Conditions: Moderate to Severe Asthma
Keywords: Tezepelumab Humoral Immune Response Quadrivalent Influenza Vaccination Antibody response Subcutaneous
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 70
Healthy volunteers: no

Brief summary:
This is a Phase 3b, multicenter, randomized, double-blind, parallel group, placebo-controlled study designed to investigate the potential effect of tezepelumab (210 mg subcutaneous \[SC\] every 4 weeks \[Q4W\]) on antibody responses following seasonal quadrivalent influenza virus vaccination in the fall/winter 2021-2022 in the USA.

Detailed description:
Participants with moderate to severe asthma will enter the screening period of a minimum of 2 weeks to allow adequate time for all of the eligibility criteria to be evaluated. They will be randomized 1:1 to receive tezepelumab 210 mg or placebo SC Q4W, administered at Weeks 0, 4, 8 and 12. Randomization will be monitored to ensure at least 50% of the randomized participants are between the ages of 12 to 17 years.

Participants will receive a single dose of inactivated quadrivalent seasonal influenza vaccine intramuscularly at Week 12, prior to the fourth dose of study intervention.

Serum samples for evaluation of antibody response will be drawn at Week 12 (pre-vaccination) and at Week 16 (4 weeks post-vaccination) when humoral response to the vaccination is expected to be fully developed.

The End of Treatment (EOT) Visit will be conducted at Week 16 and a final Follow-up Visit and the End of Study Visit will be conducted at Week 28.

Arms:
arm 1: Participants will be randomized to receive tezepelumab 210 mg administered at Weeks 0, 4, 8 and 12. Participants will also receive a single dose of inactivated quadrivalent seasonal influenza vaccine intramuscularly at Week 12, prior to the fourth dose of study intervention. arm 2: Participants will be randomized to receive placebo SC Q4W, administered at Weeks 0, 4, 8 and 12. Participants will also receive a single dose of inactivated quadrivalent seasonal influenza vaccine intramuscularly at Week 12, prior to the fourth dose of study intervention.

Interventions: intervention 1: Tezepelumab intervention 2: Placebo
Intervention descriptions: intervention 1: 210 mg SC injection Q4W. intervention 2: SC injection Q4W.

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol
Study Intervention
Tezepelumab
Study Code
D5180C00031
Version
3.0
Date
22 Feb 2022
A Multicenter, Randomized, Double-blind, Parallel Group, 
Placebo-controlled, Phase 3b Study to Evaluate the Potential 
Effect of Tezepelumab on the Humoral Immune Response to 
Seasonal Quadrivalent Influenza Vaccination in Adolescent and 
Young Adult Participants with Moderate to Severe Asthma 
(VECTOR)
Sponsor Name: AstraZeneca AB
Legal Registered Address: 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s)
IND number: 103031
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.
Protocol Number: D5180C00031
Amendment Number: 2.0
Study Intervention: Tezepelumab
Study Phase: 3b
Short Title: Tezepelumab Humoral Immune Response to Influenza Vaccine Study
Acronym: VECTOR
Parexel Medical Monitor Name and Contact Information will be provided separately


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N ati o n al c o -or di n ati n g i n vesti g at or
 
E d m o n d, O K 7 3 0 3 4, U S A.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Version 1.0
02 Jun 2021
Amendment 1, Version 2.0
07 Sep 2021
Amendment 2, Version 3.0
22 Feb 2022
The Protocol Amendment Summary of Changes table is provided below for the current 
amendment.
Amendment 2 (22 Feb 2022)
Overall Rationale for the Amendment:
The primary rationale for this amendment is to introduce a primary database lock after the end 
of treatment at Visit 7 (Week 16) and to update safety information based on the most recent 
Investigator’s Brochure, Version 5.0, dated 21 Oct 2021. Additional changes include APFS 
device malfunction, medical device deficiencies, and Appendix F Medical Device Adverse 
Events (AEs) to align with International Organisation for Standardisation 14155 and European 
Medical Device Regulation. In addition, the vaccine immunogenicity analysis set definition
was updated to exclude patients who experience influenza infection prior to Visit 7 (Week 16). 
Other minor changes included clarification of Schedule of Assessments for participants who 
prematurely discontinue study intervention. In addition, minor formatting and editorial 
administrative revisions were made throughout the protocol for clarification purposes.
The Clinical Study Protocol (CSP), Version 2.0, dated 07 Sep 2021, was updated with the 
following changes:


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Synopsis, Safety 
Endpoints; Section 
6.3.4 Ensuring 
Blinding; Section 
6.3.5 Methods of 
Unblinding; Section 
9.3 Populations for 
Analyses, Table 10; 
Section 9.4 Statistical 
Analyses; Section 
9.4.1 General 
Considerations; 
Section 9.4.3.1 Safety 
Endpoint(s); 
Section 9.5 Interim 
Analyses
Language relating to primary 
and final database locks was 
added.
To add primary analysis of 
data at Visit 7 (Week 16).
Substantial
Section 1.3 Schedule 
of Activities, Table 2; 
Footnote ‘b’ was added 
explaining procedures which 
are to occur at the 
investigational product 
discontinuation (IPD) visit.
To clarify that if the IPD or 
follow-up safety visit were to 
occur at the scheduled Visit 6 
(Week 12) or Visit 7 
(Week 16), that participants 
should have the flu vaccine 
and antibody assessments per 
Visit 6 (Week 12) and Visit 7
(Week 16).
Substantial
Section 2.2 
Background
Updated to reflect new 
information based on 
Investigator’s Brochure (IB) 
V 5.0
IB V5.0 has been updated to 
reflect new data from Phase 2 
and Phase 3 asthma studies 
which have been reported.
Substantial
Section 2.2 
Background; Section 
11 References
CINQAERO Summary of 
Product Characteristics (SmPc) 
reference was updated to the 
current version.
The SmPc was updated in 
2021.
Non-Substantial
Section 6.1.3 Medical 
Devices
Added section regarding 
sponsor manufactured medical 
device use in this study and all 
medical device deficiencies 
should be documented and 
reported by the investigator 
throughout the study
To align with International 
Organization for 
Standardization 14155 and 
European Medical Device 
Regulation
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 6.2.3
Reporting Product 
Complaints
Added section regarding any 
defects with IP that must be 
reported immediately to the 
AstraZeneca representative as 
per the Parexel study-specific 
Investigator Manual and defects 
will be investigated further with 
AstraZeneca.
To align with Parexel 
study-specific Investigator
Manual.
Non-substantial
Section 6.2.4 
Reporting Product 
Defects
Added section regarding 
product defects that should be 
reported to the AstraZeneca 
representative as per the 
study-specific Investigator 
Manual.
To align with Parexel 
study-specific Investigator 
Manual.
Non-substantial
Section 6.2.5 Single 
Use APFS device 
malfunction
Added section regarding Device 
malfunctions that should be 
reported using appropriate form 
as per the Parexel study-specific 
Investigator Manual.
To align with Parexel 
study-specific Investigator
Manual.
Non-substantial
Section 7.1 
Discontinuation of 
study Intervention
Language was added explaining 
procedures which are to occur 
at the investigational product 
discontinuation (IPD) visit.
To clarify that if the IPD or 
follow-up safety visit were to 
occur at the scheduled Visit 6 
(Week 12) or Visit 7 
(Week 16), that participants 
should have the flu vaccine 
and antibody assessments per 
Visit 6 (Week 12) or Visit 7 
(Week 16).
Substantial
Section 7.1 
Discontinuation of 
study Intervention
Language was added explaining 
procedures to be followed if the 
follow-up visit occurs on the 
same date as the scheduled 
Visit 7 (Week 16).
To clarify the procedures to be 
followed at the Follow-up 
visit.
Substantial
Section 8.1.2.5 
Reversibility Test and 
Post-BD FEV1 
Assessment
Second post-BD spirometry was 
updated to third post-BD 
spirometry.
Correction of an error.
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 8.3.12 
Medical Device 
Deficiencies
Added Section 8.3.12 
definitions of medical device 
deficiency and requirements to 
fulfil regulatory reporting 
obligations worldwide and 
investigator’s responsibility for 
detection and documentation of 
events meeting the definition of 
device deficiency occur during 
the study.
To align with International 
Organization for 
Standardization 14155 and 
European Medical Device 
Regulation.
Substantial
Section 9.3
Populations for 
Analyses Table 10
and Table 11
Vaccine immunogenicity 
analysis set population updated 
to exclude participants who 
experience an influenza 
infection prior to Visit 7 
(Week 16) assessments.
To reduce the potential to 
interfere with the generation 
or interpretation of an 
antibody response.
Substantial
Section 9.4 Statistical 
Analyses
Added wording to indicate 
selected safety objectives will 
be performed based on the 
primary database lock data.
To allow for review of 
selected safety outputs at 
primary database lock.
Non-substantial
Appendix D Actions 
Required in Cases of 
Increases in Liver 
Biochemistry and 
Evaluation of Hy’s 
Law
Investigational Medicinal 
Product was updated to study 
intervention.
To align with other sections.
Non-substantial
Appendix F Medical 
Device AEs, ADEs, 
SAEs, SADEs, US 
ADEs and Medical 
Device Deficiencies: 
Definitions and 
Procedures for 
Recording, 
Evaluating and 
Follow-up
Added Appendix F Medical 
Device AEs, ADEs, SAEs, 
SADEs, US ADEs and Medical 
Device Deficiencies: 
Definitions and Procedures for 
Recording, Evaluating and 
Follow-up.
To align with International 
Organization for 
Standardization 14155 and 
European Medical Device 
Regulation.
Substantial
Appendix H 
Maintenance Therapy 
Equivalence Table
Reference to GINA 2018 was 
updated to GINA 2021.
Correction of footnote to align 
with the current version.
Non-substantial
Appendix I 
Abbreviations
New abbreviations were added.
To include all abbreviations in 
the document.
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Appendix J Protocol 
Amendment History
Appendix J was added.
Appendix was added to 
include previous amendments 
summaries of changes.
Non-substantial


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS ...................................................................................................... 8
1
PROTOCOL SUMMARY ................................................................................ 13
1.1
Synopsis ........................................................................................................... 13
1.2
Schema............................................................................................................. 17
1.3
Schedule of Activities ....................................................................................... 18
2
INTRODUCTION............................................................................................ 22
2.1
Study Rationale ................................................................................................ 22
2.2
Background ...................................................................................................... 23
2.3
Benefit/Risk Assessment................................................................................... 26
2.3.1
Risk Assessment ............................................................................................... 26
2.3.1.1
Important Identified Risks................................................................................. 26
2.3.1.2
Important Potential Risks.................................................................................. 26
2.3.2
Benefit Assessment........................................................................................... 28
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 28
3
OBJECTIVES AND ENDPOINTS................................................................... 29
4
STUDY DESIGN ............................................................................................. 31
4.1
Overall Design.................................................................................................. 31
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 32
4.2
Scientific Rationale for Study Design ............................................................... 32
4.3
Justification for Dose........................................................................................ 33
4.4
End of Study Definition.................................................................................... 33
5
STUDY POPULATION.................................................................................... 33
5.1
Inclusion Criteria .............................................................................................. 33
5.1.1
Study Eligibility................................................................................................ 33
5.1.2
At Randomization............................................................................................. 34
5.2
Exclusion Criteria ............................................................................................. 35
5.2.1
Study Eligibility................................................................................................ 35
5.2.2
At Randomization............................................................................................. 37
5.3
Lifestyle Considerations ................................................................................... 38
5.3.1
Meals and Dietary Restrictions ......................................................................... 38
5.3.2
Caffeine, Alcohol, and Tobacco......................................................................... 38
5.3.3
Activity............................................................................................................. 38
5.3.4
Contraception ................................................................................................... 38
5.4
Screen Failures ................................................................................................. 39
6
STUDY INTERVENTION ............................................................................... 40


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6.1
Study Intervention(s) Administered................................................................... 40
6.1.1
Investigational Products.................................................................................... 40
6.1.1.1
Management of Study Intervention Related Reactions ...................................... 41
6.1.2
Non-Investigational Product ............................................................................. 41
6.1.3
Medical Devices ............................................................................................... 42
6.2
Preparation/Handling/Storage/Accountability ................................................... 42
6.2.1
Tezepelumab..................................................................................................... 42
6.2.1.1
Preparation and Handling.................................................................................. 42
6.2.1.2
Dose Preparation............................................................................................... 43
6.2.1.3
Dose Administration ......................................................................................... 44
6.2.2
Influenza vaccine.............................................................................................. 46
6.2.2.1
Preparation and Handling.................................................................................. 46
6.2.2.2
Dose Administration ......................................................................................... 46
6.2.3
Reporting Product Complaints .......................................................................... 47
6.2.4
Reporting Product Defects ................................................................................ 47
6.2.5
Single Use APFS Device Malfunction............................................................... 47
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 48
6.3.1
Participant Enrollment and Randomization ....................................................... 48
6.3.2
Procedures for Handling Incorrectly Enrolled or Randomized Participants........ 48
6.3.3
Methods for Assigning Treatment Groups......................................................... 49
6.3.4
Ensuring Blinding............................................................................................. 49
6.3.5
Methods for Unblinding.................................................................................... 50
6.4
Study Intervention Compliance......................................................................... 51
6.5
Concomitant Therapy........................................................................................ 51
6.5.1
Rescue Medicine............................................................................................... 54
6.5.2
Asthma Medication Restrictions ....................................................................... 54
6.6
Dose Modification ............................................................................................ 54
6.7
Intervention After the End of the Study............................................................. 54
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 54
7.1
Discontinuation of Study Intervention............................................................... 54
7.2
Participant Withdrawal from the Study.............................................................. 56
7.3
Lost to Follow-up ............................................................................................. 56
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 57
8.1
Efficacy Assessments........................................................................................ 57
8.1.1
Humoral Response to Influenza Vaccine ........................................................... 57
8.1.2
Spirometry........................................................................................................ 57
8.1.2.1
General requirements........................................................................................ 57
8.1.2.2
Spirometry Technique....................................................................................... 58
8.1.2.3
Post-bronchodilator Spirometry ........................................................................ 59
8.1.2.4
Order of Administration.................................................................................... 59
8.1.2.5
Reversibility Test and Post-BD FEV1 Assessment............................................. 59
8.1.2.6
Record Keeping ................................................................................................ 61


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8. 1. 3
Assess me nt of Ast h m a E xacer bat i ons ...............................................................6 1
8. 1. 4
8. 2
S af et y Assess me nts ...........................................................................................6 2
8. 2. 1
P h ysical E xa mi nat i ons ......................................................................................6 2
8. 2. 2
Vit al Sig ns........................................................................................................ 6 3
8. 2. 3
L ocal  Electr ocar dio gra ms .................................................................................6 3
8. 2. 4
Cli nical Safet y  La b orat or y Assess me nts............................................................6 3
8. 2. 5
Ot her Safet y As sess me nts .................................................................................6 5
8. 2. 5. 1
Pre g na nc y T est ..................................................................................................6 5
8. 2. 5. 2
We i g ht a n d Hei g ht ............................................................................................6 5
8. 2. 5. 3
S er ol o g y ...........................................................................................................6 5
8. 2. 5. 4
S A R S -C o V -2 Di a g n ostic Test ...........................................................................6 5
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts .....................................................6 6
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y f or C ollect i n g A E a n d S A E I nf or mati on ................6 6
8. 3. 2
F o ll ow- u p of  A Es a n d S A Es .............................................................................6 6
8. 3. 3
Ca usalit y C o llecti on ..........................................................................................6 7
8. 3. 4
A d verse E ve nts Base d o n Si g ns a n d S y m pt o ms ................................................6 7
8. 3. 5
A d verse E ve nts Base d o n E xa mi nat i ons a n d T ests ............................................6 7
8. 3. 6
A d verse E ve nts of S pecial I nterest ....................................................................6 8
8. 3. 7
H y ’s La w ..........................................................................................................6 8
8. 3. 8
Di sease U n der St u d y.........................................................................................6 9
8. 3. 9
Re p orti n g of Seri o us A d verse E ve nts ................................................................6 9
8. 3. 1 0
Pre g na nc y .........................................................................................................7 0
8. 3. 1 0. 1
Mater nal E x p os ure ............................................................................................7 0
8. 3. 1 0. 2
Pater nal  E x p os ure.............................................................................................7 0
8. 3. 1 1
Me dicat i on Err or ...............................................................................................7 1
8. 3. 1 2
Me dical De vice Deficie ncies .............................................................................7 1
8. 3. 1 2. 1
Ti me Peri o d f or Detecti n g Me dical De vice Deficie ncies ...................................7 1
8. 3. 1 2. 2
F o ll ow- u p of  Me dical De vice Deficie ncies .......................................................7 2
8. 3. 1 2. 3
Pr o m pt Re p orti n g of Me dical De vice Deficie ncies t o S p o ns or ..........................7 2
8. 3. 1 2. 4
Re g ulat or y  Re p orti n g Re q uire me nts f or De vice Deficie ncies ............................7 2
8. 4
O ver d ose ..........................................................................................................7 3
8. 5
H u m a n Biol o gi c al  Sa m ples...............................................................................7 3
8. 5. 1
P har mac o ki net ics..............................................................................................7 4
8. 5. 1. 1
Deter mi nat i on of Dr u g C o nce ntrati o n ...............................................................7 4
8. 5. 2
I mm u n o ge nicit y Assess me nts ...........................................................................7 4
8. 5. 3
P har mac o d y na mics ...........................................................................................7 4
8. 6
H u m a n Biol o gi c al  Sa m ple Bio m ar kers .............................................................7 4
8. 7
O pti o nal  Ge n o mics I nitiat i ve Sa m ple................................................................7 4
8. 8
Heal t h Ec o n o mics O R Me dical Res o urce Utilizati o n a n d Healt h Ec o n omics .....7 5
9
S T A T I S TI C A L C O N SI D E RA T I O N S................................................................7 5
9. 1
Stati stical H y p ot heses.......................................................................................7 5
9. 2
S a m ple Si ze Deter mi nat i on ...............................................................................7 5
9. 3
P o p ul at i ons f or A nal yses ...................................................................................7 5
C CI


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9.4
Statistical Analyses ........................................................................................... 78
9.4.1
General Considerations..................................................................................... 78
9.4.2
Efficacy ............................................................................................................ 78
9.4.2.1
Primary Endpoint(s).......................................................................................... 78
9.4.2.2
Secondary Endpoint(s)...................................................................................... 80
9.4.2.3
Exploratory Endpoint(s).................................................................................... 81
9.4.3
Safety ............................................................................................................... 81
9.4.3.1
Safety Endpoint(s) ............................................................................................ 81
9.5
Interim Analyses............................................................................................... 82
9.6
Data Monitoring Committee ............................................................................. 82
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS ........................................................................................ 82
11
REFERENCES............................................................................................... 118
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 17
Figure 2
Suggested Schema of Rotation of Injection Sites...................................... 45
Figure 3
Reversibility Testing Algorithm............................................................... 60
LIST OF TABLES
Table 1
Schedule of Activities (Screening)........................................................... 18
Table 2
Schedule of Activities (Randomization, Treatment, and Follow-up)......... 20
Table 3
Objectives and Endpoints......................................................................... 29
Table 4
Investigational Medicinal Products .......................................................... 40
Table 5
Non-Investigational Medicinal Product.................................................... 41
Table 6
Permitted Medications ............................................................................. 52
Table 7
Restricted Medications............................................................................. 52
Table 8
Prohibited Medications............................................................................ 53
Table 9
Laboratory Safety Variables..................................................................... 64
Table 10
Populations for Analysis .......................................................................... 75
Table 11
Primary Analysis Estimands .................................................................... 76


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LIST OF APPENDICES
Appendix A
Anaphylaxis: Signs and Symptoms, Management .................................... 83
Appendix B
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis .............................. 87
Appendix C
Regulatory, Ethical, and Study Oversight Considerations......................... 89
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 94
Appendix E
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 100
Appendix F
Medical Device AEs, ADEs, SAEs, SADEs, USADEs and Medical 
Device Deficiencies: Definitions and Procedures for Recording, 
Evaluating and Follow-up...................................................................... 105
Appendix G
Handling of Human Biological Samples ................................................ 109
Appendix H
Maintenance Therapy Equivalence Table............................................... 111
Appendix I
Abbreviations ........................................................................................ 112
Appendix J
Protocol Amendment History................................................................. 115


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-
controlled, Phase 3b Study to Evaluate the Potential Effect of Tezepelumab on the Humoral 
Immune Response to Seasonal Quadrivalent Influenza Vaccination in Adolescent and Young 
Adult Participants with Moderate to Severe Asthma (VECTOR)
Short Title: Tezepelumab Humoral Immune Response to Influenza Vaccine Study
Rationale: The epithelial cell-derived cytokine, thymic stromal lymphopoietin (TSLP), is 
produced in response to proinflammatory stimuli and drives allergic inflammatory responses, 
primarily through its activity on type 2 innate lymphoid cells (ILC-2), dendritic and mast 
cells. Human TSLP expression is reported to be increased in asthmatic airways correlating 
with disease severity.
Owing to its immunomodulating effect, it is important to determine if tezepelumab affects 
functioning of the immune system. In this study, a functional response of the immune system 
will be assessed by measuring antibody responses to the influenza vaccine in adolescents and 
young adults with moderate to severe asthma.
The rationale for selecting this population is based on precedence from a similar study with 
anti-IL5 biologic drug benralizumab, in which humoral immune response was assessed in 
adolescents and young adults (12 to 21 years old) with severe asthma. In that study, the 
humoral antibody responses induced by seasonal influenza virus vaccination do not appear to 
be affected by benralizumab treatment.
Objectives and Endpoints
Please note: If influenza vaccine administration is delayed, some participants’ assessments at 
Visit 6 (Week 12) and Visit 7 (Week 16) may be performed at later timepoints.




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Disclosure Statement: This is a parallel group treatment study with 2 arms that is participant 
and investigator blinded.Number of Participants:
Approximately 135 participants aged 12 to 21 years with moderate to severe asthma will be 
enrolled into screening to provide a target sample size of approximately 100 randomized 
participants for the study.
Intervention Groups and Duration:
Participants with moderate to severe asthma will be randomized 1:1 to receive tezepelumab 
210 mg or placebo SC Q4W, administered at Weeks 0, 4, 8 and 12. Enrollment into screening
will be monitored to ensure at least 50% of the randomized participants are between the ages 
of 12 to 17 years. Treatment allocation will be stratified by age at the time of informed 
consent/assent (12 to 17 years, and 18 to 21 years) to ensure equitable distribution of
tezepelumab and placebo treatment in each age group.
Please note: If influenza vaccine administration is delayed, the treatment period may be 
extended and therefore participants may be given an additional 1 to 2 study intervention doses 
(as needed) every 4 weeks for a longer period than initially planned.
Data Monitoring Committee: No
Statistical Methods
Primary Endpoints
For the analysis of the anti-influenza antibody response endpoints, GMFRs and GMTs for 
HAI and MN antibody measurements will be summarized by treatment group and by strain, 
and the least square geometric mean ratio of GMFRs and GMTs between treatment groups 
(influenza vaccine divided by tezepelumab and influenza vaccine) will be calculated via an 
ANCOVA model on the log-transformed variable, adjusting for treatment group and age 
stratum (adolescents aged 12 to 17 or young adults aged 18 to 21). The least square geometric 
mean ratio will be provided with associated 90% CI.
The antibody response to the quadrivalent influenza vaccine strain is defined as a ≥ 4-fold rise 
in HAI or a ≥4-fold rise in MN from pre-dose antibody measure to post-dose antibody 
measure. The proportion of participants who experience a post-dose antibody response at 
Week 16 (EOT) for HAI and the proportion of participants who experience a post-dose 
antibody response at Week 16 (EOT) for MN and corresponding 90% Clopper-Pearson exact 
CIs will be summarized by treatment group and by strain. 
The proportion of participants who achieve a post-dose HAI antibody titer ≥ 40 and the 
proportion of participants who achieve a post-dose MN antibody titer ≥ 40 at Week 16 (EOT) 
and corresponding 90% Clopper-Pearson exact CIs will be summarized by treatment group
and by strain.


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Secondary Endpoints
Tezepelumab serum concentrations will be summarized using descriptive statistics at each 
visit. ADA to tezepelumab will be summarized using descriptive statistics at each visit.
Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version in force at the primary database lock. The definition of on-treatment and 
on-study for AE analyses will be given in the statistical analysis plan.
The number and percentage of participants with on-treatment and on-study AEs 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 participants in the safety population. On-
treatment AEs will also be summarized by intensity/severity and separately, by 
causality/relatedness (as determined by the investigator).
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. 


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1.2
Schema
Figure 1
Study Design
Abbreviations: n=number of participants.


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1.3
Schedule of Activities
Table 1
Schedule of Activities (Screening)
Assessment/activity
Screening
Details in CSP 
Section or Appendix
Visit
V1
(Week -2 to -3)
V2a
(V1 plus maximum 7 days)
Informed consent/assent
X
Section 5.1
Inclusion and exclusion criteria
X
X
Sections 5.1 and 5.2
Demography
X
Section 5.1
Medical and asthma historyb
X
Section 5.1
Complete physical examination
X
Section 8.2.1
Weight, height, and BMI
X
Section 8.2.5.2
Vital signs
X
X
Section 8.2.2
Local 12-lead ECG
X
Section 8.2.3
Serum chemistry
X
Section 8.2.4
Hematology
X
Section 8.2.4
Local urinalysis
X
Section 8.2.4
Serum concentration (theophylline)c
X
Section 8.2.4
Serology (hepatitis B, C; HIV-1; HIV-2)
X
Section 8.2.5.3
Local SARS-CoV-2 viral diagnostic testd
X
Section 8.2.5.4
Serum pregnancy teste
X
Section 8.2.5.1
Pre-bronchodilator FEV1f
X
X
Section 8.1.2.2
Post-bronchodilator FEV1f
X
X
Section 8.1.2.3
Adverse Events
X
X
Section 8.3


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Assessment/activity
Screening
Details in CSP 
Section or Appendix
Visit
V1
(Week -2 to -3)
V2a
(V1 plus maximum 7 days)
Concomitant medication 
X
X
Section 6.5
a
Visit 1 and Visit 2 can be combined if the participant has the time and they have not taken SABAs for 6 hours or their long-acting bronchodilator-containing therapy for 
12-24 hours. If spirometry/reversibility procedures are actually planned at Visit 1 as a convenience, then the ICF/assent must be signed prior to Visit 1 and prior to instructing 
the participant to withhold any medication.
b
To include influenza vaccination history.
c
For participants on theophylline, the serum concentration testing will be performed locally.
d
SARS-CoV-2 viral diagnostic test to be performed locally (local COVID-19 viral test).
e
For women of childbearing potential only.
f
Pre and post-bronchodilator spirometry can be done at Visit 1 OR Visit 2. If participants do not demonstrate airway reversibility at either Visit 1 or Visit 2 and this is needed 
to qualify the participant for randomization, the site should screen fail the participant.
Abbreviations: AE=adverse event; BMI=body mass index; CSP=clinical study protocol; COVID-19=Coronavirus disease 2019; ECG=electrocardiogram; FEV1=forced expiratory 
volume in 1 second; HIV=human immunodeficiency virus; ICF=informed consent form; SABA=short-acting β-agonist; SARS-CoV-2= severe acute respiratory syndrome 
coronavirus 2; V=visit.


Cli nical St u d y Pr ot oc ol – 3 . 0
Astra Ze neca
Teze pel u ma b – D 5 1 8 0 C 0 0 0 3 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 0 of 1 2 3
Ta ble 2
Sc he d ule of Acti vities ( R a n d o miz ati o n , Tre at me nt, a n d F oll o w -u p)
Assess me nt/ acti vit y
Tre at me nt
A nti b o d y res p o nse 
e v al u ati o n /
E O T
a
I P D b
F U /
E n d of 
St u d y 
Visit
U nsc h
Det ails i n C S P Secti o n or 
A p pe n di x
Visit
V 3  
V 4  
V 5  
V 6
V 7
V 8
W 0  
W 4  
W 8  
W 1 2  
W 1 6
W 2 8
Visit wi n d o w ( d a ys)
c
± 0 
± 3 
± 3 
± 3
± 3
± 3 
± 3
I ncl usi o n a n d e xcl usi o n criteria
X
Secti o ns 5. 1 a n d 5. 2
Ra n d o mi zati o n
X
Secti o n 6. 3. 1
C o m plete p h ysical e xa mi nati o n
X
X
X  
X
Secti o n 8. 2. 1
Brief p h ysical e xa mi nati o n
X  
X  
X
X
Secti o n 8. 2. 1
Vital si g ns
X  
X  
X  
X
X
X  
X  
X
Secti o n 8. 2. 2
Ser u m c he mistr y
X
X
X  
X
Secti o n 8. 2. 4
He mat ol o g y
d
X
X
X  
X
Secti o n 8. 2. 4
L ocal u ri nal ysis
X
X
X  
X
Secti o n 8. 2. 4
Uri ne pre g na nc y test ( di pstic k)
e
X  
X  
X  
X
X
X  
X
Secti o n 8. 2. 5. 1
P K
X
f
X
f
X
X  
X
Secti o n 8. 5. 1
A D A
X
f
X
X  
X
Secti o n 8. 5. 2
Ser u m a nti b o dies t o i nfl ue nza vir us
X
g
X
A d mi nistrati o n of i nfl ue nza vacci ne
h
X
Secti o n 6. 2. 1. 3
A d mi nistrati o n of st u d y i nter ve nti o n
X  
X  
X  
X
X
i
Secti o n 6. 2. 1. 3
C CI
C CI


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Teze pel u ma b – D 5 1 8 0 C 0 0 0 3 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 1 of 1 2 3
Assess me nt/ acti vit y
Tre at me nt
A nti b o d y res p o nse 
e v al u ati o n /
E O T
a
I P D b
F U /
E n d of 
St u d y 
Visit
U nsc h
Det ails i n C S P Secti o n or 
A p pe n di x
Visit
V 3  
V 4  
V 5  
V 6
V 7
V 8
W 0  
W 4  
W 8  
W 1 2  
W 1 6
W 2 8
Visit wi n d o w ( d a ys)
c
± 0 
± 3 
± 3 
± 3
± 3
± 3 
± 3
A d verse E ve nts
X  
X  
X  
X
X
X  
X  
X
Secti o n 8. 3
C o nc o mita nt me dicati o n 
X  
X  
X  
X
X
X  
X  
X
Secti o n 6. 5
a
If i nfl ue nza vacci ne a d mi nistrati o n is dela ye d, u nsc he d ule d st u d y i nter ve nti o n visits ma y occ ur pri or t o Visit 6 u ntil t he i nfl ue nza vacci ne is a vaila ble at 
st u d y sites. E O T assess me nts s ho ul d be perf or me d 4 wee ks after last d ose of st u d y i nter ve nti o n.
b
If I P D visit occ urs at t he sa me ti me as t he sc he d ule d Visit 6 ( Wee k 1 2 ), partici pa nts s h o ul d perf or m all assess me nts, i ncl u di n g i nfl ue nza a nti b o dies 
f oll o we d b y i nfl ue nza vacci nati o n. Partici pa nts s h o ul d t he n ret ur n t o t he st u d y site f or Visit 7 ( Wee k 1 6 ) a n d perf or m all assess me nts, i ncl u di n g i nfl ue nza 
a nti b o dies. Refer t o C S P Secti o n  7. 1 f or a d diti o nal i nf or mati o n.
c
All visits are t o be sc he d ule d fr o m t he date of ra n d o mizati o n, n ot fr o m t he date of pre vi o us visit, e xce pt i n t he case of earl y disc o nti n uati o n fr o m st u d y 
i nter ve nti on (see Secti o n 7. 1 f or details).
d
E osi n o p hils, bas o p hil , a n d m on oc y te c o u nts will be re dacte d fr o m t he ce ntral la b orat or y re p orts e xce pt at Visit 3 pri or t o st u d y i nter ve nti o n a d mi nistrati o n.
e
F or w o me n of c hil d beari n g p ote ntial o nl y , uri ne H C G test t o be c o m plete d at st u d y site o n eac h st u d y visit ( bef ore st u d y i nter ve nti o n a d mi nistrati o n o n 
V isit 3 t o Visit 6).
f
P K a n d A D A t o be c ollecte d P RI O R t o st u d y i nter ve nti o n d ose at Visit 3 a n d P K t o be c ollecte d P R I O R t o i nfl ue nza vacci nati o n at Visit 6.
g
Bl o o d dra w f or ser u m a nti b o dies t o i nfl ue nza vacci ne s h o ul d occ ur pri or t o a d mi nistrati o n of i nfl ue nza vacci ne. If i nfl ue nza vacci ne a d mi nistrati o n is 
dela ye d fr o m Visit 6 ( Wee k 1 2 ), pre-i nfl ue nza vacci ne bl o o d dra w f or ser u m a nti b o dies s h o ul d onl y  occ ur o n t he wee k of i nfl ue nza vacci ne a d mi nistrati o n.
h
I nfl ue nza vacci ne is t o be a d mi nistere d at a differe nt site t ha n st u d y i nter ve nti o n a n d site of i njecti o n n ote d. Partici pa nt is t o be o bser ve d f or 1 5 mi n utes 
after i njecti o n a n d bef ore a d mi nisteri n g st u d y i nter ve nti o n. I nfl ue nza vacci ne is t o be a d mi nistere d after sc he d ule d bl o o d sa m ples are ta ke n a n d pri or t o 
st u d y i nter ve nti o n a d mi nistrati o n.
i
If i nfl ue nza vacci ne a d mi nistrati o n is dela ye d, a n a d diti o nal 1 t o 2 u nsc he d ule d st u d y i nter ve nti o n visits ma y occ ur pri or t o Visit 6, u ntil t he i nfl ue nza 
vacci ne is a vaila ble at st u d y sites. All assess me nts d uri n g t he u nsc he d ule d visit ma y n ot be necessaril y c o m plete d.
A b bre viati o ns: 
 A D A =a nti-dr u g a nti b o dies; A E =a d verse e ve nt; C S P =cli nical st u d y pr ot oc ol ; E O T =e n d of treat me nt; 
F U = f oll o w-u p; H C G = h u ma n c h ori o nic g o na d otr o pi n; I P D =i n vesti gati o nal pr o d uct disc o nti n uati o n; P K = p har mac o ki netics; U n sc h = u nsc he d ule d; V = visit ; 
W = wee k .
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2
INTRODUCTION
This is a Phase 3b, multicenter, randomized, double-blind, parallel group, placebo-controlled 
study investigating the potential effect of tezepelumab on antibody responses following 
seasonal quadrivalent influenza virus vaccination. 
2.1
Study Rationale
The epithelial cell-derived cytokine, TSLP, is produced in response to proinflammatory 
stimuli and drives allergic inflammatory responses, primarily through its activity on ILC-2, 
dendritic (Gilliet et al 2003, Soumelis et al 2002, Reche et al 2001) and mast cells 
(Allakhverdi et al 2007). Human TSLP expression is reported to be increased in asthmatic 
airways correlating with disease severity (Ying et al 2005).
Tezepelumab is a human mAb IgG2λ directed against TSLP, expressed in a CHO CS-9 cell 
line. The molecule is a heterotetramer consisting of 2 heavy chains of the IgG2 subclass and 
2 light chains of the lambda subclass, which are covalently linked through disulfide bonds. 
Tezepelumab binds with human TSLP and prevents its interaction with TSLP receptor 
complex. As a result, targeting TSLP may inhibit multiple biologic pathways involved in 
asthma (Gauvreau et al 2014).
In the Phase 3 NAVIGATOR and Phase 2b PATHWAY studies, tezepelumab reduced 
exacerbations compared with placebo in participants with moderate to severe, uncontrolled 
asthma, irrespective of baseline levels of T2 inflammatory biomarkers (blood eosinophil 
counts, fractional exhaled nitric oxide, and serum total IgE) (Corren et al 2017, Menzies-Gow 
et al 2021). In these studies, tezepelumab also improved lung function, asthma control and 
patient health-related quality of life in the overall population. In addition, in these studies, 
tezepelumab has been shown to decrease IgE levels; however, its administration did not affect 
IgG, IgM or IgA. In a preclinical toxicology study with cynomolgus monkeys the IgG 
response to keyhole limpet antigen was suppressed but only at doses much higher than used in 
human studies (50 mg/kg subcutaneously [SC] weekly) (Investigator’s Brochure for 
tezepelumab). 
Owing to its immunomodulating effect, it is important to determine if tezepelumab affects 
functioning of the immune system. In this study, a functional response of the immune system 
will be assessed by measuring antibody responses to the influenza vaccine in adolescents and 
young adults with moderate to severe asthma.
The influenza vaccine was chosen for this study as GINA Guidelines recommend yearly 
influenza vaccination for asthmatics, in particular those with moderate to severe disease. The 
Center for Disease Control also recommends yearly influenza vaccination for asthmatics 
(GINA , CDC Asthma 2021). Quadrivalent, inactive influenza vaccine containing 4 strains (2 


Cli nical St u d y Pr ot oc ol – 3 . 0
Astra Ze neca
Teze pel u ma b – D 5 1 8 0 C 0 0 0 3 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 3 of 1 2 3
f or infl ue nza A a n d 2 f or i nfl ue nza B) selecte d f or t he i nfl ue nza seas o n 2 0 2 1/ 2 0 2 2 f or t he 
n ort her n he mis p here will be use d ( F D A 2 0 2 1 ).
I mm u n o ge nicit y will  be assesse d usi n g 2 t y pes of  strai n-s pecific assa ys ( d ual pri mar y 
e n d p o i nt) detecti n g vacci ne h u m oral res p o nse:

H e m a g gl ut i ni n i n hi biti on ( H AI) assa y a n d micr o ne utralizat i on ( M N) assa y.
H e m a g gl ut i ni n i n hi biti on assa y meas ures t he a bilit y of  ser u m t o bloc k hae ma g gl uti nati o n, 
w hic h is t he a g gre gati o n of re d bl o o d cells ca use d b y i nfl ue nza vir us. T he res ult i n g 
hae ma g gl ut i nati on i n hi biti on a nti b o dies tit er is a c orrelate of pr otecti o n f or i nfl ue nza vir us 
t hat is acce pte d b y ma n y re g ulat or y  a ge ncies. Micr o ne utralizat i on assa y  detect a nti b o dies t hat 
di rectl y ne utralize vir us (Ha n n o u n et al 2 0 0 4 , H o bs o n et al 1 9 7 2 , Kra m mer 2 0 1 9 ).
T he d ual pri ma r y e n d p oi nt i ncl u des ser oc o n versi on o utc o m e meas ures ( 4-f ol d rise i n titer a n d 
tit er ≥ 1: 4 0) pr o vi de d as res p o nse rates , a n d ce ntral meas ures of  te n de nc y for t he i m m u ne 
res p o nse (ge o m etric mea n f o l d rises [G M F R ] a n d ge o m etric me a n titers [G M T ]) f or t he H AI
a n d M N assa y res ults . F or t he I nfl ue nza A H 3 N 2-strai n, o nl y t he M N assa y  will be perf or me d 
o wi n g t o t he k n o w n l o w he m a g g l uti nati o n effect of t he strai n (Si cca et al 2 0 2 0).
I n t his st u d y, a f u ncti onal res p o nse of t he i m m u ne s yste m t o t he i nfl ue nza vacci ne will be 
assesse d i n a d o lesce nts a n d y o u n g a d ults wit h m o derate t o se vere ast h ma. T he rati o nale f or 
selecti ng t hi s p o p ulat i on is base d o n t he pre vi o us si milar st u d y  wit h a nti-I L 5 bi ol ogic dr u g 
be nraliz u ma b i n w hic h h u m oral i m m u ne res p o nse was assesse d i n a d o lesce nt a n d y o u n g a d ult 
( 1 2 t o 2 1 years o l d) se vere ast h matics (Zei tli n et al 2 0 1 8). A t otal of 1 0 3 parti ci pa nts were 
ra n d omize d a n d recei ve d be nraliz u ma b ( n = 5 1) or place b o ( n = 5 2). T here were n o c o nsiste nt 
differe nces i n H AI or M N a nti b o d y  res p o nses 4 wee k s after t he i nact i ve q ua dri vale nt 
i nfl ue nza vacci ne a d mi nistrati o n bet wee n part ici pa nts recei vi n g be nraliz u ma b or place b o.
P arti cipa nt e ntr y  will be stratifie d b y a ge ( 1 2 t o 1 7-year a ge gr o u p a n d 1 8 t o 2 1 -year a ge 
gr o u p) t o e ns ure e q uita ble distri b uti o n of  treat me nt allo c ati o n f or a nal ysis.
I n a d diti on t o t he i m m u ne res p o nse t o vacci ne, t he teze pelu ma b i m pact o n 
n u m ber of e xacer bat i ons, ser u m tr o u g h teze pel u ma b c o nce ntrati o ns , a n d a nt i-dr u g a nt i b o dies 
( A D As) will be i n vest i gate d.
2. 2
B ac k gr o u n d
Ast h ma i s a c hr o nic i nfla m mat or y dis or der of t he air wa ys ca use d b y t he i nteracti o n of ge netic 
a n d e n vir o n me ntal fact ors. It is c haracterize d b y wi des prea d, varia ble, a n d re versi ble airfl o w 
o bstr ucti o n , air w a y infla m mat i on, e xcessi ve m uc us pr o d ucti o n; a nd ai r w a y 
h y perres p o nsi ve ness t hat lea d t o rec urre nt e pis o des of w heezi n g, breat hless ness, c hest 
tig ht ness, a n d c o u g hi n g ( C S G A  1 9 9 7). Pr o gressi ve pat h olo gic ai r wa y r e mo deli n g a n d scarri n g 
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may occur in persistent asthma resulting in 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. Approximately 19 million adult patients and 5.5 million children 
under 18 years of age in the USA are thought to have asthma (Asthma and Allergy Foundation 
of America 2017). Worldwide, asthma currently affects approximately 339 million people 
(Global Asthma Network 2018); yearly asthma accounts for an estimated 9.8 million 
physician office visits, 1.6 million emergency room visits, and over 3500 deaths in the USA 
(Asthma and Allergy Foundation of America).
Tezepelumab is being developed for the treatment of moderate to severe, uncontrolled asthma. 
Approximately 5% to 10% of asthma patients have severe asthma (based on 2018 estimates 
[Global Asthma Network 2018]), 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). 
Study D5180C00007 (NAVIGATOR) was a Phase 3, multicenter, global, randomized, 
double-blind, placebo-controlled study to assess the efficacy and safety of 210 mg 
tezepelumab administered SC Q4W for 52 weeks. The population of interest was adults and 
adolescents with severe, uncontrolled asthma between the ages of 12 and 80 years and both 
overall and across a broad spectrum of asthma phenotypes as determined by participants with 
blood eosinophils above and below 300 cells/μL, FeNO above and below 25 ppb, as well as 
allergic and non-allergic status. A total of 1061 participants were randomized in a 1:1 ratio to 
tezepelumab or placebo and 1059 participants (including 82 adolescents) received at least one 
dose of study intervention. Tezepelumab treatment resulted in a statistically significant and 
clinically meaningful reduction in annualised asthma exacerbation rate (AAER) by 56% 
(p < 0.001) compared with placebo in the overall population and by 41% compared with 
placebo in participants with baseline blood eosinophils <300 cells/μL (p < 0.001). The mean 
serum trough concentration of tezepelumab increased over time and approached steady state 
by 12 weeks. Treatment-emergent ADAs were detected at any time during the study in 4.9% 
(26) of participants treated with tezepelumab. Neutralizing antibodies to tezepelumab were 
detected in only one (0.2%) of the participants treated with tezepelumab. On-treatment AEs 
were similar between the placebo (80.8%) and the total tezepelumab (77.1%) dose groups and
the majority of participants had on-treatment AEs that were mild or moderate in severity and 
not related to the study intervention. The percentage of participants who discontinued the trial 
regimen was 6.8% in the tezepelumab group and 10.7% in the placebo group. On-treatment 


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AEs that resulted in permanent discontinuation of study intervention was 2.1% in the 
tezepelumab group and 3.6% in the placebo group. Overall, tezepelumab was well tolerated 
with an acceptable safety profile and no safety signals in both adult and adolescent 
participants with severe, uncontrolled asthma (Menzies-Gow et al 2021, TEZSPIRE FDA 
Prescribing Information 2021).
For moderate to severe asthma patients who are uncontrolled on ICS, LABA and other 
controllers, biologic therapies may provide benefit. Omalizumab may be suitable for a 
subgroup of patients with proven reactivity to an aeroallergen and elevated serum IgE levels 
who remain inadequately controlled with ICS plus LABA (XOLAIR US PI 2019, XOLAIR 
SmPC 2019). Four additional biologics, mepolizumab, reslizumab, benralizumab, and 
dupilumab, have been approved for severe asthma with an eosinophilic phenotype and/or 
those requiring oral corticosteroid (OCS) therapy (NUCALA SmPC 2019, NUCALA US PI 
2019, CINQAERO SmPC 2021, CINQAIR US PI 2020, FASENRA SmPC 2019, FASENRA 
US PI 2019, DUPIXENT SmPC 2020, DUPIXENT US PI 2019). 
Biologics targeting IL-4, IL-5, and IgE are now included in international treatment guidelines 
(GINA ) as add-on treatments to patients whose asthma remains uncontrolled with LABA/ICS 
treatment. However, even when using currently available biologics, substantial proportions of 
patients continue to experience exacerbations and may benefit from agents that target different 
molecular pathways (Wenzel 2016, Froidure et al 2016, Swedin et al 2017). Therefore, despite 
these additional therapeutic options, there is still a clear unmet medical need among patients 
with moderate to severe asthma, independently of IgE status or eosinophil level, who are 
unable to gain asthma control using currently available therapies.
Both GINA and CDC recommend annual influenza vaccines for children and adults with 
asthma because they are at high risk of developing serious flu complications, even if their 
asthma is mild or their symptoms are well-controlled by medication. Influenza can result in 
airway and lung inflammation which can contribute to acute asthma exacerbations. Asthma is 
the most common medical condition among children hospitalized with influenza and one of 
the more common medical conditions among hospitalized adults (CDC Asthma 2021). Recent 
systematic review and meta-analysis that included observational studies designs suggested 
that influenza vaccination reduced the risk of asthma exacerbations (GINA 2021).
Tezepelumab is currently being developed as a potential treatment option for the management 
of moderate to severe, uncontrolled asthma in adolescent and adult patients. By blocking 
TSLP, tezepelumab has been shown to have a broader impact on the inflammatory responses 
seen in asthma than other biologics.
Additional studies with tezepelumab have been completed. These include a mechanistic study 
(D5180C00013; CASCADE) conducted in adults with inadequately controlled asthma, an OCS 
sparing study (D5180C00009; SOURCE) conducted in adults with OCS-dependent asthma, an 


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at-home use study in adults and adolescents with severe asthma study (D5180C00011; PATH-
HOME), and a Japanese long-term safety study in participants with inadequately controlled 
asthma (D5180C00019; NOZOMI).
A detailed description of the above-mentioned additional studies and chemistry, 
pharmacology, efficacy, and safety of tezepelumab is provided in the current Investigator’s 
Brochure.
2.3
Benefit/Risk Assessment
2.3.1
Risk Assessment
Tezepelumab has been well-tolerated with no identified risks in the completed clinical studies 
to date. No serious allergic reactions or anaphylactic reactions causally related to tezepelumab 
were reported in the Phase 2 and Phase 3 studies. Although TSLP suppression could 
theoretically have unanticipated immune-related side effects impairing host defense against 
certain infections, there is no clear preclinical or clinical evidence supporting such a role, and 
no safety signals related to infections have been detected in the tezepelumab program.
Mild problems following inactivated influenza vaccine may include soreness, redness, or 
swelling where the injection was given, as well as headache (low grade), fever, muscle aches, 
nausea, and fatigue (CDC Influenza 2021). Very rarely, as with all vaccines, anaphylaxis may 
occur.
2.3.1.1
Important Identified Risks
To date there are no important identified risks in the tezepelumab clinical development 
program.
2.3.1.2
Important Potential Risks
The mechanism of action of tezepelumab suggests potential inhibitory effects on immune 
responses mediated by Th2 cells, leading to the possibility of diminution of the host’s 
protective response to infection.
Severe infections
Severe infections are defined as infections that are SAEs, require treatment with systemic 
antiviral medications, intravenous antibiotics or medications for helminth parasitic infection, 
or require permanent discontinuation of study intervention.
To mitigate the potential risk of severe infections eligibility criteria will exclude vulnerable 
participants, and included participants will be monitored for infection with complete blood 
counts, including differential white cell count throughout the study; and through standard 
AE/SAE reporting. Participants using immunosuppressive medication within 3 months prior 
to screening; who have a history of a known immunosuppressive disorder; who have a history 


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of clinically significant infection prior to screening; and who have known active or suspected 
tuberculosis either treated or untreated, will be excluded.
Parasitic infestation/infections
Tezepelumab may decrease the protective response to helminth infection by blockade of 
TSLP. 
To decrease the risk of parasitic infestation or infection, participants who have a history of 
clinically significant infection prior to screening and at screening, and participants with 
untreated systemic helminth parasitic infections or those at significant increased risk of 
systemic helminth parasitic infestations will all be excluded.
Serious hypersensitivity/allergic reactions (including immune complex disease)
As with any large molecule therapeutics, administration of tezepelumab may result in 
systematic and/or local reactions. Systemic reactions to large molecule therapeutics can be IgE 
or non-IgE-mediated and are generally characterized by signs and symptoms such as skin 
rash, urticaria, pruritus, local or diffuse erythema, angioedema, fever, chills, cough, dyspnea, 
wheezing, bronchospasm, nausea/vomiting, diaphoresis, chest pain, tachycardia or 
bradycardia, and/or hypotension, which can all be severe or life-threatening. Effects typically 
occur during or within several hours after study intervention, but may be delayed.
To mitigate the potential risk of serious hypersensitivity reactions, during and after 
administration of tezepelumab, specific requirements for observing participants for AEs/SAEs
and for monitoring vital signs before, during, and after administration of tezepelumab are 
included in the CSP. In addition, medical equipment to treat acute anaphylactic reactions will 
be immediately available and site staff will be trained to recognize and treat anaphylaxis.
The administration of a mAb can result in the formation of ADA. The occurrence of ADA 
could result in immune complex disease (Type 3 hypersensitivity reactions) with 
manifestations such as serum sickness, nephritis, and vasculitis, or altered tezepelumab levels 
or activity.
To mitigate the potential risk of immune complex disease participants will be monitored for 
the presence of ADA and confirmed immune complex disease through routine monitoring of 
AEs/SAEs. Participants with a prior history of immune complex disease will be excluded.
More detailed information about the known and expected benefits and potential risks of 
tezepelumab may be found in the current Investigator’s Brochure.


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2.3.2 Benefit Assessment
Benefits for tezepelumab over placebo include a clinically meaningful reduction in asthma 
exacerbations, improvement in lung function and asthma control metrics (Corren et al 2017).
Participants in this study may benefit from the continuous monitoring of all AEs arising 
during the clinical study, related or not related to the study intervention. In addition, 
participants will be contributing to the development of new therapies for moderate to severe 
asthma.
Benefits of seasonal influenza vaccination would include probable protection against 
developing influenza in the upcoming influenza season. GINA Guidelines recommend patients 
with moderate and severe asthma receive influenza vaccination every year to decrease risk of 
influenza and potential asthma exacerbation.
2.3.3 Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to participants enrolling in this study
(see Section 2.3.1.2), the potential risks identified in association with tezepelumab are 
justified by the anticipated benefits that may be afforded to participants with moderate to 
severe asthma.




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Ta ble 3
O bjecti ves a n d E n d p oi nts
O bjecti ves
E n d p oi nts
A b bre viati o ns: 
 A Es =a d verse e ve nts; P K = p har mac o ki netic; 
S A E =seri o us a d verse e ve nts.
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3b, multicenter, randomized, double-blind, parallel group, placebo-controlled 
study designed to investigate the potential effect of tezepelumab (210 mg SC Q4W) on 
antibody responses following seasonal quadrivalent influenza virus vaccination in the 
fall/winter 2021-2022 in the USA. 
Approximately 135 participants aged 12 to 21 years with moderate to severe asthma will be 
enrolled into screening to provide a target sample size of approximately 100 randomized 
participants for the study. Participants will be randomized 1:1 to receive tezepelumab 210 mg 
or placebo SC Q4W, administered at Weeks 0, 4, 8 and 12. Randomization will be monitored 
to ensure at least 50% of the enrolled participants are between the ages of 12 to 17 years. 
Treatment allocation will be stratified by age at the time of informed consent/assent (12 to 17
years, and 18 to 21 years) to ensure equitable distribution of tezepelumab and placebo 
treatment in the 2 age groups. To ensure that at least 50% of the enrolled participants are 12 to 
17 years old, the IWRS/IVRS will be set up with a 50% cap on the 18 to 21-year age group. 
Once this cap is reached, no more participants will be enrolled into the 18 to 21-year age 
group. Once an age group is closed, participants in the screening period in the closed age 
group will not be allowed to be randomized and will be considered a screen failure.
After enrollment and confirmation of entry criteria, participants will enter the screening period 
of a minimum of 2 weeks to allow adequate time for all of the eligibility criteria to be 
evaluated before being randomized. Participants who meet the eligibility criteria will be 
randomized at Visit 3 [Week 0] and will receive either tezepelumab 210 mg or placebo by SC
injection at intervals of 4 weeks, ie doses of study intervention will be administered at 
Weeks 0, 4, 8 and 12. The study schema is presented in Figure 1.
Participants will receive a single dose of inactivated quadrivalent seasonal influenza vaccine 
IM at Week 12, prior to the fourth dose of study intervention. Steady-state of tezepelumab is 
achieved at Week 12. Serum samples for evaluation of antibody response will be drawn at 
Week 12 (pre-vaccination) and at Week 16 (4 weeks post-vaccination) when humoral response 
to the vaccination is expected to be fully developed.
The EOT Visit will be conducted at Week 16 and a final Follow-up Visit and the End of Study 
Visit will be conducted at Week 28. 
Please note: If influenza vaccine administration is delayed, the treatment period may be 
extended and therefore participants may be given an additional 1 to 2 study intervention doses 
(as needed) every 4 weeks for a longer period than initially planned.
Participants will be maintained on their currently prescribed ICS-LABA therapies without 


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change from enrollment throughout the screening and treatment period. If asthma 
exacerbations occur during the treatment period, participants can be treated with oral or other 
systemic corticosteroids or other asthma therapies according to standard practice.
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study participants become infected with SARS-CoV-2 or similar pandemic 
infection) which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the participant’s ability to conduct the study. The 
investigator or designee should contact the study sponsor to discuss whether the mitigation 
plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with Good Clinical Practice, and minimize risks to study integrity. 
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options: 

Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the ICF should be signed at the participant’s next contact with the 
study site).

Re-screening: One additional re-screening to confirm eligibility to participate in the 
clinical study can be performed in previously screened participants. The investigator 
should confirm this with the designated Parexel Medical Monitor. 

Home or Remote visit: Performed by a site qualified HCP or HCP provided by a TPV
only during safety follow-up (after Visit 7).

Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls and virtual or video visits only during safety follow-up 
(after Visit 7).
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix B.
4.2
Scientific Rationale for Study Design
This study is designed to investigate the potential effect of tezepelumab on the antibody 
response to the quadrivalent seasonal influenza virus vaccine in participants 12 to 21 years of 


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age with moderate to severe asthma (see Section 2.1).
4.3
Justification for Dose
The selection of the 210 mg SC Q4W dose was based on efficacy and safety results from the 
Phase 2b PATHWAY study. In PATHWAY, 210 mg tezepelumab Q4W led to numerically 
improved efficacy compared with 70 mg Q4W, whereas the 280 mg Q2W dose did not 
increase efficacy further with the 210 mg Q4W dose. Tezepelumab was well-tolerated at all 
3 doses and the safety profile was well balanced between the tezepelumab and placebo groups 
with no evidence of a dose relationship to AEs. Efficacy and safety of the 210 mg SC Q4W 
dose was further confirmed in the Phase 3 NAVIGATOR study in adults and adolescents with 
severe asthma.
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all visits of 
the study including the End of Study Visit or the last scheduled procedure shown in the SoA.
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure for the last participant in the study.
5
STUDY POPULATION
Prospective approval of CSP deviations to recruitment and enrollment criteria, also known as 
CSP waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
5.1.1
Study Eligibility
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent
1
Capable of giving signed informed consent/assent as described in Appendix C which 
includes compliance with the requirements and restrictions listed in the ICF/assent and in 
this CSP.
Age
2
Participant must be 12 to 21 years of age inclusive, at the time of signing the ICF/assent.
Type of Participant and Disease Characteristics
3
Documented physician-diagnosed asthma for at least 12 months prior to Visit 1.
4
Evidence of asthma as documented by either:

Post-bronchodilator airway reversibility (FEV1 ≥ 12% and ≥ 200 mL) demonstrated 
at Visit 1 or Visit 2 using the Maximum Post-bronchodilator Procedure.


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O R 

Air wa y  re versi bilit y d oc u me nte d i n t he pre vi o us 1 2 m o nt hs pri or t o Visit 1.
N ote: All part ici pa nts must ha ve re versi bilit y testi n g perf or me d bef ore ra n d o mi zat i on t o 
est a blis h a baseli ne c haracterist ic e ve n if hist orical d oc u me ntati o n is use d t o meet t his 
crit erio n.
5
D oc u m e nte d hist or y of sta ble treat me nt wit h I C S a n d L A B A f or at least 3 0 da ys pri or t o 
Vi sit 1.

T he I C S a n d L A B A ca n be parts of a c o m bi nat i on pr o d uct or gi ve n b y se parate 
i n halers. F or I C S/ L A B A c om bi nati o n pre parat i ons, b ot h t he mi d a n d hi g h -stre n gt h 
mai nte na nce d oses a p pr o ve d i n t he U S A will meet t his I C S criteri o n.

T he I C S d ose m ust be > 2 5 0 μ g fl uticas o ne pr o pi o nate dr y p o w der i n haler or 
e q ui vale nt dail y. E q ui vale nt I C S d oses as detaile d i n  A p pe n di x H.

A d dit i onal ast h ma c o ntr oller me dicati o ns (e g, L T R As, s h ort a n d l o n g -act i n g 
a nt i-m u scari nics, t he o p h ylli ne, or al  c ortic oster oids, et c) t hat ha ve bee n use d f or at 
least 3 0 da ys pri or t o Visit 1 are all o we d.
6
M or ni n g pre -br o nc h o dilat or F E V 1 of  > 5 0 % pre dict e d n or mal val ue at Visit 1 or Visit 2.
Wei g ht
7
B o d y  wei g ht ≥4 0 k g.
Se x
8
Male a n d fe male parti ci pa nts.
C o ntrace pti ve use b y w o me n of  c hil d beari n g p ote ntial s h o uld be c o nsiste nt wit h l ocal 
re g ulat i ons re gar di n g t he met h o ds of c o ntrace pti o n f or t h ose partici pat i n g i n cli nical st u dies
(see Secti o n 5. 3. 4 ).
5. 1. 2
At R a n d o mi zati o n
P arti cipa nts are eli gi ble t o be ra n d o mi z e d if all of t he f o ll owi n g cri t eria a p pl y:
1
F or w o me n of c hil d beari n g p ote ntial , a ne gati ve uri ne pre g na nc y test is re q uire d pri or t o 
a d mi nistrati o n of st u d y int er ve nt i on at Vi sit 3 (ra n d o mi zat i on).
2  
M ust ha ve ' n ot well -c o ntr olle d' ast h ma as d oc u me nte d b y eit her :

or

A pea k e x pir at or y fl ow of  6 0-8 0 % pre di cte d.
or

A n e xacer bat i on, o ne or m ore, t hat re q ui re d oral c ortic oster oids i n t he pre vi o us 
1 2 m o nt hs.
or
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
Any one of the following assessed by a participant recall over the previous 
2-4 weeks:
o
Asthma symptoms > 2 days/week.
o
Night-time awakenings once or more per week.
o
SABA use for symptom control (not for the prevention of exercise-induced 
asthma) > 2 days/week.
NOTE: A participant’s verbal history suggestive of asthma symptoms, but without supporting 
documentation, is not sufficient to satisfy these inclusion criteria.
5.2
Exclusion Criteria 
5.2.1
Study Eligibility
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Clinically important pulmonary disease other than asthma (eg, active lung infection, 
bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated 
with obesity, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or ever been 
diagnosed with pulmonary or systemic disease, other than asthma, that are associated with 
elevated peripheral eosinophil counts (eg, allergic bronchopulmonary 
aspergillosis/mycosis, eosinophilic granulomatosis with polyangitis (EGPA), 
hypereosinophilic syndrome), or prior history of immune complex disease.
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 participant throughout the study.

Influence the findings of the studies or their interpretations.

Impede the participant's ability to complete the entire duration of study.
3
Life-threatening asthma defined as episodes requiring intubation associated with 
hypercapnia, respiratory arrest, hypoxic seizures, or asthma-related syncopal episodes.
4
History of cancer

Participants who have had basal cell carcinoma, localized squamous cell carcinoma 
of the skin, or in situ carcinoma of the cervix are eligible provided that the participant
is in remission and have had their curative therapy completed at least 12 months prior 
to Visit 1.


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
Participants who have had other malignancies are eligible provided that the 
participant is in remission and have had their curative therapy completed at least 5 
years prior to Visit 1.
5
Allergy to eggs, if egg based influenza vaccine will be administered.
6
History of anaphylaxis to any biologic therapy.
7
History of Guillain-Barré syndrome.
8
Known or suspected active tuberculosis either treated or untreated.
9
A helminth parasitic infection diagnosed within 24 weeks prior to Visit 1 that has not 
been treated with, or has failed to respond to standard of care therapy.
10 Current smokers or participants with smoking history ≥10 pack-years and participants 
using vaping products, including electronic cigarettes. Former smokers with a smoking 
history of < 10 pack-years and users of vaping or e-cigarette products must have stopped 
for at least 6 months prior to Visit 1 to be eligible.
11 History of alcohol or drug abuse within 12 months prior to the date of informed consent.
12 Major surgery within 8 weeks prior to Visit 1 or planned surgical procedures during the 
conduct of the study.
Prior/Concomitant Therapy
13 If on allergen immunotherapy, participants must be on a stable maintenance dose and 
schedule for at least 30 days prior to Visit 1 with no anticipated change in therapy during 
the conduct of the study.
14 Use of immunosuppressive medication (including but not limited to methotrexate, 
troleandomycin, cyclosporine, azathioprine, tacrolimus, mycofenolate mofetil, 
intramuscular long-acting depot corticosteroid, or any experimental anti-inflammatory
therapy) within 3 months prior to Visit 1.
15 Receipt of immunoglobulin or blood products within 30 days prior to Visit 1.
16 Receipt of live attenuated vaccines 30 days prior to the date of randomization.
17 Receipt of influenza vaccine for season 2021/22 prior to Visit 1.
18 COVID-19 vaccination within 6 days prior to randomization.
Prior/Concurrent Clinical Study Experience
19 Participants with a known history of allergy or reaction to the study intervention 
formulations or influenza vaccine.
20 Receipt of any marketed or investigational biologic within 16 weeks or 5 half-lives prior 
to Visit 1, whichever is longer.
21 Receipt of any non-biologic investigational medication within 30 days or 5 half-lives 
prior to randomization, whichever is longer.


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22 Previously received tezepelumab.
23 Concurrent enrollment in another drug-related interventional clinical trial.
Diagnostic Assessments
24 Any clinically significant abnormal findings in physical examination, vital signs, baseline 
ECG, hematology, clinical chemistry, or urinalysis during screening period, which in the 
opinion of the investigator, may put the participant at risk because of his/her participation 
in the study, or may influence the results of the study, or the participant's ability to 
complete entire duration of the study.
25 Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive 
medical history for hepatitis B or C. Participants with a history of hepatitis B vaccination 
without history of hepatitis B are allowed to enroll.
26 A history of known immunodeficiency disorder including a positive HIV test at V1, or the 
participant is taking antiretroviral medications as determined by medical history and/or 
participant’s verbal report.
27 Positive SARS-Cov2 test during the screening period.
28 ALT or AST level ≥2 times the ULN confirmed during screening period.
Other Exclusions
29 For women only - currently pregnant (confirmed with positive pregnancy test), 
breastfeeding, or lactating women.
30 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
31 Employees of the study center or any other individuals involved with the conduct of the 
study or immediate family members of such individuals.
32 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements.
5.2.2
At Randomization
Participants are excluded from randomization if any of the following criteria apply:
1
Asthma exacerbation during the screening period that requires treatment with oral 
corticosteroids or a hospitalization/emergency room visit for the treatment of asthma.
2
Acute illness or evidence of significant active infection (eg COVID-19) or known 
influenza infection during the current influenza season.


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5.3
Lifestyle Considerations
Participants must abstain from donating blood and plasma from the time of informed 
consent/assent, and for 16 weeks (5 half-lives) after last dose of study intervention.
5.3.1
Meals and Dietary Restrictions

Participants should avoid eating a large meal for at least 2 hours prior to all lung function 
assessments at the study site.
5.3.2
Caffeine, Alcohol, and Tobacco

Chronic alcohol or drug abuse within 12 months is restricted prior to Visit 1 and 
throughout the conduct of the study.

Smoking is not allowed throughout the course of the study.

The use of e-cigarettes is also not allowed during the course of the study.
5.3.3
Activity

Participants should avoid engaging in strenuous exertion for at least 30 minutes prior to 
all lung function assessments at the study site.
5.3.4
Contraception
Female participants:

Female participants of childbearing potential who are sexually active with a non-sterilized 
male partner must use a highly effective method of contraception from screening, and 
must agree to continue using such precautions for 16 weeks after the final dose of study 
intervention. 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.

A highly effective method of contraception is defined as one that results in a low failure 
rate (ie, less than 1% per year) when used consistently and correctly. Highly effective 
forms of birth control include: true sexual abstinence, a vasectomised sexual partner, 
Implanon™, female sterilization by tubal occlusion, any effective intrauterine 
device/system, Depo-Provera™ injections, oral contraceptive, and Evra Patch™ or 
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Adolescent specific information: 

If participant is female and has reached menarche, or has reached Tanner Stage 3 breast 
development (even if not having reached menarche), the participant will be considered a 
female of childbearing potential.
5.4
Screen Failures
Screen failures are defined as participants who complete informed consent/assent to
participate in the clinical study but are not subsequently randomly assigned to study 
intervention. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure participants to meet the Consolidated Standards of Reporting Trials
(CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE.
These participants should have the reason for study withdrawal recorded as ‘Screen Failure’ 
(ie, participant does not meet the required inclusion/exclusion criteria) in the eCRF. This 
reason for study withdrawal is only valid for screen failures, and not randomized participants.
Re-screening is allowed only once under the following circumstances:

If the reason for screen failure was transient (including but not limited to study-supplied
equipment failure, unforeseen personal events that mandate missed screening visits), 
participants may potentially be re-screened. These cases should be discussed with the 
Parexel Medical Monitor and documented in the investigator study file.

Any re-screened participant will be re-enrolled and reassigned their originally assigned 
enrollment number after signing a new informed consent/assent form, and after all Visit 1
assessments have been performed as listed in Table 1 (with the exception of testing for 
HIV-1 and HIV-2, hepatitis B and C). If the timeframe between screening and re-
screening is more than 30 days, then all Visit 1 assessments should be repeated.

Participants who experience an asthma exacerbation during the screening/run-in period 
will be screen failed and may be re-screened after 14 days of complete resolution of the 
asthma exacerbation, and when the subjects return to baseline, at Investigator’s discretion
(the extension of the screening period beyond 14 days should be discussed with Parexel 
Medical Monitor).
Re-screened participants should be assigned the same enrollment number as for the initial 
screening.
However, re-screening should be documented so that its effect on study results, if any, can be 
assessed.


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Re -scree ni n g of a parti ci pa nt f or a n y ot her reas o n will be all o we d o nl y u p o n a p pr o val of t he 
Pare xel Me dical M o nit or . A d oc u m e nte d a p pr o val for r e -scree ni n g s h o ul d be file d i n t he 
i n vesti gat or st u d y file.
6
S T U D Y I N T E R V E N TI O N
St u d y  i nter ve nt i on is defi ne d as a ny i n vesti gati onal i nter ve nt i on (s), mar kete d pr o d uct(s) or 
pl ace b o i nte n de d t o be a d mi nistere d t o a st u d y partici pa nt acc or di n g t o t he C S P .
I n t his st u d y, a d mi nistratio n of  t he i nacti vate d q ua dri vale nt i nfl ue nza vacci ne is c o nsi dere d a 
bac k gr o u n d i nter ve nt i on , n ot a st u d y int er ve nt i on .
6. 1
St u d y I nter ve nti o n(s) A d mi nistere d
6. 1. 1
I n vesti g ati o n al Pr o d ucts
Ta ble 4
I n vesti g ati o n al Me dici n al
Pr o d ucts
I nter ve nti o n n a me
T e ze pel u ma b
Place b o
T y pe
Bi ol o gic
Place b o
D ose f or m ul ati o n
 
 
 
 
 
U n it d ose stre n gt h(s)
2 1 0 m g
N/ A
D os a ge le vel(s)
2 1 0 m g Q 4 W
Place b o Q 4 W
R o ute of 
a d mi nistr ati o n
S C i njecti o n
S C i njecti o n
Use
E x peri me ntal
Place b o
I M P a n d NI M P
I M P
I M P
S o urci n g
Pr o vi de d ce ntrall y b y t he s p o ns or.
Pr o vi de d ce ntrall y b y t he s p o ns or.
P ac k a gi n g a n d 
l a belli n g
St u d y I nter ve nti o n will be pr o vi de d 
i n A P F S w it h 1. 9 1 m L fill v ol u me. 
Eac h s yri n ge will be la belle d i n 
acc or da nce wit h G M P.
St u d y I nter ve nti o n will be pr o vi de d 
i n A P F S w it h 1. 9 1 m L fill v ol u me. 
Eac h s yri n ge will be la belle d i n 
acc or da nce wit h G M P.
A b bre viati o ns: A P F S = a ccess orize d p r e-fille d syr i n ge; I M P =i n vesti gati o nal me dici nal pr o d uct; N/ A = n ot 
a p plica ble; NI M P = n o n i n vesti gati o nal me dici nal pr o d uct; S C =s u bc uta ne o us; Q 4 W =e ver y 4 wee ks ; U SA = U nite d 
States of A merica .
T he Access orize d P r e- Fille d S yr i n ge (A P F S ) is a si n gle use, dis p osa ble s yste m t hat is 
C CI
C CI


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designed to deliver the labelled dose to the SC space during one injection and automatically 
provide a safety mechanism to reduce the occurrence of accidental needle sticks during 
disposal of the system. The APFS consists of a pre-filled syringe sub-assembly (PFS-SA; 
2.25 mL syringe barrel - pre-filled to 1.91 mL with a 1/2-inch 27-gauge thin wall staked in 
needle, rigid needle shield, plunger stopper) and safety device.
6.1.1.1
Management of Study Intervention Related Reactions
Appropriate drugs (eg, epinephrine, H1 and H2 antihistamines, and corticosteroids), and 
medical equipment to treat acute anaphylactic reactions must be immediately available. Site 
staff must be trained to recognize and treat anaphylaxis (Kroger et al 2011, Lieberman et al
2010). Management of anaphylaxis must be in accordance with current standard of care and 
clinical guidelines. Details on anaphylaxis management are provided in Appendix A.
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Simpson et al 2006). Anaphylaxis typically manifests as 1 of 3 clinical scenarios:
1
The acute onset of a reaction (minutes to hours) with involvement of the skin, mucosal 
tissue, or both, and at least 1 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.
At Visits 3 and 4, participants will have a pre-assessment (ie, vital signs) prior to study 
intervention administration) and should be observed after study intervention administration for 
a minimum of 2 hours for the appearance of any acute drug reactions. For the remaining visits 
involving study intervention administration, participants will be observed for a minimum of 
1 hour after study intervention administration for any such reaction.
In order to help understand the potential drug-relatedness of any acute reaction, a blood 
sample should be drawn as close as possible to the event for possible additional ADA testing 
(if not already scheduled for this visit). Serum tryptase or other blood or urine testing relevant 
to the diagnosis of anaphylaxis may be obtained at a local lab at the discretion of the 
investigator.
6.1.2
Non-Investigational Product
Table 5
Non-Investigational Medicinal Product
Intervention name
Inactivated Quadrivalent influenza vaccine
Type
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Dose formulation
Pre-filled syringe
Unit dose strength(s)
Background intervention
Dosage level(s)
0.5 mL once
Route of 
administration
IM injection
Use
Background intervention
IMP and NIMP
NIMP
Sourcing
Provided centrally by the sponsor.
Packaging and 
labelling
Provided as per manufacturer’s packaging
Abbreviations: IM=intramuscular; IMP=investigational medicinal product; NIMP=non investigational medicinal 
product.
6.1.3
Medical Devices
The Sponsor-manufactured medical device, which forms part of the combination product and 
is referred to as a device constituent part, provided for use in this study is:

Accessorised pre-filled syringe (APFS)
Instructions for medical device use are provided in study intervention Handling Instructions.
All medical device deficiencies (including malfunction, use error and inadequate labelling) 
should be documented and reported by the investigator throughout the study (see 
Section 8.3.12) and appropriately managed by the manufacturer.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Tezepelumab
6.2.1.1
Preparation and Handling
Blinded study intervention will be supplied to the site in a kit containing APFS tezepelumab or 
matching placebo. The kit has a unique number that is printed on all labels within the kit (ie, 
the outer carton label and the label of the APFS within the carton).
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
The study intervention is to be stored at the study center in a secured facility with limited 
access and controlled temperature. The temperature should be monitored on a daily basis and 
documented in the temperature monitoring log while study intervention is stored at the study 
center. The study intervention must be kept in the original outer container and under 


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conditions specified on the label (between 36 °F to 46 °F [2 °C to 8 °C], protected from light).
In the following cases neither the center staff should use the affected study intervention and 
should immediately contact a Parexel representative for further guidance:

Temperature excursion upon receipt or during storage at the study center

Storage conditions were not met (eg, frozen) or cannot be confirmed

Damaged kit upon receipt

Damaged APFS device

Security seal on the carton has been broken

The expiration date has passed

Other reason(s) that may have affected the study intervention
Damaged study intervention should be documented via IWRS/IVRS (please refer to 
IWRS/IVRS manual for further details).
6.2.1.2
Dose Preparation
Prior to each study intervention administration at the study site:

Investigator/authorized delegate will assess injection site as per standards of medical care.

For women of childbearing potential, urine pregnancy test will be done; study 
intervention will be administered only when the result of the test is negative (see 
Section 8.2.5.1).
The APFS should be visually inspected prior to dose preparation. The study intervention will 
be provided to the study sites as a clear to slightly opalescent, colorless to light yellow liquid, 
practically free from particles contained in a pre-filled syringe to be stored between 36 °F to 
46 °F (2 °C to 8 °C) until used.
If defects are noted with the study intervention, the investigator and site monitor should be 
notified immediately. Preparation of the study intervention must be performed by a qualified 
person (eg, pharmacist, investigator or nurse) at the site.
The study intervention does not contain preservatives and any unused portion must be 
discarded. Total in-use storage time from removal of the study intervention from the 
refrigerator to start of administration must not exceed 8 hours. If storage time exceeds this 
limit, a new dose must be prepared with a new study intervention kit.
To prepare the participant’s dose, a study intervention kit will be selected for administration 
according to the kit identification number assigned by IWRS/IVRS.


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Dose preparation steps:
1
Allow the study intervention to equilibrate to room temperature 68 °F to 77 °F (20 °C to 
25 °C) for at least 60 minutes prior to dose administration. Ensure that the APFS is 
adequately protected from light during the warming process.
2
To prepare the study intervention for administration, remove the syringe from the carton 
by holding the middle of the syringe body.
3
Unwrap, but do not detach, the wrap-around label attached to syringe body to view the 
syringe contents.
4
Look at the liquid through the viewing window. The liquid should be clear to slightly 
opalescent, colorless to light yellow liquid, practically free from particles. Do not inject 
the study intervention if the liquid is cloudy, discolored, or contains large particles.
5
Re-wrap the label around the syringe body.
Unused product in opened and dispensed study intervention kits should not be used for 
subsequent dosing and should be stored for study intervention accountability. If the opened 
and dispensed APFS must be discarded immediately after dose preparation as per the site’s 
standard operating procedures, the kit boxes must be retained for study intervention 
accountability.
6.2.1.3
Dose Administration
The administration of all study intervention should be recorded in the appropriate sections of 
the eCRF. The study intervention will be administered at the study center. The study 
intervention will be administered by the investigator/authorized delegate or qualified 
healthcare professional (eg, pharmacist or study nurse) as specified in the SoA (Section 1.3). 
Each participant will receive tezepelumab 210 mg (one 1.91 mL injection) or matching 
placebo administered SC Q4W for 4 doses in the abdomen, thigh, or upper arm by APFS. 
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 fully inserted at a 45-degree angle approximately into the 
SC tissue. The injection site should not be rubbed after each injection. It is suggested that the 
site of injection of study intervention be rotated such that the participant receives study 
intervention at a different anatomical site each time. Suggested injection site rotation sequence 
is presented below (see Figure 2). In cases when rotation of the injection site is not favorable
for the participant and/or investigator, the reason should be recorded in the source documents. 
The injection site must be recorded in the source documents and the eCRF at each treatment 
visit.


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Figure 2
Suggested Schema of Rotation of Injection Sites
Further details on study intervention administration are provided in the study intervention 
handling instructions. Study intervention administration must be carried out in line with the 
instructions provided.
At Visits 3 and 4 (Weeks 0 and 4), participants should be observed by the qualified healthcare 
professional for a minimum of 2 hours after study intervention administration for the 
appearance of any acute drug reactions. For the remaining visits involving study intervention 
administration, participants will be observed by the qualified healthcare professional for a 
minimum of 1 hour after study intervention administration for the appearance of any such 
reaction.
If any of the following occur, the investigator should reschedule the visit and the study 
intervention should not be administered until the rescheduled visit:

The participant received allergen immunotherapy injection on the same day as scheduled 
study intervention administration.

The participant has an intercurrent illness that in the opinion of the investigator may 
compromise the safety of the participant in the study (eg, viral illnesses).

The participant was febrile (≥ 100.4 °F; ≥ 38 °C) within 72 hours prior to study 
intervention administration.

The participant is confirmed to have an active COVID-19 infection based on positive 
SARS-CoV-2 test results.

The participant is suspected to have an active COVID-19 infection based on assessment 
of COVID-19 symptoms.
The visit should be rescheduled within the allowed visit window and study intervention should 


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be administered at that rescheduled visit.
If the participant is suspected to have an active COVID-19 infection or fever (≥100.4 °F; 
≥38 °C) suspected due to COVID-19 infection, the visit should be rescheduled (and study 
intervention administration deferred) and participant should be re-assessed for symptoms of 
COVID-19 prior to re-scheduled visit.
The Parexel Medical Monitor should be contacted to discuss further participation in the 
following situations:

The participant has been diagnosed with an active COVID-19 infection.

The participant skips 2 consecutive study intervention administrations.
If the participant reports an injection site reaction, the investigator or qualified designee will 
complete the AE eCRF page and an additional eCRF page with questions about the injection 
site reaction.
1)
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2)
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure facility with limited access.
3)
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4)
Further guidance and information for the final disposition of unused study interventions 
are provided in the investigator instructions document.
6.2.2
Influenza vaccine
6.2.2.1
Preparation and Handling
Inactivated quadrivalent influenza vaccine will be provided to the study sites in the 
manufacturer’s packaging and will be in Pre-Filled Syringes. Influenza vaccine will be stored 
in the refrigerator at 35 °F to 46 °F (2 °C to 8 °C).
6.2.2.2
Dose Administration
The influenza vaccine will be administered by a qualified healthcare professional at the site at 
Week 12. The influenza vaccine should be injected IM, in the deltoid muscle and should be 
administered prior to study intervention. After influenza vaccine administration, the 
participant should be observed for a minimum of 15 minutes for the appearance of any acute 


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drug reaction and prior to administration of study intervention. A different injection site 
should be used for SC injection of study intervention on that day (ie, not the same upper arm). 
The injection sites must be recorded in the source documents and the eCRF.
6.2.3
Reporting Product Complaints
Any defects with the study intervention must be reported immediately to the Site Monitor. All 
defects will be communicated to the Sponsor and investigated further with the AstraZeneca 
Supply Chain Group.
During the investigation of the product complaint, all study intervention must be stored at 
labelled conditions 2°C to 8°C (36°F to 46°F), separated from other study intervention kits, 
unless otherwise instructed.
6.2.4
Reporting Product Defects
Product defects may be related to component, product, or packaging and labelling issues prior 
to or during use. Product defects should be reported to the Study Monitor. The list below 
includes the 3 categories of product complaints that should be reported as defects. 
Descriptions of product complaints in these 3 categories include, but are not limited to:

Component Issue: Defect in the container or dosing mechanism of the study 
intervention. The component may be damaged, missing, or broken. For the APFS, 
component examples include syringes and the accessory housing the syringe.

Product Issue: Defect in the product itself. The product appearance has visual
imperfections such as foreign particles, crystallization, discoloration, turbidity,
insufficient volume, or anything that does not apply to the product description in the 
Parexel study-specific Investigator Manual.

Packaging/Labelling Issue: Defect in the packaging or labelling of the product. The
packaging (eg, carton, thermo-fitted tray, or tamper-evident seal) or labelling may be 
damaged or unreadable, or the label may be missing.
6.2.5
Single Use APFS Device Malfunction
An APFS malfunction is when the APFS appeared normal during verification of shipment and
then does not work during administration, eg, the safety feature activated prematurely, part of 
the device (finger flange, plunger rod, etc.) came off or broke, the needle shield could not be
removed, only a partial dose was administered, the needle guard safety feature did not 
activate, needle bent or broke upon use.
Device malfunctions should be reported using the “Defect Malfunction Return Form” and the
Study Monitor should be notified.


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If a device malfunction is identified:

Before study intervention administration has started, another kit (replacement) should be 
dispensed to perform study intervention administration;

After study intervention administration has started and participant has been administered 
partial dose of study intervention, another kit must not be dispensed, and the participant 
must not be administered with another study intervention kit. The Parexel Medical 
Monitor and Study Monitor should be notified.
The return address and attention for malfunctioning device is available in the Device 
Malfunction Return Instructions.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Participant Enrollment and Randomization
The investigator(s) will:
1
Obtain signed informed consent/assent from the potential participant, or their 
guardian/legal representative, before any study specific procedures are performed.
2
Assign the potential participant a unique enrollment number via the IWRS/IVRS.
3
Determine participant eligibility.
4
Assign the eligible participant unique randomization code via the IWRS/IVRS.
5
Participants will be allocated to receive tezepelumab or placebo in a 1:1 ratio and 
according to the stratification factor listed in Section 4.1. Randomization numbers will be 
grouped in blocks. If a participant withdraws from the study, then his/her 
enrollment/randomization code cannot be reused. Withdrawn participants will not be 
replaced.
Specific information concerning the use of the IWRS/IVRS will be provided in a separate 
manual.
6.3.2
Procedures for Handling Incorrectly Enrolled or Randomized 
Participants
Participants who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive study intervention. There can be no exceptions to this rule. Participants 
who are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment and must be withdrawn from the study. These 
participants are defined as screen failures.
Where a participant does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the investigator should inform the Parexel Medical Monitor


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immediately, and a discussion should occur between the Parexel Medical Monitor and the 
investigator regarding whether to continue or discontinue the participant from treatment. 
Study intervention must be discontinued in all cases where continued treatment is deemed to 
pose a safety risk to the participant and the Parexel Medical Monitor must ensure the decision 
is appropriately documented. Participants that are discontinued from treatment should be 
followed up according to the options described in Section 7.1.
In those cases where continuation of the study intervention is judged not to present a concern 
related to safety and disease management, the rationale for continuing study intervention must 
be clearly documented.
6.3.3
Methods for Assigning Treatment Groups
Randomization codes will be assigned strictly sequentially in each stratum as participants 
become eligible for randomization.
The randomization code will be assigned from a randomization list prepared by a 
computerized system provided by CALYX on behalf of AstraZeneca in accordance with the 
AZRand process. All participants will be stratified at randomization by age group at the time 
of informed consent/assent (12 to 17 years and 18 to 21 years). The randomization will be set 
up to ensure that at least 50% of enrolled participants are in the 12 to 17-year age group. This 
will be accomplished by placing a 50% cap on the 18 to 21-year age group in the IWRS/IVRS 
such that enrollment in this age group stops once this cap is reached.
6.3.4
Ensuring Blinding
This is a double-blind study in which tezepelumab and placebo are not visually distinct from
each other. All packaging and labelling of study intervention will be done in such way as to 
ensure blinding for all sponsor and investigational site staff. Neither the participant nor any of 
the investigators or sponsor staff who are involved in the treatment or clinical evaluation and 
monitoring of the participants will be aware of the treatment received. Since tezepelumab and 
placebo are not visually distinct, study intervention will be handled by a qualified person (eg, 
pharmacist or study nurse) at the site.
A Parexel site monitor will perform study intervention accountability. In the event that the 
treatment allocation for a participant becomes known to the investigator or other study staff 
involved in the management of study participants, or needs to be known to treat an individual 
participant for an AE, the sponsor must be notified immediately by the investigator and, if 
possible, before unblinding.
The following personnel will have access to the randomization list:

Those carrying out the packaging and labelling of study intervention


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
Those generating the randomization list (CALYX)

Supply Chain Management department

Patient Safety department at AstraZeneca

Bioanalytical lab analyst performing the PK sample analysis
No other member of the extended study team at AstraZeneca, or any contract research 
organization (CRO) handling data, will have access to the randomization scheme during the 
conduct of the study until after the planned unblinding at the primary database lock after the 
last participant (enrolled in the 2021/2022 flu season) completes Visit 7 (Week 16).
The information in the randomization list will be kept from other personnel involved in the
conduct of the study and in a secure location until the end of the study.
Maintaining the blind to the participant’s blood eosinophil counts
While not entirely specific, participants on active tezepelumab treatment are expected to have 
lower blood eosinophil counts than participants on placebo. Procedures to mitigate unblinding 
on this basis include:

From Week 4 onward, eosinophil, monocyte, and basophil counts will be redacted from 
central laboratory reports to prevent the investigator/designee from possibly deducing the 
eosinophil contribution to the complete blood count.

If the investigator orders any local safety laboratory assessments, the requested tests 
should be restricted to the question at hand. For example, if a hemoglobin is desired, the 
investigator should avoid ordering a complete blood cell count with differential.

Handling of labs obtained during the treatment period but ordered outside of the clinical 
trial. Site staff who are directly involved in the participant’s management should remain 
blinded to any eosinophil, basophil, and monocyte results included as part of outside 
laboratory reports. To help ensure this, each investigational site will designate an 
individual (eg, administrator or another ancillary person) not directly involved in 
participant management, to receive and blind any eosinophil, basophil, and monocyte 
results prior to the report being handed over to the site staff involved in the participant’s 
management and prior to filing as a source document. Similarly, eosinophil, monocyte,
and basophil results must be redacted from all communications with the sponsor.

In cases where the investigator requires an eosinophil, basophil, or monocyte count for 
managing safety issues he/she may order these tests. AstraZeneca should be notified of all 
such cases.
6.3.5
Methods for Unblinding
Individual treatment codes, indicating the treatment randomization for each randomized 


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participant, will be available to the investigator(s) and delegate(s) at the study sites from the 
IWRS/IVRS. Routines for this will be described in the IWRS/IVRS user manual that will be 
provided to each site.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the participant requires knowledge of the treatment randomization. The 
investigator should document and report the action to Parexel, without revealing the treatment 
given to participant to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to a study intervention and that potentially require expedited 
reporting to regulatory authorities. Treatment codes will not be broken for the planned 
analyses of data until all decisions on the evaluability of the data from each individual 
participant have been made and until the primary database lock - after the last participant has 
completed Visit 7 (Week 16) - has been documented.
6.4
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF.
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.
6.5
Concomitant Therapy
To satisfy inclusion criterion 5, a history of treatment with medium or high-dose ICS plus 
LABA and a history of treatment with additional asthma controller medications for at least 
30 days prior to Visit 1 should be documented in source and recorded in the eCRF, along with 
reason for treatment, prior to the date of randomization. Changes are discouraged to 
background asthma 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 30 days 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 SoA Section 1.3).
As theophylline has a narrow therapeutic window, please note that participants on 
maintenance treatment with theophylline should have blood concentration levels within 
therapeutic range documented before Visit 1. If this is not documented before signing the 
informed consent/assent, it can be obtained after informed consent/assent has been given or as 
part of the Visit 1 procedures. The sample can be analyzed at the local lab as applicable. The 
investigator can use their clinical judgment about the therapeutic range of theophylline levels 
on the basis of sampling time and other factors that may impact the results.


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Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Treatment for any exacerbation that occurred within 12 months prior to Visit 1 should be 
recorded

Dosage information including dose and frequency for asthma medications
The Parexel Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Table 6
Permitted Medications
Type of medication/treatment
Usage
The ICS and LABA can be parts of a combination 
product or given by separate inhalers.
The ICS dose must be > 250 μg fluticasone 
propionate dry powder inhaler or equivalent daily.
Additional asthma controller medications (eg, 
LTRAs, short and long-acting anti-muscarinics, 
theophylline, oral corticosteroids, etc).
These must have been used for at least 30 days prior 
to Visit 1.
Background controller regimen.
Changes are discouraged throughout the study unless 
judged medically necessary by the investigator or the 
participant’s health care practitioner.
Oral or other systemic corticosteroids or other asthma 
therapies.
Asthma exacerbations can be treated according to 
standard practice.
Abbreviations: ICS=inhaled corticosteroids; LABA=long-acting β2 agonist; LTRA=leukotriene receptor 
antagonist.
Table 7
Restricted Medications
Type of medication/treatment
Usage
Allergen therapy.
These should not be administered within 7 days of 
study intervention administration.
Medication with narrow therapeutic range.
The level of theophylline or other drugs with a 
narrow therapeutic range should not exceed the upper 
limit of therapeutic range at the time of enrollment.


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Table 7
Restricted Medications
Type of medication/treatment
Usage
Scheduled inactivated/killed vaccines, including the 
COVID-19 vaccination
These are allowed, provided they are not 
administered within 6 days before or after study 
intervention administration.
Scheduled influenza vaccination at Visit 6 is not 
allowed within 6 days after the COVID-19 
vaccination.
Administration timing of COVID-19 vaccination 
should be discussed with Parexel Medical Monitor.
Abbreviations: COVID-19= Coronavirus disease 2019; OCS=oral corticosteroids.
Table 8
Prohibited Medications
Type of medication/treatment
Usage
Influenza vaccine.
Not allowed for the fall/winter 2021/22 season prior 
to randomization or throughout study period (except 
for the influenza vaccine given at Visit 6 per CSP).
Any immunomodulators or immunosuppressives.
Not allowed 3 months prior to Visit 1, throughout the 
treatment period or until the End of Study Visit at 
Week 28 is complete.
Live attenuated vaccines.
Not permitted 30 days prior to randomization, 
throughout the treatment period or until the End of 
Study Visit at Week 28 is complete.
Any marketed or investigational biologic product.
Not allowed 16 weeks or 5 half-lives prior to Visit 1, 
throughout the treatment period or until the End of 
Study Visit at Week 28 is complete.
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, or throughout the treatment 
period.
Blood products or immunoglobulin therapy.
Not allowed 30 days prior to date of Visit 1 and 
throughout the treatment period.
Regular use of SABA
Regular scheduled use of SABA is not allowed from 
Visit 1 and throughout the study intervention 
treatment and preferably 4 weeks after the last dose 
of study intervention, 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 at site with the exception of any 
unscheduled visits due to asthma worsening.
Abbreviations: CSP=clinical study protocol; SABA=short-acting β2 agonists.


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6.5.1 Rescue Medicine
Short-acting bronchodilators may be used as rescue medication during the study in the event 
of a worsening of asthma symptoms.
6.5.2
Asthma Medication Restrictions

Changes to the participant’s background controller regimen are discouraged during 
the study unless judged medically necessary by the investigator or the participant’s HCP; 
ideally such changes should be discussed with the Parexel Medical Monitor. All changes 
in the participant’s background medication should be documented in source along with 
rational for change and recorded in the eCRF.
Asthma exacerbations can be treated with oral or other systemic corticosteroids or other 
asthma therapies according to standard practice.

Asthma medication restrictions on the days of scheduled spirometry visits
Pre and/or post-dose spirometry assessments will be performed at the study center at 
scheduled visits (see SoA, Section 1.3). Restrictions to the participant’s background 
medication are required prior to the spirometry as described below (also see 
Section 8.1.2).
Screening Visit 1 or 2: Participants will be asked to withhold their usual bronchodilator 
medications on the morning of scheduled spirometry measurements (see Section 8.1.2.1). 
The participant’s usual asthma medications may be administered following completion of 
the screening lung function procedures.
6.6
Dose Modification
If influenza vaccine administration is delayed, an additional 1 to 2 unscheduled study 
intervention visits may occur prior to Visit 6 until the influenza vaccine is available at study 
sites.
6.7
Intervention After the End of the Study
Participants who complete Week 28 should continue to receive standard of care asthma 
medication at the discretion of the investigator.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
An individual participant will not receive any further study intervention in the following 
situations.

Participant decision. The participant is at any time free to discontinue study intervention, 
without prejudice to further treatment.


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
An AE considered to jeopardize the safety of a participant in the study.

Pregnancy.

Severe noncompliance with the CSP.

Development of any study specific criteria for discontinuation, including:

An anaphylactic reaction to the study intervention requiring administration of 
epinephrine.

A helminth parasitic infestation requiring hospitalization.

An asthma-related event requiring intubation.

Any malignancy except participants who develop basal cell carcinoma or localized 
squamous cell carcinoma of the skin, provided that the malignancy is excised and 
determined to have clean margins.

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%).
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
Participants who discontinue study intervention should return to the study center and complete 
the procedures described for the IPD visit (refer to Section 1.3, SoA, IPD visit) at 4 weeks (±3 
days) post last study intervention administration. If the IPD visit occurs on the same date as 
the scheduled Visit 6 (Week 12), all IPD assessments should be performed, in addition to 
influenza antibodies and influenza vaccine administration. The participant should then return 
for the scheduled Visit 7 (Week 16) visit and have all scheduled assessments performed, 
including the influenza antibodies, as per the SoA.
All participants who discontinue study intervention should be encouraged to return for all 
regularly scheduled visits for safety and efficacy assessments.
The participant should return for a Follow-up Visit 16 weeks (± 3 days) post last study 
intervention administration (refer to Section 1.3, SoA, V8 – Week 28). If the follow-up visit 
occurs on the same date as the scheduled Visit 7 (Week 16), all follow-up assessments should 
be performed, in addition to influenza antibodies.
See the SoA for data to be collected and for any further evaluations that need to be completed
in case of discontinuation from study intervention.


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7.2
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own (parent or legal 
guardian) request, or may be withdrawn at any time at the discretion of the investigator
for safety, behavioral, compliance, or administrative reasons. This is expected to be 
uncommon.

A participant 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).

At the time of withdrawal from the study, if possible, an IPD Visit should be conducted, 
as shown in the SoA (Section 1.3). See SoA for data to be collected at the time of study 
withdrawal and for any further evaluations that need to be completed.

The participant will discontinue the study intervention and be withdrawn from the 
study at that time.

If the participant (parent or legal guardian) withdraws informed consent/assent for 
disclosure of future information, the sponsor may retain and continue to use any data 
collected before such a withdrawal of informed consent/assent.

If a participant withdraws from the study, it should be confirmed if he/she (parent or legal 
guardian) still agrees for existing samples to be used in line with the original informed 
consent/assent. If he/she (parent or legal guardian) requests withdrawal of informed 
consent/assent for use of samples, destruction of any samples taken and not tested should 
be carried out in line with what was stated in the informed consent/assent and local 
regulation. The investigator must document the decision on use of existing samples in the 
site study records and inform the Global Study Team.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and,
if necessary, a certified letter to the participant’s last known mailing address or local 


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equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix C.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol
waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

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 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the informed consent/assent may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified criteria 
and were performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 150 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
Humoral Response to Influenza Vaccine
Serum HAI and MN antibody testing for antibody responses will be performed on blood 
samples taken at Week 12 (pre-dose antibody measure) and at Week 16 (EOT) from all study 
participants. Methods for these analyses will be described in the Laboratory Manual.
8.1.2
Spirometry
8.1.2.1
General requirements
Lung function (reversibility, FEV1 and FVC) at the study center will be measured by 
spirometry using the sites own equipment. Spirometry should be performed by the investigator 


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or authorized delegate according to ATS/ERS or local guideline recommendations.
The PI/authorized delegate is responsible for assuring that the spirometer is in good working 
condition, calibrated and meets the ATS/ERS or local guidelines recommendations, and that 
the study center personnel who will perform the test are properly certified.
IMPORTANT: Participants should withhold their usual maintenance therapies on the day(s) 
when lung function testing is being performed as below:

SABAs or SAMAs 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 restricted for at least 24 hours prior to scheduled spirometry at site.

Twice daily theophylline should be withheld for at least 12 hours prior to scheduled 
spirometry at site.

Once daily theophylline should be withheld for at least 24 hours prior to scheduled 
spirometry at site.
If Visits 1 and 2 are combined, bronchodilator therapy(ies) with or without ICS should be 
withheld for 12 to 24 hours depending on whether the participant is using twice or once daily 
bronchodilator-containing therapy.
Options for handling participants who have inadvertently taken their asthma medication 
within the restricted window are described in Section 6.5.2.
8.1.2.2
Spirometry Technique
Participants should avoid engaging in strenuous exertion for at least 30 minutes prior to 
spirometry measurements. Participants should avoid eating a large meal for at least 2 hours 
prior to spirometry measurements at the center. Forced expiratory maneuvers should be 
performed with the participant seated in an upright position. If this is not comfortable for the 
participant, standing is permitted. The same position should be used by the participant for 
each forced expiratory maneuver. The head must not be tilted during maneuvers and the 
thorax should be able to move freely; hence, tight clothing should be loosened. A nose-clip 
should be used for the maneuver. Mouthpieces of the same dimension and shape should be 
used by the participant.
The forced expiratory maneuver (FEV1 and FVC) should start with a maximal inspiration and 
then followed by a fast and forceful expiration that should last for at least 6 seconds. It is 


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important to encourage the participant to continue the expiration to be fast and forceful 
throughout the maneuver. Ensure that none of the following has occurred: coughing during the 
first second, glottis closure, leak or obstruction of the mouthpiece (by the tongue).
Multiple forced expiratory efforts (at least 3 but no more than 8) will be performed for each 
center spirometry session and the 2 best efforts that meet the American Thoracic 
Society/European Respiratory Society acceptability and reproducibility criteria will be 
recorded. The best efforts will be based on the highest FEV1.
The absolute measurement (for FEV1 and FVC), and the percentage of predicted normal value 
will be recorded using the local spirometer at the site with predicted values derived from the 
reference value of choice, eg, NHANES III 2010, Quanjer et al 2012, etc. The highest FVC 
will also be reported regardless of the effort in which it occurred (even if the effort did not 
result in the highest FEV1).
8.1.2.3
Post-bronchodilator Spirometry
All participants must meet inclusion criterion 3 either by having documented historical 
reversibility or by demonstrating reversibility either at Visit 1 or Visit 2. Even if documented 
historical reversibility is available, the post-BD spirometry procedures must be performed at 
Visit 1 to categorize participants (establish baseline characteristic) prior to randomization. The 
documented historical reversibility must be recorded in the eCRF/spirometer prior to 
randomization. 
The post-BD spirometry procedure should commence within 30 ± 15 minutes according to the 
regimen for reversibility testing outlined in Section 8.1.2.5 and Figure 3.
8.1.2.4
Order of Administration
Order of administration of usual asthma controller medication and study intervention 
relative to scheduled pre and post-bronchodilator spirograms.
The participant’s usual morning asthma controller therapy must not be given until after the 
initial pre-medication, pre-BD spirogram is complete for the reasons discussed above; usual 
asthma controller may be given after the post-BD spirogram.
8.1.2.5
Reversibility Test and Post-BD FEV1 Assessment
The procedure described in this section refers to the reversibility testing at Visit 1 or Visit 2. 
Bronchodilatation can be induced using albuterol (90 μg metered dose), salbutamol (100 μg 
metered dose) or levalbuterol (45 μg metered dose) up to a maximum of 8 inhalations. It is 
highly recommended to use a spacer device for this procedure. The algorithm for reversibility 
testing is outlined in Figure 3.


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Figure 3
Reversibility Testing Algorithm
Abbreviations: BD=bronchodilator; FEV1=forced expiratory volume in 1 second; SABA=short-acting β2 
agonists.
1
Verify with the participant that the medication restrictions to allow the reversibility 
assessment have been met (Section 6.5.2).
2
After a gentle and complete expiration, albuterol, salbutamol or levalbuterol is inhaled in 
one breath to total lung capacity from a spacer device. The breath is then held for 5 to 10 
seconds before the participant exhales. Four separate inhalations are delivered at 
approximately 30 second intervals. Post-BD spirometry should be performed 15 to 20 
minutes later.
3
If the participant has not met reversibility criteria, an additional 2 inhalations of albuterol, 
salbutamol, or levalbuterol can be administered as single inhalations, 30 seconds apart 
(for a total of 6 inhalations). Second post-BD spirometry should be performed 15 to 
20 minutes later.


Cli nical St u d y Pr ot oc ol – 3 . 0
Astra Ze neca
Teze pel u ma b – D 5 1 8 0 C 0 0 0 3 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 1 of 1 2 3
4
If t he parti ci pa nt still has n ot met re versi bilit y crit eria, a n a d dit i onal 2 i n halat i ons of 
al b uter ol, sal b uta mol , or le val b uter ol ca n be a d mi nistere d as si n gle i n halati ons, 
3 0 sec o n ds a part (f or a t otal of 8 i n halat i ons). T hi r d p ost -B D s pi r o metr y s h o uld be 
perf or m e d 1 5 t o 2 0 mi n utes later.
A l ower t otal d ose, e g, 2 i n halat i ons i nstea d of 4 i n t he first r o u n d of p uffs ca n be use d if t here 
is a c o ncer n a b o ut a n y effect o n t he partici pa nt’s heart rate, tre m or, or safety.  T he 
br o nc h o dilat or al g orit h m ca n be st o p pe d at a n y  ti me o nce a partici pa nt has met re versi bility 
criteria.
T he hi g hest pre a n d p ost -B D F E V 1 s h o ul d be use d t o deter mi ne re versi bility.
Re versi bilit y is calc ulate d as f oll ows:
% Re versi bilit y = ( p ost-B D F E V 1- pre B D F E V 1) × 1 0 0
pre -B D F E V 1
8. 1. 2. 6
Rec or d Kee pi n g
A si g ne d a n d date d c o p y of t he pre- a n d p ost- B D pri nt o ut m ust be ke pt at t he st u d y ce nter f or 
s o urce data verificati on. T he pri nt o ut m ust be mar ke d wit h t he st u d y c o de, e nr oll me nt c o de, 
date a n d ti me of meas ure me nt, a n d visit n u m ber .
C CI


Cli nical St u d y Pr ot oc ol – 3 . 0
Astra Ze neca
Teze pel u ma b – D 5 1 8 0 C 0 0 0 3 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 2 of 1 2 3
8. 2
S afet y Assess me nts
8. 2. 1
P h ysic al E x a mi n ati o ns
P h ysical e xa mi nat i on will be perf or me d at ti me p oi nts as s pecifie d i n t he S o A (Secti o n 1. 3 ). 
Baseli ne data will be c ollecte d at V isit 1. A n y ne w fi n di n g(s) or a g gra vate d e xist i n g fi n di n g(s), 
j u d ge d as cli nicall y si g nifica nt b y t he i n vesti gat or, will be re p orte d as a n A E as descri b e d i n 
Secti o n 8. 3 .

A c o m p lete p h ysical e xa mi nat i on will be perf or m e d a n d i ncl u de assess me nts of  t he 
f oll owi n g; ge neral a p peara nce, res pir at or y, car dio vasc ular , a b d o me n, s ki n, hea d a n d nec k 
(incl u di n g ears, e yes, n ose , a n d t hr oat), l y m p h n o des, t h yr oid, m usc ular -s keletal 
(incl u di n g s pi ne a n d e xtre mit ies) a n d ne ur ol o gical s yste ms. 
C CI
C CI


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
A brief physical examination will include, at a minimum, assessments of the general 
appearance, abdomen, cardiovascular, and respiratory system. For the brief physical 
examination only information on whether the assessment was performed or not is to be 
recorded.
8.2.2
Vital Signs
Pre-dose vital signs (pulse, blood pressure, respiration rate, and body temperature) are to be 
obtained in accordance with the SoA (Section 1.3).
Body temperature is to be recorded in degrees Fahrenheit/Celsius.
8.2.3
Local Electrocardiograms
An ECG will be performed at Visit 1 as specified in the SoA (Section 1.3).
A single 12-lead ECG will be taken in supine position, after the participant has been resting 
for at least 5 minutes. The assessment should be performed before interventions with the 
participant (eg, spirometry). Measurements will be performed on site supplied equipment.
A standard ECG with a recommended paper speed of 25 or 50 mm/second covering at least 
6 sequential beats will be used. The investigator or authorized delegate will be responsible for 
the overall interpretation and determination of clinical significance of any potential ECG 
findings. In case of discrepancy between the investigator’s interpretation and that provided by 
the ECG machine (if applicable), the investigator’s interpretation takes precedence and should 
be noted on the printout and recorded in the eCRF. Two identical copies of the ECG will be 
produced, quality checked, and kept in case of further need for re-evaluation. The ECG 
printouts will be signed and dated by the investigator and stored at the study center.
ECG data and evaluation will be recorded in the eCRF.
8.2.4
Clinical Safety Laboratory Assessments
All CSP-required laboratory assessments, as defined in Table 9 for the determination of 
clinical chemistry, hematology, and urinalysis, must be conducted in accordance with the 
Laboratory Manual and the SoA (Section 1.3). Fasting before blood draw is recommended but 
not mandatory.
Additional safety samples (repeated or scheduled) may be collected if clinically indicated at 
the discretion of the investigator.
The clinical chemistry and hematology will be performed at a central laboratory. Urinalysis, 
theophylline level, and SARS-CoV-2 viral diagnostic test will be performed at a local 
laboratory at the investigator site. Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site.


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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 site 
as source data for laboratory variables.
The following laboratory variables listed in Table 9 will be measured.
Table 9
Laboratory Safety Variables
Hematology / Hemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Hemaglobin
S-ALP
B-Leukocyte count
S-ALT
B-Leukocyte differential count (absolute count)a
S-AST
B-Platelet count
S-Bilirubin, total
B-Hematocrit 
S-BUN
B-MCV
S-Calcium, total
B-RBC count
S-Chloride
Urinalysis (dipstick) – local laboratory
S-Creatinine
U- Hemaglobin/Erythrocytes/Blood
S-Creatinine kinase (CK)
U-Protein/Albumin
S-CRP
U-Glucose
S-GGT
S-Glucose
U-Microscopy and culture as requiredb
S-Phosphorus
S-Potassium
SARS-Cov-2 (swab) – local laboratory
S-Sodium
SARS-CoV-2 viral test
S-Total cholesterol
S-Uric acid
S- Theophylline level (local laboratory)c
a
Eosinophil, basophil and monocyte counts will be redacted from the central laboratory reports, except for 
Visit 1 and Visit 3 (see Section 6.3.4).
b
Urine samples will be analyzed locally and sent to the central laboratory only for analysis when a positive 
dipstick result for any parameter is observed.
c
For participants on theophylline see Section 6.5.
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; GGT=gamma glutamyl transpeptidase; HPF=high power field; MCV=mean 
corpuscular volume; RBC=red blood cell; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; 
WBC=white blood cell
NB. In case a participant shows an AST or ALT ≥3 × ULN together with total bilirubin 
≥2 × ULN please refer to Appendix D. Actions required in cases of increases in liver 
biochemistry and evaluation of Hy’s Law, for further instructions.


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8.2.5
Other Safety Assessments
8.2.5.1
Pregnancy Test
The following tests are applicable to female participants only and will be conducted at the 
timepoints specified in the SoA (Section 1.3).

Serum β-HCG: To be done at screening Visit 1 only, for women of childbearing potential
(analyzed at central laboratory).

Urine pregnancy test: To be performed at the study center for women of childbearing 
potential at each treatment visit (before study intervention administration on Visit 3 to 
Visit 6) using a dipstick. A positive urine test result must be confirmed with serum β-
HCG (analyzed at central laboratory).
8.2.5.2
Weight and Height
Weight and height will be measured, and BMI calculated in accordance with the SoA 
(Section 1.3).
The participant’s weight will be recorded in pounds/kg; height will be recorded in 
inches/meters.
8.2.5.3
Serology

Hepatitis B surface antigen and hepatitis C antibody
To be done at screening Visit 1 only (Section 1.3); test to be performed at central 
laboratory.

HIV-1 and HIV-2 antibodies
To be done at screening Visit 1 only (Section 1.3); test to be performed at central 
laboratory.
Instructions for sample collection, processing, storage, and shipment can be found in the 
separate Laboratory Manual provided to the study centers.
8.2.5.4
SARS-CoV-2 Diagnostic Test

Local viral testing to be performed at screening Visit 1 to confirm exclusion criterion 27
(Section 1.3).

Results of local negative viral SARS-Cov-2 testing must be available and recorded in the 
eCRF before Visit 3.
Local COVID-19 viral test results must be recorded in the eCRF.


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8.3
Adverse Events and Serious Adverse Events
The PI 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 E.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from time of signature of the ICF, throughout the treatment 
period and including the follow-up period.
SAEs will be recorded from the time of signing of the informed consent form.
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the sponsor.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’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, but without further recording in the eCRF. AstraZeneca retains the right to request 
additional information for any participant with ongoing AE(s)/SAE(s) at the end of the study, 
if judged necessary.
Adverse event variables
'The following variables will be collected 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 study intervention(s) (yes or no)

Action taken with regard to study intervention(s)

AE caused participant’s withdrawal from study (yes or no)

Outcome


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In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

AE is serious due to

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication
8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the study intervention?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix E to the CSP.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or care provider 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.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the CSP mandated laboratory tests and vital signs will be summarized in the 
CSR. 
Deterioration as compared to baseline in CSP mandated laboratory values, vital signs and 


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other safety assessments should therefore only be reported as AEs if they fulfill any of the 
SAE criteria, are the reason for discontinuation of treatment with the study intervention or are 
considered to be clinically relevant as judged by the investigator (which may include but not 
limited to consideration as to whether treatment or non-planned visits were required or other 
action was taken with the study intervention, eg, dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in 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 unless unequivocally 
related to the disease under study.
8.3.6
Adverse Events of Special Interest
An AESI is an event of scientific and medical interest towards improving the understanding of 
the study intervention. An AESI may be serious or non-serious. For this study, AESIs include:

Anaphylactic reactions

Immune complex disease (Type 3 hypersensitivity reactions)

Malignancy

Helminth infections

Severe infections which are defined as:

SAEs or

Requiring treatment with systemic antiviral medications, intravenous antibiotics or 
medications for helminth parasitic infection or

Requiring a permanent discontinuation of study intervention

Injection site reactions

Opportunistic infections

Guillain-Barré Syndrome
8.3.7 Hy’s Law
Cases where a participant shows elevations 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 D for further instruction on cases 


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of  increases i n li ver bi oc he mistr y  a n d e val uati on of H y ’s La w .
8. 3. 8
Dise ase U n der S t u d y
W he n c o llecti n g A Es, t he rec or di n g of dia g n oses is preferre d, w he n p ossi ble, t o rec or di n g a 
list of si g ns a n d s y m pt o ms. Ast h ma s y m pt o ms or si g ns, s uc h as w heeze, c o u g h, c hest 
tig ht ness, d y s p nea, breat hless ness a n d p hle g m, will be rec or de d as A Es o nl y w he n:

T he si g n or s y m pt o m is seri o us acc or di n g t o defi niti o ns, see A p pe n di x E 2 .

T he parti ci pa nt disc o nt i n ues t he st u d y d ue t o the si g n or s y m pt o m .

T he si g n or s y m pt o m is ne w t o t he partici pa nt or n ot c o nsiste nt wit h t he partici pa nt’s 
pre -e xist i n g ast h ma hist or y ( defi ne d as withi n 1 year of Visit 1) as j u d ge d b y t he 
i n vesti gat or.
 s h o ul d be rec or de d as a n A E or S A E o nl y if it f ulfills a n y o f t he a b o ve 
criteria.
8. 3. 9
Re p orti n g of Seri o us A d verse E ve nts
All S A Es ha ve t o be re p orte d, w het her or n ot c o nsi dere d ca usall y relate d t o t he i n vest i gati onal 
pr o d uct, or t o t he st u d y  pr oce d ure(s). All S A Es will be rec or de d i n t he eC R F .
If a n y S A E occ urs i n t he c o urse of t he st u d y, i n vesti gat ors or ot her site pers o n nel will i nf or m 
t he a p pr o priate Pare xel re prese ntati ves wit hi n o ne da y ie, i m me diatel y b ut n o l ater  t h a n 2 4 
h o urs of w he n he or s he bec o me s a ware of it.
T he desi g nate d Pare xel re prese ntati ve will  w or k wit h t he i n vesti gat or t o e ns ure t hat all t he 
necessar y  inf or mat i on is pr o vi de d t o t he Astra Ze neca Patie nt Safet y data e ntr y  sit e wit hi n 
o ne c ale n d ar d a y of  init ial recei pt f or fatal a n d life-t hreate ni n g e ve nts a n d wit hi n 5 c ale n d ar
d a ys of  init ial recei pt f or all ot her S A Es.
F or fatal  or life-t hreate ni n g A E s w here i m p orta nt or rele va nt i nf or mati on is missi n g, acti ve 
f oll ow- u p will be u n derta ke n i m me diatel y. In vest i gat ors or ot her site pers o n nel will  i nf or m 
Pare xel re prese ntati ves of a n y f oll ow- u p i nf or m at i o n o n a pre vi o usl y re p orte d S A E wit hi n o ne 
cale n dar da y, ie, i m me diatel y b ut n o l ater  t h a n 2 4 h o urs of  w he n he or s he bec o mes a ware of 
it.
O nce t he i n vesti gat ors or ot her site pers o n nel i n dicate a n A E i s serio us i n t he E D C s yste m , a n 
a ut o mat e d e mail alert is se nt t o t he desi g nate d Pare xel re prese ntati ve.
If t he E D C s yste m is n ot a vaila ble, t he n t he i n vesti gat or or ot her st u d y  sit e st aff re p orts a S A E 
t o t he a p pr opriate Pare xel re prese ntati ve b y tele p h o ne.
T he Pare xel re prese ntati ve will a d vise t he i n vesti gat or /st u d y site staff h o w t o pr ocee d.
C CI


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For further guidance on the definition of a SAE, see Appendix E 2 of the CSP.
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure for the AstraZeneca drug. 
8.3.10
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study participant has received any study 
intervention
8.3.10.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, study intervention should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomalies/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 anomaly/birth defect) should be followed up and documented even 
if the participant was discontinued from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate Parexel representatives within 1 day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated Parexel 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 Section 8.3.9 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 and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy.
8.3.10.2
Paternal Exposure 
Pregnancy of the participant’s partners is not considered to be an AE. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly), occurring from the date of the first dose until 16 weeks 
(5 half-lives) after the last administration of study intervention, if possible, be followed up and 
documented in the Pregnancy Report Form. Consent from the partner must be obtained before 


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the Pregnancy Report Form is completed. 
8.3.11
Medication Error
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate Parexel representatives within 1 day, ie, immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated Parexel 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 8.3.9) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix E 4.
8.3.12
Medical Device Deficiencies
Device constituents of the combination product (APFS) are being provided for use in this 
study. In order to fulfil regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of events meeting the definitions of medical 
device deficiency that occur during the study with the device constituent of the study drug 
combination product.
The definition of a deficiency in the device constituent of a combination product (APFS) is an 
inadequacy of a medical device with respect to its identity, quality, durability, reliability, 
safety, or performance. Medical device deficiencies include malfunctions, use errors, and 
issues with information supplied by the manufacturer. For simplicity, the term medical device 
deficiency will be used for deficiency in the device constituent of a combination product.
NOTE: Additional guidance, including expanded definitions, can be found in Appendix F of 
the protocol. 
The AstraZeneca Report Form will be used to collect the deficiency as per the Parexel study-
specific Investigator Manual.
8.3.12.1
Time Period for Detecting Medical Device Deficiencies

Medical device incidents or malfunctions of the medical device will be detected, 
documented, and reported during all periods of the study in which the medical device is 
used.

If the investigator learns of any medical device deficiency at any time after a participant 
has been discharged from the study, and such incident is considered reasonably related to 
a medical device provided for the study, the investigator will promptly notify the sponsor.


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The method of documenting medical device deficiency is provided in Appendix F and the 
Parexel study-specific Investigator Manual.
8.3.12.2
Follow-up of Medical Device Deficiencies

Follow-up applies to all participants, including those who discontinue study intervention.

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.

New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator.
8.3.12.3
Prompt Reporting of Medical Device Deficiencies to Sponsor

Deficiencies associated with the device constituent part of the combination product 
should be reported to the Sponsor.

Medical device deficiencies will be reported to the Sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical device 
deficiency.

The AstraZeneca Report Form will be sent to the sponsor via email

Medical device deficiency with an associated adverse event
o
AEMailboxClinicalTrialTCS@astrazeneca.com
o
AstraZeneca complaint representative(s), as per the Parexel study-specific 
Investigator Manual
NOTE: For  AEs and SAE’s, the eCRF must also be populated - see Section 8.3.9.

Medical Device Deficiency without an associated adverse or serious adverse event
o
AstraZeneca complaint representative(s), as per the Investigator Manual

The Sponsor will be the contact for the receipt of medical device deficiency reports.
8.3.12.4
Regulatory Reporting Requirements for Device Deficiencies

The investigator will promptly report all medical device deficiencies occurring with any 
medical device provided for use in the study in order for the sponsor to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (eg, the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of medical device deficiencies to the IRB/IEC.

For further guidance on the definitions, see Appendix F of the CSP.


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8.4
Overdose
For this study, any dose of study intervention greater than 700 mg SC within a 2-week period
will be considered an overdose.
There is currently no specific treatment in the event of overdose of study intervention 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 intervention occurs in the course of the study, the 
investigator or other site personnel inform appropriate Parexel representatives immediately, 
but no later than 24 hours of when he or she becomes aware of it.
The designated Parexel representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within one or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.9) and within 30 days
for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific Laboratory Manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Samples see Appendix G.
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated. 

Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses. 

Pharmacokinetic samples may be disposed of or anonymized by pooling. Additional 
analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR.

Remaining ADA sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 15 years following issue of the CSR. Additional use includes but is not 
limited to further characterization of any ADAs, confirmation and/or requalification of 


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the assay as well as additional assay development work. The results from future analysis 
will not be reported in the CSR.
8.5.1
Pharmacokinetics
Serum samples will be collected for measurement of serum concentrations of tezepelumab as 
specified in the SoA (Section 1.3). Samples will be collected, labelled, stored, and shipped as 
detailed in the Laboratory Manual.
8.5.1.1
Determination of Drug Concentration
Samples for determination of tezepelumab concentration in serum will be assayed by 
bioanalytical test sites operated by or on behalf of AstraZeneca, using an appropriately 
validated bioanalytical method. Full details of the analytical method used will be described in 
a separate Bioanalytical Report.
Drug concentration information that may/would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded (see Section 6.3.4
for maintaining the study blind).
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.5.2
Immunogenicity Assessments
Blood samples for determination of ADA in serum from both tezepelumab and placebo groups 
will be assayed by bioanalytical test sites operated by or on behalf of AstraZeneca, using an 
appropriately validated bioanalytical method. Full details of the methods used will be 
described in a separate Bioanalytical Report.
ADA samples may also be further tested for characterization of the ADA response.
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
8.5.3
Pharmacodynamics
Samples for the analysis of peripheral blood eosinophils will be performed in a central 
laboratory as part of the routine hematology assessment.
8.6
Human Biological Sample Biomarkers
Biomarker research is not applicable in this study.
8.7
Optional Genomics Initiative Sample
Optional Genomics Initiative research is not applicable in this study.


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8.8
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
No formal statistical hypotheses will be tested.
9.2
Sample Size Determination
The sample size justification is based on the desired precision of the estimate of the ratio of 
the GMTs (as GMTvaccine / GMTtezepelumab+vaccine). With 50 participants per arm, the 90% CI for 
the GMT ratio would be 0.67 to 1.48, assuming an observed ratio of 1, and that the log (post-
dose HAI antibody titer or post-dose MN antibody titer) is normally distributed with a 
standard deviation (SD) of 1.2 on the natural log scale (Langley et al 2013).
9.3
Populations for Analyses
Antibody endpoints to the influenza vaccine—strain-specific HAI and MN antibody GMFRs 
and GMTs—will be analyzed using the vaccine immunogenicity analysis set. All remaining 
efficacy analyses will be performed using an ITT approach based on the full analysis set. 
Demographic and baseline characteristics will be presented for both the full analysis set and 
the vaccine immunogenicity analysis set. Safety objectives and ADA will be analyzed based 
on the Safety analysis set. The population analysis sets are defined in Table 10.
Table 10
Populations for Analysis
Population/Analysis set
Description
All participant analysis set
All participants screened for the study will be included in the 'All participant 
analysis set' and will be used for reporting of disposition and screening 
failures.
Full (ITT) analysis set
All participants randomized and receiving any study intervention will be 
included in the 'Full analysis set', irrespective of their CSP adherence and 
continued participation in the study. 
Participants will be analyzed according to their randomized treatment, 
irrespective of whether or not they have prematurely discontinued, 
according to the ITT principle. 
Participants who withdraw informed consent/assent to participate in the 
study will be included up to the date of their study termination.
Vaccine immunogenicity 
analysis set
All randomized participants who received the influenza vaccine plus at least 
1 dose of tezepelumab or placebo, had pre and post-dose HAI or MN 
antibody measurements, had no influenza infection prior to Visit 7


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Table 10
Populations for Analysis
Population/Analysis set
Description
(Week 16), and had no protocol deviation, judged to have the potential to 
interfere with the generation or interpretation of an antibody response, will 
be included in the 'vaccine immunogenicity analysis set'.
The analyses conducted using this analysis set will be based on the actual 
treatment received. Protocol deviations will be reviewed by the study team 
before unblinding at the primary database lock (Visit 7 [Week 16]).
Safety analysis set
All participants who received at least 1 dose of study intervention will be 
included in the safety analysis set. 
Participants will be classified according to the treatment they actually 
received. A participant who has on one or several occasions received active 
treatment will be classified as active. All safety and ADA summaries will be 
based on this analysis set.
PK analysis set
All participants who received tezepelumab and from whom PK blood 
samples were obtained and assumed not to be affected by factors such as 
CSP deviations will be included in the 'PK analysis set'.
Those participants who had at least 1 quantifiable serum PK observation 
post first dose will be included in the PK analysis dataset. All PK 
summaries will be based on this analysis set.
Abbreviations: ADA=anti-drug antibody; CSP=clinical study protocol; HAI=hemagglutination-inhibition; 
ITT=intent to treat; MN=microneutralization; PK=pharmacokinetic.
Primary Analyses Estimands
Table 11 provides the parameters to follow for each set of primary analyses. Please note: If 
influenza vaccine administration is delayed, some participants’ assessments at Week 12 and 
Week 16 may be performed at later timepoints.
Table 11
Primary Analysis Estimands
Primary Endpoints
Parameters

Post-dose strain-specific 
hemagglutination-inhibition (HAI) 
antibody geometric mean fold rises 
(GMFRs) from Week 12 (pre-dose 
antibody measure) to Week 16 (EOT)

Post-dose strain-specific 
microneutralization (MN) antibody 
GMFRs from Week 12 (pre-dose 
antibody measure) to Week 16 (EOT)

Post-dose strain-specific serum HAI 
antibody geometric mean titers (GMTs) 
obtained at Week 16 (EOT)
Population: Vaccine immunogenicity analysis set, defined as 
all randomized participants who received the influenza vaccine 
plus at least 1 dose of tezepelumab or placebo, had pre- and 
post-dose HAI or MN antibody measurements, had no 
influenza infection prior to Visit 7 (Week 16), and had no 
protocol deviation judged to have the potential to interfere 
with the generation or interpretation of an antibody response.
Intercurrent Events:
Treatment discontinuation: All data up to timepoint of post-
dose antibody measurements will be included for participants 
in the vaccine immunogenicity analysis set.


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Table 11
Primary Analysis Estimands
Primary Endpoints
Parameters

Post-dose strain-specific serum MN 
antibody GMTs obtained at Week 16
(EOT)
Initiation of other medication: All data up to timepoint of post-
dose antibody measurements will be included for participants 
in the vaccine immunogenicity analysis set.
Summary Measure: Least square geometric mean ratio 
estimates for placebo vs. tezepelumab and corresponding 90% 
CIs.

Post-dose strain-specific antibody 
response at Week 16 (EOT) with 
antibody response defined as a ≥4-fold 
rise in HAI antibody titer from 
Week 12 (pre-dose antibody measure) 
to Week 16 (EOT)

Post-dose strain-specific antibody 
response at Week 16 (EOT) with 
antibody response defined as a ≥4-fold 
rise in MN antibody titer from 
Week 12 (pre-dose antibody measure) 
to Week 16 (EOT)

Post-dose strain-specific HAI antibody 
titer ≥40 at Week 16 (EOT)

Post-dose strain-specific MN antibody 
titer ≥40 at Week 16 (EOT)
Population: Vaccine immunogenicity analysis set, defined as 
all randomized participants who received the influenza vaccine 
plus at least 1 dose of tezepelumab or placebo, had pre- and 
post-dose HAI or MN antibody measurements, had no 
influenza infection prior to Visit 7 (Week 16), and had no 
protocol deviation judged to have the potential to interfere 
with the generation or interpretation of an antibody response.
Intercurrent Events:
Treatment discontinuation: All data up to timepoint of post-
dose antibody measurements will be included for participants 
in the vaccine immunogenicity analysis set.
Initiation of other medication: All data up to timepoint of post-
dose antibody measurements will be included for participants 
in the vaccine immunogenicity analysis set.
Summary Measure: Number and % of participants in each 
treatment group meeting the specified threshold and 
corresponding 90% CI.


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9.4
Statistical Analyses
There will be two database locks in this study. The primary database lock and analysis will be 
conducted after the last participant (enrolled in the 2021/2022 flu season) completes Visit 7
(Week 16), and the final database lock and analysis will be conducted once all participants
have completed the follow-up period, Visit 8 (Week 28). All analyses of the primary 
objectives and selected safety objectives will be performed based on the primary database lock 
data.
The SAP will be finalized and signed-off prior to the primary database lock. It will include a 
more technical and detailed description of the statistical analyses described in this section. 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and secondary endpoints.
9.4.1
General Considerations
All statistical analyses will be performed by Parexel International Biostatistics or other 
designated third-party providers, under the direction of the Biostatistics Group, AstraZeneca. 
Further details will be provided in the SAP. The SAP will be prepared prior to first participant 
randomized and any subsequent amendments will be documented, with final amendments 
completed prior to unblinding of the data. All statistical analyses presented in the CSP will be 
performed using the latest available version of SAS® (SAS Institute Inc., Cary, North 
Carolina, US), version 9.4 or higher.
All personnel involved with the analysis and conduct of the study will remain blinded until the 
primary database lock and important protocol deviations have been identified. After the
primary database lock, treatment allocation for participants during this study will become 
known to the sponsor staff and designated CRO. The blind will be maintained for the 
investigator, investigational site staff, and for the participant.
9.4.2
Efficacy 
All efficacy objectives will be evaluated for the double-blind treatment period, defined as the 
period after administration of randomized study intervention at Week 0 and the conclusion of 
Week 16 (EOT) Visit, inclusive.
The tezepelumab versus placebo humoral immune responses following seasonal influenza 
virus vaccination will be assessed by the following endpoints.
9.4.2.1
Primary Endpoint(s)

Post-dose strain-specific HAI antibody GMFRs from Week 12 (pre-dose antibody 
measure) to Week 16 (EOT).

Post-dose strain-specific MN antibody GMFRs from Week 12 (pre-dose antibody 
measure) to Week 16 (EOT).


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
Post-dose strain-specific serum HAI antibody GMTs obtained at Week 16 (EOT).

Post-dose strain-specific serum MN antibody GMTs obtained at Week 16 (EOT).

Post-dose strain-specific antibody response at Week 16 (EOT) with antibody response 
defined as a ≥ 4-fold rise in HAI antibody titer from Week 12 (pre-dose antibody 
measure) to Week 16 (EOT).

Post-dose strain-specific antibody response at Week 16 (EOT) with antibody response 
defined as a ≥ 4-fold rise in MN antibody titer from Week 12 (pre-dose antibody 
measure) to Week 16 (EOT).

Post-dose strain-specific HAI antibody titer ≥ 40 at Week 16 (EOT).

Post-dose strain-specific MN antibody titer ≥ 40 at Week 16 (EOT).
As the HAI assay may not work for one of the influenza virus strains (Influenza A H3N2), the 
corresponding MN result for that strain will only be used. Hence, both the HAI and MN 
results will serve as the dual primary endpoints for this study such that results from both 
assays can be used for the analyses of the primary objective. This dual endpoint approach 
allows for a broader characterization of the immune response and flexibility in case the results 
for either assay are missing.
Analysis Methods for Efficacy Variables
The analyses of the primary endpoints will use the vaccine immunogenicity analysis set. If 
informed consent/assent to the study was withdrawn, all data up until the date of withdrawn 
informed consent/assent will be included. The full analysis set will be used for the other non-
primary efficacy analyses.
Analysis methods for antibody endpoints
Geometric mean fold rises for the HAI and MN antibody measurements are defined as:
GMFR = antilogz (mean [loge x])
Where x is the post-dose (EOT) HAI or MN antibody titer fold rise from Week 12 (pre-dose 
antibody measure) and e is the natural logarithm.
Geometric mean titers for the HAI and MN antibody measurements are defined as:
GMT = antilogz (mean [loge y])
Where y is the HAI or MN antibody titer and e is the natural logarithm.
The analysis of the anti-influenza antibody response endpoints–strain-specific GMFRs and 
GMTs–will be performed on the vaccine immunogenicity analysis set. Geometric mean fold 


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rises and GMTs will be summarized by treatment group and by strain, and the least square 
geometric mean ratio of GMFRs and GMTs between treatment groups (influenza vaccine 
divided by tezepelumab and influenza vaccine) will be calculated via an ANCOVA model on 
the log-transformed variable, adjusting for treatment group and age stratum (adolescents aged 
12 to17 or young adults aged 18 to 21). The least square geometric mean ratio will be 
provided with associated 90% CI.
The antibody response to the quadrivalent influenza vaccine strain is defined as a ≥ 4-fold rise 
in HAI or a ≥ 4-fold rise in MN from Week 12 (pre-dose antibody measure) to Week 16
(EOT). The proportion of participants who experience a post-dose antibody response at 
Week 16 (EOT) for HAI and the proportion of participants who experience a post-dose 
antibody response at Week 16 (EOT) for MN and corresponding 90% Clopper-Pearson exact 
CIs will be summarized by treatment group and by strain. 
The proportion of participants who achieve a post-dose HAI antibody titer ≥ 40 and the 
proportion of participants who achieve a post-dose MN antibody titer ≥ 40 at Week 16 (EOT) 
and corresponding 90% Clopper-Pearson exact CIs will be summarized by treatment group
and by strain.
No interim blinded review is planned.
9.4.2.2
Secondary Endpoint(s)
Calculation or Derivation of PK Variables
Due to the limited sampling schedule, the PK assessment will be primarily based on the 
observed serum trough concentrations.
Analysis Methods for PK Variables
The PK analyses will be performed by a third-party vendor under the guidance of AstraZeneca 
Research and Development.
Tezepelumab serum concentrations will be summarized using descriptive statistics at each 
visit.
Calculation or Derivation of Tezepelumab Immunogenicity Variables
ADA assessments will be conducted utilizing a tiered approach (screen, confirm, titer).
Analysis Method for Tezepelumab Immunogenicity Variables
ADA to tezepelumab will be summarized using descriptive statistics at each visit by treatment 
group.


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9. 4. 3
S afet y
9. 4. 3. 1
S afet y E n d p oi nt(s)
C alc ul ati o n or D eri v ati o n of S afet y V ari a ble(s)
T he f o ll owi n g safet y  data will be c ollecte d: vital si g ns, p h ysical e xa mi nat i on, he mat ol o g y, 
ser u m c he mistr y, uri nal ysis, a n d re p orte d A Es.
C ha n ge fr o m baseli ne ( W ee k 0) t o eac h p ost -treat me nt visit w here sc he d ule d assess me nts 
were m a de will be calc ulate d f or rele va nt meas ure me nts. A d verse e ve nts will be s u m marize d 
b y mea ns of descri pt i ve statistics a n d q ualitati ve s u m maries.
A n al ysis Met h o ds f or S afet y V ari a bles
A d verse e ve nts will be c o de d usi n g t he Me d D R A versi o n i n f orce at t he pri mar y data base 
l oc k. T he defi nit i on of o n -treat me nt a n d o n-st u d y for A E a nal yses will be gi ve n i n t he S A P.
T he n u m ber a n d perce nta ge of parti ci pa nts wi t h o n-treat me nt a n d o n-st u d y A Es will  be
ta b ulate d se paratel y b y preferre d ter m a n d s yste m or ga n class. A n e ve nt t hat occ urre d o ne or
C CI


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more times during a period will contribute 1 observation to the numerator of the proportion. 
The denominator of the proportion will comprise all participants in the safety population. On-
treatment AEs will also be summarized by intensity/severity and separately, by
causality/relatedness (as determined by the investigator). Should a participant report the same
preferred term/system organ class within multiple intensity/severity or causality/relatedness
categories, the participant’s worst occurrence (most severe/most related) will be tabulated. 
Serious AEs, AEs leading to discontinuation from study intervention, 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 study intervention will be summarized 
for each treatment group as applicable.
An overall summary of on-treatment AEs will be presented by treatment group.
AEs of special interest (AESIs), as defined in Section 8.3.6 will also be summarized
descriptively by treatment group.
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. 
9.5
Interim Analyses 
There is neither an unblinded data review nor interim analysis planned for this study prior to 
primary database lock.
9.6
Data Monitoring Committee
Not Applicable.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS


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Appendix A
Anaphylaxis: Signs and Symptoms, Management
A 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 A 2. A guide to the signs and 
symptoms and management of acute anaphylaxis is provided in Appendix A 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 participant as soon 
as possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge for 
analysis of serum tryptase.
A 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-tongueuvula)
AND AT LEAST ONE OF THE FOLLOWING
(a) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia).
(b) Reduced 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 3 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.
A 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

Light headedness

Headache

Uterine cramps

Generalized warmth


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A 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 participant 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 (eg, dopamine).
(f) Consider glucagon for subject taking β-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.
A 5
References
Johansson et al 2004
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. A revised 


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nomenclature for allergy for global use: report of the nomenclature review committee of world 
allergy organization. J Allergy Clin Immunol. 2004;113:832-6.


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Appendix B
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.
Please note that during civil crisis, natural disaster, or public health crisis, some study 
assessments and procedures may not be conducted due to international or local policies or 
guidelines, hospital or clinic restrictions and other measures implemented to ensure the 
participant’s safety. If in doubt, please contact the Parexel Medical Monitor.
B 1
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on-site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections B 2 to B 5. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided. 
B 2
Re-screening of Participants To Reconfirm Study Eligibility
One additional re-screening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
Parexel Medical Monitor.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participant and either enrollment into the study or commencing of dosing with IP. If this delay 
is outside the screening window specified in Section 1.3 the participant will need to be 
re-screened to reconfirm eligibility before commencing study procedures. This will provide 
another opportunity to re-screen a participant in addition to that detailed in Section 5.4. The 
procedures detailed in Section 5.1.1 must be undertaken to confirm eligibility using the same 
randomization number as for the participant.


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B 3
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified HCP from the study site or TPV service will visit the participants home / or other 
remote location as per local standard of procedures, as applicable, only during safety 
follow-up (after Visit 7). Supplies will be provided for a safe and efficient visit. The qualified 
HCP will be expected to collect information per the CSP.
B 4
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the participants 
using telecommunications technology including phone calls and virtual or video visits only 
during safety follow-up (after Visit 7).
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow adverse events, concomitant medication to be reported and 
documented.
B 5
Data Capture During Telemedicine or Home / Remote Visits
Data collected during telemedicine or home / remote visits will be captured by the qualified 
HCP from the study site or TPV service, or by the participant themselves.


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Appendix C
Regulatory, Ethical, and Study Oversight Considerations
C 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the CSP 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 ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The CSP, CSP amendments, ICF, Investigator’s Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.

Any amendments to the CSP will require IRB/IEC and applicable Regulatory Authority
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with AstraZeneca.

The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with US-specific regulatory requirements relating 
to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for SUSAR according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations


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
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the [Investigator’s Brochure or state other documents] and will 
notify the IRB/IEC, if appropriate according to local requirements.
C 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.
C 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her parent/legally authorized representative and answer all questions 
regarding the study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their informed consent/assent at any time and for 
any reason during the study. Participants or their parent/legally authorized representative 
will be required to sign a statement of informed consent/assent 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 center.

The medical record must include a statement that written informed consent/assent was 
obtained before the participant was enrolled in the study and the date the written informed 
consent/assent was obtained. The authorized person obtaining the informed 
consent/assent must also sign the ICF.

Participants 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 participant or the participant’s legally 
authorized representative.

Participants who are re-screened are required to sign a new ICF.
C 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.


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
The participant 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 and use 
of their data must also be explained to the participant in the informed consent/assent.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
C 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
Parexel representatives in consultation with Patient Safety. Issues identified will be addressed; 
for instance, this could involve amendments to the CSP and letters to investigators.
C 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the main study results when they are available. The clinical study 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.
C 7
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF 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 electronically 
signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg,
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 


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source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved CSP 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.
C 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data entered in the eCRF 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.

Definition of what constitutes source data can be found in the Monitoring Plan.
C 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is when the first participant consents to take part in the study and 
will be the study start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator


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
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites may have the opportunity to be transferred to another site to 
continue the study.
C 10
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 multicenter studies only in their entirety and not as individual site data. In 
this case, a co-ordinating 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 D
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
D 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. 
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review AE 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 HL criteria are met. 
Hy’s Law criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than DILI) caused by the study intervention. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
D 2
Definitions
Potential Hy’s Law
AST or ALT ≥3 × ULN together with TBL ≥2× ULN at any point during the study 
following the start of study medication irrespective of an increase in ALP.
Hy’s Law
AST or ALT ≥3× ULN together with TBL ≥2× ULN, where no other reason, other than the 
study intervention, can be found to explain the combination of increases, eg, elevated ALP 
indicating cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 


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elevations in transaminases and TBL must occur.
D 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 participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥3 × ULN

AST ≥3 × ULN

TBL ≥2 × ULN
Central Laboratories Being Used:
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the investigator (also sent to 
AstraZeneca representative). 
The investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the investigator will:

Notify the AstraZeneca representative

Request a repeat of the test (new blood draw) by the central laboratory without 
delay

Complete the appropriate unscheduled laboratory eCRF module(s) with the 
original local laboratory test result
When the identification criteria are met from central or local laboratory results the investigator 
will without delay:

Determine whether the participant meets PHL criteria (see Section D 2 for 
definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)
D 4
Follow-up
D 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the investigator will:

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the CSP.


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D 4.2
Potential Hy’s Law Criteria met
If the participant does meet PHL criteria the investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting.

For participants that met PHL criteria prior to starting study intervention, the investigator 
is not required to submit a PHL SAE unless there is a significant change* in the 
participant’s condition.

The Parexel Medical Monitor contacts the investigator, to provide guidance, discuss and 
agree an approach for the study participants’ follow-up (including any further laboratory 
testing) and the continuous review of data.

Subsequent to this contact the investigator will:

Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.

Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Parexel Medical Monitor. This includes deciding which the tests 
available in the Hy’s Law lab kit should be used.

Complete the 3 Liver eCRF Modules as information becomes available.
*A ‘significant’ change in the participant’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 Parexel Medical Monitor if there is any 
uncertainty.
D 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 Parexel 
Medical Monitor 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 study intervention, 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. 


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According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF.

If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study intervention:

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 study 
intervention and seriousness criteria is medically important, according to CSP process for 
SAE reporting.

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
D 6
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Intervention 


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This section is applicable to participants who meet PHL criteria on study intervention, having 
previously met PHL criteria at a study visit prior to starting study intervention.
At the first on-study intervention occurrence of PHL criteria being met the investigator will 
determine if there has been a significant change in the participants’ condition compared with 
the last visit where PHL criteria were met 

If there is no significant change no action is required

If there is a significant change, notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Section D 4.2
D 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a participant meets PHL criteria on study intervention and has 
already met PHL criteria at a previous on study intervention visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found 
to be the disease under study eg, chronic or progressing malignant disease, severe 
infection or liver?
If No: follow the process described in Section D 4.2 for reporting PHL as an SAE
If Yes: Determine if there has been a significant change in the participant’s condition#
compared with when PHL criteria were previously met

If there is no significant change no action is required

If there is a significant change# follow the process described in Section D 4.2 for 
reporting PHL as an SAE
A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation 
or in combination, or a clinically relevant change in associated symptoms. The determination 
of whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.


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D 8
Laboratory Tests
Hy’s Law Lab Kit for Central Laboratories 
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
HBsAg
IgM and IgG anti-HBc
HBV DNAa
IgG anti-HCV
HCV RNAb
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
aHBV DNA is only recommended when IgG anti-HBc is positive
bHCV RNA is only recommended when IgG anti-HCV is positive or inconclusive 
D 9
References
Aithal et al, 2011
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation.


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Appendix E
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
E 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered 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 intervention has been administered.
E 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study period (ie, run-in, treatment, washout, 
follow-up), that fulfills one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability or incapacity

Is a congenital anomaly or birth defect

Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above
Adverse Events (AEs) for malignant tumors reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘important medical event’ 
criterion should be used. In certain situations, however, medical judgment on an individual 
event basis should be applied to clarify that the malignant tumor event should be assessed and 
reported as a non-serious AE. For example, if the tumor is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumor, the AE may not fulfill the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumor as an AE is valid and 
should occur. Also, some types of malignant tumors, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as non-serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy.


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Life-threatening
‘Life-threatening’ means that the participant 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 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the participant 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 
judgment must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
Intensity Rating Scale:

Mild (awareness of sign or symptom, but easily tolerated)

Moderate (discomfort sufficient to cause interference with normal activities)

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 E 2. An AE of severe 


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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 E 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 E 2.
E 3
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 participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.


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Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
E 4
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 intervention 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
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication (excluding IRT/RTSM errors)

Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTSM - 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) eg, 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 AstraZeneca product 


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Medication errors are not regarded as AEs but AEs may occur as a consequence of the medication 
error.


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Appendix F
Medical Device AEs, ADEs, SAEs, SADEs, USADEs and 
Medical Device Deficiencies: Definitions and Procedures for 
Recording, Evaluating and Follow-up 

This appendix supports the activities described in section 8.3.12

The definitions and procedures detailed in this appendix are in accordance with 
International Organization for Standardization 14155 and European Medical Device 
Regulation (MDR) 2017/745 for clinical device research (if applicable).

Both the investigator and the Sponsor will comply with all local reporting requirements 
for medical devices.

The detection and documentation procedures described in this protocol apply to all 
Sponsor medical devices provided for use in the study. See Section 6.1.1 for the list of 
sponsor medical devices.

For simplicity, medical device will be used to cover device constituent parts of 
combination products and standalone medical device whether investigational or approved.
F 1
Definition of Medical Device AE and ADE
Medical Device AE and ADE Definition

An AE is any untoward medical occurrence in a clinical study participant, users, or other 
persons, temporally associated with the use of study intervention, whether or not 
considered related to the investigational medical device. A medical device AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of 
an investigational medical device. This definition includes events related to the 
investigational medical device or comparator and events related to the procedures 
involved.

An adverse device effect (ADE) is defined as an AE related to the use of an 
investigational medical device. This definition includes any AE resulting from 
insufficient or inadequate instructions for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device as well as any event 
resulting from use error or from intentional misuse of the investigational medical device.
F 2
Definition of Medical Device SAE, SADE and USADE
A Medical Device SAE is any medical device adverse event that: 
a.
Led to death.
b.
Led to serious deterioration in the health of the participant, that either resulted in:


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
A life-threatening illness or injury. The term “life-threatening” in the definition of 
“serious” refers to an event in which the participant was at risk of death at the time of the 
event. It does not refer to an event, which hypothetically might have caused death if it 
were more severe.

A permanent impairment of a body structure or a body function.

Inpatient or prolonged hospitalization. Planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in health, 
is not considered an SAE.

Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function.

Chronic disease (MDR 2017/745).
c.
Led to fetal distress, fetal death, or a congenital anomaly or birth defect.
SADE definition

A serious adverse device effect (SADE) is defined as an adverse medical device effect 
that has resulted in any of the consequences characteristic of an SAE (eg, needle stick 
requiring surgical intervention or battery leakage chemical burn causing scaring).

Any medical device deficiency that might have led to an SAE if appropriate action had 
not been taken, intervention had not occurred, or circumstances had been less fortunate.
Unanticipated SADE (USADE) definition

An unanticipated serious adverse device effect (USADE) (also identified as UADE in 
United States Regulations 21 CFR 813.3), is defined as a serious adverse medical device 
effect that by its nature, incidence, severity, or outcome has not been identified in the 
current version of the risk analysis report (see Section 2.3).
F 3
Definition of Medical Device Deficiency
Medical Device Deficiency Definition

A medical device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Medical device 
deficiencies include malfunctions, use errors, and inadequacy in the information supplied 
by the manufacturer including labelling.


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F 4
Recording and Follow-up of AE and/or SAE and Medical Device 
Deficiencies
AE, SAE, and Medical Device Deficiency Recording

When an AE/SAE/medical device deficiency occurs, it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory reports, 
and diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE/medical device deficiency 
information in the participant’s medical records, in accordance with the investigator’s 
normal clinical practice and on the appropriate form.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor in lieu of completion of the AE/SAE/medical device deficiency form.

There may be instances when copies of medical records for certain cases are requested by 
Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.

For medical device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency.

A remedial action is any action other than routine maintenance or servicing of a medical 
device where such action is necessary to prevent recurrence of a medical device 
deficiency. This includes any amendment to the medical device design to prevent 
recurrence.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE/SAE/medical device 
deficiency reported during the study and assign it to one of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. “Severe” is a category used for rating the 
intensity of an event; both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.


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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE/medical device deficiency.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship, cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure or Product Information in 
his/her assessment.

For each AE/SAE/medical device deficiency, the investigator must document in the 
medical notes that he/she has reviewed the AE/SAE/medical device deficiency and has 
provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.

The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE/SAE/Medical Device Deficiency

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE/SAE/medical device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Sponsor with a copy of any post-mortem findings 
including histopathology.

New or updated information will be recorded in the originally completed form.
The investigator will submit any updated SAE data to Sponsor within 24 hours of receipt 
of the information.


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Appendix G
Handling of Human Biological Samples
G 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each center keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
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 record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives 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 AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
G 2
Withdrawal of Informed Consent for Donated Biological Samples 
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent.
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analyzed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.

Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 


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withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified.
G 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
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. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
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, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf)

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry ice content


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Appendix H
Maintenance Therapy Equivalence Table
Asthma Therapy 
Total Daily Dose (μg/day)
Inhaled Corticosteroida
Medium
High
Beclomethasone dipropionate (pMDI, standard 
particle, HFA)
>500-1000
>1000
Beclomethasone dipropionate (DPI or pMDI, 
extrafine particle, HFA)
>200-400
>400
Budesonide (DPI, or pMDI, standard particle, HFA)
>400-800
>800
Ciclesonide (pMDI, extrafine particle, HFA)
>160-320
>320
Fluticasone furoate (DPI, eg Arnuity® Ellipta®
Breo®)
100
200
Fluticasone propionate (DPI)
>250-500
>500
Fluticasone propionate (pMDI, standard particle, 
HFA)
>250-500
>500
Mometasone furoate (DPI)
Depends on DPI device – see product 
information
Mometasone furoate (pMDI, standard particle, 
HFA) 
>200-400
>400
Inhaled Corticosteroid in ICS/LABA 
combinationa
Medium
High
Beclomethasone dipropionate (eg. Fostair®)
>200-400
>400
Fluticasone propionate HFA (eg. Seretide®, 
Advair®)
>250-500
>500
Fluticasone furoate (eg. Relvar® Ellipta®, Breo®
Ellipta®)
92-100
184-200
Budesonide, if as delivered dose (eg. Symbicort®)
>400-640
>640
Mometasone Furoate (eg. Dulera®)
>220-400
>400
a
The ICS doses were derived from GINA 2021 and the ICS/LABA combinations were derived from GINA 
2017, 2018, and 2021 and using prescribing information.
Abbreviations: DPI=dry powder inhaler; HFA=hydrofluoroalkane propellant; ICS=inhaled corticosteroid; 
LABA=long-acting β2 agonist; pMDI=pressurized metered dose inhaler.
ICS by pMDI should preferably be used with a spacer.


Cli nical St u d y Pr ot oc ol – 3 . 0
Astra Ze neca
Teze pel u ma b – D 5 1 8 0 C 0 0 0 3 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 1 2 of 1 2 3
A p pe n di x I
A b bre vi ati o ns
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
A D A
a nti -dr u g a nti b o d y
A D E
a d verse de vice effect
A E
a d verse e ve nt
A E SI
a d verse e ve nt of s pecial i nterest
A L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase/tra nsa mi nase
A N C O V A
a nal ysis of c o varia nce
A P F S
Access orize d pre -fille d s yri n ge
A S T
as partate a mi n otra nsferase/tra nsa mi nase
B A L F
br o nc h oal ve olar la va ge fl ui d
B D
br o nc h o dilat or
B MI
b o d y mass i n de x
B U N
bl o o d urea nitr o ge n
C D C
Ce nters f or Disease C o ntr ol a n d Pre ve nti o n
C H O
C hi nese ha mster o var y
CI
c o nfi de nce i nter val
C O VI D - 1 9
C or o na vir us disease 2 0 1 9
C R O
C o ntract Researc h Or ga nizati o n
C S P
Cli nical St u d y Pr ot oc ol
C S R
Cli nical St u d y Re p ort
C V
c oefficie nt of variati o n
DI LI
Dr u g I n d uce d Li ver I nj ur y
E C G
electr ocar di o gra m
e C R F
electr o nic Case Re p ort F or m
E D C
electr o nic data ca pt ure
E O T
e n d of treat me nt
E R
e mer ge nc y r o o m
F E V 1
for ce d e x pirat or y v ol u me i n 1 sec o n d
F V C
f orce d vital ca pacit y
G C P
G o o d Cli nical Practice
GI N A
Gl o bal I nitiati ve f or Ast h ma
C CI
C CI


Cli nical St u d y Pr ot oc ol – 3 . 0
Astra Ze neca
Teze pel u ma b – D 5 1 8 0 C 0 0 0 3 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 1 3 of 1 2 3
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
G M F R
ge o metric mea n f ol d rise
G M T
ge o metric mea n titer
H AI
he ma g gl uti nati o n -i n hi biti o n
H C G
h u ma n c h ori o nic g o na d otr o pi n
H C P
healt h care pr o vi der
HI V
h u ma n i m m u n o deficie nc y vir uses
H L
H y’s La w
H P F
hi g h p o wer fiel d
I A T A
I nter nati o nal Airli ne Tra ns p ortati o n Ass ociati o n
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I C S
i n hale d c ortic oster oi ds
I D
i de ntificati o n
I E C
I n de pe n de nt Et hics C o m mittee
I g A
i m m u n o gl o b uli n A
I g E
i m m u n o gl o b uli n E
I g G
i m m u n o gl o b uli n G
I g G 2 λ
i m m u n o gl o b uli n G 2 λ
I g M
i m m u n o gl o b uli n M
I L- 1 3
I nterle u ki n- 1 3
I L- 4
I nterle u ki n- 4
I L- 5
I nterle u ki n- 5
I L C- 2
t ype 2 i n nate l y m p h oi d cells
I M
i ntra m usc ular
I M P
I n vesti gati o nal Me dici nal Pr o d uct
I P D
I n vesti gati o nal Pr o d uct Disc o nti n uati o n
I R B
I nstit uti onal Re vie w B oar d
I T T
i nte nt t o treat
I V
i ntra ve n o us
I V R S
i nteracti ve v oice res p o nse s yste m
I W R S
i nteracti ve we b res p o nse s yste m
L A B A
l o n g-acti n g β 2 a g o nist
L A M A
l o n g-acti n g m uscari nic a nta g o nists
L P L V
last partici pa nt last visit
C CI


Cli nical St u d y Pr ot oc ol – 3 . 0
Astra Ze neca
Teze pel u ma b – D 5 1 8 0 C 0 0 0 3 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 1 4 of 1 2 3
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
L T R A
le u k otrie ne rece pt or a nta g o nists
m A b
m o n ocl o nal a nti b o d y
M C V
mea n c or p usc ular v ol u me
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M N
micr o ne utralizati o n
NI M P
n o n i n vesti gati o nal me dici nal pr o d uct;
O C S
or al c ortic oster oi ds
P H L
p ote ntial H y’s La w
PI
pri nci pal i n vesti gat or 
P K
p har mac o ki netic
Q 2 W
e ver y 2 wee ks
Q 4 W
e ver y 4 wee ks
R B C
re d bl o o d cell
S A B A
s h ort-acti n g β 2 a g o nist
S A D E
seri o us a d verse de vice effect
S A E
seri o us a d verse e ve nts
S A P
statistical a nal ysis pla n
S A R S -C o V - 2
se vere ac ute res pirat or y s y n dr o me c or o na vir us 2
S C
s u bc uta ne o us
S o A
Sc he d ule of Acti vities
T 2
t ype 2
T B L
t otal bilir u bi n
T h 2
T hel per t y pe 2
T P V
t hir d part y ve n d or
T S L P
t h ymic str o mal l y m p h o p oieti n
U L N
u p per li mit of n or mal
U S A/ U S
U n ite d States of A merica/ U nite d States
U S A D E
u na ntici pate d a d verse de vice effect
W B C
w h ite bl o o d cell
C CI


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Appendix J
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment, 
Amendment 2, is located directly before the Table of Contents.
Amendment 1 (07 Sep 2021)
Overall Rationale for the Amendment:
The Clinical Study Protocol (CSP), Version 1.0, dated 02 June 2021, was updated with the 
following changes:
Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-su
bstantial
Title Page
Text was deleted.
As Amgen is not a co-sponsor of 
study conduct, their name is not 
required in the protocol. This is 
consistent with other AZ run 
tezepelumab clinical studies.
Non-substantial
Synopsis; Section 
9.4.2.1 Primary 
Endpoints
Analysis will be 
summarized by 
treatment group and by 
strain.
To add additional details.
Non-substantial
Synopsis; Section 
9.4.2.1 Primary 
Endpoints
Text was updated.
To clarify that there are four 
strains of the influenza vaccine
Non-substantial
Section 1.3 Schedule 
of Activities, Table 2
Text related to serum 
antibody testing being 
done prior to influenza 
vaccination was 
deleted.
To add clarity that serum 
antibody testing is done not only 
prior to influenza vaccine, but 
also 4 weeks later.
Non-substantial
Section 1.3 Schedule 
of Activities, Table 2, 
footnote g
Text was updated.
To clarify that unscheduled study 
intervention visits may be done 
prior to V6, if needed.
Non-substantial
Section 1.3 Schedule 
of Activities, Table 2, 
footnote h; Section 6.6 
Dose Modification
Text was updated.
To clarify that unscheduled study 
intervention visits may be done 
prior to V6, if needed.
Non-substantial
Section 3 Objectives 
and Endpoints
‘Not controlled’ was 
updated to ‘not well-
controlled’
Correction of ‘not controlled’ to 
‘not well-controlled’ based on 
Juniper et al 2006 reference
Non-substantial
Section 5.2.1 Study 
Eligibility
Exclusion criterion #5 
regarding allergy to 
eggs was updated.
To clarify that if cell based 
vaccine is used, this is not 
considered an exclusion criterion.
Non-substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-su
bstantial
Section 5.2.1 Study 
Eligibility
Exclusion criterion #18 
regarding COVID-19 
vaccine was updated.
To accommodate changing 
environment with booster 
COVID-19 vaccines 
recommended for high-priority 
groups including people with 
underlying health conditions.
Non-substantial
Section 6.1.1.1 
Management of Study 
Intervention Related 
Reactions
Lung function 
assessment was 
removed. 
Correction of Error: Lung 
function assessments are not 
performed at V3 and V4.
Non-substantial
Section 6.5 
Concomitant Therapy, 
Table 7
Scheduled 
inactivated/killed 
vaccines, including the 
COVID-19 
vaccination, were 
added.
To ensure safety and well-being 
of participants and clarify that 
inactivated vaccines are permitted 
within specified timeframes.
Non-substantial
Section 6.5 
Concomitant Therapy, 
Table 7
Contraception was 
removed from the table 
of restricted 
medications.
Clarification to indicate this is not 
a restriction as contraception must 
be used for women of child 
bearing potential throughout the 
study.
Non-substantial
Section 6.5 
Concomitant Therapy, 
Table 8
COVID-19 vaccination 
was deleted from the 
table of restricted 
medications.
Ensure safety and well-being of 
participants and allow COVID-19 
vaccination which is 
recommended for high-priority 
groups, including people with 
underlying health conditions.
Non-substantial
Section 7.1 
Discontinuation of 
Study Intervention
Language regarding 
Investigational Product 
Discontinuation visit 
and End of Study visit 
was added.
To clarify that study participants 
should continue in the study even 
if study intervention is 
prematurely withdrawn.
Non-substantial
Section 7.2 Participant 
Withdrawal from the 
Study
‘End of Treatment’ 
visit was updated to 
‘Investigational 
Product 
Discontinuation’ visit.
To clarify that upon withdrawal, 
an IPD visit needs to be 
conducted.
Non-substantial
Section 7.2 Participant 
Withdrawal from the 
Study
Follow-up was 
removed from the 
sentence on data to be 
collected at the time of 
study withdrawal.
Correction of error.
Non-substantial


Cli nical St u d y Pr ot oc ol – 3 . 0
Astra Ze neca
Teze pel u ma b – D 5 1 8 0 C 0 0 0 3 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 1 7 of 1 2 3
Secti o n # a n d N a me
Descri pti o n of 
C h a n ge
Brief R ati o n ale
S u bst a nti al/ N o n -s u
bst a nti al
Secti o n 8. 1. 2. 2 
S pir o metr y Tec h ni q ue
La n g ua ge was re m o ve d 
t o ali g n wit h Sc he d ule 
of Acti vities.
T o a dj ust w or di n g t o pr ot oc ol 
re q uire me nts - s pir o metr y is 
perf or me d o nl y d uri n g scree ni n g.
N o n -s u bsta ntial
 
 
 
 
Secti o n 8. 2. 4 Cli nical 
Safet y La b orat or y 
Assess me nts
La n g ua ge re gar di n g 
rec or di n g t he date, ti me 
of c ollecti o n, a n d 
res ults bei n g rec or de d 
o n t he a p pr o priate 
electr o nic case re p ort 
f or m, was delete d.
Ot her t ha n f or se vere i nfecti o ns, 
i nf or mati o n re gar di n g l ocal 
la b orat or y tests d o ne o utsi de of 
t he Sc he d ule of Acti vities are n ot 
c ollecte d i n t he electr o nic case 
re p ort f or m.
N o n -s u bsta ntial
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I n a d diti on, mi n or f or matti n g a n d e dit orial re visi o ns were ma de t hr o u g h o ut t he pr ot oc ol.
C CI
C CI


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11
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Sicca F, Martinuzzi D, Montomoli E, Huckriede A. Comparison of influenza-specific 
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Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment 
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trigger dendritic cell-mediated allergic inflammation by producing TSLP. Nat Immunol.
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Swedin L, Saarne T, Rehnberg M, Glader P, Niedzielska M, Johansson G, et al. Patient 
stratification and the unmet need in asthma. Pharmacol Ther. 2017;169:13-34.
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TEZSPIRE (tezepelumab-ekko) Prescribing Information. Amgen Inc., One Amgen Center 
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Zeitlin PL, Leong M, Cole J, Mallory RM, Shih VH, Olsson RF, Benralizumab does not 
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stromal lymphopoietin (TSLP). Adv Pharmacol. 2013;66:129-55.


SI G N A T U R E P A G E
T his is a re prese nt ati o n of a n electr o nic rec or d t h at w as si g ne d
electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
D oc u me nt N a me: d 5 1 8 0c 0 0 0 3 1-cs p- v 3
D oc u me nt Title:
D 5 1 8 0 C 0 0 0 3 1 Cli nical St u d y Pr ot oc ol versi o n 3
D oc u me nt I D:
Versi o n L a bel:
4. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
2 3- Fe b- 2 0 2 2 1 3: 0 9 U T C
C o nte nt A p pr o val
2 3- Fe b- 2 0 2 2 1 1: 4 0 U T C
C o nte nt A p pr o val
2 3- Fe b- 2 0 2 2 2 2: 0 7 U T C
C o nte nt A p pr o val
N otes: ( 1) D oc u me nt details as st ore d i n  
, a n Astra Ze neca d oc u me nt ma na ge me nt s yste m.
P P D
P P D
P P D
C CI
C CI

SAP_001.pdf: 
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D5180C00031 – ed. 2.0
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STATISTICAL ANALYSIS PLAN
Study Code
D5180C00031
Edition Number
2.0
Date
24-Mar-2022
A Multicenter, Randomized, Double-blind, Parallel Group,
Placebo-controlled, Phase 3b Study to Evaluate the Potential 
Effect of Tezepelumab on the Humoral Immune Response to 
Seasonal Quadrivalent Influenza Vaccination in Adolescent and 
Young Adult Participants with Moderate to Severe Asthma 
(VECTOR)


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TABLE OF CONTENTS
TITLE PAGE................................................................................................................1
TABLE OF CONTENTS..............................................................................................2
LIST OF ABBREVIATIONS .......................................................................................5
AMENDMENT HISTORY...........................................................................................7
1
INTRODUCTION......................................................................................8
2
CHANGES TO PROTOCOL PLANNED ANALYSES..............................8
3
DATA ANALYSIS CONSIDERATIONS ..................................................8
3.1
Timing of Analyses.....................................................................................8
3.2
Analysis Populations...................................................................................8
3.3
General Considerations...............................................................................9
3.3.1
General Study Level Definitions ...............................................................10
3.3.2
Visit Window ...........................................................................................10
3.3.3
Handling of Unscheduled Visits................................................................10
3.3.4
Multiplicity/Multiple Comparisons ...........................................................10
3.3.5
Handling of Protocol Deviations in Study Analysis...................................11
3.3.6
Definition of baseline................................................................................11
3.3.7
Change from baseline ...............................................................................12
4
STATISTICAL ANALYSIS.....................................................................12
4.1
Study Population.......................................................................................12
4.1.1
Patient Disposition and Completion Status................................................12
4.1.1.1
Definitions and Derivations ......................................................................12
4.1.1.2
Presentation ..............................................................................................12
4.1.2
Analysis Sets ............................................................................................12
4.1.2.1
Definitions and Derivations ......................................................................12
4.1.2.2
Presentation ..............................................................................................12
4.1.3
Protocol Deviations...................................................................................13
4.1.3.1
Definitions and Derivations ......................................................................13
4.1.3.2
Presentation ..............................................................................................13
4.1.4
Demographics...........................................................................................13
4.1.4.1
Definitions and Derivations ......................................................................13
4.1.4.2
Presentation ..............................................................................................13
4.1.5
Baseline Characteristics ............................................................................13
4.1.5.1
Definitions and Derivations ......................................................................13
4.1.5.2
Presentation ..............................................................................................13
4.1.6
Disease Characteristics .............................................................................13
4.1.6.1
Definitions and Derivations ......................................................................13
4.1.6.2
Presentation ..............................................................................................14
4.1.7
Medical History and Concomitant Disease................................................14
4.1.7.1
Definitions and Derivations ......................................................................14
4.1.7.2
Presentation ..............................................................................................14
4.1.8
Prior and Concomitant Medications ..........................................................14


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4.1.8.1
Definitions and Derivations ......................................................................14
4.1.8.2
Presentation ..............................................................................................15
4.1.9
Study Drug Compliance............................................................................15
4.1.9.1
Definitions and Derivations ......................................................................15
4.1.9.2
Presentation ..............................................................................................15
4.2
Endpoint Analyses....................................................................................15
4.2.1
Primary Endpoint......................................................................................17
4.2.1.1
Definition .................................................................................................17
4.2.1.2
Derivations ...............................................................................................17
4.2.1.3
Handling of Dropouts and Missing Data ...................................................18
4.2.1.4
Primary Analysis of Primary Endpoint......................................................18
4.2.1.5
Sensitivity Analyses of the Primary Endpoint ...........................................18
4.2.2
Secondary Endpoint..................................................................................19
4.2.2.1
Definition .................................................................................................19
4.2.2.2
Derivations ...............................................................................................19
4.2.2.3
Handling of Dropouts and Missing Data ...................................................19
4.2.2.4
Primary Analysis of Secondary Endpoint..................................................19
4.2.3
Other Endpoint .........................................................................................21
4.2.3.1
Definition .................................................................................................21
4.2.3.2
Derivations ...............................................................................................21
4.2.3.3
Handling of Dropouts and Missing Data ...................................................22
4.2.3.4
Primary Analysis of Other Endpoint .........................................................22
4.3
Pharmacodynamic Endpoint(s) .................................................................22
4.4
Pharmacokinetics......................................................................................22
4.5
Immunogenicity........................................................................................22
4.6
Safety Analyses ........................................................................................22
4.6.1
Exposure...................................................................................................23
4.6.1.1
Definitions and Derivations ......................................................................23
4.6.1.2
Presentation ..............................................................................................23
4.6.2
Adverse Events.........................................................................................23
4.6.2.1
Definitions and Derivations ......................................................................23
4.6.2.2
Presentation ..............................................................................................24
4.6.3
Clinical Laboratory, Blood Sample ...........................................................24
4.6.3.1
Definitions and Derivations ......................................................................24
4.6.3.2
Presentations.............................................................................................24
4.6.4
Clinical Laboratory, Urinalysis .................................................................25
4.6.4.1
Definitions and Derivations ......................................................................25
4.6.4.2
Presentations.............................................................................................25
4.6.5
Other Laboratory Evaluations ...................................................................25
4.6.6
Vital Signs................................................................................................25
4.6.6.1
Definitions and Derivations ......................................................................25
4.6.6.2
Presentations.............................................................................................25
4.6.7
Electrocardiogram.....................................................................................25
4.6.7.1
Definitions and Derivations ......................................................................25
4.6.7.2
Presentations.............................................................................................26


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4.6.8
Other Safety Assessments.........................................................................26
4.6.8.1
Definitions and Derivations ......................................................................26
4.6.8.2
Presentations.............................................................................................26
5
INTERIM ANALYSIS .............................................................................26
6
REFERENCES.........................................................................................27
7
APPENDIX ..............................................................................................28
7.1
Appendix A: Partial Date Conventions for Adverse Events.......................28
7.2
Appendix B: Imputation Rules for Missing/Partially Missing 
Prior/Concomitant Medication Dates ........................................................29
7.3
Appendix C: Adverse events of special interest.........................................30


S T A TI S TI C A L A N A L Y SI S P L A N
Astra Ze neca
D 5 1 8 0 C 0 0 0 3 1 – e d. 2. 0
2 4- Mar -2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 of 3 1
LI S T O F A B B R E VI A TI O N S
A b bre vi ati o n or 
S peci alize d 
Ter m
Defi niti o n
A D A 
A nti- Dr u g A nti b o d y
A E
A d verse e ve nt
A E SIs
A Es of s pecial i nterest
A L T
Ala ni ne A mi n otra nsferase
A N C O V A
A nal y sis of c o varia nce
A S T
As partate A mi n otra nsferase
A T C
A nat o mical T hera pe utic C he mical
B MI
B o d y mass i n de x
CIs
C o nfi de nce I nter vals 
C O VI D - 1 9
C or o na vir us disease 2 0 1 9
C R F
Case Re p ort F or m
C S P
Cli nical St u d y Pr ot oc ol
C S R
Cli nical St u d y Re p ort
E C G
Electr ocar di o gra m
E O T
E n d of Treat me nt
F E V 1
F orce d E x pirat or y V ol u me i n 1 sec o n d  
F V C
F orce d Vital Ca pacit y
G C V
Ge o metric C oefficie nt of Variati o n
G M F R
Ge o metric Mea n F ol d Rise
G M T
Ge o metric Mea n Titer 
H AI 
He ma g gl uti nati o n -I n hi biti o n
I P D
I m p orta nt Pr ot oc ol De viati o n
I S S
I nte grate d S u m mar y of Safet y 
I T T
I nte nt-t o-Treat
L L O Q
L o wer Li mit of Q ua ntificati o n 
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M N 
Micr o ne utralizati o n
n A b
Ne utralizi n g A nti b o dies 
N C
N o n -Calc ula ble
N Q
N o n -Q ua ntifia ble
C CI


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Abbreviation or 
Specialized 
Term
Definition
PD
Protocol Deviation
PK
Pharmacokinetics
PT 
Preferred Term
SAE
Serious AEs
SAP
Statistical Analysis Plan 
SD 
Standard Deviation 
SMQ
Standardized MedDRA Query 
SOC
System Organ Class
TBL
Total Bilirubin
ULN
Upper Limit of Normal


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AMENDMENT HISTORY
CATEGORY
Change refers to:
Date
Description of change
In line with CSP?
Rationale
N/A
08/11/2021
Initial approved SAP
N/A
N/A
Primary endpoint(s)
24/03/2022
Language relating to primary and final 
database locks was added. 
Yes (V3)
To add primary analysis of data 
at Visit 7 (Week 16).
Data presentation
24/03/2022
Vaccine immunogenicity analysis set 
population updated to exclude participants 
who experience an influenza infection 
prior to Visit 7 (Week 16) assessments.
Yes (V3)
To reduce the potential to 
interfere with the generation or 
interpretation of an antibody 
response.
Data presentation
24/03/2022
Updated from ‘Visit’ to ‘Week’ 
throughout for data presentation.
Yes (V3)
Displaying as ‘week’ is more 
clear and aligns with other 
studies. 
Other
24/03/2022
Added language to describe when 
unblinding will occur. 
Yes (V3)
To clarify when unblinding will 
occur in relation to the primary 
analysis. 
Other 
24/03/2022
Updated appendix B to add further rules 
on partially missing concomitant 
medication dates. 
N/A


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1
INTRODUCTION
The purpose of this document is to give details for the statistical analysis of study 
D5180C00031. This study is a Phase 3b, multicenter, randomized, double-blind, parallel 
group, placebo-controlled study investigating the potential effect of tezepelumab on 
antibody responses following seasonal quadrivalent influenza virus vaccination. The reader 
is referred to the clinical study protocol (CSP) and the case report form (CRF) for details of 
study conduct and data collection.
2
CHANGES TO PROTOCOL PLANNED ANALYSES
Pre- and post-dose wording in CSP was updated to pre- and post-vaccination in the 
statistical analysis plan (SAP), when referring to the influenza vaccine. 
Hypersensitivity reactions was added as an AESI in Appendix 7.3.
3
DATA ANALYSIS CONSIDERATIONS
3.1
Timing of Analyses
There is neither an unblinded data review nor interim analysis planned for this study prior 
to primary database lock. There will be two database locks in this study. The primary 
database lock and analysis will be conducted after the last participant (enrolled in the 
2021/2022 flu season) completes Visit 7 (Week 16), and the final database lock and 
analysis will be conducted once all participants have completed the follow-up period, Visit 
8 (Week 28). All analyses of the primary objectives and selected safety objectives will be 
performed based on the primary database lock data.
3.2
Analysis Populations
Antibody endpoints to the influenza vaccine—strain-specific hemagglutination-inhibition 
(HAI) and microneutralization (MN) antibody geometric mean fold rises (GMFRs) and 
geometric mean titers (GMTs)—will be analyzed using the vaccine immunogenicity 
analysis set. All remaining efficacy analyses will be performed using an Intent-to-Treat 
(ITT) approach based on the Full analysis set. Demographic and baseline characteristics 
will be presented for the Full analysis set, and separately for the Vaccine immunogenicity 
analysis set if the difference between the number of participants in the two analysis sets is 
>=5%. Safety objectives and anti-drug antibody (ADA) summaries will be analyzed based 
on the Safety analysis set. The population analysis sets are defined in Table 1.


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Table 1 Populations for Analysis
Population/ Analysis set 
Description 
All participant analysis set
All participants screened for the study will be included in the ‘All 
participant analysis set’ and will be used for reporting of disposition and 
screening failures.
Full analysis set
All participants randomized and receiving any study intervention will be 
included in the ‘Full analysis set’, irrespective of their CSP adherence 
and continued participation in the study.
Participants will be analyzed according to their randomized treatment, 
irrespective of whether or not they have prematurely discontinued, 
according to the ITT principle.
Participants who withdraw informed consent/assent to participate in the 
study will be included up to the date of their study termination.
Vaccine immunogenicity 
analysis set
All randomized participants who received the influenza vaccine plus at 
least 1 dose of tezepelumab or placebo, had pre- and post-vaccination 
HAI or MN antibody measurements, had no influenza infection prior to 
Visit 7 (Week 16), and had no protocol deviation, judged to have the 
potential to interfere with the generation or interpretation of an antibody 
response, will be included in the 'vaccine immunogenicity analysis set'.
The analyses conducted using this analysis set will be based on the actual 
treatment received. Protocol deviations (PDs) will be specified in the PD 
specification and reviewed by the study team before unblinding at the 
primary database lock (Visit 7 [Week 16]).
Safety analysis set
All participants who received at least 1 dose of study intervention will be 
included in the ‘safety analysis set’.
Participants will be classified according to the treatment they actually 
received. A participant who has on one or several occasions received 
active treatment will be classified as active. All safety and ADA 
summaries will be based on this analysis set.
Pharmacokinetic (PK) 
analysis set
All participants who received tezepelumab and from whom PK blood 
samples were obtained and assumed not to be affected by factors such as 
CSP deviations will be included in the 'PK analysis set'.
Those participants who had at least 1 quantifiable serum PK observation 
post first dose will be included in the PK analysis dataset. All PK 
summaries will be based on this analysis set.
Abbreviations: ADA=anti-drug antibody; CSP=clinical study protocol; HAI=hemagglutination-inhibition; 
ITT=intent to treat; MN=microneutralization; PD=protocol deviation; PK=pharmacokinetic.
3.3
General Considerations
All statistical analyses will be performed by Parexel International, under the direction of the 
Late Stage Respiratory and Immunology Biometrics Group, AstraZeneca. All statistical 
analyses will be performed using the latest available version of SAS® (SAS Institute Inc., 
Cary, North Carolina, US), version 9.4 or higher.
All personnel involved with the analysis and conduct of the study will remain blinded until 
the primary database lock and important protocol deviations, have been identified. After the 
primary database lock, treatment allocation for participants during this study will become 
known to the sponsor staff and designated CRO. The blind will be maintained for the 
investigator, investigational site staff, and for the participant.


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3.3.1
General Study Level Definitions
Unless stated otherwise, continuous variables will be summarized by descriptive statistics 
(number of participants [n], arithmetic mean, standard deviation (SD), minimum, median 
and maximum).  Categorical variables will be summarized in frequency tables (frequencies 
and percentages). 
Mean(s), median(s), SD(s) and quartiles (where applicable) will be displayed with one 
more decimal place than the collected data. Minimum(s) and maximum(s) will be displayed 
with the same number of decimal places as the collected data.  For discrete variables, 
population size (N for analysis set size and n for available data) and percentage will be 
presented.  Percentages will be displayed with one decimal place.
As no statistical testing is planned, no p-values will be presented.
If influenza vaccine administration is delayed, an additional one to two study intervention 
doses may be administered to participants during unscheduled visits prior to visit 6 (as 
needed) until the influenza vaccine is available at study sites. Throughout this document 
End of Treatment (EOT) refers to the end of treatment visit, which is four weeks after the 
last dose of study intervention and could be either week 16, 20 or 24 for each participant. 
The end of study visit is 16 weeks after last dose of study intervention. 
3.3.2
Visit Window
All summaries and analyses which are presented by visit will use the nominal visit label. 
This will allow for correct classification of Visit 6 (pre-vaccination antibody measure), 
Visit 7 (EOT), and Visit 8 (End of Study) at different time points for different participants 
due to influenza vaccination delay should it occur, as described in section 3.3.1. 
Participants who discontinue study intervention early should attend all further study visits 
as defined in the CSP, hence any collected data will be used as planned. 
3.3.3
Handling of Unscheduled Visits 
All assessments during the unscheduled visits, due to delayed influenza vaccine 
administration, may not necessarily be completed. All available data will be included in 
analyses. 
3.3.4
Multiplicity/Multiple Comparisons
The statistical analysis of each of the four primary variables will be performed separately 
for each strain and separately for both HAI and MN antibody titers; except for the Influenza 
A H3N2-strain, where only the MN assay will be performed owing to the known low 
hemagglutination effect of the strain (Sicca et al 2020). No adjustment of multiplicity will 
be performed.


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The secondary endpoint variables will be summarized using descriptive statistics.
3.3.5
Handling of Protocol Deviations in Study Analysis
Only important protocol deviations (IPDs) will be listed and tabulated, and only for 
randomized participants (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 participant’s rights, safety or well-being. They may include (but 
not be limited to):

Participants who were randomized even though they did not meet key inclusion criteria 
or who met at least one key exclusion criteria 

Participants who met discontinuation criteria for study treatment but were not 
withdrawn from study treatment

Participants who developed withdrawal criteria during the study but were not 
withdrawn

Participants who received the wrong treatment or an incorrect dose

Participants who received a restricted or prohibited concomitant treatment.
All PDs will be listed and identified as important or non-important in the PD specification. 
All IPDs will be identified and documented by the study team prior to unblinding of the 
trial at primary database lock. The occurrence of IPDs will be monitored, in a blinded 
fashion during the trial, with the emphasis on their future prevention. 
Except for the vaccine immunogenicity analysis set and PK analysis set, PDs including 
important PDs, will not be used to exclude any participant from any analysis set, nor to 
exclude any data from participants included in an analysis set.
Any PDs which are not defined as important, except Coronavirus disease 2019 (COVID-
19) related PDs, will not be reported or discussed in the Clinical Study Report (CSR).
3.3.6
Definition of baseline
In general, the last non-missing measurement on or prior to the date of randomization will 
serve as the baseline measurement for efficacy variables. If there is no value on or prior to 
the date of randomization, then the baseline value will not be imputed, and will be set to 
missing. 
In general, the last non-missing measurement prior to first dose of study treatment will 
serve as the baseline measurement for safety and pharmacokinetic variables. 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.


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3.3.7
Change from baseline 
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 change from 
baseline will also be missing. 
4
STATISTICAL ANALYSIS
This section provides information on definitions, derivation and analysis/data presentation 
per domain.
4.1
Study Population
The domain study population covers participant disposition, analysis sets, protocol 
deviations, demographics, baseline characteristics, medical history, prior and concomitant 
medications and study drug compliance. 
4.1.1
Patient Disposition and Completion Status
4.1.1.1
Definitions and Derivations
Screen failures are defined as participants who complete informed consent/assent to 
participate in the clinical study but are not subsequently randomly assigned to study 
intervention.
4.1.1.2
Presentation
Participant disposition will be summarized using the all participants analysis set. The 
number of participants screened will be summarized. The number and percentage of 
participants within each treatment group will be presented by the following categories: 
randomized, randomized but not treated (and reason), started treatment, completed 
treatment, discontinued treatment (and reason), completed study, and withdrawn from 
study. Participant recruitment by center will also be summarized. 
4.1.2
Analysis Sets
4.1.2.1
Definitions and Derivations
See section 0 for full definitions of the analysis sets.  
4.1.2.2
Presentation
The number and percentage of participants in each of the analysis sets will be summarized 
by treatment group, along with reason for exclusion for participants not included in each 
set. Refer to Table 1 Populations for Analysis for full definitions of each analysis sets. 


S T A TI S TI C A L A N A L Y SI S P L A N
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4. 1. 3
Pr ot oc ol De vi ati o ns
4. 1. 3. 1
Defi niti o ns a n d Deri v ati o ns
See secti o n  3. 3. 5 f or defi niti on o f I P Ds. 
4. 1. 3. 2
Prese nt ati o n
I P Ds will be s u m marize d f or t he f ull a nal ysis set, b y treat me nt gr o u p a n d o verall. All 
C O VI D -1 9 rel ate d I P Ds will be s u m marize d t o get her wit h all n o n -C O VI D -1 9 rel ate d I P Ds, 
alo n g wi t h a n a d ditio n al  s u m mar y of I P Ds relate d t o C O VI D-1 9, a n d I P Ds e xcl u di n g 
C O VI D -1 9 rel ate d I P Ds se paratel y. 
A listi n g of all C O VI D-1 9 r el ate d P Ds (i m p orta nt a n d n o n-i m p orta nt P Ds) will be 
pr o vi de d. 
4. 1. 4
De m o gr a p hics
4. 1. 4. 1
Defi niti o ns a n d Deri v ati o ns
D e m o gra p hic data will i ncl u de a ge at ti me of i nf or me d c o nse nt, se x, race, a n d et h nicit y.  
A ge wi ll be s u m marize d b ot h c o nti n u o usl y a n d b y gr o u p, s plit b y t he stratificat i on fact ors: 
> = 1 2 t o < 1 8 a n d > = 1 8 t o < = 2 1. 
4. 1. 4. 2
Prese nt ati o n
D e m o gra p hics will be s u m marize d b y tr e at me nt gr o u p a n d prese nte d f or t he f ull a nal ysis 
set, a n d t he vacci ne i m m u n o ge nicity a nal ysis set if a p plica ble, as detaile d i n secti on  0 . 
4. 1. 5
B aseli ne C h ar acteristics
4. 1. 5. 1
Defi niti o ns a n d Deri v ati o ns
Baseli ne c haracterist ics ( weig ht [ k g], hei g ht [c m ], a n d b o d y mass i n de x ( B MI) [ k g/ m 2]) are 
c ollecte d at visit 1. 
4. 1. 5. 2
Prese nt ati o n
Baseli ne c haracterist ics will be s u m marize d b y tr e at me nt gr o u p a n d prese nte d f or b ot h t he 
f ull a nal ysis set a n d t he vacci ne i m m u n o ge nicity a nal ysis set if a p plica ble, as detaile d i n 
secti on  0.
4. 1. 6
Dise ase C h ar acteristics
4. 1. 6. 1
Defi niti o ns a n d Deri v ati o ns
Di sease c haracteristics will i ncl u de, b ut is n ot li mite d t o; s m o ki n g stat us, hist or y of aller g y, 
ast h ma me dicat i ons, t he n u m ber of ast h ma e xacer bati o ns i n t he pre vi o us 1 2 m o nt hs, 
n u m ber of ast h ma e xacer bat i ons re q ui rin g h os pi talizati ons i n t he pre vi o us 1 2 m o nt hs, a n d 
. 
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Baseline lung function is collected at either visit 1 or visit 2, and is assessed for both pre-
and post-bronchodilator spirometry. Measures include Forced Vital Capacity (FVC) (L), 
FVC (%), Forced Expiratory Volume in 1 second (FEV1) (L), FEV1 (% of predicted 
normal), FEV1 reversibility (L), FEV1 reversibility (%), and FEV1/FVC Ratio (%). 
Historical reversibility will be listed, where available. 
4.1.6.2
Presentation
Disease characteristics will be summarized by treatment group and presented for both the 
full analysis set and the vaccine immunogenicity analysis set if applicable, as detailed in 
section 0.
4.1.7
Medical History and Concomitant Disease
4.1.7.1
Definitions and Derivations
Medical and surgical histories are reported at screening.  
4.1.7.2
Presentation
Medical and surgical histories will be summarized by treatment group and Medical 
Dictionary for Regulatory Activities (MedDRA) Preferred Term (PT) within the System 
Organ Class (SOC) level of MedDRA, and will be presented for the full analysis set. 
4.1.8
Prior and Concomitant Medications
4.1.8.1
Definitions and Derivations
A list of permitted, restricted and prohibited medications can be found in section 6.5 of the 
CSP. Please refer to Appendix B: Imputation Rules for Missing/Partially Missing 
Prior/Concomitant Medication for the method of imputation of missing concomitant 
medication onset/start and end/stop dates.
Medications will be categorized for analysis according to their onset and end dates as 
follows:

Prior medications: 

end date ≤ date of first dose of study intervention 

Concomitant medications during on-treatment period: 

end date > date of first dose of study intervention and start date ≤ minimum (date 
of last dose of study intervention + 33 days, date of death, date of study 
withdrawal), or 

end date ongoing and start date ≤ minimum (date of last dose of study intervention 
+ 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 study intervention + 33 days.
4.1.8.2
Presentation
Prior, concomitant and disallowed medications will be summarized by their Anatomical 
Therapeutic Chemical (ATC) classification system codes and generic name, by treatment 
group. Each will be presented for the full analysis set. On-treatment and post-treatment 
concomitant medications will be summarized separately. 
4.1.9
Study Drug Compliance
4.1.9.1
Definitions and Derivations
Treatment compliance will be calculated as follows: 
	
 	
 (%) =  total number of actual dosing occasions
total number of expected dosing occasions' × 100
In order to allow for participants who discontinue study intervention early or who receive 
additional doses due to delayed flu vaccine administration, in the compliance calculation, 
the number of expected dosing occasions will be calculated as the number of dosing visits 
up to and including the last available dosing visit for that participant.
4.1.9.2
Presentation
Treatment compliance will be summarized by treatment group and presented for the full 
analysis set. The date and time of study intervention administrations, and all missed doses 
will be listed. 
4.2
Endpoint Analyses
This section covers details related to the efficacy endpoint analyses such as primary, 
secondary, other endpoints including sensitivity and supportive analyses. Table 2 gives 
details of the primary analysis estimands. 




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4.2.1
Primary Endpoint
4.2.1.1
Definition
The primary objective is to evaluate the effect of tezepelumab on the humoral immune 
response following seasonal influenza virus vaccination in adolescent and young adult 
participants with moderate to severe asthma. 
The primary endpoints are defined as follows: 

Post-vaccination strain-specific HAI antibody GMFRs from Week 12 (pre-vaccination 
antibody measure) to Week 16 (EOT). 

Post-vaccination strain-specific MN antibody GMFRs from Week 12 (pre-vaccination 
antibody measure) to Week 16 (EOT). 

Post-vaccination strain-specific serum HAI antibody GMTs obtained at Week 16 
(EOT). 

Post-vaccination strain-specific serum MN antibody GMTs obtained at Week 16 
(EOT). 

Post-vaccination strain-specific antibody response at Week 16 (EOT) with antibody 
response defined as a ≥ 4-fold rise in HAI antibody titer from Week 12 (pre-
vaccination antibody measure) to Week 16 (EOT). 

Post-vaccination strain-specific antibody response at Week 16 (EOT) with antibody 
response defined as a ≥ 4-fold rise in MN antibody titer from Week 12 (pre-vaccination 
antibody measure) to Week 16 (EOT).

Post-vaccination strain-specific HAI antibody titer ≥ 40 at Week 16 (EOT). 

Post-vaccination strain-specific MN antibody titer ≥ 40 at Week 16 (EOT).
As the HAI assay may not work for one of the influenza virus strains (Influenza A H3N2), 
the corresponding MN result for that strain will only be used, please see CSP for more 
details on the influenza virus strains. Hence, both the HAI and MN results will serve as the 
dual primary endpoints for this study such that results from both assays can be used for the 
analyses of the primary objective. This dual endpoint approach allows for a broader 
characterization of the immune response and flexibility in case the results for either assay 
are missing. The analyses of the primary endpoints will be summarized separately for each 
influenza virus strain, using the vaccine immunogenicity analysis set. 
4.2.1.2
Derivations
Geometric mean fold rises for the HAI and MN antibody measurements are defined as: 
GMFR = antiloge (mean [loge x])
Where x is the post-vaccination (EOT) HAI or MN antibody titer fold rise from Week 12 
(pre-vaccination antibody measure) and e is the natural logarithm.


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Geometric mean titers for the HAI and MN antibody measurements are defined as:
GMT = antiloge (mean [loge y])
Where y is the HAI or MN antibody titer and e is the natural logarithm.
For HAI & MN assay results reported as lower than the lower limit of quantification 
(LLOQ), a value equal to half of the LLOQ will be imputed and used for analysis purposes.
4.2.1.3
Handling of Dropouts and Missing Data
If informed consent/assent to the study was withdrawn, all data up until the date of 
withdrawn informed consent/assent will be included. 
4.2.1.4
Primary Analysis of Primary Endpoint
Geometric mean fold rises and GMTs will be summarized by influenza virus strain and 
treatment group, and the least square geometric mean ratio of GMFRs and GMTs between 
treatment groups (influenza vaccine divided by tezepelumab and influenza vaccine) will be 
calculated via an analysis of covariance (ANCOVA) model on the log-transformed
variable, adjusting for treatment group and age stratum (adolescents aged 12 to 17 or young 
adults aged 18 to 21). The least square geometric mean ratio and mean difference will be 
provided with associated 90% CIs. The results of this analysis will also be presented in 
forest plots.  
The antibody response to the influenza vaccine is defined as a ≥ 4-fold rise in HAI or a ≥ 
4-fold rise in MN from Week 12 (pre-vaccination antibody measure) to Week 16 (EOT). 
The proportion of participants who experience a post-vaccination antibody response at 
Week 16 (EOT) for HAI and the proportion of participants who experience a post-
vaccination antibody response at Week 16 (EOT) for MN and corresponding 90% Clopper-
Pearson exact CIs (Clopper et al 1934) will be summarized by treatment group.
The proportion of participants who achieve a post-vaccination HAI antibody titer ≥ 40 and 
the proportion of participants who achieve a post-vaccination MN antibody titer ≥ 40 at 
Week 16 (EOT) and corresponding 90% Clopper-Pearson exact CIs will be summarized by 
treatment group.
4.2.1.5
Sensitivity Analyses of the Primary Endpoint
The eight primary endpoints, as described in section 4.2.1.1, may be analyzed separately for 
the following, to show robustness around the specified intercurrent event strategies. 

Excluding participants who discontinue treatment 

Excluding participants who initiate any another medication, in line with IPDs listed in 
the PD specification. 


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4.2.2
Secondary Endpoint
4.2.2.1
Definition
The secondary objective is to assess the PK and immunogenicity, which will be done 
through serum trough tezepelumab concentrations and ADA. The analyses of the secondary 
endpoints will use the PK analysis set for the PK summaries and the safety analysis set for 
the ADA summaries. 
4.2.2.2
Derivations
Due to the limited sampling schedule, the PK assessment will be based on the observed 
serum trough concentrations.
ADA assessments will be conducted utilizing a tiered approach (screen, confirm, titer).
For ADA and PK results reported as lower than the LLOQ, a value equal to half of the 
LLOQ will be imputed and used for analysis purposes.
4.2.2.3
Handling of Dropouts and Missing Data
If informed consent/assent to the study was withdrawn, all data up until the date of 
withdrawn informed consent/assent will be included. 
4.2.2.4
Primary Analysis of Secondary Endpoint
4.2.2.4.1
Analysis of pharmacokinetics 
The PK analyses will be performed by a third-party vendor under the guidance of 
AstraZeneca Research and Development.
Tezepelumab serum concentrations will be summarized using descriptive statistics at each 
visit. The following criteria will apply for data to be included in the summary table:

Only samples collected prior to the first study intervention dose for baseline samples

Only samples collected prior to influenza vaccination administration for pre-
vaccination samples
For descriptive statistics of tezepelumab concentrations:

If, at a given time point, 50% or less of the concentrations are non-quantifiable (NQ), 
the geometric mean, geometric coefficient of variation (GCV), arithmetic mean and SD 
will be calculated by substituting the LLOQ divided by 2 for values which are NQ.

If more than 50%, but not all, of the concentrations are NQ, the geometric mean, GCV, 
arithmetic mean and SD will be reported as not calculable (NC)

If all the concentrations are NQ, the geometric mean and arithmetic mean will be 
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
The median, minimum and maximum will also be reported. 
The LLOQ of tezepelumab in serum will be 0.010 μg/mL.
4.2.2.4.2
Analysis of immunogenicity 
ADA to tezepelumab will be summarized using descriptive statistics at each visit by 
treatment group.
The ADA status across the study for each subject will also be classified and summarized by 
treatment group. Specifically, the following ADA results will be evaluated as number and 
proportion of subjects in cohorts together with corresponding titre summaries. However, if 
the number of ADA positive subjects in the safety analysis set is small then the ADA 
variables may be listed only in the CSR:

Subjects who are ADA positive at any time including baseline (ADA prevalence).

Subjects who are ADA positive at baseline only.

Subjects who are ADA positive at baseline and positive in at least one post baseline 
measurement.

Subjects who are ADA positive at baseline regardless of post-baseline result.

Subjects who are ADA positive post-baseline.

Subjects who are ADA positive post-baseline and ADA negative at baseline (treatment 
induced ADA)

Subjects who are persistently positive; persistently positive is defined as having at least 
two post-baseline ADA positive measurements (with≥ 16 weeks between first and last 
positive) or an ADA positive result at the last available post-baseline assessment.

Subjects who are transiently positive; transiently positive is defined as having at least 
one post-baseline ADA positive measurement and not fulfilling the conditions for 
persistently positive.

Subjects with treatment boosted ADA, defined as baseline positive ADA titre that was 
boosted to a 4-fold or higher level following study intervention administration

Subjects with treatment emergent ADA (ADA incidence): defined as the sum of 
treatment induced ADA and treatment boosted ADA.
For ADA summaries at a single time point (e.g. baseline ADA or by visit) the 
corresponding titre summary will be based on the titre of the positive sample for that 
particular visit.
For summaries across visits (e.g. ADA positive at any visit) the corresponding titre 
summaries will be based on the maximum titre of all positive samples for each subject.


S T A TI S TI C A L A N A L Y SI S P L A N
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2 1 of 3 1
Ne utralizi n g A D A e val uati o ns will be c o n d ucte d o n c o nfir me d A D A p ositi ve sa m ples. T he 
test sa m ple is dee me d p ositi ve or ne gati ve f or t he prese nce of ne utralizi n g a nti b o dies ( n A b) 
t o teze pel u ma b relati ve t o a pre-deter mi ne d (i n assa y  vali dat i on) statisticall y deri ve d c ut 
p oi nt. T he n u m ber a n d pr o p orti o n of s u bjects w h o are n A b p osit i ve at a n y ti me will be 
e val uate d.
If a p pr o priate, t he ass ociati on of A D A stat us acr oss t he st u d y  wit h pri mar y a nd ke y  
sec o n dar y efficac y, bio m ar kers a n d A Es/seri o us A Es ( S A Es) ma y be e val uate d.
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S T A TI S TI C A L A N A L Y SI S P L A N
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4. 3
P h ar m ac o d y n a mic E n d p oi nt(s) 
Refer t o secti o n  4. 6. 3 4. 2. 2 f or details.
4. 4
P h ar m ac o ki netics 
Refer t o secti o n  4. 2. 2 f or details.
4. 5
I m m u n o ge nicit y 
Refer t o secti o n  4. 2. 2 f or details.
4. 6
S afet y A n al yses 
T he d o m ai n safet y c o vers e x p os ure, a d verse e ve nts, cli nical la b orat or y, a n d vital si g ns. 
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Tables are provided for the safety analysis set; listings are provided for all participants or 
the safety analysis set depending on the availability of data.
4.6.1
Exposure
4.6.1.1
Definitions and Derivations
Duration of exposure to study intervention is defined as the number of days between the 
date of first dose and the date of last dose of study intervention inclusive, calculated as 
follows:
+,
 - ./, (01/)
= 	
	,	(0 - / 0/ - study intervention
+ 33 01/; 0 - 0ℎ; 0 - /,01 8ℎ08)
−0 - -/ 0/ - study intervention + 1
This calculation does not consider any gaps in exposure caused by the participant missing 
one or more intermediate scheduled weekly doses. Such cases will be identified in the CSR 
if they occur but will not explicitly be accounted for in any analysis. Date of last dose will 
include the unscheduled visits due to delayed flu vaccine administration, if applicable. 
4.6.1.2
Presentation
Duration of exposure (days) will be summarized by treatment group and presented for the 
safety analysis set. 
4.6.2
Adverse Events
4.6.2.1
Definitions and Derivations
Adverse Events (AEs) will be summarized for analysis according to their onset date into the 
following study periods: 

AEs occurring during screening: date of Visit 1 ≤ AE onset date < date of first dose 
of study intervention

AEs occurring during on-treatment period: date of first dose of study intervention ≤ 
AE onset date ≤ minimum (date of last dose of study intervention +33 days, date of 
death, or date of study withdrawal)

AEs occurring during on-study period: date of first dose of study intervention ≤ AE 
onset date ≤ study completion or date of study withdrawal. 
Rules for imputing AE start/stop dates which are partially missing can be found in 
Appendix A: Partial Date Conventions for Adverse Events. Partially missing start/stop 
dates will appear as such in the participant data listings but will be imputed to permit proper 
tabulation of AE data.


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AEs of special interest (AESIs) are an event of scientific and medical interest towards 
improving the understanding of the study intervention. An AESI may be serious or non-
serious. Similar considerations apply to any additional supporting analysis of AESIs, in 
which MedDRA dictionary-based definitions are used. 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 7.3. 
4.6.2.2
Presentation
All AE summaries will be presented by actual treatment group for the safety analysis set. A 
by- participant listing of all AEs will be provided; AEs occurring during screening will be 
included in the listing, but not summarized separately. The number and percentage of 
participants with on-treatment and on-study AEs will be tabulated separately by system 
organ class and preferred term. An event that occurred one or more times during a period 
will contribute one observation to the numerator of the proportion. The denominator of the 
proportion will comprise all participants in the safety population. On-treatment AEs will 
also be summarized by intensity/severity and separately, by causality/relatedness (as 
determined by the investigator). Should a participant report the same preferred term/system 
organ class within multiple intensity/severity or causality/relatedness categories, the 
participant’s worst occurrence (most severe/most related) will be tabulated. Serious AEs, 
AEs leading to death, AEs leading to discontinuation from study intervention, and 
commonly occurring AEs (defined as those occurring in >5% of subjects in either treatment 
group) will be summarized by treatment group. AESIs will also be summarized 
descriptively by treatment group; serious infections will be summarized as part of the SAE 
by SOC and PT table in the SOC of infections and infestations and not in a separate table. 
4.6.3
Clinical Laboratory, Blood Sample
4.6.3.1
Definitions and Derivations
A list of clinical chemistry and hematology variables can be found in the CSP. Baseline is 
defined as last available non-missing data collected prior to first dose of study intervention. 
Potential Hy’s law definition and case confirmation are given in Appendix D of the CSP.
For results reported as lower than the LLOQ, a value equal to the LLOQ will be imputed 
and used for analysis purposes.
4.6.3.2
Presentations
Clinical chemistry and hematology data will be summarized by presenting shift tables and 
plots using normal ranges (baseline to minimum post-baseline value, baseline to maximum 
post-baseline value, and baseline to last observation on-study) and by presenting summary 
statistics of observed and change from baseline values (means, SDs, medians, quartiles, 
ranges). The incidence of clinically notable laboratory abnormalities will be summarized. 


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In order to identify potential Hy’s Law cases, maximum post-baseline total bilirubin (TBL) 
will be plotted separately against both maximum post-baseline alanine aminotransferase 
(ALT) and aspartate aminotransferase (AST), expressed as multiples of the upper limit of 
normal (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.
4.6.4
Clinical Laboratory, Urinalysis
4.6.4.1
Definitions and Derivations
A list of urinalysis variables can be found in the CSP. For results reported as lower than the 
LLOQ, a value equal to the LLOQ will be imputed and used for analysis purposes.
4.6.4.2
Presentations
Urinalysis data will be summarized by presenting shift tables (baseline to maximum post-
baseline value, and baseline to last observation on-study).
4.6.5
Other Laboratory Evaluations
Not applicable. 
4.6.6
Vital Signs
4.6.6.1
Definitions and Derivations
Vital signs collected include pulse rate, blood pressure, respiratory rate, and body 
temperature. Baseline is defined as last available non-missing data collected prior to the 
first dose of study intervention. 
4.6.6.2
Presentations
Vital signs data will be summarized by presenting summary statistics of observed and 
change from baseline values by visit and treatment group. The frequency of changes 
(baseline to minimum post-baseline value, baseline to maximum post-baseline value, and 
baseline to last observation on-study) with respect to normal ranges (high/low/normal 
findings) will be tabulated and plotted by treatment group.
4.6.7
Electrocardiogram
4.6.7.1
Definitions and Derivations
Twelve-lead electrocardiogram (ECG) measurements are performed locally and will be 
recorded in accordance with the CSP at visit 1 only. The outcome of the overall evaluation 


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is to be recorded as normal/abnormal in the eCRF, with any abnormalities being recorded 
as not clinically significant or clinically significant.
4.6.7.2
Presentations
All ECG measurements will be listed, along with the overall evaluation and significance of 
abnormality, if applicable. 
4.6.8
Other Safety Assessments
4.6.8.1
Definitions and Derivations
Any new physical exam finding(s) or aggravated existing finding(s), judged as clinically 
significant by the Investigator, will be reported as an AE in AE reporting.
Any device malfunctions relating to an AE, will be reported as an AE. 
4.6.8.2
Presentations
Physical exam findings and device malfunctions reported as an AE will be summarized as 
described in section 4.6.2. Any reported device malfunctions will be listed. 
5
INTERIM ANALYSIS
There is neither an unblinded data review nor interim analysis planned for this study prior 
to primary database lock.


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6
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Clopper et al 1934
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika. 1934 Dec 1:404-13.
Juniper et al 2005
Juniper EF, Svensson K, Mörk AK, Ståhl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respir Med. 2005;99:553-58.
Juniper et al 2006
Juniper EF, Bousquet J, Abetz L, Bateman ED. The GOAL Committee. Identifying 
‘wellcontrolled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. 
Respir Med. 2006;100:616-21.
Sampson et al 2006
Sampson H.A, A. Munoz-Furlong, R.L. Campbell, N.F. Adkinson Jr., S.A. Bock, A. ranum 
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
Sicca et al 2020
Sicca F, Martinuzzi D, Montomoli E, Huckriede A. Comparison of influenza-specific 
neutralizing antibody titers determined using different assay readouts and hemagglutination 
inhibition titers: good correlation but poor agreement. Vaccine. 2020;38(11):2527-2541.


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7
APPENDIX
7.1
Appendix A: Partial Date Conventions for Adverse Events
Missing type
Action
If only the day part of the AE onset date is 
missing the missing day of onset of AE will be 
set to:

First day of the month that the event 
occurred, if the onset YYYY-MM is after 
the YYYY-MM of first study treatment

The day of the first study treatment, if the 
onset YYYY-MM is the same as YYYY-
MM of the first study treatment

The date of informed consent, if the onset 
YYYY-MM is before the YYYY-MM of 
the first treatment.
If the day and month parts of the AE onset 
date are missing the date of onset of AE will 
be set to:

January 1 of the year of onset, if the onset 
year is after the year of the first study 
treatment

The date of the first treatment, if the onset 
year is the same as the year of the first study 
treatment

The date of informed consent, if the onset 
year is before the year of the first treatment
If only the day part of the AE resolution date
is missing the missing day of resolution of AE 
will be set to:
The last day of the month of the occurrence. If 
the participant died in the same month, then 
set the imputed date as the death date.
If the day and month parts of the AE
resolution date are missing, the date of 
resolution of AE will be set to:
December 31 of the year of occurrence. If the 
participant died in the same year, then set the 
imputed date as the death date.  


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7.2
Appendix B: Imputation Rules for Missing/Partially Missing 
Prior/Concomitant Medication Dates 
DATE MISSING
ACTION
Completely missing 
start date 
Assume participant had been on the medication since the date of the first 
study procedure.
Partially missing start 
date (month/year or 
year only)
If the partially missing onset date is the same as that for the end of study 
intervention treatment, it will be assumed to have started on-treatment. 
If the partially missing onset date is the same as that for the start of IP 
treatment, it will be assumed to have started before treatment.
If the partially missing onset date is prior to start of IP treatment, it will be 
assumed to have started January 1st if only year is present and assumed to 
have started the 1st day of the respective month if year and month are present. 
Completely missing 
end date 
Assume participant had been on the medication on the date of study 
completion or withdrawal. 
Partially missing end 
date (month/year or 
year only)
If the partially missing end date is the same as that for the start of IP 
treatment, it will be assumed to have ended on-treatment.
If the partially missing end date is the same as that for the end of IP 
treatment, it will be assumed to have ended post-treatment. 
If the partially missing end date is after the end of IP treatment, it will be 
assumed to have ended December 31st if only year is present and assumed to 
have ended the last day of the respective month if year and month are present.


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7.3
Appendix C: Adverse events of special interest 
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.
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.
Guillain-Barre syndrome
Guillain-Barre syndrome will be defined using an SMQ.
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.
Hypersensitivity reactions 
Hypersensitivity reactions will be defined using a narrow SMQ excel file according to 
Integrated Summary of Safety (ISS) reporting.
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.
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.


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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”.
Malignancy
Malignancy will be defined on the basis of an SMQ.
Opportunistic infections
Opportunistic infections will be defined using a pre-specified list of preferred terms (AZ 
defined SMQ).
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”).


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