visit.

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1.5
Study governance and oversight
1.5.1
Scientific Committee
A Scientific Committee consisting of internal AstraZeneca and external experts 
(pulmonologists, allergists, and endocrinologists) who have been involved in the design of the 
clinical study will advise the sponsor on changes to the study design and provide 
recommendations on issues related to the study conduct, if required. In addition, the 
committee will be involved in the review and interpretation of the study results. The 
Scientific Committee will be governed by a charter, detailing roles and responsibilities and 
processes.
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective
Endpoints/Outcome Variables
To assess the ability to reduce OCS dose in 
adult patients with severe eosinophilic 
asthma treated with benralizumab 30 mg 
SC 
Primary outcome measures

Patients who achieve 100% reduction in daily OCS 
dose that is sustained over at least 4 weeks without 
worsening of asthma 

Patients who achieve 100% reduction or a daily OCS 
dose ≤5 mg, if reason for no further OCS reduction 
is AI, that is sustained over at least 4 weeks without 
worsening of asthma
Key supportive outcome measures

Patients who achieve a daily OCS dose of ≤5 mg that 
is sustained over at least 4 weeks without worsening 
of asthma

Patients who achieve a ≥90%, ≥75%, ≥50%, and 
>0% reduction in daily OCS dose, sustained over at 
least 4 weeks without worsening of asthma

Change from baseline in daily OCS dose (mg) from 
start of OCS reduction to end of the OCS reduction 
phase

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2.2
Secondary objectives
Secondary Objective
Outcome Measure
To assess the sustained reduction of daily 
OCS dose while not losing asthma control 
during approximately 6 months after the 
end of OCS down-titration (maintenance 
phase) in adult patients with severe 
eosinophilic asthma treated with 
benralizumab 30 mg SC
Key outcome measure

Change in daily OCS dose from the end of OCS 
reduction phase to the end of the maintenance phase 
(EOT visit)

Time to first increase in OCS dose during 
maintenance phase, after achieving the minimum 
OCS dose during the OCS reduction phase 
To assess the effect of OCS down-titration 
protocol on asthma control in adult patients 
with severe eosinophilic asthma treated 
with benralizumab 30 mg SC
Key outcome measure

Asthma Control Questionnaire 6 (ACQ-6) scores at 
baseline (Visit 2), Visit 3, end of OCS reduction 
phase, and monthly from end of OCS reduction 
phase to end of maintenance phase (EOT visit)

Change from baseline in ACQ-6 to Visit 3, end of 
OCS reduction phase, and end of maintenance phase 
(EOT visit)

Responder analysis of ACQ-6 scores from Visit 2 
through end of maintenance phase
To assess the effect of OCS down-titration 
protocol on quality of life in adult patients 
with severe eosinophilic asthma treated 
with benralizumab 30 mg SC
Key outcome measure

Change from baseline (Visit 2) in St. George’s 
Respiratory Questionnaire (SGRQ) total scores to the 
end of maintenance phase (EOT visit)

Responder analysis of SGRQ total scores at the end 
of maintenance phase
2.3
Safety objectives
Safety Objective
Outcome Measure
To evaluate the occurrence of AI when 
reducing OCS
Key outcome measure

Patients with complete AI 
To assess the effect of OCS down-titration 
protocol on asthma exacerbations in adult 
patients with severe asthma treated with 
benralizumab 30 mg SC
Key outcome measures

Annualized asthma exacerbation rate

Annualized asthma exacerbation rate leading to 
hospitalization or emergency room visit
To assess the safety and tolerability of 
benralizumab in patients who reduce their 
chronic OCS dose

Adverse events/Serious adverse events

Laboratory parameters and vital signs
To evaluate corticosteroid toxicity after 
OCS reduction

Glucocorticoid toxicity index (GTI)

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2.4
Exploratory objectives
Exploratory Objective
Outcome Measure
To investigate the contribution of genomic 
variants to the study outcomes

Association of common and rare genomic variants 
with patient responses
To assess early improvements in asthma 
status during the first 4 weeks of 
benralizumab treatment before initiation of 
OCS reduction

Patient Global Impression of Change (PGIC)
To assess the impact of OCS 
down-titration on blood eosinophil levels
Key outcome measure

Change from baseline blood eosinophils
To investigate biomarkers for predicting 
response to benralizumab
Key biomarker parameters

Serum samples at baseline for protein biomarkers

Plasma for eosinophil-derived neurotoxin
Please refer to Appendix K for the objectives of the PONENTE Long Term Follow Up 
Substudy.
3.
PATIENT SELECTION, ENROLLMENT, RESTRICTIONS, 
DISCONTINUATION, AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study, patients should fulfil the following criteria:
1.
Provision of informed consent prior to any study-specific procedures 
2.
Female or male aged ≥18 years at the time of Visit 1 
3.
Women of childbearing potential (WOCBP) must agree to use one highly effective 
form of birth control (confirmed by the Investigator) from 48inimizin throughout the 
study duration and within 16 weeks after last dose of IP. Highly effective forms of 
birth control include: 

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation- oral, intravaginal, or transdermal

Progestogen-only hormonal contraception associated with inhibition of 
ovulation- oral, injectable, or implantable

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
Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Sexual abstinence, i.e. refraining from heterosexual intercourse (The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the patient.)

Vasectomized sexual partner provided that partner is the sole sexual partner of 
the WOCBP study patient and that the vasectomized partner has received 
medical assessment of the surgical success 
Women not of childbearing potential are defined as women who are either 
permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) or who are postmenopausal.  Women will be considered 
postmenopausal if they have been amenorrhoeic for 12 months prior to the planned 
start date of the induction phase without an alternative medical cause.  The 
age-specific requirements that apply are as follows:
-
Women <50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous 
hormonal treatment and have follicle-stimulating hormone levels in the 
postmenopausal range
-
Women ≥50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous 
hormonal treatment
4.
Weight of ≥40 kg
5.
Nonsmokers, current smokers, or former smokers with a smoking history of 
≤20 pack-years at Visit 1
6.
Peripheral blood eosinophil count of ≥150 cells/μL assessed by central laboratory at 
Visit 1 or documented eosinophil count of ≥ 300 cells/μL in the past 12 months
7.
History of physician-diagnosed asthma that requires continuous treatment with 
high-dose ICS (high-dose ICS is budesonide/formoterol HFA ≥640/18 per day or 
equivalent, fluticasone propionate DPI > 500/day or equivalent, or authorized generics 
for these products; see Appendix E and GINA 2018 guidelines for more 
recommendations) plus a LABA for at least 6 months prior to Visit 1. The ICS and 
LABA can be contained within a combination product or given by separate inhalers. 
The ICS can also be given via nebulized solution for inhalation: 

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
In order to aid the dose assessment, ICS equivalents for high-dose fluticasone 
propionate dry powder, as published by the Global Initiative for Asthma 
(GINA) guidelines, are presented in Appendix E

For ICS monotherapy preparations, or ICS/LABA combination preparations 
not specifically mentioned in GINA (e.g. newer formulations, authorized 
generics), the highest approved maintenance dose in the local label will also 
meet this ICS criterion. Additionally, in countries where the high-dose ICS or 
ICS/LABA is not available (e.g. only the medium-dose ICS or ICS/LABA is 
available in that country), the highest approved maintenance dose in the local 
label will also meet this ICS criterion
Note: Additional maintenance asthma controller medications (eg, LTRAs, 
tiotropium, cromone, theophylline) are allowed.
8.
Chronic OCS therapy equivalent to a daily dose of at least 5 mg of prednisone for at 
least 3 continuous months directly preceding Visit 1 (to be documented in medical 
records)
Note: Alternate intake of OCS (ie, every other day) or other frequency is allowed 
provided the average daily dose is equivalent to at least 5 mg of prednisone and the 
patient is switched to a daily intake of prednisone/prednisolone at Visit 1.  Systemic 
corticosteroid doses administered by any route other than oral cannot be used to 
determine the average daily dose preceding Visit 1
9.
Patient should be on a stable OCS dose for at least 4 weeks prior to Visit 1. To aid the 
dose assessment, a guide for OCS dose equivalence is presented in Appendix F. 
Patients must agree to switch to study-required prednisone/prednisolone as their OCS 
for the duration of the study
See Appendix K for inclusion/exclusion criteria, and restrictions related to the PONENTE 
Long Term Follow Up substudy.
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Clinically important pulmonary disease other than asthma (eg, active lung infection, 
chronic obstructive pulmonary disease [COPD], asthma-COPD overlap [ACO] 
bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome 
associated with obesity, lung cancer, alpha-1 antitrypsin deficiency, primary ciliary 
dyskinesia) or have ever been diagnosed with pulmonary or systemic diseases, other 
than asthma, that are associated with elevated peripheral eosinophil counts (eg, allergic 
bronchopulmonary aspergillosis/mycosis, eosinophilic granulomatous polyangiitis 
[EGPA], hypereosinophilic syndrome [HES])
2.
Known history of allergy or reaction to the study drug formulation

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3.
History of anaphylaxis to any biologic therapy
4.
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
5.
Asthma exacerbation requiring use of systemic corticosteroids, increase in 
maintenance dose of OCS, or acute upper/lower respiratory infection that requires 
antibiotics or antiviral medication within 30 days prior to Visit 2 (first benralizumab 
dose) 
An extension of the screening period up to 3 months is allowed to ensure that a patient 
recovers from any asthma exacerbation or acute upper/lower respiratory infection 
(refer Section 4.1.1 for more details)
6.
Intention to use any concomitant medication that is not permitted by this protocol or 
failure to undergo the required washout period for a particular prohibited medication
Explanatory note: Refer to Section 7.8 for washout periods of prohibited medications 
7.
History of alcohol or drug abuse within 12 months prior to the date informed consent 
is obtained
8.
History of known immunodeficiency disorder, including history of a positive HIV test
9.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥3 × upper 
limit of normal (ULN) confirmed at Visit 1 
10.
Receipt of immunoglobulin or blood products within 30 days prior to the date 
informed consent is obtained 
11.
Concurrent enrollment in another interventional clinical trial
12.
AstraZeneca staff involved in the planning and/or conduct of the study
13.
Employees of the study site or any other individuals involved with the conduct of the 
study, or immediate family members of such individuals
14.
Currently pregnant, breastfeeding, or lactating
15.
Received previous treatment with benralizumab in the present study (patients may not 
re-enter the study after completion or premature discontinuation).
16.
Coincident primary adrenal failure (Addison’s disease) or irreversible secondary 
hypoadrenalism due to another independent cause (eg, pituitary tumor or its treatment)
17.
Coexistent inflammatory conditions for which chronic OCS doses are part of their 
maintenance treatment such as, but not limited, giant cell arteritis or polymyalgia 
rheumatica
18.
Exclusion from genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following:
-
Previous allogeneic bone marrow transplant

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Non-leukocyte depleted whole blood transfusion within 120 days of genetic 
sample collection
19.
Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, 
psychiatric, or major physical impairment that is not stable in the opinion of the 
investigator and could:
-
Affect the safety of the patient throughout the study
-
Confound the study results; or would impact the scientific validity of the data 
outcome. Impede the subject’s ability to complete the entire duration of study
20.
Any clinically significant abnormal findings in physical examination, medical history, 
vital signs, hematology, clinical chemistry, or urinalysis during the enrollment period, 
which in the opinion of the Investigator, may put the patient at risk because of his/her 
participation in the study, or may influence the results of the study, or the patient’s 
ability to complete entire duration of the study.
21.
History of cancer. Patients who have had basal cell carcinoma, localized squamous cell 
carcinoma of the skin, or in situ carcinoma of the cervix are eligible provided that the 
patient is in remission and curative therapy was completed at least 12 months prior to 
the date informed consent was obtained.
-
Patients who have had other malignancies are eligible provided that the patient is 
in remission and curative therapy was completed at least 5 years prior to the date 
informed consent was obtained
22.
Any other (non-asthma related) disease flare-up or AE/SAE during the screening 
period that requires the temporary use of systemic corticosteroids, increase in 
maintenance OCS, or requires antibiotics or antiviral medication within 30 days prior 
to Visit 2 (first benralizumab dose). However, an extension of 3 months of the 
screening period is allowed to ensure that a patient recovers from any non-asthma 
related disease flare-up or AE/SAE. See Section 7.8 Table 6 for more detail.
23.
Current night-shift workers.
See Appendix K for inclusion/exclusion criteria, and restrictions related to the PONENTE 
Long Term Follow Up substudy.
Procedures for withdrawal of incorrectly enrolled patients are discussed in Section 3.4.
3.3
Patient enrollment 
Investigators will keep a record of patients considered for and included in the study.  This 
prescreening/screening log will be evaluated periodically by AstraZeneca or its delegates 
during routine monitoring visits.

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The Investigators will do the following:
1.
Obtain signed informed consent from the potential patient before any study-specific 
procedures are performed
2.
Assign each potential patient a unique enrollment number, beginning with ‘E#’ via 
an interactive web/voice response system (IWRS/IVRS)
3.
Determine patient eligibility. See Sections 3.1 and 3.2
Specific information concerning the use of the IWRS/IVRS will be provided in a separate 
manual. 
If a patient withdraws from participation in the study, then his/her enrollment code cannot be 
reused.  Withdrawn patients will not be replaced in the study.
3.4
Procedures for handling incorrectly enrolled patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  Patients who are enrolled but are subsequently found 
not to meet all the eligibility criteria must be withdrawn from the study.  If a patient who does 
not meet all the eligibility criteria is incorrectly started on treatment, the Investigator should 
inform the AstraZeneca Physician immediately.  A discussion should occur between the 
AstraZeneca Physician and the Investigator regarding whether to continue or discontinue the 
patient from treatment.
The AstraZeneca Physician must ensure all decisions are appropriately documented.
3.5
Restrictions
After enrollment, the patient should continue their usual asthma controller medication regimen 
without change during the study.  Any changes deemed essential for patient safety or any 
other reason should be brought to the attention of the Medical Monitor or AstraZeneca 
Physician.  The rationale for any change in the patient’s usual controller medication should be 
documented in the source as well as in the medication electronic case report form (eCRF).  
Asthma exacerbations should be treated with oral or other systemic corticosteroids according 
to standard practice.  Section 7.8 describes the concomitant medications allowed and 
prohibited during the study period.
Treatment with prednisone/prednisolone should be withheld until the morning of serum 
cortisol measurement/ACTH stimulation test as defined below: 

Prednisone/prednisolone:  24 hours prior to morning cortisol level testing

High-dose ICS:  No ICS (or ICS/LABA if in single inhaler) treatment on the 
morning of the cortisol testing
The visit should be rescheduled if the above medications are not withheld properly (note: 
SABA rescue is allowed throughout the study). Use of ICS/LABA as a reliever (eg, Symbicort 

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Maintenance and Reliever Treatment) that was part of the patient’s usual asthma controller 
regimen at baseline is allowed; however, it should also be withheld before cortisol testing as 
described above. Any maintenance therapy such as long-acting muscarinic antagonists used 
prior to study entry should not be changed during the study.
3.5.1
Other restrictions

Fertile and sexually active patients and their partners must use highly effective 
contraceptive methods throughout the study and at least for 16 weeks (5 half-lives) 
after last administration of the study drug  

Patients must abstain from donating blood or plasma from the time of informed 
consent and for 16 weeks (5 half-lives) after last dose of study drug
3.6
Discontinuation of study drug and criteria for withdrawal
Patients may be discontinued from study drug in the following situations:

Patient decision—the patient is free at any time to discontinue treatment, without 
prejudice to further treatment

Severe noncompliance with the Clinical Study Protocol 

Eligibility requirement found not to be fulfilled

Pregnancy

AE that, in the opinion of the Investigator, contraindicates further dosing

Lost to follow-up when the following three attempts at contact have failed:
-
Three (3) attempts of either phone calls, faxes, or emails
-
Having sent 1 registered letter/certified mail
-
One unsuccessful effort to check the vital status of the patient using publicly 
available sources, if allowed by local regulations 

Development of any study-specific criteria for discontinuation:
-
Anaphylactic reaction to the study drug
-
Development of helminth parasitic infestations requiring hospitalization
-
An asthma-related event requiring mechanical ventilation
3.6.1
Procedures for discontinuation of a patient from study drug 
A patient who decides to discontinue study drug will always be asked about the reason(s) and 
the presence of any AEs.  
All patients who prematurely discontinue study drug should return to the study center and 
complete the procedures described for the IPD visit within 4 weeks (± 7 days) after last study 
drug administration.  The reason for premature discontinuation of study drug should be 

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documented in the source documentation and recorded in the eCRF.  Patients will be required 
to return to the study center one last time at 12 weeks (± 7 days) after the last dose of study 
drug for final study-related assessments (see Table 1).
3.6.2
Screen failures 
Screen failures are patients who do not fulfill the inclusion criteria (see Section 3.1) or who 
meet an exclusion criterion (see Section 3.2) during the enrollment period.  These patients 
should have the reason for study withdrawal recorded as ‘screen failure’ (the potential patient 
does not meet one or more criteria required for participation in a trial; this reason for study 
withdrawal is only valid for not enrolled patients). 
3.6.3
Withdrawal of informed consent
Patients are free to withdraw from the study at any time (study drug and assessments), without 
prejudice to further treatment.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs.  The Investigator will follow up AEs outside of the clinical study. The patient will 
return the electronic patient-reported outcome device (ePRO).
If a patient withdraws from participation in the study, then his/her enrollment code cannot be 
reused.  Withdrawn patients will not be replaced. 
If the patient agrees, he/she will be asked to return to the study site to complete procedures 
described for the IPD visit and follow-up visits (Table 1).
4.3.1.1
Withdrawal of consent for genetic research 
Patients may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study.  Voluntary withdrawal will not 
prejudice further treatment.
3.7
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings that:

Meet individual stopping criteria or are otherwise considered significant 

Are assessed as causally related to study drug

Are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.

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4.
STUDY PLAN AND TIMING OF PROCEDURES 

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Table 1
Study plan – Treatment period and follow-up
Assessment*
Protocol 
section
Screening 
(starting 
Week -2)
Induction 
phase 
(starting 
Week 0)
OCS reduction phase 
(Week 4 onwards)
Maintenance phasee
IPD
Follow-
upg
Unscheduled 
visit q
V1
V2
+7 days
Benralizumab 
dosing visita  
(V3 onwards) 
OCS
≤5 mg/day 
(Morning 
Cortisol Visit)b
Phone 
calld
Maintenance 
Phase 
benralizumab 
visit
EOTf
± 7 days
± 7 daysc
± 7 days
± 7 
days
± 7 
days
± 7 days
Written 
informed 
consent
10.4
X
Demographicsh
4.1.1
X
Verify 
inclusion/exclus
ion criteria
3.1/3.2
X
X
Medical/surgical 
and asthma 
history
4.1.1
X
Complete 
physical 
examination
5.2.5.1
X
Brief physical 
examination
5.2.5.2
X
X
X
X
X
X
X
Weight and 
heighti
5.3.1
X
X
X
X
ACQ-6j and 
maintenance 
medication 
assessment
5.3.4.1
X
<<Weekly from Visit 2 until EOT visit>>
X
X
SGRQ
5.3.4.1
X
X
X
PGICk
5.3.4.1
X
X

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Table 1
Study plan – Treatment period and follow-up
Assessment*
Protocol 
section
Screening 
(starting 
Week -2)
Induction 
phase 
(starting 
Week 0)
OCS reduction phase 
(Week 4 onwards)
Maintenance phasee
IPD
Follow-
upg
Unscheduled 
visit q
V1
V2
+7 days
Benralizumab 
dosing visita  
(V3 onwards) 
OCS
≤5 mg/day 
(Morning 
Cortisol Visit)b
Phone 
calld
Maintenance 
Phase 
benralizumab 
visit
EOTf
± 7 days
± 7 daysc
± 7 days
± 7 
days
± 7 
days
± 7 days
Train on and 
dispense ePRO
5.3.4.1
X
Check ePRO 
compliance
5.3.4.1
X
X
X
X
X
X
X
Vital signs
5.2.6
X
X
X
X
X
X
X
X
Serum 
chemistry
5.2.4
X
X
X
X
Hematology
5.2.4
X
X
X
X
Serum 
pregnancy test 
and FSH testl
5.2.4.1/
3.1
X
X
X
Urine pregnancy 
test
5.2.4.1
X
X
X
X
Prednisone/
prednisolone 
levelsm
5.3.2
X
Serum for total 
IgE
5.3.3
X
Serum for 
Phadiatop test
5.3.3
X
Blood sample 
for genomic 
analysis
5.6
X

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Table 1
Study plan – Treatment period and follow-up
Assessment*
Protocol 
section
Screening 
(starting 
Week -2)
Induction 
phase 
(starting 
Week 0)
OCS reduction phase 
(Week 4 onwards)
Maintenance phasee
IPD
Follow-
upg
Unscheduled 
visit q
V1
V2
+7 days
Benralizumab 
dosing visita  
(V3 onwards) 
OCS
≤5 mg/day 
(Morning 
Cortisol Visit)b
Phone 
calld
Maintenance 
Phase 
benralizumab 
visit
EOTf
± 7 days
± 7 daysc
± 7 days
± 7 
days
± 7 
days
± 7 days
Plasma for 
eosinophil-deriv
ed neurotoxin
5.7.2
X
X
X
Serum for 
biomarkers
5.7.1
X
X
Sputum 
inductionn
5.7.3
Not applicable due to protocol amendment
Morning 
cortisol testingc
5.2.1.1
X
Xr
Xr
AI symptom 
evaluation
5.2.1/
5.2.1.2
X
Glucocorticoid 
toxicity index
5.2.7
X 
X
X
X
Assessment of 
asthma 
exacerbations
5.2.2/
5.2.3
X
X
Ongoing based on investigators’ 
indication
X
X
X
X
X
OCS dose 
reduction o
5.1.2
Ongoing based on investigator’s 
indication
Adverse events
6.1
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication
7.8
X
X
X
X
X
X
X
X
X
X

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Study Code D3250C00065
Version 4
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Table 1
Study plan – Treatment period and follow-up
Assessment*
Protocol 
section
Screening 
(starting 
Week -2)
Induction 
phase 
(starting 
Week 0)
OCS reduction phase 
(Week 4 onwards)
Maintenance phasee
IPD
Follow-
upg
Unscheduled 
visit q
V1
V2
+7 days
Benralizumab 
dosing visita  
(V3 onwards) 
OCS
≤5 mg/day 
(Morning 
Cortisol Visit)b
Phone 
calld
Maintenance 
Phase 
benralizumab 
visit
EOTf
± 7 days
± 7 daysc
± 7 days
± 7 
days
± 7 
days
± 7 days
Switch to 
prednisone/
prednisolone
Appen-
dix G
X
Administration 
of benralizumab 4.2
X
X
Xp
X
a 
Benralizumab dosing will be administered as Q4W dosing up until the third dose of benralizumab (Visits 2 to 4) and Q8W for each subsequent 
dose (8 weeks between the 3rd and 4th benralizumab dose).
b 
For patients who have reached OCS doses equal to 5 mg/day, HPA axis integrity will be assessed after 4 weeks have passed on 5 mg/day 
(8-9 am morning cortisol level, followed by an ACTH stimulation test within approximately 1 week, in case of partial AI).  For those patients 
who had baseline OCS doses equal to 5 mg/day, HPA axis integrity will be assessed 4 weeks after first dose of benralizumab administration 
and before initiation of the OCS reduction phase.  
c 
Benralizumab administration should be delayed/advanced to match the visit where HPA axis evaluation will be tested, provided the period 
between benralizumab administration is no longer than 10 weeks.
d 
During the OCS reduction phase, the Investigator and/or an authorized delegate should call the patient for his/her OCS reduction.  OCS 
reduction could also coincide with a benralizumab dosing visit, or unscheduled visit (due to other clinical issue, per Investigator discretion).
e 
Maintenance phase will last approximately 24 to 32 weeks from the time the patient reaches a complete withdrawal of OCS without worsening 
of asthma control.  The length of the maintenance phase will vary depending on when the patient enters the maintenance phase.
f 
The EOT visit will occur 8 weeks (± 7 days) after the last dose of benralizumab.  Patients who prematurely discontinue study drug should 
return to the study site and complete the procedures described for the Premature IP Discontinuation Visit (IPD) within 4 weeks (± 7 days) after 
the last dose of benralizumab.
g 
For all patients who receive benralizumab, a follow-up contact will be scheduled 12 weeks (± 7 days) after their last dose of benralizumab.
h
Demographic information includes date of birth, age, sex, race, and ethnicity (as per local regulations).
i     Height to be measured only at screening
j 
Patients will complete the ACQ-6 weekly (± 2 days) from Visit 2 until EOT using the ePRO.
k 
The PGIC will be completed on a weekly (± 2 days) basis (starting at Week 0) during the first month of treatment using the ePRO.

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l 
FSH will be analyzed at the screening visit to confirm postmenopausal status only in women <50 years of age who have been amenorrhoeic 
for ≥12 months.
m
Done only for patients who switch to prednisone/prednisolone at V1. If this test is required, the laboratory tests should be delayed (for all parameters, not 
just prednisone levels) by 3 to 7 days after having switched the OCS and V2 can be done up to 2 weeks after collection of laboratory samples.  
Prednisone/prednisolone levels should be measured approximately 1 to 2 hours after prednisone/prednisolone intake on the same day.
n      Not applicable due to protocol amendment
o        The OCS reduction will continue until the patient reaches an OCS dose of 0 mg/day (or lowest OCS dose possible in case no further OCS down-titration 
is allowed because of the presence of AI as measured by cortisol levels or in case of inadequate asthma control) without losing asthma control.
p 
Benralizumab administration to follow Q8W periodicity, so it may or may not occur at the same time as morning cortisol testing.  
q 
The following instances should also be captured as an UNS visit: 1) unscheduled blood collection (ex. Hy’s Law); 2) replacement genetic 
blood sample in case of DNA extraction failure.
r
Patients who have Partial AI after the repeat morning cortisol test, will undergo an additional morning cortisol test (and if required, ACTH 
stimulation test for indeterminate result) approximately 1-2 weeks prior to the end of the OCS Reduction phase. Patients who have Complete 
AI or Partial AI at the end of the OCS Reduction phase, will undergo a final morning cortisol test (and if required, ACTH stimulation test for 
indeterminate result) approximately 1-2 weeks prior to the end of the OCS Maintenance phase (prior to EOT visit).
*for the PONENTE Long Term Follow Up Substudy, please refer to Appendix K. 

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4.1
Enrollment period 
4.1.1
Screening visit – Visit 1 (Week -2)
Each patient will provide written informed consent prior to any study-specific procedures and 
will undergo assessments applicable for each visit as outlined in Table 1.  Registration of the 
patient’s enrollment via IWRS/IVRS should occur on the day that Visit 1 procedures are 
performed.
At screening, consenting patients will be assessed to ensure that they meet all eligibility 
criteria.  Visit 1 assessments are primarily concerned with assessment of eligibility 
(inclusion/exclusion criteria), including asthma disease state, requisite level of severity based 
on background medications and eosinophil count.
Demographic information, including date of birth, age, sex, race, and ethnicity, will be 
collected during the screening visit as per local regulations.  All patients who are not already 
taking prednisone/prednisolone as their OCS treatment will be switched to 
prednisone/prednisolone. Testing of prednisone/prednisolone levels will be done only for 
patients who switch to prednisone/prednisolone. If this test is required, all laboratory tests 
should be delayed by 3 to 7 days after having switched the OCS (Appendix F).  
Prednisone/prednisolone levels should be measured approximately 1 to 2 hours after 
prednisone/prednisolone intake on the same day.
At the screening visit, blood samples will be collected for assessments such as laboratory 
tests, genomic analysis, serum biomarkers, total IgE, Phadiatop test, EDN, eosinophil count, 
etc., as mentioned in Table 1.  Current, regular use of a high-dose ICS and LABA for 
≥6 months prior to enrollment will be recorded.  Additionally, patients must be on chronic 
daily OCS therapy (equivalent to ≥5 mg/day of prednisone) for ≥3 continuous months directly 
preceding Visit 1, and this must be documented in the medical records.  Inhaled 
corticosteroids and LABAs may have been administered as either a fixed dose or 2 separate 
inhalers and must be consistent with the highest approved maintenance dose in the local 
country (Inclusion Criterion 6).  A stable dose of OCS must have been maintained for 
≥4 weeks prior to Visit 1.
Patients can proceed directly to Visit 2 once central laboratory results are received, and all 
eligibility requirements are confirmed.  Visit 2 should be done up to 2 weeks after Visit 1. For 
patients switching to prednisone/prednisolone at V1 and who thus require a delay in 
laboratory tests, Visit 2 can be done up to 2 weeks after the collection of laboratory samples. 
Patients will continue to receive treatment with their current ICS/LABA and other 
controller(s) (if applicable) with no changes.
If the patient experiences an asthma exacerbation during screening that requires evaluation in 
an urgent care center or emergency department, hospitalization, or temporary increase 
(bolus/burst) of systemic steroids, they will not be screen failed, but an extension of the 
screening period up to 3 months will be allowed to ensure that the patient recovers from the 
asthma exacerbation and the OCS dose is stabilized. Additionally, if a patient experiences
acute upper/lower respiratory infection that requires antibiotics or antiviral medication during 

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screening, then they also will not be screen failed and an extension of the screening period of 
up to 3 months will be allowed. If the patient recovers from the asthma exacerbation or acute 
upper/lower respiratory infection and is stable for ≥2 weeks, then the patient will be allowed 
to continue in the study.  Patients must enter the treatment phase within 3 months of
screening; if it has been longer than 3 months, then the patient may be rescreened.
If the patient experiences a non-asthma related event requiring temporary increase 
(bolus/burst) of systemic steroids, an extension of the screening period of up to 3 months may 
be allowed (AZ study physician can be consulted if required).
Patient’s eligibility should be evaluated at the screening visit with the relevant documentation 
entered in the source and eCRF.
4.1.2
Rescreening
Rescreening of patients for any reason will be allowed only once for each patient and only 
upon approval of the AstraZeneca Physician.  Patients will keep the same e-code.
4.2
Open-label treatment period
The open-label treatment period is divided into 3 phases based on the OCS dose adjustment: 
induction phase (Section 4.2.1), reduction phase (Section 4.2.2), and maintenance phase 
(Section 4.2.3).  Patients will complete the ACQ-6 and maintenance medication assessment 
weekly using the ePRO throughout the treatment period (see Section 5.3.4 for details).
4.2.1
Induction phase
The induction phase will start at Visit 2 (Week 0) and will continue until the day prior to Visit 
3.  Inclusion and exclusion criteria will be confirmed at Visit 2 and the patient will complete 
the ACQ-6, maintenance medication assessment, and SGRQ on the ePRO, prior to 
benralizumab administration, to establish baseline scores. Additionally, during the induction 
phase only, patients will complete the Patient Global Assessment of Change (PGIC) on a 
weekly basis on the ePRO in addition to weekly completion of the ACQ-6 and maintenance 
medication assessments.  All patients who meet eligibility criteria and enter the study will 
receive open-label benralizumab.  The first dose of the study drug will be administered SC as 
Q4W dosing at Visit 2.  Patients will be observed at the site for 2 hours after dosing.  During 
this time, patients will remain on their regular asthma controller medications, and no dose 
adjustments to OCS will be made.  Patients who experience asthma exacerbations that require 
evaluation in an urgent care center or emergency department, hospitalization, or temporary 
increase of systemic steroids (bolus/burst dosing) will be managed as per Section 5.2.3.  
4.2.2
OCS Reduction phase
The reduction phase will start at Visit 3 (Week 4) after the dose of benralizumab, and 
subsequent OCS dose reductions will occur according to the schema defined for each baseline 
OCS dose until patients reach a 5 mg/day dose (Table 2).  

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The study drug will be administered SC as Q4W dosing up until the third dose of 
benralizumab (therefore at Visits 3 and 4 during the OCS reduction phase) and then Q8W 
thereafter (8 weeks between the 3rd and 4th benralizumab dose). Patients will be observed at 
the site for 2 hours after dosing for the first 3 study drug administrations (therefore at Visits 3 
and 4 during the OCS reduction phase) and for 1 hour after subsequent study drug 
administrations for any acute drug reactions.
For all patients, HPA axis integrity will be evaluated after 4-weeks on 5 mg/day and prior to 
tapering down the OCS dose (for patients with baseline OCS doses equal to 5 mg/day, this 
will be assessed 4 weeks after the first dose of benralizumab administration and before 
initiation of the OCS reduction phase)
First, a screening method with morning serum cortisol is done (8-9 am morning cortisol level), 
to evaluate whether the patient has:

Normal cortisol levels

Complete AI
Cortisol levels from the morning cortisol test that are below normal range and above the 
Complete AI range are considered “Indeterminate;” and require additional testing described 
below.
Secondly, the ACTH stimulation test (ie, Synacthen®, Cortrosyn™) is done within 
approximately 1 week in the subset of patients with indeterminate results from the morning 
cortisol test [see also Section 5.2.1.2 for details). The ACTH stimulation test is more specific 
than the morning cortisol test, and can determine whether the patient has:

Normal cortisol levels

Complete AI

Partial AI
Dose reduction of OCS should be interrupted if the patient suffers an asthma exacerbation 
(Section 5.2.3) or in case the Investigator considers the patient to be having a significant 
deterioration of his/her asthma disease (Section 5.1.2.1).  After the OCS bolus/burst to treat an 
exacerbation is completed, or after recovery from an asthma deterioration, the Investigator 
may either return the OCS dose to a one-step higher dose level (or more if considered 
necessary by the Investigator) than what was prescribed when the exacerbation or asthma 
worsening occurred or continue with the same OCS dose, which must be maintained at a 
stable dosage for at least two weeks.
After recovery from the first exacerbation or asthma deterioration, the patient will be allowed 
to proceed with another attempt to reduce their OCS dose; however, the patient will follow a 
lower speed for OCS down-titration (reductions Q4W; Table 3).
In case of a second exacerbation or asthma deterioration, no further OCS dose reduction will 
be allowed, and the patient will remain on the same OCS dose or return to a one-step higher 
dose level (or more as considered necessary by the Investigator) than what was prescribed 

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when the exacerbation/worsening occurred.  The OCS dose reduction phase will then be 
terminated, and the patient will enter the maintenance phase.  Further details are provided in 
Section 5.2.3. 
Patients who experience asthma exacerbations that require evaluation in an urgent care center 
or emergency department, hospitalization, or temporary increase of systemic steroids 
(bolus/burst dosing) will be managed as per details in Section 5.2.3. 
To help investigators evaluate the occurrence of a significant asthma deterioration, 
investigators will have access to the patient’s weekly ACQ-6 scores (completed by means of 
an ePRO).  A significant deterioration is defined as a worsening in ACQ-6 score of at least 0.5
from value at Visit 2. If the ACQ-6 score at Visit 2 is missing, the 1st score recorded post-Visit 
2 and pre-OCS reduction may be used as baseline for the 0.5-point increase (note, however, 
that it will not be used to impute the baseline value for ACQ-6 analysis). Investigators should 
consider this information together with any other information reported by patients on 
signs/symptoms of the disease as well as compliance with maintenance asthma therapy.  
Based on the totality of the information, investigators can decide whether the patient can 
continue with the OCS dose reduction until the patient reaches an OCS dose of 0 mg/day (or 
lowest OCS dose possible in case no further OCS down-titration is allowed because of the 
presence of AI as measured by cortisol levels or in case of inadequate asthma control) without 
losing asthma control.  The other patient-reported outcomes (PROs) will be carried out per the 
schedule in Table 1.
The length of the benralizumab treatment period will depend on the baseline OCS dose, 
occurrence of asthma exacerbation(s) or asthma worsening, and whether the patient 
experiences AI.  Procedures specific for the visits are listed in Table 1.  Restrictions as set out 
in Section 3.5 will continue to apply throughout the treatment period.
From Visit 3 onwards, the dose of OCS may be reduced only when conditions listed in 
Section 5.1.2 are met.  The reductions will occur at an interval according to the titration 
schedule.  The first OCS dose reduction can occur at Visit 3 after the dose of benralizumab at 
the site.
Patients will reduce OCS following confirmation from the Investigator/study site personnel at 
site visits or via telephone calls.  Phone calls can be scheduled as required to assess the 
occurrence of exacerbations, asthma control (ACQ-6 scores), AEs, and concomitant 
medication use. Additional site visits can be scheduled for patients in case of poor asthma 
control.  
Table 2 depicts the proposed dose reduction schedule, provided the patient does not 
experience an exacerbation, worsening of asthma control, or AI.  In case of asthma 
exacerbation or worsening, the dose reduction schedule will be longer (Table 3) and will vary 
depending on HPA axis integrity and/or on the patient’s recovery from an exacerbation.

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Depending on the baseline OCS dose and on the possibility of experiencing AI symptoms, 
each patient will spend a different amount of time in the reduction phase and the number of 
visits will be adjusted accordingly.  
Approximately 1-2 weeks prior to end of the OCS reduction phase, the patients who have 
Partial AI, will undergo an additional morning cortisol test (and if required, ACTH stimulation 
test for indeterminate result) at the end of the OCS Reduction phase.
4.2.3
Maintenance phase
A patient will enter the approximately 24- to 32-week maintenance phase when they reach an 
OCS dose of 0 mg/day (or lowest OCS dose possible in case no further OCS down-titration is 
allowed because of the presence of AI as measured by cortisol levels or in case of inadequate 
asthma control) without losing asthma control. This could be earlier if OCS dose reduction 
fails due to clinical deterioration or if the patient experiences an asthma exacerbation. The 
duration of the maintenance phase will depend on when the patient enters the maintenance 
phase relative to the dosing cycle of benralizumab. During this phase, patients will continue 
benralizumab Q8W for 3 doses and then the EOT visit will be scheduled 8 weeks (± 7 days) 
after the last dose of benralizumab (assessments performed as per Table 1). However, if 
during this period, the patient experiences asthma deterioration or an exacerbation, the length 
of the maintenance phase will not be extended and the patient will continue on 3 doses of 
benralizumab Q8W. Additionally increases in the maintenance OCS dose due to an asthma 
exacerbation is permitted per investigator discretion.  Patients who experience an asthma 
exacerbation that requires evaluation in an urgent care center or emergency department, 
hospitalization, or temporary increase of systemic steroids (bolus/burst dosing) will be 
managed as per details in Section 5.2.3.  
Patients who have Complete AI or Partial AI at the end of the OCS Reduction phase, will 
undergo a final morning cortisol test (and if required, ACTH stimulation test for indeterminate 
result) approximately 1-2 weeks prior to end of the OCS Maintenance phase (prior to EOT 
visit).
Patients will return the ePRO at the EOT visit.  Completion of the treatment will be registered 
in IWRS/IVRS at the EOT visit for each patient. After stopping study drug, the patient will be 
adjusted to a post-study asthma maintenance regimen (which may include a respiratory 
biologic, if needed), per Investigator discretion.    
Patients who prematurely discontinue study drug (see Section 3.6) should return to the study 
site and complete procedures described for the IPD visit and follow-up visit within 4 weeks 
(± 7 days) and 12 weeks (± 7 days) after the last dose of study drug, respectively.  Study 
assessments and procedures to be performed at the IPD and follow-up visits are outlined in 
Table 1.  Reasons for premature discontinuation of study drug should be recorded in the 
eCRF.

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4.3
Follow-up period
All patients who complete the maintenance phase or who prematurely discontinue study drug 
will have a follow-up contact after 12 weeks of the last dose of benralizumab. The follow-up 
contact can be done either on-site or via telephone contact. During this visit, patients will be 
assessed for any ongoing safety issues, and AEs and concomitant medications will be 
collected. Patients who have Partial AI or Complete AI at the end of the Maintenance phase, 
should be followed-up by an endocrinologist or other appropriate specialist, if deemed 
necessary by the Investigator.
4.4
PONENTE Long Term Follow Up Substudy: Study Plan 
and Timing of Procedures
At the end of the PONENTE EOT visit, patients will be invited to participate in a long term 
follow up visit 12- to 18-months after completion of the main PONENTE study. This substudy 
is intended to further assess changes in asthma maintenance therapy in a real-world setting, 
i.e., according to the treatment prescribed by their healthcare provider. Additionally, there will 
be assessment of recovery from AI as well as assessment of glucocorticoid toxicity by means 
of GTI.  
Between the EOT visit of the main PONENTE study and the long term follow up visit, 
patients will be treated according to standard practice; for example, any changes to 
maintenance asthma regimens are allowed, including further reductions of OCS as 
recommended in the GINA 2020 report. There will be one on-site visit 12-18 months after the 
EOT visit of the main PONENTE study. Patients who enrol in the long term follow up visit 
substudy will still complete the follow-up visit at the end of the main PONENTE study. See 
Appendix K for further details.
4.5
Study Conduct Mitigation During Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study patients become infected with severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) or similar pandemic infection) which would prevent the conduct 
of study-related activities at study sites, thereby compromising the study site staff or the 
patient’s ability to conduct the study. The investigator or designee should contact the study 
Sponsor to discuss whether the mitigation plans below should be implemented.  
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study patients, maintain 
compliance with Good Clinical Practice, and minimize risks to study integrity. 
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options: 

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•
Obtaining consent for the mitigation procedures (note, in the case of verbal consent, 
the Informed Consent Form (ICF) should be signed at the patient’s next contact with the study 
site).
•
Home or Remote visit: Performed by a site qualified Health Care Professional (HCP) 
or HCP provided by a third-party vendor (TPV).
•
Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 
•
At-home Investigational Product (IP) administration: Performed by a site qualified 
HCP, HCP provided by a TPV, if possible. Additional information related to the visit can be 
obtained via telemedicine. 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix L.
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 Clinical 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.
Please refer to Appendix K for details on study assessments conducted during the PONENTE 
Long Term Follow Up substudy.
5.1
Efficacy assessments
5.1.1
Assessment of OCS dose
All patients who meet eligibility criteria and enter the study will receive open-label 
benralizumab and reduce their OCS dose until the patient reaches an OCS dose of 0 mg/day 
(or lowest OCS dose possible in case no further OCS down-titration is allowed because of the 
presence of AI as measured by cortisol levels or in case of inadequate asthma control) as per 
the details provided in Section 4.2.2 and the schedule provided in Table 2 and Section 5.1.2
No further reductions will be made to OCS dose after completion of the reduction phase, and 
the patient will enter an approximately 24- to 32-week maintenance phase.  In case of 
exacerbations, patients will be managed as per details provided in Section 5.2.3.  Additionally, 
in case the patient experiences asthma deterioration or an exacerbation, increase in the 
maintenance OCS dose is permitted per investigator discretion.

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All OCS dose changes will be documented in the source documentation and recorded in the 
appropriate eCRF form.  Moreover, in case of OCS reduction being temporarily interrupted 
(in case of an exacerbation or asthma deterioration) or permanently interrupted (exacerbation, 
asthma deterioration, AI based on cortisol tests, or occurrence of an adrenal crisis), the reason 
should be documented in the appropriate eCRF, and reduction will be done slowly as per 
Table 3.
5.1.2
OCS dose titration
At Visit 1, patients will continue with or be switched to prednisone/prednisolone.  For patients 
not previously receiving prednisone/prednisolone as OCS, the conversion table shown in 
Appendix F will be used to calculate the equivalent prednisone/prednisolone dose for dose 
titration.
The OCS dose titration in the reduction phase will be followed as per Table 2 depending on 
the initial OCS dose and HPA axis evaluation. If Table 2 instructs to reduce dose by 5mg 
increments, but the initial OCS dose is <5 mg to the nearest dosing level: The 1st reduction 
would be smaller, rounding down to the nearest 5 mg, then continue on with 5 mg Q2W 
reductions (examples below):

e.g. 12.5 →10 mg →etc.

e.g 23→20→15→10 mg →etc.

e.g. 19→15→10 mg →etc.
If Table 2 instructs to reduce the initial dose by 2.5mg increments, but the initial dose is 
<2.5mg to the next dosing level: The 1st reduction would be smaller, rounding down to the 
nearest 2.5mg, then continue on with 2.5 Q4W reductions (examples below):

e.g. 8→7.5→5→etc.  

e.g. 6.25→5→etc.
For all patients, HPA axis integrity will be evaluated after 4-weeks on 5 mg/day and prior to 
tapering down the OCS dose (for patients with baseline OCS doses equal to 5 mg/day, this 
will be assessed 4 weeks after the first dose of benralizumab administration and before 
initiation of the OCS reduction phase)
First, a screening method with morning serum cortisol is done (8-9 am morning cortisol level), 
to evaluate whether the patient has:
•
Normal cortisol levels
•
Complete adrenal insufficiency (AI)
Cortisol levels from the morning cortisol test that are below normal range and above the 
Complete AI range are considered “Indeterminate,” and require additional testing described 
below.

Clinical Study Protocol
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Secondly, the ACTH stimulation test (ie, Synacthen®, Cortrosyn™) is done within 
approximately 1 week in the subset of patients with indeterminate results from the morning 
cortisol test [see also Section 5.2.1.2 for details). The ACTH stimulation test is more specific 
than the morning cortisol test, and can determine whether the patient has:
•
Normal cortisol levels
•
Complete AI
•
Partial AI.
Investigators may also choose to slow the down-titration to 1 mg Q4W once the patient 
reaches a OCS dose of 5 mg/day based on patient symptoms alone regardless of cortisol 
levels.  Once there is evidence of recovery, OCS reduction will continue until the patient 
reaches an OCS dose of 0 mg/day (or lowest OCS dose possible in case no further OCS 
down-titration is allowed because of the presence of AI as measured by cortisol levels or in 
case of inadequate asthma control) without losing asthma control.

Clinical Study Protocol
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Table 2
OCS down-titration approaches
Initial OCS 
dose/day
OCS down-titration to reach an OCS dose of:
20 mg
10 mg
7.5 mg
5 mg
0 mg
>20 mg
Reduction of 
5 mg weekly 
until reaching 
dose of 
20 mg/day
Reduction of 
5 mg Q2W 
until reaching 
dose of 
10 mg/day
2.5 mg 
Q2W until 
reaching 
dose of 
7.5 mg/day
2.5 mg Q4W until 
reaching dose of 
5 mg/day
No AI: reductions of 2.5 mg Q4W until reaching dose of 
0 mg/day
Risk AI: reductions of 1 mg Q4W and repeat test 2 months latera
Complete AI: No OCS dose reduction and repeat test 3 months 
laterb
>10 mg to 
≤20 mg
Reduction of 
5 mg Q2W 
until reaching 
dose of 
10 mg/day
2.5 mg 
Q2W until 
reaching 
dose of 
7.5 mg/day
2.5 mg Q4W until 
reaching dose of 
5 mg/day
No AI: reductions of 2.5 mg Q4W until reaching dose of 
0 mg/day
Risk AI: reductions of 1 mg Q4W and repeat test 2 months latera
Complete AI: No OCS dose reduction and repeat test 3 months 
laterb
>7.5 mg to 
≤10 mg 
2.5 mg 
Q2W until 
reaching 
dose of 
7.5 mg/day
2.5 mg Q4W until 
reaching dose of 
5 mg/day
No AI: reductions of 2.5 mg Q4W until reaching dose of 
0 mg/day
Risk AI: reductions of 1 mg Q4W and repeat test 2 months latera
Complete AI: No OCS dose reduction and repeat test 3 months 
laterb
>5 mg to 
≤7.5 mg
2.5 mg Q4W until 
reaching dose of 
5 mg/day
No AI: reductions of 2.5 mg Q4W until reaching dose of 
0 mg/day
Risk AI: reductions of 1 mg Q4W and repeat test 2 months latera
Complete AI: No OCS dose reduction and repeat test 3 months 
laterb
5 mg
No AI: reductions of 2.5 mg Q4W until reaching dose of 
0 mg/day
Risk AI: reductions of 1 mg Q4W and repeat test 2 months latera
Complete AI: No OCS dose reduction and repeat test 3 months 
laterb
a
Risk AI means “partial AI” cortisol testing confirmed with ACTH stimulation testing. After repetition of the test 2 months later, the decision to further 
reduce OCS dose will be based on the morning cortisol test results. If test results are normal, the OCS dose may be reduced directly to 0 mg/day (if 
patient is receiving ≤3 mg); the patient will continue receiving 1 mg Q4W if still at risk. If complete AI is indicated, OCS dose will not be modified.
b
If morning cortisol test results again indicate complete AI at 3 months, the OCS dose will not be modified as this is the final attempt.  If morning cortisol 
test results indicate risk AI, then reductions will be 1 mg Q4W and, if normal, then reductions will be 2.5 mg Q4W.

Clinical Study Protocol
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Table 3
“Rescue” OCS down-titration after recovery from an asthma exacerbation or deterioration
Initial OCS 
dose/day
“Rescue” OCS down-titration after recovery from an asthma exacerbation or deterioration to reach an OCS dose of:
10 mg
5 mg
0 mg
>20 mg
Reduction of 5 mg Q4W 
until reaching a dose of 
10 mg/day
Reduction of 2.5 mg 
Q4W until reaching a 
dose of 5 mg/day
No AI: Reduction of 2.5 mg Q4W
Risk AI: 1 mg/day Q4W and repeat test 2 months latera
Complete AI: No OCS dose reduction and repeat test 3 months laterb
>10 mg to 
≤20 mg
Reduction of 5 mg Q4W 
until reaching a dose of 
10 mg/day 
Reduction of 2.5 mg 
Q4W until reaching a 
dose of 5 mg/day
No AI: Reduction of 2.5 mg Q4W
Risk AI: 1 mg/day Q4W and repeat test 2 months latera
Complete AI: No OCS dose reduction and repeat test 3 months laterb
>5 mg to 
≤10 mg
Reduction of 2.5 mg 
Q4W until reaching a 
dose of 5 mg/day
No AI: Reduction of 2.5 mg Q4W
Risk AI: 1 mg/day Q4W and repeat test 2 months latera
Complete AI: No OCS dose reduction and repeat test 3 months laterb
5 mg
No AI: Reduction of 2.5 mg Q4W
Risk AI: 1 mg/day Q4W and repeat test 2 months latera
Complete AI: No OCS dose reduction and repeat test 3 months laterb
a
After repetition of the test 2 months later, the decision to further reduce OCS dose will be based on the morning cortisol test results. If test results are 
normal the OCS dose may be reduced directly to 0 mg/day (if patient was receiving ≤3 mg); the patient will continue receiving 1 mg Q4W if still at risk.
b
If morning cortisol test results again indicate complete AI at 3 months, the OCS dose will not be modified as this is the last attempt.  If morning cortisol 
test results indicate risk AI, then reductions will be 1 mg Q4W and, if normal, then reductions will be 2.5mg Q4W.

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For prednisone doses below 5 mg, if the exact dose strength is not available in the country, the 
daily dose to be administered could be achieved by dosing every other day.  Daily dose will be 
the average of 2 days.  See Appendix G for help dosing <5 mg in relation to tablet strength.
5.1.2.1
Asthma worsening or asthma exacerbation preventing OCS down-titration 
The OCS dose titration will be interrupted in case of one of the following circumstances 
related to the asthma condition:

Asthma deterioration will be assessed by the investigators when there is an increase 
in ACQ-6 scores of ≥0.5 from the value at Visit 2. If the ACQ-6 score at Visit 2 is 
missing, the 1st score recorded post-Visit 2 and pre-OCS reduction may be used as 
baseline value for the 0.5-point increase (note, however, that it will not be used to 
impute the baseline for ACQ-6 analysis). The Investigator will decide whether the 
worsening of asthma should lead to an interruption in tapering of OCS dose until 
asthma control improves.  

In case of an asthma exacerbation that requires treatment with systemic 
corticosteroids for at least 3 consecutive days, hospitalization, or emergency room 
admission, the OCS dose titration will be interrupted, and appropriate treatment will 
be administered as described in Section 5.2.3.
After recovery from the first asthma deterioration or exacerbation, patients will be offered to 
continue OCS tapering down at a slower speed (ie, Q4W); however, in the case of a second 
event of asthma deterioration or exacerbation, the OCS reduction will be stopped.
The lower OCS dose (0 mg or above, if required to control asthma disease) that is not changed 
during a period of 4 weeks and that ensures a patient does not suffer from an asthma 
exacerbation or that avoids the occurrence of an asthma deterioration/worsening requiring an 
increase in OCS dose, based on investigator criteria, will be considered the final OCS dose of 
the OCS reduction phase, and, thereafter, the patient will initiate the OCS maintenance phase 
on that OCS dose.
5.2
Safety assessments
5.2.1
HPA axis evaluation
For all patients, HPA axis integrity will be evaluated after 4-weeks on 5 mg/day and prior to 
tapering down the OCS dose (for patients with baseline OCS doses equal to 5 mg/day, this 
will be assessed 4 weeks after the first dose of benralizumab administration and before 
initiation of the OCS reduction phase)
First, a screening method with morning serum cortisol is done (8-9 am morning cortisol level), 
to evaluate whether the patient has:
•
Normal cortisol levels
•
Complete adrenal insufficiency (AI)

Clinical Study Protocol
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Study Code D3250C00065
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Cortisol levels from the morning cortisol test that are below normal range and above the 
Complete AI range are considered “Indeterminate,” and require additional testing described 
below.
Secondly, the ACTH stimulation test (ie, Synacthen®, Cortrosyn™) is done within 
approximately 1 week in the subset of patients with indeterminate results from the morning 
cortisol test [see also Section 5.2.1.2 for details). The ACTH stimulation test is more specific 
than the morning cortisol test, and can determine whether the patient has:
•
Normal cortisol levels
•
Complete AI
•
Partial AI.
The process will be as described in Figure 2.
For females using oral estrogen-containing contraceptives or oral estrogen-containing 
hormone replacement therapy, the threshold for normal values will be 2 times the normal 
morning cortisol levels and 1.5 times the normal ACTH stimulation test cortisol levels. Details 
related to values for normal, partial AI, and complete AI for these patients are provided in the 
laboratory manual. 
For the morning cortisol test, the last OCS dose should be taken ≥ 24 hours prior to testing. 
Additionally, patients must not take ICS (or ICS/LABA if in single inhaler) treatment on the 
morning of the cortisol testing (for patients taking a once-daily ICS/LABA formulation, e.g. 
fluticasone furoate/vilanterol patients must not take the treatment ≤ 24 hours prior to the 
morning of the cortisol testing). If a patient requires a short course of macrolides, antivirals, or 
azoles, there must be a window of ≥1 week prior to the testing of cortisol levels (see Section 
7.8).

Clinical Study Protocol
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Figure 2
HPA axis evaluation
Figure 2: For normal cortisol levels with concurrent signs/symptoms of AI, OCS down-titration should continue 
at a slower pace (1 mg Q4W). For complete AI identified via morning cortisol testing, refer to section 5.2.1.1 for 
instructions on 3-month repeat testing. For partial AI or complete AI identified via ACTH stimulation test see 
Section 5.2.1.2 for instructions on 2-month or 3-month repeat testing respectively. Patients who have Partial AI 
will undergo an additional morning cortisol test (and if required, ACTH stimulation test for indeterminate result) 
approximately 1-2 weeks prior to the end of the OCS Reduction phase. Patients who have Complete AI or Partial 
AI at the end of the OCS Reduction Phase, will undergo a final morning cortisol test (and if required, ACTH 
stimulation test for indeterminate result) approximately 1-2 weeks prior to the end of the Maintenance phase 
(prior to EOT).
Note: Central lab reports list reference ranges that are different than this study-reference ranges. To interpret 
laboratory results for each morning cortisol or ACTH stimulation test, please look for the study-specific lab alerts 
indicating normal, partial AI, and complete AI on the lab reports provided by central labs. The study-specific 
reference ranges for normal, partial AI, and complete AI are provided in the laboratory 
manual. 
5.2.1.1
Morning cortisol test (done at “OCS ≤ 5mg/day [morning cortisol]” visit)
For the morning cortisol test, hold OCS dose and other concomitant medications that could 
interfere with cortisol results per Section 5.2.1. Serum samples for cortisol will be collected 
between 8 and 9 am and will be sent to a central laboratory for evaluation.  Once the results 
are available, the site will inform the patient of the results via telephone.  Depending on the 
result, the actions that will be implemented are as follows:

If cortisol levels are within normal range and the patient does not exhibit any signs 
and/or symptoms of AI, the patient will continue OCS down-titration by 2.5 mg 
Q4W 

Clinical Study Protocol
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
If cortisol levels are within normal range but the patient exhibits signs and/or 
symptoms of AI, then OCS down-titration should continue at a slower pace 
(1 mg Q4W).  

If cortisol levels are below the normal range and above the complete AI range 
(indeterminate result), then the patient will be instructed to maintain the current 
OCS dose and come back to the site within 1 week for an ACTH stimulation test 
(Section 5.2.1.2)

If complete AI is confirmed, sites will inform patients that the OCS dose will 
remain the same without further reduction until there is evidence of recovery from 
the complete AI without worsening of asthma control.  The morning cortisol test 
will be repeated 3 months later, and patients will be educated for symptom 
awareness of adrenal suppression and use of steroid emergency cards.  During this 
repeat test 3 months later, the patient would also repeat all clinical assessments that 
were done with the initial morning cortisol test (see Table 1). After the repeat 
morning cortisol test, the site will inform the patient based on the results as follows:
-
If morning cortisol results at 3 months indicate normal cortisol values, then 
reductions will be 2.5 mg Q4W, and the patient would subsequently move to 
maintenance phase at OCS 0mg (or lowest possible dose)
-
If morning cortisol tests at 3 months are indeterminate, then reductions will be 
delayed further, and the patient would return approximately 1-week later for an 
ACTH stimulation test:

If normal result after ACTH stimulation: Reduce by 2.5mg Q4W then 
move to maintenance phase at 0mg (or lowest possible dose)

If the result is Partial AI after ACTH stimulation: Reduce by 1mg Q4W 
then move to maintenance phase at 0mg (or lowest possible dose)

If complete AI result after ACTH stimulation: OCS dose will not be 
reduced further, move to maintenance phase at current OCS dose
-
If morning cortisol tests again indicate complete AI at 3 months, the OCS dose 
will not be modified as this is the final attempt. The patient would move to 
maintenance phase at OCS 5mg (or lowest possible dose). 
Patients who have Partial AI will undergo an additional morning cortisol test (and if required, 
ACTH stimulation test for indeterminate result) approximately 1-2 weeks prior to the end of 
the OCS Reduction phase. Patients who have Complete AI or Partial AI at the end of the OCS 
Reduction Phase, will undergo a final morning cortisol test (and if required, ACTH 
stimulation test for indeterminate result) approximately 1-2 weeks prior to the end of the 
Maintenance phase (prior to EOT). In the absence of evidence of HPA axis recovery, 
corticosteroid supplementation is recommended during situations of stress (ie, fractures, 
surgery, trauma, labor, invasive dental procedures, severe systemic infections, major burns, 
and fever >38.5ºC). Additionally, patients with Partial AI or Complete AI at the end of the 
Maintenance phase should be referred to an endocrinologist or other appropriate specialist, per 
Investigator discretion.

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Details related to values for normal, partial AI and complete AI are provided in the laboratory 
manual.
5.2.1.2
ACTH stimulation test 
The ACTH stimulation test (e.g., Synacthen®, Cortrosyn™, etc.) test will be performed when 
morning cortisol levels are below the normal range (but above complete AI levels). Please 
refer to the package insert of the product used locally for further guidance on preparation and 
administration. The sites will inform the patients of the morning cortisol results via phone call, 
and a visit will be scheduled within 1 week for the ACTH stimulation test. In the event of any 
issues with availability of the product used for the ACTH stimulation test, please consult with 
AZ study physician for further guidance.
For the ACTH stimulation test, hold OCS dose and other concomitant medications that could 
interfere with cortisol results per Section 5.2.1. An injection of the fast-acting ACTH 
stimulant will be given intravenously.  Serum samples for cortisol will be collected between 8 
and 9 am and will be sent to a central laboratory for evaluation as follows: a blood sample for 
serum cortisol will be collected at 0 minutes (before injection) and 30 minutes after the 
injection.  Peak cortisol response at 30 minutes will be selected to assess AI, and the OCS 
taper will follow the applicable scenario below:

If a normal peak cortisol level is demonstrated at 30 minutes, the site will inform 
the patient via phone call, and the patient will continue OCS dose titration by 
2.5 mg Q4W, and subsequently would move to the maintenance phase at OCS dose 
of 0mg (or lowest possible dose). 

If the peak cortisol level at 30 minutes is below the normal range yet above the 
level of complete AI (“partial AI”), or there are some signs/symptoms of AI or 
corticosteroid withdrawal syndrome, the site will inform the patient to continue 
OCS down-titration at a slower speed (1 mg Q4W). The morning cortisol test will 
be repeated 2 months later, as per the process described in Figure 2. During this 
repeat test 2 months later, the patient would also repeat all clinical assessments that 
were done with the initial morning cortisol test (see Table 1).
-
If morning cortisol test results indicate normal cortisol values, then reductions 
will be up to 2.5 mg Q4W (based on patient’s current OCS dose), and the 
patient would subsequently move to maintenance phase at OCS 0mg (or lowest 
possible dose)
-
If morning cortisol test results at 2 months are indeterminate, then reductions 
will be delayed, and the patient would return approximately 1-week later for an 
ACTH stimulation test.

If normal result after ACTH stimulation: Reduce by 2.5mg Q4W then 
move to maintenance phase at 0mg (or lowest possible dose)

If the result is Partial AI after ACTH stimulation: Reduce by 1mg Q4W 
then move to maintenance phase at 0mg (or lowest possible dose)

Clinical Study Protocol
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Study Code D3250C00065
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
If complete AI result after ACTH stimulation: OCS dose will not be 
reduced further, move to maintenance phase at current OCS dose
-
If morning cortisol test results at 2 months indicate complete AI, the OCS dose 
will not be modified as this is the final attempt. The patient would move to 
maintenance phase at OCS 5mg (or lowest possible dose). 

If peak cortisol level at 30 minutes indicates complete AI, sites will inform patients 
that the OCS dose will remain the same without further reduction until there is 
evidence of recovery from the complete AI without worsening of asthma control.  
The morning cortisol test will be repeated 3 months later and patients will be 
educated for symptom awareness of adrenal suppression and use of steroid 
emergency cards. During this repeat test 3 months later, the patient would also 
repeat all clinical assessments that were done with the initial morning cortisol test 
(see Table 1). After the repeat morning cortisol, the site will inform the patient 
based on the results as follows:
-
If results indicate normal cortisol values, then reductions will be 2.5 mg Q4W, 
and the patient would subsequently move to maintenance phase at OCS 0mg 
(or lowest possible dose)
-
If morning cortisol tests at 3 months indicate indeterminate results, then 
reductions will be delayed further, and the patient would return approximately 
1-week later for an ACTH stimulation test.

If normal result after ACTH stimulation: Reduce by 2.5mg Q4W then 
move to maintenance phase at 0mg (or lowest possible dose)

If the result is Partial AI after ACTH stimulation: Reduce by 1mg Q4W 
then move to maintenance phase at 0mg (or lowest possible dose)

If complete AI result after ACTH stimulation: OCS dose will not be 
reduced further, move to maintenance phase at current OCS dose
-
If morning cortisol tests again indicate complete AI at 3 months, the OCS dose 
will not be modified as this is the final attempt. The patient would move to 
maintenance phase at OCS 5mg (or lowest possible dose).
Patients who have Partial AI will undergo an additional morning cortisol test (and if required, 
ACTH stimulation test for indeterminate result) approximately 1-2 weeks prior to the end of 
the OCS Reduction phase. Patients who have Complete AI or Partial AI at the end of the OCS 
Reduction Phase, will undergo a final morning cortisol test (and if required, ACTH 
stimulation test for indeterminate result) approximately 1-2 weeks prior to the end of the 
Maintenance phase (prior to EOT).
In the absence of evidence of HPA axis recovery, patients should be instructed to carry some 
type of identification (worn around the neck or wrist or carried as a card) warning of their 
clinical status of corticosteroid dependence along with a medical report detailing the treatment 
measures needed, including intramuscular hydrocortisone requirements.  Corticosteroid 
supplementation is recommended during situations of stress (ie, fractures, surgery, trauma, 

Clinical Study Protocol
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Study Code D3250C00065
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labor, invasive dental procedures, severe systemic infections, major burns, and fever >38.5ºC). 
Additionally, patients with Partial AI or Complete AI at the end of the study should be 
referred to an endocrinologist or other appropriate specialist, per Investigator discretion.
Details related to values for normal, partial AI and complete AI are provided in the laboratory 
manual.
5.2.2
Assessment of asthma exacerbations
During the study, an asthma exacerbation will be defined as a worsening of asthma symptoms 
that leads to any of the following:

A temporary bolus/burst of systemic corticosteroids (at a dose above one level 
higher than the current titration step) for at least 3 consecutive days to treat 
symptoms of asthma worsening; a single depo-injectable dose of corticosteroids 
will be considered equivalent to a 3-day bolus/burst of systemic corticosteroids. 
Note: Per-protocol up-titration of the OCS dose to one level higher is not 
necessarily considered to be an exacerbation event
-
Patients who experience an exacerbation during the screening period (between 
Visits 1 and 2) can be granted an extension of the screening period to ensure that a 
patient recovers from an asthma exacerbation and the OCS dose is stabilized.  

An emergency room or urgent care visit (defined as evaluation and treatment for 
<24 hours in an emergency department or urgent care center) due to asthma that 
required systemic corticosteroids (as per the above)

Inpatient hospitalization (defined as admission to an inpatient facility and/or 
evaluation and treatment in a healthcare facility for ≥24 hours) due to asthma
The Investigator must justify the decision for defining an event of worsening asthma as an 
exacerbation and record it in the source documents and eCRF.  An asthma exacerbation that 
occurs within 7 days of the last dose of systemic steroids, prescribed for a prior exacerbation, 
will be counted as the same exacerbation event.
The patient may remain in the study after an exacerbation and continue to receive study drug 
if the Investigator judges that it is medically appropriate for the patient to do so and will be 
managed as per the details provided in Section 5.2.3.
Reasonable attempts should be made by the Investigator to bring the patient into the study site 
for patient-initiated asthma worsening, particularly when it results in additional treatment 
being prescribed.  Study site evaluations for asthma worsening may occur as an unscheduled 
visit or as part of a routine center visit if the worsening happens to occur in line with a 
scheduled visit.  A copy of the medical record should be obtained for exacerbations evaluated 
and treated at non-study sites (eg, by the primary care provider or at an emergency 
department/hospital).  Details should be entered into the exacerbation eCRF in a timely 
fashion.  Changes in concomitant medications due to exacerbations must be recorded in the 
appropriate module of the eCRF.

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5.2.3
Management of asthma exacerbations during treatment period
Patients who experience an exacerbation during the treatment period may remain on the study 
drug at the Investigator’s discretion.  Asthma exacerbations will be treated with oral or other 
systemic corticosteroids according to standard clinical practice.

Induction phase: If a patient experiences an exacerbation during the induction 
phase, the start of the OCS dose reductions may be delayed.  After the OCS 
bolus/burst to treat an exacerbation is complete, the patient may be returned to a 
one-step higher dose level (or more if considered necessary by the Investigator) 
than what was prescribed when the exacerbation occurred.  The Investigator may 
decide to maintain the same OCS dose.  The patient’s OCS dose should be stable 
for at least two weeks before entering the OCS reduction phase 

Reduction phase: If a patient experiences an exacerbation during the reduction 
phase, the Investigator may do one of the following for at least two weeks after 
completion of the OCS bolus/burst:
-
The patient may be returned to a one-step higher dose level (or more if 
considered necessary by the Investigator) than what was prescribed when the 
exacerbation occurred 
or
-
The same OCS dose may be maintained at a stable dosage and then OCS 
down-titration may be continued once the patient recovers from the 
exacerbation
Further dose reductions during this phase will be considered as per the 
Investigator’s opinion.  After recovery from the first exacerbation, the patient will 
be allowed to proceed with another attempt to reduce their OCS dose; however, 
they would follow a lower speed of OCS down-titration (reductions every 4 weeks) 
(Table 3).
In case of a second exacerbation, no further OCS dose reduction will be allowed, 
and the patient will continue the same dose or will return to a one-step higher dose 
level (or more as considered necessary by the Investigator) than what was 
prescribed when the exacerbation occurred.  The patient will then enter the 
maintenance phase and continue the same dose through the end of study.

Maintenance phase: If a patient experiences an exacerbation during the 
maintenance phase, the length of the maintenance phase will not be extended; and 
the patient will continue on 3 doses of benralizumab Q8W. After the OCS 
bolus/burst is complete, the patient may then be returned to a one-step higher dose 
level (or more if considered necessary by the Investigator) than the OCS dose they 
were on when the exacerbation occurred, or the Investigator may decide to maintain 
the same OCS dose throughout the maintenance phase.

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5.2.4
Laboratory safety assessments
Laboratory safety assessments (listed in Table 4) 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 
according to the schedule provided in Table 1. 
Laboratory results should be reviewed by the Investigator/authorized delegate and evaluated 
for abnormalities.  Any laboratory abnormalities considered to be significant in the 
Investigator/authorized delegate’s judgement should be reported as AEs, as described in 
Section 6.
The copy of the laboratory results report should be signed and dated by the 
Investigator/authorized delegate and retained at the study site.
Table 4
Laboratory safety variables
Hematology/Hemostasis (whole blood)
Serum chemistry
Hematocrit
Alanine aminotransferase
Hemoglobin
Alkaline phosphatase 
Platelet count
Aspartate aminotransferase
Red blood cell count
Creatinine 
Absolute Leukocyte count (White blood cell count) and 
differential 
Low-density lipoprotein
Glycated hemoglobin (HbA1c)
Gammaglutamyl transpeptidase
Potassium 
Sodium
Total bilirubin 
Glucose 
5.2.4.1
Pregnancy test
The following tests are applicable to female patients only and will be conducted according to 
the schedule provided in Table 1. 

Serum beta-HCG (beta-human chorionic gonadotropin):  To be done at screening 
visit (Visit 1) and EOT only for WOCBP (analyzed at central laboratory).

Follicle-stimulating hormone:  To be done at screening visit (Visit 1) only for 
female patients <50 years who have been amenorrhoeic for ≥12months to confirm 
postmenopausal status 

Urine HCG:  To be performed at the study site for WOCBP at each treatment visit 
using a dipstick before any invasive study procedures (eg, blood sampling) are 
performed and before study drug administration.  Positive urine test result must be 
confirmed with serum beta-HCG.

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5.2.5
Physical examination
Physical examination will be done according to the schedule provided in Table 1.
Baseline data will be collected at Visit 1.  Any new finding(s) or aggravated existing 
finding(s), judged as clinically significant by the Investigator, will be reported as AEs as 
described in Section 6.1.
5.2.5.1
Complete physical examination
The complete physical examination will include an assessment of the following: general 
appearance, skin, head and neck (including eyes, ears, nose, mouth, and throat), lymph nodes, 
abdomen, musculoskeletal (including spine and extremities), cardiovascular, respiratory, and 
neurological systems.
5.2.5.2
Brief physical examination
The brief physical examination will include an assessment of the general appearance, 
abdomen, cardiovascular, and respiratory system. For the brief physical examination, only 
information on whether the assessment was performed or not is to be recorded.
5.2.6
Vital signs
Predose vital signs (pulse, blood pressure [BP], respiration rate and body temperature), will be 
recorded according to the schedule provided in Table 1. 
The vital signs will be recorded prior to blood draw, administration of study drug, and, if 
possible, administration of usual asthma controller medication. 
Pulse rate and BP should be measured after the patient has been resting for at least 5 minutes. 
The measurement will be taken in sitting position. Pulse rate will be obtained before BP.
Body temperature will be measured in Celsius before administration of study drug and in 
accordance with local standards.
5.2.7
Glucocorticoid toxicity index
Glucocorticoid toxicity index will be assessed as described by Miloslavsky et al 2017 (see 
Appendix H for details).  The composite GTI captures common GC toxicities that are 
sensitive to differing cumulative GC doses over the period of a typical clinical trial (6 months 
to 3 years).  The individual items within the GTI are weighted relative to each other for 
severity, and the instrument has the capability of measuring not only worsening of GC toxicity 
from baseline, but also improvement.
The composite GTI measures change in GC toxicity rather than absolute GC toxicity in order 
to account for the effects of prior GC therapy.  Scoring should be performed as per the 
schedule of assessments, using entry assessment as the baseline.  The GTI items were ranked 
in order of severity within each domain.  The relative weights for each toxicity item were 
derived using multicriteria decision analysis.  Multicriteria decision analysis has been used for 

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the creation of multiple classification criteria sets in a variety of inflammatory diseases, 
including rheumatoid arthritis (Neogi et al 2010), systemic sclerosis (Johnson et al 2014), and 
systemic lupus erythematosus (Tedeschi et al 2018).
The composite GTI will be assessed at the time points given in Table 1.  Only a subset of 
items from the composite GTI will be assessed in PONENTE: body mass index, glucose 
tolerance (glycosylated hemoglobin), BP, low-density lipoprotein, steroid myopathy, skin 
toxicity, neuropsychiatric toxicity, and infection (items from the Specific List will not be 
assessed).
5.3
Other assessments
5.3.1
Weight and height
Weight and height will be measured according to the schedule provided in Table 1. Height 
will be taken at screening Visit 1 only. The patient’s weight will be recorded in kilograms, and 
height in centimeters. Weight and height measurements will be performed in light clothing 
and with shoes off.
5.3.2
Prednisone/Prednisolone levels
For patients who switch to prednisone/prednisolone only, a prednisone/prednisolone test will 
be done with V1 laboratory work. For these patients, the site should delay the laboratory test 
(for all parameters, not just prednisone/prednisolone levels) by 3 to 7 days after the patient has 
switched their OCS.  Importantly, prednisone/prednisolone levels should be measured 1 to 
2 hours after prednisone/prednisolone intake on that day to ensure levels are detectable. This 
test is not required for patients entering the study on prednisone/prednisolone.
5.3.3
Total IgE and Phadiatop
The tests will be performed at screening according to Table 1 and will be used to characterize 
patients at baseline.  Analysis will be performed by the central laboratory.  Instructions for 
sample collection, processing, storage, and shipment can be found in the separate laboratory 
manual provided to the centers.
5.3.4
Clinical outcome assessments
5.3.4.1
Patient-reported outcomes
Patient-reported outcomes data will be captured electronically using a handheld device 
(ePRO).  Site personnel will be trained on using the ePRO.  Detailed procedures for using the 
ePRO and training the patients will be described in a separate instruction manual.  Patients 
will be trained on at-home use of the ePRO at Visit 2.  Training will include explanation of 
device functionality and its proper use.  Patients will also be asked to verify completion of 
training on the ePRO.  Patients will be asked to bring the device back at each study visit.  
On-site PRO questionnaires should be completed prior to any other assessments.  Data for all 
PROs will be collected in accordance with Table 1.  Patients should be informed that the 
recording made electronically cannot be retrospectively or prospectively entered and must be 
completed within a defined time window.  Patients will also be provided with information 
about when and where to request help if problems occur.  The Investigator/authorized delegate 

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will check the patient’s adherence to completing the ePRO as described in Table 1. There will 
be triggers in the PROs to alert investigators to signs of worsening of asthma and advising 
them to contact the patient for evaluation.  These alerts will be described in a separate guide.  
Asthma Control Questionnaire 6
The ACQ-6 is a shortened version of the ACQ that assesses asthma symptoms (nighttime 
waking, symptoms on waking, activity limitation, shortness of breath, wheezing, and use of 
short-acting β2 agonists), omitting the forced expiratory volume in 1 second measurement 
from the original ACQ score.
Patients will be asked to recall how their asthma has been during the previous week by 
responding to 1 bronchodilator use question and 5 symptom questions.
Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely 
uncontrolled).  The mean ACQ-6 score is the mean of the responses.  Mean scores of ≤0.75 
indicate well-controlled asthma, scores between 0.75 and ≤1.5 indicate partly controlled 
asthma, and scores >1.5 indicate not well-controlled asthma (Juniper et al 2006).  Individual 
changes of ≥0.5 are considered to be clinically meaningful.
From Visit 2 onwards, the patient will complete the ACQ-6 at home every 1 week (± 2 days) 
until the EOT visit.  The ePRO device will be set up with functionality to collect unscheduled 
ACQ-6 assessments on site if required by investigators at a visit.
At each clinic/phone call visit, in addition to the information provided by the patient on 
his/her asthma disease, investigators will have access to the patient’s ACQ-6 scores 
(completed by means of an ePRO) to evaluate whether the patient’s condition has not 
significantly deteriorated (ie, increase in score of ≥0.5 from baseline [baseline defined as 
value at Visit 2 before benralizumab administration]) and take the final decision to further 
reduce the OCS dose until the patient reaches an OCS dose of 0 mg/day (or lowest OCS dose 
possible in case no further OCS down-titration is allowed because of the presence of AI as 
measured by cortisol levels or in case of inadequate asthma control) while not losing asthma 
control.
St. George’s Respiratory Questionnaire
The SGRQ is a 50-item PRO instrument developed to measure the health status of subjects 
with airway obstruction diseases (Jones et al 1991).  The questionnaire is divided into 2 parts: 
Part 1 consists of 8 items that pertain to the severity of respiratory symptoms in the preceding 
4 weeks, and Part 2 consists of 42 items related to the daily activity and psychosocial impacts 
of the individual’s respiratory condition.  The SGRQ yields a total score and 3 domain scores 
(symptoms, activity, and impacts).  The total score indicates the impact of disease on overall 
health status.  This total score is expressed as a percentage of overall impairment, in which 
100 represents the worst possible health status and 0 indicates the best possible health status.  
Likewise, the domain scores range from 0 to 100, with higher scores indicative of greater 
impairment.  Specific details on the scoring algorithms are provided by the developer in a user 
manual (Jones et al 2009).  A decrease of 4 units in the SGRQ total score has been established 

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as the criterion for minimal meaningful improvement (Jones 2005).  SGRQ responders will be 
those with ≥4-unit decreases in SGRQ total score. 
The SGRQ will be completed on site at the beginning of Visit 2 and EOT/IPD Visit using the 
ePRO. 
Maintenance medication adherence assessment
Adherence with maintenance medication over the past week will be captured using a single 
question that asks the respondent to report the number of days they took their maintenance 
medication per their physician’s instructions.  Patients will respond to the maintenance 
medication query on a weekly (± 2 days) basis using the ePRO beginning at Visit 2 and 
ending at EOT/IPD Visit.
Patient Global Impression of Change assessment
The PGIC instrument is used for an overall evaluation of response to treatment.  The patient 
will be asked to rate the degree of change in the overall asthma status compared to the first 
dosing using the following 7-point scale: Much Better (+3), Moderately Better (+2), A Little 
Better (+1), About the Same (0), A Little Worse (-1), Moderately Worse (-2), and Much 
Worse (-3).  
The PGIC will be captured at Visit 2 as well as weekly (± 2 days) until the end of the 
Induction phase (day prior to Visit 3) by using the ePRO.
5.4
Pharmacokinetics
Pharmacokinetic samples will not be taken during the study.
5.5
Pharmacodynamics
Samples for the analysis of peripheral blood eosinophils will be analyzed in a central 
laboratory as part of the routine hematology assessment (complete blood count).  Refer to 
Section 5.2.4.
5.6
Genomics
Approximately 10 mL blood samples for DNA isolation will be collected from patients who 
have consented to participate in the genetic analysis component of the study.  Participation is 
optional.  Patients who do not wish to participate in the genetic research may still participate 
in the main study.
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the patient.  
The genomic sample will be used to explore how genomic variation may be associated with 
study outcomes.  In addition, the genomic sample may be used for further genetic research to 
explore how genetic variations may affect clinical parameters, risk and prognosis of diseases, 
and response to medications.  Genetic research may lead to better understanding of diseases, 

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better diagnosis of diseases, or other improvements in health care and to the discovery of new 
diagnostics, treatments, or medications.
Additional information regarding the genetics research component of the study is provided in 
Appendix C.
5.7
Biomarker collections and analysis
The patient’s consent to the use of donated biological samples is mandatory.
Biological samples will be collected for exploratory analyses to investigate the effect of 
benralizumab on biomarkers of inflammation, asthma disease, pharmacology of benralizumab, 
and potential predictors of response.
Instructions for sample collection, processing, storage, and shipment can be found in the 
separate laboratory manual provided to the sites.
The results of the exploratory biomarker analyses will be reported separately from the Clinical 
Study Report (CSR) in a scientific report or publication.
5.7.1
Serum for biomarkers
Whole blood for the preparation of serum for analysis of proteins and inflammatory markers 
will be collected at the screening visit (Visit 1) and at the visit to assess morning cortisol 
levels, according to Table 1.  
5.7.2
Plasma for eosinophil-derived neurotoxin 
Plasma samples will be collected according to the schedule in Table 1 to evaluate EDN, a 
biomarker of eosinophil level and activation. 
5.7.3
Sputum collection and biomarkers
Not applicable due to protocol amendment. 
5.7.4
Storage, reuse, and destruction of biomarker samples
AstraZeneca or a designee will retain biomarker samples for investigation of asthma, the 
pharmacology of benralizumab, and potential predictors of response for a maximum of 
15 years following the last patient’s last visit, after which they will be destroyed.
The results of this biomarker research may be pooled with biomarker data from other studies 
with the study treatment to generate hypotheses to be tested in future research.  Any residual 
samples may be used for future biomarker research.  If a patient does not allow samples to be 
used for future biomarker research, they may continue with their samples being used for the 
main study.
The results of any investigation will not be reported in the CSR but separately in a scientific 
report or publication.

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5.7.5
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.
Any samples identified as Infectious Category A materials are not shipped, and no further 
samples will be taken from the patient unless agreed upon with AstraZeneca, and appropriate 
labelling, shipment, and containment provisions are approved.
5.7.6
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their life cycle.
The Principal Investigator at each site keeps full traceability of collected biological samples 
from the patients while the samples are in storage at the center until shipment or disposal 
(where appropriate) and keeps documentation of receipt of arrival (if applicable).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites, and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca biobank system during the 
entire life cycle.
5.7.7
Withdrawal of informed consent for donated biological samples
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analyzed, 
AstraZeneca is not obliged to destroy the results of this research.
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 AE is the development of any untoward medical occurrence in a patient or clinical study 
patient administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.   An AE can therefore be any unfavorable and unintended 
sign (eg, an abnormal laboratory finding), symptom (for example, nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
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The term AE is used to include both serious and nonserious AEs and can include a 
deterioration of a preexisting medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
6.2
Definitions of serious adverse events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires inpatient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above
For further guidance on the definition of an SAE, see Appendix A to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse events and SAEs will be collected from time of signature of informed consent
throughout the treatment period and including the follow-up period (12 weeks after the last
dose of study drug). 
Please refer to Appendix K for details regarding safety reporting in the PONENTE Long Term 
Follow Up substudy.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last AE in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF.  
AstraZeneca retains the right to request additional information for any patient with ongoing
AEs/SAEs at the end of the study, if judged necessary. 
6.3.3
Variables 
All AEs will be recorded in the eCRF.  The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

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
Maximum intensity of the AE

Whether the AE is serious or not

Investigator causality rating against the study drug (yes or no)

Action taken with regard to study drug

AE caused patient’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication

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 an SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4
Causality collection
The Investigator will assess the causal relationship between the study drug 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 study drug?’
For SAEs, the 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 Clinical 
Study Protocol.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient, reported in response to the open question from 
the study site staff, ‘Have you had any health problems since the previous visit/you were last 
asked?’, or revealed by observation will be collected and recorded in the eCRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
6.3.6
Adverse events based on examinations and tests
The results from the Clinical Study Protocol–mandated laboratory tests and vital signs will be 
summarized in the CSR.  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 study drug.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible, the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in nonmandated 
parameters should be reported as AEs.
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
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.
The signs and symptoms of AI will not be considered as AEs except under certain 
circumstances (eg, adrenal crisis Appendix J). 
6.3.7
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation, 
and occurrences of AST or ALT levels ≥3 × ULN together with total bilirubin (TBL) levels 
≥2 × ULN may need to be reported as SAEs.  
Any potential Hy’s Law case should be handled as a serious unexpected adverse event 
associated with the use of the drug and reported promptly (i.e., even before all other possible 
causes of liver injury have been excluded). It should be promptly reported to the appropriate 
regulatory/ethics authority before fully working up the patient to rule out other etiologies. 
Reporting should include all available information, especially that needed for evaluating the 
severity and likelihood that the drug caused the reaction, and should initiate a close follow-up 

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until complete resolution of the problem and completion of all attempts to obtain 
supplementary data.
Please refer to Appendix D for further instruction regarding cases of increases in liver 
biochemistry and evaluation of Hy’s Law (HL).
6.3.8
Disease under study
When collecting AEs, the recording of diagnoses is preferred, when possible, to recording a 
list of signs and symptoms.  Asthma symptoms or signs, such as wheeze, cough, chest 
tightness, dyspnea, breathlessness, and phlegm, will be recorded as AEs only when:

The sign or symptom is serious according to definitions; see Section 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 
preexisting asthma history (defined as within 1 year prior to Visit 1) as judged by 
the Investigator
Asthma exacerbations occurring during the treatment period should be recorded in the eCRF.  
An asthma exacerbation should be recorded as an AE or SAE only if it fulfills any of the 
above criteria.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the study drug, or 
to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.

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If the WBDC system is not available, then the Investigator or other study site staff reports a 
SAE to the appropriate AstraZeneca representative by telephone.  The AstraZeneca 
representative will advise the Investigator/study site staff how to proceed.
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure for the AstraZeneca drug.
4.3.1
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators.
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.An 
investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the Investigator’s Brochure or and will notify the IRB/IEC, if appropriate 
according to local requirements.
6.5
Overdose

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and in the overdose eCRF module

An overdose without associated symptoms is only reported on the overdose eCRF 
module
If an overdose on an AstraZeneca study drug occurs during the study, then the Investigator or 
other site personnel will inform appropriate AstraZeneca representatives immediately, or no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 6.4.  
For other overdoses, reporting must occur within 30 days.

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6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
If a patient becomes pregnant during the study, study drug should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug under 
study may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.
If any pregnancy occurs during the study, then the Investigator or other site personnel will 
inform the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF will be used to report the pregnancy, and the pregnancy 
outcome (PREGOUT) form will be used to report the outcome of the pregnancy.
6.6.2
Paternal exposure
Pregnancy of the patients’ partners will not be considered an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality) should be followed up and documented for conceptions occurring 
from the date of the first administration of study drug until 16 weeks (approximately 5 half-
lives) after the last administration of study drug. 
6.7
Medication error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an AstraZeneca study drug that either causes harm to the patient 
or has the potential to cause harm to the patient. 
A medication error is not lack of efficacy of the drug, but rather a human or process-related 
failure while the drug is in control of the study site staff or patient.
Medication error includes situations where an error: 

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
Occurred

Was identified and intercepted before the patient received the drug

Did not occur, but circumstances are recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error, eg, medication prepared incorrectly, even if it was not actually 
given to the patient

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as 
a solid tablet 

Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature 

Wrong patient received the medication (excluding IWRS/IVRS errors)

Wrong drug administered to patient (excluding IWRS/IVRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IWRS/IVRS, including those which lead to one 
of the above listed events that would otherwise have been a medication error 

Patient accidentally missed drug dose(s), eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Patient failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication 
in open-label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.  
If a medication error occurs during the study, then the Investigator or other site personnel will 
inform the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors.

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7.
STUDY DRUG AND OTHER TREATMENTS
7.1
Identity of study drug(s)
Study drug will be manufactured in accordance with Good Manufacturing Practice (GMP).
Benralizumab administered in the study will be a clear to opalescent, colorless to yellow 
solution.
Study drug
Dosage form and strength
Manufacturer
Benralizumab
30 mg/mL solution for injection in prefilled syringe, 
1 mL fill volume
MedImmune
7.2
Dose and treatment regimens
Benralizumab 30 mg/mL solution for injection in an APFS will be administered SC at the 
study site Q4W for the first 3 doses and then Q8W thereafter (8 weeks between the 3rd and 4th
benralizumab doses).  See Table 1 for more details.
Before study drug administration
The Investigator or authorized delegate will assess the injection site as per standards of 
medical care.  For WOCBP, a urine pregnancy test will be performed, and study drug will be 
administered when the result of the test is negative (Section 5.2.4.1).
Study drug administration
The study drug will be administered by the Investigator and/or authorized delegate.  It is 
advised that the site of injection of the study drug be rotated such that the patient receives 
study drug at a different anatomical site at each treatment visit.  A suggested injection site 
rotation sequence is presented below (see Figure 3).

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Figure 3
Injection sites and rotation scheme
In cases where rotation of the injection site is not favorable for the patient and/or the 
Investigator, the reason should be recorded in the source documents.  Further details on study 
drug administration can be found in applicable guidance outside of this Clinical Study 
Protocol.  Study drug administration must be carried out in line with this guidance.
After study drug administration
After study drug administration, the patient should be observed for a minimum of 2 hours in 
case of any acute drug reactions for the first 3 doses of study drug.  For the fourth dose and 
onwards, the patient should be observed for 1 hour.
Conditions that will require rescheduling of study drug administration 
The Investigator should reschedule the visit and the study drug should not be administered 
until the rescheduled visit if either of the following occur:

The patient has an intercurrent illness that, in the opinion of the Investigator, may 
compromise the safety of the patient in the study (eg, viral illnesses)

The patient is febrile (≥38°C; ≥100.4°F) within 72 hours prior to administration of 
the study drug
Every possible effort should be made to bring the patient in within the allowed visit window 
and study drug should be administered at that visit. If this is not possible, the AZ study 
physician should be contacted to discuss further. 

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7.3
Management of study drug–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.  Details on anaphylaxis 
management are provided in Appendix I. 
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: 

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 BP or symptoms of end-organ dysfunction 

Two or more of the following that occur rapidly after exposure: involvement of 
the skin/mucosal tissue, respiratory compromise, reduced BP or associated 
symptoms, and/or persistent gastrointestinal symptoms

Reduced BP after exposure
Patients will have had a pre-assessment (ie, vital signs) prior to study drug administration and 
should be observed after study drug administration for a minimum of 2 hours for the 
appearance of any acute drug reactions for the first 3 doses of study drug.  For the fourth dose 
onwards, patients should be observed for 1 hour after study drug administration.
7.4
Labelling
Labels will be prepared in accordance with GMP and local regulatory guidelines.  The labels 
will fulfil GMP Annex 13 requirements for labelling.  Label text will be translated into local 
language where applicable. The label will include the following information:

Study code

Study drug dosage form, route of administration, and quantity of dosage units

Kit identification

P lot identification 

Expiry date

Investigator name (if applicable locally; to be written on label)

E-code (to be written on label)

Sponsor name and contact details

Directions for use

Storage condition

Standard statements required by regulatory authorities

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
Storage
7.5
Storage
All study drugs should be kept in a secure place with limited access and under appropriate 
temperature-controlled storage conditions.  The temperature should be monitored daily, and 
monitoring should be documented in a temperature monitoring log.  The study drug must be 
kept in the original outer container and under conditions specified on the label (between 2°C 
and 8°C [36°F and 46°F] and protected from light).
The site should not use affected study drug and should immediately contact an AstraZeneca 
representative for further guidance in the following cases:

Temperature excursion upon receipt or during storage at the study

Damaged kit upon receipt

Damaged syringe/cartridge
The center staff should not use affected study drug and should immediately contact an 
AstraZeneca representative for further guidance.  Damaged study drug should be documented 
via IWRS/IVRS (please refer to the IWRS/IVRS manual for further details).
7.6
Compliance
The administration of all study drugs (including study drugs) should be recorded in the 
appropriate sections of the eCRF.  Study drug will be administered at the study site during 
treatment visits as outlined in Table 1.
7.7
Accountability
The study drug provided for this study will be used only as directed in the Clinical Study 
Protocol.  The study site staff will account for all study drugs dispensed to the patient.  The 
monitor will account for all study drugs received at the site, for unused study drugs, and for 
appropriate destruction according to local procedures.  Certificates of delivery, destruction, 
and/or return should be signed. 
In case of malfunctioning APFS, the site should contact the study monitor to initiate return of 
the APFS according to the procedures described in the separate pharmacy manual.
7.8
Concomitant and other treatments
Information about any treatments received in the 3 months prior to the date of informed 
consent and all the concomitant treatments given during the study (through follow-up period) 
with reason for the treatment will be collected by the Investigator/authorized delegate at each 
visit (as shown in Table 1) and recorded in the eCRF.
Use of ICS/LABA as a reliever (eg, Symbicort Maintenance and Reliever Treatment) that was 
part of the patient’s usual asthma controller regimen at baseline is allowed.  Any maintenance 

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therapy (in addition to ICS/LABA) such as long-acting muscarinic antagonists used prior to 
study entry should not be changed during the study. The ‘as-needed’ use of short-acting 
bronchodilators for relief of acute asthma symptoms is permitted throughout the study.
Please refer to Appendix K for details on concomitant medications and other treatments in the 
PONENTE Long Term Follow Up substudy.
Table 5
Medication Restrictions 
Allowed medication/Class of drug
Usage
Inactive/killed vaccinations
Allowed provided they are not administered within 5 days 
before or after dosing with benralizumab
Allergen immunotherapy
Allowed if patient has been receiving stable therapy for at 
least 30 days prior to Visit 1 and there is no anticipated 
change during the treatment period.  Allergen 
immunotherapy should not be administered on the same 
day as study drug
Prednisone/prednisolone
Allowed provided it is not administered 24 hours prior to 
morning cortisol level/ACTH stimulation test
High-dose ICS
Allowed; however, ICS (or ICS/LABA if in single 
inhaler) treatment should not be administered on the same 
day as morning cortisol/ACTH stimulation test (for 
patients taking a once-daily ICS/LABA formulation, e.g. 
fluticasone furoate/vilanterol; patients must not take the 
treatment the night prior or the morning of the cortisol 
testing).
Immunosuppressive medication  
Topical or nasal administration may be allowed at the 
discretion of the Investigator  
Table 6
Prohibited Medications 
Prohibited medication/Class of drug
Usage
Macrolides, antivirals, and azole 
therapies
Chronic treatment with macrolides, antivirals, or azole 
therapies are not allowed during the study.  If a patient 
has been receiving long-term treatment of these therapies, 
all such medications need to be stopped 30 days or 5 half-
lives, whichever is the longer, prior to the date informed 
consent is obtained.  If a patient requires short courses of 
these medications (short course defined as ≤ 2 weeks), 
they should be stopped at least 1 week prior to testing of 
cortisol levels 

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Prohibited medication/Class of drug
Usage
Benralizumab and other marketed 
respiratory biologics.
Any marketed respiratory biologic treatment (eg, 
omalizumab, mepolizumab, reslizumab, benralizumab) is 
not allowed 4 months or 5 half-lives (whichever is longer) 
prior to the date informed consent is obtained and 
throughout the entire treatment period.
-
For patients who have previously not tolerated 
or have not responded to marketed 
mepolizumab, omalizumab or reslizumab (as
assessed by the treating physician), a shorter 
washout period of ≥ 30 days between the last dose 
of mepolizumab, omalizumab or reslizumab and the 
first dose of open label benralizumab (Visit 2), is 
allowed. 
-
Patients who have previously received benralizumab 
still require a complete washout prior to date of 
informed consent; those who have not tolerated or 
have not responded to benralizumab would not be a 
candidate for this study.
Non-respiratory marketed biologics or 
any investigational biologics
Any marketed (non-respiratory) or investigational 
biologic treatment is not allowed 4 months or 5 half-lives 
(whichever is longer) prior to the date informed consent is 
obtained and throughout the entire treatment period
Immunosuppressive medications
Use of immunosuppressive medications (including, but 
not limited to, methotrexate, troleandomycin, 
cyclosporine, azathioprine, intramuscular long-acting 
depot corticosteroid, any experimental anti-inflammatory 
therapy, or oral/parenteral/intra-articular corticosteroids 
for reasons other than asthma) is not allowed except 
maintenance use of OCS for asthma if present at baseline 
and rescue use of systemic corticosteroids (oral, 
intravenous, or intramuscular) to treat an asthma 
exacerbation.  Immunosuppressive medications must be 
discontinued 3 months or 5 half-lives (whichever is 
longer) prior to Visit 1; during the treatment period; and 
3 months or 5 half-lives (whichever is longer) after the 
last dose. For flare-ups of non-asthma related indications 
(e.g. arthritis, crohn’s disease, atopic dermatitis) or 
AE/SAE requiring temporary OCS use (or temporary 
increase in maintenance OCS), a short course of OCS (≤ 
2 weeks) use is allowed anytime during the study. Use of 
OCS for nasal polyposis, allergic rhinitis, or related 
eosinophilic conditions is not allowed.
Blood products or immunoglobulin 
therapy
Receipt of immunoglobulin or blood products is not 
allowed within 30 days prior to the date informed consent 
is obtained and throughout the entire treatment period

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Prohibited medication/Class of drug
Usage
Live attenuated vaccines
Not allowed within 30 days of Visit 1 or during treatment 
period
Lipoxygenase inhibitors
Five-lipoxygenase inhibitors (eg, zileuton) are prohibited 
and are not allowed within 30 days of Visit 1 or during 
the treatment period
7.8.1
Other concomitant treatment
Medications other than those described in Section 3.5, which are considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF.
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
The statistical analyses will be fully described in a Statistical Analysis Plan (SAP), as 
appropriate.  Data from the main PONENTE study will be summarized for the population 
overall and by prespecified subgroups: baseline OCS dose, baseline blood eosinophil count, 
and duration of chronic OCS.  Additional subgroups of interest will be further defined in more 
detail in the SAP.
Due to the single-arm study design, external data sources may be used to contextualize any 
change seen in asthma control, asthma exacerbation rate, or other safety endpoints in patients 
treated with benralizumab following reduction of OCS.  Any data sources identified, together 
with planned analyses, will be described in a separate analysis plan. 
Statistical analyses for this study will be conducted using SAS (Cary, NC) version 9.3 or 
higher and will be performed by AstraZeneca or a designated representative. The data cutoff 
for the primary analysis will occur when the last patient completes the follow up visit of the 
PONENTE main study. A separate document (SAP) to address detailed statistical analysis 
issues for the PONENTE main study will be developed and approved by the time the first 
patient is enrolled to the study. A second and separate SAP detailing the analyses for the 
PONENTE Long Term Follow Up substudy will be developed and approved prior to the final 
database lock (DBL) of the main study.
8.2
Sample size estimate
There is no predefined study hypothesis to test in this study.  The sample size for this study is 
based on the ability to provide sufficient precision in point estimates, both in the FAS and in 
subgroups for statistical analysis.
The primary outcome, the observed proportion of patients down-titrated and maintained for at 
least 4 weeks, is expected to be equal to or greater than 50%.  For the sample size estimation, 

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a success rate of 50% is assumed.  Estimate precision is expressed in a two-sided 95% 
confidence interval (CI) distance from the point estimate of a 50% success rate for a total of 
approximately 600 patients. CI calculations were conducted using the exact Clopper-Pearson 
CI formula for a single proportion in SAS version 9.4M5.
A total sample size of approximately 600 patients is expected to provide a 95% CI extending 
approximately 4.1% from the point estimate of a 50% success rate.  Estimates of the 95% CI 
for a >50% success rate are incrementally smaller, as is shown in the following table:
Table 7
Expected distance between observed proportion and confidence limit 
(Clopper-Pearson 95% CI width)
Proportion of Patients with Total 
OCS Reduction
Sample Size
100
150
300
600
50
±10.2
±8.3
±5.8
±4.1
60
-10.3, +9.7  
-8.3, +7.9
-5.8, +5.6  
-4.0, +4.0
70
-10.0, +8.8 
-8.0, +7.2 
-5.5, +5.1  
-3.8, +3.6
80
  -9.2, +7.3 
-7.3, +6.1  
-5.0, +4.4 
-3.4, +3.1
The table also shows that the 95% Cis for subpopulation analyses as small as 100 are ≤10% 
from the point estimate for proportions between 70% and 80% and 10.2% for a proportion of 
50%.
A sample size of 300 patients is expected to provide 95% Cis for a single proportion 
extending approximately 5.8% from the point estimate of a 50% success rate.
8.3
Definitions of analysis sets
The following statistical analysis sets will be defined to support data analyses of the study.
8.3.1
All patients analysis set
This analysis set comprises all patients screened for the study and will be used for reporting of 
disposition and screening failures.
8.3.2
Full analysis set
All enrolled patients who received at least one dose of benralizumab will be included in the 
FAS, irrespective of their protocol adherence and continued participation in the study.  
Patients will be analyzed irrespective of whether they prematurely discontinue, according to 
the intent-to-treat principle.  Patients who withdraw from the study will be included up to the 
date of their study termination.  
All efficacy analyses will be performed using the FAS.  For consistency, demographic and 
baseline characteristics will be presented using the FAS.

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8.3.3
Safety analysis set
The FAS will be used for all safety analyses.
Analysis sets for the PONENTE Long Term Follow Up substudy will be detailed in Appendix 
K.
8.4
Outcome measures for analyses
The following study outcome measures are designed to support primary, secondary, and 
exploratory objectives of the study.  
For a response outcome, if a patient withdraws from the study before reaching the defined 
endpoint, the patient will be considered as non-successful.
For a time-to-event outcome, if a patient withdraws from the study before reaching the defined 
endpoint or does not reach the endpoint by the end of the predefined study phase, the patient 
will be censored at the withdrawal date or at the end date of the corresponding study phase, 
whichever is earlier. 
For outcomes measured in continuous data such as cumulative dose, ACQ-6 score, and SGRQ 
score, no imputation will be performed for missing outcomes.
Primary efficacy outcome variables

Patients who achieve 100% reduction in daily OCS dose that is sustained over at 
least 4 weeks without worsening of asthma (as defined in Section 5.1.2.1 of the 
protocol)

Patients who achieve 100% reduction or daily OCS doses of ≤5 mg, if reason for no 
further OCS reduction is AI, that are sustained over at least 4 weeks without 
worsening of asthma
Key supportive outcome variables

Patients who achieve a daily OCS dose of ≤5 mg that is sustained over at least 
4 weeks without worsening of asthma

Patients who achieve a ≥90%, ≥75%, and ≥50% reduction in daily OCS dose, 
sustained over at least 4 weeks without worsening of asthma

Change from baseline in daily OCS dose (mg) from start of OCS reduction to end 
of the OCS reduction phase
Secondary efficacy outcome variables

Change in daily OCS dose from the end of OCS reduction phase to the end of the 
maintenance phase (at EOT visit)

Time to first increase in OCS dose during the maintenance phase, after achieving 
the minimum OCS dose during the OCS reduction phase 

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
ACQ-6 scores at baseline (Visit 2), Visit 3, initial morning cortisol test, end of OCS 
reduction phase, and monthly from end of OCS reduction phase to end of 
maintenance phase (EOT visit)

Change from baseline in ACQ-6 score to Visit 3, end of OCS reduction phase, and 
end of maintenance phase (EOT visit)

Responder analysis of ACQ-6 scores from Visit 2 through end of maintenance 
phase

Change from baseline (Visit 2) in SGRQ total scores to the end of maintenance 
phase (EOT visit)

Responder analysis of SGRQ total scores at the end of maintenance phase 
Safety outcome variables

Patients with complete AI 

Annualized asthma exacerbation rate

Annualized asthma exacerbation rate leading to hospitalization or emergency room 
visit

AEs

SAEs

GTI
Exploratory outcome variables

Change from baseline (Visit 1) blood eosinophils

PGIC at Weeks 1, 2, 3, and 4
Outcome variables for the PONENTE Long Term Follow Up substudy will be detailed in 
Appendix K.  
8.5
Methods for statistical analyses
Statistical tabulation will be presented for overall patients and by baseline OCS dose level, 
category of baseline eosinophil count, and category of duration of chronic OCS use.  
Continuous variables will be summarized using the mean, two-sided 95% CI of the mean, the 
standard deviation, median, minimum value, and maximum value.  Categorical variables will 
be summarized using frequency counts and percentages, as well as a two-sided 95% CI for 
proportions computed using exact Clopper-Pearson method.  Time to event data will be 
summarized using median and 25th and 75th percentiles with 95% Cis.  Data will be listed in 
patient-level data listings. 

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No formal hypothesis will be tested in this study, and no multiplicity adjustment will be 
applied in the statistical analysis.  No imputation will be performed beyond the approach 
defined for outcome measures in Section 8.4.  Imputation for partial date will be detailed in 
the SAP document.
Analysis methods for the PONENTE Long Term Follow Up substudy will be detailed in 
Appendix K. 
8.5.1
Analysis of the primary variables
The count and proportion (with 95% CI) of patients who achieve 100% reduction in their OCS 
dose, sustained for at least 4 weeks without worsening of asthma or resumed OCS treatment, 
and the count and proportion of patients who achieve 100% reduction or a daily OCS dose of 
≤5 mg, if reason for no further OCS reduction is AI, sustained over at least 4 weeks without 
worsening of asthma, will be tabulated. 
The same analysis will be carried out for the supporting endpoints: patients who reduce to a 
daily OCS dose of ≤5 mg sustained over at least 4 weeks without worsening of asthma; and 
patients who achieve a ≥90%, ≥75% and ≥50% reduction in their daily OCS dose without 
worsening of asthma. 
All 95% Cis for proportions will be calculated using the Clopper-Pearson exact method. 
For patients who do not achieve 100% reduction in their daily OCS dose, the reason for no 
further reduction will be listed.
Change from baseline in OCS dose variables will be summarized using descriptive statistics in 
tables and graphs (supporting primary and secondary endpoints).
8.5.2
Analysis of the secondary variables
8.5.2.1
Time to 1st OCS increase
Time to first OCS increase in the maintenance phase will be summarized using median, 25th
and 75th percentiles (with 95% Cis) and Kaplan Meier plots.  The start time for the analysis 
will be the time, in the OCS reduction phase, at which the patient first reaches the minimum 
stable dose that is continued into the start of the maintenance phase.
Cox-regression model analysis will also be used to summarize and analyze time to first OCS 
increase; covariates will include at least baseline OCS daily dose and baseline eosinophil 
count (categorized).  If a patient withdraws from the study before reaching the defined 
endpoint or does not reach the endpoint by the end of the study, whichever is earlier, the 
patient will be censored at that time point.
8.5.2.2
ACQ-6
Change from baseline ACQ-6 score will be summarized by study visit using descriptive 
statistics and analyzed using a mixed model for repeated measures, with change from baseline 
in ACQ-6 score as the response variable, and baseline ACQ-6 score, baseline OCS dose, and 
baseline categories of serum eosinophil count as covariates.  Results of the mixed model 

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analyses will be presented in terms of least square mean with 95% CI of change from Visit 2 
in ACQ-6 score.
Asthma control responders will be evaluated as a supportive analysis outcome measure.  
Patients will be categorized according to the following limits (Juniper et al 2005), where 
observed study time points include, but are not limited to, Visit 3, initial morning cortisol test 
(time point at which OCS dose equals 5mg for 4 weeks), end of OCS reduction phase, and end 
of maintenance phase (EOT visit) from Visit 2:

Improvement: Change from baseline in ACQ-6 score of ≤ -0.5

No change: Change from baseline in ACQ-6 score of > -0.5 and < +0.5

Deterioration: Change from baseline in ACQ-6 score of ≥ +0.5
Asthma control responders will be defined as patients who had improvements based on 
changes from baseline in their ACQ-6 scores.  Patients with no change or deterioration 
according to ACQ-6 score evaluation will be defined as nonresponders.  Patients with missing 
or nonevaluable ACQ-6 scores at a postbaseline assessment time point will be considered 
nonresponders at the time point.  
Furthermore, patients will be categorized according to their ACQ-6 score–defined asthma 
control status at post Visit 2 assessments using the following score thresholds (Juniper et 
al 2006):

Well controlled: ACQ-6 score of ≤0.75

Partially controlled: ACQ-6 score of >0.75 and <1.5 

Not well controlled: ACQ-6 score of ≥1.5 
Asthma control responders will be summarized in count and proportion with 95% Cis 
estimated using the Clopper-Pearson method.  Patients with missing or nonevaluable ACQ-6 
scores will be considered nonresponders. 
In the event that there is a differential proportion of patients with missing ACQ-6 score results 
at postbaseline study visits, based on review of an ACQ-6 reporting compliance summary, a 
sensitivity analysis will be performed using a hybrid last-observation-carried-forward 
approach.  For this analysis, patients who complete the study visit and have missing ACQ-6 
scores at the visit will have their last non-missing score carried forward.  Patients who 
terminate early prior to the study visit will be treated as nonresponders. 
The number and percentage of patients who achieve improvements, no change, or 
deterioration, and the number and percentage of patients who achieve ACQ-6 scores of ≤0.75 
(well controlled), >0.75 to <1.5 (partially controlled), or ≥1.5 (not well controlled) will be 
summarized in a table. Clopper-Pearson 95% Cis will be presented, Patient with missing or 
nonevaluable ACQ-6 scores will be classified as “Not well controlled”.

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8.5.2.3
SGRQ
Potential changes in health status will be evaluated by assessing the change from baseline to 
EOT visit in SGRQ total scores.  
Summary statistics for SGRQ total score and domain scores (symptoms, activity, and impacts) 
at Visit 2 (baseline) and EOT visit along with change from baseline to EOT visit will be 
produced.  Change from baseline in SGRQ total score and the three domain scores will also be 
analyzed separately using an analysis of covariance (ANCOVA) with change from baseline in 
SGRQ score as response variable and baseline SGRQ score and baseline OCS dose and 
baseline categories of serum eosinophil count as covariates.  Results will be presented in terms 
of least square mean with 95% CI of change from baseline in SGRQ total score.
A 4-point threshold will be used to define the response.  If there is a ≥4-point decrease from 
baseline in SGRQ total score, it will be defined as ‘improvement’; if there is a ≥4-point 
increase at EOT from baseline, it will be defined as ‘worsening’; if the change is not more 
than 4 points at EOT, it will be defined as ‘no change’. 
Missing SGRQ total score change at end of the study or assessment time points will be 
considered as ‘not evaluable’. 
For the responder analysis of SGRQ, a responder will be defined as a patient who had 
‘improvement’ (ie, ≥4-point decrease in SGRQ total score). Patients who had SGRQ total 
score changes defined as ‘no change’ or ‘worsening’ will be considered nonresponders.  If 
SGRQ total score change is not evaluable due to missing data, then the patient will also be 
treated as a nonresponder.  
8.5.2.4
PGIC
PGIC will be presented descriptively by week during the induction phase.  Calculation of 
percentages will be based on the number of patients in the full analysis set with a completed 
assessment.  There will be no imputation for missing values.
Patients will also be categorized according to the following three responses starting at Visit 2 
and through the induction phase:

Much Better (+3), Moderately Better (+2), A Little Better (+1) → Improved

Much Better (+3), Moderately Better (+2) → Moderately improved

Much Better (+3) → Much improved.
These three categorized variables will be presented descriptively by week.
8.5.3
Analysis of safety outcomes
The number and percentage of patients diagnosed with AI will be tabulated as follows: 

Patients with complete AI 

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In addition, the number and percentage of patients diagnosed with AI will be tabulated 
according to the way of diagnosis.  The association between AI diagnosis and OCS 
down-titration will be explored.
Spaghetti plots may be produced for patients with Partial AI throughout the OCS reduction 
phase, showing cortisol levels over time.
The incidence of AEs and SAEs will be summarized overall and stratified by relationship to 
study intervention and severity grade. 
The annualized rate of asthma exacerbations will be summarized using mean, 95% CI, and 
dispersion based on the negative binomial distribution. 
Glucocorticoid toxicity index will be summarized over time.  Statistical correlation between 
GTI and daily OCS dose will be explored.
The number and percentage of patients diagnosed with AI will be tabulated overall and by 
baseline OCS dose according to the way of diagnosis: morning cortisol or ACTH stimulation 
test, morning cortisol test, intermediate morning cortisol and ACTH stimulation test, and 
intermediate morning cortisol and intermediate ACTH stimulation test.
In addition, the number and percentage of patients diagnosed with AI will be tabulated by 
subgroup according to duration of chronic OCS treatment.  
8.5.4
Subgroup analysis
Prespecified subpopulations will include the following:

Patients with baseline OCS dose >10 mg/day, >5 mg/day to ≤10 mg/day, and 5 
mg/day

Patients with baseline blood eosinophil count:
-
<150/µL and ≥150/µL; 
-
<300/µL and ≥300/µL; and 
-
<150, ≥150 to <300, and ≥300 cells/μL

Patients with duration of chronic OCS use <1 year and ≥1 year
Additional subgroups may be described in the SAP. 
8.5.5
Interim review and Analysis
One interim review may be performed after approximately 90-100 patients have completed (or 
have had the opportunity to complete) their OCS down-titration; further details will be 
described in a separate interim review plan. 

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An additional database lock and analysis of all relevant data collected through the end of the 
OCS reduction phase, may be performed after the final patient has had the opportunity to 
complete the OCS reduction phase. The purpose of this analysis is to generate a sub-set of the 
pre-planned analysis outputs of all relevant data for all patients up to the end of the OCS 
reduction phase. Further details will be provided in the SAP.
8.5.6
Sensitivity analysis
The primary efficacy outcome based on data as observed with exclusion of the early 
withdrawn patients will be analyzed using the same method used for the primary analysis of 
the FAS.
Further sensitivity analyses and missing data strategies will be specified in the SAP.
8.5.7
Exploratory analysis
Statistical analysis of the following exploratory outcomes will be detailed in the SAP for this 
study:

Change from baseline in blood eosinophils
-
Baseline blood eosinophil counts may be further investigated by summarizing 
vs. baseline OCS dose and/or by region/country.

Serum samples at baseline for protein biomarkers

Plasma for EDN

Association of common and rare genomic variants with patient responses
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site staff
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them on any study-specific procedures and the WBDC, 
IxRS, ePRO, and other systems to be utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).

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9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contact with the study site, 
including visits to:

Provide information and support to the investigators

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the Clinical Study Protocol, that 
data are being accurately and timely recorded in the eCRFs, that biological samples 
are handled in accordance with the laboratory manual, and that study drug 
accountability checks are being performed

Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study), including verification of informed consent of participating patients.  This 
will require direct access to all original records for each patient (eg, clinic charts)

Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported, that the biological samples are identified and disposed 
of/destroyed accordingly, and that the action is documented and reported to the 
patient
The AstraZeneca representative will be available between visits if the investigators or other 
staff at the center needs information and advice about the study conduct.
9.2.1
Source data
Please refer to the Clinical Study Agreement for the location of source data.
9.2.2
Study agreements
The Principal Investigator at each/the center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of the Clinical Study Protocol shall prevail with respect to the conduct of the study and 
the treatment of patients, and, in all other respects, not relating to study conduct or treatment 
of patients, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures take place or patients are enrolled.
9.2.3
Archiving of study documents
The Investigator will follow the principles outlined in the Clinical Study Agreement.
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.  A 
patient is considered to have completed the study when he/she has completed his/her last

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scheduled contact.
The study may be terminated at individual sites if the study procedures are not being 
performed according to Good Clinical Practice (GCP) or if recruitment is slow.  AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with benralizumab.
9.4
Data management by AstraZeneca
Data management will be performed by AstraZeneca Data Management Center staff, 
according to the Data Management Plan.
The data collected through third-party sources will be obtained and reconciled against study 
data.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of the Medical Dictionary for Regulatory Activities.  Medications will be 
classified according to the WHO Drug Dictionary.  All coding will be performed by the 
Medical Coding Team at the AstraZeneca Data Management Center.
The WBDC system will be used for data collection and query handling.  The Investigator will 
ensure that data are recorded on the eCRF as specified in the study protocol and in accordance 
with the instructions provided.
Data queries will be raised for inconsistent, impossible, or missing data.  All entries to the 
study database will be available in an audit trail.
The 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 eCRFs.  A copy of the completed eCRFs will be 
archived by the Investigator.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  
When all activities have been performed to ensure data are complete and accurate, a clean file 
will be declared.
Serious Adverse Event Reconciliation
The SAE reconciliation will be performed by comparing the safety database standard reports 
with relevant AE/SAE listings from the clinical study database. 

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10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH)/GCP, applicable regulatory requirements, and the AstraZeneca policy on Bioethics and 
Human Biological Samples.
10.2
Patient data protection
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation.
10.3
Ethics and regulatory review
An Ethics Committee (EC) should approve the final Clinical Study Protocol, including the 
final version of the ICF and any other written information and/or materials to be provided to 
the patients.  The Investigator will ensure the distribution of these documents to the applicable 
EC and to the study site staff.
The opinion of the EC should be given in writing. The Investigator should submit the written 
approval to AstraZeneca before enrollment of any patient into the study. 
The EC should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the Clinical Study Protocol should be reapproved by the EC 
annually.
Before enrollment of any patient into the study, the final Clinical Study Protocol, including 
the final version of the ICF, is approved by the national regulatory authority or a notification 
to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide regulatory authorities, Ecs, and Principal Investigators with safety 
updates/reports according to local requirements.
Each Principal Investigator is responsible for providing the EC with reports of any serious and 
unexpected adverse drug reactions from any other study conducted with the study drug.  
AstraZeneca will provide this information to the Principal Investigator so that he/she can meet 
these reporting requirements.

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10.4
Informed consent
The Principal Investigator(s) at each center will:

Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study (before any procedures 
are performed) as per local requirements. 

Ensure each patient is notified that they are free to discontinue from the study at any 
time

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided

Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study

Ensure the original, signed ICFs are stored in the Investigator’s Study File and kept 
for a period that is compliant with GCP/local regulatory requirements, whichever is 
longer

Ensure a copy of the signed ICF is given to the patient

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC

The genetic component of this study is optional, and the patient may participate in 
other components of the main study without participating in the genetic component.  
To participate in the genetic component of the study, the patient must provide their 
signed and dated consent for both the main study and the genetic component of the 
study.  A copy of the signed and dated consent form(s) must be given to the patient 
with the original filed at the study center.  The Principal Investigator is responsible 
for ensuring that consent is given freely and that the patient understands that they 
may freely withdrawal from the genetic aspect of the study at any time
10.5
Changes to the Clinical Study Protocol and informed 
consent form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a new version of the study protocol.
The new version of the Clinical Study Protocol is to be approved by the relevant EC and, if 
applicable, also the national regulatory authority, before implementation.  Local requirements 
are to be followed for new versions of clinical study protocols.

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AstraZeneca will distribute any new versions of the Clinical Study Protocol to each Principal 
Investigator for distribution to Ecs (see Section 10.3).
If a change to a Clinical Study Protocol requires a change to a site’s ICF, AstraZeneca and the 
site’s EC are to approve the revised ICF before the revised form is used. 
10.6
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an EC may perform 
audits or inspections at the center, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents and to determine whether these activities were conducted and data were recorded, 
analyzed, and accurately reported according to the Clinical Study Protocol, GCP, guidelines of 
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 site.
11.
LIST OF REFERENCES
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Bateman ED, Reddel HK, Eriksson G, Peterson S, Ostlund O, Sears MR et al. Overall asthma 
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Broersen LH, Pereira AM, Jørgensen JO, Dekkers OM. Adrenal insufficiency in 
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Blanchard C, Rothenberg ME. Biology of the eosinophil. Adv Immunol 2009;101:81-121. 
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GINA 2018
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma
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Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. 
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Jones 2005
Jones PW. St. George’s Respiratory Questionnaire: MCID. COPD 2005;2(1):75-9.
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Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first 
validation of the COPD Assessment Test. Eur Respir J 2009;34(3):648-54.
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Joseph RM, Hunter AL, Ray DW, Dixon WG. Systemic glucocorticoid therapy and adrenal 
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Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respir Med 2005;99(5):553-8.
Juniper et al 2006
Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee. Identifying 
‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. 
Respir Med 2006;100(4):616-21.
Kerstjens et al 2012
Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M et al. Tiotropium in 
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Kwong FK, Sue MA, Klaustermeyer WB. Corticosteroid complications in respiratory disease. 
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Masoli et al 2004
Masoli M, Holt S, Weatherall M, Beasley R. The dose-response relationship of inhaled 
corticosteroids in asthma. Curr Allergy Asthma Rep 2004;4(2):144-8.
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Miloslavsky EM, Naden RP, Bijlsma JW, Brogan PA, Brown ES, Brunetta P et al. 
Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. 
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Moore et al 2007
Moore WC, Bleecker ER, Curran-Everett D, Erzurum SC, Ameredes BT, Bacharier L et al. 
Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood 
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National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for 
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Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, ZONDA Trial Investigators 
et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. 
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Nicholas MN, Li SK, Dytoc M. An approach to 116inimizing risk of adrenal insufficiency 
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Shaw DE, Sousa AR, Fowler SJ, Fleming LJ, Roberts G, Corfield J et al. Clinical and 
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Tedeschi et al 2018
Tedeschi SK, Johnson SR, Boumpas D, Daikh D, Dörner T, Jayne D et al. Developing and 
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Takatsu K, Takaki S, Hitoshi Y. Interleukin-5 and its receptor system: implications in the 
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Toba K, Koike T, Shibata A, Hashimoto S, Takahashi M, Masuko M et al. Novel technique 
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Cytometry 1999;35(3):249-59.

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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 patient 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 
patient’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).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient 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, hospitalization, disability, or incapacity but may jeopardize the patient 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 intravenous 
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 anemia requiring blood transfusion) or 
convulsions that do not result in hospitalization

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.

Time course.  Exposure to suspect drug.  Has the patient actually received the 
suspect drug? Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?

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
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 etiology 
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

Clinical Study Protocol Appendix C
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Study Code D3250C00065
Version 4
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Appendix C:
Genetic Research 
Rationale and Objectives
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications.  Genetic research may lead to better understanding of diseases, better diagnosis 
of diseases, or other improvements in health care and to the discovery of new diagnostics, 
treatments, or medications. 
In addition, collection of DNA samples from populations with well-described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic Research Plan and Procedures
Selection of genetic research population
Study selection record
All patients will be asked to participate in this genetic research.  Participation is voluntary and, 
if a patient declines to participate, there will be no penalty or loss of benefit.  The patient will 
not be excluded from any aspect of the main study.
Inclusion criteria
For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described 
in the main body of the Clinical Study Protocol and:

Provide informed consent for the genetic sampling and analyses
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant

Non–leukocyte-depleted whole blood transfusion in 120 days of genetic sample 
collection
Discontinuation of patients from this genetic research
Specific reasons for discontinuing a patient from this genetic research are as follows:
Withdrawal of consent for genetic research:  Patients may withdraw from this genetic research 
at any time, independent of any decision concerning participation in other aspects of the main 
study.  Voluntary discontinuation will not prejudice further treatment.  Procedures for 
discontinuation are outlined in Section 3.6.1 of the main Clinical Study Protocol.

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Collection of samples for genetic research
The blood sample for genetic research will be obtained from the patients at Visit 1. Although 
DNA is stable, early sample collection is preferred to avoid introducing bias through 
excluding patients who may withdraw due to an adverse event (AE), such patients would be 
important to include in any genetic analysis.  If for any reason the sample is not drawn at Visit 
1 it may be taken at any visit until the last study visit.  Only one sample should be collected 
per patient for genetics during the study.  Samples will be collected, labelled, stored and 
shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 
15 years, from the date of last patient last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable by the second, unique number only.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organization. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organizations working with the DNA).
The link between the patient enrollment and the second number will be maintained and stored 
in a secure environment, with restricted access at AstraZeneca or designated organizations.  
The link will be used to identify the relevant DNA samples for analysis, to facilitate 
correlation of genotypic results with clinical data, to allow regulatory audit, and to trace 
samples for destruction in the case of withdrawal of consent.
Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 10 of the main Clinical Study Protocol.
Informed consent
The genetic component of this study is optional, and the patient may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study, the patient must provide their signed and dated consent 
for both the main study and the genetic component of the study.  A copy of the signed and 
dated consent form(s) must be given to the patient with the original filed at the study center.  
The Principal Investigators is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely discontinue from the genetic aspect of the study at 
any time.

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Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, or general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data.  Also, regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.
Data management
Any genotype data generated during this study will be stored at a secure system at 
AstraZeneca and/or designated organizations to analyze the samples.
The results from this genetic research may be reported in a separate report from the CSR or 
published in scientific journals.
AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organization, or health insurance companies.  This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease.  The researchers can 
only use this information for health-related research purposes.  Researchers may see summary 
results, but they will not be able to see individual patient data or any personal identifiers. 
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical Methods and Determination of Sample Size
The number of patients who will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A Statistical 
Analysis Plan will be prepared where appropriate.

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Study Code D3250C00065
Version 4
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Appendix D:
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
1. INTRODUCTION
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.  
Specific guidance on managing liver abnormalities can be found in Section 6.3.7 of the 
Clinical Study Protocol.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
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.
2. 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 drug 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.  

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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
3. IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the PHL 
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 without 
delay

Complete the appropriate unscheduled laboratory eCRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results, the 
Investigator will, without delay:

Determine whether the patient meets PHL criteria (see Section 2 within this 
appendix for definitions) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results)
4. FOLLOW-UP
4.1. Potential Hy’s Law criteria not met
If the patient does not meet PHL criteria, the Investigator will:

Inform the AstraZeneca representative that the patient has not met PHL criteria

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
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol
4.2. Potential Hy’s Law criteria met
If the patient does meet PHL criteria, the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team

Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting. This should be reported 
promptly to the appropriate regulatory/ethics authority (i.e., even before all other possible 
causes of liver injury have been excluded) before fully working up the patient to rule out 
other etiologies. Reporting should include all available information, especially that 
needed for evaluating the severity and likelihood that the drug caused the reaction, and 
should initiate a close follow-up until complete resolution of the problem and completion 
of all attempts to obtain supplementary data.

For subjects that met PHL criteria prior to starting IMP, the investigator is not required to 
submit a PHL SAE unless there is a significant change# in the subject’s condition

The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up (including any further laboratory testing) 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. Completes follow-up SAE Form as required.

Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. << For studies using a central laboratory add: 
This includes deciding which the tests available in the Hy’s law lab kit should be 
used>> 

Complete the three Liver CRF Modules as information becomes available 
# 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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5. REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible 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, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from date PHL criteria was met.  The AstraZeneca Global Clinical Lead or equivalent 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.
Where 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: update the previously submitted 
Potential Hy’s Law SAE and AE CRFs accordingly with the new information 
(reassessing event term; causality and seriousness criteria) following the AZ 
standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated 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 15 calendar days 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:

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
Provides any further update to the previously submitted SAE of Potential Hy’s 
Law, (report term now ‘Hy’s Law case’) ensuring causality assessment is related 
to IMP and seriousness criteria is medically important, according to CSP process 
for SAE reporting.

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 still met.  Update the previously submitted PHL 
SAE report following CSP process for SAE reporting, according to the outcome of 
the review and amending the reported term if an alternative explanation for the 
liver biochemistry elevations is determined.
No later than 3 weeks after the biochemistry abnormality is initially detected, the Study 
Physician will contact the Investigator to review available data and agree on whether there is 
an alternative explanation for meeting PHL criteria other than drug-induced liver injury 
caused by the investigational medicinal product.  The AstraZeneca Global Clinical Lead or 
equivalent and Global Safety Physician will also be involved in this review together with 
other patient 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 upon alternative explanation for the elevations in ALT or AST and TBL
levels, a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for an SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF

If the alternative explanation is an AE/SAE, record the AE/SAE in the eCRF 
accordingly and follow the AstraZeneca standard processes
If it is agreed that there is no explanation that would explain the elevations in ALT or AST 
and TBL levels other than the investigational medicinal product:

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

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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 amending the reported term if an alternative explanation for 
the liver biochemistry elevations is determined
6. Actions Required When Potential Hy’s Law Criteria Are Met Before and After 
Starting Study Treatment 
Not applicable in PONENTE 
7. ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:

Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study, eg, chronic or progressing malignant disease, 
severe infection or liver disease? 
If No: follow the process described in Appendix D, Section 4.2 for reporting PHL as an SAE
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 Appendix D, 
Section 4.2 for reporting PHL as an SAE

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# 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
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’

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Study Code D3250C00065
Version 4
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Appendix E:
Estimated Daily Doses for Inhaled Corticosteroids
Asthma therapy (adults and adolescents 12 years and older)
Total daily dose (µg/day)b
Inhaled corticosteroida
Medium
High
Beclomethasone dipropionate CFCc
> 500 -1000
>1000
Beclomethasone dipropionate HFA
>200 – 400
>400
Budesonide DPI
> 400 – 800
>800
Ciclesonide HFA
> 160 – 320
>320
Flunisolided
2000
>2000
Fluticasone furoate DPI (eg, Arnuity® Ellipta®)d
n.a.
200
Fluticasone propionate DPI
> 250 – 500
>500
Fluticasone propionate HFA
> 250-500
>500
Mometasone furoate
>220 – 440
>440
Triamcinolone acetonide
> 1000 – 2000
>2000
Inhaled corticosteroid in ICS/LABA combinationd
Medium
High
Beclomethasone dipropionate (eg, Fostair®)
400
>400
Fluticasone furoate (eg, Relvar® Ellipta®, Breo® Ellipta®)
n.a.
184,200
Fluticasone propionate HFA (eg, Seretide®, Advair®)
>320 – 460
>460
Fluticasone propionate DPI (eg, Seretide® Diskus®, Advair® 
Diskus®)
> 250 – 500
>500
Budesonide HFA (eg, Symbicort®)
320 to <640
640
Budesonide DPI (eg, Symbicort® Turbuhaler®)
400 to <800
800
Mometasone furoate HFA (eg, Dulera®)
400
800
Mometasone DPI (eg Asmanex® Twisthaler®)
330 – 440
>440
CFC = chlorofluorocarbon propellant; DPI = dry powder inhaler; HFA = hydrofluoroalkane propellant; ICS = inhaled corticosteroid; 
LABA = long-acting beta2 agonist; n.a. = not applicable
a 
Modified from the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2018. Available 
from: http://ginasthma.org/2018-gina-report-global-strategy-for-asthma-management-and-prevention. 
b.
This protocol also allows any product with clinically comparable doses, including newer products and authorized generics. High-
dose ICS via nebulized solution for inhalation is also allowed. For products not listed in this table, the highest approved maintenance 
ICS or ICS/LABA dose in the local country label will meet the protocol-defined criterion for “high-dose ICS.” See Section 3.1). 
Additionally, in countries where the high-dose ICS or ICS/LABA is not available (e.g. only the medium-dose ICS or ICS/LABA is 
available in that country), the highest approved maintenance dose in the local label will also meet this ICS criterion
c.
Beclomethasone dipropionate CFC is included for comparison with older literature
d.
See local label.
Note: Data provided from GINA 2018 is not a table of equivalence, but of estimated clinical comparability. Categories of “low,” 
“medium,” and “high” doses are based on published information and available studies (at the time of GINA 2018 publication), 
including direct comparisons where available. Doses may be country-specific depending on labelling requirements. Most of the 
clinical benefit from ICS is seen at low doses, and clear evidence of dose-response relationships is seldom available within the dose 
ranges evaluated for regulatory purposes. “High” doses are arbitrary, but for most ICS are those that, with prolonged use, are 
associated with increased risk of systemic side-effects. For new preparations, manufacturer’s information should be reviewed 
carefully; products containing the same molecule may not be clinical equivalent (GINA 2018).

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Appendix F:
Estimated OCS Dose Therapy Equivalence
Oral corticosteroid
Approximate equivalence dose
Prednisone
10 mg
Prednisolone
10 mg
Cortisone
50 mg
Hydrocortisone
40 mg
Methylprednisolone
8 mg
Triamcinolone
8 mg
Betamethasone
1.2 mg
Dexamethasone
1.5 mg
Deflazacort
12 mg
For conversions of other OCS doses or other OCS products, please see local label of OCS product or online conversion 
calculators (e.g. https://clincalc.com/corticosteroids/)

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Appendix G:
Prednisone/Prednisolone Doses <5 mg in Relation to 
Available Tablet Strengths
Desirable daily dose
Available tablet strength
Administered number of tablets and 
frequency
0.5 mg
1 mg
½ tablet each day, or 1 tablet every other 
day
1.5 mg
1 mg
If divisible – 1½ tablets each day
If non-divisible – Dose over 2 days as 
follows: 1 tablet on day 1 and 2 tablets 
on day 2.
2 mg
1 mg
2 tablets each day
2.5 mg
1 mg
If divisible – 2½ tablets each day 
If non-divisible – dose over 2 days as 
follows: 2 tablets on day 1 and 3 tablets 
on day 2.
2.5 mg
5 mg
½ tablet each day, or 1 tablet every other 
day
3 mg
1 mg
3 tablets each day
4 mg
1 mg
4 tablets each day

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Appendix H:
Glucocorticoid Toxicity Index

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Appendix H
(continued)

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Appendix H
(continued)

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Appendix H
(continued)

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Appendix H
(continued)

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Appendix H
(continued)

Clinical Study Protocol Appendix I
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Appendix I:
Anaphylaxis: Signs, Symptoms, and 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:

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 peak 
expiratory flow, hypoxemia)
(b)
Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence)

Two or more of the following 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 peak 
expiratory flow, hypoxemia)
(c)
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
(d)
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)

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 value

Clinical Study Protocol Appendix I
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
141(157)
3. Signs, Symptoms, and Management of Acute Anaphylaxis
Anaphylaxis is an acute and potentially lethal multisystem 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 the following:

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

Generalized warmth
4. Management of Acute Anaphylaxis
4.1 Immediate intervention

Assessment of airway, breathing, circulation, and adequacy of mentation

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 

Clinical Study Protocol Appendix I
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Study Code D3250C00065
Version 4
Date 17 October 2020
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severe symptoms such as respiratory distress, hypotension, shock, and 
unconsciousness
4.2 Possibly appropriate, subsequent measures depending on response to epinephrine
(e)
Place patient in recumbent position and elevate lower extremities
(f)
Establish and maintain airway
(g)
Administer oxygen
(h)
Establish venous access.
(i)
Normal saline IV for fluid replacement.
Specific measures to consider after epinephrine injections, where appropriate
(j)
Consider epinephrine infusion.
(k)
Consider H1 and H2 antihistamines
(l)
Consider nebulized β2 agonist (eg, albuterol [salbutamol]) for bronchospasm 
resistant to epinephrine
(m)
Consider systemic corticosteroids
(n)
Consider vasopressor (eg, dopamine)
(o)
Consider glucagon for patient taking a β -blocker
(p)
Consider atropine for symptomatic bradycardia
(q)
Consider transportation to an emergency department or an intensive care facility
(r)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and 
prolonged resuscitation efforts are encouraged, if necessary
Adapted from: Kemp SF, Lockey RF, Simons FE; World Allergy Organization ad hoc 
Committee on Epinephrine in Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. 
A statement of the World Allergy Organization. Allergy 2008;63(8):1061-70.

Clinical Study Protocol Appendix J
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
143(157)
Appendix J:
Adrenal Crisis Guidelines
Management of Acute Adrenal Insufficiency Secondary to Glucocorticoid 
Withdrawal
National or local guidelines for the management of acute adrenal insufficiency (adrenal crisis), 
where they exist, should be followed. The following guidelines have been adapted from the 
guidelines of the Society for Endocrinology. They are intended for guidance subject to clinical 
judgement only.
The possibility of acute adrenal insufficiency should be considered in any acutely unwell 
patient undergoing withdrawal of chronic systemic corticosteroid treatment.
Recognition

Clinical signs and symptoms

Fatigue, lack of energy, weight loss

Low blood pressure, postural dizziness and hypotension (≥20 mmHg drop in 
systolic BP from supine to standing position), dizziness, collapse, and in severe 
cases hypovolaemic shock

Abdominal pain, tenderness and guarding, nausea, vomiting

Fever

Confusion, somnolence, in severe cases delirium or coma

Back and leg cramps/spasms may be reported

Lab findings:

Hyponatraemia

Pre-renal failure (increased serum creatinine due to hypovolaemia)

Normochromic anaemia, sometimes also lymphocytosis and eosinophilia

Hypoglycaemia
Management

Hydrocortisone (immediate bolus injection of 100 mg hydrocortisone i.v. or i.m. 
followed by continuous intravenous infusion of 200 mg of hydrocortisone per 
24 hours (alternatively 50 mg of hydrocortisone per intravenous or intramuscular 
injection every 6 hours)

Rehydrate with intravenous 0.9% sodium chloride in hypotensive patients. The 
rate and total volume of infusate must be decided on an individual patient basis with 
continuous monitoring for fluid overload. Correction of hyponatremia must be 
according to relevant local guidelines

Clinical Study Protocol Appendix J
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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
Consider any other potential precipitating factors (in addition to corticosteroid 
withdrawal), eg, infection; investigate and treat as appropriate
Contact an endocrinologist at an early stage to advise on ongoing management.
Reference
Arlt W; Society for Endocrinology Clinical Committee. Society for Endocrinology Endocrine 
Emergency Guidance: Emergency management of acute adrenal insufficiency (adrenal crisis) 
in adult patients. Endocr Connect 2016;(5):G1-G3.

Clinical Study Protocol Appendix K
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
145(157)
Appendix K:
PONENTE Long Term Follow Up Substudy
1. PONENTE Long Term Follow Up Substudy Background and Rationale
The PONENTE study assesses an algorithm for OCS reduction that also defines when OCS 
reduction should be interrupted (i.e. after 2 exacerbations, or after two laboratory tests 
showing complete AI within a 3-month period). Once the OCS dose has been completely 
reduced or the lowest OCS dose achieved based on the OCS reduction treatment algorithm, 
patients enter a maintenance phase where no further reductions in OCS dose are allowed. 
After completing the 6-month OCS maintenance phase, patients who couldn’t completely 
reduce OCS may have been well-controlled on the lowest OCS dose achieved during the OCS 
reduction phase or may have recovered from AI, and, therefore, healthcare providers may 
decide to further reduce OCS or other background asthma medication, which is in line with 
the GINA report on severe asthma management (i.e. first reducing OCS and then, reducing 
ICS dose as tolerated according to clinical assessment) (GINA 2020).
According to the GINA report, asthma therapy should be periodically reviewed to assess 
patient’s response to therapy. For patients who have had a good response to biologic therapy, 
the treating physician should consider not only the reduction or elimination of maintenance 
OCS, but also reducing the ICS dose from high to medium dose (GINA 2020). GINA 
describes this guidance as “consensus advice” recognizing that no data are available to guide 
this clinical decision. 
However, it is anticipated that in the future healthcare providers are likely to reduce the ICS 
dose significantly or completely at the behest of patients whose asthma becomes well-
controlled after the addition of biologic therapy.
This long term follow up substudy aims to observe changes in the OCS dose and other 
background asthma therapy, and to assess the amount of recovery from AI, in a real-world 
setting as well as assessment of glucocorticoid toxicity by means of GTI. 
2. PONENTE Long Term Follow Up Substudy Design
After completion of the EOT visit procedures, eligible patients (See Appendix K – Section 4
and 5) may consent to a long term follow up visit 12 to 18 months after completion of the 
main PONENTE study. Accordingly, the long term follow up visit  can occur in a range of 12 
to 18 months after an eligible patient completes the EOT visit such that the last visit of the 
PONENTE Long Term Follow Up will take place 1-year after the last patient completes the 
EOT of the main PONENTE study.
Patients will be treated according to healthcare provider discretion and therefore no IP (i.e. 
Benralizumab) will be provided by the sponsor. Between the EOT visit of the main 
PONENTE study and the Long Term Follow Up visit, any changes in the maintenance 
asthma regimen are allowed, including further reductions of OCS as recommended in the 
GINA report (GINA 2020).

Clinical Study Protocol Appendix K
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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2.1
Consent:
Written consent must be obtained at any time from the EOT visit to prior to the Long Term 
Follow Up visit. Patients will complete the 4-week follow-up visit after EOT, regardless of 
whether they enrol in the long term follow up substudy, as this is the last visit of the 
PONENTE study.  
Patients who have already completed the EOT visit or the follow-up visit before the start of 
the PONENTE Long Term Follow Up may be contacted after EOT for participation. In this 
case, all assessments previously captured during the EOT visit will be included in the analysis 
of the PONENTE Long Term Follow Up.
Enrolment into the long term follow up substudy will remain open until the last PONENTE 
patient has completed the EOT visit.
2.2
Long Term Follow Up Visit: 
At the Long Term Follow Up visit, the patient will undergo an on-site visit for assessment of 
daily OCS dose, concomitant medications (including changes in background asthma regimen), 
asthma exacerbations, laboratory assessments, vital signs, and items for the GTI assessments.  
Additionally, patients who had Complete or Partial AI at the end of the OCS maintenance 
phase (EOT visit) of the primary PONENTE study, will undergo morning cortisol testing. 
Patients with indeterminate results from the morning cortisol test at the Long Term Follow Up
visit will return on-site to conduct ACTH stimulation test within a week after the Long Term 
Follow Up visit.
2.3
Assessment and collection of asthma exacerbations:
Asthma exacerbations will be defined per Section 5.2.2.  The Investigator will assess 
exacerbations at the PONENTE Long Term Follow Up, and if applicable, at any other time 
when made aware by the patient (Table 8). The Investigator must justify the decision for 
defining an event of worsening asthma as an exacerbation, and document this justification, 
including symptoms, in the source documents and the eCRF.
2.4
Safety reporting: 
Any event that occurs from the time period between the main PONENTE study follow up visit 
and the patient signing the ICF will be captured as part of the medical history for the 
PONENTE Long Term Follow Up. After PONENTE Long Term Follow Up informed consent 
up until the Long Term Follow Up visit, any events will be captured as AEs/SAEs. Any 
AE/SAE that are unresolved at the Long Term Follow Up visit will be followed-up by the 
Investigator as long as medically necessary but will not be captured in the eCRF. Causality 
will be confirmed by the investigator per Section 6.3.4. Adverse events based on signs and 
symptoms, or based on examinations and tests, will be reported per Sections 6.3.5 and 6.3.6, 
respectively.
Any spontaneous reports of AE/SAE related to any drug products other than benralizumab 
will not be captured in the eCRF but will be reported as spontaneous reports to the drug 

Clinical Study Protocol Appendix K
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
147(157)
manufacturer (e.g. to AstraZeneca or other manufacturer) and/or local regulatory agencies as 
required by local regulations. 
3. PONENTE Long Term Follow Up Substudy objectives
The main objective of the PONENTE Long Term Follow Up Substudy is to retrospectively 
collect changes of OCS and other background asthma maintenance medications, in a real-
world setting 12 to 18 months after completion of the main PONENTE study. Additionally, 
the substudy aims to further observe shifts in the AI status in patients who had Complete or 
Partial AI at the end of the PONENTE study and to further evaluate the GTI over time.
Observational Objectives:
Outcome Measures:
To observe real-world clinical management of 
OCS dose 12 to 18 months after completion of 
the main PONENTE study

Patients who achieve 100% reduction in 
daily OCS dose from baseline* OCS 
dose to the end of the long term follow 
up substudy

Patients who achieve a daily OCS dose 
of ≤5 mg at the end of the long term 
follow up substudy

Patients who achieve ≥90%, ≥75%, 
≥50% or >0% OCS reduction from 
baseline* OCS dose to the end of the 
long term follow up substudy.

Change in daily OCS dose from 
baseline* to the end of the long term 
follow up substudy
To observe real-world clinical management of 
background maintenance asthma regimen

Change in background asthma 
maintenance medication from EOT of 
PONENTE main study* to the end of 
the long term follow up substudy
Safety Objectives:
Outcome Measures:
To observe shift in AI status in patients who had 
Complete AI or Partial AI at the end of the 
PONENTE study

Shifts in AI status and further OCS dose 
changes from the main PONENTE study to 
the long term follow up visit
To observe asthma exacerbations in adult 
patients from the main PONENTE study to the 
long term follow up visit

Annualized asthma exacerbation rate

Percentage of patients without exacerbation
To assess the safety and tolerability from the 
main PONENTE study to the long term follow 
up visit

Adverse events / Serious adverse events

Laboratory parameters and vital signs

Clinical Study Protocol Appendix K
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
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To evaluate corticosteroid toxicity from the main 
PONENTE study to the long term follow up visit

Glucocorticoid toxicity index
*the PONENTE main study baseline
4. Inclusion criteria
For inclusion in the PONENTE Long Term Follow Up  substudy, patients should fulfil the 
following criteria:
a. Patients must have completed the PONENTE EOT visit. 
b. Written informed consent to participate in the observational PONENTE  Long Term Follow 
Up
5. Exclusion criteria
Patients should not enter the PONENTE Long Term Follow Up if any of the following 
exclusion criteria are fulfilled: 
a.
Concurrent enrolment in another interventional clinical trial
b. AstraZeneca staff involved in the planning and/or conduct of the study
c.
Employees of the study site or any other individuals involved with the conduct of 
the study, or immediate family members of such individuals

Clinical Study Protocol Appendix K
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
149(157)
6. Study Plan and timing of procedures
Table 8
PONENTE Long Term Follow Up Substudy – Study plan: Enrolment to End of Study
Assessment/Activity
Protocol section 
Enrollment
Long Term Follow Up Period
Withdrawal
Unscheduled Visit
PONENTE Long Term 
Follow Up Enrolment
(after EOT procedures)a
PONENTE Long Term Follow 
Up Visit
Written Informed consent for long term follow up 
substudyb
Appendix K: 2.1
X
Medical History
X
Review EOT Visit Assessments
Table 1
X
Brief physical examination
5.2.5.2
N/A
X
X
Vital signs
5.2.6
N/A
X
X
X
Weight
5.3.1
N/A
X
X
Serum chemistry
5.2.4
N/A
X
X
Hematology
5.2.4
N/A
X
X
Morning Cortisol testingc
5.2.4
N/A
X
X
Glucocorticoid toxicity index
5.2.1.1
N/A
X
X
Assessment of asthma exacerbations
5.2.2/5.2.3
N/A
X
X
X
Adverse events
6.1
N/A
X
X
X
Concomitant medication
7.8 / 
Appendix K: 7
N/A
X
X
X
OCS and asthma medications
Appendix K: 7
N/A
X
X
X

Clinical Study Protocol Appendix K
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
150(157)
a.
Enrolment for the PONENTE Long Term Follow Up substudy can occur any time after all PONENTE EOT procedures are completed. Patients who have already 
completed EOT prior to the start of the PONENTE Long Term Follow Up substudy may be contacted for participation at any time up to 18 months after the EOT 
visit. Assessments labeled N/A are not applicable because they will be collected as a part of the PONENTE EOT visit.
b.
ICF for the PONENTE Long Term Follow Up substudy must be obtained any time from EOT of the main PONENTE study and prior to any activities of the 
PONENTE Long Term Follow Up visit
c.
Patients who have Complete AI or Partial AI at the end of the primary PONENTE study will undergo a morning cortisol test at the  Long Term Follow Up visit. 
Patients with indeterminate results will return to the site within a week after the Long Term Follow Up visit to conduct an ACTH stimulation test.

Clinical Study Protocol Appendix K
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Study Code D3250C00065
Version 4
Date 17 October 2020
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7. Concomitant medication and other treatments
The PONENTE Long Term Follow Up is observational only. There are no sponsor-provided 
investigational products, restrictions related to concomitant medications other than those 
detailed in Section 3.5, or restrictions on concurrent disease. Restrictions described in Section
7.8 do not apply in the PONENTE Long Term Follow Up.
Additionally, from the EOT visit of the main PONENTE study to the Long Term Follow Up
visit, any changes in the maintenance asthma regimen are allowed, including reductions of 
maintenance OCS therapy as recommended in the GINA report.
Due to potential interactions with morning cortisol and ACTH stimulation testing, the 
restrictions on concomitant medications detailed in Section 3.5 remain in place for the 
PONENTE Long Term Follow Up substudy.
8. Statistical Analyses by AstraZeneca
8.1 
Statistical Analysis Plan
The PONENTE Long Term Follow Up will be managed under a separate SAP from the 
PONENTE main study and reported by way of an addendum to the PONENTE CSR.
8.2
Sample Size Estimate for PONENTE Long Term Follow Up substudy
The PONENTE Long Term Follow Up is not formally powered; all patients from the 
PONENTE main study meeting all inclusion criteria and no exclusion criteria of this long 
term follow up substudy will be eligible to enrol. 
8.3
Definition of analysis sets for PONENTE Long Term Follow Up substudy
Observational and safety analyses will use a common analysis set – the Long Term Follow Up 
Analysis Set - which will include all patients who sign informed consent to continue into the 
PONENTE Long Term Follow Up .  Two further analysis sets are defined as follows:
The "Biologic" Analysis Set will include all patients in the Long Term Follow Up Analysis set 
with >=50% exposure to any biologic treatment for asthma during the PONENTE Long Term 
Follow Up ; and
The "Benralizumab" Analysis Set will include all patients in the Long Term Follow Up 
Analysis set with >=50% exposure to commercial Benralizumab during the PONENTE  Long 
Term Follow Up.
Additional analysis sets may be defined in the SAP.
8.4
Outcome measures for the PONENTE Long Term Follow Up substudy
Definition of baseline
Baseline definitions will be as per definitions for the PONENTE main study (see the main 
PONENTE SAP for full definitions).

Clinical Study Protocol Appendix K
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
152(157)
Outcome variables

Patients who achieve 100% reduction in daily OCS dose from PONENTE baseline 
dose to the Long Term Follow Up visit

Patients who achieve a daily OCS dose of ≤5mg (prednisone equivalent dose) at the 
Long Term Follow Up visit

Patients who achieve ≥90%, ≥75%, ≥50% and >0% reduction in daily OCS dose 
from PONENTE baseline dose to the Long Term Follow Up visit

Change in daily OCS dose (mg prednisone equivalent dose) from the baseline dose 
of the PONENTE main study to the Long Term Follow Up visit

Change in background asthma maintenance medication from baseline of the 
PONENTE main study to the Long Term Follow Up visit
Change from baseline will be calculated as the post-baseline assessment value minus the 
baseline assessment value.  If either value is missing, then the change from baseline value will 
be missing. Full details will be defined in the PONENTE Long Term Follow Up substudy
SAP.
Safety outcome variables

Patients with complete AI and changes in AI status

Annualized asthma exacerbation rate

AEs, SAEs

Laboratory parameters and vital signs

GTI
8.5
Methods for statistical analyses for the PONENTE Long Term Follow Up
substudy
Statistical tabulation will be presented for all patients in the long term follow up analysis set, 
biologic analysis set and Benralizumab analysis set. Continuous variables will be summarized 
using the mean, two-sided 95% CI of the mean, the standard deviation, median, minimum 
value, and maximum value.  Categorical variables will be summarized using frequency counts 
and percentages, as well as a two-sided 95% CI for proportions computed using exact 
Clopper-Pearson method.  Data will be listed in patient-level data listings. 
No formal hypothesis will be tested and no multiplicity adjustment will be applied in the 
statistical analysis.  No imputation of observational or safety data will be performed.  
Imputation for partial dates will be detailed in the SAP.

Clinical Study Protocol Appendix K
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
153(157)
Analysis of the observational variables
Changes in OCS dose over time will be summarized using descriptive statistics in tables and 
presented graphically for the long term follow up analysis set, biologic analysis set and 
Benralizumab analysis set.  Percentages achieving 100% reduction in OCS daily dose, a ≤5mg 
daily dose, other pre-specified percentage reductions in OCS daily dose and reductions in 
background asthma medications will be reported with nominal 95% CIs derived using the 
exact Clopper-Pearson method.
Additional analyses will be detailed in the PONENTE Long Term Follow Up substudy SAP.
Analysis of safety outcomes 
The number and percentage of patients with complete AI at the  Long Term Follow Up visit 
will be presented for the long term follow up analysis set, biologic analysis set and 
Benralizumab analysis set.  A logistic regression model will be developed to identify factors 
potentially predictive of long-term adrenal insufficiency.  Complete AI status at the  Long 
Term Follow Up visit will be the dichotomous response variable with demographic, 
respiratory and metabolic baseline characteristics as explanatory variables.  Full details will be 
provided in the SAP.
Spaghetti plots will be produced for patients in the long term follow up analysis set, biologic 
analysis set and Benralizumab analysis set with partial AI throughout the OCS reduction 
phase of the main PONENTE study, showing cortisol levels over time until the  Long Term 
Follow Up visit.
The incidence of AEs and SAEs will be summarized over the PONENTE Long Term Follow 
Up substudy for comparison with incidence rates during the PONENTE main study. 
Summaries of laboratory parameters and vital signs may be provided, including absolute 
values and changes over time.  Full details will be provided in the SAP.
The annualized rate of asthma exacerbations during the PONENTE Long Term Follow Up 
substudy will be summarized using mean, 95% CI and dispersion based on the negative 
binomial distribution, for the long term follow up analysis set, biologic analysis set and 
Benralizumab analysis set.  This will be repeated for exacerbations resulting in hospitalization 
or an ER visit.  Rates will be compared with those recorded during the PONENTE main study.  
The number and percentage of patients remaining exacerbation-free during the PONENTE 
Long Term Follow Up substudy will be presented.
Glucocorticoid toxicity index will be summarized over time from the start of the PONENTE 
main study to the end of the PONENTE Long Term Follow Up substudy, for the long term 
follow up analysis set, biologic analysis set and Benralizumab analysis set.  Statistical 
correlation between GTI and daily OCS dose will be explored.
Subgroup analysis
Any subgroup analyses will be defined in the PONENTE Long Term Follow Up SAP.

Clinical Study Protocol Appendix K
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
154(157)
9. Study timetable and end-of-study
Enrolment for the PONENTE Long Term Follow Up substudy will be closed once the final 
PONENTE patient completes the EOT visit. For patients who participate in the PONENTE  
Long Term Follow Up substudy, the final study visit will be the  Long Term Follow Up visit 
except for patients with indeterminate morning cortisol results at this visit who will return 
within 1 week after Long Term Follow Up visit to conduct the ACTH stimulation test. 

Clinical Study Protocol Appendix L
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
155(157)
Appendix L:    Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
patients become infected with SARS-CoV-2 or similar pandemic infection) during which 
patients may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
agreement from the Sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.
Please note that during civil crisis, natural disaster, or public health crisis, some study 
assessments and procedures may not be conducted due to international or local policies or 
guidelines, hospital or clinic restrictions and other measures implemented to ensure the 
patient’s safety. If in doubt, please contact the AZ Study Physician. 
1
Reconsent of Study Patients During Study Interruptions
During study interruptions, it may not be possible for the patients to complete study visits and 
assessments on site and alternative means for carrying out the visits and assessments may be 
necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Section 2 to Section 5. Local and regional regulations and/or guidelines regarding 
reconsent of study patients should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the patient’s next contact with the study site). Visiting the study sites for the sole 
purpose of obtaining reconsent should be avoided. 
2
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified HCP from the study site or TPV service may visit the patients home / or other 
remote location as per local Standard Operating Procedures (SOPs), as applicable. Supplies 
will be provided for a safe and efficient visit. The qualified HCP will be expected to collect 
information per the clinical study protocol (CSP). If applicable, assessments will be performed 
according a the revised Schedule of Assessments (SoA) in the Study Instruction Manual for 
Mitigation Due to Civil Crisis, Natural Disaster, or Public Health Crisis. 

Clinical Study Protocol Appendix L
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
156(157)
3
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the patients using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the patients will allow adverse events, concomitant medication, exacerbations, OCS dose 
(including reasons for no OCS reduction in an otherwise controlled patient), GTI data, blood 
sample collection for central lab analysis, etc to be reported and documented. If applicable, 
safety procedures and blood sample collection will be performed according to the revised SoA 
in the Study Instruction Manual for Mitigation Due to Civil Crisis, Natural Disaster, or Public 
Health Crisis.
4
At-home or Remote Location IP Administration Instructions
If a site visit is not possible, at-home or remote location administration of IP may be 
performed by a qualified HCP, provided this is acceptable within local regulation/guidance. 
The option of at-home or remote location IP administration ensures patients safety in cases of 
a pandemic where patients may be at increased risk by traveling to the site/clinic. This will 
also minimize interruption of IP administration during other study disruptions, e.g., site 
closures due to natural disaster. 
4.1 - At-home or Remote Location IP Administration by a Qualified HCP 
or TPV Service
A qualified HCP from the study site or TPV service may administer the IP at the patient’s
home or other remote location according to the CSP. All necessary supplies and instructions 
for administration and documentation of IP administration will be provided. Additional 
information related to the visit can be obtained via a telemedicine or home visit.
5
Data Capture During Telemedicine or Home / Remote Visits
Data collected during telemedicine or home / remote visits will be captured by the qualified 
HCP from the study site or TPV service in the source documents, or by the patient themselves 
if applicable. 
Refer to the Study Instruction Manual for Mitigation Due to Civil Crisis, Natural Disaster, or 
Public Health Crisis for step by step guidance.
6
Changes to Statistical Analyses

Clinical Study Protocol Appendix L
Drug Substance Benralizumab
Study Code D3250C00065
Version 4
Date 17 October 2020
157(157)
Additional sensitivity and supportive analyses to assess the impact of study disruption (e.g. 
effects of the COVID-19 pandemic) on the primary, secondary and key supportive efficacy 
endpoints may be defined.  Full details will be included in the Statistical Analysis Plan.

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d3250c00065-csp-v4
Document Title:
D3250C00065 Clinical Study Protocol version 4
Document ID:
Doc ID-003819839
Version Label:
4.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
19-Oct-2020 15:40 UTC
Content Approval
19-Oct-2020 14:26 UTC
Management Approval
19-Oct-2020 21:15 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.