Clinical trial NCT04048343
Conditions: Severe Asthma
Keywords: Asthma Uncontrolled Asthma Severe Uncontrolled Asthma
Sponsor: AstraZeneca
Start date: 2019-06-10; Completion date: 2021-03-18
Enrollment: 65 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, single arm study designed to evaluate the safety of tezepelumab administered subcutaneously every 4 weeks in Japanese adult and adolescent subjects with inadequately controlled severe asthma.

Detailed description:
This is open-label, single arm study designed to evaluate the safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma on medium to high-dose ICS and at least one additional asthma controller medication with or without OCS. Approximately 66 subjects will be dosed in Japan. Subjects will receive tezepelumab administered via subcutaneous injection at the study site, over a 52-week treatment period. The study also includes a post-treatment follow-up period of 12 weeks.

Arms: arm 1: Tezepelumab: Tezepelumab subcutaneous injection
Interventions: intervention 1: Biological: Experimental: Tezepelumab
Intervention descriptions: intervention 1: Tezepelumab subcutaneous injection every 4 weeks

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol
Drug Substance
Tezepelumab
Study Code
D5180C00019
Version
3.0
Date
09 July 2020
A 52-Week, Open-Label, Multicentre Study to Evaluate the Safety of 
Tezepelumab in Japanese Adults and Adolescents with Inadequately 
Controlled Severe Asthma (NOZOMI)
Sponsor:
AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Regulatory Agency Identifying Number(s): Not applicable


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VERSION HISTORY
Version 3.0, 09 July 2020
Changes to the protocol are summarized below.
Section 1.1, SoA, Table 2 –Added footnote a “Spirometry should be tested only if allowed 
by local guidelines during the COVID-19 pandemic.” due to COVID-19 pandemic.  Under 
Table 2 added guidance on how to proceed with respect to Schedule of Activities during the 
COVID-19 pandemic to ensure the safety of the study subjects, to maintain compliance 
with GCP and to minimize risks to data integrity.
Section 1.2, Synopsis – Treatments and treatment duration - Added a note to refer to 
Appendix J for further guidance if subjects are unable to come to the site during the 
COVID-19 pandemic.
Section 6.2, Preparation/handling/storage/accountability – Added a note to clarify that 
during the COVID-19 pandemic, if allowed by local/regional guidelines, IP preparation and 
administration may be performed at the subject’s home by a qualified HCP.  This change is 
to reduce the risk to subjects of COVID-19 exposure with clinic visits. 
Section 6.5, Table 7, Prohibited medications – For any immunomodulators or 
immunosuppressives, revised the text “(except for OCS used in the treatment of 
asthma/asthma exacerbations)” to “(except for OCS used in the maintenance treatment of
asthma, asthma exacerbations in screening, and protocol defined asthma exacerbations on or 
after Visit 2)”. This is to clarify the wording “except for OCS used in the treatment of 
asthma” is applicable for subjects on OCS maintenance treatment for asthma and “asthma 
exacerbation” is applicable if it was a protocol defined exacerbation occurring on or after 
Visit 2. 
Section 6.5, Table 7, Prohibited medications – For other investigational products (including 
investigational use of an approved drug), revised the text “preferably 4 weeks after the last 
dose of IP” to “until the follow up visit week 64”. 
Section 8, Study Assessments and Procedures – Added “Additional data to assess the impact 
of COVID-19 pandemic will be collected.”
Section 8.1.3.1, Asthma Control Questionnaire (ACQ-6) – Revised ACQ-6 score from 
“≤1.5” to “<1.5” to indicate partly controlled asthma and from “>1.5” to “≥1.5” to indicate 
uncontrolled asthma. This change aligns with the thresholds for partly 
controlled/uncontrolled asthma established by Juniper et al 2006.


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Section 9.4.5, Safety analyses – Replaced “post-treatment” with “on-study”, to clarify the 
periods of interest.
Section 9.4.6, Other analyses – Added “additional analyses assessing the impact of COVID-
19 may be included in the SAP”.
Appendix A 3 – Added “During the COVID-19 pandemic, re-consent may be obtained 
remotely and/or verbally if local/regional guidelines allow in order to reduce the risk to 
subjects of COVID-19 exposure during clinic visits. For further details please refer to 
Appendix J” to accommodate the changes made in the protocol.
Appendix I, Table of Abbreviations – Added 1) COVID-19 and 2) HCP 
Appendix J – Added Appendix J to describe in more detail the changes made during the 
COVID-19 pandemic.
Version 2.0, 12 April 2019
Changes to the protocol are summarized below.
Study Title, added “(NOZOMI)” at the end of study title. Study name was created.
 
 
Section 1.2, Synopsis – Coordinating investigator – added “see Clinical Study Protocol 
Addendum”. Coordinating investigator was decided.
Section 1.2, Synopsis – Study Period – changed “Estimated date of last patient completed: 
Q2 2021”. To correct a typo error.
Section 1.2, Synopsis – Number of Subjects – Replaced the underlined words “The sample 
size of this study will be determined after the last Japanese subject randomization and
confirmation of the number of randomized Japanese subjects in NAVIGATOR study 
(D5180C00007) to ensure that there are 100 total Japanese subjects who receive 
tezepelumab for 52 weeks.” with “The actual number of Japanese subjects registered into 
the study will be determined after the confirmation of the number of randomized Japanese 
subjects in NAVIGATOR study (D5180C00007) to ensure that there are 100 total Japanese 
subjects who receive tezepelumab for 52 weeks.”. To clarify the number of subjects.
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Section 1.2, Synopsis – Statistical methods – added underlined words “An interim analysis 
will be performed when all subjects complete Visit 8 (24-week of treatment period) for 
marketing application submission purposes.” To clarify purposes of interim analaysis.
Section 5.1, Inclusion Criteria #13 – Removed all. To align with the revised IB.
Section 5.3.5, Contraception – Removed the wording “Nonsterilized males who are sexually 
active with a female partner of childbearing potential must use a male condom from the date 
of the first administration of IP through 16 weeks after receipt of the final dose of IP. Male 
subjects must not donate or bank sperm during this same time period.”. To align with the 
revised IB.
 
 
 
Section 8.4.2.2, Paternal exposure – Removed wording “Male subjects should refrain from 
fathering a child or donating sperm during the study and for 16 weeks (5 half-lives) 
following the last dose.”. To align with the revised IB.
Section 8.4.5, Management of IP-related toxicities – Replaced “a local laboratory where 
applicable” with “central laboratory”. Tryptase will be evaluate at central laboratory.
 
Version 1.0, 5 February 2019
Initial creation
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.
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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY........................................................................................................... 2
TABLE OF CONTENTS...................................................................................................... 5
1
PROTOCOL SUMMARY.................................................................................. 9
1.1
Schedule of Activities (SoA)............................................................................... 9
1.2
Synopsis ........................................................................................................... 13
1.3
Schema............................................................................................................. 15
2
INTRODUCTION............................................................................................ 16
2.1
Study rationale.................................................................................................. 17
2.2
Background ...................................................................................................... 17
2.3
Benefit/risk assessment..................................................................................... 19
3
OBJECTIVES AND ENDPOINTS................................................................... 20
4
STUDY DESIGN ............................................................................................. 20
4.1
Overall design................................................................................................... 20
4.2
Scientific rationale for study design .................................................................. 21
4.3
Justification for dose......................................................................................... 21
4.4
End of study definition...................................................................................... 22
5
STUDY POPULATION ................................................................................... 22
5.1
Inclusion criteria............................................................................................... 23
5.2
Exclusion criteria.............................................................................................. 26
5.3
Lifestyle restrictions ......................................................................................... 28
5.3.1
Meals and dietary restrictions............................................................................ 28
5.3.2
Alcohol and tobacco ......................................................................................... 28
5.3.3
Activity............................................................................................................. 29
5.3.4
Blood donation ................................................................................................. 29
5.3.5
Contraception ................................................................................................... 29
5.4
Screen failures .................................................................................................. 29
5.4.1
Re-screening..................................................................................................... 29
6
STUDY TREATMENTS.................................................................................. 30
6.1
Treatments administered................................................................................... 30
6.1.1
Investigational products.................................................................................... 30
6.2
Preparation/handling/storage/accountability...................................................... 30
6.3
Measures to minimise bias: randomisation and blinding.................................... 33
6.4
Treatment compliance....................................................................................... 34
6.5
Concomitant therapy......................................................................................... 34
6.5.1
Other concomitant treatment............................................................................. 38
6.5.2
Rescue medication............................................................................................ 38


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6.5.3
Bronchial Thermoplasty.................................................................................... 38
6.6
Dose modification............................................................................................. 38
6.7
Treatment after the end of the study.................................................................. 38
7
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL . 38
7.1
Discontinuation of study treatment.................................................................... 38
7.1.1
Procedures for discontinuation of study treatment............................................. 39
7.2
Lost to follow-up .............................................................................................. 40
7.3
Withdrawal from the study................................................................................ 41
7.3.1
Withdrawal due to recruitment completion........................................................ 42
7.3.2
Discontinuation or suspension of the whole study program............................... 42
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 42
8.1
Efficacy assessments......................................................................................... 43
8.1.1
Assessment of asthma exacerbation .................................................................. 43
8.1.2
Spirometry........................................................................................................ 44
8.1.2.1
General Requirements....................................................................................... 44
8.1.3
Patient reported outcome (PRO) ....................................................................... 46
8.2
Safety assessments............................................................................................ 46
8.2.1
Clinical safety laboratory assessments............................................................... 47
8.2.1.1
Pregnancy Test ................................................................................................. 48
8.2.2
Weight and height............................................................................................. 48
8.2.3
Physical examinations....................................................................................... 48
8.2.4
Vital signs......................................................................................................... 48
8.2.5
Electrocardiograms ........................................................................................... 49
8.2.6
Other safety assessments................................................................................... 49
8.2.6.1
Serology ........................................................................................................... 49
8.3
Collection of adverse events ............................................................................. 50
8.3.1
Method of detecting AEs and SAEs .................................................................. 50
8.3.2
Time period and frequency for collecting AE and SAE information.................. 50
8.3.3
Follow-up of AEs and SAEs ............................................................................. 50
8.3.4
Adverse event data collection............................................................................ 51
8.3.5
Causality collection........................................................................................... 51
8.3.6
Adverse events based on signs and symptoms................................................... 52
8.3.7
Adverse events based on examinations and tests ............................................... 52
8.3.8
Adverse Events of Special Interest.................................................................... 53
8.3.9
Hy’s law ........................................................................................................... 53
8.4
Safety reporting and medical management........................................................ 53
8.4.1
Reporting of serious adverse events .................................................................. 53
8.4.2
Pregnancy......................................................................................................... 54
8.4.2.1
Maternal exposure ............................................................................................ 54
8.4.2.2
Paternal exposure.............................................................................................. 55
8.4.3
Overdose .......................................................................................................... 55
8.4.4
Medication error ............................................................................................... 56
8.4.5
Management of IP-related toxicities.................................................................. 56
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8.5.1
Collection of samples and determination of drug concentration......................... 57
8.6
Pharmacodynamics........................................................................................... 57
8.7
Genetics............................................................................................................ 57
8.7.2
Storage and destruction of genetic samples ....................................................... 58
8.8
Biomarkers ....................................................................................................... 58
8.9
Medical Resource Utilization and Health Economics ........................................ 58
9
STATISTICAL CONSIDERATIONS............................................................... 58
9.1
Statistical hypotheses........................................................................................ 58
9.2
Sample size determination ................................................................................ 58
9.3
Populations for analyses.................................................................................... 58
9.4
Statistical analyses............................................................................................ 59
9.4.1
Subject disposition, demography and baseline characteristics............................ 59
9.4.2
Prior and concomitant medication..................................................................... 60
9.4.3
Definition of baseline........................................................................................ 60
9.4.4
Efficacy analyses .............................................................................................. 60
9.4.5
Safety analyses ................................................................................................. 60
9.4.6
Other analyses .................................................................................................. 61
9.5
Interim analyses................................................................................................ 61
10
REFERENCES................................................................................................. 62
11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 66
LIST OF TABLES
Table 1
Study of Assessments - Screening.............................................................. 9
Table 2
Study of Assessments- Registration, treatment period, follow-up............. 10
Table 3
Study objectives....................................................................................... 20
Table 4
Study Treatments..................................................................................... 30
Table 5
Investigational Product Dose Preparation................................................. 32
Table 6
Restricted medications............................................................................. 35
Table 7
Prohibited medications............................................................................. 37
Table 8
Laboratory safety variables...................................................................... 47
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LIST OF FIGURES
Figure 1
Study design............................................................................................ 16
Figure 2
Suggested schema of Rotation of Injection Sites ...................................... 33
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations............................. 66
Appendix B
Adverse event definitions and additional safety information .................... 70
Appendix C
Handling of Human Biological Samples .................................................. 74
Appendix D
Genetics................................................................................................... 76
Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law............................................................................ 80
Appendix F
Maintenance Therapy Equivalence Table................................................. 85
Appendix G
Anaphylaxis: Signs and Symptoms, Management .................................... 86
Appendix H
ACQ-6..................................................................................................... 90
Appendix I
Abbreviations .......................................................................................... 93
Appendix J
Changes Related to COVID-19 Pandemic................................................ 96


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1
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)
Table 1
Study of Assessments - Screening
Screening
Details in CSP section or 
Appendix
Visit
1
Week
-2 - 0
Visit window
NA
Procedures
Informed consent 
X
A 3
Inclusion /exclusion criteria
X
5.1, 5.2
Demography
X
5.1
Patient Reported Outcome Assessments at Visit
ACQ-6
X
8.1.3.1
Routine Safety Measurements
Complete physical examination
X
8.2.3
Vital signs
X
8.2.4
Weight, Height
X
8.2.2
12-lead ECG
X
8.2.5
Adverse events (AEs/SAEs)
X
8.3
Medical and asthma history
X
5.1
Assessment of historical asthma exacerbations in the 
past 12 months
X
8.1.1
Concomitant medication
X
6.5
Laboratory Assessments 
Serum chemistry
X
8.2.1
Haematology
X
8.2.1
Urinalysis 
X
8.2.1
Pregnancy or FSHtesta
X
8.2.1.1
Serology (Hepatitis B, C; HIV-1; HIV-2)
X 
8.2.6.1
a
For WOCBP and adolescent females, serum β-hCG will be confirmed. FSH test done only in women < 50 
years who have been amenorrheic for > 12 months to confirm postmenopausal status.
ACQ-6: Asthma Control Questionnaire-6, AE: Adverse Event, BD: Bronchodilator, β-hCG: β-human chorionic 
gonadotropin, CSP: Clinical Study Protocol, ECG: Electrocardiogram, 
 
, FSH: Follicle Stimulating Hormone, 
, HIV: Human Immunodeficiency 
Virus, SAE: Serious Adverse Event, WOCBP: Women of Childbearing Potential.
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Table 2
Study of Assessments- Registration, treatment period, follow-up
Registr
ation
Treatment
EOT
IPD
FU
1
FU
2
UNSi
Details in 
CSP 
section or 
Appendix
Visit
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
Day (visit window)
0
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
Procedures
Inclusion /exclusion criteria
X
5.1, 5.2
Lung Function Assessments
Spirometry 
 
X
X
X
X
X
X
X
X
X
8.1.2
Patient Reported Outcome Assessments at Visit
ACQ-6b
X
X
X
X
X
X
X
X
8.1.3.1
Routine Safety Measurements
Complete physical examination
X
X
X
X
8.2.3
Brief physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.3
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.4
Heightc
X
X
8.2.2
Weight
X
X
X
8.2.2
12-lead ECGd
X
X
X
X
X
8.2.5
Adverse events (AEs/SAEs)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3
Assessment of asthma exacerbation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
Laboratory Assessmentse
Serum Chemistry
X
X
X
X
X
X
X
X
8.2.1
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Table 2
Study of Assessments- Registration, treatment period, follow-up
Registr
ation
Treatment
EOT
IPD
FU
1
FU
2
UNSi
Details in 
CSP 
section or 
Appendix
Visit
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
Day (visit window)
0
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
Haematology
X
X
X
X
X
X
X
X
X
8.2.1
Urinalysis
X
X
X
X
X
X
X
X
8.2.1
Urine pregnancy test, dipstickf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.1.1
Serum for immunogenicityg
X
X
X
X
X
8.5
Blood sample for Gx (Optional)
X
8.7
Study Treatment Administration
Registration
X
6.1
Administration of IP h
X
X
X
X
X
X
X
X
X
X
X
X
X
6.2
a
Spirometry should be tested only if allowed by local guidelines during the COVID pandemic.
b
ACQ-6 should be completed at the beginning of site visits.
c
Only to be measured for the adolescent subject.
d
ECG must be collected prior to any blood draws, spirometry, BD administration and IP administration.
e
All blood sampling should be done prior to IP administration.
f
For WOCBP and adolescent females, urine pregnancy test (dipstick) will only be performed at each treatment visit, prior to IP administration. Positive urine 
test result must be confirmed with serum β-hCG.
h
IP should be administered after all other assessments have been completed to a scheduled visit.
i
At unscheduled visits for assessing an asthma exacerbation, the assessment/activity listed above is only the minimum needed to be performed. Other 
unscheduled visits may be initiated as needed, and assessments performed as per investigator’s judgement. 
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, AE: Adverse Event, BD: Bronchodilator, β-hCG: β-human chorionic gonadotropin, CSP: Clinical Study Protocol, 
ECG: Electrocardiogram, EOT: End of Treatment, 
, FSH: Follicle Stimulating Hormone, FU: Follow-up, 
 
 Gx: Genetic research, HIV: Human Immunodeficiency Virus, IP: Investigational Product, IPD: Investigational Product Discontinuation,  
 SAE: Serious Adverse Event, UNS: Unscheduled, WOCBP: Women of Childbearing Potential.
CHANGES REQUIRED DURING THE COVID-19 PANDEMIC
Please Note: Changes below should only be implemented during the COVID-19 pandemic.
During the COVID-19 pandemic, changes are being implemented in order to ensure the safety of study subjects, to maintain 
compliance with good clinical practices, and to minimize risks to data integrity. Where allowable by local health authorities, ethics 
committees and healthcare provider guidelines (e.g. hospital policies), these changes include:
!
The option of home visits including home administration of Investigational Product (IP) performed by a qualified Health Care 
Professional (HCP). Additional information related to the visit can be obtained remotely by phone call and/or video conference. 
The rationale for this change is to minimize the risk of subjects missing scheduled IP administration and visit assessments due 
to inability/unwillingness to visit the site during the COVID-19 pandemic.
!
Remote visits (phone call and/or video conference) to replace on-site visits, if subjects cannot attend the visits at the study site, 
at an alternate site or have home visits. The rationale for this change is to ensure that assessments and collection of information 
continue for visits that cannot be done at the site, at an alternate site or at the subject’s home. This will reduce the risk of 
subject exposure to COVID-19
!
Re-consent will be obtained remotely and/or verbally if allowed by local and regional guidelines. The rationale for this change 
is to ensure that the subject agrees to the changes implemented during the COVID-19 pandemic while minimizing the risk to 
subjects of COVID-19 exposure.
For further details, please refer to Appendix J.
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1.2
Synopsis
Principal investigator
The names and addresses of principal investigators are shown in Clinical Study Protocol 
Addendum.
Coordinating investigator, see Clinical Study Protocol Addendum.
For contact details of AstraZeneca personnel, see Clinical Study Protocol Addendum.
Protocol Title: 
A 52-Week, Open-Label, Multicentre Study to Evaluate the Safety of Tezepelumab in 
Japanese Adults and Adolescents with Inadequately Controlled Severe Asthma
Short Title: 
Tezepelumab Japan long-term safety study
Rationale: 
This is a Japan long-term safety study to demonstrate the safety of tezepelumab in Japanese 
adults and adolescents (12 years of age and older) with a history of asthma exacerbations and 
inadequately controlled severe asthma receiving medium-or high dose inhaled corticosteroid 
(ICS) plus at least one additional asthma controller medication with or without oral 
corticosteroids (OCS).
The results from the previous Ph2b study (CD-RI-MEDI9929-1146) have been used to select 
the target population for Ph3 studies. It is expected that adolescent patients (12-17 years of 
age) in the target population will respond similarly to adults and are therefore included as part 
of the study population. Pharmacokinetic evaluations in adolescents with asthma confirm the 
same dose can be given to adolescents as to adults. Japanese patients with severe asthma are 
participating in the ongoing pivotal Ph3 study (NAVIGATOR study [D5180C00007]) to 
assess the efficacy and safety of tezepelumab in Japanese asthma subjects. The purpose of this 
open label long term safety study is to provide additional long-term safety data of 
tezepelumab to meet the regulatory requirement of one-year exposure to tezepelumab of 100 
Japanese patients at the time of the Japan New Drug Application. The study will evaluate the 
safety of tezepelumab with regards to adverse events, as well as other safety parameters.


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Objectives and Endpoints
Primary objective:
Endpoint/variable:
To evaluate the safety and tolerability of 
tezepelumab
Adverse events/Serious adverse events
Vital signs
Clinical chemistry/haematology/urinalysis 
parameters
Electrocardiograms
Exploratory objectives:
Endpoint/variable:
 
 
 
 
 
 
 
 
 
 
Overall design: 
This is an open-label, single arm study designed to evaluate the safety of a 210 mg dose of 
tezepelumab administered subcutaneously every 4 weeks in Japanese adult and adolescent 
subjects with inadequately controlled severe asthma. Patients will have a history of at least 
one exacerbation in the past year and background asthma therapy of medium- or high dose 
ICS plus at least one additional asthma controller medication (long-acting β2 agonist, 
[LABA], leukotriene receptor antagonists [LTRA], long-acting muscarinic antagonists 
[LAMA], cromones, and theophylline) with or without maintenance OCS from screening and 
throughout the study including the follow-up period.
The study will consist of a screening period of 2 weeks, a treatment period of 52 weeks and a 
post-treatment follow-up period of 12 weeks. 
After the informed consent is obtained, subjects will proceed to a screening period of 2 weeks 
maximum to allow adequate time for all of the eligibility criteria to be evaluated. Subjects 
who meet all the eligibility criteria will be registered to a treatment period. Subjects will be 
maintained on their currently prescribed ICS and at least one additional asthma controller 
medication at their dose they entered screening, without change, from screening throughout 
the treatment period.
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Study Period: 
Estimated date of first patient enrolled: Q2 2019
Estimated date of last patient completed: Q2 2021
Number of Subjects: 
Approximately 66 Japanese subjects will be registered into the study and receive tezepelumab 
in order to reach 59 completed. The actual number of Japanese subjects registered into the 
study will be determined after the confirmation of the number of randomized Japanese 
subjects in NAVIGATOR study (D5180C00007) to ensure that there are 100 total Japanese 
subjects who receive tezepelumab for 52 weeks. 
Treatments and treatment duration:
All subjects will receive tezepelumab 210 mg every 4 weeks via subcutaneous injection at the 
study site, over a 52-week treatment period.
Please note: If subjects are unable to come to the site during the COVID-19 pandemic, 
please refer to Appendix J for further guidance.
Statistical methods
No formal sample size calculation was conducted for this study. Approximately 66 Japanese 
patients are required to enter treatment period to obtain 59 patients who complete the planned 
52-weeks treatment period assuming a drop-out rate of 10% during the 52-weeks treatment 
period. 
All variables will be summarised descriptively. No hypothesis testing will be conducted for 
this study.
An interim analysis will be performed when all subjects complete Visit 8 (24-week of 
treatment period) for marketing application submission purposes.
1.3
Schema
The general study design is summarised in Figure 1.


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Figure 1
Study design 
Visit 1
Visit 2
Visit 3 to 14
Visit 15
Week
-2 to 0
Week
0
Week
4 to 48
Week
52
Week
58, 64
Screening
Registration (Visit 2) & Treatment Period (Visit 2 to 14)
End of 
Treatment
Follow-up
Tezepelumab 210 mg, SC every 4 weeks
SC: Subcutaneous
2
INTRODUCTION 
Asthma is a chronic inflammatory airway disorder caused by the interaction of genetic and 
environmental factors. It is characterized by widespread, variable, and reversible airflow 
obstruction, airway inflammation, excessive mucus production; and airway 
hyperresponsiveness that lead to recurrent episodes of wheezing, breathlessness, chest 
tightness, and coughing (The Collaborative Study on the Genetics of Asthma (CSGA) 1997).
Progressive pathologic airway remodelling and scarring may occur in persistent asthma 
resulting in only partially reversible or irreversible airway obstruction (Pascual and Peters 
2005).
The etiology of asthma is thought to be multi-factorial, influenced by both genetic and 
environmental mechanisms. The majority of cases arise when a person becomes 
hypersensitive to allergens. Despite the availability of multiple therapeutic options, asthma 
continues to be a major health problem. Worldwide, asthma currently affects approximately 
300 million people; by 2020, asthma is expected to affect 400 million people (Partridge 2007). 
Each year in the US, asthma accounts for an estimated 8.9 million outpatient visits, 1.9 million 
emergency room visits, 479,000 hospitalizations (DeFrances et al 2008), and 3400 deaths 
(Centers for Disease Control and Prevention 2017). According to a patient survey conducted 
by Ministry of Health, Labor and Welfare of Japan in 2014, the number of patients in Japan 
suffering from asthma was 1.31 million (Statistics and Information Department, Minister’s 
Secretariat, Ministry of Health, Labour and Welfare 2014).
Approximately 5% to 10% of asthma patients have severe asthma, which may be inadequately 
controlled by ICS and LABA combinations together with additional controller therapies 
(Brightling et al 2008). These patients are at risk of asthma exacerbations (Tough et al 1998, 
Turner et al 1998) and have the greatest medical need among the asthmatic population today. 
Patients with severe asthma represent the greatest economic cost (>50% of total asthma-
related health care costs) (Antonicelli et al 2004, Serra Batlles et al 1998, Barnes and Kuitert 
1996).


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2.1
Study rationale 
This is a Japan long-term safety study to demonstrate the safety of tezepelumab in Japanese 
adults and adolescents (12 years of age and older) with a history of asthma exacerbations and 
inadequately controlled severe asthma receiving medium-or high dose ICS plus at least one 
additional asthma controller medication with or without OCS.
The results from the previous Ph2b study (CD-RI-MEDI9929-1146) have been used to select 
the target population for Ph3 studies. It is expected that adolescent patients (12-17 years of 
age) in the target population will respond similarly to adults and are therefore included as part 
of the study population. Pharmacokinetic evaluations in adolescents with asthma confirm the 
same dose can be given to adolescents as to adults. Japanese patients with severe asthma are 
participating in the ongoing pivotal Ph3 study (NAVIGATOR study [D5180C00007]) to 
assess the efficacy and safety of tezepelumab in Japanese asthma subjects. The purpose of this 
open label long term safety study is to provide additional long-term safety data of 
tezepelumab to meet the regulatory requirement of one-year exposure to tezepelumab of 100 
Japanese patients at the time of the Japan New Drug Application. The study will evaluate the 
safety of tezepelumab with regards to adverse events, as well as other safety parameters.
2.2
Background 
Biologic therapies have been shown to reduce AAER in severe asthma subjects who are 
uncontrolled with medium to high dose ICS and additional asthma controller medications. 
Omalizumab provided benefit for a subgroup of subjects with proven reactivity to an 
aeroallergen and elevated serum immunoglobulin E (IgE) levels who remain inadequately 
controlled with ICS plus LABA (XOLAIR US PI 2018, Xolair JP PI 2017). Three additional 
biologics, mepolizumab, reslizumab and benralizumab, have recently been approved for 
severe asthma with an eosinophilic phenotype (XOLAIR US PI 2018, Xolair JP PI 2017, 
CINQAIR US PI 2016, Fasenra US PI 2017, Fasenra JP PI 2018).  Biologics targeting 
interleukin (IL)-5 and IgE are now included in international treatment guidelines (GINA 
2018) as an add-on treatment to subjects uncontrolled with ICS/LABA treatment. However, 
even when using currently available biologics, substantial proportions of subjects continue to 
experience exacerbations and may benefit from agents that target different molecular 
pathways (Wenzel 2016, Fasenra US PI 2017, Fasenra JP PI 2018). Therefore, despite these 
additional therapeutic options, there is still a clear unmet medical need among subjects with 
severe asthma, independently of IgE status or eosinophil level, who are unable to gain 
complete asthma control using currently available therapies.
Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that is produced 
in responses to proinflammatory stimuli (e.g., infectious, allergic and environmental stimuli) 
and trauma. TSLP has an upstream and central role in the initiation of immune responses, and 
can activate a broad range of cell types including eosinophils, mast cells, T cells, dendritic 


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cells, type 2 innate lymphoid cells and basophils (Watson and Gauvreau, 2014). Classically, 
TSLP may be a critical component in the initiation and perpetuation of the T helper cell type 2 
(Th2) response and the resulting cascade of cytokines associated with Th2 driven asthma 
(Kaur and Brightling, 2012). Asthma is recognized as a heterogeneous disease. There are 
subsets of subjects that do not exhibit Th2-associated disease (Wenzel 2012), and there are 
emerging data that TSLP may also mediate non-allergic (non-T helper cell 2) inflammation 
(Tanaka et al, 2009, Ziegler et al, 2013).
Given that TSLP is an upstream and pleiotropic cytokine, the blockade of TSLP is therefore 
anticipated to have broad impact on the spectrum of inflammatory responses seen in asthma.
Tezepelumab is a fully human immunoglobulin G2λ (IgG2λ) monoclonal antibody (mAb) 
directed against TSLP. Tezepelumab binds to human TSLP and prevents its interaction with 
TSLP receptor (TSLPR). Owing to the central role of TSLP in initiating and maintaining a 
Th2 response, anti-TSLP therapy may provide an opportunity to treat the upstream underlying 
mechanisms of asthma by reversing the established inflammatory responses to asthma 
triggers.
Results of a completed inhaled allergen challenge study in 31 adult subjects with mild atopic 
asthma (Study 20101183) demonstrated that tezepelumab attenuated the late asthmatic 
response (LAR) and early asthmatic response (EAR) to allergen challenge, as measured by the 
area under the curve (AUC) for the percent fall in FEV1 and the maximum percent fall in 
FEV1. Tezepelumab also attenuated the increase in fractional exhaled nitric oxide (FeNO) 
value on the post-allergen day compared with the pre-allergen day. Multiple doses of 700 mg 
intravenous (IV) tezepelumab demonstrated an acceptable safety profile in subjects with mild 
atopic asthma. No subjects developed ADA after receiving tezepelumab. Based upon these 
data, MedImmune/AZ have conducted a randomized, double-blind, placebo-controlled, dose 
range finding study in asthmatics who were inadequately controlled with medium or high dose 
ICS/ LABA with or without other controller medications.
Study CD-RI-MEDI9929-1146 was a Phase 2b multicenter, multinational, dose-ranging, 
double-blind, randomized, parallel-arm, placebo-controlled study to evaluate the effect of 3 
dose levels of tezepelumab on the asthma exacerbation rate (AER) in adult subjects with 
inadequately controlled, severe asthma. Subjects were randomized in a 1:1:1:1 ratio to 1 of 3 
dose levels of subcutaneous (SC) tezepelumab (280 mg every 2 weeks [Q2W], 210 mg every 
4 weeks [Q4W], 70 mg Q4W) or placebo (Q2W) for 50 weeks. Anomalous data at a single 
site was identified following completion of this study and due to Good Clinical Practice 
(GCP) non-compliance, all data relating to 34 patients from this site were excluded and the 
Clinical Study Report (CSR) revised. Consequently, a total of 550 subjects received at least 1 
dose of tezepelumab or placebo. Statistically significant annualized AER reductions of 62%, 
71%, and 66% for the 70 mg Q4W, 210 mg Q4W, and 280 mg Q2W tezepelumab groups, 


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respectively, compared with placebo were observed in the Intent-to-Treat (ITT) population 
(p<0.001).
After repeated SC administration, mean serum trough concentration increased over time and 
achieved steady-state by week 12. Tezepelumab exhibited linear pharmacokinetics (PK) 
across 3 doses. A low incidence of ADA was observed across all treatment subjects. 6 (4.3%) 
placebo subjects and 7 (1.7%) total tezepelumab subjects who had no detectable ADA at 
baseline had detectable ADA post-treatment; no subjects developed neutralizing ADA in the 
study. There was no impact of ADA on tezepelumab PK. The results of this study did not 
identify safety signals associated with tezepelumab for any dosing regimen. The overall 
incidence of treatment-emergent adverse events (TEAEs) were similar between the placebo 
(65.9%) and the tezepelumab (66.0%) dose groups. A majority of subjects had TEAEs that 
were Grade 1(mild) or Grade 2 (moderate) in severity and not related to investigational 
product. TEAEs that resulted in permanent discontinuation of investigational product occurred 
in few subjects, and at a similar incidence between the tezepelumab (5 subjects [1.2%] 
overall) and placebo (1 subject [0.7%]) groups.  Overall, tezepelumab was well-tolerated with 
an acceptable safety profile and no safety signals were identified.
2.3
Benefit/risk assessment 
In order to evaluate the clinical benefit-risk balance for tezepelumab, preclinical and clinical 
data have been taken into consideration, as well as a review of the available information for 
monoclonal antibodies that are approved for and are in development for the treatment of 
severe asthma. Benefits for tezepelumab may include a clinically meaningful reduction in 
asthma exacerbations, and improvements in lung function and asthma control metrics. 
Tezepelumab has been well tolerated with no safety concerns identified in studies to date. No 
serious allergic reactions or anaphylactic reactions considered related to tezepelumab were 
reported in the Phase 2 program. Although TSLP suppression could theoretically have 
unanticipated immune-related side effects impairing host defence against certain infections, 
there is no clear preclinical or clinical evidence supporting such a role, and no safety concerns 
related to infections have been detected in the tezepelumab program.
The benefit/risk assessment for tezepelumab in severe asthma based on the development 
through Phase 2 is favourable. The benefit/risk assessment will be further defined by results 
from the Phase 3 program.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of tezepelumab may be found in the Investigator’s Brochure.


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3
OBJECTIVES AND ENDPOINTS
Table 3
Study objectives 
Primary objective:
Endpoint/variable:
To evaluate the safety and tolerability of 
tezepelumab
Adverse events/Serious adverse events
Vital signs
Clinical chemistry/haematology/urinalysis 
parameters
Electrocardiograms
 
 
 
 
4
STUDY DESIGN
4.1
Overall design 
For an overview of the study design see Figure 1, Section 1.3. For details on treatments given 
during the study, see Section 6.1 Treatments Administered.  
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives 
and Endpoints.  
This is an open-label, single arm study designed to evaluate the safety of a 210 mg dose of 
tezepelumab administered subcutaneously every 4 weeks in Japanese adult and adolescent 
subjects with inadequately controlled severe asthma. Patients will have a history of at least 
one exacerbation in the past year and background asthma therapy of medium- or high dose 
ICS plus at least one additional asthma controller medication (LABA, LTRA, LAMA, 
cromones, and theophylline) with or without maintenance OCS from screening and 
throughout the study including the follow-up period.
The study will consist of a screening period of 2 weeks, a treatment period of 52 weeks and a 
post-treatment follow-up period of 12 weeks.
The investigator will obtain signed informed consent from the potential subject, or their legal 
representative, before any study specific procedures are performed (For subjects aged <20 
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years, in addition to the subject providing signed informed consent or assent, the subject’s 
legally acceptable representative must also provide their informed consent.). And then the 
investigator will assign the potential subject a unique enrolment number via the Interactive 
Voice Response System (IVRS) / Interactive Web Response System (IWRS). Subjects will 
proceed to a screening period of 2 weeks maximum to allow adequate time for all of the 
eligibility criteria to be evaluated by the investigator. Subjects who meet all the eligibility 
criteria will be registered to a treatment period. Subjects will be maintained on their currently 
prescribed ICS and at least one additional asthma controller medication at their dose they 
entered screening, without change, from screening throughout the treatment period. During 
the treatment period, Investigational product (IP) will be administered subcutaneously every 4 
weeks starting at Day 0 with the last dose at Week 48. IP will not be administered on Week 
52. Subjects who discontinue IP during the study will be encouraged to undergo appropriate 
study visits/procedures for the full 52-week period. Further information is provided in section 
7.1.1. Any new treatments that are initiated will be recorded in the electronic case report form 
(eCRF). Subjects who complete the 52-week study visit will complete a 12-week post 
treatment follow-up period for the assessment of safety and anti-drug antibodies.
4.2
Scientific rationale for study design 
Pharmacokinetic evaluations in adolescents with asthma confirm the same dose can be given 
to adolescents as to adults. Japanese patients with severe asthma are participating in the 
ongoing pivotal Ph3 study (NAVIGATOR study [D5180C00007]) to assess the efficacy and 
safety of tezepelumab in Japanese asthma subjects. The purpose of this open label long term 
safety study is to provide additional long-term safety data of tezepelumab to meet the 
regulatory requirement of one-year exposure to tezepelumab of 100 Japanese patients at the 
time of the Japan New Drug Application. The study will evaluate the safety of tezepelumab 
with regards to adverse events, as well as other safety parameters.
4.3
Justification for dose 
A 210 mg Q4W dosing regimen was selected for the Phase 3 studies based on efficacy data 
and an exposure-response analysis from the Phase 2b Study CD-RI-MEDI9929-1146 using 
population analysis methodology. The population PK model of tezepelumab was developed 
based on all available data from 5 Phase 1 studies (Study 20070620, Study 20080390, Study 
2010118, Study D5180C00003, Study D5180C00002), and 2 Phase 2 studies (Study 
D5240C00001 and Study CD-RI-MEDI9929-1146). The exposure-response analysis was 
based on the Phase 2b Study CD-RI-MEDI9929-1146.
Analysis of data from the phase 2b study identified a statistically significant exposure-
response against the primary efficacy endpoint of AAER and the pharmacodynamic (PD) 
endpoint of FeNO. These relationships indicate that the dose of 70 mg Q4W is a sub-
optimally effective dose and the dose of 210 mg Q4W is optimally effective. In summary, 


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characterization of AAER data from Study CD-RI-MEDI9929-1146 indicate the 210 mg Q4W 
dose provides improved efficacy over the 70 mg Q4W dose, whereas the 280 mg Q2W dose 
did not further reduce AAER. Tezepelumab was well-tolerated at all investigated doses and 
the safety profile was well balanced between the tezepelumab and placebo groups with no 
evidence of a dose relationship to TEAEs in the adult population.
From the results of PK simulations, the mean exposure in the adolescent population as a 
whole was expected to be 1.67-fold higher in adolescents than in adults at the 210 mg Q4W 
dose.  However, because of the fact that tezepelumab has been shown to be well-tolerated at 
the 280 mg Q2W dose (which resulted in approximately 2.7-fold higher exposure than at the 
210 mg Q4W dose in adults), and considering the overall variability in the PK of tezepelumab 
(coefficient of variation [CV] approximately 45% to 50%), the adolescent exposures at the 
210 mg SC dose are considered unlikely to pose a safety risk.
The dose of 210 mg SC Q4W has been selected for evaluation in both the adult and adolescent 
populations with a body weight of ≥40 kg.
The study is designed to dose subjects at Q4W with the last dose given at Week 48, a visit at 
Week 52, and a 12-week follow-up period.
4.4
End of study definition
The end of study is defined as the last expected visit/contact of the last subject undergoing the 
study.
A subject is considered to have completed the study when he/she has completed his/her last 
scheduled contact.
See Appendix A 6 for guidelines for the dissemination of study results.
5
STUDY POPULATION
Prospective approval of protocol deviations to eligibility criteria, also known as protocol 
waivers or exemptions, is not permitted.
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be registered to a study intervention.  Under no circumstances can there be 
exceptions to this rule. Subjects who do not meet the eligibility criteria are screen failures, 
refer to section 5.4.
For procedures for withdrawal of incorrectly registered subjects see Section 7.3.


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5.1
Inclusion criteria
Subjects are eligible to be registered in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply:
(Subjects who have no written informed consent for genetic research [Gx] are eligible for the 
study without meeting inclusion criteria 2 provided that all the following inclusion criteria and 
none of the exclusion criteria apply)
Informed consent
1
Provision of signed and dated written informed consent form prior to any mandatory 
study specific procedures, sampling, and analyses for subjects who are 20 years of age or 
over. For subjects aged <20 years, in addition to the subject providing signed informed 
consent or assent, the subject’s legally acceptable representative must also provide their 
informed consent.
2
Provision of written informed consent for Gx prior to collection of the optional sample for 
genetic analysis. Applicable to adult subjects only (20 years old or over).
The Informed Consent Form (ICF) process is described in Appendix A 3.
Age
3
Subjects must be 12 to 80 years of age inclusive at the time of signing the informed 
consent form.
Type of subject and disease characteristics
4
Documented physician-diagnosed asthma for at least 12 months prior to Visit 1.
5
Subjects who have received a physician-prescribed asthma controller medication with 
medium or high dose ICS as per Global Initiative for Asthma (GINA) guideline (GINA 
2018) for subjects with ≥16 years of age and The Japanese Pediatric Guideline for the 
Treatment and Management of Asthma 2017 (Japanese Society of Pediatric Allergy and 
Clinical Immunology 2017) for subjects with <16 years of age for at least 12 months prior 
to Visit 1. 
6
Documented treatment with a total daily dose of either medium or high dose ICS (≥ 
500μg fluticasone propionate dry powder formulation equivalent total daily dose) for at 
least 3 months prior to Visit 1. The ICS can be contained within an ICS/LABA 
combination product.
Equivalent ICS doses are detailed in Appendix F
7
At least one additional maintenance asthma controller medication is required according to 
standard practice of care; e.g. LABA, LTRA, theophylline, LAMA, cromones etc. Use of 
additional asthma controller medications must be documented for at least 3 months prior 
to Visit 1.


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8
Documented history of at least one asthma exacerbation events within 12 months prior to 
Visit 1. These can be as follows:

An asthma exacerbation is defined as a worsening of asthma that required treatment 
with systemic corticosteroids for at least 3 consecutive days (a single depo-injectable
dose of corticosteroids will be considered equivalent to a 3-day course of systemic 
corticosteroids).
OR

An emergency room visit (defined as evaluation and treatment for <24 hours in an 
emergency room [ER] or urgent care center) that required systemic corticosteroids 
(as per above).
OR

An inpatient hospitalisation due to asthma (defined as admission to an inpatient 
facility and/or evaluation and treatment in a healthcare facility for ≥24 hours).
NOTE: For subjects receiving a stable maintenance dose of OCS, a temporary increase 
for at least 3 consecutive days over and above the stable existing maintenance dose 
qualifies as an exacerbation.
The below defines what is acceptable to document exacerbations in this program:

Discharge summaries from a hospital, emergency room, or an urgent care facility 
indicating that a subject was hospitalized/treated with systemic steroids for an asthma 
exacerbation.

Signed and dated notes from a referring physician, including information regarding 
diagnosis and treatment of an exacerbation with systemic steroids.

Subjects can provide evidence of prescriptions for systemic steroids used during an 
exacerbation.

A documented conversation that is recorded in a timely manner between the 
investigator/nurse and a subject who is already on an OCS action plan, detailing the 
diagnosis and treatment of an asthma exacerbation.

A documented conversation between the treating/referral physician or nurse 
certifying that a subject was treated for an exacerbation with steroids at their clinic or 
under their supervision. The dates (month/year) of the exacerbations and verbal 
confirmation that appropriate prescriptions were provided is necessary. This option 
should be used only if reasonable attempts to procure subject records have been 
unsuccessful.
9
ACQ-6 score ≥1.5 at Visit 1. The subject who does not meet at Visit 1, but meet on the 
day of registration (Visit 2) is also eligible for the study.


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Weight
10 Weight ≥40 kg at Visit 1.
Reproduction
11 Female patients who are not of child-bearing potential, or female subjects of childbearing 
potential with negative serum pregnancy test at Visit 1.
Women not of childbearing potential are defined as women who are either permanently 
sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are 
postmenopausal. Women will be considered postmenopausal if they have been 
amenorrheic for 12 months prior to the planned date of registration without an alternative 
medical cause. The following age specific requirements apply:

Women <50 years old would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range.

Women ≥50 years old would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatment.
12 Females of childbearing potential who are sexually active with a nonsterilized male 
partner must use a highly effective method of contraception from time of signature of 
consent form, and must agree to continue using such precautions for 16 weeks after the 
final dose of IP. Cessation of contraception after this point should be discussed with a 
responsible physician. Periodic abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of contraception.

Adolescent specific recommendations: If subject is female and has reached 
menarche, or has reached Tanner stage 3 breast development (even if not having 
reached menarche), the subject will be considered a female of child bearing potential.

A highly effective method of contraception is defined as one that results in a low 
failure rate (i.e., less than 1% per year) when used consistently and correctly. Highly 
effective forms of birth control include: a vasectomised sexual partner, female 
sterilization by tubal occlusion, any effective intrauterine device/system (IUD/IUS), 
and oral contraceptive.
Inclusion criteria at registration (Visit 2)
13 ACQ-6 score ≥1.5 on the day of registration if not met at Visit 1
14 Acceptable inhaler and spirometry techniques during the screening period as judged by 
the investigator(s).


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5.2
Exclusion criteria
Medical conditions
1
Any clinically important pulmonary disease other than asthma (e.g., active lung infection, 
Chronic Obstructive Pulmonary Disease (COPD), bronchiectasis, pulmonary fibrosis, 
cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 
anti-trypsin deficiency, and primary ciliary dyskinesia) or pulmonary or systemic 
diseases, other than asthma, that are associated with elevated peripheral eosinophil counts 
(e.g., allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, 
hypereosinophilic syndrome).
2
Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, 
neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, 
psychiatric, or major physical impairment that is not stable in the opinion of the 
Investigator and could: 

Affect the safety of the subject throughout the study

Influence the findings of the study or the interpretation

Impede the subject's ability to complete the entire duration of study
3
History of cancer: 

Subjects who have had basal cell carcinoma, localized squamous cell carcinoma of 
the skin or in situ carcinoma of the cervix are eligible to participate in the study 
provided that curative therapy was completed at least 12 months prior to Visit 1. 

Subjects who have had other malignancies are eligible provided that curative therapy 
was completed at least 5 years prior to Visit 1.
4
History of a clinically significant infection, including upper respiratory tract infection 
(URTI) or lower respiratory tract infection (LRTI), requiring treatment with antibiotics or 
antiviral medications finalized <2 weeks before Visit 1 or during the screening period.
5
A helminth parasitic infection diagnosed within 6 months prior to Visit 1 that has not 
been treated with, or has failed to respond to, standard of care therapy. 
6
Current smokers or subjects with smoking history ≥10 pack-years. Former smokers with 
smoking history of <10 pack years must have stopped for at least 6 months prior to Visit 1 
to be eligible.
7
History of chronic alcohol or drug abuse within 12 months prior to Visit 1. 
8
Tuberculosis requiring treatment within 12 months prior to Visit 1.
9
History of known immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test at Visit 1, or the subject taking antiretroviral 
medications as determined by medical history and/or subject’s verbal report.
10 Major surgery within 8 weeks prior to Visit 1 or planned surgical procedures requiring 
general anaesthesia or in-patient status for >1 day during the conduct of the study.


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Prior/concomitant therapy
11 Receipt of any marketed or investigational biologic agent within 4 months or 5 half-lives 
(whichever is longer) prior to Visit 1 or receipt of any investigational non-biologic agent 
within 30 days or 5 half-lives (whichever is longest) prior to Visit 1.  
Note: Subjects on previous biologics treatment are allowed to register in the study 
treatment provided the appropriate washout period is fulfilled.
12 Treatment with the following medications within last 12 weeks prior to registration: 
Systemic immunosuppressive/immunomodulating drugs (e.g. methotrexate, cyclosporine, 
etc.) except for OCS used in the treatment of asthma/asthma exacerbations.
13 Receipt of immunoglobulin or blood products within 30 days prior to Visit 1.  
14 Receipt of the Th2 cytokine inhibitor Suplatast tosilate within 15 days prior to Visit 1. 
15 Receipt of live attenuated vaccines 30 days prior to the date of registration and during the 
study including the follow-up period. 
16 Subjects that have been treated with bronchial thermoplasty in the last 24 months prior to 
Visit 1.
Prior/concurrent clinical study experience
17 Known history of sensitivity to any component of the IP formulation or a history of drug 
or other allergy that, in the opinion of the investigator or the Study Physician, 
contraindicates their participation 
18 History of anaphylaxis or documented immune complex disease (Type III 
hypersensitivity reactions) following any biologic therapy. 
19 Concurrent enrolment in another clinical study involving an IP.
20 Subject registered in the current study or randomized in previous Tezepelumab studies.
21 Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff 
and/or site staff), or subjects employed by or relatives of the employees of the site or 
sponsor.
Diagnostic assessments
22 Any clinically meaningful abnormal finding in physical examination, vital signs, 
electrocardiogram (ECG), haematology, clinical chemistry, or urinalysis during the 
screening period, which in the opinion of the Investigator, may put the subject at risk 
because of his/her participation in the study, or may influence the results of the study, or 
the subject's ability to complete the entire duration of the study.
23 Evidence of active liver disease, including jaundice or aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), or alkaline phosphatase (ALP) > 2 times the upper limit 
of normal (ULN) at Visit 1.


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24 Positive hepatitis B surface antigen, or hepatitis C virus antibody serology at screening, or 
a positive medical history for hepatitis B or C. Subjects with a history of hepatitis B 
vaccination without a history of hepatitis B are allowed to participate.
Other exclusions
25 Pregnant, breastfeeding, or lactating women.
A serum β-human chorionic gonadotropin (β-hCG) pregnancy test must be drawn for 
women of childbearing potential (WOCBP) (including adolescent females) at the 
screening visit. If the results of the serum β-hCG cannot be obtained prior to dosing of the 
IP, a subject may be enrolled on the basis of a negative urine pregnancy test, though 
serum β-hCG must still be obtained.  If either test is positive, the subject should be 
excluded.  Since urine and serum tests may miss a pregnancy in the first days after 
conception, relevant menstrual history and sexual history, including methods of 
contraception, should be considered.  Any subject whose menstrual and/or sexual history 
suggests the possibility of early pregnancy should be excluded. 
26 Unwillingness or inability to follow the study procedures, in the opinion of the 
investigator.
27 Judgment by the investigator that the subject should not participate in the study if the 
subject is unlikely to comply with study procedures, restrictions and requirements.
Genetic Research exclusion criteria
28 Previous allogeneic bone marrow transplant.
29 Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.
5.3
Lifestyle restrictions
The following restrictions apply while the patient is receiving study medication and for the 
specific times before and after.
5.3.1
Meals and dietary restrictions
Subjects should avoid eating a large meal for at least 2 hours prior to all lung function 
assessments at the center.
5.3.2
Alcohol and tobacco
Chronic alcohol or drug abuse within 12 months is restricted prior to Visit 1 and throughout 
the conduct of the study.
Current smokers or subjects with smoking history ≥10 pack-years at Visit 1 are not allowed.  
Former smokers with a smoking history of <10 pack years must have stopped for at least 6 
months prior to Visit 1 to be eligible. Smoking is not allowed throughout the course of the 
study.


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The use of e-cigarettes is also not allowed during the course of the study.
5.3.3
Activity
Subjects should avoid engaging in strenuous exertion for at least 30 minutes prior to all lung 
function assessments at the center.
5.3.4
Blood donation
Subjects must abstain from donating blood and plasma from the time of informed consent, and 
for 16 weeks (5 half-lives) after last dose of IP.
5.3.5
Contraception
Females of childbearing potential who are sexually active with a nonsterilized male partner 
must use a highly effective method of contraception from time of signature of consent form, 
and must continue using such precautions for 16 weeks after the final dose of IP. Cessation of 
contraception after this point should be discussed with a responsible physician. See inclusion 
criterion 12 in Section 5.1 for the details.
5.4
Screen failures
Screen failures are defined as subjects who signed the ICF to participate in the clinical study 
but are not subsequently entered in the treatment period.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to respond to 
queries from regulatory authorities.  Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse event (SAE).
These subjects should have the reason for study withdrawal recorded as ‘Screen failures’ (i.e., 
subject does not meet the required inclusion/exclusion criteria) in the eCRF. This reason for 
study withdrawal is only valid for screen failures, and not registered subjects. 
5.4.1
Re-screening
Re-screening is allowed only once under the following circumstances: 
Subjects with respiratory infections requiring antibiotics or antiviral medication within 14 
days prior to Visit 1 or during the screening period may be re-screened (exclusion criterion 4) 
14 days after recovery, i.e., completion of the therapy.
If the reason for screen failure was transient (including but not limited to equipment failure, 
unforeseen personal events that mandate missed screening visits), subjects may potentially be 
re-screened. These cases should be discussed with the AstraZeneca study physician and 
documented in the Investigator Study File.


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After signing a new ICF or assent form, subjects will be assigned the same enrolment code as 
for the initial screening via the IVRS/IWRS and performed Visit 1 assessments as listed in 
Table 1 (with the exception of testing for HIV1 and HIV2, hepatitis B and C, and FSH). 
Rescreening should be documented so that its effect on study results, if any, can be assessed.
Subjects who experience an asthma exacerbation during the screening period may remain in 
screening and proceed with study visits 14 days after they have completed their course of oral 
corticosteroids or returned to their maintenance dose of oral corticosteroids.
IMPORTANT! Re-screening for subjects who have screen-failed due to patient reported 
outcome (PRO) criteria (e.g. ACQ-6 score <1.5, did not meet minimum symptom 
requirement, or did not report adequate compliance with maintenance medications) is not 
allowed. 
6
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study 
participant according to the study protocol. Study treatment in this study refers to 
tezepelumab.
6.1
Treatments administered
6.1.1
Investigational products
Table 4
Study Treatments
Study treatment name:
Tezepelumab (MEDI9929)
Dosage formulation:
110 mg/mL in 10 mM acetate, 3.0% (weight per volume [w/v]) L-
proline, 0.01% (w/v) polysorbate 80, pH 5.2
Route of administration:
Subcutaneous
Dosing instructions:
Refer to section 6.2
Packaging and labelling:
Study treatment will be provided in 5cc vial. Each vial will be 
labelled in accordance with Good Manufacturing Practice (GMP) 
Annex 13 and per country regulatory requirement.
6.2
Preparation/handling/storage/accountability
IP will be supplied to the site in a kit with one vial of tezepelumab. Each kit has a unique 
number that is printed on all labels within the kit (i.e., the outer carton label and the label of 
vial within the carton).


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The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only subjects enrolled in the study may receive study treatment and only authorised site staff 
may supply or administer study treatment.  All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the investigator and authorised site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
Please note: During the COVID-19 pandemic, if allowed by local/regional guidelines, IP 
preparation and administration may be performed at the subject’s home by a qualified 
HCP. Please refer to Appendix J for further details.
Dose Preparation
Each vial should be visually inspected prior to dose preparation. The IP will be provided to the 
study sites as a colorless to slightly yellow clear solution contained in a 5 mL single use glass 
vial to be stored at 2°C to 8°C until used. If defects are noted with the IP, the investigator and 
site monitor should be notified immediately. Preparation of IP must be performed by a 
qualified person (e.g., pharmacist or investigator) at the site.
The IP does not contain preservatives and any unused portion must be discarded. Preparation 
of the IP is to be performed aseptically. Total in-use storage time from needle puncture of the 
IP vial to start of administration should not exceed 4 hours at room temperature. If storage 
time exceeds this limit, a new dose must be prepared from new vials.
To prepare the subject’s dose, the IP will be selected for administration according to the kit 
identification numbers assigned by the IVRS/IWRS.  One vial of IP will be assigned by 
IVRS/IWRS for each dose. 
Dose preparation steps:
1
Allow the vial to equilibrate at room temperature (about 30 minutes to 1 hour). Ensure 
that the vial is adequately protected from light during the warming process. Gently swirl 
the vial to ensure the contents are mixed to a clear, homogeneous solution. Do not shake.
2
To prepare IP for administration remove the tab portion of the vial cap and clean the 
stopper with 70% ethyl alcohol or equivalent. 
3
Attach a 21G 1½-inch sterile disposable needle to a 3mL sterile syringe. 
4
Withdraw 1.9 mL of the IP from the vial.


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5
Remove and discard the 21G 1½-inch sterile disposable needle from the syringe. 
6
Attach a new 27G ½-inch sterile disposable needle to the same syringe in step 5. 
7
Apply the appropriate label to the syringe.
The assigned vial should be used at one time to prepare the dose required at each visit. Unused 
product in opened and dispensed vials should not be used for subsequent dosing and should be 
stored for IP accountability. If the opened and dispensed vials must be discarded immediately
after dose preparation as per site’s Standard Operating Procedures (SOP), the vial labels along 
with the kit boxes must be retained for IP accountability.
The IP will be administered by one SC injection (see Table 5) and must be prepared using 
disposable plastic syringes and aseptic technique.
Table 5
Investigational Product Dose Preparation
Dose
Number of vial(s) 
required
Syringe size required
Total volume 
administered
210 mga
1
3 mL
1.9 mL
a
Due to the gradations available on 3 mL disposable plastic syringe, dose based on 1.9 mL administered 
volume is 209 mg.
Dose Administration
IP will be administered by a qualified healthcare professional (e.g., the investigator or study 
nurse) at the site. The injection site must be recorded in the source documents at each 
treatment visit and in the eCRF. The person administering the dose will wipe the skin surface 
of the upper arm, anterior thigh or abdomen with alcohol and allow to air dry. The skin will be 
pinched to isolate the SC tissue from the muscle. The needle will be inserted at a 90 degree 
angle approximately halfway into the SC tissue. The IP will be slowly injected (at least 5 
second duration is recommended) into the SC tissue using gentle pressure. The area should not 
be massaged after injection. It is advised that the site of injection of IP be rotated such that the 
subject receives IP at a different anatomical site at each treatment visit. Injection site must be 
documented on the eCRF and in the source documents at each treatment visit. In cases when 
rotation of the injection site is not feasible and/or the subject prefers not to rotate injection 
sites, the reason for not rotating the injection site should be documented in the source 
documents. The suggested injection site rotation sequence is presented below in Figure 2.


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Figure 2
Suggested schema of Rotation of Injection Sites
Subjects should be observed for a minimum of 2 hours after administration of the first two IP 
administrations for the appearance of any acute drug reactions. For the remaining doses, 
subjects will be observed for a minimum of 1 hour after IP administration for any such 
reaction.
If any of the following should occur, the IP should not be administered: 

The subject received allergen immunotherapy injection on the same day as scheduled IP 
administration. 

The subject has an intercurrent illness that in the opinion of the investigator and/or the 
Study Physician may compromise the safety of the subject in the study (e.g., viral 
illnesses). 

The subject, in the opinion of the investigator, is experiencing an acute or emerging 
asthma exacerbation.

The subject is febrile (≥ 38°C; ≥ 100.4°F) within 72 hours prior to IP administration. 
The visit should be rescheduled within the allowed visit window and IP should be 
administered at that visit. If this is not possible the IP administration should be skipped. If a 
subject skips 2 consecutive IP administrations, the AZ study physician should be contacted to 
discuss further participation.
If the subject reports an injection site reaction, the investigator or qualified designee will 
complete the Adverse Event (AE) eCRF page and an additional eCRF page with questions 
about the injection site reaction.
6.3
Measures to minimise bias: randomisation and blinding
This is an open-label, non-randomised study.


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All subjects will be assigned to the study treatment using the IVRS/IWRS.  Before the study is 
initiated, the telephone number and call-in directions for the IVRS and/or the log-in 
information and directions for the IWRS will be provided to each site.
If a subject withdraws from the study, then his/her enrolment code cannot be reused.  
Withdrawn subjects will not be replaced
6.4
Treatment compliance
Any change from the dosing schedule or dose discontinuations should be recorded in eCRF.
The IP Storage Manager is responsible for managing the IP from receipt by the study site until 
the destruction or return of all unused IP. The date and time of all IP administrations, as well 
as any missed doses, should be recorded in the appropriate section of the eCRF.
6.5
Concomitant therapy
All ICS asthma medications taken in the 12 months prior to Visit 1 must be recorded in the 
eCRF along with reason for treatment.
To satisfy inclusion criterion 6, a history of continuous treatment with medium or high dose 
ICS plus a second controller medication for at least 3 months prior to Visit 1 should be 
documented in source and recorded in the eCRF prior to the date of registration. 
In order to satisfy inclusion criterion 7, a history of all asthma controller medications for the 3 
months prior to Visit 1 until the end of the study should be documented in source and recorded 
in the eCRF. No changes are allowed to asthma background medications throughout the 
duration of the study except during the treatment of an asthma exacerbation.
All other medications taken for conditions other than asthma in the 3 months prior to Visit 1 
must be recorded in the eCRF along with reason for treatment by the Investigator/authorized 
delegate at each visit (as shown in Table 1 and Table 2). 
Maintenance asthma medication is not regarded as an IP, but will be provided/reimbursed by 
AstraZeneca according to local regulations in order to maintain appropriate oversight and 
access to this concomitant therapy.
As theophylline has a narrow therapeutic window, please note that subjects on maintenance 
treatment with theophylline should have blood concentration levels within therapeutic range 
and documented before Visit 1. If this is not documented before signing the informed consent, 
it can be obtained after informed consent has been given or as part of the Visit 1 procedures. 
The sample can be analysed at a local laboratory as applicable. Investigator can use their time 
and other factors that may impact the results. Investigator can use their clinical judgement 


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about the therapeutic range of theophylline levels on the basis of sampling time and other 
factors that may impact the results.
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the subject is receiving at the time of enrolment or receives 
during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates
Table 6
Restricted medications
Medication/class of drug:
Usage:
Maintenance treatment with ICS and 
long-acting bronchodilators 
(including ICS/LABA 
combinations)
No changes in either dose or regimen are allowed from V1 and 
throughout the IP treatment and preferably 4 weeks after the last 
dose of IP. 
The patients should be instructed not to take their usual asthma 
controller medication (i.e., LABA) prior to scheduled ECG 
assessment (please refer below for long-acting bronchodilator 
restrictions). Use of SABA should be avoided within 6 hours 
before ECG assessments. The medication restrictions are 
waived for the screening ECG at Visit 1.
Twice daily bronchodilators should be withheld for at least 12 
hours prior to the scheduled spirometry at site. 
Once daily bronchodilators should be withheld for at least 24 
hours prior to the scheduled spirometry at site.
Subjects will not need a washout of their asthma medications for 
unscheduled visits due to asthma worsening.
Short-acting beta-agonists (SABA)
Regular scheduled use of SABA is not allowed from V1 and 
throughout the IP treatment and preferably 4 weeks after the last 
dose of IP, PRN use is allowed if needed, however attention 
should be paid to the following restrictions.
SABA should be withheld for at least 6 hours prior to scheduled 
spirometry and ECG at site with the exception of any 
unscheduled visits due to asthma worsening. 


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Table 6
Restricted medications
Medication/class of drug:
Usage:
Additional Maintenance Controllers
No changes in either dose or regimen are allowed from V1 and 
throughout the IP treatment and preferably 4 weeks after the last 
dose of IP.
Once daily LABA and LAMA should be withheld for at least 24 
hours prior scheduled spirometry at site visits with the exception 
of any unscheduled visits due to asthma worsening.
Twice daily LABA or LAMA containing therapies should be 
withheld for at least 12 hours prior to scheduled spirometry at 
site with the exception of any unscheduled visits due to asthma 
worsening.
LTRA should be withheld for at least 24 hours prior to 
scheduled spirometry at site with the exception of any 
unscheduled visits due to asthma worsening.
Subjects on theophylline should have blood concentration levels 
within therapeutic range documented before proceeding in the 
study.
Twice daily theophyllines should be withheld for at least 12 
hours prior to scheduled spirometry at site with the exception of
any unscheduled visits due to asthma worsening.
Once daily theophyllines should be withheld for at least 24 
hours prior to scheduled spirometry at site with the exception of 
any unscheduled visits due to asthma worsening.
Short-acting anticholinergics (e.g. 
ipratropium)
These are not allowed as a rescue treatment for worsening 
asthma symptoms from V1 and throughout the IP treatment and 
preferably 4 weeks after the last dose of IP. They may be used 
for managing an asthma exacerbation event.
Inactive/killed vaccinations (e.g. 
inactive influenza)
Allowed provided they are not administered within 5 days 
before or after any study visit.
Allergen Immunotherapy
Allowed, if on stable therapy for at least 2 months prior to date 
of Visit 1 with no anticipated change during the treatment 
period. 
These should not be administered on the same day as IP 
administration.


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Table 7
Prohibited medications
Prohibited medication/class of drug:
Usage:
Long-acting beta-agonists as a
reliever (e.g. Symbicort Maintenance and 
Reliever Treatment)
Not allowed 15 days prior to Visit 1, during screening 
and throughout the IP treatment and preferably 4 
weeks after the last dose of IP.
Suplatast tosilate (Th2 cytokine inhibitor) 
Not allowed within 15 days prior to Visit 1, during 
screening and throughout the IP treatment and 
preferably 4 weeks after the last dose of IP.
Live Attenuated Vaccines
Not allowed 30 days prior to the date of registration, 
and during the study including the follow-up period.
Any immunomodulators or
immunosuppressives (except for OCS used in 
the maintenance treatment of asthma/asthma 
exacerbations in screening, and protocol 
defined asthma exacerbations on or after Visit 
2)
Not allowed 12 weeks prior to registration, during 
screening and throughout the IP treatment and 
preferably 4 weeks after the last dose of IP.
Immunoglobulin or blood products
Not allowed 30 days prior to Visit 1, during screening 
and throughout the IP treatment and preferably 4 
weeks after the last dose of IP.
Any marketed (e.g. omalizumab, 
mepolizumab, reslizumab, benralizumab) or to 
be marketed or investigational biologic 
treatment
Not allowed 4 months or 5 half-lives (whichever is 
longer) prior to the date of Visit 1, throughout the 
entire, screening period, treatment period (even if the 
subject has discontinued IP) and until the follow up 
visit week 64.  
Other investigational products (including 
investigational use of an approved drug)
Not allowed 30 days or 5 half-lives (whichever is 
longer) prior to Visit 1, during screening and 
throughout the IP treatment and until the follow up 
visit week 64.
Herbal remedies for the treatment of allergic, 
inflammatory, or respiratory diseases
Not allowed 30 days prior to Visit 1, during screening 
and throughout the IP treatment and preferably 4 
weeks after the last dose of IP. 
Medications not currently licensed for use in 
the treatment of asthma, for example 
medications approved for Chronic Obstructive 
Pulmonary Disease and not part of current 
standard of care.
Not allowed 30 days prior to Visit 1, during screening 
and throughout the IP treatment and preferably 4 
weeks after the last dose of IP.


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6.5.1
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
subject’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF.
6.5.2
Rescue medication
Short-acting β2-agonist (SABA) should be withheld for at least 6 hours prior to scheduled site 
visit spirometry and ECG at site with the exception of any unscheduled visits due to asthma 
worsening.
Rescue use of SABA administered via nebulization is discouraged, except as urgent treatment 
during an asthma exacerbation.
Rescue medication will not be provided by the sponsor.
6.5.3
Bronchial Thermoplasty
Subjects should not be treated with bronchial thermoplasty during the study.
6.6
Dose modification
Not applicable
6.7
Treatment after the end of the study
Subjects who complete week 64 should be given standard of care at the discretion of the 
investigator.
7
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
7.1
Discontinuation of study treatment
Subjects may be discontinued from investigational product (IP) in the following situations. 
Note that discontinuation from study treatment is NOT the same thing as a complete 
withdrawal from the study.

Subject decision. The subject is at any time free to discontinue IP, without prejudice to 
further treatment

Adverse Event considered to jeopardise the safety of a subject participating in the study 
by the investigator

Pregnancy

Severe non-compliance with the Clinical Study Protocol as judged by the investigator

Development of any study specific criteria for discontinuation, including:


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
An anaphylactic reaction to the IP requiring administration of epinephrine

A helminth parasitic infestation requiring hospitalization

An asthma-related event requiring intubation

Any malignancy

Development of one or more of the following:

Confirmed ALT or AST increase of ≥8 × ULN

Confirmed ALT or AST increase of ≥5 × ULN for more than 2 weeks

Confirmed ALT or AST increase of ≥3 × ULN and total bilirubin of ≥2 × ULN

ALT or AST of ≥3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (≥5%)
See the Schedule of Assessment (SoA) for data to be collected at the time of IP 
discontinuation and follow-up and for any further evaluations that need to be completed.
7.1.1
Procedures for discontinuation of study treatment
Subjects are free to discontinue IP or withdraw from the study at any time without prejudice to 
further treatment. Discontinuing study treatment is not the same as study withdrawal. 
Procedures to follow for study withdrawal are detailed below in section 7.3. If the subject 
decides to withdraw consent, then the reason for this must be recorded separately in the eCRF.
A subject that decides to discontinue IP should always be asked about the reason(s) and the 
presence of any adverse events. The reason for discontinuing treatment and the date of last IP 
administration should be recorded in the eCRF. Subjects permanently discontinuing IP 
administration should be given locally available standard of care therapy, at the discretion of 
the Investigator. However, treatment with marketed or investigational biologics is not allowed 
until Week 64 even if the subject has discontinued IP. Interaction studies between 
tezepelumab and other biologics indicated for the treatment of asthma have not been 
conducted. For additional information regarding pharmacokinetic and pharmacodynamic 
effects of tezepelumab reference should be made to the investigator brochure. 
All subjects who prematurely discontinue IP should return to the study center and 
complete the procedures described for the premature Investigational Product 
Discontinuation (IPD) visit at 4 weeks (+/-5 days) post last IP administration. Subjects 
who discontinue treatment should be encouraged to return for all regularly scheduled visits for 
safety and efficacy assessments.
At the IPD visit the subject will be given three options as to how they will be followed as 
follows:


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1
The subject should be encouraged to return for all regular clinic visits and perform all 
scheduled assessments until he/she completes a total of 52 weeks treatment period. 
2
The subject will be offered follow-up on a monthly basis via telephone calls until the 
subject completes 52 weeks in the study. The subject should return for a follow-up visit 
16 weeks (+/- 7 days) (refer to SoA, FU2 visit – Week 64) post last IP administration and 
for the end of treatment (EOT) visit at Week 52 (+/-5 days). 
3
If the subject cannot or does not wish to comply with any of the options above, they will 
complete a follow-up visit at 16 weeks (+/- 7 days) (refer to SoA, FU2 visit – Week 64) 
post last IP administration. After this visit the Investigator will only contact the subject at 
52 weeks post registration. No other study assessments will be performed prior to this 
contact.
If the last IP administration was after week 36 for options 1 or 2, the subject will return to the 
clinic for an EOT visit at Week 52 (+/- 5 days), and for option 3, the investigator will contact 
the subject at 52 weeks post registration. The subject for options 1, 2 and 3 will then return for 
a follow-up visit 16 weeks (+/- 7 days) post last IP administration (refer to SoA, FU2 visit –
Week 64). If the last IP administration was at Week 36, the subject will follow EOT 
assessment rather than FU2 visit.
The EOT visit will be completed immediately in the case of subsequent early withdrawal from 
option 1 or 2. Subjects who do not wish to have any follow-up contacts will be discontinued 
from the study. 
If the subject chooses option 1, all assessments will be completed as per the SoA as indicated 
in Section 1.1. If the subject chooses 2 or 3, the key information to be collected during the 
telephone calls are AEs/SAEs, changes in concomitant medication, and asthma exacerbation 
information. 
Subjects who initially choose options 1or 2 and subsequently cannot or do not wish to comply 
with the requirements of their option can continue with a less intensive option (i.e. subject 
initially choosing option 1 can continue with options 2 or 3, subjects initially choosing option 
2 can continue with option 3).
If a subject discontinues IP due to a study specific discontinuation criterion, this should 
always be recorded as ’Development of study specific withdrawal’ on the termination form in 
the eCRF.
7.2
Lost to follow-up
A subject will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.  


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The following actions must be taken if a subject fails to return to the clinic for a required 
study visit:

The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule.

Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject or next of kin by either repeated 
telephone calls, certified letter to the subject´s last known mailing address or local 
equivalent methods. These contact attempts should be documented in the subject’s 
medical record. 

Efforts to reach the subject should continue until the end of the study. Should the 
subject be unreachable at the end of the study the subject should be considered to be 
lost to follow up with unknown vital status at end of study and censored at latest 
follow up contact.
A subject is considered lost to follow-up when any of the following attempts of contact 
are failed.
o
3 attempts of either phone calls, faxes or emails
o
Having sent 1 registered letter/certified mail
o
One unsuccessful effort to check the status of the subject using publicly available 
sources.
7.3
Withdrawal from the study
A subject may withdraw from the study (eg, withdraw consent), at any time (investigational 
product and assessments) at his/her own request, without prejudice to further treatment.
A subject who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records) as per Section 7.1.1.
A subject who withdraws consent will always be asked by the Investigator about the reason(s) 
and the presence of any AEs.  The Investigator will follow-up subjects as medically indicated. 
A withdrawal visit is essential to collect as much data as possible for the subject as per EOT 
visit described in SoA, Table 2. 
If the subject withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a subject withdraws from the study, he/she may request destruction of any samples taken, 
and the investigator must document this in the site study records.  


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If the subject only withdraws consent for the retention of blood samples for Gx, the subject 
will not be withdrawn from the study.
Withdrawal of consent from the study must be ascertained and documented by the Investigator 
and recorded in the eCRF.
7.3.1
Withdrawal due to recruitment completion
When the required number of subjects are registered in the study, ongoing subjects in 
screening will not be registered and will be withdrawn from the study. The reason of the 
withdrawal should be documented in the source and eCRF. As with screen failures, no further 
study related follow-up of these patients is required.
7.3.2
Discontinuation or suspension of the whole study program
If AstraZeneca decides to prematurely terminate or suspend the study, the Principal 
Investigator, and regulatory authorities should receive written notification of the reasons for 
the premature termination or suspension. The Principal Investigator will immediately notify 
the decision to the subjects and if relevant give appropriate medical treatment; take necessary 
measures and document these in the source notes.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA.  
The investigator will ensure that data are recorded on the eCRF. The Web Based Data Capture 
(WBDC) system will be used for data collection and query handling.
The investigator ensures the accuracy, completeness, legibility 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 eCRF.  A copy of the completed eCRF 
will be archived at the study site. Additional data to assess the impact of COVID-19 pandemic 
will be collected.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue Study treatment.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria.  The investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
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The amount of blood collected from each subject over the duration of the study (excluding 
optional blood samples) will be approximately 115 mL including any extra assessments that 
may be required, and will not exceed 140 mL. Repeat or unscheduled samples may be taken 
for safety reasons or for technical issues with the samples.
8.1
Efficacy assessments
8.1.1
Assessment of asthma exacerbation
Subjects enrolled in the study should have had at least one exacerbation in the prior 12 months 
before Visit 1. The list below defines what is acceptable documentation for historical 
exacerbations:

Discharge summaries from a hospital, emergency room, or an urgent care facility 
indicating that a subject was hospitalized/treated with systemic steroids for an asthma 
exacerbation.

Signed and dated notes from a referring physician, including information regarding 
diagnosis and treatment of an exacerbation with systemic steroids.

Evidence of prescriptions for systemic steroids used during an exacerbation.

A documented conversation that is recorded in a timely manner between the 
investigator/nurse and a subject who is already on an OCS action plan, detailing the 
diagnosis and treatment of an asthma exacerbation.

A documented conversation between the treating/referral physician or nurse certifying 
that a subject was treated for an exacerbation with steroids at their clinic or under their 
supervision. The dates (month/year) of the exacerbations and verbal confirmation that 
appropriate prescriptions were provided is necessary. This option should be used only if 
reasonable attempts to procure subject records have been unsuccessful.
During the study, an asthma exacerbation will be defined as a worsening of asthma that leads 
to any of the following:

A temporary bolus/burst of systemic corticosteroids (or a temporary increase in stable 
OCS background dose) for at least consecutive 3 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.

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).

An in-patient hospitalization (defined as admission to an inpatient facility and/or 
evaluation and treatment in a healthcare facility for ≥ 24 hours) due to asthma.
The start of an exacerbation is defined as the start date of systemic corticosteroids or of a 
temporary increase in a stable OCS background dose, date of ER or urgent care visits 
requiring systemic corticosteroids, or date of hospital admission due to asthma, whichever 
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The end date of an exacerbation is defined as the last date of systemic corticosteroids or of a 
temporary increase in a stable OCS background dose, date of ER or urgent care visit, or date 
of hospital discharge, whichever occurs later.
If less than 7 days have elapsed since the end date of an asthma exacerbation and the start date 
of a new asthma exacerbation, the second event will be considered a relapse of the prior 
asthma exacerbation.
All asthma exacerbations that occur during the treatment period and follow up, must be 
recorded in the exacerbation eCRF.  See section 8.3.7 for additional information on recording 
asthma exacerbations as an AE/SAE during the study.
8.1.2
Spirometry
8.1.2.1
General Requirements
Pulmonary function will be measured by spirometry at the study site using the site’s own 
equipment. Spirometry will be performed by the Investigator or authorized delegate according 
to the respiratory function test guideline. (The Japanese Respiratory Society 2004).
Important!

Subjects should avoid engaging in strenuous exertion for at least 30 minutes prior to all 
lung function assessments at the center.

Subjects should avoid eating a large meal for at least 2 hours prior to all lung function 
assessments at the center. 

Subjects should withhold their usual maintenance therapies on the day(s) when lung 
function testing is being performed as below:

SABAs should be withheld at least 6 hours prior to scheduled spirometry at site. 

Twice daily LABA or LAMA-containing therapies should be withheld for at least 12 
hours prior to scheduled spirometry at site.

Once daily LABA or LAMA-containing therapies should be withheld for at least 24 
hours prior to scheduled spirometry at site.

LTRA should be withheld for at least 24 hours prior to scheduled spirometry at site.

Twice daily theophyllines should be withheld for at least 12 hours prior to scheduled 
spirometry at site.

Once daily theophyllines for at least 24 hours prior to scheduled spirometry at site. 
Note: If any of the above restriction are not met, the spirometry assessment should be 
rescheduled within the allowed visit window.
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Spirometry testing should be done according to the SoA. For adult subjects, spirometry testing 
must be initiated in the morning between 6:00 AM and 11:00 AM during the screening period 
and at registration visit (Visit 2). Spirometry testing can be initiated during the whole day for 
adolescent subjects.
All post- registration spirometry assessments should be performed within ± 1.5 hours of the 
time that the registration spirometry was performed. For example, if the registration 
spirometry was started at 8:00 AM, then all subsequent spirometry testing needs to be initiated 
between 6:30 AM and 9:30 AM.
Spirometry technique 
Subjects should avoid engaging in strenuous exertion for at least 30 minutes prior to 
spirometry measurements. Subjects should avoid eating a large meal for at least 2 hours prior 
to spirometry measurements at the site. All spirometry manoeuvres 
 
 should be performed with the subject 
seated in an upright position. If this is not comfortable for the subject, standing is permitted. 
The same position should be used by the subject for each forced expiratory manoeuvre from 
enrolment throughout the study. The head must not be tilted during manoeuvres and the thorax 
should be able to move freely; hence tight clothing should be loosened. A nose-clip should be 
used for the manoeuvre. Mouthpieces of the same dimension and shape should be used by the 
subject from enrolment throughout the study.
The spirometry manoeuvre consists of three phases, the first is the maximal inspiration, the 
second is a “blast” of exhalation (
) and the last is a continuation to 
complete exhalation. The subject should inhale rapidly and completely from functional 
residual capacity. It is important that the preceding inspiration is fast and that any pause at full 
inspiration be minimal (i.e. only for 1-2 seconds). The subject should be prompted to “blast”, 
not just “blow”, and they should be encouraged to fully exhale until the end of test criteria are 
met. If the patient feels dizzy, the manoeuvre should be stopped, since syncope could follow 
due to prolonged interruption of venous return to the thorax. Manoeuvres that do not meet the 
end of test criteria should not be used to satisfy the requirement of three acceptable 
manoeuvres. However early termination, by itself, is not a reason to eliminate all the results 
from such a manoeuvre from further consideration.
 
 
Multiple forced expiratory efforts (at least 3 but no more than 8) will be performed for each 
spirometry session. 
 
CCI
CCI
CCI
CCI


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Record keeping
A signed and dated copy of the pre- BD printout must be kept at study centre for source data 
verification. The printout must be marked with the study code, enrolment code, date and time 
of measurement, visit number. If a printout cannot be printed, the mean value of the 
measurements will be recorded in the subject’s charts.
8.1.3
Patient reported outcome (PRO)
PRO paper form will be filled in by patient at the site under the supervision of the study staff. 
The study staff will transfer the responses into the eCRF. 
8.1.3.1
Asthma Control Questionnaire-6 (ACQ-6)
The ACQ-6 captures asthma symptoms (night-time waking, symptoms on waking, activity 
limitation, shortness of breath, wheezing) and SABA use via subject-report.
Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely 
uncontrolled). The mean ACQ-6 score is the mean of the responses. Mean scores of ≤ 0.75 
indicate well-controlled asthma, scores between 0.75 and <1.5 indicate partly controlled 
asthma, and a score ≥1.5 indicates uncontrolled asthma (Juniper et al 2006). 
 
 
 
8.2
Safety assessments 
Planned time points for all safety assessments are provided in the SoA.
CCI
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8.2.1
Clinical safety laboratory assessments
See Table 8 for the list of clinical safety laboratory tests to be performed and to the SoA for 
the timing and frequency.  All protocol-required laboratory assessments, as defined in the 
table, must be conducted in accordance with the laboratory manual and the SoA.  
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at 
study centre as source data for laboratory variables.  
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7.
The clinical chemistry, haematology and urinalysis will be performed at a local laboratory or 
near to the Investigator site.  Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site.
Table 8
Laboratory safety variables
Haematology (whole blood)
Clinical Chemistry (serum)
B-Haemoglobin
S-ALP
B-Leukocyte count
S-ALT
B-Leukocyte differential count (absolute count)
S-AST
B-Platelet count
S-Bilirubin, total
B-Hematocrit
S-Blood urea nitrogen
B-Mean Corpuscular Volume 
S-Calcium, total
B-Red blood cell (RBC) count
S-Chloride
S-Creatinine
Urinalysis (dipstick)
S-Creatinine kinase (CK)
U-Occult blood
S-CRP
U-Protein
S-Gamma-glutamyl transferase (GGT)
U-Glucose 
S-Glucose
U-Microscopy and culture as required *
S-Phosphorus
S-Potassium
Pregnancy test (Blood or urine) **
S-Sodium
S-β-hCG, FSH, U- hCG
S-Total cholesterol
S-Uric acid
*
Only when a positive dipstick result for any parameter is observed. Only the results to be reported as adverse 
events are recorded in AE section of the eCRF.
** See Section 8.2.1.1.


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NB. In case a subject shows an AST or ALT ≥3×ULN together with total bilirubin ≥2×ULN 
please refer to Appendix E ‘Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law’, for further instructions.
8.2.1.1
Pregnancy Test
The following tests are applicable to female subjects only, and will be conducted in 
accordance with the schedule provided in Section 1.1.

Serum β-hCG – the test done at enrolment (Visit 1) only, for WOCBP and adolescent 
females (analysed at a local laboratory or near to the Investigator site).

FSH – the test done at enrolment (Visit 1) only, for female subjects to confirm 
postmenopausal status in women <50 years who have been amenorrheic for >12 months. 
(analysed at a local laboratory or near to the Investigator site)

Urine human Chorionic Gonadotropin (hCG) – the test will be performed at the study site 
for WOCBP and adolescent females at each treatment visit before IP administration using 
a dipstick. Positive urine test result must be confirmed with serum β-hCG.
8.2.2
Weight and height
Weight and height will be measured in accordance with the SoA. The subject’s weight will be 
recorded in kilograms, and height will be recorded in centimeters. Weight and height 
measurements will be performed in light clothing and with shoes off.
8.2.3
Physical examinations
A complete physical examination will be performed and include an assessment of the 
following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including 
spine and extremities) and neurological systems. Brief physical examination will also be
performed and 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 will be recorded.
Physical examination (complete and brief) will be performed at timelines as specified in the 
SoA. Investigators should pay special attention to clinical signs related to previous serious 
illnesses, new or worsening abnormalities may qualify as adverse events, see Section 8.3.7 for 
details.
8.2.4
Vital signs
Vital signs (i.e. pulse, blood pressure, respiration rate and body temperature) will be obtained 
in accordance with SoA.


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Vital signs will be taken prior to blood drawing, IP administration, and, if possible, usual 
asthma controller medication.
Blood pressure and pulse measurements will be assessed in sitting position with a completely 
automated device.  Manual techniques will be used only if an automated device is not 
available.
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the subject in a quiet setting without distractions (eg, television, cell phones).
Pulse rate will be obtained before blood pressure.
Respiration rate will be obtained after subject has been resting for at least 5 minutes, by 
counting number of breaths (i.e., how many times the chest rises) for one minute.
Body temperature will be measured in degrees Celsius prior to IP administration, in 
accordance with local standards.
8.2.5
Electrocardiograms
A 12-lead ECG will be taken in supine position, prior to blood draw, spirometry, BD 
administration and IP administration. 12-lead ECG will be performed at a local laboratory or 
near to the Investigator site.
The investigator or authorized delegate will be responsible for the overall interpretation and 
determination of clinical significance of any potential ECG findings. In case of discrepancy 
between the investigator's interpretation and that provided by the ECG machine (if 
applicable), the investigator's interpretation will take precedence and should be noted on the 
printout and recorded in the eCRF. A copy of the ECG will be produced and quality checked 
and kept in case of further need for re-evaluation.
It is highly recommended that the same machine is used for assessment throughout the 
subject’s participation in the study.
ECG data and evaluation will be recorded in the eCRF.
8.2.6
Other safety assessments
8.2.6.1
Serology
Hepatitis B surface antigen, hepatitis C antibody, HIV-1 and HIV-2 antibodies will be 
assessed at enrolment (Visit 1) only.  All testing for these will be performed at a local 
laboratory or near to the Investigator site.


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8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs 
see Section 8.3.3.  
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.3.2
Time period and frequency for collecting AE and SAE information 
AEs, including SAEs will be collected from time of signature of ICF throughout the treatment 
period and the follow-up periods.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix B.  The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject’s last visit 
and he/she considers the event to be reasonably related to the Study treatment or study 
participation, the investigator must notify the sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts.  All SAE/non-serious AEs/AEs of special interest will be 
followed until resolution, stabilization, the event is otherwise explained, or the subject is lost 
to follow-up. 
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the Investigator for as long as medically indicated, 


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but without further recording in the eCRF.  AstraZeneca retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.
8.3.4
Adverse event data collection
The following variables will be collect for each AE;

AE (verbatim)

The date when the AE started and stopped

Maximum intensity

Whether the AE is serious or not

Investigator causality rating against the Investigational Product(s) (yes or no)

Action taken with regard to Investigational Product(s)

AE caused subject’s withdrawal from study (yes or no)

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)

Causality assessment to other medication
8.3.5
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.


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A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: ‘Have you/the child 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.
8.3.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the CSR.  Deterioration as compared to baseline in protocol-mandated 
laboratory values/vital signs should therefore only be reported as AEs if they fulfil any of the 
SAE criteria or are the reason for discontinuation of treatment with the investigational 
product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin 
value).  In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
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 Appendix B

The patient discontinues IP 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 of Visit 1) as judged by the Investigator.
Asthma exacerbation should be recorded as an AE or SAE only if it fulfils any of the above 
criteria.


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8.3.8
Adverse Events of Special Interest
An adverse event of special interest (AESI) is an event of scientific and medical interest 
towards improving the understanding of the IP. An AESI may be serious or non-serious. For 
this study, AESIs include:

Anaphylactic reactions 

Immune complex disease (Type III hypersensitivity reactions)

Malignancy

Helminth infections 

Severe infections which are defined as:

SAEs or 

Requiring treatment with antiviral medications, intravenous antibiotics or 
medications for helminth parasitic infection or

Requiring a permanent discontinuation of study drug

Injection site reactions 

Opportunistic infections

Guillain Barre Syndrome
8.3.9
Hy’s law
Cases where a subject shows elevation in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3×ULN together with total bilirubin ≥ 2×ULN may need to 
be reported as SAEs.  Please refer to Appendix E for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.


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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 i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system,
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site 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 IP.
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study 
Protocol.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study subject has received any study drug.  
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the subject was discontinued from the study.


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If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Appendix B) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy.
8.4.2.2
Paternal exposure
Pregnancy of the subject’s partners will not be considered an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) should be followed up and documented for conceptions occurring 
from the date of the first administration of IP until 16 weeks (5 half-lives) after the last 
administration of IP.
8.4.3
Overdose
A dose in excess of 280 mg administered within a 2-week period will be considered an 
overdose.
There is currently no specific treatment in the event of overdose of IP and possible symptoms 
of an overdose are not established.
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose eCRF module.
An overdose without associated symptoms is only reported on the Overdose eCRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 
8.3.2.  For other overdoses, reporting must occur within 30 days.


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8.4.4
Medication error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening)or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B 8.
8.4.5
Management of IP-related toxicities
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 when IP is being administered.  Study site personnel must be trained to recognize 
and treat anaphylaxis (Lieberman et al. 2010). Details on anaphylaxis management are 
provided in Appendix G.
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Sampson et al. 2006). Anaphylaxis typically manifest as 1 of 3 clinical scenarios:
1
The acute onset of a reaction (minutes to hours) with involvement of the skin, mucosal 
tissue or both and at least one of the following: a) respiratory compromise; or b) reduced 
blood pressure or symptoms of end-organ dysfunction 
2
Two or more of the following that occur rapidly after exposure: involvement of the 
skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated 
symptoms and/or persistent gastrointestinal symptoms
3
Reduced blood pressure after exposure.
Subjects will have had a pre-assessment (i.e., vital signs and lung function, if applicable) prior 
to IP administration. At Visits 2 and 3, subjects should be observed for a minimum of 2 hours 
after IP administration for the appearance of any acute drug reactions. For the remaining visits 
involving IP administration, subjects will be observed for a minimum of 1 hour after IP 
administration for any such reaction.
If an anaphylactic reaction occurs, a blood sample will be drawn from the subject as soon as 
possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge for 
analysis of serum tryptase. The sample will be tested at central laboratory.


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8.6
Pharmacodynamics
Pharmacodynamics is not evaluated in this study. 
8.7
Genetics
 
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8.7.2
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality. Samples may be stored for a maximum of 15 
years or as per local regulations from the date of the Last Subject’s Last Visit, after which 
they will be destroyed. DNA is a finite resource that may be used up during analyses. The 
results of any further analyses will be reported either in the CSR itself or as an addendum, or 
separately in a scientific report or publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical hypotheses
No hypothesis testing will be conducted for this study.
9.2
Sample size determination 
No formal sample size calculation was conducted for this study. Approximately 66 Japanese 
patients are required to enter treatment period to obtain 59 patients who complete the planned 
52-weeks treatment period assuming a drop-out rate of 10% during the 52-weeks treatment 
period.
9.3
Populations for analyses 
For purposes of analysis, the following populations are defined:
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Population
Description
Enrolled 
All subjects who sign the ICF
Assigned to Study treatment
All subjects registered to study treatment (irrespective of whether treatment 
is subsequently taken)
Safety Analysis Set
All subjects who received at least one dose of IP.
 
 
 
 
Safety, efficacy and 
 presentations will be based on the safety analysis set. 
 
9.4
Statistical analyses 
Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan (SAP) will be developed and finalised before database lock and will describe the 
subject populations to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data.  This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints.  Any deviations from this plan will be reported in the CSR.
Important protocol deviations will be defined at subject level prior to database lock and will 
be summarized. Subjects will not be excluded from analysis sets on the basis of any important 
protocol deviations. The definitions of each category of important protocol deviation will be 
fully specified in the SAP and will include (but may not be limited to): subjects who entered 
to treatment period without fulfilling key entry criteria; subjects who received prohibited or 
restricted concomitant medications during IP treatment.
9.4.1
Subject disposition, demography and baseline characteristics
Frequency and percentages of subject disposition and reasons for discontinuation of IP will be 
presented. Subjects who prematurely discontinue the IP will be listed along with the reason for 
discontinuation. In addition, frequency and percentages of withdrawal from the study together 
with reasons will be presented. 
Demographics and subject characteristics will be summarized using frequency and 
percentages (for categorical variables) and n, mean, standard deviation, minimum, median and 
maximum (for continuous variables) using the safety analysis set.
Relevant medical history/current medical conditions will be summarized by system organ 
class and preferred term of the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary using frequency and percentage of subjects.
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9.4.2
Prior and concomitant medication
Prior and concomitant medications, categorized according to the World Health Organization 
(WHO) Drug Reference List dictionary which employs the Anatomical Therapeutic Chemical 
(ATC) classification system, will be summarized as frequency and percentage of subjects 
reporting usage. Prior medications are defined as those which stopped before first dose of IP. 
Concomitant medications are defined as those which either started or continued after first dose 
of IP.
9.4.3
Definition of baseline
In general, the last measurement on or prior to the date of first dose of study treatment will 
serve as the baseline measurement. If there is no value on or prior to the date of first dose of 
study treatment, then the baseline value will not be imputed and will be set to missing.
Further details regarding baseline definitions will be provided in the SAP.
Change from baseline is defined as the absolute difference between the measurement at the 
relevant time point during treatment period and the baseline value.
9.4.4
Efficacy analyses
All efficacy variables will be summarised using descriptive statistics. Where appropriate, 
change from baseline will also be summarised descriptively.
9.4.5
Safety analyses
Adverse events will be coded using the MedDRA version in force at database lock. The 
definition of on-treatment and on-study for adverse event analyses will be given in the SAP.
The number and percentage of subjects with on-treatment and on-study adverse events will be 
tabulated separately by preferred term and system organ class. An event that occurred one or 
more times during a period will contribute 1 observation to the numerator of the proportion. 
The denominator of the proportion will comprise all subjects in the safety population. On-
treatment adverse events will also be summarized by intensity/severity and separately, by 
causality/relatedness (as determined by the investigator). Should a subject report the same 
preferred term/system organ class within multiple intensity/severity or causality/relatedness 
categories, the subject’s worst occurrence (most severe/most related) will be tabulated. 
Serious AEs, AEs leading to discontinuation from IP, and commonly occurring AEs will be 
summarized in a generally similar manner. Adverse events, SAEs, AEs leading to death, and 
AEs leading to discontinuation of IP will be summarized as applicable. An overall summary 
of on-treatment AEs adjusted for subject exposure to treatment will be presented.
AESIs, as defined in Section 8.3.8 will also be summarized descriptively.


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Laboratory data will be summarized by presenting shift tables using normal ranges (baseline 
to most extreme post-baseline value) and by presenting summary statistics of observed and 
change from baseline values (means, medians, quartiles, ranges). The incidence of clinically 
notable laboratory abnormalities will be summarized.
Vital signs data will be summarized by presenting summary statistics of observed and change 
from baseline values. The incidence of clinically notable vital signs abnormalities will be 
summarized. Abnormal ECGs as per Investigator's overall interpretation will be summarized.
9.4.6
Other analyses 
 
 
 
9.5
Interim analyses 
An interim analysis to summarise 6 months safety data will be performed when all subjects 
complete Visit 8 (24-week of treatment period) for submission.
The SAP will describe the planned interim analyses in greater detail.
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Fasenra (benralizumab). Prescribing information. AstraZeneca AB, Södertälje, Sweden; 2017. 
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Kaur D, Brightling C. OX40/OX40 ligand interactions in T-cell regulation and asthma. Chest. 
2012;141:494-9.
Lieberman et al. 2010
Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM, Bernstein DI, et al. The 
diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin 
Immunol. 2010 Sep;126(3):477-80.e1-42.
 
 
Partridge 2007
Partridge MR. Examining the unmet need in adults with severe asthma. Eur Resp Rev. 
2007;16:67-72.
Pascual and Peters 2005
Pascual RM, Peters SP. Airway remodeling contributes to the progressive loss of lung 
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Sampson H.A, A. Munoz-Furlong, R.L. Campbell, N.F. Adkinson Jr., S.A. Bock, A. Branum 
et al. Second symposium on the definition and management of anaphylaxis: summary report: 
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Statistics and Information Department, Minister’s Secretariat, Ministry of Health, Labour and 
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11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Appendix A
Regulatory, ethical and study oversight considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines

Applicable International Conference on Harmonisation (ICH) GCP Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an Institutional Review Board (IRB) / Independent 
Ethics Committee (IEC) by the investigator and reviewed and approved by the IRB/IEC 
before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects.  
The head of the study site will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
A 2
Financial disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.


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A 3
Informed consent process
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorised representative and answer all questions regarding the study.  
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorised representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
centre.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained.  
The authorised person obtaining the informed consent must also sign the ICF.
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative.  
 
Subjects who are rescreened are required to sign a new ICF.
 
 
 
 
 
 
 
 
 
During the COVID-19 pandemic, re-consent may be obtained remotely and/or verbally if 
local/regional guidelines allow in order to reduce the risk of subjects of COVID-19 exposure 
during clinic visits. For further details please refer to Appendix J.
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A 4
Data protection
Each subject will be assigned a unique identifier by the sponsor.  Any subject records or data 
sets transferred to the sponsor will contain only the identifier; subject names or any 
information which would make the subject identifiable will not be transferred.  
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the subject.  
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
Any committee will not have.
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and 
letters to Investigators.
A 6
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical trial and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the main study is 
conducted.
A 7
Data quality assurance
All subject data relating to the study will be recorded on printed or electronic Case Report 
Form (CRF) unless transmitted to the sponsor or designee electronically (eg, laboratory data).  
The investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  


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The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor. 
A 8
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained.  The investigator may need to 
request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available.
Definitions of what constitutes source data can be found in Clinical Study Agreement and/or 
other documents.
A 9
Publication policy
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission.  This allows the sponsor to protect proprietary information and to provide 
comments.  
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.


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Appendix B
Adverse event definitions and additional safety information
B 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a subject or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment.   An AE can therefore be any unfavourable and 
unintended sign (e.g.  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 related to the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-subject hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity.  

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require medical 
treatment to prevent one of the outcomes listed above.
B 3
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (e.g., hepatitis that resolved without hepatic failure).
B 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.


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B 5
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
B 6
Intensity rating scale:
1
mild (awareness of sign or symptom, but easily tolerated)
2
moderate (discomfort sufficient to cause interference with normal activities)
3
severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 7
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 subject actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 


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pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 8
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 participant 
or has the potential to cause harm to the participant.  
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 participant.
Medication error includes situations where an error.  

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognized that could have led to an error


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Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g.  medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated e.g.  tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed 

Wrong participant received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) e.g.  forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant 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 AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Appendix C
Handling of Human Biological Samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
subjects while in storage at the centre until shipment or disposal (where appropriate).
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 will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers.
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
C 2
Withdrawal of Informed Consent for donated biological samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the subject is 
withdrawn from further study participation.
The Investigator:

Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site

Ensures that the subject and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action
documented and returned to the study site.


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C 3
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 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 types 1 and 2. They are assigned the following UN number 
and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.


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Appendix D
Genetics
D 1
Use/analysis of DNA
Genetic variation may impact a subject’s response to therapy, susceptibility to, and severity 
and progression of disease.  Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease aetiology; and/or molecular subtype of the disease being treated.  Therefore, 
where local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis from consenting subjects.
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 may consist of the analysis of the structure of the subject´s DNA, i.e. the 
entire genome. 
The results of genetic analyses may be reported in the CSR or in a separate study summary.
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on Tezepelumab continues but no longer than 15 
years or other period as per local requirements.
D 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All subjects will be asked to participate in this genetic research.  Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit.  The subject will 
not be excluded from any aspect of the main study.


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Inclusion criteria
For inclusion in this genetic research, subjects 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
Withdrawal of consent for genetic research:
Subjects 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.  Procedures for withdrawal are outlined in Section 7 of the main 
Clinical Study Protocol.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the subjects at Visit 2
(Registration). Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding subjects who may withdraw due to an adverse event (AE), 
such subjects would be important to include in any genetic analysis. If for any reason the 
sample is not drawn at Visit 2 (Registration), it may be taken at any visit until the last study 
visit. Only one sample should be collected per subject 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 subject confidentiality.  Samples will be stored for a maximum of 15
years, from the date of last subject 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 only by the second, unique number.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organisation.  No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA).


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The link between the subject enrolment code and the second number will be maintained and 
stored in a secure environment, with restricted access at AstraZeneca or designated 
organisations.  The link will be used to identify the relevant DNA samples for analysis, 
facilitate correlation of genotypic results with clinical data, allow regulatory audit, and permit 
tracing of 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 Appendix A.
Informed consent
The genetic component of this study is optional and the subject 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 subject must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the subject and the original filed at the study centre.  The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
subject understands that they may freely withdrawal from the genetic aspect of the study at 
any time.
Subject data protection
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, 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 subject.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an investigator might know a subject’s 
identity and also have access to his or her genetic data.  In addition, Regulatory authorities 
may require access to the relevant files, though the subject’s medical information and the 
genetic files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.
AstraZeneca and its designated organisations 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 organisations 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 


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only use this information for health related research purposes.  Researchers may see summary 
results but they will not be able to see individual subject 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 subjects that 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 may be prepared where appropriate.


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Appendix E
Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases.  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 7.1 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 subject meets 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 Total 
Bilirubin (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 Serious Adverse Events (SAEs) and Adverse Events (AEs) according to the 
outcome of the review and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3× Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2×ULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).  


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Hy’s Law (HL)
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 ×ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e., on 
the same day) the elevation in TBL, but there is no specified time frame within which the 
elevations in transaminases and TBL must occur.
E 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 subject who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the AstraZeneca representative

Determine whether the subject meets PHL criteria (see Appendix E 2 for definition) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not met
If the subject does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the subject has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol.
E 4.2
Potential Hy’s Law Criteria met
If the subject does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Section 8.3.9)


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
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 Clinical Study Protocol process for SAE reporting.

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
# 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.
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 aetiology of the event and perform diagnostic investigations as discussed 
with the Study Physician. 

Complete the three Liver CRF Modules as information becomes available 
E 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:


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
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:

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 Clinical Study Protocol 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 Clinical Study Protocol 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.
E 6
Laboratory tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended when using a central laboratory. For individual studies, the list may be reduced 
to a subset of tests after consultation with the Hepatic Safety Knowledge Group.
Some of the tests may also be considered for use with local laboratories that have respective 
testing capabilities. Any test results need to be recorded in the CRF.


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Hy’s Law lab kit for central laboratories
Additional standard chemistry and coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgM and IgG anti-HCV
HCV RNA
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
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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Appendix F
Maintenance Therapy Equivalence Table
Estimated daily doses for inhaled corticosteroidsa
Asthma Therapy
Total Daily Dose (μg/day)
Inhaled Corticosteroid
Medium
High
Beclomethasone dipropionate (non HFA)
1000
>1000
Beclomethasone dipropionate (HFA)
400
>400
Ciclesonide
320
>320
Triamcinolone acetonide
2000
>2000
Flunisolide
2000
>2000
Fluticasone furoate (e.g. Arnuity® Ellipta®)
n.a.
200
Fluticasone propionate
500
>500
Fluticasone propionate HFA
440-500
>500
Budesonide
800
>800
Mometasone furoate
440
>440
Inhaled Corticosteroid in ICS/LABA combinationb
Medium
High
Beclomethasone dipropionate (e.g. Fostair®)
400
>400
Fluticasone propionate HFA (e.g. Seretide®, Advair®)
500
>500
Fluticasone furoate (e.g. Relvar® Ellipta®, Breo® Ellipta®)
n.a.
184-200
Budesonide, if as delivered dose (e.g. Symbicort®)
640
>640
Mometasone Furoate (e.g. Dulera®)
400
>400
a
The Japanese asthma pediatric guidelines will be followed for the Japanese adolescent subject (the medium 
to high dose for Japanese adolescent subjects 15 years or younger will be ≥ 200 μg/day of FP or other ICSs 
of equivalent dose).
b
The ICS doses for the ICS/LABA combinations were derived from GINA 2018 and using prescribing 
information.
FP: Fluticasone Propionate, GINA: Global Initiative for Asthma, HFA: Hydrofluoroalkane, ICS: Inhaled 
Corticosteroid, LABA: Long-Acting β2-Agonist.


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Appendix G
Anaphylaxis: Signs and Symptoms, Management
G 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 Appendix G 2. A guide to the signs and 
symptoms and management of acute anaphylaxis is provided in Appendix G 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 subject as soon as 
possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge for 
analysis of serum tryptase.
G 2
Clinical Criteria for Defining Anaphylaxis and Immune Complex 
Disease
Anaphylaxis
In adults, anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled:
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
(a) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia).
(b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence).
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
subject (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula).
(b) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia).
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence).
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting).


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


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G 4
Management of Acute Anaphylaxis
Immediate intervention
1
Assessment of airway, breathing, circulation, and adequacy of mentation
2
Administer epinephrine intramuscularly every 5-15 minutes, in appropriate doses, as 
necessary, depending on the presenting signs and symptoms of anaphylaxis, to control 
signs and symptoms and prevent progression to more severe symptoms such as 
respiratory distress, hypotension, shock and unconsciousness.
Possibly appropriate, subsequent measures depending on response to epinephrine
(a) Place subject in recumbent position and elevate lower extremities.
(b) Establish and maintain airway.
(c) Administer oxygen.
(d) Establish venous access.
(e) Normal saline IV for fluid replacement.
Specific measures to consider after epinephrine injections, where appropriate
(a) Consider epinephrine infusion.
(b) Consider H1 and H2 antihistamines.
(c) Consider nebulized β2 agonist [eg, albuterol (salbutamol)] for bronchospasm 
resistant to epinephrine.
(d) Consider systemic corticosteroids.
(e) Consider vasopressor (e.g. dopamine).
(f) Consider glucagon for subject taking b-blocker.
(g) Consider atropine for symptomatic bradycardia.
(h) Consider transportation to an emergency department or an intensive care facility.
(i)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged 
resuscitation efforts are encouraged, if necessary.
Adapted from: Kemp SF, Lockey RF, Simons FE; World Allergy Organization ad hoc 
Committee on Epinephrine in Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. 
A statement of the World Allergy Organization. Allergy. 2008; 63(8):1061-70.


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G 5
References
Johansson et al 2004
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised 
nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the 
World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004May;113(5):832-6


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Appendix H
ACQ-6


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Appendix I
Abbreviations 
Abbreviation or special 
term
Explanation
AAER
Annualized Asthma Exacerbation Rate
ACQ-6
Asthma Control Questionnaire-6
AE
Adverse Event
AER
Asthma Exacerbation Rate
AESI
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BD
Bronchodilator
β-hCG
Beta-Human Chorionic Gonadotropin
CFR
Code of Federal Regulations
CK
Creatinine Kinase
COPD
Chronic Obstructive Pulmonary Disease
COVID-19
Corona Virus Disease 2019
CRF
Case Report Form
CSGA
The Collaborative Study on the Genetics of Asthma
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CV
Coefficient of Variation
DILI
Drug Induced Liver Injury
DNA
Deoxyribonucleic acid 
EAR
Early Asthmatic Response
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOT
End of Treatment 
ER
Emergency Room
EU
European Union
FeNO
Fractional Exhaled Nitric Oxide
FSH
Follicle Stimulating Hormone
FU
Follow-Up
FVC
Forced Vital Capacity
CCI
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Abbreviation or special 
term
Explanation
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
GINA
Global Initiative for Asthma
GLI
Global Lung Function Initiative
GMP
Good Manufacturing Practice
Gx
Genetic research
hCG
Human Chorionic Gonadotropin
HCP
Health Care Professional
HIV
Human Immunodeficiency Virus
HL
Hy’s Law
IATA
International Airline Transportation Association
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICS
Inhaled Corticosteroid
IEC
Independent Ethics Committee
IgE
Immunoglobulin E
IgG2λ
Immunoglobulin G2λ
IL
Interleukin
IMP
Investigational Medicinal Product
IP
Investigational Product 
IPD
Investigational Product Discontinuation
IRB
Institutional Review Board
ITT
Intent-to-Treat
IUD
Intrauterine device
IUS
Intrauterine system
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
JRS
Japanese Respiratory Society
LABA
Long-Acting β2-Agonist
LAMA
Long-Acting Muscarinic Antagonists
LAR
Late Asthmatic Response
LRTI
Lower Respiratory Tract Infection
LTRA
Leukotriene Receptor Antagonists
mAb
Monoclonal Antibody


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Abbreviation or special 
term
Explanation
MedDRA
Medical Dictionary for Regulatory Activities
nAb
Neutralizing Antibodies
OCS
Oral Corticosteroid(s)
PD
Pharmacodynamic
PEF
Peak Expiratory Flow
PHL
Potential Hy’s Law
PNV
Predicted Normal Value
PRO
Patient Reported Outcome
Q2W
Every 2 Weeks
Q4W
Every 4 Weeks
SABA
Short-Acting β2-Agonist
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SC
Subcutaneous
SoA
Schedule of Activities
SOP
Standard Operating Procedures
TBL
Total Bilirubin
TEAE
Treatment-emergent adverse event
Th2
T helper cell type 2
TSLP
Thymic Stromal Lymphopoietin
TSLPR
Thymic Stromal Lymphopoietin Receptor
ULN
Upper Limit of Normal
UNS
Unscheduled
URTI
Upper Respiratory Tract Infection
WBDC
Web Based Data Capture
WOCBP
Women of Childbearing Potential
w/v
Weight per Volume
WHO
World Health Organization
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Appendix J
Changes Related to COVID-19 Pandemic
Please Note: Changes below should only be implemented during the COVID-19 pandemic 
and if allowable by local/regional guidelines.
J 1
Home Visits to Replace On-Site Visits (where applicable)
Due to local travel restrictions and/or site restrictions, subjects may not wish to or may not be 
able to go to the study site for study visits and related procedures. If an on-site visit is not 
possible, it is recommended to have a home visit with home administration of IP by a 
qualified HCP (up to Visit 14) or without administration of IP for EOT Visit and FU1 Visit 
and FU2 Visit, provided this is acceptable within local regulation/guidance. Additional 
information related to the visit can be obtained remotely by phone call and/or video 
conference. This is to ensure safety of the study subjects and minimum disruption to IP 
administration that may occur during the COVID-19 pandemic.
Study assessments, where possible to be performed at home, should be conducted according to 
the SoA. At minimum, during home visit the qualified HCP is expected to:

Perform a physical examination

Collect vital signs

Collect adverse events

Collect information on asthma exacerbation

Review concomitant medications

If possible, collect blood sample according to the SoA

Conduct urine pregnancy test (dipstick), prior to IP administration, if applicable

Administer IP

Observe the subject for one hour after IP administration for the signs or symptoms of 
any acute drug reactions

Document the visit
Please refer to the separate IP Home (or Alternative Site) Administration Instructions for more 
information.
J 2
Visits at an Alternate Location (where applicable)
Study visits including administration of IP and study assessments according to the SoA can 
take place at an alternative location away from infection risk zones, or closer to the subject’s 
home, provided this is acceptable within local regulation/guidance. 
Please refer to the separate IP Home (or Alternative Site) Administration Instructions for more 
information.
J 3
Remote Visits to Replace On-Site Visits (where applicable)
During the COVID-19 pandemic, on-site visits may be replaced by a remote visit (phone call 
and/or video conference) if subjects cannot attend the visits at the study site, at an alternate 
site or have home visits and if allowed by local/regional guidelines. 


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Having a phone call and/or a video conference with the subject will allow conduct of study 
procedures including reporting of adverse events, concomitant medication, information on 
asthma exacerbation while minimizing the risk to subjects of COVID-19 exposure.
J 4
End of Treatment Visit
If the EOT visit at Week 52 cannot be performed on-site, at an alternate site or at the subject’s 
home, the EOT visit should be conducted as a remote visit. 
J 5
Re-consenting of Subjects During the COVID-19 Pandemic
If a subject is unable to travel to the site due to the COVID-19 pandemic, it is necessary to 
obtain re-consent remotely and/or verbally for the implementation of the new urgent changes 
in the study during the COVID-19 pandemic. This will minimize the risk to the subject of 
COVID-19 exposure with clinic visits. Applicable local guidelines and regulations on re-
consenting process should be followed.


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Statistical Analysis Plan
Study Code
D5180C00019
Edition Number
3
Date
2 September 2020
A 52-Week, Open-Label, Multicentre Study to Evaluate the Safety 
of Tezepelumab in Japanese Adults and Adolescents with 
Inadequately Controlled Severe Asthma (NOZOMI)


Statistical Analysis Plan 
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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
TABLE OF CONTENTS...................................................................................................... 2
LIST OF ABBREVIATIONS ............................................................................................... 4
AMENDMENT HISTORY................................................................................................... 6
1
STUDY DETAILS ............................................................................................. 9
1.1
Study objectives.................................................................................................. 9
1.1.1
Primary objective................................................................................................ 9
1.2
Study design ....................................................................................................... 9
1.3
Number of subjects........................................................................................... 10
2
ANALYSIS SETS ............................................................................................ 10
2.1
Definition of analysis sets................................................................................. 10
2.1.1
Safety analysis set............................................................................................. 10
2.2
Violations and deviations.................................................................................. 10
3
PRIMARY AND SECONDARY VARIABLES ............................................... 11
3.1
General definitions............................................................................................ 11
3.1.1
Definition of baseline........................................................................................ 11
3.1.2
Absolute change from baseline ......................................................................... 11
3.1.3
Study periods.................................................................................................... 11
3.1.4
Visit windows................................................................................................... 12
3.1.5
Prior and concomitant medication..................................................................... 14
3.2
Derivation of safety variables............................................................................ 15
3.2.1
Exposure to IP and treatment compliance.......................................................... 15
3.2.2
Adverse events – general .................................................................................. 16
3.2.3
Adverse events of special interest ..................................................................... 17
3.2.4
Laboratory variables ......................................................................................... 17
3.2.5
Vital signs......................................................................................................... 18
3.2.6
12-lead ECG..................................................................................................... 18
3.2.7
Physical examination ........................................................................................ 18
3.2.8
Medical history................................................................................................. 18
3.3
Derivation of efficacy variables ........................................................................ 19
4
ANALYSIS METHODS................................................................................... 23
4.1
General principles............................................................................................. 23
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4.2
Analysis methods.............................................................................................. 23
4.2.1
Subject disposition, demography and baseline characteristics............................ 23
4.2.2
Prior and concomitant medication..................................................................... 23
4.2.3
Exposure and compliance ................................................................................. 24
4.2.4
Safety analysis.................................................................................................. 24
4.2.4.1
Adverse events.................................................................................................. 25
4.2.4.2
Laboratory data................................................................................................. 26
4.2.4.3
Vital signs......................................................................................................... 27
4.2.4.4
12-lead ECG..................................................................................................... 27
4.2.4.5
Physical examination ........................................................................................ 28
4.2.5
Efficacy analysis............................................................................................... 28
5
INTERIM ANALYSES.................................................................................... 30
6
CHANGES OF ANALYSIS FROM PROTOCOL............................................ 30
7
REFERENCES................................................................................................. 30
8
APPENDIX ...................................................................................................... 32
8.1
Adverse events of special interest ..................................................................... 32
8.1.1
Anaphylactic reactions...................................................................................... 32
8.1.2
Immune complex disease (Type III hypersensitivity reactions) ......................... 32
8.1.3
Malignancy....................................................................................................... 32
8.1.4
Helminth infections........................................................................................... 32
8.1.5
Severe infections (as defined in the protocol).................................................... 33
8.1.6
Injection site reactions ...................................................................................... 33
8.1.7
Opportunistic infections.................................................................................... 33
8.1.8
Guillain-Barre syndrome................................................................................... 33
8.2
OCS conversion factors for prednisone equivalents........................................... 35
8.3
Additional reporting to assess the impact of the COVID-19 pandemic .............. 36
LIST OF TABLES
Table 1
Visit windows – all variables where not specified otherwise .................... 14
Table 2
Vital signs reference ranges ..................................................................... 18
Table 3
Estimated OCS dose therapy equivalence ................................................ 35
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LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AZ
AstraZeneca
BD
Bronchodilator
BMI
Body Mass Index
BP
Blood Pressure
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTD
Common Technical Document
DAE
Adverse Event Leading to Discontinuation of Investigational Product
DBL
Database Lock
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOS
End of Study
EOT
End of Treatment
ER
Emergency Room
GCP
Good Clinical Practice
ICS
Inhaled Corticosteroids
IP
Investigational Product
IPD
Investigational Product Discontinuation
L
Litre
LLOQ
Lower Limit of Quantification
MedDRA
Medical Dictionary for Regulatory Activities
N/A
Not Applicable
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Abbreviation or special 
term
Explanation
NC
Not Calculable
NQ
Non-quantifiable
OCS
Oral Corticosteroids
PD
Protocol Deviation
PT
Preferred Term
Q4W
Every 4 Weeks
QTc
Corrected QT Interval
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SMQ
Standardized MedDRA Query
SOC
System Organ Class
TBL
Total Bilirubin
UC
Urgent Care
ULN
Upper Limit of Normal
ULOQ
Upper Limit of Quantification
WHO
World Health Organisation
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AMENDMENT HISTORY
Category:
Change refers to
Date
Description of change
In line with 
the CSP?
Rationale
N/A
04Jun2019
Initially Approved SAP
Yes (V2.0)
Data presentations
28Feb2020
Section 3.1.1: Definition of baseline was made consistent 
with CSP.
Yes (V2.0)
To be in line with CSP.
Other
28Feb2020
Section 3.1.4: Deleted sentences “In the case of a missing 
value at a scheduled visit, which is then followed by a non-
missing value at an unscheduled or repeat assessment 
within the same visit window, the non-missing value at the 
unscheduled/repeat assessment will replace the missing 
value at the scheduled visit.”
N/A
The explanation was deleted for 
clarity. 
Data presentations
28Feb2020
Section 3.1.4: Added the handling of more than one non-
missing value within the same visit window for categorical 
variable case.
N/A
To clarify the handling of data in 
analysis. 
Other
28Feb2020
Section 3.2.2: Reference to “treatment-emergent” was 
replaced by “occurring during on-treatment period”.
N/A
To clarify the handling of AEs with 
missing or incomplete start date.
Data presentations
28Feb2020
Section 3.2.2: Derivation of exposure adjusted incidence 
rate for AEs updated.
N/A
In line with AZ guideline on 
reporting safety data.
Data presentations
28Feb2020
Section 3.2.4: Values below the Lower Limit of 
Quantification (LLOQ) will be set to LLOQ, instead of 
LLOQ/2.
N/A
In line with AZ guideline on 
reporting safety data.
 
 
 
Other
28Feb2020
Section 4.2.1: Delete the descriptions related to extension 
study.
N/A
This study has no extension study. 
It was mentioned in SAP edition 1 
by error. 
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Category:
Change refers to
Date
Description of change
In line with 
the CSP?
Rationale
Other
28Feb2020
Section 4.2.1: All references to FAS were deleted.
N/A
FAS is not used in this study and 
was mentioned in error in SAP 
edition 1. 
Data presentations
28Feb2020
Section 4.2.1: Added analysis set to be used for each 
summary. 
N/A
To clarify the analysis set to be 
used when summarising each 
variable. 
Data presentations
28Feb2020
Section 4.2.1: Clarified that age “at the informed consent” 
will be summarised.
N/A
To clarify the reference point in 
which age will be calculated. 
Data presentations
28Feb2020
A section for prior and concomitant medication and its 
associated appendix was added. (Sections 4.2.2 and 8.2)
Yes (V2.0)
To be in line with CSP.
Other
28Feb2020
Sections 4.2.1, 4.2.4.1, and 4.2.4.4: All references to 
treatment group were deleted.
N/A
This is single arm study and 
treatment groups were mentioned in 
error in SAP edition 1. 
Data presentations
28Feb2020
Sections 4.2.4.2, 4.2.4.3, 4.2.4.4 and 4.2.6.1: Updated to 
present visit based summaries over time using the on-study 
period instead of the on-treatment period
N/A
Required for CSR
Data presentations
28Feb2020
Section 4.2.5.1: Clarified that data during planned 
treatment period will be summarised.
N/A
To clarify the scope of data to be 
summarised.
Data presentations
28Feb2020
Sections 4.2.5.2, 4.2.5.3: Clarified that data during on-
study period will be summarised.
N/A
To clarify the scope of data to be 
summarised.
Data presentations
28Feb2020
Section 4.2.6.2: Descriptive statistics were updated to 
“median, range, 1st and 3rd quartiles”.
N/A
To use more appropriate descriptive 
statistics.
Data presentations
28Feb2020
Section 5: Updated the scope of data to be analysed at the 
interim analysis. 
N/A
To clarify the scope of interim 
analysis. 
 
 
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Category:
Change refers to
Date
Description of change
In line with 
the CSP?
Rationale
 
 
 
Data presentations
02Sep2020
Table 1: Removed time window for Week 2 since there is 
no Week 2 visit in the study.
N/A
To be in line with CSP visit 
schedule.
Data presentations
02Sep2020
Section 3.2.2: Added the definition of study adjusted 
incidence rate for adverse events.
N/A
Required for CSR.
Data presentations
02Sep2020
Section 3.3.1: Time at risk derivation updated to allow the 
date of last exacerbation status to be considered in 
derivation.
N/A
To simplify and clarify the text. 
 
Data presentations
02Sep2020
Section 4.2.4.1: Deleted presentation of SOC for AE 
summary by causality and maximum intensity. 
Yes (V3.0)
To be in line with requirement for 
CSR.
Data presentations
02Sep2020
Section 4.2.6.1: Clarified data to be included in the 
summary of serum tezepelumab concentrations.
N/A
To provide clarification for TFLs.
Data presentations
02Sep2020
Section 4.2.6.1: Added the presentation of minimum, 
median and maximum when there is a value that is NQ.
N/A
To provide clarification for TFLs.
Data presentations
02Sep2020
Section 5: Added time at risk derivation at the time of 
interim analysis.
N/A
To provide additional clarification
on interim analysis-specific 
derivation of time at risk.
Data presentations
02Sep2020
Added Appendix 8.3 to describe COVID-19 outputs for 
final analysis.
N/A
Required for CSR to assess the 
impact of COVID-19 pandemic.
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1
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
Objective:
Endpoint/variable:
To evaluate the safety and tolerability of 
tezepelumab
Adverse events/Serious adverse events
Vital signs
Clinical chemistry/haematology/urinalysis parameters
Electrocardiograms
 
 
 
 
 
 
 
 
 
1.2
Study design
This is an open-label, single arm study designed to evaluate the safety of a 210 mg dose of 
tezepelumab administered subcutaneously every 4 weeks in Japanese adult and adolescent 
subjects with inadequately controlled severe asthma. Patients will have a history of at least 
one exacerbation in the past year and background asthma therapy of medium- or high dose 
ICS plus at least one additional asthma controller medication (long-acting β2 agonist, 
[LABA], leukotriene receptor antagonists [LTRA], long-acting muscarinic antagonists 
[LAMA], cromones, and theophylline) with or without maintenance OCS from screening and 
throughout the study including the follow-up period.
The study will consist of a screening period of 2 weeks, a treatment period of 52 weeks and a 
post-treatment follow-up period of 12 weeks. 
After the informed consent is obtained, subjects will proceed to a screening period of 2 weeks 
maximum to allow adequate time for all of the eligibility criteria to be evaluated. Subjects 
who meet all the eligibility criteria will be registered to a treatment period. Subjects will be 
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maintained on their currently prescribed ICS and at least one additional asthma controller 
medication at their dose they entered screening, without change, from screening throughout 
the treatment period.
1.3
Number of subjects
Approximately 66 Japanese subjects will be registered into the study and receive tezepelumab 
in order to reach 59 completed. The actual number of Japanese subjects registered into the 
study will be determined after the confirmation of the number of randomized Japanese 
subjects in NAVIGATOR study (D5180C00007) to ensure that there are 100 total Japanese 
subjects who receive tezepelumab for 52 weeks.
2
ANALYSIS SETS
2.1
Definition of analysis sets
All subjects analysis set
This analysis set comprises all enrolled subjects who signed the informed consent form, 
including screening failures, and will be used for the reporting of disposition.
Registered subjects analysis set
This analysis set comprises all subjects registered to study treatment, irrespective of whether 
IP was subsequently taken, and will also be used for the reporting of disposition.
2.1.1
Safety analysis set
This analysis set comprises all subjects who received at least one dose of IP. 
Safety, efficacy and 
 data will be summarised using the safety analysis set.
 
 
2.2
Violations and deviations
Only important PDs will be listed and tabulated in the CSR, and only for registered subjects 
(i.e. not screening failures). These are defined as PDs which may significantly affect the 
completeness, accuracy and/or reliability of the study data, or which may significantly affect a 
subject’s rights, safety or well-being. They may include (but not be limited to):
!
Subjects who were registered even though they did not meet key entry criteria
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
Subjects who developed withdrawal criteria during the study but were not withdrawn

Subjects who received an incorrect dose

Subjects who received an excluded concomitant treatment.
All important PDs will be identified and documented by the study team prior to the database 
lock. 
With the exception of the PK analyses, important PDs will not be used to exclude any subject 
from any analysis set, nor to exclude any data from subjects included in an analysis set.
The study non-compliance handling plan (NHP) outlines the management of PDs, and 
includes the proposed categories of PDs in this trial. Any PDs which are not defined as 
important will not be reported and discussed in the CSR.
3
PRIMARY AND SECONDARY VARIABLES
3.1
General definitions
3.1.1
Definition of baseline
In general, the last non-missing measurement on or prior to first dose of study treatment will 
serve as the baseline measurement. If there is no value prior to first dose of study treatment, 
then the baseline value will not be imputed, and will be set to missing.
Where unscheduled/repeat assessments are relevant and exist for any subject, they will also be 
considered in the baseline definitions, provided they remain prior to the date of first dose of 
study treatment.
3.1.2
Absolute change from baseline
Absolute change from baseline is defined as (post-baseline value - baseline value).
If either the post-baseline value or the baseline value is missing, then the absolute change 
from baseline will also be missing.
Unless otherwise specified, “change from baseline” is assumed to be the absolute change from 
baseline.
3.1.3
Study periods
The following study periods are defined for analysis purposes:


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Screening period
Starting on the date of the first study procedure and ending one day prior to registration (for 
registered subjects) or on the date of the last study procedure (for screening failures). If any 
subject is re-screened, the latest available screening will be used for this purpose.
Planned treatment period (on-treatment and off-treatment)
Starting on the date of registration (efficacy) / date of first dose of IP (safety) and ending on 
the date of the Week 52 visit or earlier study withdrawal date (for subjects not followed up 
until Week 52)
On-treatment period
Starting on the date of registration (efficacy) / date of first dose of IP (safety) and ending on 
the minimum (date of last dose of IP + 33 days, date of death, date of study withdrawal).
Post-treatment period
Starting one day after the end date of on-treatment period and ending on the study completion 
or withdrawal date. 
On-study period (planned treatment and follow-up)
Starting on the date of registration (efficacy) / date of first dose of IP (safety) and ending on 
the study completion or withdrawal date. 
3.1.4
Visit windows
All summaries and analyses, both efficacy and safety, which are presented by time point (e.g. 
“Week 52”) will use a visit window to classify the data record, which is derived from the 
assessment date relative to date of registration (efficacy) / date of first dose of IP (safety). This 
approach allows appropriate classification of visits which may have occurred significantly 
earlier or later than the protocol assessment schedule, as well as the use of data captured at 
visits which have no fixed timing (notably the IPD visit), and the handling of data captured at 
visits for which the database label is incorrect and unresolvable.
Nominal database visit numbers will not be used in any summary or analysis by visit.
Any data collected at unscheduled or repeat visits will be listed, and will be included in 
baseline definitions (see Section 3.1.1), and in any definitions of maximum value, minimum 
value or last value within the relevant study period.
Data collected at unscheduled or repeat visits will also be included in visit windows, and 
therefore may be included in summaries or analyses by visit. 


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If a subject has more than one non-missing value within the same visit window, the following 
rules will apply:

The non-missing value closest to the target day will be selected for analysis at that visit

If two non-missing values are the same distance from the target day, the earlier of the two 
values will be selected for analysis at that visit

If two non-missing values are recorded on the same day and have a different assessment 
time associated with both of them, the value with the earliest assessment time will be 
selected for analysis at that visit.

If two non-missing values are recorded on the same day and have no assessment time 
associated with at least one of them, or the same assessment time associated with both of 
them, the average of the two values will be selected for analysis at that visit. For 
categorical variables in this situation, the worst case will be used.

If there are multiple ADA samples in the same visit window with both positive and 
negative results, the sample with a positive result and the highest titer value should be 
selected.
If a subject has no value within a particular visit window, then the subject will have a missing 
value at that visit in summaries and analysis.
The same visit window definitions below will be used regardless of whether the planned 
treatment period or the on-treatment period is used for analysis (see Section 3.1.3). In practice, 
each data record in the planned treatment period will be first identified, and then further 
flagged according to whether it is on-treatment or off-treatment. This flag will be used to 
select all eligible records for subsequent visit windowing, according to whether the derived 
visits are to be used in a planned treatment period or an on-treatment period analysis. It should 
be noted that, if treatment was discontinued within a particular visit window, the rules above 
for handling multiple values within the same visit window could select a different record 
according to whether a planned treatment period analysis or an on-treatment period analysis is 
needed.  
In planned treatment period analysis, any off-treatment assessments measured at a follow-up 
visit (scheduled 16 weeks after last IP administration) which occurred earlier than scheduled 
follow-up visits Week 58 or Week 64 will be considered in earlier planned treatment period 
visit windows, where applicable. 
Table 1 summarises the visit windows to be used for all variables unless specified otherwise. 
It corresponds to the full (mostly 4-weekly) protocol scheduling for clinic visits, and will be 
used for all variables by default, including those variables which are not captured at every 
clinic visit.


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Table 1
Visit windows – all variables where not specified otherwise
Time Point
Target Day
Visit Window
Baseline
(Week 0)
1
See Section 3.1.1 for baseline definitions
Week 4
29
2-42
Week 8
57
43-70
Week 12
85
71-98
Week 16
113
99-126
Week 20
141
127-154
Week 24
169
155-182
Week 28
197
183-210
Week 32
225
211-238
Week 36
253
239-266
Week 40
281
267-294
Week 44
309
295-322
Week 48
337
323-350
Week 52
365
351-385
Follow-up 
Week 58
407
386-427
Follow-up 
Week 64
449
428-469
3.1.5
Prior and concomitant medication
Medications taken by any subject at any time during the study will be coded using the ATC 
classification system within the WHO Drug Dictionary.
Medications will be categorised for analysis according to their onset and end dates as follows:

Prior medications: 

end date ≤ date of first dose of IP 

Concomitant medications during on-treatment period: 

end date > date of first dose of IP and start date ≤ minimum (date of last dose of IP + 
33 days, date of death, date of study withdrawal), or

end date ongoing and start date ≤ minimum (date of last dose of IP + 33 days, date of 
death, date of study withdrawal)

Concomitant medications during post-treatment period (for subjects still being followed 
up then):


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
start date > date of last dose of IP + 33 days.
Essentially the above says that:

Prior and concomitant medications are mutually exclusive.

Concomitant medications on-treatment and post-treatment are also mutually exclusive 
(here, the word “concomitant” means concomitant with study procedures, irrespective of 
whether IP was still being taken). Specifically, a concomitant medication which started 
on-treatment and ended post-treatment will only be considered on-treatment.
If the medication record has a completely missing onset date, the subject will be assumed to 
have been on the medication on the date of the first study procedure. If the medication record 
has a partially missing onset date (month/year or year only) which is the same as that for the 
end of IP treatment, it will be assumed to have started on-treatment. If the medication record 
has a partially missing onset date (month/year or year only) which is the same as that for the 
start of IP treatment, it will be assumed to have started before treatment.
If the medication record has a completely missing end date, the subject will be assumed to 
have been on the medication on the date of study completion or withdrawal. If the medication 
record has a partially missing end date (month/year or year only) which is the same as that for 
start of IP treatment, it will be assumed to have ended on-treatment. If the medication record 
has a partially missing end date (month/year or year only) which is the same as that for end of 
IP treatment, it will be assumed to have ended post-treatment.
3.2
Derivation of safety variables
3.2.1
Exposure to IP and treatment compliance
Extent of exposure to IP will be calculated as follows:
Extent of exposure (days) = minimum (date of last dose of IP + 33 days; date of death; date of 
study withdrawal) – date of first dose of IP + 1
This calculation does not consider any gaps in exposure caused by the subject missing one or 
more intermediate scheduled 4-weekly doses. Such cases will be identified in the CSR if they 
occur, but will not explicitly be accounted for in any analysis. 
The total subject-years exposure will be derived as the sum of the individual subject extents of 
exposure (days) divided by 365.25.
Treatment compliance will be calculated as follows:
Treatment compliance (%) = [(Total number of actual dosing occasions/total number of 
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In order to allow for subjects who discontinue IP early in the compliance calculation, the 
number of expected dosing occasions will be calculated as the number of scheduled dosing 
visits up to and including the last available dosing visit for that subject.
3.2.2
Adverse events – general
Adverse events (AEs) experienced by any subject at any time during the entire study will be 
coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA).
AEs will be categorised for analysis according to their onset date into the following study 
periods:

AEs occurring during screening period:  date of Visit 1 ≤ AE onset date < date of first 
dose of IP

AEs occurring during on-treatment period: date of first dose of IP ≤ AE onset date ≤ 
minimum (date of last dose of IP + 33 days, date of death, date of study withdrawal)

AEs occurring during post-treatment period (for subjects still being followed up then): 
date of last dose of IP + 33 days < AE onset date ≤ study completion or withdrawal date

AEs occurring during on-study period: date of first dose of IP ≤ AE onset date ≤ study 
completion or withdrawal date.
If the AE has a completely missing (and unresolvable) onset date, then the AE will be 
assumed to be occurring during on-treatment period, unless the end date indicates
unambiguously that the AE resolved before treatment started. If the AE has a partially missing 
(and unresolvable) onset date, then the AE will also be assumed to be occurring during on-
treatment period, unless either the end date indicates unambiguously that the AE resolved 
before treatment started, or the partial onset date is in the month/year prior to start of 
treatment.
Exposure adjusted incidence rates will be defined as the number of subjects reporting adverse 
events divided by extent of exposure for each subject, where exposure will be defined 
(irrespective of whether they have had the AE) as in 3.2.1 for extent of exposure for the on-
treatment summaries. 
Study adjusted incidence rates will be defined as the number of subjects reporting adverse 
events divided by duration of the on-study period for each subject as defined in Section 3.1.3.
The total time at risk (years) will be derived as the sum of the individual subject times at risk 
(days) divided by 365.25.
In all exposure-adjusted summaries of AEs, multiple occurrences of the same event for a 
particular subject will not be counted as separate events. A subject will either be considered to 
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3.2.3
Adverse events of special interest
The protocol specifies Adverse Events of Special Interest (AESIs) as those which merit 
special attention in this trial, and for which derivation details (for those derived from the 
eCRF), or a statement when the derivation needs to be referenced externally to the SAP (for 
those derived from MedDRA dictionary terms), are given in Appendix 8.1.
3.2.4
Laboratory variables
Clinical chemistry, haematology and urinalysis will be performed by local laboratories 
according to the schedule and the variable specifications described in the CSP.
Changes from baseline in continuous laboratory variables will be calculated at relevant visits 
as specified in Section 3.1.1 and Section 3.1.2.
In all analysis of continuous laboratory variables, any value recorded only as below Lower 
Limit of Quantification (LLOQ) will be set to LLOQ and included in the analysis. Any value 
recorded only as above Upper Limit of Quantification (ULOQ) will be set to ULOQ and 
included in the analysis.
Absolute values will be compared to the relevant normal reference range, as provided by the 
central laboratory, and classified as low (below range), normal (within range or on the limits) 
or high (above range). All values falling outside the normal reference ranges will be flagged. 
These classifications will also be used for shift tables.
For the purposes of shift tables, baseline will be defined as specified in Section 3.1.1. 
Minimum, maximum and last values calculated across all visits in the relevant study period 
will use all available values including those from unscheduled and repeat visits, and 
irrespective of whether the values have been selected for use in summaries using visit 
windows (see Section 3.1.4).
Liver function tests will also be evaluated as multiples of the upper limit of the normal 
reference range (ULN). Subjects who meet any of the following criteria at any time during the 
study will be flagged:
•
AST ≥ 3 x ULN
•
ALT ≥ 3 x ULN
•
TBL ≥ 2 x ULN
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3.2.5
Vital signs
Changes from baseline in vital signs variables (pulse rate, systolic blood pressure (BP), 
diastolic BP, respiratory rate, body temperature, body weight, body mass index (BMI)) will be 
calculated at relevant visits as specified in Section 3.1.1 and Section 3.1.2.
BMI is calculated as:
BMI = Weight (kg) / [Height (m)]2.
Absolute values and changes from baseline (where applicable) will be compared to the 
relevant reference range tabulated below, and classified as low (below range), normal (within 
range or on the limits) or high (above range). All values falling outside the reference ranges 
will be flagged.
Table 2
Vital signs reference ranges
Parameter
Standard Units
Lower Limit
Upper Limit
Change from 
Baseline Criteria
Diastolic BP 
(sitting)
mmHg
60
100
±15
Systolic BP (sitting)
mmHg
90
160
±30
Pulse rate (sitting)
beats/min
50
100
±20
Respiratory rate
breaths/min
8
20
Body temperature
Celsius
36.0
37.5
Weight
kg
40
150
3.2.6
12-lead ECG
The outcome of the overall evaluation (normal, abnormal or borderline) will be taken directly 
from the eCRF, as will the assessment of clinical significance.
Changes from baseline in continuous 12-lead ECG variables (data provided external to the 
eCRF) will be calculated at relevant visits as specified in Section 3.1.1 and Section 3.1.2.
3.2.7
Physical examination
No physical examination results are captured in this trial, unless judged a new clinically 
significant finding or a clinically significant aggravation of an existing finding by the 
investigator, and consequently reported as an AE.
3.2.8
Medical history
If a partial diagnosis date is available only, the following rules will be used to impute a 
complete date (e.g. for derivation of time since diagnosis):


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If both the month and the year are available, the first of the recorded month will be imputed, 
unless the date of birth is within the same month and year (where date of birth is available, 
which will not be the case in all countries). In this case, the date of birth will be imputed 
instead.
If only the year is available, 1st January will be imputed, unless the date of birth is within that 
same year (where date of birth is available). In this case, the date of birth will be imputed 
instead.
3.3
Derivation of efficacy variables
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4
ANALYSIS METHODS
4.1
General principles
All data will be summarised using appropriate descriptive statistics. No statistical hypothesis 
tests will be made. 
4.2
Analysis methods
4.2.1
Subject disposition, demography and baseline characteristics
Subject disposition will be summarised using the all subjects analysis set. The number of 
enrolled subjects will be summarised. The number and percentage of subjects will be 
presented by the following categories; registered, not registered (and reason), received IP, did 
not receive IP (and reason), completed treatment, discontinued treatment (and reason), 
completed study (subjects who completed IP and study, and subjects who discontinued IP but 
completed study assessments), and discontinued study (including reason). Subject recruitment 
by centre will be summarised using registered subjects analysis set.
The number and percentage of subjects, who discontinued IP, but remained in the study will 
be presented and option of follow up using safety analysis set.
Demographic data such as age at informed consent, gender, and race will be summarised 
using safety analysis set. 
Various baseline characteristics will also be summarised using safety analysis set. These 
include medical, surgical and respiratory disease histories, weight, height and BMI, smoking 
status, history of allergy, pre-BD FEV1, asthma duration, age at onset of asthma, asthma 
medications, the number of asthma exacerbations in the previous 12 months, number of 
asthma exacerbations requiring hospitalisations in the previous 12 months, and ACQ 6. 
Medical and surgical histories will be summarised using safety analysis set by MedDRA 
Preferred Term (PT) within the System Organ Class (SOC) level of MedDRA.
Important PDs will be summarised using safety analysis set.
The number and percentage of subjects in each of the analysis sets defined in Section 2.1 will 
be summarised.
4.2.2
Prior and concomitant medication
The number and percentage of subjects receiving each medication (by ATC classification 
system codes and generic name) will be presented by treatment for the safety analysis set. 
Separate tables will be presented for all medications received during each of the following 


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periods as defined in Section 3.1.5: Prior, Concomitant (on-treatment), Concomitant (post-
treatment).
Tables for maintenance medications (started prior to and ongoing after the first day of IP) will 
be produced displaying the baseline total daily dose of ICS medications. The number of 
subjects using other maintenance asthma medications at baseline will also be summarised. In 
addition, the total number of days of systemic corticosteroid treatment associated with asthma 
exacerbations per patient from the first day of IP up to Week 52 will also be summarised.
Summary statistics will be produced of total daily OCS dose converted to a prednisone
equivalent (for subjects taking OCS at baseline). Conversion factors to be applied for this 
purpose are given in Appendix 8.2.
A separate table will be presented for subjects who took disallowed concomitant medications.
Disallowed medications will include medications defined as prohibited according to Section 
6.5 of the CSP. They will be defined following a physician review (prior to primary database 
lock) of the unique combinations of ATC code classifications and generic terms captured.
Medications will be classified using the latest version of the WHO Drug Dictionary.
Percentages will be calculated relative to the number of subjects in the safety analysis set.
Data from subjects who discontinued IP, regardless of level of follow up chosen will, where 
possible and relevant, be included in the appropriate medication summaries.
Potential prior biologics use will be summarised separately, similarly to above.
4.2.3
Exposure and compliance
Exposure and treatment compliance derivation details are defined in Section 3.2.1.
Extent of exposure to IP, compliance, and total number of dosing occasions will be 
summarised for the safety analysis set.
The date and time of IP administrations, and all missed doses will be listed using the safety 
analysis set.
4.2.4
Safety analysis
All safety variables will be summarised using the safety analysis set (see Section 2.1.1 for 
details).


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4.2.4.1
Adverse events
AEs will be summarised separately for the on-treatment and on-study periods as defined in 
Section 3.1.3 unless stated otherwise. AEs occurring during the screening period, or occurring 
post-treatment will be listed, but not summarised separately.
An overall summary table will be produced showing the number and percentage of subjects 
with at least one AE in each of the following categories: any AEs, serious adverse events 
(SAEs), AEs with a fatal outcome, AEs leading to discontinuation of IP (DAEs), and adverse 
events of special interest (AESIs). SAEs, AEs with a fatal outcome, DAEs and AESIs will 
also be listed. The total number of AEs in the different AE categories will also be presented as 
well as the number of subjects (i.e. accounting for multiple occurrences of the same event in a 
subject).
All AEs will be summarised by system organ class (SOC) and preferred term (PT) assigned to 
the event using the MedDRA dictionary. For each PT, the number and percentage of subjects 
reporting at least one occurrence of the event will be presented (i.e. subjects with multiple 
occurrences of the same PT will only be counted once).
Similar summaries by SOC and PT will also be presented for:

SAEs

Fatal AEs

DAEs

DAEs causally related to IP

Each AESI category separately 

The most common AEs (defined as those occurring in >3% of subjects) – by PT only
All AEs (by PT) will be summarised additionally by causality and maximum intensity. If a 
subject reports multiple occurrences within each PT, the maximum intensity will be taken as 
the highest recorded (the order being mild, moderate and severe) respectively.
In addition, each AESI category will be summarised by causality.
The AESI of injection site reactions will be further summarised by:

Site of injection (arm, thigh, abdominal wall)

Total number of doses administered (1, 2, …, 13), irrespective of timing of the injection 
site reaction event.
Exposure-adjusted AE incidence rate for on-treatment summaries and study-adjusted 
incidence rate for on-study summaries will be presented by SOC and PT for each of the 
following (on-treatment summaries only):


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
All AEs

Each AESI separately
In these summaries, the exposure-adjusted rate will be defined as the number of subjects 
reporting the AE divided by the total time at risk for all subjects, the latter as defined in 
Section 3.2.2. Rates will be reported as events per 100 subject-years.
4.2.4.2
Laboratory data
All continuous laboratory variables will be summarised by absolute value at each visit, 
together with the corresponding changes from baseline. These summaries will be produced for 
the on-study period, as defined in Section 3.1.3. The summary statistics presented will be the 
minimum, 1st quartile, median, 3rd quartile, maximum, mean and SD. Mean changes from 
baseline over time will also be plotted.
Local laboratory normal reference ranges will be used for the identification of individual 
clinically important abnormalities. A shift table will be produced for each laboratory variable 
to display low, normal, high and missing values. The shift tables will present baseline and 
maximum/minimum/last post-baseline values for each variable.
Shift plots showing each individual subject’s laboratory value at baseline and at 
maximum/minimum/last value post-baseline will be produced for each continuous laboratory 
variable. If any laboratory variables show any unusual features (high or low values or a 
general shift in the data points) at other time points then shift plots of these data may be 
produced. The diagonal line of no change will also be displayed on the shift plots.
Both shift tables and shift plots will be produced using all data for the on-study period, as 
defined in Section 3.1.3.
The frequencies of clinically noteworthy values (using normal reference ranges) occurring 
during the study will also be given. 
In order to identify potential Hy’s Law cases, maximum post-baseline TBL will be plotted 
separately against both maximum post-baseline ALT and AST, expressed as multiples of 
ULN. These plots will be produced on a log scale, with reference lines included at 2xULN for 
TBL, and at 3xULN for both ALT and AST. These plots will be produced using all data for 
the on-study period.
For all subjects who meet the biochemical criteria for Hy’s Law (potential Hy’s Law cases), 
the relevant laboratory variables will be tabulated showing all visits for these subjects. 
Subjects with elevated ALT or AST in addition to elevated TBL at any time may be explored 
further graphically using individual subject profile plots.


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For urinalysis data, a shift table will be generated to present changes from baseline to 
maximum/last value post-baseline. All data for the on-study period will be used.
4.2.4.3
Vital signs
All vital signs variables will be summarised by absolute value at each visit, together with the 
corresponding changes from baseline. This will also include weight and BMI. These 
summaries will be produced for the on-study period, as defined in Section 3.1.3. The summary 
statistics presented will be the minimum, 1st quartile, median, 3rd quartile, maximum, mean 
and SD. 
AZ-defined reference ranges (see Section 3.2.5) will be used for the identification of 
individual abnormalities. A shift table will be produced for each vital signs variable to display 
low, normal, high and missing values. The shift tables will present baseline and 
maximum/minimum/last post-baseline values for each variable.
Shift plots showing each individual subject’s vital signs value at baseline and at 
maximum/minimum/last value post-baseline will be produced for each continuous vital signs 
variable.
Both shift tables and shift plots will be produced using all data for the on-study period, as 
defined in Section 3.1.3.
Subjects who have changes from baseline outside the pre-defined AZ clinically important 
change criteria in Section 3.2.5 will be summarised. All data for the on-study period will be 
used.
4.2.4.4
12-lead ECG
Continuous 12-lead ECG variables will be summarised by absolute value at each visit, 
together with the corresponding changes from baseline. These summaries will be produced for 
the on-study period, as defined in Section 3.1.3. The summary statistics presented will be the 
minimum, 1st quartile, median, 3rd quartile, maximum, mean and SD. 
A shift table will be produced to display the investigator assessment of normal, abnormal –
not clinically significant, abnormal – clinically significant and not done between baseline and 
end of study. For this purpose, borderline (also recorded on the eCRF) will be grouped with 
normal.
A frequency table showing subjects with corrected QT (QTc) values and increases from 
baseline at any time during the on-study period using standard pre-specified thresholds will be 
produced.


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4.2.4.5
Physical examination
No separate summaries of physical examination findings will be produced since there are no 
physical examination results reported outside of AE reporting.
4.2.5
Efficacy analysis
All efficacy variables will be summarised using the safety analysis set.
 
 
 
 
 
 
. 
4.2.6
Pharmacokinetics and immunogenicity
 
 
 
 
 
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!
 
 
 
 
 
 
5
INTERIM ANALYSES
An interim analysis to summarise 6 months safety data will be performed when all subjects 
complete Visit 8 (24-week of treatment period) for submission.
In principle, all data up to and including 182 days after the first dose of IP will be summarised 
according to methods described in this document. When calculating exposure and on-
treatment period, the following end date will be used: minimum (date of last dose of IP + 33 
days, date of death, date of study withdrawal, date of first dose of IP +182 days). When 
calculating other study periods, date of first dose of IP + 182 will be used instead of 
completion date. When calculating the time at risk for asthma exacerbation (Section 3.3.1), 
“registration date + 182 days” will be used instead of “date of Visit 15” and “registration date 
+ 364 days + 5 days”.
6
CHANGES OF ANALYSIS FROM PROTOCOL
None.
7
REFERENCES
 
 
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Sampson et al., 2006
Sampson H.A, A. Munoz-Furlong, R.L. Campbell, N.F. Adkinson Jr., S.A. Bock, A. Branum 
et al. Second symposium on the definition and management of anaphylaxis: summary report: 
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol, 117 (2006), pp. 391–397.
Takase et al., 2008
Takase M, Sakata H, Shikada M, Tatara K, Fukushima T, Miyagawa T. Nihonjinshōni niokeru 
supairoguramu-kijyunchi no sakusei (saishūhōkoku) [Creation of reference value for 
spirogram in Japanese paediatrics (final report)]. Japanese Journal of Pediatric Pulmonology. 
2008, 19 (2), pp.164-176 (in Japanese).
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8
APPENDIX
8.1
Adverse events of special interest
8.1.1
Anaphylactic reactions
Potential anaphylactic reactions will be defined on the basis of Sampson’s criteria (see
Sampson et al., 2006). These will be identified using a modified Standardized MedDRA 
Query (SMQ), with additional constraints on the timing of the AE onset date relative to the 
timing of the injection.
Confirmed anaphylactic reactions will be those defined following medical review of the 
preferred terms identified as potential anaphylactic reactions, as well as any relevant 
supporting data.
AESIs and related definitions based on MedDRA terms are not included in this SAP to 
facilitate their maintenance (e.g. management of MedDRA version changes), and for 
convenience in using them directly in SAS programming. These detailed definitions will be 
finalised by the study team prior to the primary database lock and provided together with the 
study datasets at the time of submission.
8.1.2
Immune complex disease (Type III hypersensitivity reactions)
Immune complex disease will be defined using a single PT of “Type III immune complex 
mediated reaction”. Since this will already be covered by the general AE reporting by 
SOC/PT, separate summary tables will not be needed for this AESI. 
8.1.3
Malignancy
Malignancy will be defined on the basis of an SMQ.
AESIs and related definitions based on MedDRA terms are not included in this SAP to 
facilitate their maintenance (e.g. management of MedDRA version changes), and for 
convenience in using them directly in SAS programming. These detailed definitions will be 
finalised by the study team prior to the primary database lock and provided together with the 
study datasets at the time of submission.
8.1.4
Helminth infections
Helminth infection will use an investigator-driven definition, i.e. will be directly determined 
from what is entered on the eCRF.
A subject will be considered to have this AESI if the subject has at least one preferred term 
where the dedicated Helminth Infection eCRF page was also completed for that event (linked 
by AE number), with AE onset date during the relevant study period for analysis.


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8.1.5
Severe infections (as defined in the protocol)
Severe infections will use an investigator-driven definition, i.e. will be directly determined 
from what is entered on the eCRF.
A subject will be considered to have this AESI if the subject has at least one preferred term 
with AE onset date during the relevant study period for analysis, which satisfies the following:

“AE Category” on Adverse Events eCRF page marked as “Severe Infection”, and one or 
more of the following:

AE is serious (“Serious” on Adverse Events eCRF page marked as “Yes”), or

AE required treatment with antiviral medications, intravenous antibiotics or 
medications for Helminth parasitic infection, or 

AE resulted in permanent discontinuation of study drug (“Action taken, 
investigational product” on Adverse Events eCRF page marked as “Drug 
permanently discontinued”).
8.1.6
Injection site reactions
Injection site reactions will use an investigator-driven definition, i.e. will be directly 
determined from what is entered on the eCRF.
A subject will be considered to have this AESI if the subject has at least one preferred term 
with AE onset date during the relevant study period for analysis, which has “AE category” on 
the Adverse Events eCRF page marked as “Injection Site Reaction”.
8.1.7
Opportunistic infections
Opportunistic infections will be defined using a pre-specified list of preferred terms (AZ 
defined SMQ).
AESIs and related definitions based on MedDRA terms are not included in this SAP to 
facilitate their maintenance (e.g. management of MedDRA version changes), and for 
convenience in using them directly in SAS programming. These detailed definitions will be 
finalised by the study team prior to the primary database lock and provided together with the 
study datasets at the time of submission.
8.1.8
Guillain-Barre syndrome
Guillain-Barre syndrome will be defined using an SMQ.
AESIs and related definitions based on MedDRA terms are not included in this SAP to 
facilitate their maintenance (e.g. management of MedDRA version changes), and for 
convenience in using them directly in SAS programming. These detailed definitions will be 


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finalised by the study team prior to the primary database lock and provided together with the 
study datasets at the time of submission.


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8.2
OCS conversion factors for prednisone equivalents
Total daily OCS dose will be converted to a prednisone equivalent using the following table:
Table 3
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 example, to convert a cortisone total daily dose to a prednisone equivalent total daily dose, 
a multiplication factor of 0.2 = 10/50 should be used.


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8.3
Additional reporting to assess the impact of the COVID-19 
pandemic
In order to assess the impact of the COVID-19 pandemic on the planned analyses, further 
additional summaries and analyses will be conducted at the final analysis. These are described 
below, with the section of the main SAP in which they relate to. The start date of the COVID-
19 pandemic is defined as 11th March 2020; the date the World Health Organisation (WHO) 
declared it a pandemic.  Where applicable, as described below, data will be presented prior to 
the start of the pandemic, and during the pandemic. No post-pandemic period is defined as it 
is expected that the majority of subjects will have completed the study before the end date of 
the pandemic can be defined.    
Section 2.2 Violations and Deviations  
All COVID-19 related IPDs will be grouped as described in Section 2.2 and summarised 
together with all non-COVID-19 related IPDs as described in Section 4.2.1. A listing of all 
COVID-19 related protocol deviations (important and non-important PDs) will be provided. 
An additional summary will be provided of IPDs related to COVID-19, and IPDs excluding 
COVID-19 related IPDs for the safety analysis set. 
Section 4.2.1 Subject disposition, demography and baseline characteristics  
The number of subjects registered prior to the COVID-19 pandemic, and number of subjects 
ongoing in the study, as well as ongoing in the planned treatment period during the COVID-
19 pandemic will be summarised. The total duration of follow-up for subjects during the study 
will be summarised, together with the duration of follow-up during the COVID-19 pandemic. 
The proportion of time on study during the pandemic will also be provided. 
The number and percentage of subjects with at least one missed scheduled visit or changed 
format of scheduled visit will be summarised. Changed format of scheduled visit will be 
grouped into “On-site, partial visit”, “Remote visit”, “Other”. The number of subjects 
discontinuing IP or withdrawing from the study due to COVID-19 will also be summarised. 
A listing of all subjects impacted by COVID-19 will be produced with details of changed or 
missed visits and change of location of IP administration  or missed IP administration.  
Section 4.2.3 Exposure and Compliance 
The number of subjects with missed IP doses due to COVID-19, including consecutive missed 
doses, will be summarised . In addition, the number of IP doses administered by location 
(home, other) will be summarised.  


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Section 4.2.4.1 Adverse Events 
The number and percentage of subjects reporting COVID-19 AEs (as defined based on the 
COVID-19 MedDRA terms) will be summarised by system organ class (SOC) and preferred 
term (PT) for the on-treatment and on-study periods. 
In addition, if there are more than 10 subjects reporting COVID-19 AEs, then the AE listing 
will be repeated including only these subjects, with details of all AEs reported by these 
subjects  
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A listing of subjects tested for COVID-19 and including test result will be provided.


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