A Regional, Multicentre, Randomized, Double-Blind, Placebo Controlled, Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Adults With Severe Uncontrolled Asthma
Phase: PHASE3
Conditions: Asthma
Sponsor: AstraZeneca

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Clinical Study Protocol   
Study Intervention 
Tezepelumab 
Study Code 
D5180C00021 
Version 
7.0 
Date 
21Sep2023 
A Regional, Multicentre, Randomized, Double-Blind, Placebo Controlled, 
Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of 
Tezepelumab in Adults with Severe Uncontrolled Asthma (DIRECTION)  
Sponsor Name: AstraZeneca AB 
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden 
Regulatory Agency Identifier Number(s):  
CFDA CTP No.: 2018L02852 
 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 
Protocol Number: Version 7.0, 21Sep2023 
Amendment Number: 6.0 
Study Intervention: Tezepelumab 
Study Phase: Phase 3 
Short Title: Study to Evaluate Tezepelumab in Adults With Severe Uncontrolled Asthma  

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Study Physician Name and Contact Information will be provided separately 
International Co-ordinating Investigator: 
 
 
 
151 Yan Jiang Road., Guangzhou 510120, P.R. China 
PPD
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 6 
21-Sep-2023 
Amendment 5 
10-Oct-2022 
Amendment 4 
17-May-2022 
Amendment 3 
25-Aug-2021 
Amendment 2 
10-Aug-2020 
Amendment 1 
18-Feb-2019 
Original Protocol 
28-Nov-2017 
 
Amendment 6 Date - 21-Sep-2023 
 
Overall Rationale for the Amendment: 
This Clinical Study Protocol has been amended to provide clarity around the timing of study 
database locks (DBLs) and unblinding of the data.  
 
 
Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non
-substantial 
Section 4.1 Overall 
Design 
 
Section 6.3 Measures to 
Minimise Bias: 
Randomization and 
Blinding 
 
Section 9.4 Statistical 
Analyses 
Added the specification of two 
database locks (DBLs): the primary 
(after completion of the treatment 
period) and final (after completion 
of the follow-up period) DBL. 
Clarified that only the sponsor staff 
will know the study treatment 
allocation for participants after the 
primary DBL, and investigators/site 
staff/participants will remain blind 
until the final DBL.    
Provide clarification 
for the timing of 
study DBLs and 
unblinding of the 
data.  
Substantial 
Section 4.3  Justification 
for Dose 
 
Corrected study number 20101183 
To keep consistent 
wording in CSP 
Non-Substantial 
Section 8.3.10.1  
Medication Error,Drug 
Abuse and Drug Misuse 
Added definition of medication 
error 
To align with  
AstraZeneca CSP 
template version 9.0 
Non-Substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non
-substantial 
Section 9.4 Statistical 
Analyses 
• 
Added the specification of 
statistical analyses at the two 
DBLs.  
• 
Clarified the final SAP 
amendment will complete prior 
to unblinding at the primary 
DBL. 
• 
Clarified the important protocol 
deviations will be identified 
prior to unblinding at the 
primary DBL.  
• 
Clarified the AEs will be coded 
using the MedDRA version in 
force at the primary DBL    
 
Provide clarification 
for the statistical 
analyses at two 
DBLs, and the timing 
of SAP completion, 
important protocol 
deviations 
identification and 
MedDRA version for 
AE coding.  
Non-Substantial 
A 3 Informed Consent 
Process 
Removed the wording related to 
genetic research 
Error correction 
Non-Substantial 
Appendix B4  
Medication Error 
Changed IVRS/IWRS into 
IRT/RTSM  
To keep consistent 
wording in CSP 
Non-Substantial 

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TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................ 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
TABLE OF CONTENTS ...................................................................................................... 5 
1 
PROTOCOL SUMMARY ................................................................................ 10 
1.1 
Synopsis ........................................................................................................... 10 
1.2 
Schema ............................................................................................................. 13 
1.3 
Schedule of Activities ....................................................................................... 15 
2 
INTRODUCTION ............................................................................................ 25 
2.1 
Study Rationale ................................................................................................ 26 
2.2 
Background ...................................................................................................... 26 
2.3 
Benefit/Risk Assessment ................................................................................... 29 
2.3.1 
Risk Assessment ............................................................................................... 29 
2.3.2 
Benefit Assessment ........................................................................................... 33 
2.3.3 
Overall Benefit: Risk Conclusion ...................................................................... 33 
3 
OBJECTIVES AND ENDPOINTS ................................................................... 33 
4 
STUDY DESIGN ............................................................................................. 37 
4.1 
Overall Design .................................................................................................. 37 
4.2 
Scientific Rationale for Study Design ............................................................... 38 
4.3 
Justification for Dose ........................................................................................ 39 
4.4 
End of Study Definition .................................................................................... 39 
5 
STUDY POPULATION .................................................................................... 40 
5.1 
Inclusion Criteria .............................................................................................. 40 
5.2 
Exclusion Criteria ............................................................................................. 44 
5.3 
Lifestyle Considerations ................................................................................... 47 
5.3.1 
Meals and Dietary Restrictions ......................................................................... 47 
5.3.2 
Caffeine, Alcohol, and Tobacco......................................................................... 47 
5.3.3 
Activity............................................................................................................. 48 
5.4 
Screen Failures ................................................................................................. 48 
5.4.1 
Re-screening ..................................................................................................... 48 
6 
STUDY INTERVENTION ............................................................................... 49 
6.1 
Study Intervention(s) Administered ................................................................... 50 
6.1.1 
Study Interventions ........................................................................................... 50 
6.1.2 
Medical Devices ............................................................................................... 50 
6.2 
Preparation/Handling/Storage/Accountability ................................................... 51 
6.3 
Measures to Minimise Bias: Randomization and Blinding ................................ 54 
6.4 
Study Intervention Compliance ......................................................................... 56 

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6.5 
Concomitant Therapy ........................................................................................ 56 
6.5.1 
Rescue Medicine............................................................................................... 61 
6.5.2 
Other concomitant treatment ............................................................................. 61 
6.5.3 
Bronchial Thermoplasty .................................................................................... 61 
6.6 
Dose Modification ............................................................................................ 61 
6.7 
Intervention After the End of the Study ............................................................. 62 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................... 62 
7.1 
Discontinuation of Study Intervention ............................................................... 62 
7.1.1 
Procedures for discontinuation of study treatment ............................................. 63 
7.2 
Participant Withdrawal from the Study.............................................................. 64 
7.2.1 
Withdrawal due to recruitment completion ........................................................ 65 
7.2.2 
Discontinuation or suspension of the whole study program ............................... 65 
7.3 
Lost to Follow up .............................................................................................. 65 
8 
STUDY ASSESSMENTS AND PROCEDURES .............................................. 66 
8.1 
Efficacy Assessments ........................................................................................ 67 
8.1.1 
Assessment of asthma exacerbation .................................................................. 67 
8.1.2 
Spirometry ........................................................................................................ 69 
8.1.2.1 
General Requirements ....................................................................................... 69 
8.1.2.2 
Post-BD spirometry and FEV1 reversibility assessment ..................................... 70 
8.1.3 
Home PEF testing ............................................................................................. 72 
8.1.4 
FENO ............................................................................................................... 72 
8.1.5 
CompEx ........................................................................................................... 73 
8.1.6 
Patient reported outcomes ................................................................................. 73 
8.1.6.1 
Daily Diary ....................................................................................................... 74 
8.1.6.2 
Asthma Control Questionnaire (ACQ-6) ........................................................... 75 
8.1.6.3 
Standardised asthma quality of life questionnaire for 12 years and older 
(AQLQ(S)+12) ................................................................................................. 76 
8.1.6.4 
St. George’s Respiratory Questionnaire (SGRQ) ............................................... 76 
8.1.6.5 
European quality of life-5 dimensions-5 levels (EQ-5D-5L).............................. 76 
8.1.6.6 
Sino-nasal Outcome Test (SNOT-22) ................................................................ 77 
8.2 
Safety Assessments ........................................................................................... 77 
8.2.1 
Physical Examinations ...................................................................................... 77 
8.2.2 
Weight and height ............................................................................................. 78 
8.2.3 
Vital Signs ........................................................................................................ 78 
8.2.4 
Electrocardiograms ........................................................................................... 78 
8.2.5 
Clinical Safety Laboratory Assessments ............................................................ 79 
8.2.5.1 
Pregnancy Test .................................................................................................. 80 
8.2.5.2 
Maintaining the blind to the participant’s blood eosinophil, basophil and 
monocyte counts in cases of local laboratory usage ........................................... 80 
8.2.6 
Other Safety Assessments ................................................................................. 81 
8.2.6.1 
Serology ........................................................................................................... 81 
8.2.7 
COVID-19 vaccination ..................................................................................... 81 
8.3 
Adverse Events and Serious Adverse Events ..................................................... 83 

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8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ................ 83 
8.3.2 
Follow-up of AEs and SAEs ............................................................................. 83 
8.3.3 
Causality Collection .......................................................................................... 84 
8.3.4 
Adverse Events Based on Signs and Symptoms ................................................ 85 
8.3.5 
Adverse Events Based on Examinations and Tests ............................................ 85 
8.3.6 
Hy’s Law .......................................................................................................... 86 
8.3.7 
Adverse Events of Special Interest .................................................................... 86 
8.3.8 
Reporting of Serious Adverse Events ................................................................ 86 
8.3.9 
Pregnancy ......................................................................................................... 87 
8.3.9.1 
Maternal Exposure ............................................................................................ 87 
8.3.9.2 
Paternal Exposure ............................................................................................. 88 
8.3.10 
Medication Error,Drug Abuse and Drug Misuse ............................................... 88 
8.3.10.1 
Medication Error............................................................................................... 89 
8.3.10.2 
Drug Abuse ....................................................................................................... 89 
8.3.10.3 
Drug Misuse ..................................................................................................... 89 
8.3.11 
Management of IP-related toxicities .................................................................. 89 
8.3.12 
Independent Adjudication Committee (IAC) ..................................................... 90 
8.3.13 
Method of detecting AEs and SAEs .................................................................. 90 
8.4 
Overdose .......................................................................................................... 90 
8.5 
Pharmacokinetics and immunogenicity ............................................................. 91 
8.5.1 
Collection of samples and drug concentration ................................................... 91 
8.5.2 
Collection of samples to measure the immunogenicity of tezepelumab.............. 91 
8.5.3 
Storage and destruction of pharmacokinetic/immunogenicity samples .............. 91 
8.5.4 
Pharmacodynamics ........................................................................................... 92 
8.6 
Biomarkers ....................................................................................................... 92 
8.6.1 
Storage, re-use and destruction of biomarker samples ....................................... 92 
8.6.2 
Serum Immunoglobulins ................................................................................... 92 
8.6.3 
Other Study Related Biomarker Research ......................................................... 92 
8.7 
Optional Genomics Initiative Sample ................................................................ 92 
8.8 
Healthcare Resource Utilization and Health Economics .................................... 92 
9 
STATISTICAL CONSIDERATIONS ................................................................ 93 
9.1 
Statistical Hypotheses ....................................................................................... 93 
9.2 
Sample Size Determination ............................................................................... 94 
9.3 
Populations for Analyses ................................................................................... 94 
9.4 
Statistical Analyses ........................................................................................... 95 
9.4.1 
General Considerations ..................................................................................... 96 
9.4.1.1 
Multiple testing procedures ............................................................................... 96 
9.4.1.2 
Definition of baseline ........................................................................................ 98 
9.4.2 
Efficacy ............................................................................................................ 98 
9.4.2.1 
Primary Endpoint(s) .......................................................................................... 98 
9.4.2.2 
Secondary Endpoint(s) ...................................................................................... 99 
9.4.2.3 
Analysis of other efficacy endpoints ............................................................... 101 
9.4.3 
Safety ............................................................................................................. 101 
9.4.4 
Other Analyses................................................................................................ 102 

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9.5 
Interim Analyses ............................................................................................. 102 
9.6 
Data Monitoring Committee ........................................................................... 102 
10 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS ...................................................................................... 102 
11 
REFERENCES ............................................................................................... 155 
 
LIST OF FIGURES 
Figure 1 
Study Design ........................................................................................... 13 
Figure 2 
Suggested Schema of Rotation of Injection Sites...................................... 53 
Figure 3 
Reversibility algorithm ............................................................................ 71 
Figure 4 
COVID-19 Vaccination Between IP dosing ............................................. 82 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments - Screening ....................................................... 15 
Table 2 
Schedule of Assessments-Randomization, treatment period (Week 0 - 
Week 52), follow-up (Week 58 - Week 64) .............................................. 19 
Table 3 
Risk Assessment ...................................................................................... 30 
Table 4                Objectives and Endpoints ......................................................................... 33 
Table 5 
Study Interventions .................................................................................. 50 
Table 6 
Study Intervention Dose Preparation ........................................................ 52 
Table 7 
Restricted medications ............................................................................. 58 
Table 8 
Prohibited medications............................................................................. 60 
Table 9 
Laboratory safety variables ...................................................................... 79 
Table 10 
COVID-19 Vaccination guidance ............................................................ 81 
 
LIST OF APPENDIX 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations ....................... 103 
Appendix B 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 109 
Appendix C 
Handling of Human Biological Samples ................................................ 115 
Appendix D 
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law .......................................................................... 117 
Appendix E 
Anaphylaxis: signs and symptoms, management .................................... 123 

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Appendix F 
Maintenance Therapy Equivalence Table ............................................... 126 
Appendix G 
Abbreviations ........................................................................................ 127 
Appendix H 
Changes Related to COVID-19 Pandemic .............................................. 131 
Appendix I 
Clarification on the post-BD spirometry at Visit 2 or Visit 2a ................ 134 
Appendix J 
Protocol Amendment History................................................................. 135 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A Regional, Multicentre, Randomized, Double-Blind, Placebo Controlled, 
Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Adults 
with Severe Uncontrolled Asthma (DIRECTION) 
Short Title: Study to Evaluate Tezepelumab in Adults With Severe Uncontrolled Asthma 
Rationale: The purpose of this regional study is to confirm the efficacy and safety of 210 mg 
dose of tezepelumab administered subcutaneously (SC) every 4 weeks (Q4W) in adults (18 to 
80 years of age inclusive) with a history of asthma exacerbations and severe, uncontrolled 
asthma receiving medium or high dose inhaled corticosteroid (ICS) plus at least one additional 
asthma controller medication with or without oral corticosteroids (OCS). The study will 
evaluate the incidence of asthma exacerbations and other efficacy parameters such as lung 
function, asthma control and quality of life as well as a safety evaluation to further 
characterize the benefit-risk profile of the drug. 
Objectives and Endpoints 
Primary Objective 
Endpoint/variable 
• 
To assess the effect of 210 mg tezepelumab SC 
Q4W on asthma exacerbations in adult participants 
with severe uncontrolled asthma compared with 
placebo 
• 
Primary endpoint: Annualized asthma 
exacerbation rate (AAER) 
• 
Primary outcome measure: AAER ratio vs 
placebo over 52 weeks 
Key Secondary Objectives 
Endpoint/variable 
• 
To assess the effect of 210 mg tezepelumab SC 
Q4W on pulmonary function compared with 
placebo 
• 
Secondary endpoint:  change from baseline 
in pre-dose/pre-bronchodilator (Pre-BD) 
forced expiratory volume in 1 second (FEV1) 
• 
Key outcome measure: Mean difference vs 
placebo at Week 52 
• 
To assess the effect of 210 mg of tezepelumab SC 
Q4W on health status/health related quality of life 
compared with placebo 
• 
Secondary endpoint: Change from baseline 
in Standardized Asthma Quality of Life 
Questionnaire for 12 years and older 
(AQLQ(S)+12) total score 
• 
Key outcome measure: Mean difference vs 
placebo at Week 52 
• 
To assess the effect of 210 mg of tezepelumab SC 
Q4W on asthma control compared with placebo 
 
• 
Secondary endpoint: Change from baseline 
in Asthma Control Questionnaire-6 (ACQ-6) 
Score 
• 
Key outcome measure: Mean difference vs 
placebo at Week 52 

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• 
To assess the effect of 210 mg of tezepelumab SC 
Q4W on asthma symptoms compared with placebo 
• 
Secondary endpoint: Change from baseline 
in weekly mean daily Asthma Symptom Diary 
(ASD) score 
• 
Key outcome measure: Mean difference vs 
placebo at Week 52 
Safety Objective 
Endpoint/variable 
• 
To evaluate the safety and tolerability of 
tezepelumab 
• 
Adverse events (including serious adverse 
events [SAEs]) 
• 
Vital signs 
• 
12-lead electrocardiograms 
• 
Clinical laboratory tests (haematology, clinical 
chemistry, urinalysis) 
 
For Tertiary/Exploratory objectives and outcome measures, see Section 3 of the protocol.  
Overall Design: 
This is a regional, multicentre, randomized, double-blind, placebo controlled, parallel group, 
phase 3 study designed to evaluate the efficacy and safety of 210 mg Q4W (SC) of 
tezepelumab in adults with severe, uncontrolled asthma on medium to high-dose ICS and at 
least one additional asthma controller medication with or without OCS. 
Study Period: 
First participant enrollment Jun 2019 
Estimated date of last participant completed Q3 2024 
Disclosure Statement:  
This is a regional, multicentre, randomized, double-blind, placebo controlled, parallel group, 
phase 3 study  
Number of Participants: 
A total of 396 participants will be randomized in the study in a 1:1 ratio to either tezepelumab 
or placebo (198 per group), with at least 70% of the participants from China. The rest of the 
participants will come from other countries. The participants will be stratified by region 
(China/non-China).  
Note: “Enrolled” means a participant's, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 
but are not randomly assigned in the study, are considered “screen failures”, unless otherwise 
specified by the protocol.  

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Intervention Groups and Duration: 
The study will consist of a screening/run in period between 5-6 weeks, a treatment period of 
52 weeks and a post-treatment follow-up period of 12 weeks. Participants will be randomized 
in a 1:1 ratio to either 210 mg of tezepelumab or matching placebo both administered Q4W 
SC. During the treatment period, IP will be administered from Day 0 until week 48. No IP will 
be administered at week 52. Participants will complete a 12 week off-treatment follow-up 
period for assessments including safety and anti-drug antibodies.  Participants who 
discontinue IP during the study will be encouraged to undergo appropriate study 
visits/procedures for the full 52 weeks period (see section 7.1.1). 
Please note: If participants are unable to come to the site during the COVID-19 
pandemic, please refer to Appendix H for further guidance. 
 
Data Monitoring Committee: No 
Independent Adjudication Committee: 
An independent adjudication committee is constituted to provide an external independent 
assessment of blinded data during the Phase 3 trials to confirm the diagnosis and causality of 
MACE events (defined in the IAC charter), serious cardiac events, deaths, as well as the 
diagnosis of malignancies that occur from randomization until the end of the follow up period. 
 
The IAC also assess whether cases of ER or urgent care visits and hospitalizations, that occur 
from randomisation until the end of the follow-up period, are due to a worsening of asthma. 
Details on the adjudication process, including scope of adjudication and the committee 
membership, is included in the Adjudication Committee Charter/Manual of Operations. 
Statistical Methods: 
Approximately 396 participants (198 per treatment group) are needed for this study to achieve 
approximately 90% power based on the primary objective (primary endpoint AAER is defined 
in section 3). The study is powered based on the primary endpoint (AAER) only and not for 
the subsequent multiple testing procedures of the key secondary endpoints (pre-BD FEV1, 
AQLQ(S)+12, ACQ-6 score and ASD score). 
Participants who meet the eligibility criteria will be randomized (1:1) to receive either 
tezepelumab 210 mg Q4W SC or placebo. Efficacy analyses will be performed using the full 
analysis set (FAS), which consists of all participants randomized and receiving any IP. All 
participants in the FAS will be included in the main efficacy analyses, including participants 
who discontinue IP prior to Week 52 (for which every attempt will be made to collect data 
after discontinuation of IP up until Week 52). 
A hierarchical testing strategy will be implemented to test for superiority of tezepelumab over 
placebo in each of the primary and key secondary endpoints, whilst controlling the overall 
Type 1 error rate at 0.05 (2-sided), as follows: 

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1.3 
Schedule of Activities 
Table 1 
Schedule of Assessments - Screening 
 
Screening 
Run-in 
Details in CSP section or Appendix 
Visit 
1 
2a 
2ab 
Details in CSP section or Appendix 
Day  
-42 to -35a 
-28 
-25 
 
Visit window (day) 
0 
±4p 
±4p 
Procedures 
Informed consent  
X 
 
 
Section 5.1 
Inclusion /exclusion criteria 
X 
X 
X 
Section 5.1 and Section  5.2 
Demography 
X 
 
 
Section 5.1 
FENOm 
 
X 
X 
Section 8.1.4 
Clinical Lung Function Assessments  
Spirometry (pre-BD FEV1, FVC and FEV1/FVC)c 
 
Xb 
X 
Section 8.1.2 
Reversibility (post-BD FEV1, FVC and FEV1/FVC)d  
 
Xb 
 
X 
 
Section 8.1.2.2 
Home peak flow monitor training and distribution 
 
Xe  
Xe  
Section 8.1.3 
Check Home peak flow compliance and technique  
 
Compliance check throughout screening 
period   
Section 8.1.3 
Home assessment every morning and evening PEF 
 
Measurements every morning and evening  
Section 8.1.3 
Patient Reported Outcome assessments at Visit 
SNOT-22  
  
Xi  
Xi  
Section 
 8.1.6.6 
Distribute ePRO device 
 
Xf  
Xf  
Section 8.1.6 

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Screening 
Run-in 
Details in CSP section or Appendix 
Visit 
1 
2a 
2ab 
Details in CSP section or Appendix 
Day  
-42 to -35a 
-28 
-25 
 
Visit window (day) 
0 
±4p 
±4p 
eDiary device training 
 
X 
X 
Section 8.1.6 
ACQ-6g 
X 
  
 
Section 8.1.6.2  
Check compliance with PRO assessments and 
follow-up as needed to maintain compliance (every 
7 days) 
 
 Compliance check throughout screening 
period   
Section 8.1.3 
Patient Reported Outcome assessments at home 
Daily Diaryh 
 
Completed twice daily at home on eDiary 
Section 8.1.6.1 
Routine safety measurements 
Complete Physical examination 
X 
 
 
Section 8.2.1 
Vital signs 
X 
 
 
Section 8.2.3 
Weight, Height 
X 
 
 
Section 8.2.2 
12-lead ECGn  
X 
 
 
Section 8.2.4 
Adverse events (AEs/SAEs) 
X 
X 
X 
Section 8.3 
Medical and asthma history 
X 
 
 
Section 5.1 
Assessment of historical asthma exacerbations in the 
past 12 months 
X 
 
 
Section 8.1.1 
Concomitant medicationj  
X 
X 
X 
Section 6.5 
Laboratory Assessments  
Serum Chemistry 
X 
 
 
Section 8.2.4 

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Screening 
Run-in 
Details in CSP section or Appendix 
Visit 
1 
2a 
2ab 
Details in CSP section or Appendix 
Day  
-42 to -35a 
-28 
-25 
 
Visit window (day) 
0 
±4p 
±4p 
Haematology (full)o 
X 
 
 
Section 8.2.4 
 
X 
 
 
Section 8.6.2 
Pregnancy or FSH testl 
X 
 
 
Section 8.2.5.1 
Serology (Hepatitis B, C; HIV-1; HIV-2) 
X  
 
 
Section 8.2.5.1 
Urinalysis  
X 
 
 
Section 8.2.4 
a  
 
Visit 2 should occur no later than 11 days after Visit 1. 
b 
Visit 2a is an optional visit. It can be performed if Pre-BD FEV1 (inclusion criteria 7) and/or reversibility (inclusion criteria 8) is not met at Visit 2. If any one of these 
inclusion criteria is met at Visit 2, there is no need to repeat the assessment that was met at Visit 2a. 
c  
Refer to section 8.1.2.1 for appropriate medication restrictions.  
d  
 
All participants must perform Post BD spirometry assessment at Visit 2. In the absence of historical reversibility, the participant must demonstrate reversibility at either 
Visit 2 or Visit 2a. Reversibility testing should be performed as per section 8.1.2.2. Refer to Footnote b for repeating the assessment if required. 
e  
Home peak flow monitor training and distribution should take place only if the participant has met inclusion criteria 7 and 8. If only one of these criteria are met at Visit 
2, the distribution of the device should be deferred to Visit 2a, after the other criteria is also met.    
f  
The ePRO home device training and distribution should take place only after the inclusion criteria 7 and 8 are both met. If only one of these criteria are met at Visit 2, the 
distribution of the device should be deferred to Visit 2a, after the other criteria is also met. 
g  
ACQ-6 will be done at the site during the visit on the ePRO device.  
h  
Daily Diary: Asthma Symptom Diary (ASD), and items related to: Rescue medication use, Global asthma severity, Night time awakenings, Adherence to maintenance 
medication. 
i  
Visit 2 on the handheld device should only be confirmed once both inclusion criteria 7 and inclusion criteria 8 have been met at either Visit 2 or at Visit 2a as per CSP. 
ePRO assessments (SNOT-22 and practice diary) need only to be collected once, either at Visit 2 or at Visit 2a if applicable. SNOT-22 questionnaire will only be 
triggered for participants that have a medical history of current/ongoing nasal polyposis at Visit 2 or Visit 2a as applicable.  
j  
 
All ICS medications in the 12 months prior to Visit 1 must be recorded in the eCRF along with reason for treatment. To satisfy inclusion criteria #6 and #7, the history of 
continuous treatment with ICS plus second controller medication for at least 3 months prior to Visit 1 should be documented in source and recorded in the eCRF prior 
to the date of randomization. All other medications taken for conditions other than asthma in the 3 months prior to Visit 1 must be recorded in the eCRF along with 
reason for treatment. 
k  
 results will be redacted from the central laboratory reports except at Visit 1, Visit 3, and prior to IP administration and any repeat testing that is 
performed during the screening/run-in period. 
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l  
 
FSH test done only in women < 50 years who have been amenorrheic for > 12 months to confirm postmenopausal status. 
m 
 test needs to be completed prior to spirometry. 
 is to be completed at either Visit 2 or Visit 2a. 
n 
ECG to be completed prior to any blood draws. 
o  
Eosinophils, basophil and monocyte counts will be redacted from the central laboratory reports except at Visit 1, Visit 3 prior to IP administration and any repeat testing 
that is performed during the screening/run-in period 
p 
If Visit 1 is conducted more than 35 days in advance of Visit 3, the Visit 2 and Visit 2a visit window is adjusted to complement the preceding visit date (Visit 1). 
 
 
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Table 2 
Schedule of Assessments-Randomization, treatment period (Week 0 - Week 52), follow-up (Week 58 - Week 64) 
 
Rando
m-
ization 
Treatment 
EOT 
Perio
d 
IPD
m 
FU 
FU UN
Sq 
Details in 
CSP 
section or 
Appendix 
Visit 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
 
18 
19 
 
Details in 
CSP 
section or 
Appendix 
Week  
0 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
 
58 
64 
Day (visit window)  
0 
±3 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
±7 
±7 
Procedures 
Inclusion /exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 
and 5.2 
Weight   
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Section 
8.2.2 
Health care resource 
Utilization 
 
 
a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 8.8 
 at clinicj 
X 
X 
X 
 X 
X 
 X 
 
X 
 
 
X 
 
 
 
X 
X 
  
X 
X 
Section 
8.1.4 
Patient Reported Outcome Assessments at Visitn 
Check compliance with 
PRO assessments and 
follow-up with participant as 
needed 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Section 
8.1.6 
ACQ-6b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
 
Section 
8.1.6.2 
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Rando
m-
ization 
Treatment 
EOT 
Perio
d 
IPD
m 
FU 
FU UN
Sq 
Details in 
CSP 
section or 
Appendix 
Visit 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
 
18 
19 
 
Details in 
CSP 
section or 
Appendix 
Week  
0 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
 
58 
64 
Day (visit window)  
0 
±3 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
±7 
±7 
AQLQ(s) +12 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
 
Section 
8.1.6.3 
SGRQo 
X 
 
   
 
   
 
 
X  
 
 
 
 
 
 
X 
X 
 
 
 
Section 
8.1.6.4 
SNOT-22c  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
Section 
8.1.6.6 
Patient Reported Outcome Assessments at Home 
Daily Diaryd 
Completed twice daily at home on the eDiary 
 
 
 
 
 
Section 
8.1.6.1 
EQ-5D-5L 
X 
Completed every 2 weeks at home on the eDiary 
 
X 
 
 
 
Section 
8.1.6.5 
Routine safety measurements 
Complete Physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
Section 
8.2.1 
Brief physical examination   
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
Section 
8.2.1 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 
8.2.3 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X Section 8.3 
Assessment of asthma 
exacerbation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Rando
m-
ization 
Treatment 
EOT 
Perio
d 
IPD
m 
FU 
FU UN
Sq 
Details in 
CSP 
section or 
Appendix 
Visit 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
 
18 
19 
 
Details in 
CSP 
section or 
Appendix 
Week  
0 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
 
58 
64 
Day (visit window)  
0 
±3 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
±7 
±7 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X Section 6.5 
12-lead ECGe 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
Section 
8.2.4 
Laboratory Assessmentsf  
Serum Chemistry 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
X 
Section 
8.2.4 
Haematology (full)g 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
X 
Section 
8.2.4 
Urinalysis  
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
 
Section 
8.2.4 
Pregnancy testh 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Section 
8.2.5.1 
Serum for Immunogenicityp 
X 
 
  
 
  
 
 
X 
 
 
  
 
 
 
X 
X 
 
X 
 
Section 8.5 
Serum for PKp 
X 
 
  
 
  
 
 
X 
 
 
  
 
 
 
X 
X 
 
X 
 
Section 8.5 
  
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
X 
Section 
8.6.2 
Lung Function Assessments  
Spirometry (pre-BD FEV1, 
FVC and FEV1/FVC)k 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
X 
X  
X 
X 
Section 
8.1.2 
Reversibility (post-BD 
FEV1, FVC and FEV1/FVC) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
Section 
8.1.2.2 
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Rando
m-
ization 
Treatment 
EOT 
Perio
d 
IPD
m 
FU 
FU UN
Sq 
Details in 
CSP 
section or 
Appendix 
Visit 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
 
18 
19 
 
Details in 
CSP 
section or 
Appendix 
Week  
0 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
 
58 
64 
Day (visit window)  
0 
±3 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
±7 
±7 
Home peak flow compliance 
and technique check  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Section 
8.1.3 
Home assessment of PEF 
Measurements every morning and evening throughout treatment period  
  
 
 
 
Section 
8.1.3 
Study treatment administration 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.1 
Administration of IPl 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Section 6.2 
 
a           Asthma specific resource utilization (eg unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications). 
b  
ACQ-6 to be completed before AQLQ(s)+12 and SGRQ.  
c 
SNOT-22 questionnaire will only be completed during the treatment period for those participants who have completed SNOT-22 at Visit 2. 
d  
Daily Diary: Asthma Symptom Diary (ASD), and items related to: Rescue medication use, Global asthma severity, Nighttime awakenings, Adherence to maintenance 
medication.  
e 
ECG must be collected prior to any blood draws, spirometry, BD administration and IP administration 
f  
All blood sampling should be done prior to IP administration. 
g  
Eosinophils, basophil and monocyte counts will be redacted from the central laboratory reports, except at Visit 1 and Visit 3 prior to IP administration and any repeat testing 
that is performed during the screening/run-in period. 
h 
For WOCBP, urine or serum pregnancy test (HCG) will only be performed at treatment visits, prior to IP administration. 
i        Total serum IgE results will be redacted from the central laboratory reports except at Visit 1, Visit 3 prior to IP administration and any repeat testing that is performed during 
the screening/run-in period. 
j 
At clinic
 must be performed prior to spirometry assessments. All 
 measurements will be blinded for sites and participants throughout. The sponsor will be 
unblinded to the FENO values prior to randomization and blinded to the 
 values post randomization. 
k 
Visit 3 spirometry must be performed on the day of randomization prior to IP administration after appropriate restriction are met as per section 8.1.2.1. For every other visit, 
pre-BD spirometry assessments must be performed only after appropriate restrictions are met as per section 8.1.2.1, if not this should be rescheduled to the earliest 
opportunity within the allowed visit window. 
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l 
IP should be administered after all other assessments have been completed to a scheduled visit. 
m      Refer to section 7.1. 
n      The ePRO questionnaires should be completed prior to FENO and spirometry assessments at clinic. 
o       SGRQ to be completed after AQLQ(s)+12 
p       Serum for PK and immunogenicity must be collected prior to IP administration. In case of re-screening, these assessments will not need to be repeated if already completed at 
the original Visit 3.   
q 
At unscheduled visits for assessing an asthma exacerbation, the assessment/activity listed above is only the minimum needed to be performed. Other unscheduled visits may 
be initiated as needed, and assessments performed as per investigator’s judgement.  
 
EOT End-of-Treatment; FU Follow-up; IPD Investigational Product Discontinuation; UNS Unscheduled; W Week. 
 
CHANGES REQUIRED DURING THE COVID-19 PANDEMIC 
Please Note:  Changes below should only be implemented during the COVID-19 pandemic. 
During the COVID-19 pandemic, changes are being implemented in order to ensure the safety of study participants, to maintain 
compliance with good clinical practices, and to minimize risks to data integrity. Where allowable by local health authorities, ethics 
committees and healthcare provider guidelines (e.g. hospital policies), these changes include: 
• Re-consent will be obtained remotely and/or verbally if allowed by local and regional guidelines. The rationale for this 
change is to ensure that the participant agrees to the changes implemented during the COVID-19 pandemic while 
minimizing the risk to participants of COVID-19 exposure. 
 
• The option of home visits including home administration of study intervention performed by a qualified Health Care 
Professional (HCP). Additional information related to the visit can be obtained remotely by phone call and/or video 
conference. The rationale for this change is to minimize the risk of participants missing scheduled IP administration and visit 
assessments due to inability/unwillingness to visit the site during the COVID-19 pandemic. Home IP administration will 
apply to participants that have completed at least two IP administrations on-site. 
 
• Remote visits (phone call and/or video conference) to replace on-site visits, if participants cannot attend the visits at the 
study site, at an alternate site or have home visits. The rationale for this change is to ensure that assessments and collection 

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of information continue for visits that cannot be done at the site, at an alternate site or at the participant’s home. This will 
reduce the risk of participant exposure to COVID-19 
 
• Screening visit and all run-in visits must be conducted on-site to complete the required assessments according SoA in order 
to confirm eligibility criteria. 
 
For further details, please refer to Appendix H. 
 

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2 
INTRODUCTION 
Asthma is a chronic inflammatory airway disorder caused by the interaction of genetic and 
environmental factors. It is characterized by widespread, variable, and reversible airflow 
obstruction, airway inflammation, excessive mucus production; and airway 
hyperresponsiveness that lead to recurrent episodes of wheezing, breathlessness, chest 
tightness, and coughing (The Collaborative Study on the Genetics of Asthma (CSGA) 1997). 
Progressive pathologic airway remodeling and scarring may occur in persistent asthma 
resulting in only partially reversible or irreversible airway obstruction (Pascual and Peters 
2005). 
The etiology of asthma is thought to be multi-factorial, influenced by both genetic and 
environmental mechanisms. The majority of cases arise when a person becomes 
hypersensitive to allergens. Despite the availability of multiple therapeutic options, asthma 
continues to be a major health problem. Worldwide, asthma currently affects approximately 
300 million people; by 2020, asthma is expected to affect 400 million people (Partridge 2007). 
Each year in the US, asthma accounts for an estimated 8.9 million outpatient visits, 1.9 million 
emergency room visits, 479,000 hospitalizations (DeFrances et al 2008), and 3400 deaths 
(Centers for Disease Control and Prevention 2017). In China the prevalence of asthma was 
reported to be 1%-5%, approximately 30 million patients. Its prevalence is in an increasing 
trend in China. A national survey conducted in 2010-2011 reported that it increased by up to 
147.9% and 190.2% in Beijing and Shanghai, respectively, as compared to that in 2002-2004 
(China Asthma Guideline 2016). In China, a recent national survey reported that in asthma 
patients receiving current therapies 40.5% reached asthma control, but the hospitalization rate 
in the past year was 22.6% (0.45/patient.year) and the ER visit rate in the past year 27.0% 
(0.67/patient.year) (Su et al 2014). 
Approximately 5% to 10% of asthma patients have severe asthma, which may be inadequately 
controlled by ICS and LABA combinations together with additional controller therapies 
(Brightling et al 2008). In China a national survey reported that 6.0% of asthma cases were 
severe (Su N et al 2016). These patients are at risk of asthma exacerbations (Tough et al 1998, 
Turner et al 1998) and have the greatest medical need among the asthmatic population today. 
Patients with severe asthma represent the greatest economic cost (>50% of total asthma-
related health care costs) (Antonicelli et al 2004, Serra Batlles et al 1998, Barnes and Kuitert 
1996). 
 
 

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2.1 
Study Rationale 
Tezepelumab is in development for the treatment of severe asthma. A proof-of-concept study 
(Gauvreau et al 2014) showed that tezepelumab attenuated the late allergic response (LAR), 
the early allergic response (EAR) and the increase in FENO levels after an allergen challenge. 
A Phase 2b study (CD-RI-MEDI9929-1146) showed that doses of 70 mg and 210 mg 
administered Q4W and 280 mg of tezepelumab administered Q2W SC resulted in a reduction 
of the AAER by 61%, 71% and 66% respectively. 
This phase 3 study is designed to evaluate the effect of tezepelumab on the AAER, lung 
function, asthma control, and safety in adult participants with uncontrolled severe asthma 
receiving medium or high-dose ICS plus at least one additional asthma controller medication 
with or without OCS. This will allow the benefit-risk profile of tezepelumab in the treatment 
of severe asthma to be further characterized and to enable a better understanding of how best 
to position tezepelumab in the severe asthma treatment pathway. 
2.2 
Background 
Biologic therapies have been shown to reduce 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 ICS plus LABA (XOLAIR US PI 2019, XOLAIR SmPC 2019). Four 
additional biologics, mepolizumab, reslizumab, benralizumab, and dupilumab, have been 
approved for severe asthma with an eosinophilic phenotype and/or those requiring oral 
corticosteroid (OCS) therapy (NUCALA SmPC 2019, NUCALA US PI 2019, CINQAERO 
SmPC 2021, CINQAIR US PI 2020, FASENRA SmPC 2019, FASENRA US PI 2019, 
DUPIXENT SmPC 2020, DUPIXENT US PI 2019).    
Biologics targeting IL-5 and IgE are now included in international treatment guidelines 
(GINA 2017) 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, 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, 

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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 Th2 driven asthma (Kaur and 
Brightling, 2012). Asthma is recognized as a heterogeneous disease. There are subsets of 
patients that do not exhibit Th2-associated disease (Wenzel et al, 2012), and there are 
emerging data that TSLP may also mediate non-allergic (non-T helper cell 2) inflammation 
(Tanaka et al 2009, Ziegler et al 2013). 
Given that TSLP is an upstream and pleiotropic cytokine, the blockade of TSLP is therefore 
anticipated to have broad impact on the spectrum of inflammatory responses seen in asthma. 
Tezepelumab is a fully human immunoglobulin G (IgG) 2λ monoclonal antibody (mAb) 
directed against TSLP. Tezepelumab binds to human TSLP and prevents its interaction with 
TSLP receptor (TSLPR). Owing to the central role of TSLP in initiating and maintaining a 
Th2 response, anti-TSLP therapy may provide an opportunity to treat the upstream underlying 
mechanisms of asthma by reversing the established inflammatory responses to asthma 
triggers. 
Results of a completed inhaled allergen challenge study in 31 adult participants with mild 
atopic asthma (Study 20101183) demonstrated that tezepelumab attenuated the LAR and EAR 
to allergen challenge, as measured by the AUC (Area Under the Curve) for the percent fall in 
FEV1 and the maximum percent fall in FEV1. Tezepelumab also attenuated the increase in 
FENO 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 participants with mild 
atopic asthma. No participants developed anti-drug antibodies (ADA) after receiving 
tezepelumab. Based upon these data, MedImmune/AZ have conducted a randomized, double-
blind, placebo-controlled, dose range finding study in asthmatics who were inadequately 
controlled with medium or high dose ICS/long-acting β2 agonist (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 participants with inadequately controlled, 
severe asthma. Participants were randomized in a 1:1:1:1 ratio to 1 of 3 dose levels of SC 
tezepelumab (280 mg Q2W, 210 mg Q4W, 70 mg Q4W) or placebo (Q2W) for 52 weeks. A 
total of 584 participants received at least 1 dose of tezepelumab or placebo. An AAER 
reduction of 61%, 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 
(ITT) population (p<0.001). After repeated SC administration, mean serum trough 
concentration increased over time and achieved steady-state by week 12. Tezepelumab 
exhibited linear pharmacokinetics (PK) across 3 doses. A total of 5 (4.1%) placebo 
participants and 8 (1.8%) tezepelumab participants who had no detectable ADA at baseline 

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had detectable ADA post-treatment; no participants developed neutralizing ADA in the study. 
The results of this study did not identify safety signals associated with tezepelumab for any 
dosing regimen. The frequencies of treatment emergent adverse events (TEAEs) were similar 
between the placebo (62.2%) and the total tezepelumab (64.2%) dose groups and a majority of 
participants had TEAEs that were mild or moderate in severity and not related to study 
intervention. Few participants had TEAEs that resulted in permanent discontinuation of IP. 
Overall, tezepelumab was well-tolerated with an acceptable safety profile and no safety 
signals were identified. 
Study D5180C00007 (NAVIGATOR) was a Phase 3, multicenter, global, randomized, double 
blind, placebo-controlled study to assess the efficacy and safety of 210 mg tezepelumab 
administered SC Q4W for 52 weeks. The population of interest was adults and adolescents 
with severe, uncontrolled asthma between the ages of 12 and 80 years and both overall and 
across a broad spectrum of asthma phenotypes as determined by participants with blood 
eosinophils above and below 300 cells/μL, FeNO above and below 25 ppb, as well as allergic 
and non-allergic status. A total of 1061 participants were randomized in a 1:1 ratio to 
tezepelumab or placebo and 1059 participants (including 82 adolescents) received at least one 
dose of study intervention. Tezepelumab treatment resulted in a statistically significant and 
clinically meaningful reduction in annualised asthma exacerbation rate (AAER) by 56% 
(p < 0.001) compared with placebo in the overall population and by 41% compared with 
placebo in participants with baseline blood eosinophils <300 cells/μL (p < 0.001). The mean 
serum trough concentration of tezepelumab increased over time and approached steady state 
by 12 weeks. Treatment-emergent ADAs were detected at any time during the study in 4.9% 
(26) of participants treated with tezepelumab. Neutralizing antibodies to tezepelumab were 
detected in only one (0.2%) of the participants treated with tezepelumab. On-treatment AEs 
were similar between the placebo (80.8%) and the total tezepelumab (77.1%) dose groups and 
the majority of participants had on-treatment AEs that were mild or moderate in severity and 
not related to the study intervention. The percentage of participants who discontinued the trial 
regimen was 6.8% in the tezepelumab group and 10.7% in the placebo group. On-treatment 
AEs that resulted in permanent discontinuation of study intervention was 2.1% in the 
tezepelumab group and 3.6% in the placebo group. Overall, tezepelumab was well tolerated 
with an acceptable safety profile and no safety signals in both adult and adolescent 
participants with severe, uncontrolled asthma (Menzies-Gow et al 2021, TEZSPIRE FDA 
Prescribing Information 2021). 
Additional studies with tezepelumab have been completed. These include a mechanistic study 
(D5180C00013; CASCADE) conducted in adults with inadequately controlled asthma, an 
OCS sparing study (D5180C00009; SOURCE) conducted in adults with OCS-dependent 
asthma, an at-home use study in adults and adolescents with severe asthma (D5180C00011; 
PATH-HOME), and a Japanese long-term safety study in participants with inadequately 
controlled asthma (D5180C00019; NOZOMI). 

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A detailed description of the above-mentioned additional studies and chemistry, 
pharmacology, efficacy, and safety of tezepelumab is provided in the Investigator’s Brochure 
(IB). 
2.3 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and safety profile 
of tezepelumab may be found in the IB.   
2.3.1 
Risk Assessment 
Use of tezepelumab has been demonstrated to show an important benefit in asthma in a phase 
2b and phase 3 studies. Tezepelumab has been well tolerated with an acceptable safety profile 
and no safety signals in participants with severe, uncontrolled asthma identified in the 
completed studies to date. No serious allergic reactions or anaphylactic reactions considered 
related to tezepelumab were reported in the Phase 3 program. To date there has been a low 
incidence of ADA and neutralising antibodies (nAb) reported with tezepelumab treatment in 
the Phase 2 or Phase 3 studies. Although TSLP suppression could theoretically have 
unanticipated immune-related side effects impairing host defense against certain infections, 
there is no clear preclinical or clinical evidence supporting such a role, and no safety concerns 
related to serious infections, severe infections or helminth infections have been detected in the 
completed studies to date.  
Risk mitigation measures for important potential risks will be in place during the conduct of 
this study (refer to Table 3), in conjunction with the performance of the AstraZeneca’s routine 
pharmacovigilance activities. 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 3 
Risk Assessment 
Important 
Potential Risk 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention 
Serious infections 
are defined as 
infections fulfilling 
criteria for 
regulatory reporting 
The mechanism of action of tezepelumab 
suggests potential inhibitory effects on 
immune responses mediated by Th2 cells, 
leading to the possibility of diminution of 
the host’s protective response to infection. 
Although there is a theoretical risk of 
serious infections with tezepelumab 
treatment, there is no data to support this 
potential risk. There is also no evidence 
for causal relationship with tezepelumab. 
Vulnerable participants will be excluded 
based on eligibility criteria, and 
randomised participants will be 
monitored for infection with complete 
blood counts, including differential 
white cell count throughout the study; 
and through standard AE/SAE reporting.  
Participants will be excluded if they 
received systemic immunosuppressive or 
immunomodulating drugs within 12 
weeks prior to randomization; or if they 
have a history of a known 
immunodeficiency disorder; or have a 
history of clinically significant infection 
requiring treatment with systemic 
antibiotics or antiviral medications 
finalized < 2 weeks before Visit 1 or 
during the run-in period or at 
randomisation; or who have evidence of 
active coronavirus disease 2019 
(COVID-19) infection during the run-in 
period; or have had tuberculosis 
requiring treatment within the 12 months 
prior to Visit 1. 
Serious infections are an AESI and 
participants who develop serious 
infection will be followed up closely 
throughout study. 
Malignancies 
Given the potential theoretical risk, the 
long-term treatment intended for a 
chronic disease, and the nature of 
malignancy development, malignancy is 
included as an important potential risk. 
There is no evidence to suggest an 
increase in malignancies in the 
tezepelumab data to-date in either pre-
clinical or clinical studies. No causal 
relationship with tezepelumab could be 
Participants with current malignancy or 
whose curative therapy was completed 
recently will be excluded from 
participation based on eligibility criteria. 
All participants will be closely followed 
during the study for any adverse events, 
including malignancies that are 
considered AESI. 
 

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Important 
Potential Risk 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention 
established for cases reported.  
Serious cardiac 
events 
A numerical imbalance in cardiac 
disorder SAEs was observed in the 
DESTINATION Long Term Extension 
study (Investigator’s Brochure) with more 
events in participants treated with 
tezepelumab versus participants treated 
with placebo. None of the cardiac 
disorder SAEs was considered causally 
related to tezepelumab by investigators or 
Independent Adjudication Committee. 
There is no known mechanism by which 
blocking TSLP would lead to cardiac 
pathophysiology. 
Participants with cardiac disorders that 
are not stable in the opinion of the 
investigator or who present meaningful 
abnormal findings in examination, lab 
assessments or ECG will be excluded 
based on eligibility criteria. All 
participants will be closely followed 
during the study for any adverse events, 
including serious cardiac events that are 
considered AESI. 
 
Potential risks 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention 
Serious 
hypersensitivity 
reactions 
Systemic reactions to large therapeutic 
molecules can be IgE or non-IgE-
mediated and are generally characterised 
by signs and symptoms such as skin rash, 
urticaria, pruritus, local or diffuse 
erythema, angioedema, fever, chills, 
cough, dyspnoea, wheezing, 
bronchospasm, nausea/vomiting, 
diaphoresis, chest pain, tachycardia or 
bradycardia, and/or hypotension, which 
can all be severe or life-threatening. 
Effects typically occur during or within 
several hours after study intervention but 
may be delayed. 
The administration of a monoclonal 
antibody can result in the formation of 
ADA. The occurrence of ADA could 
result in immune complex disease (Type 
3 hypersensitivity reactions) with 
manifestations such as serum sickness, 
nephritis, and vasculitis, or altered 
tezepelumab levels or activity.  
To mitigate the potential risk of serious 
hypersensitivity reactions during and 
after administration of tezepelumab, 
specific requirements for observing 
participants for AEs/SAEs and for 
monitoring vital signs are included in 
this CSP. In addition, medical equipment 
to treat acute anaphylactic reactions will 
be immediately available and site staff 
will be trained to recognise and treat 
anaphylaxis. 
Participants with sensitivity to any 
component of the study intervention or a 
history of drug or other allergy that, in 
the opinion of the investigator or 
medical monitor, contraindicates their 
participation will be excluded. 
Participants who have a history of 
anaphylaxis or documented immune 
complex disease following any biologic 
therapy will also be excluded. 
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Important 
Potential Risk 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention 
AESI and these events will be monitored 
closely throughout the study. 
Helminth 
infections 
Potential inhibitory effects on immune 
responses mediated by Th2 cells, leading 
to the possibility of diminution of the 
host’s protective response to parasitic 
infestation/infection. 
To decrease the risk of parasitic 
infestation or infection, participants who 
have a history of clinically significant 
infection, requiring treatment with 
systemic antibiotics or antiviral 
medications finalized < 2 weeks before 
Visit 1 or during the run-in period or at 
randomisation; and  participants with a 
helminth 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 will be 
excluded. 
Helminth infections are an AESI. 
Participants who develop such infections 
will be monitored closely throughout the 
study. 
Study procedures 
COVID-19 
Pandemic, risk of 
COVID-19 
infection 
There is the risk of exposure to COVID-
19 to participants during site visits 
Local guidelines will be followed to 
mitigate risk of participant’s exposure to 
COVID-19. 
To identify potential COVID-19 
infection during the study a COVID-19-
related questionnaire is recommended 
prior to every visit. Visits will be 
deferred if abnormalities noted. 
Sites are recommended to follow local 
severe acute respiratory coronavirus 2 
(SARS-CoV-2) testing guidelines, if 
applicable. 
COVID-19 vaccination is allowed 
during the study (see section 8.2.7 and 
Table 9). 
Refer to Appendix H Changes related to 

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• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
a Terminology to describe emergency room/department and urgent care visits may differ between countries. All such visits 
have been captured as emergency room (ER) visits, which will be included in the analyses and outputs. 
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4 
STUDY DESIGN 
4.1 
Overall Design 
For an overview of the study design see Figure 1. For details on treatments given during the 
study, see Section 6.1Treatments Administered.   
For details on the efficacy and safety endpoints, see Section 3.   
This is a Phase 3, regional, multicentre, randomized, double-blind, placebo-controlled, parallel 
group study to evaluate the effect of 210 mg of tezepelumab administered Q4W SC in adult 
participants with severe uncontrolled asthma.  
A total of 396 participants will be randomized in the study in a 1:1 ratio to either tezepelumab 
or placebo (198 per group), with at least 70% of the participants from China. The rest of the 
participants will come from other countries. The participants will be stratified by region 
(China/non-China). 
All participants must have been on a medium to high dose ICS for at least 3 months prior to 
screening (see Appendix F for definitions of medium to high dose ICS) and have been on at 
least one asthma controller medication with or without OCS in the 3 months prior to date of 
informed consent as per inclusion criteria 5 and 6. 
The total study population will be monitored to ensure a broad participant distribution across 3 
different key clinical factors. Approximately 40% of the total study population will be 
participants who are treated with a total daily dose of medium dose ICS as well as on at least 
one additional maintenance asthma controller medication with or without OCS in the previous 
3 months prior to date of informed consent. 
Approximately 40% of participants in the study will be required to have had at least 3 
exacerbations in the past 12 months, with the remaining participants having had exactly 2 
exacerbations. Details on acceptable documentation is specified in section 8.1.1.  
The study will also aim to randomize approximately 55% of participants with <300 
eosinophils/μl and approximately 45% of participants with ≥ 300 eosinophils/μl. In addition, a 
reasonable number of participants is expected to be randomized with < 150 eosinophils/μl and 
> 450 eosinophils/μl. 
The anticipated percentages for the factors of historical exacerbations and blood eosinophils 
will be applied to the overall population as well as the China/non-China sub-population. The 
anticipated percentages for the factor of ICS dose will be different between China and non-
China sub-population (with approximately 20% medium dose ICS participants in non-China 
region and approximately 50% medium dose ICS participants in China). When the target 

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percentage of participants for the ICS, exacerbations or eosinophil subgroup in a region 
(China or non-China) is reached, consideration will be given to closing the IRT/RTSM 
randomization for that subgroup within the specific region. Once a subgroup is closed, 
participants in the screening/run-in period in the closed subgroup will not be allowed to be 
randomized and will be screen failed. 
Section 6.5 (Table 7 and Table 8) provides a list of medication restrictions and prohibitions to 
be followed throughout the conduct of the clinical trial. 
The study will consist of a screening/run in period between 5-6 weeks, a treatment period of 
52 weeks and a post-treatment follow-up period of 12 weeks. During the treatment period, IP 
will be administered starting at Day 0 until week 48. IP will not be administered on week 52. 
Participants who discontinue IP during the study will be encouraged to undergo appropriate 
study visits/procedures for the full 52-week period. Further information is provided in section 
7.1. Any new treatments that are initiated will be recorded in the eCRF.  
Participants will complete a 12-week post treatment - follow-up period for the assessment of 
safety and anti-drug antibodies.  
Two database locks (DBLs) are planned in this study. The primary DBL will be conducted 
after the last participant completes the 52-week double-blind treatment period; and the final 
DBL will be conducted after the last participant completes the last safety follow-up visit 
(Week 64). After the primary DBL, the study treatment allocation for participants will become 
known to the sponsor staff. The blind will be maintained for the investigators, investigational 
site staff and participants until the final DBL. 
During the screening/run-in period the participant must undergo all assessments per Table 1. 
Prior to randomization the participants must meet all inclusion /exclusion criteria. If a 
participant does not meet all inclusion criteria or meets any exclusion criteria as per section 
5.1 and section 5.2, the participant will be screen failed. Rescreening is allowed only once. 
Further details are specified in section 5.4.  
4.2 
Scientific Rationale for Study Design 
The purpose of this study is to provide evidence of the efficacy and safety of 210 mg dose of 
tezepelumab administered Q4W SC in participants with a history of asthma exacerbations and 
severe uncontrolled asthma receiving medium or high dose ICS plus at least one additional 
asthma controller medication with or without OCS.  
The primary (AAER) and key secondary endpoints (lung function and asthma control) are 
well accepted measures for a study in severe asthma.  These endpoints have been shown in the 
Phase 2b and Phase 3 studies to clearly differentiate the tezepelumab benefit from placebo. In 

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order to avoid bias the study will be randomized and double blinded.  Participant entry will be 
stratified by region (China/non-China) to ensure equitable distribution for analysis. 
Given that TSLP is an upstream and pleiotropic cytokine, the blockade of TSLP is anticipated 
to have broad impact on the spectrum of inflammatory responses seen in asthma. Due to the 
mechanism of action, it is expected that severe asthmatics irrespective of their phenotype of 
asthma would benefit from treatment with tezepelumab. Participant entry into the study will 
be monitored to ensure that there are adequate numbers of participants within different 
phenotypes (high and low eosinophils, medium and high dose ICS, and number of 
exacerbations in the previous year) for analysis. 
4.3 
Justification for Dose 
A 210 mg Q4W dosing regimen was selected for the Phase 3 studies based on efficacy data 
and an exposure-response analysis from the Phase 2b Study CD-RI-MEDI9929-1146 using 
population 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 
20101183, 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 that 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.  
The dose of 
 has been selected for evaluation in asthma populations with a 
body weight of ≥40 kg. 
The study is designed to dose participants at Q4W with the last dose given at week 48, EOT 
visit at week 52, and a 12-week follow-up period. 
4.4 
End of Study Definition 
For the purpose of Clinical Trial Transparency (CTT) the definition of the end of the study 
differs under Food and Drug Administration (FDA) and European Union (EU) regulatory 
requirements: 
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EU requirements define study completion as the last visit of the last participant for any 
protocol related activity. 
FDA requirements define two completion dates: 
Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure with 
different completion dates, this term refers to the date on which data collection is completed 
for all of the primary outcomes. 
Study Completion Date – the date the final participant is examined or receives an intervention 
for purposes of final collection of data for the primary and secondary outcome measures and 
AEs (for example, last participant’s last visit), whether the clinical study concludes according 
to the pre-specified protocol or is terminated. 
In this study, the end of study is defined as when the last participant has completed his/her last 
scheduled contact.  
In this study, a participant is considered to have completed the study when he/she has 
completed his/her last scheduled contact. 
See Appendix A 6 for guidelines for the dissemination of study results 
 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
Each participant should meet all of the inclusion criteria and none of the exclusion criteria for 
this study in order to assigned/randomized to a study intervention.  Under no circumstances 
can there be exceptions to this rule. Participants who do not meet the entry requirements are 
screen failures, refer to section 5.4. 
In this protocol, “enrolled” participants are defined as those who sign informed consent.  
“Randomized” participants are defined as those who undergo randomization and receive a 
randomization number. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following inclusion 
criteria and none of the exclusion criteria apply: 

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Informed consent 
1. 
Provision of signed and dated written informed consent form prior to any 
mandatory study specific procedures, sampling, and analyses for participants who 
are at, or over the age of majority (as per local law).  
The ICF process is described in Appendix A 3. 
Age 
2. 
Participants must be 18 to 80 years of age inclusive at the time of signing the 
informed consent form. 
Type of participant and disease characteristics 
3. 
Documented physician-diagnosed asthma for at least 12 months prior to Visit 1. 
4. 
Participants who have received a physician-prescribed asthma controller medication 
with medium or high dose ICS as per GINA guideline (GINA 2017) for at least 6 
months prior to Visit 1.  
5. 
Documented treatment with a total daily dose of either medium or high dose ICS (≥ 
500μg fluticasone propionate dry powder formulation equivalent total daily dose) 
for at least 3 months prior to Visit 1. The ICS can be contained within an 
ICS/LABA combination product. 
• 
Equivalent ICS doses as detailed in Appendix F.  
6. 
At least one additional maintenance asthma controller medication is required 
according to standard practice of care; e.g. LABA, LTRA, theophylline, LAMA, 
cromones etc. Use of additional asthma controller medications must be documented 
for at least 3 months prior to Visit 1.  
7. 
Morning pre-BD FEV1 <80% predicted normal at either Visit 2 or Visit 2a. 
8. 
Evidence of asthma as documented by either: 
Documented historical reversibility of FEV1 ≥12% and ≥200 mL in the previous 12 
months prior to Visit 1. 
 OR 
Post-BD (albuterol/salbutamol) reversibility of FEV1 ≥12% and ≥200 mL during 
screening (15-30 min after administration of 4 puffs of albuterol/salbutamol) at 
either Visit 2 or at Visit 2a. 
Note: refer to Appendix I - Clarification on the post-BD spirometry at Visit 2 or 
Visit 2a.  
 

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9. 
Documented history of at least 2 asthma exacerbation events within 12 months prior 
to Visit 1, and at least one of the exacerbations should occur during the treatment of 
medium-to-high dose ICS. These can be as follows: 
• 
An asthma exacerbation is defined as a worsening of asthma that required 
treatment with systemic corticosteroids for at least 3 consecutive days (a 
single depo-injectable dose of corticosteroids will be considered equivalent 
to a 3-day course of systemic corticosteroids). 
OR 
• 
An emergency room visit (defined as evaluation and treatment for <24 hours 
in an ER or urgent care center) that required systemic corticosteroids (as per 
above). 
 
OR 
 
• 
An inpatient hospitalisation due to asthma (defined as admission to an 
inpatient facility and/or evaluation and treatment in a healthcare facility for 
≥24 hours. 
NOTE: For participants receiving a stable maintenance dose of OCS, a temporary 
increase for at least 3 consecutive days over and above the stable existing 
maintenance dose qualifies as an exacerbation. 
The below defines what is acceptable to document exacerbations in this program: 
˗ Discharge summaries from a hospital, emergency room, or an urgent care 
facility indicating that a participant 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. 
˗ Participants can provide evidence of prescriptions for systemic steroids used 
during an exacerbation. 
˗ A documented conversation that is recorded in a timely manner between the 
investigator/nurse or nurse practitioner and a participant 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 participant 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 

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prescriptions were provided is necessary. This option should be used only if 
reasonable attempts to procure participant records have been unsuccessful. 
10. 
ACQ-6 score ≥1.5 at Visit 1 
Weight 
11. 
Weight ≥40 kg at Visit 1 
Reproduction 
12. 
Negative serum pregnancy test for female participants of childbearing potential at 
Visit 1. 
13. 
Females of childbearing potential who are sexually active with a nonsterilized male 
partner must use a highly effective method of contraception from screening, and 
must agree to continue using such precautions for 16 weeks after the final dose of 
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 vasectomised sexual partner, Implanon™, female sterilization 
by tubal occlusion, any effective intrauterine device/system (IUD/IUS), 
Depo-Provera™ injections, oral contraceptive, and Evra Patch ™ or 
Nuvaring™. 
• 
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: 
• 
Women <50 years old would be considered postmenopausal if they 
have been amenorrheic for 12 months or more following cessation 
of exogenous hormonal treatment and follicle stimulating hormone 
(FSH) levels in the postmenopausal range. 
• 
Women ≥50 years old would be considered postmenopausal if they 
have been amenorrheic for 12 months or more following cessation 
of all exogenous hormonal treatment. 
14. 
Inclusion Criterion# 14 removed with Version 3.0 of Clinical Study Protocol. 
Inclusion criteria at randomization:  

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15. 
ACQ-6 score ≥1.5 on the day of randomization 
16. 
Fulfilment of at least one of the following conditions over the 7 days prior to 
randomization: 
• 
≥ 2 days with a daytime or night-time symptoms score ≥1 
• 
Reliever SABA use on > 2 days  
• 
≥ 1 awakening due to asthma requiring SABA use 
17. 
Minimum compliance of 70% with daily eDiary during the run-in (having a 
minimum of 15 fully compliant days in the 21 days up to and including the day of 
randomization - Day 0). 
A compliant day requires completion of evening eDiary and subsequent morning 
eDiary such that an ASD daily score can be calculated. 
• 
The run-in period for this criterion is defined as the period between eDiary 
assignment (evening assessment) and the randomization visit (morning 
assessment). 
18. 
Minimum of 4 days with complete (Evening and subsequent morning) daily eDiary 
in the 7 days prior to randomization (Evening assessment Day -7 to Morning 
assessment Day 0 - randomization visit). 
19. 
Minimum of 70% with background asthma medication(s) as captured in the eDiary 
during the run-in period (having a minimum of 15 fully compliant days in the 21 
days up to and including the day of randomization - Day 0). 
• 
Days with missing eDiary data treated as non-compliant for this criterion 
20. 
Acceptable inhaler, peak flow meter, and spirometry techniques during the run-in 
period. 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
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). 

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2. 
Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, 
hematological, psychiatric, or major physical impairment that is not stable in the 
opinion of the Investigator and could:  
˗ Affect the safety of the participant throughout the study 
˗ Influence the findings of the study or the interpretation 
˗ Impede the participant's ability to complete the entire duration of study 
3. 
History of cancer:  
− 
Participants who have had basal cell carcinoma, localized squamous cell 
carcinoma of the skin or in situ carcinoma of the cervix are eligible to 
participate in the study provided that curative therapy was completed at least 12 
months prior to Visit 1.  
− 
Participants who have had other malignancies are eligible provided that 
curative therapy was completed at least 5 years prior to Visit 1. 
4. 
History of a clinically significant infection, including upper (URTI) or lower 
respiratory tract infection (LRTI), requiring treatment with antibiotics or antiviral 
medications finalized < 2 weeks before Visit 1 or during the 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 participants with smoking history ≥ 10 pack-years and 
participants using vaping products, including electronic cigarettes. Former smokers 
with a smoking history of <10 pack years and users of vaping or e-cigarette 
products must have stopped for at least 6 months prior to Visit 1 to be eligible. 
7. 
History of chronic alcohol or drug abuse within 12 months prior to Visit 1.  
8. 
Tuberculosis requiring treatment within the 12 months prior to Visit 1. 
9. 
History of known immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test at Visit 1, or the participant taking antiretroviral 
medications as determined by medical history and/or participant’s verbal report. 
10. 
Major surgery within 8 weeks prior to Visit 1 or planned surgical procedures 
requiring general anaesthesia or in-patient status for >1 day during the conduct of 
the study. 
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11. 
Receipt of any marketed or investigational biologic agent within 4 months or 5 half-
lives (whichever is longer) prior to Visit 1 or receipt of any investigational non-
biologic agent within 30 days or 5 half-lives (whichever is longest) prior to Visit 1.   
Note: Participants on previous biologics treatment are allowed to enter the study 
provided the appropriate washout period is fulfilled. 
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 immunoglobulin or blood products within 30 days prior to Visit 1.   
14. 
Receipt of the T2 cytokine inhibitor Suplatast tosilate within 15 days prior to Visit 
1.  
15. 
Receipt of live attenuated vaccines 30 days prior to the date of randomization and 
during the study including the follow-up period, and/or receipt of any COVID-19 
vaccine within 28 days prior to date of randomization.  
16. 
Participants that have been treated with bronchial thermoplasty in the last 12 
months prior to Visit 1. 
Prior/concurrent clinical study experience 
17. 
Known history of sensitivity to any component of the IP formulation or a history of 
drug or other allergy that, in the opinion of the investigator, contraindicates their 
participation (see section 6.1.1). 
18. 
History of anaphylaxis or documented immune complex disease (Type III 
hypersensitivity reactions) following any biologic therapy.  
19. 
Concurrent enrolment in another clinical study involving an IP. 
20. 
Participant randomization in the current study or previous Tezepelumab studies.  
21. 
Involvement in the planning and/or conduct of the study (applies to AstraZeneca 
staff and/or site staff), or participants employed by or relatives of the employees of 
the site or sponsor. 
Diagnostic assessments 
22. 
Any clinically meaningful abnormal finding in physical examination, vital signs, 
ECG, haematology, clinical chemistry, or urinalysis during the run-in period, which 
in the opinion of the Investigator, may put the participant at risk because of his/her 
participation in the study, or may influence the results of the study, or the 
participant's ability to complete the entire duration of the study. 

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23. 
Evidence of active liver disease, including jaundice or aspartate transaminase, 
alanine transaminase, or alkaline phosphatase > 2 times the upper limit of normal 
(ULN) at Visit 1.  
24. 
Positive hepatitis B surface antigen, or hepatitis C virus antibody serology at 
screening, or a positive medical history for hepatitis B or C. Participants with a 
history of hepatitis B vaccination without a history of hepatitis B are allowed to 
participate.    
Other exclusions 
25. 
Pregnant, breastfeeding, or lactating women.   
A serum β-HCG pregnancy test (by central laboratory) must be drawn for women of 
childbearing potential at the screening visit. If the results of the serum β-HCG (from 
central laboratory) cannot be obtained prior to dosing of the IP, a participant may be 
enrolled on the basis of a negative urine/serum pregnancy test (by local laboratory, 
following local requirement), though serum β-HCG must be obtained.  If either test 
is positive, the participant should be excluded.  Since urine and serum tests may 
miss a pregnancy in the first days after conception, relevant menstrual history and 
sexual history, including methods of contraception, should be considered.  Any 
participant whose menstrual and/or sexual history suggests the possibility of early 
pregnancy should be excluded.  
26. 
Unwillingness or inability to follow the study procedures, in the opinion of the 
investigator. 
5.3 
Lifestyle Considerations 
Participants must abstain from donating blood and plasma from the time of informed consent, 
and for 16 weeks (5 half-lives) after last dose of IP. 
5.3.1 
Meals and Dietary Restrictions 
Participants should avoid eating a large meal for at least 2 hours prior to all lung function 
assessments at the center. 
Participants should not eat or drink 1 hour prior to having FENO assessment. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
Chronic alcohol or drug abuse within 12 months is restricted prior to Visit 1 and throughout 
the conduct of the study. 
Current smokers or participants 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 to be eligible. Smoking is not allowed throughout the course of the study. 

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The use of e-cigarettes is also not allowed during the course of the study. 
5.3.3 
Activity 
Participants should avoid engaging in strenuous exertion for at least 30 minutes prior to all 
lung function assessments at the center. 
5.4 
Screen Failures  
Screen failures are defined as participants who consent 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 participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
These participants should have the reason for study withdrawal recorded as ‘Screen Failure’ 
(i.e., participant does not meet the required inclusion/exclusion criteria) in the eCRF. This 
reason for study withdrawal is only valid for screen failures, and not randomized participants. 
5.4.1 
Re-screening  
Re-screening is allowed only once under the following circumstances:  
Participants with respiratory infections requiring antibiotics or antiviral medication within 14 
days prior to Visit 1or 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), 
participants may potentially be re-screened. These cases should be discussed with the 
AstraZeneca study physician and documented in the Investigator Study File (ISF). 
Any re-screened participant will be re-enrolled and reassigned their originally assigned 
enrolment number after signing a new Informed Consent Form (ICF) 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). If the timeframe between screening and re-screening 
is more than 30 days, then all Visit 1 assessments should be repeated.  
Participants who experience an asthma exacerbation during the screening/run-in period 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. 

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Rescreened participants should be assigned the same participant number as for the initial 
screening. However, rescreening should be documented so that its effect on study results, if 
any, can be assessed.  
IMPORTANT: Re-screening for participants who have screen-failed due to PRO criteria 
(e.g. ACQ-6 score <1.5, did not meet minimum symptom requirement, or did not report 
adequate compliance with maintenance medications) is not allowed.  
Re-screening of a participant for any other reason will be allowed only upon approval of the 
AstraZeneca Study Physician. A documented approval for re-screening should be filed in the 
Investigator Study File (ISF). 
 
6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s) or placebo intended to be 
administered to a study participant according to the study protocol. 
Study intervention in this study refers to tezepelumab or placebo. 

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6.1 
Study Intervention(s) Administered 
6.1.1 
Study Interventions 
Table 5 
Study Interventions 
Arm name 
Treatment 1 
Treatment 2 
Intervention 
name 
Tezepelumab 
Placebo 
Type  
Drug 
Drug 
Dose 
formulation 
 
 
0.7% (w/v) sodium carboxy methyl 
cellulose in 10 mM acetate, 250 mM 
L-proline, 0.01% (w/v) polysorbate 
80, pH 5.0 
Unit dose 
strength(s) 
210 mg 
NA 
Dosage level(s) 
Refer to section 6.2 
 
Refer to section 6.2 
 
Route of 
administration 
Subcutaneous (SC) Injection 
Subcutaneous (SC) Injection 
Use 
Experimental 
Placebo 
IMP and NIMP 
IMP  
IMP  
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Packaging and 
labelling 
Study treatment will be provided in 5 
mL vial. Each vial will be labelled in 
accordance with Good Manufacturing 
Practice (GMP) Annex 13 and per 
country regulatory requirement. 
Study treatment will be provided in 
5 mL vial. Each vial will be labelled 
in accordance with Good 
Manufacturing Practice (GMP) 
Annex 13 and per country 
regulatory requirement. 
6.1.2 
Medical Devices 
The MasterScope with integrated ECG (manufactured by eResearchTechnology®) and NIOX 
VERO (manufactured by Circassia®) are provided for use in this study. 
Instructions for medical device use are provided in the device user manuals.  
CCI

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6.2 
Preparation/Handling/Storage/Accountability 
IP will be supplied to the site in a kit with one vial of either tezepelumab or placebo. Each kit 
has a unique number that is printed on all labels within the kit (i.e., the outer carton label and 
the label of each container within the carton). 
1) The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2) Only participants enrolled in the study may receive study intervention and only authorised 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff. 
3) The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
 
Please note: During the COVID-19 pandemic, if allowed by local/regional guidelines, IP 
preparation and administration may be performed at the participant’s home by a 
qualified HCP. Please refer to Appendix H for further details. 
Dose Preparation  
Each vial should be visually inspected prior to dose preparation. The IP will be provided to the 
study sites as a colorless to slightly yellow clear solution contained in a 5 mL single use glass 
vial to be stored at 2°C to 8°C until used. If defects are noted with the IP, the investigator and 
site monitor should be notified immediately. Preparation of IP must be performed by a 
qualified person (e.g., pharmacist or investigator) at the site. 
The IP does not contain preservatives and any unused portion must be discarded. Preparation 
of the IP is to be performed aseptically. Total in-use storage time from needle puncture of the 
IP vial to start of administration should not exceed 4 hours at room temperature. If storage 
time exceeds this limit, a new dose must be prepared from new vials. 
To prepare the participant’s dose, the IP will be selected for administration according to the 
kit identification numbers assigned by the IRT/RTSM.  One vial of IP will be assigned by 
IRT/RTSM for each dose.  
Dose preparation steps: 

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1. 
Allow the vial to equilibrate at room temperature (about 30 minutes to 1 hour). 
Ensure that the vial is adequately protected from light during the warming 
process. Gently swirl the vial to ensure the contents are mixed to a clear, 
homogeneous solution. Do not shake. 
2. 
To prepare IP for administration remove the tab portion of the vial cap and 
clean the stopper with 70% ethyl alcohol or equivalent.  
3. 
Attach a 21G 1½-inch sterile disposable needle to a 2mL or 3mL sterile 
syringe.  
4. 
Withdraw 1.9 mL of the IP from the vial. 
5. 
Remove and discard the 21G 1½-inch sterile disposable needle from the 
syringe.  
6. 
Attach a new 27G ½-inch sterile disposable needle to the same syringe in step 
5.  
7. 
Apply the appropriate label to the syringe. 
The assigned vial should be used at one time to prepare the dose required at each visit. Unused 
product in opened and dispensed vials should not be used for subsequent dosing and should be 
stored for IP accountability. If the opened and dispensed vials must be discarded immediately 
after dose preparation as per site’s SOP, the kit boxes must be retained for IP accountability. 
The IP will be administered by one SC injection (see Table 6) and must be prepared using 
disposable plastic syringes and aseptic technique. 
Table 6 
Study Intervention Dose Preparation 
Dose 
Number of vial(s) 
required 
Syringe size required 
Total volume 
administered 
 
1 
2mL or 3 mL 
1.9 mL 
Placebo 
1 
2mL or 3 mL 
1.9 mL 
a 
Due to the gradations available on 2mL or 3 mL disposable plastic syringe, dose based on 1.9 mL administered volume 
is 209 mg. 
 
Dose Administration 
IP will be administered by a qualified healthcare professional (e.g., pharmacist or study nurse) 
at the site. The injection site must be recorded in the source documents at each treatment visit 
and in the eCRF. The person administering the dose will wipe the skin surface of the upper 
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arm, anterior thigh or abdomen with alcohol and allow to air dry. The skin will be pinched to 
isolate the SC tissue from the muscle. The needle will be inserted at a 90 degree angle 
approximately halfway into the SC tissue. The IP will be slowly injected (at least 5 second 
duration is recommended) into the SC tissue using gentle pressure. The area should not be 
massaged after injection. It is advised that the site of injection of IP be rotated such that the 
participant receives IP at a different anatomical site at each treatment visit. In cases when 
rotation of the injection site is not feasible and/or the participant prefers not to rotate injection 
sites, the reason for not rotating the injection site should be documented in the source 
documents. The suggested injection site rotation sequence is presented below in Figure 2. 
Figure 2 
Suggested Schema of Rotation of Injection Sites 
 
Participants should be observed for a minimum of 2 hours after administration of the first two 
IP administrations for the appearance of any acute drug reactions. For the remaining doses, 
participants will be observed for a minimum of 1 hour after IP administration for any such 
reaction. 
If any of the following should occur, the IP should not be administered:  
• The participant received allergen immunotherapy injection on the same day as 
scheduled IP administration.  
• The participant has an intercurrent illness that in the opinion of the investigator may 
compromise the safety of the participant in the study (e.g., viral illnesses).  
• The participant is febrile (≥ 38°C; ≥ 100.4°F) within 72 hours prior to IP 
administration.  
 
The visit should be rescheduled within the allowed visit window and IP should be 
administered at that visit. If this is not possible the IP administration should be skipped. If a 
participant skips 2 consecutive IP administrations, the AZ study physician should be contacted 
to discuss further participation.   

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If the participant reports an injection site reaction, the investigator or qualified designee will 
complete the AE eCRF page and additional questions about the injection site reaction. 
6.3 
Measures to Minimise Bias: Randomization and Blinding 
Participant enrolment and randomization 
The Investigator(s) will: 
1. 
Obtain signed informed consent from the potential participant before any study 
specific procedures are performed. 
2. 
Assign the potential participant a unique enrolment number (which begins with an ‘E’) 
via the Interactive Web Response System/Interactive Voice Response System 
(IRT/RTSM). 
3. 
Determine participant eligibility. 
4. 
Assign the eligible participant a unique randomization code via the IRT/RTSM.   
5. 
Participants will be allocated to receive tezepelumab or placebo in a 1:1 ratio. 
Randomization will be stratified by region (China /non-China). Randomization 
numbers will be grouped in blocks. If a participant withdraws from the study, then 
his/her enrolment/randomization code cannot be reused. Withdrawn participants will 
not be replaced. 
Specific information concerning the use of the IRT/RTSM will be provided in a separate 
manual. 
Procedures for handling incorrectly enrolled or randomized participants 
Participants who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive study medication. There can be no exceptions to this rule. Participants 
who are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment and must be withdrawn from the study. 
Where a participant does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the Investigator regarding whether to continue or discontinue the participant 
from treatment. Study treatment must be discontinued in all cases where continued treatment 
is deemed to pose a safety risk to the participant and AstraZeneca study physician must ensure 
the decision is appropriately documented. Participants that are discontinued from treatment 
should be followed up according to the options described in section 7.1.1. In those cases 
where continuation of the study therapy is judged not to present a concern related to safety 

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and disease management, the rationale for continuing study therapy must be clearly 
documented.  
Methods for assigning treatment groups 
Randomization codes will be assigned strictly sequentially in each stratum as participants 
become eligible for randomization. 
The randomization code will be assigned from a randomization list prepared by a 
computerized system provided by Parexel Informatics on behalf of AZ (AZRand). All 
participants will be stratified at randomization by region (China versus non-China). At least 
70% of the participants will come from China. The rest of the participants will come from 
other countries. 
Ensuring blinding 
This is a double-blind study in which tezepelumab and placebo are not visually distinct from 
each other. All packaging and labelling of IP will be done in such way as to ensure blinding 
for all sponsor and investigational site staff. Neither the participant nor any of the 
Investigators or sponsor staff who are involved in the treatment or clinical evaluation and 
monitoring of the participants will be aware of the treatment received. Since tezepelumab and 
placebo are not visually distinct, IP will be handled by a qualified person (e.g., pharmacist or 
study nurse) at the site. 
An AstraZeneca site monitor will perform IP accountability. In the event that the treatment 
allocation for a participant becomes known to the Investigator or other study staff involved in 
the management of study participants, or needs to be known to treat an individual participant 
for an AE, the sponsor must be notified immediately by the Investigator and, if possible, 
before unblinding. 
The following personnel will have access to the randomization list: 
• 
Those carrying out the packaging and labelling of IP 
• 
Those generating the randomization list 
• 
Personnel at the IXRS company 
• 
Supply Chain Management department 
• 
Patient Safety department at AstraZeneca 
• 
Bioanalytical lab analyst performing the PK sample analysis 
The information in the randomisation list will be kept from other personnel involved in the 
conduct of the study and in a seure location until agreed to break the blind. 

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After the primary DBL, the study treatment allocation for participants will become known to 
the sponsor staff. The blind will be maintained for the investigators, investigational site staff 
and participants until the final DBL.  
Additional procedures to ensuring blinding in case of local laboratory usage can be found in 
section 8.2.5.2. 
Methods for unblinding 
Individual treatment codes, indicating the treatment randomization for each randomized 
participant, will be available to the Investigator(s) and delegate(s) at the study sites from the 
IVRS/IWRS. Routines for this will be described in the IVRS/IWRS user manual that will be 
provided to each site. 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the participant requires knowledge of the treatment randomization. The 
Investigator should document and report the action to AstraZeneca, without revealing the 
treatment given to participant to the AstraZeneca staff. 
AstraZeneca retains the right to break the treatment code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities. Treatment codes will not be broken for the planned analyses of data 
until all decisions on the evaluability of the data from each individual participant have been 
made and until the primary DBL has been documented. 
6.4 
Study Intervention 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. 
6.5 
Concomitant Therapy 
All ICS asthma medications taken in the 12 months prior to Visit 1 must be recorded in the 
eCRF along with reason for treatment. 
To satisfy inclusion criteria 5, a history of continuous treatment with medium or high dose 
ICS plus a second controller medication for at least 3 months prior to Visit 1 should be 
documented in source and recorded in the eCRF prior to the date of randomization.  

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In order to satisfy inclusion criterion 6, a history of all asthma controller medications for the 3 
months prior to Visit 1 until the end of the study should be documented in source and recorded 
in the eCRF. No changes are allowed to background asthma medications throughout the 
duration of the study except during the treatment of an asthma exacerbation. 
All other medications taken for conditions other than asthma in the 3 months prior to Visit 1 
and COVID-19 vaccine given at any time must be recorded in the eCRF along with reason for 
treatment by the Investigator/authorized delegate at each visit (as shown in Table 1 and 
Table 2).  
Maintenance asthma medication is not regarded as an IP, but will be provided/reimbursed by 
AstraZeneca according to local regulations in order to maintain appropriate oversight and 
access to this concomitant therapy. 
As theophylline has a narrow therapeutic window, please note that participants on 
maintenance treatment with theophylline should have blood concentration levels within 
therapeutic range documented before Visit 1. If this is not documented before signing the 
informed consent, it can be obtained after informed consent has been given or as part of the 
Visit 1 procedures. The sample can be analysed at the central or local lab as applicable. 
Investigator can use their time and other factors that may impact the results. 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 participant 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 

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Table 7 
Restricted medications 
Medication/class of drug: 
Usage  
Maintenance treatment with ICS and long-
acting bronchodilators (including 
ICS/LABA combinations) 
 
No changes in either dose or regimen are allowed from V1 
and throughout the IP treatment and preferably 4 weeks after 
the last dose of IP. 
 
The participants should be instructed not to take their usual 
asthma controller medication (i.e., LABA) prior to scheduled 
ECG assessment (please refer below for long-acting 
bronchodilator restrictions). Use of SABA should be avoided 
within 6 hours before ECG assessments. The medication 
restrictions are waived for the screening ECG at Visit 1.  
 
Twice daily bronchodilators should be withheld for at least 12 
hours prior to the scheduled FENO and spirometry at site.  
 
Once daily bronchodilators should be withheld for at least 24 
hours prior to the scheduled FENO and spirometry at site. 
 
Participants will not need a washout of their asthma 
medications for unscheduled visits due to asthma worsening. 
Short-acting beta-agonists 
(SABA) 
 
Regular scheduled use of SABA is not allowed from V1 and 
throughout the IP treatment and preferably 4 weeks after the 
last dose of IP. PRN use is allowed if needed, however 
attention should be paid to the following restrictions. 
 
SABA should be withheld for at least 6 hours prior to 
scheduled spirometry, FENO, ECG at site with the exception 
of any unscheduled visits due to asthma worsening.  
 
When possible, home PEF assessments should be taken after 
the SABA is withheld for at least 6 hours. 

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Table 7 
Restricted medications 
Medication/class of drug: 
Usage  
Additional Maintenance 
Controllers 
No changes in either dose or regimen are allowed from V1 
and throughout the IP treatment and preferably 4 weeks after 
the last dose of IP. 
 
Once daily LABA or LAMA should be withheld for at least 
24 hours prior scheduled spirometry and FENO at site visits 
with the exception of any unscheduled visits due to asthma 
worsening. 
 
Twice daily LABA or LAMA containing therapies should be 
withheld for at least 12 hours prior to scheduled spirometry 
and FENO at site with the exception of any unscheduled visits 
due to asthma worsening. 
LTRA should be restricted for at least 24 hours prior to 
scheduled spirometry and FENO at site with the exception of 
any unscheduled visits due to asthma worsening. 
Participants on theophylline should have blood concentration 
levels within therapeutic range documented before proceeding 
in the study. 
 
Twice daily theophyllines should be withheld for at least 12 
hours prior to scheduled spirometry and FENO at site with the 
exception of any unscheduled visits due to asthma worsening. 
 
Once daily theophyllines should be withheld for at least 24 
hours prior to scheduled spirometry and FENO at site with the 
exception of any unscheduled visits due to asthma worsening. 
Short-acting anticholinergics (e.g. 
ipratropium) 
 
These are not allowed as a rescue treatment for worsening 
asthma symptoms from V1 and throughout the IP treatment 
and preferably 4 weeks after the last dose of IP. They may be 
used for managing an asthma exacerbation event. 
Inactive/killed vaccinations (e.g. inactive 
influenza) 
Allowed provided they are not administered within 5 days 
before or after any IP dosing visit. 
COVID-19 vaccination 
Refer to Section 8.2.7 

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Table 7 
Restricted medications 
Medication/class of drug: 
Usage  
Allergen immunotherapy 
 
Allowed, if on stable therapy for at least 2 months prior to 
date of Visit 1 with no anticipated change during the 
treatment period.  
These should not be administered on the same day as IP 
administration. 
 
Table 8 
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 
maintenance treatment of asthma, asthma 
exacerbations in screening/run-in, and protocol 
defined asthma exacerbations on or after Visit 3) 
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. 
Any marketed (e.g. omalizumab, mepolizumab, 
reslizumab) or to be marketed 
or investigational biologic treatment 
Not allowed 4 months or 5 half-lives (whichever is 
longer) prior to the date of Visit 1, throughout the 
entire, screening run in period, treatment period (even 
if the participant has discontinued IP) and until the 
follow up visit week 64.    
Other study interventions 
(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 until the follow up 
visit week 64. 

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Table 8 
Prohibited medications 
Prohibited medication/class of drug: 
Usage 
Herbal remedies for the treatment of 
bronchodilation (refer to the product label) 
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. 
 
6.5.1 Rescue Medicine 
SABA should be withheld for at least 6 hours prior to scheduled site visit spirometry, FENO, 
ECG at site with the exception of any unscheduled visits due to asthma worsening. When 
possible, home lung function measurements should be taken at least 6 hours after the last dose 
of SABA rescue medication. 
Albuterol (US)/salbutamol (ex US) rescue medication will be provided by the sponsor and 
obtained locally.  
Regularly scheduled SABA use in the absence of any asthma symptoms is not allowed from 
enrolment (Visit 1) and throughout the study duration. Prophylactic use of SABA (e.g. prior to 
planned exercise) or any other use than to curb worsening of asthma symptoms should be 
documented in medical notes and entered in the eCRF. Any such prophylactic use of SABA 
must not be recorded in the Asthma Daily Diary. 
Rescue use of SABA administered via nebulization is discouraged, except as urgent treatment 
during an asthma exacerbation. Occasions where SABA is administered via nebulization will 
be recorded separately from metered dose inhaler inhalations in the eDiary. 
6.5.2 
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the 
participant’s safety and wellbeing, may be given at the discretion of the Investigator and 
recorded in the appropriate sections of the Case Report Form. 
6.5.3 
Bronchial Thermoplasty 
Participants should not be treated with bronchial thermoplasty during the study. 
6.6 
Dose Modification 
Not applicable. 

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6.7 
Intervention After the End of the Study 
Participants who complete week 64 should be given standard of care at the discretion of the 
investigator. 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
Participants may be discontinued from study intervention in the following situations.  
Note that discontinuation from study treatment is NOT the same thing as a complete 
withdrawal from the study. Participants who discontinue study treatment will be encouraged 
to remain in the study to complete all remaining study visits during the 48 weeks treatment 
period. 
• 
Participant decision. The participant is at any time free to discontinue IP treatment, 
without prejudice to further treatment 
• 
Adverse Event considered to jeopardize the safety of a participant participating in 
the study 
• 
Pregnancy 
• 
Severe non-compliance with the Clinical Study Protocol 
• 
Development of any study specific criteria for discontinuation, including: 
• 
An anaphylactic reaction to the IP requiring administration of epinephrine 
• 
A helminth parasitic infestation requiring hospitalization 
• 
An asthma-related event requiring intubation 
• 
Any malignancy except participants who develop basal cell carcinoma or 
localized squamous cell carcinoma of the skin, provided that the malignancy 
is excised and determined to have clean margins 
• 
Development of one or more of the following: 
• 
Confirmed ALT or AST increase of ≥ 8 x ULN 
• 
Confirmed ALT or AST increase of ≥ 5 x ULN for more than 2 weeks 
• 
Confirmed ALT or AST increase of ≥ 3 x ULN and total bilirubin of ≥ 2 x 
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• 
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 intervention discontinuation and follow-up 
and for any further evaluations that need to be completed. 
7.1.1 
Procedures for discontinuation of study treatment 
Participants 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 the study withdrawal are detailed below in section 7.2. If 
the participants decide to withdraw consent, then the reason for this must be recorded 
separately in the eCRF. 
A participant 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. Participants permanently discontinuing IP 
administration should be given locally available standard of care therapy, at the discretion of 
the Investigator. However, treatment with marketed or investigational biologics is not allowed 
until week 64 even if the participant 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 pharmacodynamics 
effects of tezepelumab reference should be made to the investigator brochure. 
All participants who prematurely discontinue IP should return to study center and complete 
the procedures described for the premature IP Discontinuation visit (IPD) at 4 weeks (+/- 5 
days) post last IP administration.  
 
Participants who discontinue treatment should be encouraged to return for all regularly 
scheduled visits for safety and efficacy assessment. 
At the IP discontinuation visit the participant will be given three options as to how they will 
be followed: 
1. The participant should be encouraged to return for all regular clinic visit and 
performed all scheduled assessments until he/she completes a total of 52 weeks 
treatment period. 
2. The participants will be offered follow-up on a monthly basis via telephone calls while 
continuing ediary and ePEF completion (no further procedures will be performed), 
until the participants completes 52 weeks in the study. In addition to the PRO 
assessments that are performed at home, the participant may also complete the other 
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participants should return for a follow up visit 16 weeks (+/-5 days) (refer to SOA, 
V19-week64) post last IP administration and for the EOT visit at Week52 (+/- 5 days). 
3. If the participants cannot or does not wish to comply with any of the options above, (or 
any component of them such as only telephone based visits without completion of the 
ediary and ePET), they will complete a follow-up visit at 16 weeks (+/- 5 days) (refer 
to SoA, Visit19-week64) post last IP administration. After this visit the Investigator 
will only contact the participant at 52 weeks post-randomization. No other study 
assessments will be performed prior to this contact. 
If the last IP administration was after week 36 for option 1 or 2, the participant will return to 
the clinical for an EOT visit at Week52 (+/- 5 days), and for option 3, the investigator will 
contact the participant at 52 weeks post randomization. The participant for option 1, 2 and 3 
will then return for a follow-up visit 16 weeks (+/- 5 days) post last IP administration (refer to 
SoA, V19-Week 64). 
The EOT visit will be completed immediately in the case of subsequent early withdrawal from 
option 1 or 2. Participants who do not wish to have any follow-up contacts will be 
discontinued from the study. All discontinued participants must return the ediary and ePEF 
devices at the EOT visit. 
If the participant choose option 1, all assessments will be completed as per the SoA as 
indicated in Section 1.3. If the participant chooses 2 or 3, the key information to be collected 
during the telephone calls are AEs/SAEs, changes in concomitant medication, health care 
utilization, and asthma exacerbation information.  
Participants who initially choose option 1 or 2 and subsequently cannot or do not wish to 
comply with the requirements of their option can continue with a less intensive option (i.e. 
participant initially choosing option 1 can continue with option 2 or 3, participants initially 
choosing option 2 can continue with option 3). 
If a participant discontinues IP due to a study specific discontinuation criterion, this should 
always be recorded as “Development of study specific discontinuation criteria” on the 
Discontinuation of Investigational Product form in the eCRF. 
7.2 
Participant Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request, without 
prejudice to further treatment, or may be withdrawn at any time at the discretion of the 
investigator for safety, behavioural, compliance, or administrative reasons. This is 
expected to be uncommon. 
• 
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records) as per section 7.1.1 

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• 
At the time of withdrawal from the study, if possible, an Early Study Intervention 
Discontinuation visit should be conducted, as shown in the SoA. See SoA for data to be 
collected at the time of study withdrawal and follow-up and for any further evaluations 
that need to be completed. 
− 
The participant will discontinue the study intervention and be withdrawn from the 
study at that time. 
• 
If the participant 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 participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried out in line with what was stated in the informed consent and local regulation The 
investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team. 
• A participant who withdraws consent will always be asked about the reason(s) and the 
presence of any adverse events (AE).  The Investigator will follow up participants as 
medically indicated. A withdrawal visit is essential to collect as much data as possible for 
the participant as per EOT visit described in SOA, Table 2. The participant will return all 
study supplied equipment including Home PEF meter and eDiary. Withdrawal of consent 
from the study must be ascertained and documented by the Investigator and recorded in 
the eCRFs as well as in the Informed Consent Form (ICF) or assent form. 
7.2.1 
Withdrawal due to recruitment completion  
When the required number of participants are randomized in the study, ongoing participants 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 and eCRF. As with screen failures, no further 
study related follow-up of these participants is required. 
7.2.2 
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 participants and if relevant give 
appropriate medical treatment, take necessary measures and document these in the source 
notes. 
7.3 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 

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The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Efforts to reach the participant should continue until the end of the study. Should the 
participant be unreachable at the end of the study, the participant should be considered to 
be lost to follow up with unknown vital status at end of study and censored at latest 
follow up contact. 
A participant 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 participant using publicly available 
sources, if allowed by local regulations. 
 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarised in the SoA. Protocol waivers or 
exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
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• 
The investigator will ensure that data are recorded on the electronic Case Report Forms 
(CRFs). 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 electronic CRFs.  A copy of the 
completed electronic CRFs will be archived at the study site. Additional data to assess the 
impact of COVID-19 pandemic will be collected. 
 
8.1 
Efficacy Assessments 
8.1.1 
Assessment of asthma exacerbation  
Participants enrolled in the study should have had at least 2 or more exacerbations in the prior 
12 months before Visit 1. The list below defines what is acceptable documentation for 
historical exacerbations: 
 
• 
Discharge summaries from a hospital, emergency room, or an urgent care facility 
indicating that a participant 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 participant 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 participant 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 
participant records have been unsuccessful. 
During the study an asthma exacerbation will be defined as a worsening of asthma that leads 
to any of the following: 
 
• 
A temporary bolus/burst of systemic corticosteroids (or a temporary increase in 
stable OCS background dose) for at least consecutive 3 days to treat symptoms of 
asthma worsening; a single depo-injectable dose of corticosteroids will be 
considered equivalent to a 3-day bolus/burst of systemic corticosteroids. 

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• 
An emergency room (ER) or urgent care visit (UC) (defined as evaluation and 
treatment for <24 hours in an emergency department or UC center) due to asthma 
that required systemic corticosteroids (as per the above). 
• 
An in-patient hospitalization (defined as admission to an inpatient facility and/or 
evaluation and treatment in a healthcare facility for ≥ 24 hours) due to asthma. 
 Note: The protocol defined exacerbations will be recorded on the exacerbation “EXACATE” 
eCRF page. Terminology to describe ER and UC visits may differ between countries. All such 
visits have been captured as ER visits on the eCRF page.   
 
The ePRO device will be programmed to alert both the participant and study centre when 
certain prespecified worsening thresholds are crossed as below. The purpose of the alerts is to 
trigger a contact between the site and participant for further evaluation if deemed necessary by 
the investigator. 
• 
Decrease in morning peak flow ≥20% on at least 2 consecutive days compared with 
baseline, and/or 
• 
An increase in rescue medication use of 4 or more puffs on at least 2 consecutive 
days compared with the average use during baseline or use of 12 puffs/day on any 
one day, and/or 
• 
An additional nebulized β2 agonist use on at least 2 consecutive days compared 
with the average use during baseline, and/or 
• 
An increase of 2 or more nights with awakenings due to asthma requiring rescue 
medication over a 7-day period compared with the average during baseline, and/or 
≥ 6 out of previous 7 nights with awakenings due to asthma requiring rescue 
medication (this criteria should be met on 2 consecutive days), and/or 
• 
An increase in total asthma symptom score (the sum single-item global assessment 
of daytime symptoms [evening assessment] and single-item global assessment of 
nighttime [morning assessment] of at least 2 units above the baseline average or the 
highest possible score (daily score of 6), on at least 2 consecutive days. 
 Where an alert is triggered as a result of the 2-consecutive day rule, the alert will be reset 
following activation such that alerts cannot be triggered on consecutive days. 
 If an exacerbation event is not associated with deterioration in at least 1 of the pre-specified 
objective measurements, the Investigator will have to justify the decision for defining the 
event as an exacerbation and record it in the eCRF. Events that are not supported by any 
objective assessment will be deemed not to be a protocol-defined exacerbation. 
The start of an exacerbation is defined as the start date of systemic corticosteroids or of a 
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requiring systemic corticosteroids, or date of hospital admission due to asthma, whichever 
occurs earlier. 
The end date of an exacerbation is defined as the last date of systemic corticosteroids or of a 
temporary increase in a stable OCS background dose, date of ER or urgent care visit, or date 
of hospital discharge, whichever occurs later. 
If less than 7 days have elapsed since the end date of an asthma exacerbation and the start date 
of a new asthma exacerbation, the second event will be considered a relapse of the prior 
asthma exacerbation. 
All asthma exacerbations that occur during the treatment period and follow up, must be 
recorded in the exacerbation eCRF.  See section 8.3.5 for additional information recording 
asthma exacerbations as an AE/SAE during the study. 
8.1.2 
Spirometry 
8.1.2.1 
General Requirements 
Lung function (FEV1 and FEF25-75%) will be measured by spirometry using equipment 
provided by a central vendor. Spirometry will be performed by the Investigator or authorized 
delegate according to American Thoracic Society/European Respiratory Society (ATS/ERS) 
guidelines (Miller et al 2005). 
 
The vendor providing central spirometry is responsible for assuring that the spirometer meets 
ATS/ERS recommendations and that the study center personnel who will be performing the 
testing are properly certified. Spirometry calibration will be detailed in a separate spirometry 
procedures manual. 
 
Important 
• 
Participants should avoid engaging in strenuous exertion for at least 30 minutes 
prior to all lung function assessments at the center. 
• 
Participants should avoid eating a large meal for at least 2 hours prior to all lung 
function assessments at the center.  
• 
Participants should withhold their usual maintenance therapies on the day(s) when 
lung function testing is being performed as below: 
• 
 
˗ SABAs should be withheld at least 6 hours prior to scheduled spirometry at site.  
˗ Twice daily LABA or LAMA-containing therapies should be withheld for at 
least 12 hours prior to scheduled spirometry at site. 
˗ Once daily LABA or LAMA-containing therapies should be withheld for at 
least 24 hours prior to scheduled spirometry at site. 

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˗ LTRA should be restricted for at least 24 hours prior to scheduled spirometry at 
site. 
˗ Twice daily theophyllines should be withheld for at least 12 hours prior to 
scheduled spirometry at site. 
˗ Once daily theophyllines for at least 24 hours prior to scheduled spirometry at 
site.  
Note: If any of the above restriction are not met, the spirometry assessment should be 
rescheduled within the allowed visit window. 
Time of day for scheduled center visit spirometry 
Spirometry testing should be done according to the SoA. For adult participants, 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 visit (Visit 3). 
 
All post-randomization spirometry assessments should be performed within ± 1.5 hours of the 
time that the randomization spirometry was performed. For example, if the randomization 
spirometry was started at 8:00 AM, then all subsequent spirometry testing needs to be initiated 
between 6:30 AM and 9:30 AM. 
Spirometry technique 
Detailed procedure for performing spirometry will be described in a separate instruction 
manual. Details regarding assessment of the quality of spirometry and the best test report 
(BTR) process will also be detailed in the manual.  
 
Spirometry references 
The Global Lung Function Initiative (GLI) equations will be used to determine the Predicted 
Normal Values (PNV) and are pre-programmed into the spirometer (Quanjer PH et al 2012).  
 
FEV1, expressed as percent of the PNV, will be calculated as follows: 
 
FEV1% of PNV = (FEV1 measured/FEV1PNV) x 100 
 
8.1.2.2 
Post-BD spirometry and FEV1 reversibility assessment  
All participants must meet inclusion criteria 8 either by having documented historical 
reversibility or by demonstrating reversibility either at Visit 2 or Visit 2a.  
If documented historical reversibility is available, the post-BD spirometry procedures must be 
performed at Visit 2 to categorize participants (establish baseline characteristic) prior to 
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The highest technically acceptable pre- and post-BD FEV1 will be used to determine 
reversibility. 
 
Reversibility is calculated as follows: 
 
% Reversibility = (post-BD FEV1- pre-BD FEV1) × 100/pre-BD FEV1 
Record keeping 
A signed and dated copy of the pre- and post- BD printout must be kept at study centre for 
source data verification. The printout must be marked with the study code, enrollment code, 
date and time of measurement, visit number. If a printout cannot be printed, the mean value of 
the measurements will be recorded in the participant’s charts.  
8.1.3 
Home PEF testing  
An electronic, hand-held spirometer to measure PEF will be provided to the participant after 
inclusion criteria 7 and 8 has been met. This can be either at Visit 2 or at Visit 2a. 
 
Home PEF testing will be performed by the participant in the morning upon awakening (and 
prior to taking their AM asthma controller) and in the evening at bedtime (and prior to taking 
their PM asthma controller). Recording of home PEF should start from the evening of Visit 2 
or Visit 2a until the morning of Visit 17 (Week 52) using an ePEF meter device supplied by 
the vendor (eResearch Technology Inc.). When possible, ambulatory lung function 
measurements should be taken at least 6 hours after the last dose of SABA rescue medication. 
 
Participants should perform 3 successive peak flow manoeuvres while sitting or standing, but 
in the same position at every testing.  
 
The Investigator/authorized delegate will check participant’s adherence to correct use of the 
peak flow meter at each visit as shown in SoA (or on EOT visit if prematurely discontinued 
from the study).  
 
 
 
 
 
 
 
 
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8.1.5 
CompEx 
CompEx is defined as follows (Fuhlbrigge et al 2017): 
 
An exacerbation (as defined in section 8.1.1) and/or 
An objective deterioration defined as 2 of the following criteria for ≥ 2 consecutive days: 
• 
≥15% decrease from baseline in morning or evening PEF 
AND at least one of the following: 
• 
≥1.5 puffs increase from baseline in rescue medication morning or evening 
• 
≥1 score increase from baseline, or the absolute maximal asthma symptom score in the 
morning or evening  
Or one of the criteria above together with all diary variable showing a slope of worsening over 
at least a 5-day period. 
8.1.6 
Patient reported outcomes 
Patient reported outcomes (PRO) data will be captured electronically using a handheld device 
at home and at the site. Site personnel will be trained on the use of both devices. Detailed 
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procedures for using both devices and participant training on use of the handheld device will 
be described in a separate instruction manual. Participants will be trained on at home use of 
the eDiary and ePEF meter at Visit 2 or 2a. The site staff will set assessment reminder alarms 
on the device. Participant training will include explanation of functionality and proper use of 
the ePEF meter. Training will emphasize the importance of completing the PRO assessments 
as scheduled to capture the participant's experience and meet the objectives of the study. The 
participant will be asked to use both devices as part of the training to verify completion of 
training on the eDiary. The questionnaires will be administered in the handheld device at 
home in the following order: Asthma Symptom Diary, Rescue medication, Total Asthma 
symptom score, nocturnal awakening, maintenance medication, peak expiratory flow 
assessment. 
At home PRO assessment will start the evening of Visit 2, if the participant meets inclusion 
criteria 7 and 8 at this visit. If only one of these criteria are met at Visit 2, the at home ePRO 
assessment should be deferred to the evening of Visit 2a, after the other criteria is also met. 
Participants will complete assessments twice daily and at other timepoints specified in the 
SOA.  
The investigator/authorized delegate will check participant’s adherence to the PRO 
assessment schedule as is necessary to maintain necessary to minimize missing data and at 
each study visit. Frequent compliance checks between visits will be necessary to ensure 
sufficient data is available to meet inclusion criteria 17, 18 and 19. 
8.1.6.1 
Daily Diary 
The daily diary will be completed each day from the evening of Visit 2 or Visit 2a to the 
morning of Visit 17. The morning eDiary will include: Asthma Symptom Diary (ASD) 
morning items, questions about rescue medication, nighttime awakening, and use of 
maintenance medications. The evening eDiary will include: ASD evening items and questions 
about rescue medications. Upon completion of the morning and evening questions the 
participant will complete the peak expiratory flow assessment. 
There will be triggers in the ePRO device to alert the participants to signs of worsening of 
asthma and to contact their physician, please refer to section 8.1.1. The participant should 
contact the investigator for evaluation after receiving a diary alert.  
ASD 
Asthma symptoms will be recorded using the ASD (Globe et al 2015), which comprises 10 
items (5 items in the morning; 5 items in the evening). The morning items assess nighttime 
symptom severity in relation to wheezing, shortness of breath, cough, and chest tightness, and 
the frequency of nighttime awakening. The evening items assess symptom severity in relation 
to wheezing, shortness of breath, cough, and chest tightness, and activity limitation since 

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waking. Items are scored from “0” (no symptom, no nighttime awakening, or no activity 
limitation) to “4” (very severe symptom, unable to sleep, or extreme activity limitation). A 
daily ASD score is the mean of the 10 items. Responses for all 10 items are required to 
calculate the daily ASD score; otherwise, it is treated as missing. Calculation of a daily ASD 
score requires data from the evening diary assessment and the subsequent morning diary 
assessment. For the 7-day average asthma symptom score, scoring is done with no imputation 
using the mean of at least 4 of the 7 daily ASD scores as a mean weekly item score. The 7-day 
average ASD score ranges from 0 to 4. 
Global asthma symptom items 
In addition to the ASD, participants will complete a single item global assessment of asthma 
symptoms (0-3) each morning and evening. The sum of evening and subsequent morning 
single global item scores (0-6) will be used for the alerts system. 
Rescue medication 
The number of rescue medication inhalations (puffs) and nebulizer treatments taken will be 
recorded by the participant in the Asthma Symptom Diary twice daily (i.e., in the morning and 
evening) beginning the evening of Visit 2 or Visit 2a until the morning of Visit 17. The 
number of inhalations taken between the morning and evening lung function assessments will 
be recorded in the evening. The number of inhalations taken between the evening and the 
morning will be recorded in the morning. 
Nocturnal awakenings 
Nocturnal awakenings due to asthma symptoms will be recorded by the participant in the 
Asthma Symptom Diary each morning, beginning in the morning after Visit 2 or Visit 2a until 
the morning of Visit 17, by answering a question as to whether he/she woke up during the 
night due to asthma symptoms by a “yes” or “no” response.  
Maintenance medication 
Maintenance medication administration will be recorded in the Asthma Symptom Diary once 
daily in the morning, beginning in the morning after Visit 2 or Visit 2a until the morning of 
Visit 17. 
8.1.6.2 
Asthma Control Questionnaire (ACQ-6)  
The ACQ-6 captures asthma symptoms (night-time waking, symptoms on waking, activity 
limitation, shortness of breath, wheezing) and short-acting β2-agonist use via participant-
report. 
Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely 
uncontrolled). The mean ACQ-6 score is the mean of the responses. Mean scores of ≤ 0.75 

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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. 
ACQ-6 will be completed at the beginning of site visits using an eDiary in accordance with 
the SoA. 
8.1.6.3 
Standardised asthma quality of life questionnaire for 12 years and older 
(AQLQ(S)+12) 
The AQLQ(S)+12 is a questionnaire that measures the health-related quality of life 
experienced by asthma participants. The questionnaire comprises 4 separate domains 
(symptoms, activity limitations, emotional function, and environmental stimuli). Participants 
are asked to recall their experiences during the previous 2 weeks and to score each of the 
questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The 
overall score is calculated as the mean response to all questions. The 4 individual domain 
scores (symptoms, activity limitations, emotional function, and environmental stimuli) are the 
means of the responses to the questions in each of the domains. The responder definition for 
AQLQ(s)+12 is 0.5-point improvement from baseline. The AQLQ(s)+12 will be completed 
using the eDiary in accordance with the SoA. 
8.1.6.4 
St. George’s Respiratory Questionnaire (SGRQ) 
The SGRQ is a 50-item PRO instrument developed to measure the health status of participants 
with airway obstruction diseases (Jones et al 1991). The questionnaire is divided into 2 parts: 
part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 
weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the 
individual’s respiratory condition. The SGRQ yields a total score and 3 domain scores 
(symptoms, activity, and impacts). The total score indicates the impact of disease on overall 
health status. This total score is expressed as a percentage of overall impairment, in which 100 
represents the worst possible health status and 0 indicates the best possible health status. 
Likewise, the domain scores range from 0 to 100, with higher scores indicative of greater 
impairment. Based on empirical data and interviews with participants, a mean change score of 
4 units is associated with a minimum clinically important difference (MCID). Specific details 
on the scoring algorithms are provided by the developer in a user manual (Jones et al 2009). 
SGRQ will be completed at the beginning of site visit using eDiary in accordance with the 
SoA. 
8.1.6.5 
European quality of life-5 dimensions-5 levels (EQ-5D-5L) 
The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, 

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slight problems, moderate problems, severe problems, and extreme problems) that reflect 
increasing levels of difficulty.  
The participant will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions. The questionnaire also includes a visual 
analogue scale, where the participant will be asked to rate current health status on a scale of 0- 
100, with 0 being the worst imaginable health state. 
The EQ-5D-5L will be completed using the eDiary in accordance with the SoA. 
8.1.6.6 
Sino-nasal Outcome Test (SNOT-22) 
The SNOT-22 is a 22-item health-related outcomes assessment for sinonasal conditions 
(Hopkins et al 2009). The tool is a modification of the SNOT-20 (Piccirillo et al 2002) where 
items related to nasal blockage and loss of sense of tastes and smell have been added and the 
importance rating has been removed. The 22-question SNOT-22 is scored as 0 (no problem) to 
5 (problem as bad as it can be) with a total range from 0 to 110 (higher scores indicate poorer 
outcomes); a MCID of 8.90 has been established (Hopkins et al 2009). 
The SNOT-22 will be completed at the site visits in accordance with the SoA. 
8.2 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1 
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 
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 8.3.5 
for details. 

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8.2.2 
Weight and height 
Weight and height will be measured in accordance with the SoA. The participant’s weight will 
be recorded in kilograms, and height will be recorded in centimeters. Weight and height 
measurements will be performed in light clothing and with shoes off. 
8.2.3 
Vital Signs 
Vital signs (i.e. pulse, blood pressure, respiration rate and body temperature) will be obtained 
in accordance with 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 participant in a quiet setting without distractions (e.g., television, cell phones).  
Pulse rate will be obtained before blood pressure, if the manual measurement technique is 
used. 
Respiration rate will be obtained after participant has been resting for at least 5 minutes, by 
counting number of breaths (i.e., how many times the chest rises) for one minute. 
Body temperature will be measured in degrees Celsius prior to IP administration, in 
accordance with local standards. 
8.2.4 
Electrocardiograms 
A 12-lead ECG will be taken in supine position, prior to blood draw, spirometry, BD 
administration and IP administration.  
The investigator or authorized delegate will be responsible for the overall interpretation and 
determination of clinical significance of any potential ECG findings. In case of discrepancy 
between the investigator's interpretation and that provided by the ECG machine (if 
applicable), the investigator's interpretation will take precedence and should be noted on the 
printout and recorded in the eCRF. A copy of the ECG will be produced and quality checked 
and kept in case of further need for re-evaluation. 
It is highly recommended that the same machine is used for assessment throughout the 
participant’s participation in the study. 
ECG data and evaluation will be recorded in the eCRF. 

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8.2.5 
Clinical Safety Laboratory Assessments 
See Table 9 for the list of clinical safety laboratory tests to be performed and to the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in the 
table, must be conducted in accordance with the laboratory manual and the SoA.   
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables.   
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.5. 
The clinical chemistry, haematology and urinalysis will be performed at a central laboratory. 
Table 9 
Laboratory safety variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Haemoglobin (Hb) 
S-Alkaline phosphoatase (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 
B-Mean Corpuscular Volume  
S-Calcium, total 
B-Red blood cell (RBC) count 
S-Chloride 
Urinalysis  
S-Creatinine 
U-Hb/Erythrocytes/Blood  
S-Creatinine kinase (CK) 
U-Protein/Albumin  
S-CRP 
U-Glucose  
S-Gamma-glutamyl transpeptidase (GGT) 
U-Microscopy and culture as required* 
S-Glucose 
 
S-Phosphorus 
 
S-Potassium 
 
S-Sodium 
 
S-Total cholesterol 
 
S-Uric acid 
*Urine samples will be analysed by the central laboratory only when a positive urinalysis result for any parameter is 
observed. 

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8.2.6 
Other Safety Assessments 
8.2.6.1 
Serology 
Hepatitis B surface antigen, hepatitis C antibody will be tested in Central lab, HIV-1 and HIV-
2 antibodies will be performed in local lab. All these testing will be assessed at enrolment 
(Visit 1) only. Instructions for sample collection, processing, storage, and shipment will be 
provided in a separate laboratory manual provided to the sites. 
8.2.7 
COVID-19 vaccination 
COVID-19 vaccines are either nucleic acid vaccines (which can include DNA plasmid and 
mRNA), recombinant vector vaccines (non-replicating viral vectors) or inactivated virus 
vaccines. DNA plasmid and mRNA vaccines are considered an inactivated vaccine. 
Recombinant vector candidates potentially may be in a new category. Based on available 
publications on mRNA and virus vector anti-SARS CoV-2 vaccines, the immune response 
developed rapidly after vaccination administration. No live attenuated COVID-19 vaccines are 
currently available. For vaccines that are currently approved under emergency use authorization 
(EUA) or approved in the future, please refer to relevant health authority websites for further 
guidance.  
 
Please note that any live attenuated vaccine is prohibited during study conduct (see Table 8).  
 
Given the limited long term safety data of COVID-19 vaccines and the potential to confound 
the interpretation of safety results in the study, the following COVID-19 vaccination guidance 
(Table 10) should be followed depending on the study period. 
Table 10 
COVID-19 Vaccination guidance 
 
Study Period 
Vaccine usage 
Participants at 
screening/run-in period 
• 
If COVID-19 vaccination is in the best interest of the participant and 
the participant is vaccinated or scheduled to be vaccinated before the 
screening or run-in visit, the randomization visit should be scheduled 
to ensure that the first IP dose is administered at least 28 days after 
any vaccination dose. As these intervals might change, please discuss 
with the study physician for most current recommended time interval 
prior to any vaccine dose.  
 
See exclusion #15 in section 5.2. 
 
Participants in treatment 
period 
 
 
 
  
 
 
• 
If COVID-19 vaccination is in the best interest of the participant and 
the participant is vaccinated during the study, IP dosing can continue 
but IP should not be administered within 14 days before or 28 days 
after a dose of vaccine. As these intervals might change, please discuss 
with study physician for the most current recommended time interval 
prior to any vaccine dose. 
 
• 
If participant receives COVID-19 vaccine less than 14 days from the 

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COVID-19 vaccine details including vaccine’s name/manufacturer, route of administration, and 
vaccination date should be entered into the eCRF CM module. 
 
If a participant experiences an AE/SAE associated with COVID-19  vaccination, the 
investigator should record this in source document and determine whether the IP should be 
continued, skipped or permanently discontinued in accordance with section 7.1 
8.3 
Adverse Events and Serious Adverse Events 
The Principal investigator (PI) is responsible for ensuring that all staff involved in the study 
are familiar with the content of this section 
The definitions of an AE or SAE can be found in Appendix B. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorised representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs 
see section 8.3.2.   
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
Adverse events will be collected from time of signature of the informed consent form, 
throughout the treatment period and the follow-up period. 
SAEs will be recorded from the time of signing of the informed consent form. 
If the investigator becomes aware of an serious adverse event with a suspected causal 
relationship to the investigational medicinal product that occurs after the end of the clinical 
study in a participant treated by him or her, the investigator shall, without undue delay, report 
the serious adverse event to the sponsor. 
8.3.2 
Follow-up of AEs and SAEs 
Any AEs that are unresolved at the participant’s last AE assessment or other assessment/visit 
as appropriate in the study are followed up by the investigator for as long as medically 
indicated, but without further recording in the eCRF. AstraZeneca retains the right to request 
additional information for any participant with ongoing AE(s)/SAE(s) at the end of the study, 
if judged necessary. 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAE/non-serious AEs/AEs of special interest, 
will be followed until resolution, stabilization, the event is otherwise explained, or the 
participant is lost to follow-up.  

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Adverse event variables 
'The following variables will be collected for each AE; 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
Whether the AE is serious or not 
• 
Maximum Intensity 
• 
Investigator causality rating against the Study Intervention(s) (yes or no) 
• 
Action taken with regard to Study Intervention(s) 
• 
AE caused participant’s withdrawal from study (yes or no) 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date investigator became aware of SAE 
• 
AE is serious due to 
• 
Date of hospitalisation 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 
• 
Description of AE 
 
8.3.3 Causality Collection 
The investigator should assess causal relationship between Study Intervention and each AE 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the study intervention?’ 
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 

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Study Protocol.  
8.3.4 Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the participant 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 eCRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 
8.3.5 Adverse Events Based on Examinations and Tests 
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the Clinical Study Report (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, are the reason 
for discontinuation of treatment with the study intervention or are considered to be clinically 
relevant as judged by the investigator (which may include but not limited to consideration as 
to whether treatment or non-planned visits were required or other action was taken with the 
study intervention, eg, dose adjustment or drug interruption).  
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
When collecting AEs, the recording of diagnoses is preferred, when possible, to recording a 
list of signs and symptoms. Asthma symptoms or signs, such as wheeze, cough, chest 
tightness, dyspnea, breathlessness and phlegm, will be recorded as AEs only when: 
• 
The sign or symptom is serious according to definitions, see Appendix B  
• 
The participant discontinues IP due to the sign or symptom 

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• 
The sign or symptom is new to the participant or not consistent with the 
participant’s pre-existing asthma history (defined as within 1 year of Visit 1) as 
judged by the Investigator. 
Asthma exacerbation should be recorded as an AE or SAE only if it fulfils any of the above 
criteria 
8.3.6 Hy’s Law 
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN 
may need to be reported as SAEs. Please refer to Appendix D for further instruction on cases 
of increases in liver biochemistry and evaluation of Hy’s Law 
8.3.7 
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: 
• 
Serious hypersensitivity reactions 
• 
Malignancy 
• 
Helminth infections  
• 
Serious infectionsa 
• 
Guillain Barre Syndrome 
• 
Serious cardiac events 
 
aeCRF 'Severe infections' pages to be completed for infections which are defined as SAE,  or requiring 
treatment with systemic antiviral medications, intravenous antibiotics or medications for helminth 
parasitic infection, or requiring a permanent discontinuation of study drug. 
 
8.3.8 
Reporting of Serious Adverse Events 
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative will work with the investigator to ensure that all 

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the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day, ie, immediately but no later than 24 hours of when he or she 
becomes aware of it. 
Once the investigators or other site personnel indicate an AE is serious in the web-based data 
capture (WBDC) system, an automated email alert is sent to the designated AstraZeneca 
representative. 
If the WBDC system is not available, then the investigator or other study site staff reports a 
SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the investigator/study site staff how to proceed.  
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study 
Protocol. 
The reference document for definition of expectedness/listedness is the IB for  tezepelumab.  
8.3.9 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for: 
• If the pregnancy is discovered before the study participant has received any study 
intervention 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy.  
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.9.1 
Maternal Exposure 
If a participant becomes pregnant during the course of the study, study intervention should be 
discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the study 
intervention under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital anomalies/birth defects and spontaneous miscarriages should be 

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reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or congenital anomaly/birth defect) should be 
followed up and documented even if the participant was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.8) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy. 
8.3.9.2 
Paternal Exposure  
Pregnancy of the participant’s partners will not be considered an AE. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital anomaly) should be followed up and documented in the Pregnancy Report 
Form for conceptions occurring from the date of the first administration of IP until 16 weeks 
(5 half-lives) after the last administration of IP. Consent from the partner must be obtained 
before the Pregnancy Report Form is completed. 
8.3.10 
Medication Error,Drug Abuse and Drug Misuse 
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one calendar day, ie, immediately but no later than 24 hours of when he or she becomes 
aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within one (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, drug abuse, or misuse (see Section 8.3.8) and 
within 30 days for all other events. 

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8.3.10.1 
 Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant. 
 
The full definition and examples of  medication error can be found in Appendix B4.  
8.3.10.2 
Drug Abuse 
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect. 
The full definition and examples of drug abuse can be found in Appendix B 4. 
8.3.10.3 
Drug Misuse 
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route. 
The full definition and examples of drug misuse can be found in Appendix B 4. 
8.3.11 
Management of IP-related toxicities 
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, and corticosteroids, as 
well as medical equipment to treat acute anaphylactic reactions, must be immediately 
available when IP is being administered.  Study site personnel must be trained to recognize 
and treat anaphylaxis (Lieberman et al 2010). Details on anaphylaxis management are 
provided in Appendix E . 
 
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Sampson et al 2006). Anaphylaxis typically manifest as 1 of 3 clinical scenarios: 
 
1. The acute onset of a reaction (minutes to hours) with involvement of the skin, 
mucosal tissue or both and at least one of the following: a) respiratory compromise; 
or b) reduced blood pressure or symptoms of end-organ dysfunction  
2. Two or more of the following that occur rapidly after exposure: involvement of the 
skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated 
symptoms and/or persistent gastrointestinal symptoms 
3. Reduced blood pressure after exposure 
Participants will have had a pre-assessment (i.e., vital signs and lung function) prior to IP 
administration. At Visits 3 and 5, participants should be observed for a minimum of 2 hours 

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after IP administration for the appearance of any acute drug reactions. For the remaining visits 
involving IP administration, participants will be observed for a minimum of 1 hour after IP 
administration for any such reaction. 
 
If an anaphylactic reaction occurs, a blood sample will be drawn from the participant 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. 
8.3.12 
Independent Adjudication Committee (IAC) 
An independent adjudication committee is constituted to provide an external independent 
assessment of blinded data during the Phase 3 trials to confirm the diagnosis and causality of 
MACE events (defined in the IAC charter), serious cardiac events, deaths, as well as the 
diagnosis of malignancies that occur from randomization until the end of the follow up period. 
This independent adjudication committee, also evaluates cases of ER or urgent care visits and 
hospitalizations that occur from randomization up to the end of follow up period, to evaluate 
whether any such event is due to a worsening of asthma. The committee includes specialists in 
pulmonology, cardiology, neurology and oncology and operates in accordance with dedicated 
Adjudication Committee Charter/Manual of Operations. 
8.3.13 
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 participant is the preferred method to inquire about 
AE occurrences.   
8.4 
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 on IMP or AstraZeneca 
NIMP and possible symptoms of an overdose are not established. 
In the event of an overdose, the investigator should: 
• Evaluate the participant to determine, in consultation with the Study Clinical Lead, if 
possible, whether study intervention should be interrupted or whether the dose should 
be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
• An overdose with associated AEs is recorded as the AE diagnosis/symptoms on 
the relevant AE modules in the eCRF and on the Overdose eCRF module. 

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• An overdose without associated symptoms is only reported on the Overdose 
eCRF module 
 
If an overdose on an IMP or AstraZeneca NIMP occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
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 one 
or 5 calendar days for overdoses associated with an SAE (see section 8.3.8) and within 
30 days for all other overdoses. 
8.5 
Pharmacokinetics and immunogenicity 
8.5.1 
Collection of samples and drug concentration 
Serum samples for determination of tezepelumab will be collected pre-dose according to the 
SoA (Table 2). 
Samples will be collected, labeled, 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. 
8.5.2 
Collection of samples to measure the immunogenicity of tezepelumab 
The immunogenicity of tezepelumab will be assessed in serum samples according to the SoA 
(section 1.3). 
Samples will be measured for the presence of ADAs and neutralizing antibodies (nAb) 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 with confirmed positive 
ADA will be analyzed for the presence of ADA-neutralizing antibodies. 
Samples will be analysed by designated third party on behalf of AstraZeneca. Samples will be 
disposed of after the Clinical Study Report finalization. 
8.5.3 
Storage and destruction of pharmacokinetic/immunogenicity samples 
 The residual pharmacokinetic/immunogenicity samples aliquots may be retained for the 
purposes of reanalysis at AstraZeneca or designee for a maximum of 5 years after publication 
of the Clinical Study Report or as per local regulation, after which they will be destroyed. This 
is intended to allow AstraZeneca to investigate any anomalous results or respond to regulatory 

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authority questions. Samples will only be re-analysed according to the original purpose for 
which they were collected (eg pharmacokinetic / immunogenicity analysis). 
8.5.4 
Pharmacodynamics 
Pharmacodynamic parameters will be evaluated using biomarkers (see section 8.6). 
8.6 
Biomarkers 
Serum samples will be collected according to the schedule in Table 2 to evaluate the 
pharmacology of tezepelumab and to evaluate changes in biomarkers related to asthma. 
Instructions for sample collection, processing, storage, and shipment can be found in a 
separate laboratory manual provided to the centers. 
8.6.1 
Storage, re-use and destruction of biomarker samples 
Samples will be stored and disposed according to local laws and regulations. Summaries and 
analyses for biomarkers will be documented in a separate analysis plan and will be reported 
outside the CSR in a separate report. The results of this biomarker research may be pooled 
with biomarker data from other studies involving tezepelumab to generate hypotheses to be 
tested in future research. 
8.6.2 
Serum Immunoglobulins 
The levels of total 
 will be tested by a central 
laboratory in accordance with the SoA. Instructions for sample collection, processing, storage 
and shipment will be provided in a separate laboratory manual. 
8.6.3 
Other Study Related Biomarker Research 
Not Applicable 
8.7 
Optional Genomics Initiative Sample 
Not applicable 
8.8 
Healthcare Resource Utilization and Health Economics 
Healthcare resource utilization and health economics data, associated with medical 
encounters, will be collected in the CRF by the investigator and study-site personnel for all 
participants throughout the study. At randomization, Healthcare Resource Utilization (HRU) 
information will be collected with a ‘one year’ recall period. All the subsequent visits will 
collect HRU information with a recall period of ‘since the last scheduled visit’. The data may 
be used as input to health economic analysis for example cost utility analysis or cost 
effectiveness analysis. Protocol-mandated procedures, tests, and encounters are excluded. Any 
results from such analyses may be reported separately from the Clinical Study Report (CSR). 
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9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The following two-sided hypotheses will be evaluated in this trial. The nominal significance 
levels and methodology for accounting for multiplicity in testing these hypotheses is described 
in Section 9.4. 
Primary endpoint 
H01: AAER ratio over 52 weeks (tezepelumab/placebo) = 1 
versus 
H11: AAER ratio over 52 weeks (tezepelumab/placebo) ≠ 1 
The direction of superiority of tezepelumab is indicated by a rate ratio less than 1. 
Key secondary endpoints 
H02: Difference in mean change from baseline in pre-BD FEV1 at 52 weeks (tezepelumab 
minus placebo) = 0 
versus 
H12: Difference in mean change from baseline in pre-BD FEV1 at 52 weeks (tezepelumab 
minus placebo) ≠ 0 
The direction of superiority of tezepelumab is indicated by a difference in means greater than 
0. 
H03a: Difference in mean change from baseline in AQLQ(S)+12 total score at 52 weeks 
(tezepelumab minus placebo) = 0 
versus 
H13a: Difference in mean change from baseline in AQLQ(S)+12 total score at 52 weeks 
(tezepelumab minus placebo) ≠ 0 
The direction of superiority of tezepelumab is indicated by a difference in means greater than 
0. 
H03b: Difference in mean change from baseline in ACQ-6 score at 52 weeks (tezepelumab 
minus placebo) = 0 
versus 

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H13b: Difference in mean change from baseline in ACQ-6 score at 52 weeks (tezepelumab 
minus placebo) ≠ 0 
The direction of superiority of tezepelumab is indicated by a difference in means less than 0. 
H04: Difference in mean change from baseline in weekly mean daily ASD score at 52 weeks 
(tezepelumab minus placebo) = 0 
versus 
H14: Difference in mean change from baseline in weekly mean daily ASD score at 52 weeks 
(tezepelumab minus placebo) ≠ 0 
The direction of superiority of tezepelumab is indicated by a difference in means less than 0. 
9.2 
Sample Size Determination 
Approximately 396 participants will be randomly assigned to study treatment using 1:1 
allocation between the two treatments. The sample size is estimated based on the primary 
endpoint (AAER) only.  
198 participants per arm are planned to be randomized assuming a 10% dropout rate to obtain 
178 completers. With 178 participants per treatment group, it is estimated that for the primary 
endpoint (AAER), assuming a placebo rate of
 and a shape parameter of
 (over-
dispersion), there will be 90% power to detect a rate reduction of
 at a 2-sided 
significance level of 5%.  The methodology used is described in Keene et al (2007) and Zhu 
and Lakkis (2014). The minimum detectable rate reduction with the above assumptions is 
. 
The study is powered based on the primary endpoint (AAER) only and not for the subsequent 
multiple testing procedures of the key secondary endpoints described in Section 9.4. 
China will contribute at least 70% of the 396 participants. The remaining participants will be 
contributed by other countries. 
9.3 
Populations for Analyses 
For purposes of analysis, the following populations are defined:  
Population 
Description 
All participants analysis set  
All enrolled participants who sign the ICF. 
Randomised participants 
analysis set 
All participants randomized to study treatment (irrespective of whether 
study treatment is subsequently taken). 
Full Analysis Set (FAS) 
All participants randomized to study treatment who received at least one 
dose of IP, irrespective of their protocol adherence and continued 
participation in the study.  
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Safety Analysis Set 
All participants who received at least one dose of IP.  
Pharmacokinetic (PK) 
Analysis Set  
All participants in the full analysis set who received active (tezepelumab) 
treatment and had at least one detectable serum concentration from a PK 
blood sample collected post first dose which is assumed not to be affected 
by factors such as protocol deviations. 
For analysis of efficacy variables, participants will be assigned to the FAS (defined above) 
according to their randomized treatment. 
Safety presentations and anti-drug antibodies (ADA) presentations will be based on the safety 
analysis set, with participants assigned according to their actual treatment. Further details of 
how actual treatment will be determined for analysis in the event of treatment dispensing 
errors etc. will be specified in the statistical analysis plan (SAP). Any important deviations 
from the randomized treatment assignment, and any participants that have received study 
intervention without being randomized, will be listed and considered when interpreting the 
safety data. 
Summaries of PK will be based on the PK analysis set. 
9.4 
Statistical Analyses 
Two DBLs are planned in this study. The primary DBL will be conducted after the last 
participant completes the 52-week double-blind treatment period. The final DBL will be 
conducted after the last participant completes the last safety follow-up visit (Week 64).  
After the primary DBL, the study treatment allocation for participants will become known to 
the sponsor staff. The blind will be maintained for the investigators, investigational site staff 
and participants until the final DBL. All personnel involved with the analysis of the study will 
remain blinded until the primary DBL. Important protocol deviations will be identified prior 
to unblinding at the primary DBL. 
All analyses of the primary and secondary endpoints will be performed based on the primary 
DBL data. Additional summaries based on the final DBL data will be produced as appropriate. 
Analyses will be performed by AstraZeneca or its representatives. A comprehensive SAP will 
be prepared prior to review of any potential treatment-revealing data is undertaken and any 
subsequent amendments will be documented, with final amendments completed prior to 
unblinding of the data at the primary DBL. The SAP will describe the participant populations 
to be included in the analyses, and procedures for accounting for missing, unused, and 
spurious data. This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints. Any deviations from this plan will be reported in the clinical study 
report. 
Frequency and percentages of participant disposition and reasons for discontinuation of IP 
will be presented. Participants who prematurely discontinue the IP will be listed along with 

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the reason for discontinuation. In addition, frequency and percentages of withdrawal from the 
study together with reasons will be presented. 
Demographics and participant characteristics will be summarized by treatment group using 
frequency and percentages (for categorical variables) and n, mean, standard deviation, 
minimum, median and maximum (for continuous variables) using the FAS. 
Relevant medical history/current medical conditions will be summarized by treatment group, 
system organ class and preferred term of the MedDRA dictionary using frequency and 
percentage of participants for each treatment group. 
Prior and concomitant medications, categorized according to the WHO Drug Reference List 
dictionary which employs the Anatomical Therapeutic Chemical (ATC) classification system, 
will be summarized by treatment group as frequency and percentage of participants reporting 
usage. Prior medications are defined as those which stopped before first dose of IP. 
Concomitant medications are defined as those which either started or continued after first dose 
of IP. 
Important protocol deviations will be defined at participant level prior to unblinding at the 
primary DBL and will be summarized by treatment group. With the exception of the PK 
analysis set, participants will not be excluded from analysis sets on the basis of any important 
protocol deviations. The definitions of each category of important protocol deviation will be 
fully specified in the study Non-compliance Handling Plan and will include (but may not be 
limited to): participants who were randomized to study treatment without fulfilling key entry 
criteria; participants who received prohibited or restricted concomitant medications during IP 
treatment, participants who received the incorrect study treatment or study dose at any time 
during the 52-week double-blind treatment period. 
9.4.1 
General Considerations 
9.4.1.1 
Multiple testing procedures 
The overall Type 1 error rate will be strongly controlled at the 0.05 level across the primary 
and key secondary endpoints. The following hierarchical testing strategy will be applied, 
ordered by clinical relevance, with the hypotheses to be tested as defined in Section 9.1: 
Level 1 
The null hypothesis H01 will be tested at a 2-sided 5% significance level with regard to the 
primary endpoint (AAER). 
Level 2 

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If H01 is rejected at the 2-sided 5% significance level, then the null hypothesis H02 will be 
tested at a 2-sided 5% significance level with regard to change from baseline in pre-BD FEV1. 
Level 3 
If H02 is rejected at the 2-sided 5% significance level, then the null hypotheses H03a and 
H03b will be simultaneously tested at an overall 2-sided 5% significance level with regard to: 
• 
change from baseline in AQLQ(S)+12 total score 
• 
change from baseline in ACQ-6 score 
using a truncated Hochberg approach. In general, under this approach, the highest of the two 
ordered p-values within Level 3 will be evaluated at a γα + (1-γ)α/2 significance level (2-
sided), and the lowest of the 2 ordered p-values within Level 3 will be evaluated at a γα/2 + 
(1-γ)α/2 significance level (2-sided), where α = 0.05, and where γ is the truncation parameter 
(0 ≤ γ ≤ 1). 
It is noted an intermediate choice 0 < γ < 1 of the truncation parameter represents a choice 
between these extremes of regular Hochberg (corresponding to γ = 1) and Bonferroni 
approaches (γ = 0), balancing considerations of how stringent hypothesis testing should be in 
Level 3 in order to claim significance, versus the ability to subsequently claim significance 
from formal hypothesis testing in Level 4. In this trial γ will be set to 0.5. 
Using this choice of truncation parameter, the highest of the two Level 3 p-values will be 
evaluated at a 3.75% significance level (2-sided). If it is significant at the 3.75% level, then 
both hypotheses H03a and H03b will be rejected, and testing will proceed to Level 4. If it is 
not significant at the 3.75% level, then the lowest of the 2 Level 3 p-values will be evaluated 
at a 2.5% significance level (2-sided). If it is significant, then the relevant null hypothesis 
(either H03a or H03b) will be rejected, and testing will proceed to Level 4. If it is (also) not 
significant, then formal testing will stop at Level 3. The significance levels for subsequent 
evaluation in Level 4 for each of these scenarios are given below. 
Level 4 
The null hypothesis H04 will be tested at the significance level retained from Level 3, which 
depends on the outcomes in Level 3 as follows: 
• 
Case 1: If both comparisons in Level 3 exhibit statistical significance, then H04 will be 
tested at a 2-sided 5% significance level with regard to change from baseline in weekly 
mean daily ASD score. 
• 
Case 2: If only one of the comparisons in Level 3 exhibits statistical significance, then 
H04 will be tested at the 2-sided significance level α – [γα + (1-γ)α/2] retained from 
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Using the proposed choice of γ = 0.5, if both H03a and H03b were rejected in Level 3, then 
H04 in Level 4 will be tested at a 2-sided 5% significance level (Case 1). If only one of H03a 
and H03b was rejected in Level 3, then H04 in Level 4 will be tested at a 2-sided 1.25% 
significance level (Case 2). 
9.4.1.2 
Definition of baseline 
In general, the last measurement on or prior to the date of randomization will serve as the 
baseline measurement for efficacy endpoints while the last measurement prior to the first dose 
of study treatment will serve as the baseline measurement for safety endpoints. If there is no 
value on or prior to randomization (or the first dose of study treatment, depending on the 
endpoint), then the baseline value will not be imputed and will be set to missing.  
For weekly means derived from participant diaries, baseline is defined as the mean of the 
available data in the most recent week prior to the date of randomization. If more than 3 days 
are missing, then the baseline weekly mean will be set to missing. The “most recent week” 
starts with the evening measurement one week prior to the date of randomization and ends 
with the morning measurement on the day of randomization. 
Further details regarding baseline definitions will be provided in the SAP. 
Change from baseline is defined as the absolute difference between the measurement at the 
relevant post-baseline time point and the baseline value. 
9.4.2 
Efficacy  
9.4.2.1 
Primary Endpoint(s) 
The primary analysis of the primary efficacy endpoint (AAER over 52 weeks) will quantify 
the effect of the initially randomized treatment, regardless of the treatments that participants 
actually received, or whether the participants received other controller therapy/rescue 
medications post IP discontinuation. This analysis will therefore include all available data 
after treatment discontinuation until the end of the planned treatment period. Participants will 
be encouraged to continue to undergo applicable study related visits/procedures for the full 
52-week period even after premature discontinuation of IP. Consequently, participants lost to 
follow-up and participants who withdraw their consent will be the only source of missing 
information for the primary analysis. Missing data will be modelled based on what was 
observed during the study using direct likelihood approaches, which is a valid approach under 
the assumption that data are missing at random (MAR). 
AAER in the tezepelumab group will be compared to that seen in the placebo group using a 
negative binomial model. This model will be used to perform the statistical test specified in 
Section 9.1, and to estimate the treatment effect and its 95% confidence intervals. The 
response variable in the model will be the number of asthma exacerbations experienced by a 

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participant over the 52-week study period (or shorter duration if not followed up for the full 
52 weeks). Treatment, region (China or non-China) and history of exacerbations (≤2 or >2 in 
previous 12 months) will be included as factors in this model. The logarithm of the time at 
risk for exacerbation in the study will be used as an offset variable in the model, to adjust for 
participants having different follow-up times during which the events occur. Time during an 
exacerbation and the 7 days following an exacerbation in which a new exacerbation cannot 
occur, will not be included in the calculation of time at risk for exacerbation. 
Descriptive summaries of the asthma exacerbations will also be presented. 
Annualized rates for the individual exacerbation criteria (emergency room visits due to asthma 
that required systemic corticosteroids, hospitalization due to asthma, or use of systemic 
corticosteroids) will be summarized descriptively. The exacerbations associated with 
emergency room visits or hospitalisations and the exacerbations associated with 
hospitalisations only will be analyzed using a similar model as for the primary endpoint, 
respectively. 
Subgroup analyses, and exact definition of all relevant categories where needed, will be pre-
specified in the SAP. 
Sensitivity analyses on the primary endpoint will be performed and will be fully specified in 
the SAP. These may include, but not necessarily be limited to: 
• 
Analysis which makes provision for data to be missing-not-at-random (MNAR) and 
which makes different assumptions regarding those participants who discontinue 
treatment or study prior to 52 weeks. 
• 
Analysis which uses the exacerbation data captured whilst receiving study treatment 
only 
• 
Analysis in which adjudication outcomes of the ER or urgent care visits, 
hospitalizations and all deaths are considered. 
9.4.2.2 
Secondary Endpoint(s) 
The main analysis of the key secondary endpoints (changes from baseline to Week 52 for each 
of pre-BD FEV1, AQLQ(S)+12 total score, ACQ-6 score and weekly mean daily ASD score) 
will quantify the effect of the initially randomized treatment at Week 52, regardless of the 
treatments that participants actually received, or whether the participants received other 
controller therapy/rescue medications, including participants who discontinued study 
treatment prior to Week 52. This analysis will therefore include all available data after 
treatment discontinuation until the end of the planned treatment period. Missing data will be 
modelled based on what was observed during the study using direct likelihood approaches, 
which is a valid approach under the assumption that data are missing at random (MAR). 

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Change from baseline for the key secondary endpoints in the tezepelumab group will be 
compared to that seen in the placebo group using a linear model for repeated measures. In this 
model, inference will be based on the restricted maximum likelihood estimation. This model 
will be used to perform the statistical tests specified in Section 9.1, and to estimate the 
treatment effect at Week 52 and its 95% confidence interval for each endpoint. The response 
variable in the model will be change from baseline at each scheduled post-randomization visit 
up to and including Week 52, and irrespective of whether the participant remained on 
treatment and/or took other treatments. Treatment, visit, region (China or non-China) and 
treatment by visit interaction will be included as factors in this model. Baseline of the 
corresponding endpoint will also be included in the model as a continuous linear covariate. 
Unstructured covariance will be assumed to model the relationship between pairs of response 
variables taken at different visits on the same participant. If this model fails to converge with 
unstructured covariance, the SAP will pre-specify the approach for selecting a simpler 
covariance structure. The Kenward-Roger approximation to estimating the degrees of freedom 
will be used for tests of fixed effects derived from this model. 
Descriptive summaries of the key secondary endpoints will also be presented. Adjusted means 
from the repeated measures model above will be displayed graphically over time and used to 
evaluate time of onset of effect. 
Subgroup analyses, and exact definition of all relevant categories where needed, will be pre-
specified in the SAP. 
Sensitivity analyses on the key secondary endpoints will be performed and will be fully 
specified in the SAP. These may include, but not necessarily be limited to, the same items 
considered for the primary endpoint in Section 9.4.2.1. 
As a supportive analysis to the analysis of change from baseline in ACQ-6, the main ACQ-6 
analysis described above will be repeated for change from baseline in ACQ-5 and ACQ-7 
score using a similar repeated measures model. Similar descriptive and graphical summaries 
will also be produced. 
As further supportive analyses to the analyses of change from baseline in ACQ-6 and 
AQLQ(S)+12, responders/non-responders (as defined in Sections 8.1.6.2 and 8.1.6.3) will be 
summarized descriptively and analyzed using a generalised linear model for repeated 
measures, using a logit link function. In this model, inference will be based on generalised 
estimating equations using the method of Liang and Zeger (1986). The response variable in 
this model will be the binary responder status at each scheduled post-randomisation visit up to 
and including Week 52, irrespective of whether the participant remained on treatment and/or 
took other treatments. Treatment, visit, region (China or non-China) and treatment by visit 
interaction will be included as factors in the model. Baseline of the corresponding endpoint 

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will also be included in the model as a continuous linear covariate. Further details will be 
specified in the SAP. 
9.4.2.3 
Analysis of other efficacy endpoints 
Annualized rates for other relevant endpoints will be summarized descriptively and analyzed 
using a similar model as for the primary endpoint (Section 9.4.2.1).    
Other binary endpoints will be summarized descriptively and analyzed using a logistic 
regression model with factors which will include treatment, region (China or non-China). 
Baseline of the corresponding endpoint will also be included in the model (where relevant) as 
a continuous linear covariate. 
Other continuous endpoints will be summarized descriptively and analyzed using a repeated 
measures model analogous to that specified for key secondary endpoints (Section 9.4.2.2). 
Log transformation of endpoints prior to implementing the repeated measures model will be 
considered for continuous endpoints which do not meet the distributional assumptions, and 
this will be pre-specified in the SAP where possible. 
Time to first asthma exacerbation will be summarized graphically using Kaplan-Meier 
estimates, and analyzed using a Cox proportional hazards model with factors for treatment, 
region (China or non-China) and history of exacerbations (≤2 or >2 in previous 12 months). 
Further details of statistical models for other efficacy endpoints will be specified in the SAP, 
including details of how missing data and data collected after premature discontinuation of 
study treatment will be handled. 
Sensitivity and subgroup analyses will not be performed on other efficacy endpoints, unless 
specified otherwise in the SAP. 
9.4.3 
Safety 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 
in force at the primary DBL. The definition of on-treatment and on-study for AE analyses will 
be given in the SAP. 
The number and percentage of participants with on-treatment and on-study AEs will be 
tabulated separately by preferred term and system organ class. An event that occurred one or 
more times during a period will contribute 1 observation to the numerator of the proportion. 
The denominator of the proportion will comprise all participants in the safety analysis set. On-
treatment AEs will also be summarized by intensity/severity and separately, by 
causality/relatedness (as determined by the investigator). Should a participant report the same 
preferred term/system organ class within multiple intensity/severity or causality/relatedness 
categories, the participant’s worst occurrence (most severe/most related) will be tabulated. 

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Serious AEs, AEs leading to discontinuation from IP, and commonly occurring AEs will be 
summarized in a generally similar manner. AEs, SAEs, AEs leading to death, and AEs leading 
to discontinuation of IP will be summarized for each treatment group as applicable. 
An overall summary of on-treatment AEs will be presented by treatment group adjusted for 
participant exposure to treatment. 
AEs of Special Interest (AESIs), as defined in Section 8.3.7 will also be summarized 
descriptively by treatment group. 
Laboratory data will be summarized by presenting shift tables using normal ranges (baseline 
to most extreme post-baseline value) and by presenting summary statistics of observed and 
change from baseline values (means, medians, quartiles, ranges). The incidence of clinically 
notable laboratory abnormalities will be summarized. 
Vital signs data will be summarized by presenting summary statistics of observed and change 
from baseline values. The incidence of clinically notable vital signs abnormalities will be 
summarized. Abnormal ECGs as per Investigator's overall interpretation will be summarized. 
9.4.4 
Other Analyses  
Tezepelumab serum concentrations will be summarized using descriptive statistics by visit. 
Observed serum concentrations of tezepelumab for each individual will be listed by visit. 
The prevalence and incidence of ADA will be reported by treatment group. ADA data will be 
summarized using descriptive statistics at each visit by treatment group. Samples confirmed 
positive for ADA will be tested for neutralizing antibodies (nAb) and the nAb status will be 
summarized by treatment group. The potential effects of ADA status and ADA titer on PK of 
tezepelumab will be evaluated. The potential association of immunogenicity with efficacy and 
safety may be evaluated if appropriate. 
Additional analyses assessing the impact of COVID-19 will be specified in the SAP. 
9.5 
Interim Analyses  
No interim analyses are planned in this trial.  
9.6 
Data Monitoring Committee 
Not applicable 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 

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Appendix A Regulatory, Ethical, and Study Oversight 
Considerations 
A 1 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants. 
• 
AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO, but the accountability remains with AstraZeneca. 
• 
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), and all other applicable 
local regulations. 
• 
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 
 
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 

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investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• 
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the [Investigator’s Brochure or state other documents] and will 
notify the IRB/IEC, if appropriate according to local requirements. 
 
Regulatory Reporting Requirements for Serious Breaches 
• 
Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met. 
− 
A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study. 
• 
If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
he or she becomes aware of it. 
• 
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches. 
− 
AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter 
details of serious breaches into the European Medicines Agency (EMA) Clinical 
Trial Information System (CTIS). It is important to note that redacted versions of 
serious breach reports will be available to the public via CTIS. 
• 
The investigator should have a process in place to ensure that: 
o 
The site staff or service providers delegated by the investigator/institution are 
able to identify the occurrence of a (potential) serious breach 
− 
A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca. 
 
 
A 2 
Financial Disclosure 

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Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
A 3 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study. 
• 
Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorised representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study centre. 
• 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative. 
 
Participants who are rescreened 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 authorised designee will explain 
to each participant the objectives of the exploratory research. Participants 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 participant will give a separate agreement to allow any 
remaining specimens to be used for exploratory research.  Participants who decline to 
participate in this optional research will indicate this in the ICF.  If a participant 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 analysed at the time of the request, 
AstraZeneca will not be obliged to destroy the results of this research. 
During the COVID-19 pandemic, re-consent may be obtained remotely and/or verbally if 
local/regional guidelines allow in order to reduce the risk of participants of COVID-19 
exposure during clinic visits. For further details please refer to Appendix H. 

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A 4 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• 
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent  
• 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 
A 5 
Committees Structure 
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://astrazenecagrouptrials.pharmacm.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 participant data relating to the study will be recorded on eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 

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noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan; Non-compliance handling plan. 
• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor. 
A 8 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
• 
Definition of what constitutes source data can be found in the monitoring plan 
A 9 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The 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 

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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 
 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
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 determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 

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

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Life-threatening 
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself an serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study. 
Important Medical Event or Medical Treatment 
Medical and scientific 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 jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
• 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation 
• 
Development of drug dependency or drug abuse 
 
Intensity Rating Scale: 
• 
Mild (awareness of sign or symptom, but easily tolerated) 
• 
Moderate (discomfort sufficient to cause interference with normal activities) 
• 
Severe (incapacitating, with inability to perform normal activities) 
 
It is important to distinguish between serious and severe AEs. Severity is a measure of 

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intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2. 
B 3 
A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
• 
Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
• 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
• 
No alternative cause. The AE cannot be reasonably explained by another 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 recognised 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 

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information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 
B 4 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error.  
• 
Occurred 
• 
Was identified and intercepted before the participant received the drug 
• 
Did not occur, but circumstances were recognised that could have led to an error 
 
Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion 
• 
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant 
• 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• 
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet  
• 
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature  
• 
Wrong participant received the medication (excluding IRT/RTSM errors) 
• 
Wrong drug administered to participant (excluding IRT/RTSM errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from IRT/RTSM - including those which led to one of the 
above listed events that would otherwise have been a medication error  
• 
Participant accidentally missed drug dose(s) eg, forgot to take medication 
• 
Accidental overdose (will be captured as an overdose) 

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• 
Participant failed to return unused medication or empty packaging 
• 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product  
 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the medication 
error. 
Drug Abuse 
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect. 
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used both 
if the drug abuse happened in a study participant or if the drug abuse involves a person not 
enrolled in the study (such as a relative of the study participant). 
Examples of drug abuse include but are not limited to: 
• The drug is used with the intent of getting a perceived reward (by the study participant 
or a person not enrolled in the study) 
• 
The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high  
Drug Misuse 
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route. 
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant). 
Examples of drug misuse include but are not limited to: 
• The drug is used with the intention to cause an effect in another person 
• The drug is sold to other people for recreational purposes  
• The drug is used to facilitate assault in another person 
• The drug is deliberately administered by the wrong route 

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• The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole 
• Only half the dose is taken because the study participant feels that he/she is feeling 
better when not taking the whole dose 
• Someone who is not enrolled in the study intentionally takes the drug 
 
 
 

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Appendix C Handling of Human Biological Samples 
C 1 
Chain of Custody 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The investigator keeps full traceability of collected biological samples from the participants 
while in storage at the centre until shipment or disposal (where appropriate) and records 
relevant processing information related to the samples whilst at site. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal. 
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers 
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle. 
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 participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research. 
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent. 
The investigator: 
• 
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate. 
• 
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented. 
• 
Ensures 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 

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• 
Ensures that the participant and AstraZeneca are informed about the sample disposal. 
 
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified. 
C 3 
International Airline Transportation Association 6.2 Guidance 
Document 
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN 3373 and IATA 650 
 
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not participant to these Regulations unless 
they meet the criteria for inclusion in another class. 
• 
Clinical study samples will fall into Category B or exempt under IATA regulations 
• 
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf). 
• 
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content 

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Appendix D Actions required in cases of increases in liver 
biochemistry and evaluation of Hy’s Law 
D 1 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. 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 participant meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met. HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the investigational 
medicinal product (IMP).   
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes. 
D 2 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× Upper Limit of 
Normal (ULN) together with total bilirubin (TBL) ≥ 2×ULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).   

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Hy’s Law (HL) 
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 ×ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g. elevated ALP indicating 
cholestasis, viral hepatitis, another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the 
elevations in transaminases and TBL must occur. 
D 3 
Identification of potential Hy’s Law cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥ 3 × ULN 
• 
AST ≥ 3 × ULN 
• 
TBL ≥ 2 × ULN 
Central laboratories being used: 
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the Investigator (also sent to 
AstraZeneca representative).   
The Investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the Investigator will: 
• 
Notify the AstraZeneca representative 
• 
Request a repeat of the test (new blood draw) by the central laboratory without 
delay 
• 
Complete the appropriate unscheduled laboratory 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 participant meets PHL criteria (see section 2 within this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results). 

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D 4 
Follow-up 
D 4.1 
Potential Hy’s Law criteria not met 
If the participant does not meet PHL criteria the Investigator will: 
• 
Inform the AstraZeneca representative that the participant has not met PHL criteria. 
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
D 4.2 
Potential Hy’s Law criteria met 
If the participant does meet PHL criteria the Investigator will: 
• 
Notify the AstraZeneca representative who will then inform the central Study Team  
• 
Within 1 day of PHL criteria being met, the Investigator will report the case as an 
SAE of Potential Hy’s Law; serious criteria ‘Important medical event’ and causality 
assessment ‘yes/related’ according to CSP process for SAE reporting. 
• 
For participants that met PHL criteria prior to starting IMP, the investigator is not 
required to submit a PHL SAE unless there is a significant change# in the 
participant’s condition 
• 
 The Study Physician contacts the Investigator, to provide guidance, discuss and 
agree an approach for the study participants’ follow-up (including any further 
laboratory testing) and the continuous review of data 
• 
Subsequent to this contact the Investigator will: 
• 
Monitor the participant until liver biochemistry parameters and appropriate 
clinical symptoms and signs return to normal or baseline levels, or as long 
as medically indicated. Completes follow-up SAE Form as required.   
• 
Investigate the 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.  
D 5 
Review and assessment of potential Hy’s Law cases 
The instructions in this section should be followed for all cases where PHL criteria are met. 
As soon as possible after the biochemistry abnormality was initially detected, the 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 

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IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from date PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and 
Global Safety Physician will also be involved in this review together with other participant 
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 

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the review and amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined 
D 6 
Laboratory tests 
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 (18 December 2018) 
Additional standard chemistry and 
coagulation tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV  
IgM and IgG anti-HBc 
HBsAg 
HBV DNA 
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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Appendix E Anaphylaxis: signs and symptoms, management 
E 1 
Introduction 
As with any antibody, allergic reactions to dose administration are possible. The World Health 
Organization has categorized anaphylaxis into 2 subgroups, which are clinically 
indistinguishable: immunologic [IgE-mediated and non-IgE-mediated (eg, IgG and immune 
complex mediated) and nonimmunologic (Johansson et al, 2004). The clinical criteria for 
defining anaphylaxis for this study are listed in section E 2. A guide to the signs and 
symptoms and management of acute anaphylaxis is provided in section E 3. Appropriate 
drugs, such as epinephrine, antihistamines, corticosteroids, etc, and medical equipment to treat 
anaphylactic reactions must be immediately available at study sites, and study personnel 
should be trained to recognize and treat anaphylaxis according to local guidelines. 
If an anaphylactic reaction occurs, a blood sample will be drawn from the participant as soon 
as possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge for 
analysis of serum tryptase. 
E 2 
Clinical Criteria for Defining Anaphylaxis and Immune 
Complex Disease 
Anaphylaxis 
In adults, anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-
tongueuvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia). 
b. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence). 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that participant (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, 
swollen lips-tongue-uvula). 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia). 
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence). 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting). 
3. Reduced BP after exposure to known allergen for that participant (minutes to several 
hours): Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that participant’s baseline. 

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Immune Complex Disease 
Immune complex disease or Hypersensitivity Type III is evoked by the deposition of 
antigenantibody 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. 
E 3 
Signs and Symptoms and Management of Acute Anaphylaxis 
Anaphylaxis is an acute and potentially lethal multi-system allergic reaction in which some or 
all of the following signs and symptoms occur: 
− Diffuse erythema 
− Pruritus 
− Urticaria and/or angioedema 
− Bronchospasm 
− Laryngeal edema 
− Hypotension 
− Cardiac arrhythmias 
− Feeling of impending doom 
− Unconsciousness 
− Shock 
Other earlier or concomitant signs and symptoms can include: 
− Itchy nose, eyes, pharynx, genitalia, palms, and soles 
− Rhinorrhea 
− Change in voice 
− Metallic taste 
− Nausea, vomiting, diarrhea, abdominal cramps and bloating 
− Lightheadedness 
− Headache 
− Uterine cramps 
− Generalized warmth 
E 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 

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a. Place participant in recumbent position and elevate lower extremities. 
b. Establish and maintain airway. 
c. Administer oxygen. 
d. Establish venous access. 
e. Normal saline IV for fluid replacement. 
Specific measures to consider after epinephrine injections, where appropriate 
a. Consider epinephrine infusion. 
b. Consider H1 and H2 antihistamines. 
c. Consider nebulized β2 agonist [eg, albuterol (salbutamol)] for bronchospasm 
resistant to epinephrine. 
d. Consider systemic corticosteroids. 
e. Consider vasopressor (e.g. dopamine). 
f. Consider glucagon for participant taking b-blocker. 
g. Consider atropine for symptomatic bradycardia. 
h. Consider transportation to an emergency department or an intensive care 
facility. 
i. For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and 
prolonged resuscitation efforts are encouraged, if necessary. 
Adapted from: Kemp SF, Lockey RF, Simons FE; World Allergy Organization ad hoc 
Committee on Epinephrine in Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. 
A statement of the World Allergy Organization. Allergy. 2008; 63(8):1061-70. 
 
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, Motala C, Ortega 
Martell JA, Platts-Mills TA, Ring J, Thien F, Van Cauwenberge P, Williams HC. A revised 
nomenclature for allergy for global use: report of the nomenclature review committee of world 
allergy organization. J Allergy Clin Immunol. 2004;113:832–6. 

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Appendix F Maintenance Therapy Equivalence Table 
Estimated daily doses for inhaled corticosteroids 
Asthma Therapy  
Total Daily Dose (μg/day) 
Inhaled Corticosteroid 
Medium 
High 
Beclomethasone dipropionate (non HFA) 
1000 
>1000 
Beclomethasone dipropionate (HFA) 
400 
>400 
Ciclesonide  
320 
>320 
Triamcinolone acetonide  
2000 
>2000 
Flunisolide  
2000 
>2000 
Fluticasone furoate (e.g. Arnuity® Ellipta®) 
n.a. 
200 
Fluticasone propionate  
500 
>500 
Fluticasone propionate HFA 
440-500 
>500 
Budesonide 
800 
>800 
Mometasone furoate  
440 
>440 
Inhaled Corticosteroid in ICS/LABA combinationa  
Medium 
High 
Beclomethasone dipropionate (e.g. Fostair®) 
400 
>400 
Fluticasone propionate HFA (e.g. Seretide®, Advair®) 
500 
>500 
Fluticasone furoate (e.g. Relvar® Ellipta®, Breo® Ellipta®) 
n.a. 
184-200 
Budesonide, if as delivered dose (e.g. Symbicort®) 
640 
>640 
Mometasone Furoate (e.g. Dulera®) 
400 
>400 
a The ICS doses for the ICS/LABA combinations were derived from GINA 2017 and using prescribing information. 
 
 
 

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Appendix G Abbreviations  
Abbreviation or 
special term 
Explanation 
AAER 
Annuallized Asthma Exacerbation Rate 
ACQ-6 
Asthma Control Questionnaire 6 
ADA 
Anti-Drug Antibodies 
AE 
Adverse Event 
AERR 
Asthma Exacerbation Reduction Rate 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ATS 
American Thoracic Society 
AQLQ(S)+12 
Standardised Asthma Quality of Life Questionnaire for 12 Years 
and 
Older 
ASD 
Asthma Symptom Diary 
AST 
Aspartate Aminotransferase 
BD 
Bronchodilator 
β-HCG 
Beta-Human Chorionic Gonadotropin 
BUN 
Blood Urea Nitrogen 
CGIC 
Clinical – Global Impression of Change 
CO2 
Carbon Dioxide 
CompEx 
Composite Endpoint for Exacerbations 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Corona Virus Disease 2019 
CRF 
Case Report Form (electronic/paper) 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
CSP 
Clinical Study Protocol 
CTCAE 
Common Terminology Criteria for Adverse Event 

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Abbreviation or 
special term 
Explanation 
DNA 
Deoxyribonucleic acid  
DSMB 
Data and Safety Monitoring Board 
DUS 
Disease under Study 
EC 
Ethics Committee, synonymous to Institutional Review Board 
(IRB) and Independent Ethics Committee (IEC) 
ER 
Emergency Room 
EOT 
End of Treatment  
ePRO 
Electronic Patient Reported Outcome device 
EQ-5D-5L 
European Quality of Life - 5 Dimensions 5 Level 
EU 
European Union 
FEIA 
Fluorescent Enzyme Immunoassay 
FEF25%-75% 
Forced expiratory flow over 25-75% of the vital capacity 
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 
GLI 
Global Lung Function Initiative 
GMP 
Good Manufacturing Practice 
HCP 
Health Care Professional 
HIV 
Human Immunodeficiency Virus 
IATA 
International Air Transport Association 
ICH 
International Conference on Harmonisation 
ICF  
Informed Consent Form  
ICS 
Inhaled Corticosteroids 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 

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Abbreviation or 
special term 
Explanation 
IL 
Interleukin 
IL-13 
Interleukin-13 
IMP 
Investigational Medicinal Product 
IP 
Investigational Product  
IPD 
Investigational Product Discontinuation 
IRB 
Institutional Review Board 
ISF 
Investigator Study File 
ITT 
Intent-to-Treat 
IUO 
Investigational Use Only 
IVRS 
Interactive Voice Response System 
IRT 
Interactive Response Technology 
IWRS 
Interactive Web Response System 
IXRS 
Interactive Voice/Web Response System 
LABA 
Long-Acting β2-Agonist 
LAMA 
Long-Acting Muscarinic Antagonists 
LAR 
Late Asthmatic Response 
LIMS 
Laboratory Information Management System 
LRTI 
Low Respiratory Tract Infection 
LTRA 
Leukotriene Receptor Antagonists 
LSLV 
Last Subject Last Visit 
MAb 
Monoclonal Antibody 
MACE 
Major Adverse Cardiac Events 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCID 
Minimum Clinically Important Difference 
MNAR 
Missing-Not-at-Random 
nAb 
Neutralizing Antibodies 
NIMP 
Non-investigational Medicinal Product 
OCS 
Oral Corticosteroids 

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Abbreviation or 
special term 
Explanation 
OAE 
Other Significant Adverse Event 
PD 
Pharmacodynamic 
PEF 
Peak Expiratory Flow 
PEO 
Performance Evaluation Only 
PI 
Principal Investigator  
PK 
Pharmacokinetic(s) 
PNV 
Predicted Normal Value 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
Q4W 
Every 4 Weeks 
RTSM 
Randomisation and Trial Supply Management 
SABA 
Short-Acting β2-Agonist 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SGRQ 
St. George’s Respiratory Questionnaire 
SOA 
Schedule of Assessment  
SOC 
System Organ Class 
SDV 
Source Data Verification 
Th2 
T Helper 2 Cells 
TLC 
Total Lung Capacity 
TSLP 
Thymic Stromal Lymphopoietin 
TSLPR 
Thymic Stromal Derived Lymphopoietin Receptor 
ULN 
Upper Limit of Normal 
UNS 
Unscheduled 
WBDC 
Web Based Data Capture 
WOCBP 
Women of Childbearing Potential 
 
 

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Appendix H Changes Related to COVID-19 Pandemic  
 
Appendix H 
Changes Related to COVID-19 Pandemic 
 
During the COVID-19 pandemic, AZ will approve the continuation of the enrolment and 
randomization or if those activities will need to be temporarily placed on hold until the 
pandemic stabilizes in the area. 
Participants who were screen failed due to a temporary recruitment pause due to the COVID-
19 pandemic may be allowed to re-screen even if the participants have already been re-
screened once before. A documented approval by study physician for re-screening due to 
COVID-19 should be filed in the Investigator Study File (ISF). 
Screening visit, all run-in and randomization visits must be conducted on-site to complete the 
required assessments according SoA in order to confirm eligibility criteria.  
If central laboratory kits are unavailable at the site due to production issues related to 
the COVID-19 pandemic, the visit window according to SoA may be extended in order 
to have the scheduled test conducted upon documented confirmation from AZ Study 
Physician.  
 
The clinical safety laboratory tests according to SoA can be performed at a local laboratory if 
clinically indicated at the discretion of the Investigator. However, all laboratory assessments 
for Visit 1, Visit 3 and EoT or IPD Visit (as per SoA) must be analysed at the central 
laboratory. 
Please Note: Changes below should only be implemented during the COVID-19 pandemic 
and if allowable by local/regional guidelines. 
H 1 
Home Visits to Replace On-Site Visits (where applicable) 
Due to local travel restrictions and/or site restrictions, participants may not wish to or may not 
be able to go to the study site for study visits and related procedures. If an on-site visit is not 
possible, it is recommended to have a home visit with home administration of IP by a 
qualified HCP (up to Visit 16) or without administration of IP for EOT Visit and Visits 18 and 
19, provided this is acceptable within local regulation/guidance. Additional information 
related to the visit can be obtained remotely by phone call and/or video conference. This is to 
ensure safety of the study participants and minimum disruption to IP administration that may 
occur during the COVID-19 pandemic. 
 
Home IP administration will apply to participants that have completed at least two IP 
administrations on-site. 
 

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Study assessments, where possible to be performed at home, should be conducted according to 
the SoA. At minimum, during home visit the qualified HCP is expected to: 
• Collect information on healthcare resources utilization 
• Perform a physical examination 
• Collect vital signs 
• Collect adverse events 
• Collect information on asthma exacerbation 
• Review concomitant medications 
• If possible, collect blood and urine sample according to the SoA 
• Conduct urine pregnancy test (dipstick), prior to IP administration, if applicable 
• eDiary data completion/review 
• Administer IP 
• Observe the participant for one hour after IP administration for the signs or symptoms 
of any acute drug reactions 
• Document the visit 
 
Please refer to the separate IP Home (or Alternative Site) Administration Instructions for more 
information. 
 
H 2 
Visits at an Alternate Location (where applicable) 
Study visits including administration of IP and study assessments according to the SoA can 
take place at an alternative location away from infection risk zones, or closer to the 
participant’s home, provided this is acceptable within local regulation/guidance and agreed 
with AstraZeneca Study Team.  
 
Please refer to the separate IP Home (or Alternative Site) Administration Instructions for more 
information. 
 
H 3 
Remote Visits to Replace On-Site Visits (where applicable) 
During the COVID-19 pandemic, on-site visits may be replaced by a remote visit (phone call 
and/or video conference) if participants cannot attend the visits at the study site, at an alternate 
site or have home visits and if allowed by local/regional guidelines.  
 
Having a phone call and/or a video conference with the participant will allow conduct of study 
procedures including reporting of adverse events, concomitant medication, information on 
asthma exacerbation, e-Diary compliance and healthcare resource utilization while 
minimizing the risk to participants of COVID-19 exposure. 
 
H 4 
End of Treatment Visit 
If the EOT visit at Week 52 cannot be performed on-site, at an alternate site or at the 
participant’s home, the EOT visit should be conducted as a remote visit.  
 

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H 5 
Re-consenting of Participants During the COVID-19 Pandemic 
COVID-19 addendum to ICF must be obtained prior to starting any procedures according to 
Appendix H. If a participant is unable to travel to the site due to the COVID-19 pandemic, it is 
necessary to obtain re-consent remotely and/or verbally for the implementation of the new 
urgent changes in the study during the COVID-19 pandemic. This will minimize the risk to 
the participant of COVID-19 exposure with clinic visits. Confirmation of participant’s re-
consent needs to be documented in the source documents. Applicable local guidelines and 
regulations on re-consenting process should be followed.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix I 
Clarification on the post-BD spirometry at Visit 2 
or Visit 2a  
 
 
All participants must perform Post BD spirometry assessment at Visit 2 or Visit 2a to 
demonstrate reversibility. The historical reversibility will be used for eligibility unless the 
participant demonstrates reversibility at either Visit 2 or Visit 2a. 
 
1.  It is mandatory to perform a post-BD spirometry at Visit 2 (V2) even if documented 
historical reversibility is available (refer to SoA, Table 1 footnote d and section 8.1.2.2).   
 
2. The historical reversibility data will not be used for eligibility if one of the following 
options is met:  
 
a. Post-BD reversibility of FEV1 ≥12% and ≥200 mL demonstrated at V2  
b. Post-BD reversibility of FEV1 ≥12% and ≥200 mL failed V2 but demonstrated at V2a  
 
As a reminder, if the reversibility was met at V2, it does not need to be repeated at V2a  (refer 
to SoA, Table 1 footnote b) 
3. If reversibility test failed at V2 and:  
 
a. no documented historical reversibility in the previous 12 months prior to visit 1 is available, 
it must be demonstrated at V2a. If the post-BD test at V2a is not positive or performed, the 
inclusion criteria #8 will not be demonstrated and the participant will have to be screen failed.  
 
b.  documented historical reversibility in the previous 12 months prior to visit 1 is available, it 
is allowed to conduct a post-BD test at V2a. If the post-BD test at V2a is not performed, no 
protocol deviations will be reported as that is not a mandatory requirement and inclusion 
criteria #8 will be confirmed based on the historical data. 
 

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