A Multicenter, Randomized, Open-label, Parallel Group, Functionality, and Performance Study of an Accessorized Pre-filled Syringe and Autoinjector With Home-administered Subcutaneous Tezepelumab in Adolescent and Adult Subjects With Severe Asthma (PATH-HOME)
Phase: PHASE3
Conditions: Asthma
Sponsor: AstraZeneca

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Clinical Study Protocol 
Drug Substance
Tezepelumab
Study Code
D5180C00011
Version
2.0
Date
03 July 2019
A Multicenter, Randomized, Open-label, Parallel-group, Functionality, and Performance Study of 
an Accessorized Pre-filled Syringe and Autoinjector with Home-administered Subcutaneous 
Tezepelumab in Adolescent and Adult Subjects with Severe Asthma (PATH-HOME)
Sponsor:  AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s):
IND number: 103031
EudraCT number: 2018-004588-30

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
Inclusion criterion #8 was updated from “One or more exacerbation that required oral 
or systemic corticosteroids in the previous year, or an exacerbation that resulted in 
inpatient hospitalization for ≥ 24 hours” to “ One or more exacerbations that required 
oral or systemic corticosteroids within 12 months prior to visit 1, or an exacerbation 
that resulted in inpatient hospitalization for ≥ 24 hours within 12 months prior to visit 
1” to clarify the language.
Section 5.2 Exclusion criteria

Exclusion criterion #4 was updated from “An acute upper or lower respiratory 
infection requiring antibiotics or antiviral medications finalized < 2 weeks before Visit 
1 or during the screening/run-in period.” to “Either an acute upper or lower respiratory 
infection requiring antibiotics or antiviral medications finalized < 2 weeks before Visit 
1 or during the screening/run-in period, or an asthma exacerbation which resolved < 2 
weeks before Visit 1 or which occurred during the screening/run-in period.” in order to 
keep the screening assessments within 2 weeks of randomization.

Exclusion criterion #6 was updated from “Current smokers or former smokers with a 
smoking history of ≥10 pack years. Former smokers with a smoking history of <10 
pack years must have stopped for at least 6 months prior to Visit 1 to be eligible.” to 
“Current smokers or former smokers with a smoking history of ≥10 pack years. 
Former smokers with a smoking history of <10 pack years must have stopped for at 
least 6 months prior to Visit 1 to be eligible.  Users of electronic cigarettes, e.g.
vaping, must have stopped for at least 6 months prior to Visit 1 to be eligible.” to 
clarify that tobacco restrictions also apply to vaping and e-cigarette products.

Added one additional exclusion criterion “Non-leukocyte depleted whole blood 
transfusion in 120 days prior to visit 1.” to keep consistency with Appendix D
Genetics.
Section 5.3.2 Alcohol, tobacco, and other

Updated from “Current smokers or subjects with smoking history ≥ 10 pack-years at 
Visit 1 are not allowed. Former smokers with a smoking history of <10 pack years 
must have stopped for at least 6 months prior to Visit 1 to be eligible. Smoking is not 
allowed throughout the course of the study. The use of e-cigarettes is also not allowed 
during the course of the study.” to “Current smokers or subjects with smoking history 
≥ 10 pack-years at Visit 1 are not allowed. Former smokers with a smoking history of 
<10 pack years must have stopped for at least 6 months prior to Visit 1 to be eligible.  
Use of electronic cigarettes, e.g. vaping, is not allowed within 6 months of Visit 1.
Smoking and vaping are not allowed throughout the course of the study." to clarify 
that tobacco restrictions also apply to vaping and e-cigarette products. 
Section 5.4 Screen failures

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
Updated from “Subjects who experience an asthma exacerbation during the 
screening/run-in period may remain in screening and proceed with study visits 14 days 
after they have completed their course of oral steroids or returned to their maintenance 
dose of oral steroids.” to “Subjects 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.” in order to keep the screening assessments 
within 2 weeks of randomization.
Section 6.2.2 Dose Administration

Updated from “The same person must administer the IP throughout the study, whether
it is the subject or caregiver. For adolescent subjects who will self-administer the IP, 
the caregiver or an adult must supervise IP administration.” to “The same person must 
administer the IP throughout the study, whether it is the subject or caregiver. The 
caregiver administering study drug must accompany the subject to all dosing visits 
after signing consent. Caregiver attendance to the EOT/IPD and Follow up visits is 
optional. For adolescent subjects who will self-administer the IP, the caregiver or an
adult must supervise IP administration.” to clarify that the caregiver attendance to the 
EOT/IPD and Follow up visits is optional.
Section 6.2.3 methods for return of used APFS/AI devices

Updated from “Instruction for Use (IFU) provided to the subject with each IP kit will 
include instructions on how to properly package the used APFS/AI device in the Bio-
bottle. Subjects will be instructed to bring the used APFS/AI device packaged in the 
Bio-bottle along with the completed administration questionnaire to the clinic during 
next center visit.” to “Instruction for Use (IFU) is provided to the subject with each IP 
kit. Subjects will be instructed on how to properly package the used APFS/AI device
in the Bio-bottle and return it along with the completed administration questionnaire to 
the clinic during next center visit.”to keep consistent.
Section 6.5 Concomitant therapy

Updated from “Prior to the date of randomization, a history of continuous treatment 
with medium or high dose ICS plus a second controller medication for at least 6 
months prior to Visit 1 should be documented in source documents and recorded in the 
eCRF.” to “Prior to the date of randomization, a history of continuous treatment with 
medium or high dose ICS for at least 6 months prior to Visit 1 plus a second controller 
medication for at least 3 months prior to Visit 1 should be documented in source 
documents and recorded in the eCRF.” to keep consistent with inclusion criterion #6.
Section 7.1 Discontinuation of study treatment

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
Removed the bullet point from “Note that discontinuation from study treatment is 
NOT the same thing as a complete withdrawal from the study. The subject is at any 
time free to discontinue treatment, or to discontinue from the study without prejudice 
to further treatment”.

Added “Subjects or subjects with caregivers who are unable or unwilling to administer 
investigational product (IP) at Week 8 (Visit 4)” to clarify that subjects/caregivers 
unwilling to administer IP is a discontinuation criterion.

Updated from “Development of any study specific criteria for discontinuation, 
including any malignancy” to “Development of any study specific criteria for 
discontinuation, including any malignancy except subjects who develop basal cell 
carcinoma or localized squamous cell carcinoma of the skin, provided the malignancy 
is excised and determined to have clean margins” for clarity.
Section 7.1.1 Procedures for discontinuation of study treatment

Updated from “All subjects who prematurely discontinue IP should return to the study 
centre and complete the procedures described in the Premature IP Discontinuation 
(IPD) visit after 4 weeks (± 3 days) and the procedures for the Follow-up visits after 
10 weeks (± 3 days) and 16 weeks (± 3 days) of the last IP administration.” to “All 
subjects who prematurely discontinue IP and who do not withdraw their consent from 
the study, should return to the study centre and complete the procedures described in 
the Premature IP Discontinuation (IPD) visit after 4 weeks (± 3 days) and the 
procedures for the Follow-up visits after 10 weeks (± 3 days) and 16 weeks (± 3 days) 
of the last IP administration.” to clarify the language.
Section 8.1.4.1 General requirements

Updated from “If possible, subjects should withhold their usual maintenance therapies 
on the day(s) when lung function testing is being performed as below” to “Subjects 
should withhold their usual maintenance therapies on the day(s) when lung function 
testing is being performed as below” to clarify the language.
Section 8.2.1.1 Pregnancy test

Updated from “Serum ß-human chorionic gonadotropin (ß-HCG) – the test will be 
mandatory at enrolment (Visit 1) and at EOT visit, for women of child-bearing 
potential (WOCBP).” to “Serum ß-human chorionic gonadotropin (ß-HCG) – the test 
will be mandatory at enrolment (Visit 1) and if any positive urine test result, for 
women of child-bearing potential (WOCBP).” to keep consistent with Section 1.1 
Schedule of Activities (SoA).
Section 8.2.4 Electrocardiograms

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Updated from “A 12-lead ECG will be taken in supine position and after the subject 
has rested for at least 15 minutes.” to “A 12-lead (or 15-lead) ECG will be taken with 
the subject in the supine position and after the subject has rested for at least 5
minutes.” to permit 15-lead ECG and clarify 5 minutes rest is sufficient to ensure 
accurate reading.
Section 8.3.1 Asthma Control Questionnaire (ACQ-6)

Updated from “Patient reported outcomes using ACQ-6 will be performed at the study 
site with paper questionnaires. Subjects will be given a paper questionnaire and be 
asked to complete and return these in accordance to the schedule provided in the 
Schedule of Activities (SoA). The Investigator/authorized delegate will check the 
questionnaires for completion to minimize missing data and record responses in the 
eCRF.” to “Patient reported outcomes using ACQ-6 will be performed at the study site 
with paper questionnaires. Subjects will be given a paper questionnaire and be asked to 
complete and return these in accordance to the schedule provided in the Schedule of 
Activities (SoA). ACQ-6 should be completed as a first procedure during the visit. The 
Investigator/authorized delegate will check the questionnaires for completion to 
minimize missing data and record responses in the eCRF.” to clarify that ACQ-6 
should be first performed during the visit.
Appendix E Actions required in cases of increases in liver biochemistry and evaluation 
of Hy’s law

Corrected a typo from “Specific guidance on managing liver abnormalities can be 
found in Section 6.1 of the Clinical Study Protocol.” to “Specific guidance on 
managing liver abnormalities can be found in Section 7.1 of the Clinical Study 
Protocol.”.
Appendix F Maintenance Therapy Equivalence Table

Removed as part of the table “Inhaled Corticosteroid in ICS/LABA combination” and 
footnote e as it is not part of GINA 2018.
Appendix I  Accessorized Prefilled Syringe Administration Questionnaire for the 
D5180C00011 Clinical Study;  Appendix J Autoinjector Administration Questionnaire 
for the D5180C00011 Clinical Study

Removed one box in the kit ID because the kit ID is comprised of 5 digits.

Added “Date and time Investigational Product (IP) is removed from the refrigerator” 
to ensure adequate documentation of IP administration.

Specified “Left and Right locators for injection in the Abdomen (belly)” to keep 
consistent with Figure 2 Suggested schema of rotation of injection sites.

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TABLE OF CONTENTS
TITLE PAGE.......................................................................................................1
VERSION HISTORY ..........................................................................................2
TABLE OF CONTENTS .....................................................................................8
PROTOCOL SUMMARY .................................................................................12
Schedule of Activities (SoA)..............................................................................12
Synopsis.............................................................................................................17
Schema ..............................................................................................................19
INTRODUCTION .............................................................................................21
Study rationale ...................................................................................................21
Background........................................................................................................21
Benefit/risk assessment ......................................................................................23
OBJECTIVES AND ENDPOINTS ....................................................................23
STUDY DESIGN...............................................................................................24
Overall design....................................................................................................24
Scientific rationale for study design....................................................................26
Justification for dose ..........................................................................................26
End of study definition.......................................................................................26
STUDY POPULATION.....................................................................................27
Inclusion criteria ................................................................................................27
Exclusion criteria ...............................................................................................29
Lifestyle restrictions...........................................................................................32
Meals and dietary restrictions.............................................................................32
Alcohol, tobacco, and other................................................................................32
Activity..............................................................................................................32
Screen failures....................................................................................................33
STUDY TREATMENTS ...................................................................................33
Treatments administered ....................................................................................34
Investigational products .....................................................................................34
Preparation/handling/storage/accountability .......................................................34
Dose Preparation................................................................................................35
Dose Administration ..........................................................................................36
Methods for return of used APFS/AI devices......................................................38
Reporting product complaints.............................................................................38

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Reporting defects ...............................................................................................38
Single Use APFS/AI device malfunction............................................................39
Measures to minimize randomization bias ..........................................................39
Treatment compliance ........................................................................................40
Concomitant therapy..........................................................................................41
Other concomitant treatment ..............................................................................43
Rescue medication .............................................................................................43
Bronchial Thermoplasty.....................................................................................43
Dose modification..............................................................................................43
Treatment after the end of the study ...................................................................43
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL...44
Discontinuation of study treatment .....................................................................44
Procedures for discontinuation of study treatment ..............................................45
Lost to follow-up................................................................................................45
Withdrawal from the study.................................................................................46
Withdrawal due to recruitment completion .........................................................46
Discontinuation or suspension of the whole study program.................................46
STUDY ASSESSMENTS AND PROCEDURES...............................................47
Efficacy assessments..........................................................................................47
Assessment of returned APFS/AI device through in vitro evaluation ..................47
Assessment of Product Complaints.....................................................................48
Assessment of historical asthma exacerbations ...................................................48
Spirometry .........................................................................................................48
General requirements .........................................................................................48
Time of day for scheduled centre visit spirometry ..............................................49
Spirometry technique .........................................................................................49
Post-BD spirometry and FEV1 reversibility assessment ......................................50
Record keeping ..................................................................................................51
Safety assessments .............................................................................................51
Clinical safety laboratory assessments................................................................52
Pregnancy Test...................................................................................................53
Serology.............................................................................................................53
Physical examinations ........................................................................................53
Vital signs..........................................................................................................54
Electrocardiograms ............................................................................................54
Weight, Height and BMI ....................................................................................54
Patient Reported Outcomes ................................................................................55
Asthma Control Questionnaire (ACQ-6) ............................................................55
Pharmacokinetics and Immunogenicity ..............................................................55
Collection of samples and drug concentration.....................................................55

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Collection of samples to measure the presence of ADAs ....................................55
Storage and destruction of pharmacokinetic/ADA samples.................................56
Pharmacodynamics ............................................................................................56
Genetics .............................................................................................................56
Optional exploratory genetic sample ..................................................................56
Storage and destruction of genetic samples.........................................................56
Collection of adverse events...............................................................................57
Method of detecting AEs and SAEs....................................................................57
Time period and frequency for collecting AE and SAE information ...................57
Follow-up of AEs and SAEs...............................................................................57
Adverse event data collection.............................................................................58
Causality collection............................................................................................58
Adverse events based on signs and symptoms ....................................................59
Adverse events based on examinations and tests.................................................59
Disease progression............................................................................................59
Adverse Events of Special Interest .....................................................................60
Hy’s law.............................................................................................................60
Safety reporting and medical management .........................................................60
Reporting of serious adverse events....................................................................60
Pregnancy ..........................................................................................................61
Maternal exposure..............................................................................................61
Paternal exposure ...............................................................................................62
Overdose............................................................................................................62
Medication error.................................................................................................62
Management of IP-related reactions ...................................................................63
STATISTICAL CONSIDERATIONS................................................................64
Statistical hypotheses .........................................................................................64
Sample size determination..................................................................................64
Populations for analyses.....................................................................................64
Statistical analyses .............................................................................................64
Efficacy analyses................................................................................................64
Safety analyses...................................................................................................65
Other analyses....................................................................................................66
Interim analyses .................................................................................................66
Data safety monitoring board (DSMB)...............................................................66
REFERENCES ..................................................................................................67
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .........................................................................................70

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LIST OF TABLES
Table 1 - Schedule of Assessments.....................................................................................12
Table 2 - Study objectives ..................................................................................................23
Table 3 - Study Treatment..................................................................................................34
Table 4 - Restricted medications ........................................................................................41
Table 5 - Prohibited medications ........................................................................................42
Table 6 - Laboratory Safety Variables ................................................................................52
LIST OF FIGURES
Figure 1
Study design..........................................................................................20
Figure 2
Suggested schema of Rotation of Injection Sites....................................37
Figure 3
Reversibility Algorithm.........................................................................51
LIST OF APPENDICES
APPENDIX A
REGULATORY, ETHICAL AND STUDY OVERSIGHT 
CONSIDERATIONS ............................................................................70
APPENDIX B
ADVERSE EVENT DEFINITIONS AND ADDITIONAL SAFETY 
INFORMATION...................................................................................75
APPENDIX C
HANDLING OF HUMAN BIOLOGICAL SAMPLES .........................79
APPENDIX D
GENETICS...........................................................................................82
APPENDIX E
ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW....................86
APPENDIX F
MAINTENANCE THERAPY EQUIVALENCE TABLE .....................92
APPENDIX G
ANAPHYLAXIS: SIGNS AND SYMPTOMS, MANAGEMENT........93
APPENDIX H
ABBREVIATIONS ..............................................................................97
APPENDIX I
ACCESSORIZED PREFILLED SYRINGE ADMINISTRATION 
QUESTIONNAIRE FOR THE D5180C00011 CLINICAL STUDY...100
APPENDIX J
AUTOINJECTOR ADMINISTRATION QUESTIONNAIRE FOR THE 
D5180C00011 CLINICAL STUDY ....................................................104

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PROTOCOL SUMMARY
For a detailed schedule of activities (SoA), please see Section 1.1 below:
Schedule of Activities (SoA)
Table 1 - Schedule of Assessments
All assessments will be done at clinic visits unless otherwise specified.
Schedule of screening, treatment, and follow-up periods 
Screening/Run-in
Randomization
Treatment
EOT
IPD
FU
FU
UNSt
Details in CSP Section 
or Appendix
Visit number
V1
V1Aa
V2
V3
V4
V5
V6
V7
V8
V9
V10
Procedure / Study week
W -2
W0
W4
W8
W12
W16
W20
W24
W30
W36
Visit window (days)b
0
V1 + 
max. 3 
days
±3
±3
±3
±3c
±3c
±3
±3
±3
±3
NA
Routine Clinical Procedures
Written informed consent
X
See Appendix A 3
Inclusion/exclusion 
criteria
X
X
X
See Section 5.1 & 5.2
Demography
X
See Section 4
Medical/surgical and 
asthma history
X
See Section 4
Weight, Height, BMI
X
See Section 8.2.5
Review of the APFS/AI 
IFU and the 
Administration 
Questionnaired
X
X
X
X
X
X
X
See Section 4.1 and 
6.2.3

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Schedule of screening, treatment, and follow-up periods 
Screening/Run-in
Randomization
Treatment
EOT
IPD
FU
FU
UNSt
Details in CSP Section 
or Appendix
Visit number
V1
V1Aa
V2
V3
V4
V5
V6
V7
V8
V9
V10
Procedure / Study week
W -2
W0
W4
W8
W12
W16
W20
W24
W30
W36
Visit window (days)b
0
V1 + 
max. 3 
days
±3
±3
±3
±3c
±3c
±3
±3
±3
±3
NA
Routine Safety Procedures
Complete physical 
examination
X
X
X
X
See Section 8.2.2
Brief physical 
examination
X
X
X
X
X
X
X
X
      See Section 8.2.2
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.2.3
12 lead (or 15 lead) 
Electrocardiogram 
X
See Section 8.2.4
Adverse Events 
(AEs/SAEs)
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.7
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
See Section 6.5
Laboratory Assessments
Serum chemistry
X
X
X
X
X
X
See Section 8.2.1
Hematology
X
X
X
X
X
X
See Section 8.2.1
Serology 
(Hepatitis B, C, HIV-1, 
HIV-2)
X
See Section 8.2.1.2
Urinalysis
X
X
X
X
X
X
See Section 8.2.1
Blood concentration 
(theophylline) e
X
See Section 6.5

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Schedule of screening, treatment, and follow-up periods 
Screening/Run-in
Randomization
Treatment
EOT
IPD
FU
FU
UNSt
Details in CSP Section 
or Appendix
Visit number
V1
V1Aa
V2
V3
V4
V5
V6
V7
V8
V9
V10
Procedure / Study week
W -2
W0
W4
W8
W12
W16
W20
W24
W30
W36
Visit window (days)b
0
V1 + 
max. 3 
days
±3
±3
±3
±3c
±3c
±3
±3
±3
±3
NA
Pregnancy test (serum 
βHCG)
X
See Section 8.2.1.1
FSHf
X
See Section 8.2.1.1
Urine pregnancy test 
(dipstick)g
X
X
X
X
X
X
X
X
X
X
See Section 8.2.1.1
At home urine pregnancy 
test before IP 
administrationg
X
X
See Section 8.2.1.1
Lung Function Assessments
Pre- and post-
bronchodilator 
spirometryh
X
X
Xi
See Section 8.1.4
Patient Reported Outcomes Assessments
ACQ-6 
X
X
X
X
X
X
X
X
X
See Section 8.3.1
Pharmacokinetic Assessments
Serum for PK
Xk
Xk
Xk
X
X
X
See Section 8.4
Serum for 
Immunogenicityj
Xk
Xk
X
X
X
See Section 8.4.2
Pharmacogenetic Sampling
Blood for DNA 
(Optional)l
X
See Section 8.6
Study Treatment Administration 

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Schedule of screening, treatment, and follow-up periods 
Screening/Run-in
Randomization
Treatment
EOT
IPD
FU
FU
UNSt
Details in CSP Section 
or Appendix
Visit number
V1
V1Aa
V2
V3
V4
V5
V6
V7
V8
V9
V10
Procedure / Study week
W -2
W0
W4
W8
W12
W16
W20
W24
W30
W36
Visit window (days)b
0
V1 + 
max. 3 
days
±3
±3
±3
±3c
±3c
±3
±3
±3
±3
NA
Randomization
X
See Section 6.3
IP Administration at site
Xm
Xn
Xo
Xo
See Section 6.2.1
At home IP 
administration 
Xo
Xo
See Section 6.2.1
Completion of 
Administration 
Questionnaire at site
Xp
Xq
Xr
Xr
See Section 4.1
At home completion of 
Administration 
Questionnaire
Xr
Xr
See Section 4.1 & 
6.2.3
Visit reminder calls
X
X
See Section 6.2.1
Return of APFS/AI and 
the Administration 
Questionnaire
X
X
See Section 6.2.3
a
Visit 1A is optional for spirometry measurement only if criteria not met at Visit 1.
b
All visits are to be scheduled from the date of Visit 2 but not from the date of previous visit except in the case of early discontinuation from IP.
c        The IP should be administered at home within a ±3-day window. The clinic visit should be done no later than 48 hours after IP administration.
d
Review of the APFS/AI IFU and the Administration Questionnaire at visit 1. Review of the APFS/AI IFU and complete the Administration Questionnaire 
at visit 2-7.
e
If not documented prior to Visit 1, to be obtained at Visit 1 for subjects who are on theophylline. 
f
FSH test done only for female subjects to confirm postmenopausal status in women <50 years who have been amenorrhoeic for >12 months.
g
For WOCBP only, a urine HCG test must be done prior to IP administration at Visits 2 (Week 0), Visit 3 (Week 4), Visit 4 (Week 8), and Visit 7 (Week 20)  
at the study center.  At-home urine pregnancy tests are to be done by WOCBP prior to IP administration at Visit 5 (Week 12) and Visit 6 (Week 16) and 
repeated by the site staff at Visits 5 and 6. In the case of a positive urine pregnancy test at home, the subject is NOT to administer IP and is to call the study 

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center. Urine pregnancy tests will also be done at the study center at the EOT Visit 8 (Week 24), Follow-up Visits 9 (Week 30) and 10 (Week 36), and IPD 
visit (if applicable).
h
Pre- and post-bronchodilator spirometry can be done at Visit 1. If not met at Visit 1, pre- and/or post-BD spirometry can be done at optional Visit 1A, OR 
Visit 2 to demonstrate reversibility.
i
Visit 2 spirometry only to be performed if criteria not met at Visit 1 or Visit 1A and if no documented historical reversibility.  
j
In the event of suspected immunologically related adverse event, an unscheduled ADA sample will be collected.
k
PK and immunogenicity samples collected on dosing visits should be collected prior to dosing. 
l
If for any reason the sample is not drawn at Visit 2, it may be taken at any visit until the last study visit (see Appendix D)
m
Study drug to be administered on site by HCP in the upper arm, thigh, or abdomen.
n
At Visit 3, the subject/caregiver has the option to administer the study drug on site under HCP supervision. 
o
At Visits 4 and 7, the subject/caregiver must administer the study drug on site under HCP supervision. At Visits 5 and 6 the subject/caregiver must 
administer the study drug at home. If self-administered by the subject, the study drug can be given in the thigh or abdomen. If administered by the 
caregiver, the sites of injection are in the arm, thigh, or abdomen. 
p
Administration questionnaire to be completed by HCP immediately after administration of IP.
q
Administration questionnaire to be completed by HCP, subject, or caregiver (whomever administered the injection) immediately after administration of IP.
r
Administration questionnaire to be completed by subject or caregiver (whomever administered the injection) immediately after administration of IP.
s
Study center to perform visit reminder call to the subject within 48 hours prior to scheduled home administration date for Visit 5 (Week 12) and Visit 6 
(Week 16).
t
At unscheduled visits, the assessment/activity listed above is only the minimum needed to be performed. Unscheduled visits may be initiated as needed, and 
assessments performed as per investigator’s judgement.
ACQ-6 Asthma Control Questionnaire; APFS Accessorized prefilled syringe; β-HCG  Beta human chorionic gonadotropin; BMI  Body-mass index; EOT  End of Treatment, FSH  
Follicle-stimulating hormone; FU  Follow Up; HCP  Health care professional; HIV  Human immunodeficiency virus; IFU  Instructions for use; IP  Investigational product; IPD  
Investigational Product Discontinuation; AI  Autoinjector; NA  Not applicable; V  Visit; WOCBP  Women of childbearing potential.

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Synopsis
International co-ordinating investigator
Dr. Sady A. Alpizar, MD
Clinical Research Trials of Florida Inc.
2713 W. Virginia Ave.
Tampa, Florida 33607
United States
Protocol Title: A Multicenter, Randomized, Open-label, Parallel-group, Functionality, and 
Performance Study of an Accessorized Pre-filled Syringe and Autoinjector with Home-
administered Subcutaneous Tezepelumab in Adolescent and Adult Subjects with Severe 
Asthma (PATH-HOME)
Short Title: Tezepelumab Home Use Study
Rationale: 
The purpose of this study is to assess the functionality and performance of the accessorized pre-
filled syringe (APFS) and autoinjector (AI) used to administer a fixed 210 mg dose of 
tezepelumab subcutaneously (SC) in the clinic and in an at-home setting.
Objectives and Endpoints
Primary objective:
Endpoint/variable:
To assess the successful administration of 
tezepelumab 210 mg SC by injection with an 
APFS or AI device in clinic and at home

Proportion of HCPs and 
subjects/caregivers who successfully 
administrated tezepelumab in clinic and 
at home with an APFS 

Proportion of HCPs and 
subjects/caregivers who successfully 
administrated tezepelumab in clinic and 
at home with an AI
Secondary objectives:
Endpoint/variable:
To assess the functionality of the APFS or 
AI devices utilized to administer 
tezepelumab in clinic and at home

Proportion of used/returned APFS 
devices that passed functional tests and 
visual inspection and showed no evidence 
of malfunction

Proportion of used/returned AI devices 
that passed functional tests and visual 
inspection and showed no evidence of 
malfunction

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Objectives and Endpoints
To assess the performance of APFS or AI 
devices used to administer tezepelumab in 
clinic and at home

Proportion of APFS devices that have 
been reported as malfunctioning (Product 
Complaints) 

Proportion of AI devices that have been 
reported as malfunctioning (Product 
Complaints)
To monitor the metrics of asthma control

Change from baseline in Asthma Control 
Questionnaire-6 (ACQ-6) score 
To assess the pharmacokinetics and 
immunogenicity of tezepelumab 
administered via APFS or AI in clinic and at 
home

Serum trough concentrations

Anti-drug antibodies (ADA)
Safety objective:
Endpoint/variable:
To assess the safety and tolerability of 
tezepelumab

Adverse events/serious adverse events

Laboratory parameters
Overall design:
This is a Phase 3, multicenter, randomized, open-label, parallel-group study designed to assess 
HCPs and subjects/caregivers reported functionality and performance of a single-use APFS and 
AI with a fixed 210 mg dose of tezepelumab administered SC in the clinic and an at-home 
setting. 
The study will consist of a screening/run-in period up to 2 weeks, a treatment period of 24 weeks 
and post-treatment follow-up period of 12 weeks. During the treatment period, one dose level of 
tezepelumab 210 mg will be administered via a single-use APFS or AI subcutaneously (SC) 
every 4 weeks (Q4W) starting at Week 0 until Week 20. IP will not be administered at Week 24. 
Study Period:
Estimated date of first subject enrolled Q2 2019.
Estimated date of last subject completed Q3 2020.
Number of Subjects:
No hypotheses will be tested statistically. Approximately 210 subjects with severe asthma will 
enter the treatment period to receive 6 SC doses (Week 0, Week 4, Week 8, Week 12, Week 16, 
and Week 20) of tezepelumab. The first 3 doses of tezepelumab will be administered in the 
clinic, the next 2 doses will be administered at home, and the last dose will be administered at the 
clinic. Approximately 20 adolescents aged ≥12 to <18 years will be included.  
Subjects will be randomized globally in a 1:1 ratio to the following groups. 

Tezepelumab 210 mg to be administered SC via APFS

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
Tezepelumab 210 mg to be administered SC via AI
It is anticipated that approximately 5% of subjects will drop out and thus it is estimated that 
approximately 100 subjects will complete the study for each device.
Treatments and treatment duration:
After initial enrolment and confirmation of entry criteria (Visit 1), subjects will proceed to a run-
in period of 2 weeks. Subjects who meet the eligibility criteria during screening and 
randomization criteria at Day 0 will be randomized to a 24-week treatment period. Follow-up 
visits will be conducted at Week 30 and Week 36. The total planned study duration is a 
maximum of 38 weeks.
Statistical methods
The primary endpoint assessing successful administrations and the secondary endpoints 
assessing the functionality and performance of the device, will be presented by visit using 
proportions and 95% confidence intervals for the proportions for each of the AI and APFS. The 
secondary endpoint, change from baseline in ACQ-6 score, will be summarized descriptively by 
device.
Safety endpoints will be analysed using the safety analysis set, with subjects assigned to the 
device they used to administer study medication. Descriptive statistics will be used to summarize 
the safety outcomes by treatment group. Laboratory data will be summarized by presenting shift 
tables and summary statistics.
Tezepelumab serum trough concentrations will be summarized using descriptive statistics at each 
visit for each device separately. The prevalence and incidence of anti-drug antibodies (ADA) 
will be reported for each device. ADA data will be summarized using descriptive statistics at 
each visit by device.
Schema
The general study design is summarised in Figure 1.

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Figure 1
Study design
Sponsor recommends home IP administration to be performed during study center working hours in case of any questions/issues
* Patient is to return used APFS or AI with completed administration questionnaire to the Study Site.
APFS - Accessorized prefilled syringe; IP - Investigational product; AI - autoinjector; SC - Subcutaneous; V - Visit

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INTRODUCTION
Study rationale
Tezepelumab is a fully human immunoglobulin G (IgG) 2λ monoclonal antibody (mAb) directed 
against TSLP and is currently being evaluated for severe asthma.
In the current global Phase 3 asthma clinical program, 210 mg of tezepelumab (or placebo) is 
administered as a single 1.91 mL subcutaneous (SC) injection (110 mg/mL) via vial (with 
disposable syringe) Q4W at the clinic. An accessorized pre-filled syringe (APFS) and auto-
injector (AI) have been developed to enable safe, effective and convenient tezepelumab 
administration by caregivers and patients in a home use environment in addition to 
administration by health care professionals (HCPs) in the clinic. The purpose of this study is to 
assess the functionality and performance of the APFS and AI used to administer a fixed 210 mg 
dose of tezepelumab SC in the clinic and an at-home setting.
Background
Biologic therapies have been shown to reduce the annualised asthma exacerbation rate (AAER) 
in severe asthma patients who are uncontrolled with medium to high dose ICS and additional 
asthma controller medications. Omalizumab provided benefit for a subgroup of patients with 
proven reactivity to an aeroallergen and elevated serum immunoglobulin E (IgE) levels who 
remain inadequately controlled with an inhaled corticosteroid (ICS) plus a long-acting beta-
agonist (LABA) (Xolair US PI 2018). Four additional biologics, mepolizumab, reslizumab, 
benralizumab and dupilumab, have recently been approved for severe asthma with an 
eosinophilic phenotype (Nucala US PI 2017;Cinqair US PI 2019; Fasenra US PI 2017; Dupixent 
US PI 2018).  Biologics targeting IL-5 and IgE are now included in international treatment 
guidelines (GINA 2018) as an add-on treatment to patients uncontrolled with ICS/LABA 
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; Fasenra US PI 2017; 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 severe asthma, independently of IgE status or eosinophil level, who are 
unable to gain complete asthma control using currently available therapies.
Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that is produced in 
responses to proinflammatory stimuli (e.g., infectious, allergic and environmental stimuli) and 
trauma. TSLP has an upstream and central role in the initiation of immune responses and can 
activate a broad range of cell types including eosinophils, mast cells, T cells, dendritic cells, 
Type 2 innate lymphoid cells and basophils (Watson and Gauvreau 2014). Classically, TSLP 
may be a critical component in the initiation and perpetuation of the T helper 2 (Th2) response 
and the resulting cascade of cytokines associated with T2 driven asthma (Kaur and Brightling 
2012). Asthma is recognized as a heterogeneous disease, though, and there are subsets of patients 
that do not exhibit T2-associated disease (Wenzel 2012). Emerging data indicates that TSLP may 
also mediate non-allergic (non-T2) inflammation (Tanaka et al. 2009, Ziegler et al. 2013).

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Tezepelumab is a fully human immunoglobulin G (IgG) 2λ monoclonal antibody (mAb) directed 
against TSLP. Tezepelumab binds to human TSLP and prevents its interaction with the TSLP 
receptor (TSLPR). Owing to the central role of TSLP as an upstream and pleiotropic cytokine in 
mediating asthma pathophysiology, anti-TSLP therapy is anticipated to have a broad impact on 
the spectrum of inflammatory responses seen in asthma.
Results of a completed inhaled allergen challenge study in 31 adult subjects with mild atopic 
asthma (Study 20101183) demonstrated that tezepelumab attenuated the late allergic response 
and the early allergic response to allergen challenge, as measured by the area-under-the-curve 
(AUC) for the percent fall in the forced expiratory volume in one second (FEV1) and the 
maximum percent fall in FEV1. Tezepelumab also attenuated the increase in fractional expired 
nitric oxide value on the post-allergen day compared with the pre-allergen day. Multiple doses of 
700 mg IV tezepelumab demonstrated an acceptable safety profile in subjects with mild atopic 
asthma. No subjects developed anti-drug antibodies (ADA) after receiving tezepelumab 
(Gauvreau et al. 2014). Based upon these data, the MedImmune/AstraZeneca conducted a 
randomized, double-blind, placebo-controlled, dose range finding study in asthmatics who were 
inadequately controlled with medium or high dose ICS/LABA with or without other controller 
medications.
Study CD-RI-MEDI9929-1146 was a Phase 2b multicenter, multinational, dose-ranging, double-
blind, randomized, parallel-arm, placebo-controlled study to evaluate the effect of 3 dose levels 
of tezepelumab on the AAER in adult subjects with inadequately controlled, severe asthma. 
Subjects were randomized in a 1:1:1:1 ratio to 1 of 3 dose levels of subcutaneous (SC) 
tezepelumab (70 mg every 4 weeks [Q4W], 210 mg Q4W, 280 mg every two weeks [Q2W]) or 
placebo (Q2W) for 52 weeks. Anomalous data at a single site was identified following 
completion of this study and due to GCP non-compliance, all data relating to 34 subjects from 
this site were excluded and the CSR revised. Consequently, a total of 550 subjects received at 
least 1 dose of tezepelumab or placebo. An AAER reduction of 62%, 71%, and 66% for the 70 
mg Q4W, 210 mg Q4W, and 280 mg Q2W tezepelumab groups, respectively, compared with 
placebo were observed in the intent-to-treat population (p<0.001). After repeated SC 
administration, mean serum trough concentration increased over time and achieved steady-state 
by week 12. Tezepelumab exhibited linear pharmacokinetics (PK) across the 3 doses. A total of 
6 (4.3%) placebo subjects and 7 (1.7%) tezepelumab subjects who had no detectable ADA at 
baseline had detectable ADA post-treatment; no subjects developed neutralizing ADA in the 
study. The results of this study did not identify safety concerns associated with tezepelumab for 
any dosing regimen. The frequencies of treatment emergent adverse events (TEAEs) were 
similar between the placebo (65.9%) and the total tezepelumab (66.0%) dose groups. A majority 
of subjects had TEAEs that were mild or moderate in severity and not related to investigational
product (IP). Few subjects had TEAEs that resulted in permanent discontinuation of IP, and at 
similar incidence between the tezepelumab (5 subjects [1.2%] overall) and placebo (1 subject 
[0.7%]) groups. Overall, tezepelumab was well-tolerated with an acceptable safety profile and no 
identified safety risks were noted (Corren et al, 2017).
A detailed description of the chemistry, pharmacology, efficacy, and safety of tezepelumab is 
provided in the Investigator’s Brochure.

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Benefit/risk assessment
In order to evaluate the clinical benefit-risk balance for tezepelumab, preclinical and clinical data 
have been taken into consideration, as well as a review of the available information for 
monoclonal antibodies that are approved for or are in development for the treatment of severe 
asthma. Benefits for tezepelumab over placebo include a clinically meaningful reduction in 
asthma exacerbations, improvement in lung function and asthma control metrics. 
Tezepelumab has been well tolerated with no identified safety risks to date in the clinical 
development program. No serious allergic reactions or anaphylactic reactions considered related 
to tezepelumab were reported in the Phase 2 program. Although TSLP suppression could 
theoretically have unanticipated immune-related side effects impairing host 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.
The benefit/risk assessment for tezepelumab in severe asthma based on the development through 
Phase 2 is favorable. The future benefit / risk assessment will largely be defined by results from 
the Phase 3 program.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of tezepelumab may be found in the Investigator’s Brochure.
OBJECTIVES AND ENDPOINTS
Table 2 - Study objectives
Objectives and Endpoints
Primary objective:
Endpoint/variable:
To assess the successful administration of 
tezepelumab 210 mg SC by injection with an 
APFS or AI device in clinic and at home

Proportion of HCPs and 
subjects/caregivers who successfully 
administrated tezepelumab in clinic and at 
home with an APFS 

Proportion of HCPs and 
subjects/caregivers who successfully 
administrated tezepelumab in clinic and at 
home with an AI
Secondary objectives:
Endpoint/variable:

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Objectives and Endpoints
To assess the functionality of the APFS or 
AI devices utilized to administer 
tezepelumab in clinic and at home

Proportion of used/returned APFS devices 
that passed functional tests and visual 
inspection and showed no evidence of 
malfunction

Proportion of used/returned AI devices 
that passed functional tests and visual 
inspection and showed no evidence of
malfunction 
To assess the performance of APFS or AI 
devices used to administer tezepelumab in 
clinic and at home

Proportion of APFS devices that have 
been reported as malfunctioning (Product 
Complaints) 

Proportion of AI devices that have been 
reported as malfunctioning (Product 
Complaints)
To monitor the metrics of asthma control

Change from baseline in Asthma Control 
Questionnaire-6 (ACQ-6) score 
To assess the pharmacokinetics and 
immunogenicity of tezepelumab 
administered via APFS or AI in clinic and at 
home

Serum trough concentrations

Anti-drug antibodies (ADA) 
Safety objective:
Endpoint/variable:
To assess the safety and tolerability of 
tezepelumab

Adverse events/serious adverse events

Laboratory parameters
STUDY DESIGN
Overall design
For an overview of the study design see Section 1.3, Figure 1. For details on treatments given 
during the study, see Section 6.1.  
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives and 
Endpoints.  
This is a Phase 3, multicenter, randomized, open-label, parallel-group study designed to assess 
the performance of a single-use APFS and AI with a fixed 210 mg dose of tezepelumab 
administered SC in the clinic and an at-home setting.

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Approximately 210 subjects with severe asthma will enter the treatment period to receive 6 SC 
doses (Week 0, Week 4, Week 8, Week 12, Week 16, and Week 20) of tezepelumab.  The first 3 
doses of tezepelumab will be administered in the clinic, the next 2 doses will be administered at 
home, and the last dose at the clinic. Approximately 20 adolescents aged ≥12 to <18 years will 
be included as subjects. 
As part of the informed consenting process, the APFS and AI Instructions For Use (IFU) and 
administration questionnaire (see Appendix I and Appendix J) will be reviewed. Following a 2-
week screening period, eligible subjects will receive 4 SC doses of tezepelumab 210 mg at the 
clinic (Week 0, Week 4, Week 8 and Week 20) and 2 SC doses of tezepelumab 210 mg at home 
(Week 12 and Week 16). At Week 0, the HCP will administer the study drug. At Week 4, the 
subject or caregiver will have the option of administering the study drug under HCP supervision 
to ensure they understand the procedure and are capable of doing so. At Week 8, the subject or 
caregiver will have to perform the injection, again under HCP supervision. Subjects or subjects 
with caregivers who are unable or unwilling to administer investigational product (IP) at Week 8 
(Visit 4) will be discontinued from the study.
At Week 12 and Week 16, tezepelumab will be self-administered by the subject or administered 
by the caregiver at home on weekdays when the physician office or clinic is open. The subject or 
caregiver will be given the IFU to refer for home administrations. After each of these 
administrations, the subject will return for a scheduled on-site visit within 48 hours. For 
adolescent subjects who will self-administer the IP, the caregiver or an adult must supervise IP 
administration.  For adult subjects who will self-administer the IP, an adult must be present for 
IP administration.  
The final dose of tezepelumab (Week 20) will be self-administered by the subject or 
administered by the caregiver at the clinic under HCP supervision in order to evaluate 
administration technique.
When IP is administered in the clinic at Week 0, Week 4, Week 8, and Week 20, the person 
administering the dose will fill out an administration questionnaire designed to indicate if the 
dose was successfully administered. The site is to subsequently return the used devices and 
completed questionnaires to the Sponsor for evaluation.
When IP is administered at home (Week 12 and Week 16), whether the subject is self-
administering, or the caregiver is administering to the subject, the person administering the dose 
will fill out an administration questionnaire designed to indicate whether the dose was 
successfully administered. Both the completed questionnaire and the used device are to be 
returned to the site during each of the on-site visits scheduled within 48 hours of the home 
administration of IP (Week 12 and Week 16). The site is to subsequently return the used devices 
and completed questionnaires to the Sponsor for evaluation. 
The same person must administer the IP at Weeks 4 (if administered by subject/caregiver), 8, 12, 
16, and 20, whether it is the subject or caregiver. The caregiver must accompany the subject to 
all dosing visits after signing consent. Caregiver attendance to the EOT/IPD and Follow up visits 
is optional.

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Section 6.5 (Table 4 and Table 5) provides a list of medication restrictions and prohibitions to be 
followed throughout the conduct of the clinical trial. In cases of asthma worsening/exacerbation 
(see Section 6.5), subjects should be evaluated at the study center when feasible. 
Scientific rationale for study design
This is a multicenter, open-label trial designed to confirm the successful use and gain relevant 
information on the HCPs and subjects/caregivers use of the AI and APFS devices with 
tezepelumab both in the clinic and an at-home setting. The study design provides for HCP 
administration at Week 0, followed by HCP or optional subject/caregiver administration at Week 
4. Subject/caregiver administration will take place at Week 8 and Week 20 in the clinic and at 
Week 12 and Week 16 at home. The design and duration of the study is intended to allow 
adequate time for HCP and subject/caregiver familiarity with the devices, provide oversight by 
site staff while in the clinic, and establish suitability of subject/caregiver use at home.
Justification for dose
A 210 mg Q4W dosing regimen was selected for the Phase 3 studies based on efficacy data and 
an exposure-response analysis from the Phase 2b Study CD-RI-MEDI9929-1146 using 
population PK/PD methodology. The population PK model of tezepelumab was developed based 
on all available data from 5 Phase 1 studies (Study 20070620, Study 20080390, Study 2010118, 
Study D5180C00003, Study D5180C00002), and 2 Phase 2 studies (Study D5240C00001 and 
Study CD-RI-MEDI9929-1146). The exposure-response analysis was based on the Phase 2b 
Study CD-RI-MEDI9929-1146.
Analysis of data from the Phase 2b study identified a statistically significant exposure-response 
against the primary efficacy endpoint of AAER and the pharmacodynamic (PD) endpoint of 
FeNO. These relationships indicate that the dose of 70 mg Q4W is a sub-optimally effective dose 
and the dose of 210 mg Q4W is optimally effective. In summary, characterization of AAER data 
from Study CD-RI-MEDI9929-1146 indicate the 210 mg Q4W dose provides improved efficacy 
over the 70 mg Q4W dose, whereas the 280 mg Q2W dose did not further reduce AAER. 
Tezepelumab was well-tolerated at all doses and the safety profile was well balanced between 
the tezepelumab and placebo groups with no evidence of a dose relationship to TEAEs in the 
adult population.
This study will use the same dose as the Phase 3 studies.
End of study definition
The end of study is defined as the last expected visit/contact of the last subject undergoing the 
study.
A subject is considered to have completed the study when he/she has completed his/her last 
scheduled visit.
See Appendix A 6 for guidelines for the dissemination of study results.

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STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Each subject should meet all the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomised to a study intervention.  Under no circumstances can 
there be exceptions to this rule. Subjects who do not meet the entry requirements are screen 
failures, refer to Section 5.4.
In this protocol, “enrolled” subjects are defined as those who sign informed consent. 
“Randomized” subjects are defined as those who undergo randomization and receive a 
randomization number.
For procedures for withdrawal of incorrectly enrolled subjects see Section 7.3.
Inclusion criteria
Subjects are eligible to be included in the study only if all the following inclusion criteria and 
none of the exclusion criteria apply:
Informed consent
1.
Provision of signed and dated written informed consent form prior to any mandatory 
study specific procedures, sampling, and analyses for subjects who are at, or over the 
age of majority (as per local law). For subjects, less than the age of majority, in 
addition to the subject providing informed assent, the subject’s legal guardian must 
also provide their informed consent.
2.
Provision of signed and dated written genetic informed consent prior to collection of 
optional sample for genetic analysis. Applicable to adult subjects only. (if applicable, 
refer to Appendix D for specific requirements for genetic sampling) 
Age
3.
Male and female subjects aged 12 to 80 years of age at the time of Visit 1.
Type of subject and disease characteristics
4.
Documented physician-diagnosed asthma for at least 12 months prior to Visit 1. 
5.
Evidence of asthma as documented by postbronchodilator (albuterol/salbutamol) 
reversibility of FEV1 ≥ 12% AND ≥200 mL (15-60 min after administration of 4 puffs 
of albuterol/salbutamol), documented either in the previous 12 months prior to V1, or 
demonstrated at V1, V1A, or at V2.
6.
Documented history of current treatment with medium- or high-dose ICS for at least 6 
months prior to Visit 1 as per GINA guideline (GINA 2018) and at least one additional 

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asthma controller medication according to standard practice of care (e.g., LABA, 
LTRA, theophylline, LAMA, cromones, etc). Use of additional asthma controller 
medications must be documented for at least 3 months prior to Visit 1.  
The ICS dose must be greater than or equal to 500 μg/day fluticasone propionate dry 
powder formulation or equivalent daily.  
7.
Morning pre-bronchodilator (pre-BD) FEV1 of >50% predicted normal at Visit 1, Visit 
1A, or Visit 2.
8.
Not well controlled asthma as documented by either: 
–
An ACQ-6 ≥1.5 at Visit 1 or Visit 2 OR
–
One or more exacerbations that required oral or systemic corticosteroids within 12 
months prior to visit 1, or an exacerbation that resulted in inpatient hospitalization 
for ≥ 24 hours within 12 months prior to visit 1
9.
Subject or caregiver must be willing and able to administer the IP. Caregiver must be 
21 years of age or older at the time of Visit 1, if applicable. 
Weight
10.
Weight of ≥40 kg at Visit 1.
Reproduction
11.
Negative serum pregnancy test for female subjects of childbearing potential at Visit 1.
12.
Females of childbearing potential who are sexually active 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 IP. Cessation of contraception after 
this point should be discussed with a responsible physician. Periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of 
contraception.  

A highly effective method of contraception is defined as one that results in a 
low failure rate (i.e., less than 1% per year) when used consistently and 
correctly. Highly effective forms of birth control include: true sexual 
abstinence, a vasectomized sexual partner, Etonogestrel (e.g. Implanon™), 
female sterilization by tubal occlusion, any effective intrauterine 
device/system (IUD/IUS), Medroxyprogesterone (e.g. Depo-Provera™) 
injections, oral contraceptive, Norelgestromin/ Ethinyl Estradiol patch (e.g. 
Evra Patch ™) or etonogestrel/ethinyl estradiol vaginal ring (e.g. 
Nuvaring™).

Adolescent specific recommendations: If subject is female and has reached 
menarche or has reached Tanner stage 3 breast development (even if not 

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having reached menarche), the subject will be considered a female of child 
bearing potential.

Women not of childbearing potential are defined as women who are either 
permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or who are postmenopausal. Women will be considered 
postmenopausal if they have been amenorrheic for 12 months prior to the 
planned date of randomization without an alternative medical cause. The 
following age specific requirements apply:
o
Women < 50 years old would be considered postmenopausal if they 
have been amenorrheic for 12 months or more following cessation of 
exogenous hormonal treatment and follicle stimulating hormone (FSH) 
levels in the postmenopausal range.
o
Women ≥ 50 years old would be considered postmenopausal if they 
have been amenorrheic for 12 months or more following cessation of 
all exogenous hormonal treatment.
Inclusion criteria at randomization 
13.
For females of childbearing potential only: Have a negative urine pregnancy test prior 
to administration of the IP at day of Visit 2 (Week 0).
Exclusion criteria
Medical conditions
1.
Any clinically important pulmonary disease other than asthma (e.g. active lung 
infection, Chronic Obstructive Pulmonary Disease (COPD), bronchiectasis, pulmonary 
fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung 
cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or pulmonary 
or systemic diseases, other than asthma, that are associated with elevated peripheral 
eosinophil counts (e.g. allergic bronchopulmonary aspergillosis/mycosis, Churg-
Strauss syndrome, hypereosinophilic syndrome).
2.
Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, 
psychiatric, or major physical impairment that is not stable in the opinion of the 
Investigator and could: 

Affect the safety of the subject throughout the study

Influence the findings of the study or the interpretation

Impede the subject's ability to complete the entire duration of study

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3.
History of cancer:

Subjects who have had basal cell carcinoma or localized squamous cell carcinoma 
of the skin or in situ carcinoma of the cervix are eligible to participate in the study 
provided that curative therapy was completed at least 12 months prior to Visit 1.

Subjects who have had other malignancies are eligible provided that curative 
therapy was completed at least 5 years prior to Visit 1.
4.
Either an acute upper or lower respiratory infection requiring antibiotics or antiviral 
medications finalized < 2 weeks before Visit 1 or during the screening/run-in period,
or an asthma exacerbation which resolved < 2 weeks before Visit 1 or which occurred 
during the screening/run-in period.
5.
A helminth parasitic infection diagnosed within 6 months prior to Visit 1 that has not 
been treated with, or has failed to respond to, standard of care therapy.
6.
Current smokers or former smokers with a smoking history of ≥10 pack years. Former 
smokers with a smoking history of <10 pack years must have stopped for at least 6 
months prior to Visit 1 to be eligible. Users of electronic cigarettes, e.g. vaping, must 
have stopped for at least 6 months prior to Visit 1 to be eligible.
7.
History of chronic alcohol or drug abuse within 12 months prior to Visit 1.
8.
Tuberculosis requiring treatment within 12 months prior to Visit 1.
9.
A history of known immunodeficiency disorder, including a positive human 
immunodeficiency virus (HIV) test at Visit 1, or the subject taking antiretroviral 
medications as determined by medical history and/or subjects verbal report.
10.
Major surgery within 8 weeks prior to Visit 1 or planned surgical procedures requiring 
general anesthesia or in-patient status for >1 day during the conduct of the study.
Prior/concomitant medication therapy
11.
Receipt of any marketed (e.g., omalizumab, mepolizumab, benralizumab, reslizumab) 
or investigational biologic agent within 4 months or 5 half-lives (whichever is longer) 
prior to Visit 1 or receipt of any investigational non-biologic agent within 30 days or 5 
half-lives (whichever is longer) prior to Visit 1.
12.
Treatment with the following medications within the last 12 weeks prior to 
randomization: Systemic immunosuppressive/immunomodulating drugs (e.g. 
methotrexate, cyclosporine, etc.) except for OCS used in the treatment of 
asthma/asthma exacerbations.
13.
Receipt of long acting beta-agonists as a reliever (e.g., Symbicort Maintenance and 
Reliever Treatment) within 15 days prior to Visit 1.

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14.
Receipt of the T2 cytokine inhibitor suplatast tosilate within 15 days 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 Visit 2 (Week 0) and 
during the study, including the follow-up period. 

Receipt of inactive/killed vaccinations (e.g., inactive influenza) is allowed 
provided they are not administered within 5 days before/after any tezepelumab 
administration.
17.
Subjects who have been treated with bronchial thermoplasty in the 24 months prior to 
Visit 1.
18.
Initiation of new allergen immunotherapy is not allowed within 2 months prior to Visit 
1. Immunotherapy initiated prior to this period or as a routine part of the subject’s 
seasonal treatment is allowed.  
Genetic Research exclusion criteria
19.
Previous allogeneic bone marrow transplant
20.
Non-leukocyte depleted whole blood transfusion in 120 days prior to visit 1.
Prior/concurrent clinical study experience
21.
Subjects with a known hypersensitivity to tezepelumab or any of the excipients of the 
product.
22.
History of anaphylaxis or documented immune complex disease (Type III 
hypersensitivity reactions) to any biologic therapy.
23.
Concurrent enrolment in another drug-related interventional clinical trial.
24.
Subject randomization in the current study or previous tezepelumab studies. 
Diagnostic assessments
25.
Any clinically significant abnormal findings in physical examination, vital signs, 
hematology, clinical chemistry, or urinalysis during screening period, which in the 
opinion of the Investigator, may put the subject at risk because of his/her participation 
in the study, or may influence the results of the study, or the subjects’ ability to 
complete entire duration of the study.
26.
Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality 
obtained during the screening/run-in period, which in the opinion of the Investigator 
may put the subject at risk or interfere with study assessments.

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27.
Evidence of active liver disease, including jaundice or aspartate transaminase, alanine 
transaminase, or alkaline phosphatase >2 times the upper limit of normal at Visit 1. 
Subjects with on-going liver disease or inexplicably elevated liver chemistry values 
should be excluded from the study.
28.
Positive hepatitis B surface antigen, or hepatitis C virus antibody serology at Visit 1, 
or a positive medical history for hepatitis B or C.  Subjects with a history of hepatitis 
B vaccination without history of hepatitis B are allowed to enroll.
Other exclusions
29.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
30.
Judgment by the investigator that the subject should not participate in the study if the 
subject is unlikely to comply with study procedures, restrictions and requirements.
31.
Pregnant, breast-feeding, or lactating women.
32.
A serum β-HCG pregnancy test must be collected for women of childbearing potential 
at Visit 1. If test result is positive, the subject should be excluded. 
Lifestyle restrictions
Subjects must abstain from donating blood and plasma from the time of informed consent and 
for 16 weeks (5 half-lives) after last dose of tezepelumab. 
Meals and dietary restrictions
Subjects should avoid eating a large meal for at least 2 hours prior to all lung function 
assessments at the center.
Alcohol, tobacco, and other
Chronic alcohol, or drug abuse within 12 months is restricted prior to Visit 1 and throughout the 
conduct of the study.
Current smokers or subjects with smoking history ≥ 10 pack-years at Visit 1 are not allowed. 
Former smokers with a smoking history of <10 pack years must have stopped for at least 6 
months prior to Visit 1 to be eligible. Use of electronic cigarettes, e.g. vaping, is not allowed 
within 6 months of Visit 1. Smoking and vaping are not allowed throughout the course of the 
study.
Activity
Subjects should avoid engaging in strenuous exertion for at least 30 minutes prior to all lung
function assessments at the center.

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Screen failures
Screen failures are defined as subjects who signed the informed consent form to participate in the 
clinical study but are not subsequently randomized. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure subjects 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 serious adverse event (SAE). 
These subjects should have the reason for study withdrawal recorded as a ‘Screen Failure’ (i.e., 
subject does not meet the required inclusion/exclusion criteria) in the eCRF. This reason for 
study withdrawal is only valid for screen failures, and not randomized subjects.
Re-screening is allowed only once under the following circumstances:
Subjects with respiratory infections requiring antibiotics or antiviral medication within 14 days 
prior to Visit 1 or during the screening/run-in period may be re-screened (exclusion criterion 4) 
14 days after recovery, (i.e., completion of the therapy).
If the reason for screen failure was transient (including but not limited to study-supplied 
equipment failure, unforeseen personal events that mandate missed screening visits), subjects 
may potentially be re-screened. These cases should be discussed with the AstraZeneca study 
physician and documented in the Investigator Study File (ISF).
Subjects 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. 
Any re-screened subject will be re-enrolled and reassigned their originally assigned enrolment 
number after signing a new Informed Consent Form (ICF), or assent form, and after all Visit 1 
assessments have been performed as listed in Table 1 (with the exception of testing for HIV1 and 
HIV2, hepatitis B and C, and FSH).
Re-screened subjects should be assigned the same subject number as for the initial screening. 
However, re-screening should be documented so that its effect on study results, if any, can be 
assessed.
Re-screening of a subject will be allowed only upon approval of the AstraZeneca Study 
Physician.
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study participant 
according to the study protocol. Study treatment in this study refers to tezepelumab.

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resolved before use of the IP. Tezepelumab must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labelled storage 
conditions with access limited to the investigator and authorized site staff. 
The IP must be kept in the original outer packaging and under conditions specified on the label 
(between 2°C to 8°C [36°F to 46°F], protected from light).
Only subjects enrolled in the study may receive and self-administer study treatment. Only 
authorized site staff may supply or administer study treatment. Only authorized caregivers may 
administer study treatment to the specific subject they have consented to provide administration 
of IP. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
For at home administration, the subject will be responsible for refrigerating the product at home. 
Subjects can transport the IP in uncontrolled temperature conditions but should return it to a 
refrigerator as soon as possible. The temperature is not monitored during storage by the subject; 
standard refrigeration is sufficient to maintain appropriate temperatures while the IP is in the 
subject’s possession. The subject will be responsible for returning used APFS/AI devices and 
completed administration questionnaires to the study center.
In the following cases neither the center staff nor the subject or caregiver should use the affected 
IP and should immediately contact an AstraZeneca representative for further guidance:

Temperature excursion upon receipt or during storage at the study center

Damaged kit upon receipt

Damaged APFS/AI device
Damaged IP should be documented via IWRS (please refer to IWRS manual for further details).
Dose Preparation
Prior to each IP administration at clinic site:

Investigator/authorized delegate will assess injection site as per standards of medical care

For WOCBP, urine pregnancy test will be done; IP will be administered only when the 
result of the test is negative (see Section 8.2.1.1)
Prior to each IP administration in at-home setting:

Investigator/authorized delegate will perform visit reminder call within 48 hours prior 
scheduled IP administration. The conversation should include only basic information and 
serve as a reminder to the subject about the next scheduled visit to occur within 48 hours 
after home administration.

For WOCBP, urine pregnancy test will be done; IP will be administered only when the
result of the test is negative (see Section 8.2.1.1)

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Dose Administration
The administration of all study drugs (including IPs) should be recorded in the appropriate 
sections of the Case Report Form (CRF). The IP will be administered at the study center for the 
first 3 doses, at home for the following 2 doses, and at the study center for the last dose. 
The IP will be administered by the Investigator/authorized delegate/subject/caregiver as specified 
in Table 1. If subject is not willing or not able to self-administer (or caregiver is not willing/able 
to administer) at Visit 4, subject will be discontinued from the IP.
Each subject will receive tezepelumab 210 mg (one 1.91 mL injection) administered SC Q4W 
for 6 doses in the abdomen, thigh, or upper arm by APFS or AI.
It is suggested that the site of injection of the IP be rotated such that the subject receives IP at a 
different anatomical site each time. Suggested injection site rotation sequence is presented below 
(see Figure 2). In the case when rotation of the injection site is not favourable for the subject 
and/or Investigator, the reason should be recorded in the source documents. The injection site 
must be recorded in the source documents and the eCRF at each treatment visit.
If IP is self-administered by the subject, the injection should be done in the abdomen or thigh; 
when the injection is performed by the health care professional (HCP) or caregiver the injection 
can be made in the abdomen, thigh or upper arm (upper arm reserved only for injections 
performed by HCP or caregiver). The same person must administer the IP throughout the study, 
whether it is the subject or caregiver. The caregiver administering study drug must accompany 
the subject to all dosing visits after signing consent. Caregiver attendance to the EOT/IPD and 
Follow up visits is optional. For adolescent subjects who will self-administer the IP, the 
caregiver or an adult must supervise IP administration.  For adult subjects who will self-
administer the IP, an adult must be present for IP administration.   
Further details on IP administration are provided in the Instruction for Use (IFU). Investigational 
product administration must be carried out in line with the instructions provided.

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Figure 2
Suggested schema of Rotation of Injection Sites
At Visits 2 and 3 (Weeks 0 and 4), subjects should be observed by the HCP for a minimum of 2 
hours after IP administration for the appearance of any acute drug reactions. For the remaining 
visits involving IP administration, subjects will be observed by the HCP (or adult if injection was 
done at home) for a minimum of 1 hour after IP administration for the appearance of any such 
reaction. If IP administration was performed at home, the subject should visit the study center for 
the previously scheduled center visit within 48 hours after IP administration.
If any of the following occur, the Investigator should reschedule the visit and the IP should not 
be administered until the rescheduled visit:

The subject received allergen immunotherapy injection on the same day as scheduled IP 
administration.

The subject has an intercurrent illness that, in the opinion of the Investigator, may 
compromise the safety of the subject in the study (e.g., viral illnesses)

The subject is febrile (≥ 38°C; ≥ 100.4°F) within 72 hours prior to IP administration.
The subject and caregiver, if applicable, should be informed about these conditions and reminded 
prior to at-home administration. In case of any doubts before at-home administration, subject 
should contact study center.
If the subject reports an injection site reaction, the Investigator or qualified designee will
complete the AE eCRF page and an additional eCRF questions about the injection site reaction.

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Methods for return of used APFS/AI devices
Study sites will be shipped an appropriate number of Bio-bottles (hard plastic, wide-mouth 
bottles approved for containing and shipping biohazardous and/or sharps materials). Subjects 
who are given IP to administer at home will also be given one Bio-bottle for each of the two 
doses to be administered at home. The Bio-bottle will be given at the time the IP is provided to 
the subject.
Instruction for Use (IFU) is provided with each IP kit. Subjects will be instructed on how to 
properly package the used APFS/AI device in the Bio-bottle and return it along with the 
completed administration questionnaire to the clinic during next center visit.
The completed administration questionnaire and the Bio-bottle containing the used APFS/AI will 
be returned to the Sponsor by the clinical site following the APFS/AI Return Working 
Instruction document provided to the study sites. Authorized site staff participating in the study 
will receive training prior to study start.
Reporting product complaints
Any defects with the IP must be reported immediately to the Site Monitor. All defects will be 
communicated to the Sponsor and investigated further with the AstraZeneca Supply Chain 
Group.
During the investigation of the product complaint, all IP must be stored at labelled conditions 
2°C to 8°C (36°F to 46°F), separated from other IP kits, unless otherwise instructed.
Reporting 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 container or dosing mechanism of the IP. The component 
defect may be damaged, missing, or broken. Component examples for the AI include the 
Autoinjector and the prefilled syringe housed within the autoinjector. 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 IFU.

Packaging/Labelling Issue: Defect in the packaging or labelling of the product. The 
packaging (e.g. carton, thermo-fitted tray, or tamper-evident seal) or labelling defects 
may be damaged or unreadable, or the label may be missing.

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Single Use APFS/AI device malfunction
An AI malfunction is when the AI device appears normal during verification of shipment and 
then does not work during administration, e.g., the autoinjector activated prematurely, the 
autoinjector stalled or did not expel the full volume, needle guard safety feature did not deploy or 
remain locked, glass syringe breakage, needle bent or broke upon use. 
An APFS malfunction is when the APFS appeared normal during verification of shipment and 
then does not work during administration, e.g., the safety feature activated prematurely, part of 
the device (finger flange, plunger rod, etc.) came off or broke, needle shield could not be 
removed only partial dose administered, needle guard safety feature did not activate, needle bent 
or broke upon use.
Device malfunctions should be reported using the Device Malfunction Return Form and the 
Study Monitor should be notified.
If a device malfunction is identified at the study center:

Before IP administration has started, another IP kit (replacement) should be dispensed to 
perform IP administration;

After IP administration has started and subject has been administered unknown dose of 
IP, another IP kit must not be dispensed, and subject must not be administered with 
another IP kit. The AstraZeneca study physician and study monitor should be notified.  
If a device malfunction occurs during home administration at Week 12 or Week 16, the subject 
or caregiver should contact the study site immediately. If it is determined that a replacement 
should be issued based on the same guidance for device malfunction at study center described 
above, the subject will return to the study site to obtain the replacement device. 
Site staff will be asked to send all devices back to the depot or local sponsor company according 
to local procedures. Address and attention for malfunctioning device is available in the Device 
Malfunction Return Instruction.
Measures to minimize randomization bias
The Investigator(s) will:
1. Obtain signed informed consent or assent from the potential subject, or their 
guardian/legal representative, before any study specific procedures are performed.
2. Assign the potential subject a unique enrolment number (which begins with an ‘E’) via 
the Interactive Web Response System/Interactive Voice Response System (IWRS).
3. Determine subject eligibility. 

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4. Assign the eligible subject unique randomization code via the Interactive Web Response 
System (IWRS).
5. Subjects will be allocated to receive tezepelumab 210 mg via a single-use APFS or AI 
subcutaneously (SC) in a 1:1 ratio and stratified. by age (adults/adolescents) and country. 
Randomization numbers will be grouped in blocks. If a subject withdraws from the study, 
then his/her enrolment/randomization code cannot be reused. Withdrawn subjects will not 
be replaced.
Specific information concerning the use of the IWRS will be provided in a separate manual.
Procedures for handling incorrectly enrolled or randomized subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive study medication. There can be no exceptions to this rule. Subjects 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.
Where a subject does not meet all the eligibility criteria but is randomized in error, or incorrectly 
started on treatment, the Investigator should inform the AstraZeneca study physician 
immediately, and a discussion should occur between the AstraZeneca study physician and the 
Investigator regarding whether to continue or discontinue the subject from treatment. Study 
treatment must be discontinued in all cases where continued treatment is deemed to pose a safety 
risk to the subject. In those cases where continuation of the study therapy is judged not to present 
a concern related to safety and disease management, the rationale for continuing study therapy 
must be clearly documented. Regardless of what is decided about IP, all randomized subjects 
should remain in the study and the subjects should continue to be followed up in accordance with 
defined study procedures.
Methods for assigning treatment groups
Randomization codes will be assigned strictly sequentially within each stratum as subjects 
become eligible for randomization.
The randomization code will be assigned from a randomization list prepared by a computerized 
system provided by PAREXEL Informatics on behalf of AZ (AZRand). All subjects will be 
stratified at randomization by age (adults/adolescents) and country. 
Treatment compliance
Any change from the dosing schedule or dose discontinuations should be recorded in the eCRF.
The IP Storage Manager is responsible for managing the IP from receipt by the study site until 
the destruction or return of all unused IP. The date and time of all IP administrations, as well as 
any missed doses, should be recorded in the appropriate section of the eCRF.

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Concomitant therapy
All prior biologics taken for asthma must be recorded in the eCRF. To satisfy inclusion criterion 
6, all ICS asthma medications taken in the 6 months prior to Visit 1 must be recorded in the 
eCRF along with reason for treatment. Prior to the date of randomization, a history of continuous 
treatment with medium or high dose ICS for at least 6 months prior to Visit 1 plus a second 
controller medication for at least 3 months prior to Visit 1 should be documented in source 
documents and recorded in the eCRF. 
A history of all asthma controller medications for the 6 months prior to Visit 1 until the end of 
the study should be documented in source documents and recorded in the eCRF. 
Changes to background asthma medications are discouraged throughout the duration of the 
study. Any and all changes to the subject’s background medication must be recorded in the eCRF 
and documented in source documents along with rationale for change. 
Asthma exacerbations should be treated with oral or other systemic corticosteroids according to 
standard practice. 
All other medications taken for conditions other than asthma in the 6 months prior to Visit 1 
must be recorded in the eCRF along with reason for treatment by the Investigator/authorized 
delegate at each visit (as shown in Table 1).
As theophylline has a narrow therapeutic window, please note that subjects 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, it can 
be obtained after informed consent has been given or as part of the Visit 1 procedures. The 
sample can be analyzed at the central or local lab as applicable. Investigator can use their clinical 
judgement about the therapeutic range of theophylline levels on the basis of sampling time and 
other factors that may impact the results.
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the subject is receiving at the time of enrolment or receives 
during the study must be recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
Table 4 - Restricted medications
Short-acting beta-agonists 
Regularly scheduled or prophylactic SABA use 
is discouraged from enrollment and throughout 
the study duration. PRN use is allowed if needed.

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Table 4 - Restricted medications
Short-acting anticholinergics (e.g. 
ipratropium)
Not allowed as a rescue treatment for worsening 
asthma symptoms from Visit 1, during 
screening/run-in and throughout the IP treatment 
and preferably 4 weeks after the last dose of IP. 
They may be used to manage an asthma 
exacerbation.
Additional maintenance controllers
Subjects on theophylline should have blood 
concentration levels that do not exceed the upper 
limit of therapeutic range documented prior to 
treatment with IP and documented in source 
documents. 
Inactivated/killed vaccines
Not allowed within 5 days before/after any IP 
administration.
Allergy immunotherapy
Not allowed if newly initiated within 2 months 
prior to Visit 1 or on the same day as IP 
administration.
Table 5 - Prohibited medications
Prohibited medication/class of drug:
Usage
Long-acting beta-agonists as a
reliever (e.g., Symbicort Maintenance and 
Reliever Treatment)
Not allowed 15 days prior to Visit 1, during 
screening/run-in and throughout the IP treatment 
and preferably 4 weeks after the last dose of IP.
Suplatast tosilate (T2 cytokine inhibitor) 
Not allowed within 15 days prior to Visit 1, 
during screening/run-in and throughout the IP 
treatment and preferably 4 weeks after the last 
dose of IP.
Live attenuated vaccines
Not allowed 30 days prior to the date of 
randomization, and during the study including 
the follow-up period.
Any immunomodulators or 
immunosuppressives (except for OCS used 
in the treatment of asthma/asthma 
exacerbations)
Not allowed 12 weeks prior to randomization, 
during screening/run-in and throughout the IP 
treatment and preferably 4 weeks after the last 
dose of IP.
Immunoglobulin or blood products
Not allowed 30 days prior to Visit 1, during 
screening/run-in and throughout the IP treatment 
and preferably 4 weeks after the last dose of IP.

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Table 5 - Prohibited medications
Prohibited medication/class of drug:
Usage
Any marketed (e.g., omalizumab, 
mepolizumab, reslizumab, benralizumab, 
dupilumab) or to be marketed or 
investigational biologic treatment
Not allowed 4 months or 5 half-lives (whichever 
is longer) prior to Visit 1, during screening/run-
in and throughout the IP treatment (even if the 
subject has discontinued IP) and until the follow 
up visit week 36.
Other investigational products
(including investigational use of an 
approved drug)
Not allowed 30 days or 5 half-lives (whichever is 
longer) prior to Visit 1, during screening/run-in 
and throughout the IP treatment and preferably 4 
weeks after the last dose of IP.
Herbal remedies for the treatment of 
allergic, inflammatory, or respiratory 
diseases
Not allowed 30 days prior to Visit 1, during 
screening/run-in and throughout the IP treatment 
and preferably 4 weeks after the last dose of IP.
Medications not currently licensed for use 
in the treatment of asthma, for example 
medications approved for Chronic 
Obstructive Pulmonary Disease and not part 
of current standard of care
Not allowed 30 days prior to Visit 1, during 
screening/run-in and throughout the IP treatment 
and preferably 4 weeks after the last dose of IP 
and for the duration of the study.
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the subject’s 
safety and well-being, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the eCRF.
Rescue medication
Short-acting bronchodilators (SABAs) may be used as rescue medication during the study in the 
event of a worsening of asthma symptoms. 
Bronchial Thermoplasty
Subjects should not be treated with bronchial thermoplasty during the study.
Dose modification
N/A
Treatment after the end of the study
Subjects who complete Week 36 should be given treatment as per standard of care at the 
discretion of the Investigator.

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DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
Discontinuation of study treatment 
Subjects may be discontinued from investigational product (IP) in the following situations. 
Note that discontinuation from study treatment is NOT the same thing as a complete withdrawal 
from the study. The subject is at any time free to discontinue treatment, or to discontinue from 
the study without prejudice to further treatment.

An Adverse Event

Severe non-compliance with the Clinical Study Protocol 

Subjects or subjects with caregivers who are unable or unwilling to administer investigational 
product (IP) at Week 8 (Visit 4) 

Pregnancy

Development of any study specific criteria for discontinuation, including:
o
An anaphylactic reaction to the IP requiring administration of epinephrine
o
A helminth parasitic infestation requiring hospitalization
o
An asthma-related event requiring intubation
o
Any malignancy except subjects who develop basal cell carcinoma or localized 
squamous cell carcinoma of the skin, provided the malignancy is excised and 
determined to have clean margins

Development of one or more of the following:
o
Confirmed ALT or AST increase of ≥8 x ULN
o
Confirmed ALT or AST increase of ≥5 x ULN for more than 2 weeks
o
Confirmed ALT or AST increase of ≥3 x ULN and total bilirubin of ≥2 x ULN
o
ALT or AST of ≥3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (≥5%)
See the SoA for data to be collected at the time of treatment discontinuation and follow up and 
for any further evaluations that need to be completed.

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Procedures for discontinuation of study treatment
Subjects are free to discontinue IP or withdraw from the study at any time without prejudice to 
further treatment. Discontinuing study treatment is not the same as study withdrawal. Procedures 
to follow for study withdrawal are detailed below. If the subject decides to withdraw consent, 
then the reason for this must be recorded separately in the eCRF. 
A subject that decides to discontinue IP should always be asked about the reason(s) and the 
presence of any adverse events. The reason for discontinuing treatment and the date of last IP 
administration should be recorded in the eCRF. Subjects permanently discontinuing IP 
administration should be given locally available standard of care therapy, at the discretion of the 
Investigator. However, treatment with marketed or investigational biologics is not allowed until 
week 36 even if the subject has discontinued IP. Interaction studies between tezepelumab and 
other biologics indicated for the treatment of asthma have not been conducted. For additional 
information regarding pharmacokinetic and pharmacodynamic effects of tezepelumab reference 
should be made to the Investigator brochure. 
All subjects who prematurely discontinue IP and who do not withdraw their consent from the 
study, should return to the study centre and complete the procedures described in the Premature 
IP Discontinuation (IPD) visit after 4 weeks (± 3 days) and the procedures for the Follow-up 
visits after 10 weeks (± 3 days) and 16 weeks (± 3 days) of the last IP administration. The reason 
for premature discontinuation of IP should be recorded in the eCRF. 
If a subject discontinues IP due to a study specific discontinuation criterion, this should always 
be recorded as ‘Development of study specific discontinuation criteria’ on the Disposition (DS) 
form in the eCRF. 
Lost to follow-up
A subject will be considered potentially lost to follow-up if he or she fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:
o
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule.
o
Before a subject is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the subject or next of kin by either repeated telephone calls, 
certified letter to the subject´s last known mailing address or local equivalent methods. 
These contact attempts should be documented in the subject’s medical record. 
o
Efforts to reach the subject should continue until the end of the study. Should the subject 
be unreachable at the end of the study, the subject should be considered to be lost to 

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follow-up with unknown vital status at end of study and censored at latest follow-up 
contact.
A subject is considered lost to follow-up when any of the following attempts of contact are 
failed: 3 attempts of either phone calls, faxes or emails; having sent 1 registered letter/certified 
mail; or one unsuccessful effort to check the status of the subject using publicly available 
sources, if allowed by local regulations.
Withdrawal from the study
A subject may withdraw from the study (e.g. withdraw consent), at any time (IP and 
assessments) at his/her own request, without prejudice to further treatment. 
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow-up subjects as medically indicated. A 
withdrawal visit is essential to collect as much data as possible for the subject as per EOT visit 
described in the SoA, Section 1.1.
If the subject withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent.
If a subject withdraws from the study, he/she may request destruction of any samples taken, and 
the Investigator must document this in the site study records.  
If the subject only withdraws consent for the retention of blood samples for future exploratory
use (e.g. DNA, study of markers of asthma, identifying potential new drug targets for asthma, or 
for assay development purposes), the subject will not be withdrawn from the study.
Withdrawal of consent from the study must be ascertained and documented by the Investigator 
and recorded in the eCRF as well as in the Informed Consent Form (ICF) or assent form.
Withdrawal due to recruitment completion
When the required number of subjects are randomized in the study, ongoing subjects in run-in 
will not be randomized and will be withdrawn from the study. The reason of the withdrawal 
should be documented in the source notes and eCRF. As with screen failures, no further study 
related follow-up of these subjects is required.
Discontinuation or suspension of the whole study program
If AstraZeneca decides to prematurely terminate or suspend the study, the PI, and regulatory 
authorities should receive written notification of the reasons for the premature termination or 
suspension. The PI will immediately notify the decision to the subjects and if relevant give 
appropriate medical treatment; take necessary measures and document these in the source notes.

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STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the Schedule of Activities (SoA).
The Investigator will ensure that data are recorded on the electronic Case Report Forms (eCRFs). 
The Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  
The Investigator ensures the accuracy, completeness, legibility and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement.  The Investigator will sign the completed eCRFs.  A copy of the completed eCRFs 
will be archived at the study site.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the subject should continue or discontinue study treatment.
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (SoA), is essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria.  The Investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, as applicable.  
The amount of blood collected from each subject over the duration of the study (excluding 
optional blood samples and any extra assessments that may be required) will be approximately 
84 mL and will not exceed 180 mL. Repeat or unscheduled samples may be taken for safety 
reasons or for technical issues with the samples.
Efficacy assessments 
The primary endpoint of interest is the proportion of HCPs and subjects/caregivers who 
successfully administered tezepelumab with an APFS/AI at the clinic and at home. A successful 
administration is defined as an injection completed based on a user-recorded answer of “Yes” to 
all 5 questions in the APFS/AI Questionnaire (please see Appendix I and Appendix J) and 
satisfactory in vitro evaluation (visual test + functional evaluation) of the returned devices.
Assessment of returned APFS/AI device through in vitro evaluation
In addition to the Questionnaire filled out and returned to the Sponsor with each administered 
dose, the used APFS/AI will be returned to the Sponsor for in vitro evaluation. The data 
collected in the vitro evaluation of the APFS/AI devices falls into 2 categories: 1) Visual 
inspection, and 2) Functional evaluation.
The visual inspection will assess the returned devices for any visible damage or disassembly, full 
plunger travel indicating a complete dose was expelled, and needle guard deployment. The 
functional evaluation will challenge the needle safety guard to assess whether it deployed 
correctly and continued to provide protection against accidental needle stick injuries. As 

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mentioned in Section 8.1.1, a satisfactory in vitro evaluation of the returned devices and a 
completed questionnaire with an answer of “Yes” to all 5 questions in the questionnaire will 
constitute a successful administration. Any device defects reported during the in vitro evaluation 
will result in a full product complaint investigation. 
In the event that the answers to one or more of the questions on the questionnaire indicate that 
the user was unable to complete a successful administration, an evaluation will be performed on 
the returned device. The evaluation will take into account information provided on the 
administration questionnaire. If the in vitro evaluation of the device shows no observable device 
defect, then the unsuccessful administration may be classified as a use error and not a device 
malfunction (e.g. user removes AI or APFS from the injection site before the injection is 
complete). 
Assessment of Product Complaints
Please refer to Sections 6.2.4 through to 6.2.6.
Assessment of historical asthma exacerbations
The list below defines what is acceptable documentation for historical exacerbations:
• Discharge summaries from a hospital, emergency room, or an urgent care facility indicating 
that a subject was hospitalized/treated with systemic steroids for an asthma exacerbation.
• Signed and dated notes from a referring physician, including information regarding diagnosis 
and treatment of an exacerbation with systemic steroids.
• Evidence of prescriptions for systemic steroids used during an exacerbation.
• A documented conversation that is recorded in a timely manner between the 
Investigator/nurse or nurse practitioner and a subject who is already on an OCS action plan, 
detailing the diagnosis and treatment of an asthma exacerbation.
• A documented conversation between the treating/referral physician or nurse/nurse practitioner 
certifying that a subject was treated for an exacerbation with steroids at their clinic or under 
their supervision. The dates (month/year) of the exacerbations and verbal confirmation that 
appropriate prescriptions were provided is necessary. This option should be used only if 
reasonable attempts to procure subject records have been unsuccessful.
During the study, asthma exacerbations should be treated with oral or other systemic 
corticosteroids according to standard practice.
Spirometry
General requirements
Lung function (Reversibility, FEV1 and FVC) will be performed by the Investigator or 
authorized delegate on site-supplied equipment according to American Thoracic 

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Society/European Respiratory Society (ATS/ERS) guidelines or local guidelines (Miller et al. 
2005).
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!
Subjects 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 for at least 24 hours prior to scheduled spirometry at site. 
Note: If any of the above restrictions are not met, the spirometry assessment should be 
rescheduled within the allowed visit window.
Time of day for scheduled centre visit spirometry
Spirometry testing should be done according to the Schedule of Activities (SoA). For adult 
subjects, spirometry testing must be initiated in the morning between 6:00 AM and 11:00 AM 
during the screening or re-screening period and at randomization visits (Visit 2). Spirometry 
testing can be initiated during the whole day for adolescent subjects. 
Spirometry technique

Subjects should avoid engaging in strenuous exertion for at least 30 minutes prior to 
all lung function assessments at the centre. 

Subjects should avoid eating a large meal for at least 2 hours prior to all lung function 
assessments at the centre.

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Forced expiratory maneuvers should be performed with the subject seated in an upright position. 
If this is not comfortable for the subject, standing is permitted. The same position should be used 
by the patient for each forced expiry maneuver. The head must not be tilted during maneuvers 
and the thorax should be able to move freely; hence tight clothing should be loosened. A nose-
clip should be used for the maneuver. 
The forced expiratory maneuvers (FEV1 and FVC) should start with a maximal inspiration and 
then followed by a fast and forceful expiration that should last for at least 6 seconds. It is 
important to encourage the subject to continue the expiration to be fast and forceful throughout 
the maneuver. Ensure that none of the following has occurred: coughing during the first second, 
glottis closure, or leak or obstruction of the mouthpiece (by the tongue). 
Multiple forced expiratory efforts (at least 3, but no more than 8) will be performed for each 
centre spirometry session and the 1 best effort (highest FEV1) that meet the ATS/ERS (or local 
guidelines) acceptability and reproducibility criteria will be recorded in the eCRF. The absolute 
measurement (for FEV1 and FVC), and the percentage of predicted normal value will be 
recorded. The best effort values will be based on the one with highest FEV1.
Post-BD spirometry and FEV1 reversibility assessment 
All subjects must meet inclusion criteria 5 either by having documented historical reversibility or 
by demonstrating reversibility either at Visit 1, optional Visit 1A, or Visit 2. Even if documented 
historical reversibility is available, the post-BD spirometry procedures must be performed at 
Visit 1 to categorize subjects (establish baseline characteristic) prior to randomization. The 
documented historical reversibility must be recorded in the eCRF/spirometer prior to 
randomization.  
Bronchodilatation can be induced using albuterol (90 μg metered dose), salbutamol (100 μg 
metered dose) or levalbuterol (45 μg metered dose) up to a maximum of 4 inhalations. It is 
highly recommended to use a spacer device for this procedure. The algorithm for reversibility 
testing is outlined in Figure 3.

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Clinical safety laboratory assessments
See Table 6 for the list of clinical safety laboratory tests to be performed, and the Schedule of 
Activities (SoA)for the timing and frequency. All protocol-required laboratory assessments, as 
defined in Table 6, must be conducted in accordance with the laboratory manual and the 
Schedule of Activities (SoA). 
The Investigator should assess the available results with regards to clinically relevant 
abnormalities.  The laboratory results should be signed and dated and retained at centre as source 
data for laboratory variables.  
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.7.7.
The clinical chemistry, hematology and urinalysis will be performed at a central laboratory.
Table 6 - Laboratory Safety Variables
Hematology/Hemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Hemoglobin (Hb)
S-Alkaline phosphatase (ALP)
B-Leukocyte count
S-Alanine transaminase (ALT)
B-Leukocyte differential count (absolute count)
S-Aspartate transaminase (AST)
B-Platelet count
S-Bilirubin, total
B-Hematocrit
S-Blood urea nitrogen (BUN)
B-Mean Corpuscular Volume 
S-Calcium, total
B-Red blood cell (RBC) count
S-Chloride
S-Creatinine
Urinalysis (dipstick)*
S-Creatinine kinase (CK)
U- Blood 
S-C Reactive Protein (CRP)
U-Protein 
S-Gamma-glutamyl transpeptidase (GGT)
U-Glucose 
S-Glucose
S-Phosphorus
U-Microscopy and culture as required**
S-Potassium
S-Sodium
S-Total cholesterol
S-Uric acid
*The urine dipstick test is not only limited to Blood, Protein and Glucose, but also additional test analytes as defined by central 
lab.

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**Urine samples will be analyzed locally with the urine dipstick test and sent to the central laboratory only for further 
microscopy and culture analysis only when a positive dipstick result for any parameter is observed.
NB. In case a subject shows an AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN 
please refer to Appendix E for further instructions.
Pregnancy Test
The following tests are applicable to female subjects only and will be conducted in accordance 
with the schedule provided in Section 1.1.

Serum ß-human chorionic gonadotropin (ß-HCG) – the test will be mandatory 
at enrolment (Visit 1) and if any positive urine test result, for women of child-
bearing potential (WOCBP).

FSH – the test done at enrolment (Visit 1) only, for female subjects to confirm 
postmenopausal status in women <50 years who have been amenorrheic for 
>12 months.

Urine HCG – the test will be performed for WOCBP at each treatment visit 
before IP administration using a dipstick. Positive urine test result must be 
confirmed with serum β-HCG.
Serology
Hepatitis B surface antigen, hepatitis C antibody, HIV-1 and HIV-2 antibodies will be assessed 
at enrolment (Visit 1) only.  All testing for these will be performed at a central laboratory.
Instructions for sample collection, processing, storage, and shipment will be provided in a 
separate laboratory manual provided to the sites.
Physical examinations
A complete physical examination will be performed and include an assessment of the following: 
general appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, 
eyes, nose and throat), lymph nodes, thyroid, musculoskeletal (including spine and extremities) 
and neurological systems. Brief physical examination will also be performed and include an 
assessment of the general appearance, abdomen, cardiovascular and respiratory system. For the 
brief physical examination, only, information on whether the assessment was performed or not 
will be recorded.
Physical examination (complete and brief) will be performed at timelines as specified in the 
Schedule of Activities (SoA). Investigators should pay special attention to clinical signs related 
to previous serious illnesses, as new or worsening abnormalities may qualify as adverse events, 
see Section 8.7.6 for details.

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Vital signs
Vital signs (e.g. pulse, blood pressure, respiration rate and body temperature) will be obtained in 
accordance with the Schedule of Activities (SoA). 
Vital signs will be taken prior to blood drawing, IP administration, and, if possible, usual asthma 
controller medication. 
Blood pressure and pulse measurements will be assessed in sitting position with a completely 
automated device. Manual techniques will be used only if an automated device is not available.
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
subject in a quiet setting without distractions (e.g. television, cell phones). 
Pulse rate will be obtained before blood pressure if the manual measuring technique is used.
Respiration rate will be obtained after subject has been resting for at least 5 minutes, by counting 
number of breaths (i.e., how many times the chest rises) for one minute.
Body temperature will be measured in degrees Celsius prior to IP administration, in accordance 
with local standards.
Electrocardiograms
A 12-lead (or 15-lead) ECG will be taken with the subject in the supine position and after the 
subject has rested for at least 5 minutes. The assessment should be performed prior to blood draw 
and spirometry. Measurements will be performed on site-supplied equipment.
The Investigator or authorized delegate will be responsible for the overall interpretation and 
determination of the clinical significance of any potential ECG findings. In case of any 
discrepancy between the Investigator's interpretation and that provided by the ECG machine (if 
applicable), the Investigator's interpretation will take precedence and should be noted on the 
printout and recorded in the eCRF. A copy of the ECG will be produced, quality checked and 
kept in case of further need for re-evaluation. The results of the ECG evaluation will be recorded 
in the eCRF.
Weight, Height and BMI
Weight and height will be measured in accordance with the SoA. The subject’s weight will be 
recorded in kilograms, and height will be recorded in centimetres. Weight and height 
measurements will be performed in light clothing and with shoes off. BMI will be automatically 
calculated in the eCRF.

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Patient Reported Outcomes
Asthma Control Questionnaire (ACQ-6)
Patient reported outcomes using ACQ-6 will be performed at the study site with paper 
questionnaires. Subjects will be given a paper questionnaire and be asked to complete and return 
these in accordance to the schedule provided in the Schedule of Activities (SoA). ACQ-6 should 
be completed as a first procedure during the visit. The Investigator/authorized delegate will 
check the questionnaires for completion to minimize missing data and record responses in the 
eCRF. 
The ACQ-6 captures asthma symptoms (night-time waking, symptoms on waking, activity 
limitation, shortness of breath, wheezing) and short-acting β2-agonist use. Questions are 
weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean 
ACQ-6 score is the mean of the responses. Mean scores of ≤ 0.75 indicate well-controlled 
asthma, scores between 0.75 and ≤1.5 indicate partly controlled asthma, and a score >1.5 
indicates uncontrolled asthma (Juniper et al 2006). Individual changes of at least 0.5 are 
considered to be clinically meaningful, and a decrease of at least 0.5 is the responder definition 
for ACQ-6.
Pharmacokinetics and Immunogenicity
Collection of samples and drug concentration
Serum determination of tezepelumab will be collected pre-dose according to the SoA (Section 
1.1).
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
Samples for determination of tezepelumab concentration in serum will be analyzed by a 
designated third party on behalf of AstraZeneca using a validated bioanalytical method. Details 
of the analytical method used will be described in a bioanalytical report.
Full details of the analytical method used will be described in a separate Bioanalytical Validation 
Report.
Collection of samples to measure the presence of ADAs
The presence of ADA will be assessed in serum samples according to the SoA (Section 1.1).
Samples will be measured for the presence of ADAs for tezepelumab using validated assays. 
Tiered analysis will be performed to include screening, confirmatory, and titer assay 
components, and positive-negative cut points statistically determined from drug-naïve samples 
will be employed. Samples confirmed positive for ADA will be archived for possible testing for 
neutralizing antibodies (nAb).  

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Storage and destruction of pharmacokinetic/ADA samples
Any residual back-up PK and ADA samples may be used for future exploratory biomarker 
research and retained for future use at AstraZeneca or designee for a maximum of 15 years 
following Last Subject’s Last Visit.
Pharmacokinetic and ADA samples may be disposed of or destroyed and anonymized by 
pooling.  Additional analyses may be conducted on the anonymized, pooled pharmacokinetic 
samples to further evaluate and validate the analytical method.  Any results from such analyses 
may be reported separately from the Clinical Study Report (CSR).
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
Genetics
Optional exploratory genetic sample
The blood sample for DNA isolation will be collected from subjects who have consented to 
participate in the genetic analysis component of the study. Participation is optional. Subjects who 
do not wish to participate in the genetic research may still participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the subject. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent.
See Appendix D for Information regarding genetic research. Details on processes for collection 
and shipment and destruction of these samples can be found in Appendix D or in the separate 
Laboratory Manual provided to the sites.
The results of the analyses will be reported separately from the CSR in a scientific report or 
publication.
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are important to 
maintain subject confidentiality. Samples may be stored for a maximum of 15 years or as per 
local regulations from the date of the Last Subject’s Last Visit, after which they will be 
destroyed. DNA is a finite resource that may be used up during analyses. The results of any 
further analyses will be reported either in the CSR itself or as an addendum, or separately in a 
scientific report or publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.

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Collection of adverse events
The Investigator is responsible for ensuring that all staff involved in the study are familiar with 
the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow-up AEs see 
Section 8.7.3. 
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
Time period and frequency for collecting AE and SAE information 
Adverse Events, including SAEs will be collected from time of signature of informed consent 
form throughout the treatment period and the follow-up periods. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix B. The Investigator will submit any updated SAE data to the sponsor within 24 
hours of it being available.
Investigators are not obligated to actively seek AE or SAE in former study subjects. However, if 
the Investigator learns of any SAE, including a death, at any time after a subject’s last visit and 
he/she considers the event to be reasonably related to the Study treatment or study participation, 
the Investigator must notify the sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix B. 
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs/non-serious AEs/AEs of special interest will be followed 
until resolution, stabilization, the event is otherwise explained, or the subject is lost to follow-up 
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the Investigator for as long as medically indicated, 
but without further recording in the CRF.  AstraZeneca retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.

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Adverse event data collection
The following variables will be collected for each AE;
o
AE (verbatim)
o
The date when the AE started and stopped
o
Whether the AE is serious or not
o
Investigator causality rating against the IP(s) (yes or no)
o
Action taken with regard to IP(s)
o
Select the appropriate as required: AE caused subject’s withdrawal from 
study (yes or no)
o
Outcome.
In addition, the following variables will be collected for SAEs:
o
Date AE met criteria for serious AE
o
Date Investigator became aware of serious AE
o
Reason of AE is being serious 
o
Date of hospitalization
o
Date of discharge
o
Probable cause of death
o
Date of death
o
Autopsy performed
o
Causality assessment in relation to Study procedure(s)
o
Causality assessment to other medication'
Causality collection
The Investigator will assess causal relationship between IP and each Adverse Event, and answer 
‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event 
may have been caused by the IP?’

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For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question from 
the study site staff: Have you had any health problems since the previous visit/you were last 
asked? or revealed by observation will be collected and recorded in the CRF. When collecting 
AEs, the recording of diagnoses is preferred (when possible) to recording a list of signs and 
symptoms. However, if a diagnosis is known and there are other signs or symptoms that are not 
generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately
Adverse events based on examinations and tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarized in the CSR. Deterioration as compared to baseline in protocol-mandated laboratory 
values/vital signs should therefore only be reported as AEs if they fulfil any of the SAE criteria 
or are the reason for discontinuation of treatment with the IP.
If deterioration in a laboratory value/vital sign/ECG is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result/vital sign will be considered as additional information. Wherever possible the reporting 
Investigator uses the clinical, rather than the laboratory term (e.g. 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. 
Disease progression
Asthma signs or symptoms such as wheeze, cough, chest tightness, breathlessness, etc. will be 
recorded as AEs only when:

The sign or symptom is serious according to definition, see Appendix B

The patient discontinues the study due to the sign or symptom.

The sign or symptom is new to the patient or is not consistent with the patient's pre-existing 
asthma history as judged by the Investigator. 
Asthma exacerbations should be recorded as an AE or SAE in the eCRF only if it fulfils any of 
the above criteria.

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Adverse Events of Special Interest
An adverse event of special interest (AESI) is an event of scientific and medical interest towards 
improving the understanding of the IP. An AESI may be serious or non-serious. For this study, 
AESIs include:
o
Anaphylactic reactions 
o
Immune complex disease (Type III hypersensitivity reactions)
o
Malignancy
o
Helminth infections 
o
Severe infections which are defined as:

SAEs or 

Requiring treatment with antiviral medications, intravenous antibiotics 
or medications for helminth parasitic infection or

Requiring a permanent discontinuation of study drug
o
Injection site reactions 
o
Opportunistic infections
o
Guillain Barre Syndrome
Hy’s law
Cases where a subject shows elevation in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to be 
reported as SAEs.  Please refer to Appendix E for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law.
Safety reporting and medical management
Reporting of serious adverse events
All SAEs must be reported, whether or not considered causally related to the IP, or to the study 
procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs during the study, then Investigators or other site personnel must inform the 
appropriate AstraZeneca representatives within one day e.g., immediately but no later than 24 
hours of when he or she becomes aware of it.

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The designated AstraZeneca representative will work with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1 
calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days of 
initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up will be undertaken immediately. Investigators or other site personnel will 
inform AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she becomes 
aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, an 
automated email alert is sent to the designated AstraZeneca representative(s).
If the WBDC system is not available, then the Investigator or other study site staff must report a 
SAE to the appropriate AstraZeneca representative(s) by telephone.
The AstraZeneca representative(s) will advise the Investigator/study site staff how to proceed.  
The reference document for definition of expectedness/listedness is the Investigator’s Brochure 
for the AstraZeneca IP.
For further guidance on the definition of a SAE, see Appendix B.
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if the 
pregnancy is discovered before the study subject has received any study drug. If a pregnancy is 
reported, the Investigator should inform the sponsor within 24 hours of learning of the 
pregnancy. 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
Maternal exposure
If a subject becomes pregnant during the course of the study, IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the IP under 
study may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality) should be followed up and documented even if the subject was 
discontinued from the study.

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If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
must inform the appropriate AstraZeneca representatives within 1 day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 calendar 
days for SAEs (see Section 8.8.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the paper-based 
pregnancy outcome report is used to report the outcome of the pregnancy. 
Paternal exposure 
Pregnancy of the subject’s partners will not be considered an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) should be followed up and documented for conceptions occurring from 
the date of the first administration of IP until 16 weeks (5 half-lives) after the last administration 
of IP.
Overdose
A dose in excess of 280 mg administered within a 2-week period is considered an overdose.
There is currently no specific treatment in the event of overdose of IP and possible symptoms of 
an overdose are not established.
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant AE 
modules in the CRF and on the Overdose CRF module.
An overdose without associated symptoms is only reported on the Overdose CRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives immediately,
or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 8.8.3.  
For other overdoses, reporting must occur within 30 days.
Medication error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately but 
no later than 24 hours of when he or she becomes aware of it.

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The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow-up Fatal/Life-
Threatening) or 5 (other serious initial and follow-up) calendar days if there is an SAE associated 
with the medication error (see Section 8.8.4) and within 30 days for all other medication errors.
The definition of a Medication Error can be found in Appendix B 8.
Management of IP-related reactions
Prior to the first 2 administrations, which will be performed at the study center, subjects will 
have had a pre-assessment (i.e., vital signs) prior to IP administration, and will be observed after 
IP administration for a minimum of 2 hours for the appearance of any acute drug reactions. 
Study site personnel should inform subjects that, for subsequent administrations, they should be 
observed for at least 1 hour after IP administration for the appearance of any such reactions. As 
with any medication, in case of anaphylactic reaction at home, the subject or caregiver should 
immediately contact an emergency care unit or emergency transportation as per standard medical 
practice, and contact study site personnel. 
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, and corticosteroids, as well 
as medical equipment to treat acute anaphylactic reactions, must be immediately available when 
IP is being administered at the study site.  Study site personnel must be trained to recognize and 
treat anaphylaxis (Lieberman et al. 2010). Details on anaphylaxis management are provided in 
Appendix G.
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Sampson et al. 2006). Anaphylaxis typically manifests as 1 of 3 clinical scenarios:
1.
The acute onset of a reaction (minutes to hours) with involvement of the skin, mucosal 
tissue or both and at least one of the following: a) respiratory compromise; or b) 
reduced blood pressure or symptoms of end-organ dysfunction.
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.
If an anaphylactic reaction occurs, a blood sample will be drawn from the subject as soon as 
possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge for analysis 
of serum tryptase. The sample will be tested at the local lab or central lab where applicable. In 
addition, in order to help understand the potential drug-relatedness of any acute reaction, a blood 
sample should be drawn during the event for ADA testing (if not already scheduled for this 
visit).

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STATISTICAL CONSIDERATIONS 
Statistical hypotheses
No statistical hypotheses will be tested in this study.
Sample size determination 
A total of 210 subjects will be randomized, out of which 105 will receive a dose of tezepelumab 
210 mg via APFS injection and 105 will receive the same dose administered via AI. 
Approximately 20 adolescents aged ≥12 to <18 years will be included. It is anticipated that 
approximately 5% of subjects will drop out and thus it is estimated that approximately 100 
subjects will complete the study for each device.
Populations for analyses
For purposes of analysis, the following populations are defined: 
Population
Description
Enrolled 
All subjects who sign the ICF
Full Analysis Set
All subjects randomized to study treatment who received or 
attempted to receive at least one dose of IP, irrespective of their 
protocol adherence and continued participation in the study
Pharmacokinetics Analysis 
Set 
All subjects in the full analysis set who received tezepelumab 
and from whom PK blood samples are assumed not to be 
affected by factors such as protocol deviations (e.g. disallowed 
medication or incorrect study medication received).
Safety Analysis Set
All subjects who received tezepelumab
Statistical analyses
Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan (SAP) will be developed prior to first patient enter treatment period, and any 
subsequent amendments will be documented, with final amendments (if any) finalized before 
database lock. This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints. Any deviations from this plan will be reported in the clinical study report.
All analyses will be descriptive only and no formal statistical testing will be performed.
Efficacy analyses
The efficacy endpoints will be summarized using the Full Analysis Set. To assess successful 
administration, functionality, and performance of the tezepelumab 210 mg injection via APFS 
and AI both in clinic and at home, 3 outcomes will be measured for APFS and AI devices 
separately: 

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
Primary endpoint: Proportion of HCPs and subjects/caregivers who successfully 
administer tezepelumab in clinic or at home. Successful administration is defined in 
Section 8.1. The denominator will be the number of subjects who received or attempted 
to receive an administration at each visit.

Secondary endpoint: Proportion of used/returned devices that pass functional tests and 
visual inspection and show no evidence of malfunction. The denominator will be the 
number of used and returned devices at each visit. 

Secondary endpoint: Proportion of devices that have been reported as malfunctioning 
(Product Complaints). The denominator will be the number of used and returned devices 
at each visit.
For each of these endpoints, proportions and 95% confidence intervals (CIs) will be presented by 
visit for AI and APFS separately. For the primary endpoint specifically, the HCP and the 
subject/caregivers will be assessed separately, which is achieved through the by-visit 
presentations described above.  
In addition, summaries combining visits may also be presented to assess at home use separately 
from clinic use as well as HCP use separately from subject/caregiver use. The details will be 
presented in the SAP.
For the additional secondary endpoint change from baseline in mean ACQ-6 score, the data will 
be summarized descriptively. Based on ACQ-6, subjects will also be categorized according to 
their asthma control and responder status. Number and percentage of subjects in these categories 
will be presented. 
Safety analyses
Safety variables will be summarized using Safety Analysis Set. Adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) version in force at database 
lock. The definition of on-treatment and post-treatment for adverse event analyses will be given 
in the SAP.
The number and percentage of subjects with on-treatment and post-treatment adverse events will
be tabulated separately by preferred term and system organ class. An event that occurred one or
more times during a period will contribute 1 observation to the numerator of the proportion. The
denominator of the proportion will comprise all subjects in the safety population. On-treatment
adverse events will also be summarized by intensity/severity and separately, by 
causality/relatedness (as determined by the investigator). Should a subject report the same 
preferred term/system organ class within multiple intensity/severity or causality/relatedness
categories, the subject’s worst occurrence (most severe/most related) will be tabulated. Serious
AEs, AEs leading to discontinuation from IP, and commonly occurring AEs will be summarized
in a generally similar manner. Adverse events, SAEs, AEs leading to death, and AEs leading to
study discontinuation will be summarized for each treatment group as applicable.
AEs of Special Interest (AESIs) will also be summarized descriptively by treatment group.

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Laboratory data will be summarized by presenting shift tables using normal ranges (baseline to
most extreme post-baseline value) and by presenting summary statistics of observed and change 
from baseline values (means, medians, quartiles, ranges). The incidence of clinically notable 
laboratory abnormalities will be summarized.
Other analyses 
PK variables will be summarized using Pharmacokinetics Analysis Set. Tezepelumab serum 
concentrations will be summarized using descriptive statistics at each visit for each device 
separately. No formal PK data analysis is planned due to sparse sampling and variations of 
sampling time following tezepelumab self-administrations. Observed serum concentrations of 
tezepelumab for each individual will be listed by visit to confirm tezepelumab administration. 
The prevalence and incidence of anti-drug antibodies (ADA) will be reported for each device 
using the Safety Analysis Set. ADA data will be summarized using descriptive statistics at each 
visit by device. Samples confirmed positive for ADA will be archived for possible testing for 
neutralizing antibodies (nAb). The potential effects of ADA status and ADA titer on 
pharmacokinetics of tezepelumab will be evaluated. The potential association of immunogenicity 
with efficacy and safety may be evaluated.
Interim analyses 
No interim analyses are planned in this trial.
Data safety monitoring board (DSMB)
A data safety monitoring board will not be utilized for this study.  

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REFERENCES
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Dupixent US PI 2018
Dupixent (dupilumab). Prescribing information. Regeneron Pharmaceuticals Inc, Tarrytown, 
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Fasenra US PI 2017
FASENRA (benralizumab). Prescribing information. AstraZeneca AB, Södertälje, Sweden; 
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Gauvreau G, O’Byrne P, Boulet LP, Wang Y, Cockcroft D, Bigler J, et al. Effects of an anti-
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Kaur D, Brightling C. OX40/OX40 ligand interactions in T-cell regulation and asthma. Chest. 
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der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, 
Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. Standardisation of 
spirometry. Eur Respir J. 2005 Aug;26(2):319-38.
Nucala US PI 2017
NUCALA (mepolizumab). Prescribing information. GlaxoSmithKline, Research Triangle Park, 
NC, USA;2017. Available from: URL: 
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Watson B, Gauvreau GM. Thymic stromal lymphopoietin: a central regulator of allergic asthma. 
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Wenzel 2016
Wenzel SE. Emergence of biomolecular pathways to define novel asthma phenotypes. Type-2 
immunity and beyond. Am J Respir Cell Mol Biol 2016;55:1-4.
Xolair US PI 2018
XOLAIR (omalizumab). Prescribing information. Novartis Pharmaceuticals Corporation, East 
Hanover, NJ, USA; 2018. Available from: URL: 
https://www.gene.com/download/pdf/xolair_prescribing.pdf
Ziegler et al. 2013
Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H. The biology of thymic stromal 
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SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Regulatory, ethical and study oversight considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., 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 protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects.  
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and Human 
Biological Samples.
A 2
Financial disclosure
Investigators and Sub-Investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators are 

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responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
A 3
Informed consent process
The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorized representative and answer all questions regarding the study.  
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center.  
The medical record must include a statement that written informed consent was obtained before 
the subject was enrolled in the study and the date the written consent was obtained.  The 
authorized person obtaining the informed consent must also sign the ICF.
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study.  
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.  
If subject declines to participate in any voluntary exploratory genetic research component of the 
study, there will be no penalty or loss of benefit to the subject and he/she will not be excluded 
from other aspects of the study.
If a subject’s partner becomes pregnant from the date of the first administration of IP until 16 
weeks (5 half-lives) after the last administration of IP, the partner is asked to sign the Adult 
Study Informed Consent Form for Pregnant Partners of Study Subjects and provide information 
about the pregnancy accordingly.
Subjects who are re-screened are required to sign a new ICF.
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research.  The Investigator or authorized designee will explain to each 
subject the objectives of the exploratory research.  Subjects will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period.  The subject will give a separate agreement to allow any remaining specimens to 
be used for exploratory research.  Subjects who decline to participate in this optional research 
will indicate this in the ICF.  If a subject withdraws consent to the use of donated biological 
samples, the samples will be disposed of/destroyed, and the action documented.  If samples 
already have been analyzed at the time of the request, AstraZeneca will not be obliged to destroy 
the results of this research.
A 4
Data protection

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Each subject will be assigned a unique identifier by the sponsor.  Any subject records or data sets 
transferred to the sponsor will contain only the identifier; subject names or any information 
which would make the subject identifiable will not be transferred.  
The subject must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law.  The level of disclosure must also be explained to 
the subject.  
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and letters 
to Investigators.
A 6
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical trial and/or summary of main study results may also be available on other 
websites according to the regulations of the countries in which the main study is conducted.
A 7
Data quality assurance
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g. laboratory data).  The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 

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Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the sponsor.  No records may be transferred to 
another location or party without written notification to the sponsor. 
A 8
Source documents
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected.  Source documents are filed at the Investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained.  The Investigator may need to 
request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available.
Definitions of what constitutes source data can be found in the monitoring plan.
A 9
Study and Site Closure
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

Discontinuation of further study intervention development
A 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 
multicentre studies only in their entirety and not as individual site data.  In this case, a 
coordinating Investigator will be designated by mutual agreement. Authorship will be 

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determined by mutual agreement and in line with International Committee of Medical Journal 
Editors authorship requirements.

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

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

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

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

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

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AstraZeneca ensures the organizations holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed and the action documented and 
returned to the study site.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories (https://www.iata.org/whatwedo/cargo/dgr/Documents/infectious-substance-
classification-DGR56-en.pdf). For transport purposes the classification of infectious substances 
according to risk groups was removed from the Dangerous Goods Regulations in the 46th edition 
(2005). Infectious substances are now classified either as Category A, Category B or Exempt. 
There is no direct relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to it 
occurs, is capable of causing permanent disability, life-threatening or fatal disease in otherwise 
healthy humans or animals. Category A pathogens are (e.g. Ebola, Lassa fever virus):

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are (e.g. Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2). They are assigned the following UN number and 
proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient

temperature in IATA 650 compliant packaging 
(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

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

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
Samples routinely transported by road or rail are subject to local regulations which 
require that they be packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used.

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Genetics
D 1
Use/analysis of DNA
Genetic variation may impact a subject’s response to therapy, susceptibility to, and severity and 
progression of disease.  Variable response to therapy may be due to genetic determinants that 
impact drug absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated.  Therefore, where 
local regulations and IRB/IEC allow, blood samples will be collected for DNA analysis from 
consenting subjects.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications.  Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications.  
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the subject´s DNA, i.e. the entire 
genome. 
The results of genetic analyses may be reported in the clinical study report (CSR) or in a separate 
study summary.
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on tezepelumab continues but no longer than 15
years or other period as per local requirements.
D 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All subjects will be asked to participate in this genetic research.  Participation is voluntary and if 
subject declines to participate there will be no penalty or loss of benefit.  The subject will not be 
excluded from any aspect of the main study.
Inclusion criteria

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
For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and: Provide informed consent 
for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection
Withdrawal of consent for genetic research:  
Subjects may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study.  Voluntary withdrawal will not 
prejudice further treatment.  Procedures for withdrawal are outlined in Section 7.3 of the main 
Clinical Study Protocol.
Collection of samples for genetic research
Blood samples for genetic research will be obtained from subjects at randomisation visit and 
only after the consent is signed. Although DNA is stable, early sample collection is preferred to 
avoid introducing bias through excluding subjects who may withdraw due to an adverse event 
(AE), such subjects would be important to include in any genetic analysis. If for any reason the 
sample is not drawn at Randomisation Visit, it may be taken at any visit until the last study visit. 
Only one sample should be collected per subject for genetics during the study. Samples will be 
collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are important to 
maintain subject confidentiality.  Samples will be stored for a maximum of 15 years, from the 
date of last subject last visit, after which they will be destroyed.  DNA is a finite resource that is 
used up during analyses.  Samples will be stored and used until no further analyses are possible 
or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable only by the second, unique number.  This number is used to identify the sample and 
corresponding data at the AstraZeneca genetics laboratories, or at the designated organization.  
No personal details identifying the individual will be available to any person (AstraZeneca 
employee or designated organizations working with the DNA).
The link between the subject enrolment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 

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designated organizations.  The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, and 
permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in this appendix.
Informed consent
The genetic component of this study is optional, and the subject may participate in other 
components of the main study without participating in the genetic component. To participate in 
the genetic component of the study the subject must sign and date both the consent form for the 
main study and the genetic component of the study as applicable. Copies of the signed and dated 
consent forms must be given to the subject and the original filed at the study centre. The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
subject understands that they may freely withdraw from the genetic aspect of the study at any 
time.
Subject data protection
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. Regulatory authorities may require access to the relevant files, though 
the subject’s medical information and the genetic files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples.
AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organizations or health insurance companies.  This can 
be done by placing the results in scientific databases, where they can be combined with the 
results of similar studies to learn even more about health and disease.  The researchers can only 
use this information for health-related research purposes.  Researchers may see summary results, 
but they will not be able to see individual subject data or any personal identifiers.  
Some or all of the clinical datasets from the main study may be merged with the genetic data in a 
suitable secure environment separate from the clinical database.
Statistical methods and determination of sample size

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The number of subjects that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A Statistical 
Analysis Plan may be prepared where appropriate.

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Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately report 
Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. 
Specific guidance on managing liver abnormalities can be found in Section 7.1 of the Clinical 
Study Protocol.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a subject meets 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 Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Serious Adverse Events (SAEs) and Adverse Events (AEs) according to the outcome of the 
review and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)

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AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the IMP, 
can be found to explain the combination of increases, e.g., elevated ALP indicating cholestasis, 
viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the elevations 
in transaminases and TBL must occur.
E 3
Identification of potential Hy’s Law cases
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any subject who meets any of the following identification criteria in isolation or in 
combination:

ALT ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN
Central laboratories being used:
When a subject 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 CRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the subject meets PHL criteria (see Section E 2 within this Appendix 
for definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)
E 4
Follow-up
E 4.1
Potential Hy’s Law criteria not met
If the subject does not meet PHL criteria the Investigator will:

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
Inform the AstraZeneca representative that the subject has not met PHL criteria. 

Perform follow-up on subsequent laboratory results according to the guidance provided 
in the Clinical Study Protocol.
E 4.2
Potential Hy’s Law criteria met
If the subject does meet PHL criteria the Investigator will:

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 subjects that met PHL criteria prior to starting IMP, the investigator is not required to 
submit a PHL SAE unless there is a significant change in the subject’s condition.

The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up (including any further laboratory testing) and 
the continuous review of data.
Subsequent to this contact the Investigator will:

Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated. 
Completes follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as discussed 
with the Study Physician. This includes deciding which the tests available in the Hy’s law 
lab kit should be used. 

Complete the three Liver CRF Modules as information becomes available.
E 5
Review and assessment of potential Hy’s Law cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP, to 
ensure timely analysis and reporting to health authorities within 15 calendar days from date PHL 
criteria was met.  The AstraZeneca Global Clinical Lead or equivalent and Global Safety 

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Physician will also be involved in this review together with other subject matter experts as 
appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the
appropriate CRF.

If the alternative explanation is an AE/SAE: update the previously submitted 
Potential Hy’s Law SAE and AE CRFs accordingly with the new information 
(reassessing event term; causality and seriousness criteria) following the AZ standard 
processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca 
standard processes. 
–
The ‘Medically Important’ serious criterion should be used if no other 
serious criteria apply.
–
As there is no alternative explanation for the HL case, a causality 
assessment of ‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information necessary 
to assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting.

Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met.  Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
E 6
Laboratory tests

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The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory when using a central laboratory. 
If required, additional assistance on which tests could be used to evaluate other potential causes of 
liver dysfunction consult with the Hepatic Safety Knowledge Group. Any test results need to be 
recorded.
Hy’s Law lab kit for central laboratories
Additional standard chemistry and 
coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgG anti-HBc
HBsAg
HBV DNA
IgM and IgG anti-HCV
HCV RNA*
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-
transferrin)**
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-
LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
*HCV RNA is only tested when IgG anti-HCV is positive or inconclusive
** Carbohydrate deficient transferrin (CD-transferrin) is not available in China. Study teams should amend this list 
accordingly
References
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.

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FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’

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Maintenance Therapy Equivalence Table
Estimated daily doses for inhaled corticosteroidsa
Asthma Therapy 
Total Daily Dose (μg/day)
Inhaled Corticosteroidb
Medium
High
Beclomethasone dipropionate (CFC)c
>500–1000
>1000
Beclomethasone dipropionate (HFA)d
>200–400
>400
Budesonide
>400–800
>800
Ciclesonide 
>160–320
>320
Fluticasone furoate (eg. Arnuity®)
n.a.
200
Fluticasone propionate 
>250–500
>500
Fluticasone propionate HFA
>250–500
>500
Mometasone furoate 
>220–440
>440
Triamcinolone acetonide 
>1000–2000
>2000
a
The Japanese asthma pediatric guidelines will be followed for the Japanese adolescent subject (the medium to high dose for 
Japanese adolescent subjects 15 years or younger will be ≥ 200 μg/day of FP or other ICSs of equivalent dose).
b
The ICS doses were derived from GINA 2018.
c
CFC: Chlorofluorocarbon propellant
d
HFA: hydrofluoroalkane propellant 

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

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

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
Lightheadedness

Headache

Uterine cramps

Generalized warmth
G 4
Management of Acute Anaphylaxis
Immediate intervention
1. Assessment of airway, breathing, circulation, and adequacy of mentation
2. Administer epinephrine intramuscularly every 5-15 minutes, in appropriate doses, as 
necessary, depending on the presenting signs and symptoms of anaphylaxis, to control 
signs and symptoms and prevent progression to more severe symptoms such as 
respiratory distress, hypotension, shock and unconsciousness.
Possibly appropriate, subsequent measures depending on response to epinephrine
(a)
Place subject in recumbent position and elevate lower extremities.
(b)
Establish and maintain airway.
(c)
Administer oxygen.
(d)
Establish venous access.
(e)
Normal saline IV for fluid replacement.
Specific measures to consider after epinephrine injections, where appropriate
(a)
Consider epinephrine infusion.
(b)
Consider H1 and H2 antihistamines.
(c)
Consider nebulized β2 agonist [eg. albuterol (salbutamol)] for bronchospasm 
resistant to epinephrine.
(d)
Consider systemic corticosteroids.
(e)
Consider vasopressor (e.g. dopamine).
(f)
Consider glucagon for subject taking β-blocker.

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(g)
Consider atropine for symptomatic bradycardia.
(h)
Consider transportation to an emergency department or an intensive care facility.
(i)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged 
resuscitation efforts are encouraged, if necessary.
Adapted from: Kemp SF, Lockey RF, Simons FE; World Allergy Organization Ad hoc 
Committee on Epinephrine in Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. A 
statement of the World Allergy Organization. Allergy. 2008; 63(8):1061-70.

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Abbreviations 
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or special 
term
Explanation
AAER
Annualized Asthma Exacerbation Rate
ACQ-6
Asthma Control Questionnaire 6
ADA
Anti-Drug Antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
AI
Autoinjector
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
APFS
Accessorized Pre-filled Syringe
ATS
American Thoracic Society
AST
Aspartate Aminotransferase
BD
Bronchodilator
β-HCG
Beta-Human Chorionic Gonadotropin
BUN
Blood Urea Nitrogen
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form 
CRP
C Reactive Protein
CSA
Clinical Study Agreement
CSR
Clinical Study Report
DNA
Deoxyribonucleic acid 
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ER
Emergency Room
EOT
End of Treatment 
FAS
Full Analysis Set

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Abbreviation or special 
term
Explanation
FeNO
Fractional Exhaled Nitric Oxide
FEV1
Forced Expiratory Volume in 1 second
FSH
Follicle-Stimulating Hormone
FU
Follow-Up
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transpeptidase
GINA
Global Initiative for Asthma
GMP
Good Manufacturing Practice
HCP
Health Care Professional
HIV
Human Immunodeficiency Virus
IATA
International Air Transport Association
ICH
International Conference on Harmonization
ICI
International Co-ordinating Investigator (If a study is conducted in 
several countries the International Co-ordinating Investigator is the 
Investigator coordinating the Investigators and/or activities 
internationally). 
ICF 
Informed Consent Form 
ICS
Inhaled Corticosteroids
IgE
Immunoglobulin E
IP
Investigational Product 
IPD
Investigational Product Discontinuation
IRB
Institutional Review Board
ISF
Investigator Study File
ITT
Intent-to-Treat
IWRS
Interactive Web Response System
LABA
Long-Acting β2-Agonist
LAMA
Long-Acting Muscarinic Antagonists
LRTI
Low Respiratory Tract Infection

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Abbreviation or special 
term
Explanation
LTRA
Leukotriene Receptor Antagonists
LSLV
Last Subject Last Visit
MAb
Monoclonal Antibody
MedDRA
Medical Dictionary for Regulatory Activities
nAB
Neutralizing Antibodies
OCS
Oral Corticosteroids
PD
Pharmacodynamic
PI
Principal Investigator 
PK
Pharmacokinetic(s)
PT
Preferred Term
Q4W
Every 4 Weeks
SABA
Short-Acting β2-Agonist
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SC
Subcutaneous
SoA
Schedule of Activities/Assessments
SOC
System Organ Class
SDV
Source Data Verification
TSLP
Thymic Stromal Lymphopoietin
ULN
Upper Limit of Normal
UNS
Unscheduled
WBDC
Web Based Data Capture
WOCBP
Women of Childbearing Potential

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Accessorized Prefilled Syringe Administration Questionnaire
for the D5180C00011 Clinical Study
1. TO BE FILLED OUT BY CLINICAL STUDY STAFF WHEN
SUPPLYING IP TO SUBJECT OR CAREGIVER
Center Number:
E-Code:
E
Kit ID (found on carton label, digits only):
2. TO BE FILLED OUT BY SUBJECT OR CAREGIVER (OR HEALTH 
CARE PROFESSIONAL AT WEEK 0 AND WEEK 4 IF ADMINISTERED 
BY HCP) AT TIME OF INJECTION
Date and time Investigational Product (IP) is removed from the refrigerator:
(YYYY/MM/DD)
/
/
(HH:MM) (24-hour clock)
:
  

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Date and time of injection:
(YYYY/MM/DD)
/
/
(HH:MM) (24-hour clock)
:
Kit ID (found on carton label, digits only):
At which location was the injection administered (Mark one)
Study site/Clinic
Home
Person giving the injection (Mark one):
Health Care Professional/Designee
Subject (self-injection)
Caregiver
Where on the body the subject was injected (Mark one):
Left Abdomen (belly)                 Right Abdomen (belly)
Left Thigh
Right Thigh 
Left Upper Arm
Right Upper Arm
Other (please specify):

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Was the device stored in the refrigerator? (Mark one):
Yes              No
If No, please specify:
                                                           
The following questions should be answered immediately after the injection by the person who
gave the injection to the subject. For example, if the subject gave himself or herself the
injection, the subject would answer the following questions. Adult caregivers should review 
all responses for accuracy if an adolescent subject self-administers the injection. If the
injection was given to the subject by a caregiver, the caregiver would answer the following
questions. For week 0 (and potentially week 4), the HCP who gave the injection will 
complete the questionnaire.
Questions
Yes      No
If answer was no, please explain
Were you able to inspect
the syringe contents?
Were you able to perform
the injection?
Were you able to fully 
depress the plunger 
during injection?
Were you able to 
administer the full dose?
Were you able to
activate the needle 
safety guard?
Date and time the questionnaire is completed by the person giving the injection:

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(YYYY/MM/DD)
/
/
(HH:MM) (24-hour clock)
:

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Autoinjector Administration Questionnaire for the 
D5180C00011 Clinical Study
1. TO BE FILLED OUT BY CLINICAL STUDY STAFF WHEN
SUPPLYING IP TO SUBJECT OR CAREGIVER
Center Number:
E-Code:
E
Kit ID (found on carton label, digits only):
2.  TO BE FILLED OUT BY SUBJECT OR CAREGIVER (OR HEALTH 
CARE PROFESSIONAL AT WEEK 0 AND WEEK 4 IF ADMINISTERED 
BY HCP) AT TIME OF INJECTION
Date and time Investigational Product (IP) is removed from the refrigerator:
(YYYY/MM/DD)
/
/
(HH:MM) (24-hour clock)
:
Date and time of injection:

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(YYYY/MM/DD)
/
/
(HH:MM) (24-hour clock)
:
Kit ID (found on carton label, digits only):
At which location was the injection administered (Mark one)
Study site/Clinic
Home
Person giving the injection (Mark one):
Health Care Professional/Designee
Subject (self-injection)
Caregiver
Where on the body the subject was injected (mark one)
Left Abdomen (belly)                 Right Abdomen (belly)
Left Thigh
Right Thigh 
Left Upper Arm
Right Upper Arm
Other (please specify):
Was the device stored in the refrigerator? (Mark one):

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Yes              No
If No, please specify:
The following questions should be answered immediately after the injection by the person who
gave the injection to the subject. For example, if the subject gave himself or herself the
injection, the subject would answer the following questions. Adult caregivers should review 
all responses for accuracy if an adolescent subject self-administers the injection. If the
injection was given to the subject by a caregiver, the caregiver would answer the following
questions. For week 0 (and potentially week 4), the HCP who gave the injection will 
complete the questionnaire.
Questions
Yes      No
If answer was no, please explain
Were you able to inspect
the liquid through the
Autoinjector viewing
window?
Were you able to perform
the injection?
Were you able to hold the
Autoinjector in place
until the injection was
completed?
Did the yellow needle
guard slide down to cover
the needle after removal
from skin?
Were you able to see the
yellow plunger in the
viewing window after
injection?
Date and time the questionnaire is completed by the person giving the injection:
(YYYY/MM/DD)

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/
/
(HH:MM) (24-hour clock)
:

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d5180c00011-csp-v2
Document Title:
D5180C00011 Clinical Study Protocol version 2
Document ID:
Doc ID-003916438
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
05-Jul-2019 12:37 UTC
Content Approval
03-Jul-2019 21:23 UTC
Content Approval
04-Jul-2019 18:04 UTC
Content Approval
04-Jul-2019 01:28 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD
PPD
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