A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Dose-Ranging, Phase 2b Study to Evaluate Efficacy and Safety of Tezepelumab for the Treatment of Chronic Spontaneous Urticaria
Phase: PHASE2
Conditions: Chronic Spontaneous Urticaria
Sponsor: Amgen

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 1 of 110 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
A Randomized, Double-Blind, 
Placebo-Controlled, Multicenter, Dose-Ranging, 
Phase 2b Study to Evaluate Efficacy and Safety 
of Tezepelumab for the Treatment of Chronic 
Spontaneous Urticaria 
Short Protocol Title: 
INCEPTION - INvestigational MultiCEnter 
TezePelumab Treatment in ChronIc 
SpONtaneous Urticaria Study 
Protocol Number: 
20190194 
Investigational Product: 
Tezepelumab 
Trade Name: 
TEZSPIRE 
Sponsor 
Name of Sponsor: 
Amgen Inc 
Address: 
One Amgen Center Drive 
Thousand Oaks, California 91320 
Telephone Number: 
+1 (805) 447-1000 
Protocol 
Approver 
Name: 
, MD 
Function: 
Vice President Global Development 
 
Key 
Sponsor 
Contact 
Name: 
, MD, MBA 
Address: 
One Amgen Center Drive 
Thousand Oaks, California 91320 
Telephone Number: 
Email Address: 
 
 
EudraCT Number: 
2020-002759-39 
NCT Number: 
NCT04833855 
Protocol Version Date: 
Document Version 
Date 
Original 
27 August 2020 
Amendment 1 
01 September 2021 
Superseding 
Amendment 1 
30 September 2021 
Amendment 2 
26 April 2022 
Data Elements Standards 
Version: 
7.0 
 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures. 
 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 2 of 110 
CONFIDENTIAL  
 
 
 
 
 
 
 
 
Confidentiality Notice 
 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 3 of 110 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Randomized, Double-Blind, 
Placebo-Controlled, Multicenter, Dose-Ranging, Phase 2b Study to Evaluate Efficacy 
and Safety of Tezepelumab for the Treatment of Chronic Spontaneous Urticaria, dated 
26 April 2022, and agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by:  me 
(including, if applicable, my spouse or legal partner and dependent children) and my sub 
investigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator Date (DD Month YYYY) 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 4 of 110 
CONFIDENTIAL  
 
 
Table of Contents 
1. 
Protocol Summary .................................................................................................. 9 
1.1 
Synopsis ..................................................................................................... 9 
1.2 
Study Schema ........................................................................................... 17 
1.3 
Schedule of Activities (SoA) ...................................................................... 18 
2. 
Introduction ........................................................................................................... 24 
2.1 
Study Rationale ......................................................................................... 24 
2.2 
Background ............................................................................................... 25 
2.2.1 
Disease ..................................................................................... 25 
2.2.2 
Amgen Investigational Product Background:  
Tezepelumab ............................................................................ 27 
2.2.3 
Non-Amgen Investigational Product Background:  
Xolair (omalizumab) ................................................................. 27 
2.3 
Risk Assessment ....................................................................................... 28 
3. 
Objectives and Endpoints ..................................................................................... 29 
4. 
Study Design ........................................................................................................ 34 
4.1 
Overall Design .......................................................................................... 34 
4.2 
Number of Subjects ................................................................................... 36 
4.2.1 
Replacement of Subjects ........................................................... 36 
4.2.2 
Number of Sites ......................................................................... 36 
4.3 
Justification for Investigational Product Dose ............................................ 36 
4.3.1 
Justification for Non-Amgen Investigational Product 
Dose ......................................................................................... 37 
4.4 
End of Study ............................................................................................. 37 
4.4.1 
End of Study Definition .............................................................. 37 
4.4.2 
Study Duration for Subjects ....................................................... 38 
4.5 
Patient Input on Study Design ................................................................... 38 
5. 
Study Population .................................................................................................. 38 
5.1 
Inclusion Criteria ....................................................................................... 38 
5.2 
Exclusion Criteria ...................................................................................... 39 
5.3 
Subject Enrollment .................................................................................... 42 
5.4 
Screen Failures ......................................................................................... 42 
5.5 
Antihistamine Stabilization Period  ............................................................ 43 
6. 
Treatments ........................................................................................................... 43 
6.1 
Treatment(s) Administered ........................................................................ 44 
6.1.1 
Investigational Products ............................................................ 44 
6.1.2 
Non-Amgen Investigational Products ......................................... 46 
6.1.3 
Medical Devices ........................................................................ 46 
6.1.4 
Other Protocol-required Therapies ............................................ 46 
6.1.5 
Other Treatment Procedures ..................................................... 46 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
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6.1.5.1 
Background Medication ........................................... 46 
6.1.5.2 
Rescue Medication .................................................. 47 
6.1.6 
Product Complaints ................................................................... 47 
6.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 47 
6.2 
Dose Modification ...................................................................................... 48 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 48 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 49 
6.2.2.1 
Amgen Investigational Product:  
Tezepelumab .......................................................... 49 
6.2.2.2 
Non-Amgen Investigational Product(s):  
Omalizumab ............................................................ 49 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 49 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 49 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 49 
6.4.1 
Method of Treatment Assignment .............................................. 49 
6.4.2 
Blinding ..................................................................................... 50 
6.4.2.1 
Site Personnel Access to Individual 
Treatment Assignments .......................................... 50 
6.4.2.2 
Access to Individual Subject Treatment 
Assignments by Amgen or Designees ..................... 51 
6.5 
Treatment Compliance .............................................................................. 51 
6.6 
Treatment of Overdose ............................................................................. 52 
6.7 
Prior and Concomitant Treatment ............................................................. 52 
6.7.1 
Prior Treatment ......................................................................... 52 
6.7.2 
Concomitant Treatment ............................................................. 52 
7. 
Discontinuation Criteria ......................................................................................... 52 
7.1 
Discontinuation of Study Treatment........................................................... 53 
7.2 
Discontinuation From the Study ................................................................ 53 
7.2.1 
Reasons for Removal From Washout Period, Run-in 
Period, or Invasive Procedures ................................................. 54 
7.2.2 
Reasons for Removal From Study ............................................. 54 
7.3 
Lost to Follow-up ....................................................................................... 54 
8. 
Study Assessments and Procedures .................................................................... 55 
8.1 
General Study Periods .............................................................................. 55 
8.1.1 
Screening, Enrollment and/or Randomization ............................ 55 
8.1.2 
Treatment Period ....................................................................... 56 
8.1.3 
Safety Follow-up ........................................................................ 56 
8.1.4 
End of Study .............................................................................. 56 
8.2 
Description of General Study Assessments and Procedures ..................... 56 
8.2.1 
General Assessments ............................................................... 56 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
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CONFIDENTIAL  
 
 
8.2.1.1 
Informed Consent .................................................... 56 
8.2.1.2 
Demographics ......................................................... 57 
8.2.1.3 
Medical History ........................................................ 57 
8.2.1.4 
Physical Examination .............................................. 57 
8.2.1.5 
Physical Measurements .......................................... 57 
8.2.1.6 
Substance Abuse History ........................................ 57 
8.2.2 
Efficacy Assessments ................................................................ 57 
8.2.2.1 
Patient-Reported Outcomes (PRO) ......................... 57 
8.2.3 
Safety Assessments .................................................................. 62 
8.2.3.1 
Vital Signs ............................................................... 62 
8.2.3.2 
Vital Status .............................................................. 63 
8.2.4 
Adverse Events and Serious Adverse Events ............................ 63 
8.2.4.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 63 
8.2.4.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 64 
8.2.4.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 64 
8.2.4.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 65 
8.2.4.5 
Safety Monitoring Plan ............................................ 65 
8.2.4.6 
Pregnancy and Lactation ......................................... 65 
8.2.4.7 
Adverse Events of Interest ...................................... 66 
8.2.5 
Clinical Laboratory Assessments ............................................... 66 
8.2.5.1 
Tuberculosis Testing ............................................... 67 
8.2.5.2 
Pregnancy Testing .................................................. 67 
8.2.6 
SARS-CoV-2 Serology (Antibody) Testing ................................. 67 
8.2.7 
Pharmacokinetic Assessments .................................................. 68 
8.2.8 
Pharmacodynamic Assessments ............................................... 68 
8.2.10 
Anti-drug Antibody Testing Procedures ..................................... 68 
9. 
Statistical Considerations ...................................................................................... 70 
9.1 
Statistical Hypotheses ............................................................................... 70 
9.2 
Sample Size Determination ....................................................................... 70 
9.3 
Analysis Sets, Subgroups, and Covariates ................................................ 71 
9.3.1 
Analysis Sets ............................................................................. 71 
9.3.1.1 
All Subjects Randomized ........................................ 71 
9.3.1.2 
Full Analysis Set (FAS) ........................................... 71 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
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CONFIDENTIAL  
 
 
9.3.1.3 
Safety Analysis Set (SAS) ....................................... 72 
9.3.1.4 
Pharmacokinetic Analysis Set ................................. 72 
9.3.2 
Covariates ................................................................................. 72 
9.3.3 
Subgroups ................................................................................. 72 
9.3.4 
Handling of Missing and Incomplete Data .................................. 73 
9.4 
Statistical Analyses ................................................................................... 73 
9.4.1 
Planned Analyses ...................................................................... 73 
9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 73 
9.4.1.2 
Primary Analysis ..................................................... 73 
9.4.1.3 
Final Analysis .......................................................... 73 
9.4.2 
Methods of Analyses ................................................................. 74 
9.4.2.1 
General Considerations ........................................... 74 
9.4.2.2 
Efficacy Analyses .................................................... 75 
9.4.2.3 
Safety Analyses ...................................................... 75 
10. 
References ........................................................................................................... 77 
11. 
Appendices ........................................................................................................... 79 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms ...................... 80 
11.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 83 
11.3 
Appendix 3.  Study Governance Considerations ....................................... 85 
Regulatory and Ethical Considerations ...................................................... 85 
Recruitment Procedures ............................................................................ 85 
Informed Consent Process ........................................................................ 86 
Data Protection/Subject Confidentiality ..................................................... 87 
Publication Policy ...................................................................................... 88 
Investigator Signatory Obligations ............................................................. 89 
Data Quality Assurance ............................................................................. 89 
Source Documents .................................................................................... 90 
Study and Site Closure.............................................................................. 91 
Compensation ........................................................................................... 91 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ....................................... 92 
Definition of Adverse Event ....................................................................... 92 
Definition of Serious Adverse Event .......................................................... 93 
Recording Adverse Events and Serious Adverse Events .......................... 94 
Evaluating Adverse Events and Serious Adverse Events .......................... 95 
Reporting of Serious Adverse Event .......................................................... 96 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 100 
Definition of Females of Childbearing Potential ....................................... 100 
Collection of Pregnancy Information ........................................................ 101 
Collection of Lactation Information .......................................................... 102 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
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CONFIDENTIAL  
 
 
11.6 
Appendix 6.  Sample Storage and Destruction ........................................ 105 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 107 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-
required Therapies Due to Potential Hepatotoxicity ................. 107 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity.......................................................................... 108 
Drug-induced Liver Injury Reporting and Additional 
Assessments ........................................................................... 108 
 
List of Tables 
Table 1-1.  Schedule of Activities ................................................................................... 18 
Table 1-2.  Schedule of Activities ................................................................................... 22 
Table 6-1.  Study Treatments ........................................................................................ 45 
Table 11-1.  Analyte Listing ........................................................................................... 83 
Table 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 108 
 
List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 17 
Figure 2-1.  EAACI/GA2LEN/EDF/WAO Guideline for the Management of 
Urticaria .................................................................................................. 27 
Figure 4-1.  Screening and Enrollment .......................................................................... 35 
Figure 9-1.  Alpha Split Between Two Populations of Interest ........................................ 74 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form .................. 97 
Figure 11-2.  Pregnancy and Lactation Notification Forms ........................................... 103 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 9 of 110 
CONFIDENTIAL  
 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled, Multicenter, 
Dose-Ranging, Phase 2b Study to Evaluate Efficacy and Safety of Tezepelumab for the 
Treatment of Chronic Spontaneous Urticaria  
Short Protocol Title:  INCEPTION - INvestigational MultiCEnter TezePelumab 
Treatment in ChronIc SpONtaneous Urticaria Study 
Study Phase:  Phase 2b 
Indication:  Chronic Spontaneous Urticaria 
Rationale 
Tezepelumab has been approved by the U.S. Food and Drug Administration (FDA) 
for the add-on maintenance treatment of adult and pediatric patients aged 12 
years and older with severe asthma.  Tezepelumab is also being developed for the 
treatment of chronic spontaneous urticaria (CSU).  Thymic stromal lymphopoietin 
(TSLP), an epithelial cytokine shown to be elevated in numerous inflammatory diseases, 
impacts multiple biological pathways involved in CSU.  Thymic stromal lymphopoietin 
has been shown to be increased in the skin of patients with CSU.  Mast cell numbers are 
also known to be increased up to 3-fold in the skin of CSU patients.  Recently, TSLP has 
been identified as a potent survival promoter of human skin mast cells and is 
hypothesized to be responsible for the increased number of mast cells in the skin of 
patients.  Blocking TSLP may reduce both problematic immunoglobulin (Ig) E species 
and mast cells, which jointly act as the central driver of CSU skin inflammation.  
Two dose levels of tezepelumab, 210 mg subcutaneous (SC) injections every 4 weeks 
(Q4W), and 420 mg SC injections every 2 weeks (Q2W) were selected based on 
available data from evaluation of tezepelumab in an asthma and asthma allergen 
challenge study.  The tezepelumab dose of 210 mg SC injection Q4W was efficacious in 
the treatment of severe asthma and impacted biomarkers including interleukin (IL)-5, 
eosinophils, and IgE.  Although the impact of tezepelumab on CSU endpoints has not 
been previously evaluated, since in CSU like in asthma, eosinophils, mast cells, and IgE 
play an important role in the pathophysiology, this dose of tezepelumab has the potential 
to show efficacy.  A higher dose, tezepelumab 420 mg Q2W will also be included to 
allow for the evaluation of tezepelumab efficacy and impact on skin mast cells at higher 
nonoverlapping exposures than with the 210 mg Q4W dose.  Inclusion of the 420 mg 
Q2W dose will also allow for exposure-response analysis to better inform dose selection 
for future CSU studies.  The safety of the selected doses is supported by clinical and 
preclinical data.  The selected doses were previously tested in clinical trials and were 
deemed safe. 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the effect of 
tezepelumab on improvement in 
the Urticaria Activity Score over 
7 days (UAS7) 
 
Change from baseline in UAS7 at 
week 16 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 10 of 110 
CONFIDENTIAL  
 
 
The first estimand of the primary objective consists of: 
 
Target population – Adults with chronic spontaneous urticaria (CSU) who are 
symptomatic (inadequately controlled) despite treatment with second generation 
H1-antihistamines (sgAH) 
 
Endpoint – Change from baseline in UAS7 score at week 16 
 
Intercurrent events –  Use of protocol-excluded medications due to CSU 
(regardless of discontinuation of IP):  treatment failure will be considered and the 
composite strategy will be applied where subject’s post-baseline effect will be 
similar as the baseline starting from the protocol-excluded medication use until the 
end of study; Use of protocol-excluded medications not due to CSU (regardless of 
discontinuation of IP): 
 
 
Discontinuation of investigational product due to reasons other than 
protocol-excluded medication use:  treatment policy will be applied, where data will 
be used as collected from these subjects regardless of whether subjects complete 
16 weeks of study treatment.   
 
Summary measure – Difference of mean change from baseline in UAS7 score 
at week 16 between tezepelumab 420 mg subcutaneous (SC) every 2 weeks 
(Q2W) or 210 mg SC every 4 weeks (Q4W) and placebo (tezepelumab 420 mg 
SC Q2W or 210 mg SC Q4W minus placebo). 
In summary, the first estimand of the primary endpoint is the difference of mean 
change from baseline in UAS7 score at week 16 between tezepelumab 420 mg SC 
Q2W or 210 mg SC Q4W and placebo, in adults with CSU who are symptomatic 
(inadequately controlled) despite treatment with sgAH, regardless of whether subjects 
complete 16 weeks of study treatment. 
The second estimand of the primary endpoint consists of the same definitions of 
endpoint, intercurrent event, and the summary measures in the target population of 
adults with CSU who are symptomatic (inadequately controlled) despite treatment with 
sgAH and are also anti-immunoglobulin (Ig) E naïve.  
The third estimand of the primary endpoint consists of the same definitions of 
endpoint, intercurrent event, and summary measures in the target population of adults 
with CSU who are symptomatic (inadequately controlled) despite treatment with sgAH 
and are anti-IgE experienced (intolerant, inadequate responder, or have discontinued 
for other reason). 
Secondary 
 
To evaluate the effect of 
tezepelumab on improvement in 
itch using the Itch Severity Score 
over 7 days (ISS7) 
 
Change from baseline in ISS7 at 
week 16 
 
To evaluate the effect of 
tezepelumab on improvement in 
hives using the Hives Severity 
Score over 7 days (HSS7) 
 
Change from baseline in HSS7 
score at week 16 
 
To evaluate the effect of 
tezepelumab on subjects 
 
UAS7  6 at week 16 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
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CONFIDENTIAL  
 
 
achieving minimal residual 
disease using the UAS7 
 
To evaluate the effect of 
tezepelumab on subjects 
achieving the minimal important 
difference (MID) on change from 
baseline in the UAS7  
 
Change from baseline in 
UAS7  -10 at week 16 
 
To evaluate the effect of 
tezepelumab compared with 
placebo in CSU subjects using 
the UAS7 
 
Complete response in UAS7 
defined as UAS7  0 at week 16 
 
To evaluate the effect of 
tezepelumab on complete 
resolution of itch using the ISS7 
 
ISS7  0 at week 16 
 
To evaluate the effect of 
tezepelumab on subjects 
achieving the MID on change from 
baseline in the ISS7  
 
Change from baseline in 
ISS7  -5 at week 16 
 
To evaluate the effect of 
tezepelumab on the complete 
resolution of hives using the HSS7 
 
HSS7  0 at week 16 
 
To evaluate the effect of 
tezepelumab on subjects 
achieving the MID on change from 
baseline in the HSS7 
 
Change from baseline in 
HSS7  -5.5 at week 16 
 
To evaluate the effect of 
tezepelumab on sleep 
interference and quality (falling 
asleep, nighttime awakenings, 
restfulness upon awakening)  
 
Change from baseline in sleep 
interference score at week 16 
 
Change from baseline in the sleep 
interference and quality diary 
items at week 16 
 
To evaluate the effect of 
tezepelumab on improvement in 
urticaria disease control using the 
Urticaria Control Test (UCT) 
 
Change from baseline UCT score 
at week 16 
 
 
To evaluate the effect of 
tezepelumab on angioedema 
using the Angioedema Activity 
Score over 7 days (AAS7) 
 
Change from baseline in AAS7 at 
week 16 
 
To evaluate the effect of 
tezepelumab on the cumulative 
time period that treated subjects 
are angioedema occurrence-free 
using the AAS7 
 
Cumulative weeks that subjects 
achieve AAS7  0 responses 
between baseline and week 16 
 
To evaluate the effect of 
tezepelumab on subject 
 
Change from baseline in the 
CU-Q2oL at week 16 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
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CONFIDENTIAL  
 
 
 
Overall Design 
A randomized, double-blind, placebo-controlled, multicenter, dose-ranging, phase 2b 
study to evaluate the efficacy and safety of tezepelumab in adults with CSU for 
 6 months at the time of screening, who remain symptomatic despite treatment with 
second generation H1-antihistamines (sgAH) and are anti-IgE naïve or who were 
previously treated with anti-IgE therapies (either intolerant, inadequate responder, or 
urticaria-specific quality of life 
(QoL) using the Chronic Urticaria 
Quality of Life Questionnaire 
(CU-Q2oL) 
 
To evaluate the effect of 
tezepelumab on subject QoL 
using the Dermatology Life Quality 
Index (DLQI) 
 
Change from baseline in DLQI at 
week 16  
 
To evaluate the effect of 
tezepelumab on subject 
angioedema-specific QoL using 
the Angioedema Quality of Life 
Questionnaire (AE-QoL) 
 
Change from baseline in the 
AE-QoL at week 16 
 
To evaluate the effect of 
tezepelumab on improvement in 
angioedema disease control using 
the Angioedema Control Test 
(AECT) 
 
Change from baseline in the 
AECT score at week 16  
 
To evaluate the effect of 
tezepelumab on subjects 
achieving complete control of 
angioedema disease using the 
AECT 
 
Complete control in AECT 
(AECT  16) at week 16 
 
To evaluate the effect of 
tezepelumab on the improvement 
in productivity and activity 
impairment using the Work 
Productivity and Activity 
Impairment Questionnaire:  
Chronic Urticaria (WPAI-CU) 
 
Change from baseline in 
WPAI-CU score at week 16 
 
To evaluate the effect of 
tezepelumab on H1-antihistamine 
rescue medication utilization 
 
Cumulative frequency of 
H1-antihistamine rescue 
medication utilization from 
baseline to week 16 
 
To characterize the 
pharmacokinetics (PK) of 
tezepelumab  
 
Serum concentrations of 
tezepelumab at scheduled visits 
 
To evaluate the safety and 
tolerability of tezepelumab  
 
Subject incidence of adverse 
events (including serious adverse 
events)  

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 13 of 110 
CONFIDENTIAL  
 
 
discontinued for other reason).  Subjects who are symptomatic despite treatment with 
sgAH and are anti-IgE naïve will be randomized to placebo, omalizumab, or 1 of 
2 tezepelumab treatment groups (30 subjects per group for a total of 120 subjects).  
Subjects who are symptomatic despite treatment with sgAH and were previously treated 
with anti-IgE therapies (intolerant, inadequate responder, or discontinued for other 
reason) will be randomized to placebo or 1 of 2 tezepelumab treatment groups 
(approximately 13 subjects per group for a total of approximately 39 subjects). 
Number of Subjects 
Approximately 159 subjects will be enrolled to the anti-IgE naïve stratum and the 
anti-IgE experienced stratum with an approximately 3:1 ratio:  120 CSU subjects who 
are symptomatic despite treatment with sgAH and are anti-IgE naïve, and 
approximately 39 subjects who were symptomatic despite treatment with sgAH and are 
anti-IgE experienced (intolerant, inadequate responder, or discontinued for other 
reason).   
Summary of Key Subject Eligibility Criteria 
Eligible subjects will include adults with a clinical diagnosis of CSU for  6 months at the 
time of screening who are symptomatic despite treatment with sgAH (up to 4x the 
approved dose) and are anti-IgE naïve or who are symptomatic despite treatment with 
sgAH (up to 4x the approved dose) and anti-IgE experienced (intolerant, inadequate 
responder, or discontinued for other reason). 
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 
Treatments 
Study treatment includes tezepelumab, omalizumab, or placebo as outlined in the table 
below. 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
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Study 
Treatment 
Name 
Amgen Investigational 
Product:a 
Tezepelumab 
Placebo 
Non-Amgen 
Investigational 
Product:b 
Omalizumab (Xolair)  
Dosage 
Formulation 
 mg/mL in 
 mM 
acetate,
 
weight/volume L-proline, 
 weight/volume 
polysorbate 80, pH 
 
 
 weight/volume 
sodium carboxy 
methyl cellulose in 
mM acetate, 
mM L-proline, 
 weight/volume 
polysorbate 80, pH 
 
150 mg/mL in a 
pre-filled syringe 
(Xolair) 
 
Unit Dose 
Strength(s)/ 
Dosage 
Level(s) and 
Dosage 
Frequency 
Each subject will receive 
2 injections per visit. 
For subjects randomized 
to 210 mg Q4W and 
420 mg Q2W, volumes 
for injections from vials 
will be detailed in the 
IPIM. 
Subjects randomized to 
Q4W dosing will receive 
placebo at intervening 
visits, such that all 
subjects receive an 
injection Q2W. 
Each subject will 
receive 2 injections 
per visit. 
For subjects 
randomized to 
placebo, volumes for 
injections from vials 
provided will be 
detailed in the IPIM. 
Subjects will receive 
placebo dosing Q2W. 
Each subject will 
receive 2 injections 
per visit. 
Subjects randomized 
to 300 mg Q4W 
dosing will receive 
placebo at intervening 
visits, such that all 
subjects receive an 
injection Q2W. 
Route of 
Administration 
SC injection 
SC injection 
SC injection 
IPIM  Investigational Product Instruction Manual; SC  subcutaneous; Q2W  every 2 weeks; 
Q4W  every 4 weeks 
a Tezepelumab will be manufactured and packaged by Amgen and distributed using Amgen clinical study 
drug distribution procedures. 
b Omalizumab will be manufactured and packaged by Novartis Pharmaceuticals Corporation and/or 
Genentech, Inc. and distributed using Amgen (or designee) clinical study drug distribution procedures.  
Procedures 
Key study procedures will include a daily assessment of Urticaria Activity Score over 
7 days (UAS7), Angioedema Activity Score over 7 days (AAS7), other measures of CSU 
disease activity, and documentation of daily sgAH dose.  Blood samples will be collected 
for pharmacokinetic (PK) analysis 
 
  
An end of study (EOS) visit will be conducted 18 weeks after the final dose of study drug 
(16 weeks after the end of treatment [EOT] visit).  Any adverse events observed by the 
investigator or reported by the subject that occur after screening visit 2 through the 
EOS/safety follow-up or 18 weeks after the last administration of investigational product 
are to be collected/reported.  Serious adverse events observed by the investigator or 
reported by the subject after the signing of informed consent through the EOS/safety 
follow-up visit or for 18 weeks after the last administration of investigational product are 
reported using the Event Case Report Form (CRF). 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 8.2 and the Schedule of Activities (SoA) in Table 1-1 and Table 1-2. 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 15 of 110 
CONFIDENTIAL  
 
 
Statistical Considerations 
Approximately 159 subjects will be enrolled in:  the anti-IgE naïve stratum (CSU 
subjects who are symptomatic despite treatment with a sgAH and anti-IgE naïve) or the 
anti-IgE experienced stratum (CSU subjects who are symptomatic despite treatment with 
a sgAH and previously treated with anti-IgE therapy [intolerant, inadequate responder, or 
discontinued for other reason]).  For the anti-IgE naïve stratum, 120 subjects will be 
randomized in a ratio of 1:1:1:1 (30 each for tezepelumab 420 mg SC Q2W, 
tezepelumab 210 mg SC Q4W, omalizumab 300 mg SC, and placebo), where the 
omalizumab group serves as an active control.  For the anti-IgE experienced stratum, 
approximately 39 subjects will be randomized in a ratio of 1:1:1 (approximately 13 
each for tezepelumab 420 mg SC Q2W, tezepelumab 210 mg SC Q4W, and placebo).  
The treatment effect comparison on the primary endpoint for the primary hypothesis will 
be made between placebo and one of the 2 tezepelumab treatment groups 
respectively in the overall CSU population.  
 
Subject disposition, demographics, and baseline disease characteristics will be 
summarized descriptively by randomized treatment group based on the full analysis set 
(FAS), or all randomized subjects.  For categorical endpoints, the descriptive statistics 
will contain frequency and percentage.  For continuous endpoints, the descriptive 
statistics will include the number of observations, mean, standard error, standard 
deviation, median, first quartile, third quartile, minimum, and maximum.   
For primary endpoint, tezepelumab 420 mg SC Q2W and 210 mg SC Q4W compared 
to placebo in the overall and the anti-IgE naïve population will be tested sequentially 
using the Bonferroni procedure to control for the type I error rate adjusting for covariates 
specified in Section 9.3.2.  
Up to 2 interim analyses will be performed:  1) the first interim analysis for futility will 
be performed after the first 60 enrolled subjects in the anti-IgE naïve stratum have had 
the opportunity to complete week 16 assessments or early terminate from the study, and 
2) the second interim analysis for administrative decision making will be 
performed after 120 subjects in the anti-IgE naïve stratum have had the opportunity to 
complete week 16 assessments or early terminate from the study.   
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
The primary hypothesis is: 
Tezepelumab effectively decreases UAS7 scores at week 16 from baseline 
compared to placebo in the overall population consisting of the anti-IgE naïve 
stratum and anti-IgE experienced stratum. 
The secondary hypothesis is: 
Tezepelumab effectively decreases UAS7 scores at week 16 from baseline 
compared to placebo within the anti-IgE naïve stratum. 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 16 of 110 
CONFIDENTIAL  
 
 
 
Sponsor Name: 
 Amgen Inc 
 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 17 of 110 
CONFIDENTIAL  
 
 
1.2 
Study Schema 
Figure 1-1.  Study Schema 
Naïve to 
anti-IgE
therapies
Screening visit 1
Screening visit 2
Randomization
Omalizumab (N = 30)
300 mg Q4W
Placebo (N = 30)
Tezepelumab (N = 30)
210 mg Q4W
Tezepelumab (N = 30)
420 mg Q2W
Previously 
treated 
with anti-IgE
therapiesb
Randomization
Placebo (N = 13)
Tezepelumab (N = 13)
210 mg Q4W
Tezepelumab (N = 13)
420 mg Q2W
Safety Follow-up
Second Generation H1 Antihistaminea
Screening Period
(Max of 42 days)
Treatment Period
(16 weeks)
Safety Follow-Up
Period
(16 weeks)
Up to 
28 days
Minimum
of 14 days
Day -42
Day -14
Day 1
Visits every 2 weeks 
(for 16 weeks)
Primary assessment of UAS7
(Week 16/EOT)
EOS 
(Week 32)
 
EOS  end of study; EOT  end of treatment; IgE  immunoglobulin E; Min  minimum; Q2W  once every 2 weeks; Q4W  once every 4 weeks; 
UAS7  Urticaria Activity Score over 7 days. 
a Subjects should maintain a stable dose of second generation H1-antihistamine as the background medication from screening visit 2 throughout the study 
until the EOS visit. 
b Subjects previously treated with anti-IgE therapies may be intolerant to or inadequate responders to anti-IgE therapies or may have discontinued for other 
reason.   

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 18 of 110 
CONFIDENTIAL  
 
 
1.3 
Schedule of Activities (SoA) 
Table 1-1.  Schedule of Activities 
PROCEDURE 
Screening Period  
Randomization 
Treatment Period 
EOTb/ 
ETl 
Notes 
Visit 1  
(a max of  
42 days 
before 
Day 1)a 
Visit 2  
(min of  
14 days 
before 
Day 1)a 
Day 1 
Wk  
2b 
Wk  
4b 
Wk 
6b 
Wk 
8b 
Wk 
10b 
Wk 
12b 
Wk 
14b 
Wk 16 
 
GENERAL AND SAFETY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Verify eligibility criteria  
X 
X 
Xc 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
 
 
 
 
 
 
 
 
 
 
Physical measurements 
X 
 
 
 
 
 
 
 
 
 
 
Height and weight 
Urticaria, Dermatology and 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
Substance use history 
X 
 
 
 
 
 
 
 
 
 
 
Substances:  
drugs, alcohol, 
tobacco, caffeine 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BP, RR, HR, and 
temperature 
Adverse eventsd 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant therapies 
review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Tuberculosis testing 
X 
 
 
 
 
 
 
 
 
 
X 
 
LABORATORY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
Serum and/or Urine 
pregnancy test (females of 
childbearing potential only)e 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum testing 
mandatory at 
screening 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 19 of 110 
CONFIDENTIAL  
 
 
PROCEDURE 
Screening Period  
Randomization 
Treatment Period 
EOTb/ 
ETl 
Notes 
Visit 1  
(a max of  
42 days 
before 
Day 1)a 
Visit 2  
(min of  
14 days 
before 
Day 1)a 
Day 1 
Wk  
2b 
Wk  
4b 
Wk 
6b 
Wk 
8b 
Wk 
10b 
Wk 
12b 
Wk 
14b 
Wk 16 
 
SARS-CoV-2 Antibody Testn 
 
 
 
 
 
 
 
 
 
 
 
Approximately 
4 weeks 
post-vaccination 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
Chemistry 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
HIV, Hepatitis B and C 
screening 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
Anti-tezepelumab antibody 
 
 
X 
 
X 
 
 
 
 
 
X 
 
PHARMACOKINETIC 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
PK Sampling  
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
STUDY-SPECIFIC 
ASSESSMENTS (eg, 
DISEASE-SPECIFIC 
ASSESSMENTS) 
 
 
 
 
 
 
 
 
 
 
 
 
Assign eDiary device 
 
X 
 
 
 
 
 
 
 
 
 
 
PATIENT-REPORTED 
OUTCOME 
ASSESSMENTSm 
 
 
 
 
 
 
 
 
 
 
 
 
eDiaryh 
 
Daily 
 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 20 of 110 
CONFIDENTIAL  
 
 
PROCEDURE 
Screening Period  
Randomization 
Treatment Period 
EOTb/ 
ETl 
Notes 
Visit 1  
(a max of  
42 days 
before 
Day 1)a 
Visit 2  
(min of  
14 days 
before 
Day 1)a 
Day 1 
Wk  
2b 
Wk  
4b 
Wk 
6b 
Wk 
8b 
Wk 
10b 
Wk 
12b 
Wk 
14b 
Wk 16 
 
UAS (daily)h 
 
Daily 
 
AAS (daily)h 
 
Daily 
 
sgAH questionnaire 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Sleep related outcomes 
(daily)h 
 
Daily 
 
PGI-S 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PGI-C 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
UCT 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
AECTi 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
CU-Q2oL 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
AE-QoLi 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
DLQI 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
WPAI-CU 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
STUDY TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
sgAH dosej 
 
Daily 
 
Document dose of sgAH 
and any rescue medication 
use  
 
Daily 
 
Administration of 
tezepelumab, omalizumab, 
or placebok 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AAS  Angioedema Activity Score; AECT  Angioedema Control Test; AE-QoL  Angioedema Quality of Life Questionnaire; BP  blood pressure;
; CSU  chronic spontaneous urticaria; CU-Q2oL  Chronic Urticaria Quality of Life Questionnaire; DLQI  Dermatology Life Quality Index; eCRF  electronic 
case report form; eDiary  electronic diary; EOT  end of treatment; ET  early termination; HIV  human immunodeficiency virus; HR  heart rate; IgE  
immunoglobulin E; Max  maximum; Min  minimum; PGI-C  Patient Global Impression of Change; PGI-S  Patient Global Impression of Severity; PK  
pharmacokinetic; Q4W  every 4 weeks; RR  respiratory rate; TSLP  thymic stromal lymphopoietin; UAS  Urticaria Activity Score; UCT  Urticaria Control Test; Wk 
Week; WPAI-CU  Work Productivity and Activity Impairment Questionnaire:  Chronic Urticaria 
a Screening visit 1 can occur up to a maximum of 42 days before the first dose of investigational product on day 1.  Screening visit 2 should occur a minimum of 
14 days before first dose of investigational product on day 1. 
b The window for visits is  3 days. 
c Only certain inclusion criteria specified in the protocol will be re-evaluated at the day 1 visit.  These criteria will be evaluated prior to any other day 1 study activities 
and are required to be met for dosing with investigational product. 
d Adverse events related to study procedures observed by the investigator or reported by the subject that occur after screening visit 2. 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 21 of 110 
CONFIDENTIAL  
 
 
e Pregnancy testing applies to females of childbearing potential only, as defined in the protocol.  The pregnancy test at screening must be a serum pregnancy test.  All 
other scheduled pregnancy tests can be urine or serum tests.  Pregnancy testing should be performed before dosing.  Additional on-treatment pregnancy testing may 
be performed at the investigator’s discretion if there is suspicion that a female subject is pregnant or per local laws and regulations.  If a urine pregnancy test is 
positive, a confirmatory serum pregnancy test will be performed by the study center and entered into the eCRF. 
 All daily assessments should be performed at the same time every day, in the morning. 
i AECT and AE-QoL will only be administered to subjects with angioedema. 
j Examples of an acceptable approved sgAH include 1 tablet daily of the following:  cetirizine 10 mg, desloratadine 5 mg, ebastine 10 mg, fexofenadine 120 mg, 
levocetirizine 5 mg, loratadine 10 mg, and rupatadine 10 mg (van den Elzen et al, 2017) 
k Administration of study drug is the final activity performed at a visit.  Subjects randomized to Q4W dosing will receive placebo at the visits between dosing with 
tezepelumab.  Subjects will be observed for 2 hour post-treatment at the day 1 and week 2 visits.  For all other visits where investigational product is administered, 
subjects will be observed for a period of time at the discretion of the investigator. 
l All subjects who terminate the study early will complete an early termination visit consisting of all assessments included in the EOT (week 16) visit.  In addition, an 
EOS visit will occur 16 weeks after the EOT visit.  In the event a patient is unable to have an EOS visit, the site will attempt to contact the subject by telephone to 
obtain safety information. 
m PROs are to be assessed prior to any other assessments at each visit. 
n SARS-COV-2 serology (antibody) test will be done approximately 4 weeks after the last dose of vaccination and at a scheduled visit. 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 22 of 110 
CONFIDENTIAL  
 
 
Table 1-2.  Schedule of Activities 
PROCEDURE 
Safety Follow-up Period 
Notes 
Wk 24a 
Wk 32a/EOSb 
 
GENERAL AND SAFETY ASSESSMENTS 
 
 
 
Vital signs  
X 
X 
BP, RR, HR, and 
temperature 
Adverse eventsc 
X 
X 
 
Serious adverse events 
X 
X 
 
Concomitant therapies review 
X 
X 
 
LABORATORY ASSESSMENTSn 
 
 
 
Serum and/or Urine pregnancy test (females of 
childbearing potential only)d 
X 
X 
 
SARS-CoV-2 Antibody Testh 
 
 
Approximately 4 weeks 
post-vaccination 
Hematology 
X 
X 
 
Chemistry 
 
X 
 
Urinalysis 
 
X 
 
Anti-tezepelumab antibody 
 
X 
 
PHARMACOKINETIC ASSESSMENTS 
 
 
 
PK Sampling  
X 
X 
 
PATIENT-REPORTED OUTCOME ASSESSMENTS  
 
 
 
eDiarye 
Daily 
 
UAS (daily)e 
Daily 
 
AAS (daily)e 
Daily 
 
sgAH questionnaire 
X 
X 
 
Sleep related outcomes (daily)e 
Daily 
 
PGI-S 
X 
X 
 
PGI-C 
X 
X 
 
UCT 
X 
X 
 
AECTf 
X 
X 
 
CU-Q2oL 
X 
X 
 
AE-QoLf 
X 
X 
 
DLQI 
 
X 
 
WPAI-CU 
 
X 
 

Product:  Tezepelumab  
Protocol Number:  20190194 
Date:  26 April 2022 
Page 23 of 110 
CONFIDENTIAL  
 
 
PROCEDURE 
Safety Follow-up Period 
Notes 
Wk 24a 
Wk 32a/EOSb 
 
STUDY TREATMENT 
 
 
 
sgAH doseg 
Daily 
 
Document dose of sgAH and any rescue medication use  
Daily 
 
AAS  Angioedema Activity Score; AECT  Angioedema Control Test; AE-QoL  Angioedema Quality of Life Questionnaire; BP  blood pressure
; CSU  chronic spontaneous urticaria; CU-Q2oL  Chronic Urticaria Quality of Life Questionnaire; DLQI  Dermatology Life Quality Index; eCRF  electronic 
case report form; eDiary  electronic diary; EOS  end of study; EOT  end of treatment; HR  heart rate; IgE  immunoglobulin E; PGI-C  Patient Global Impression 
of Change; PGI-S  Patient Global Impression of Severity; PK  pharmacokinetic; RR  respiratory rate; sgAH  second generation H1-antihistamine; TSLP  thymic 
stromal lymphopoietin; UAS  Urticaria Activity Score; UCT  Urticaria Control Test; Wk  Week; WPAI-CU  Work Productivity and Activity Impairment Questionnaire:  
Chronic Urticaria 
a The window for visits is  3 days. 
b An EOS visit will occur 16 weeks after the EOT visit.  In the event a patient is unable to have an EOS visit, the site will attempt to contact the subject by telephone to 
obtain safety information. 
c Adverse events related to study procedures observed by the investigator or reported by the subject that occur after screening visit 2. 
d Pregnancy testing applies to females of childbearing potential only, as defined in the protocol.  The pregnancy test at screening must be a serum pregnancy test.  All 
other scheduled pregnancy tests can be urine or serum tests.  Pregnancy testing should be performed before dosing.  Additional on-treatment pregnancy testing may 
be performed at the investigator’s discretion if there is suspicion that a female subject is pregnant or per local laws and regulations.  If a urine pregnancy test is 
positive, a confirmatory serum pregnancy test will be performed by the study center and entered into the eCRF. 
e All daily assessments should be performed at the same time every day, in the morning. 
f AECT and AE-QoL will only be administered to subjects with angioedema. 
g Examples of an acceptable approved sgAH include 1 tablet daily of the following:  cetirizine 10 mg, desloratadine 5 mg, ebastine 10 mg, fexofenadine 120 mg, 
levocetirizine 5 mg, loratadine 10 mg, rupatadine 10 mg (van den Elzen et al, 2017) 
h SARS-COV-2 serology (antibody) test will be done approximately 4 weeks after the last dose of vaccination and at a scheduled visit. 
 
 

Product:  Tezepelumab  
Protocol Number:  20190194  
Date:  26 April 2022 
Page 24 of 110 
CONFIDENTIAL  
 
 
2. 
Introduction 
2.1 
Study Rationale 
Tezepelumab has been approved by the U.S. Food and Drug Administration (FDA) 
for the add-on maintenance treatment of adult and pediatric patients aged 
12 years and older with severe asthma.  Tezepelumab is an anti-thymic stromal 
lymphopoietin (TSLP) monoclonal antibody, currently also in development for other 
potential indications including chronic obstructive pulmonary disease, chronic 
rhinosinusitis with nasal polyps, chronic spontaneous urticaria (CSU), and additional 
indications.  Thymic stromal lymphopoietin is an epithelial cell-derived cytokine that is 
produced in response to proinflammatory stimuli (eg, infectious, allergic, and 
environmental stimuli) and trauma; it plays an upstream, pivotal role in the initiation of 
widespread allergic responses, and drives activation of 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), which perpetuate the T helper 2 (Th2) 
response.  The resulting cascade of cytokines associated with this type 2 polarizing 
phenotype (Kaur and Brightling, 2012), have grave consequences for human health. 
Tezepelumab binds with high affinity to human TSLP and inhibits the TSLP-mediated 
signaling initiated by the TSLP:  TSLP receptor binding.  It has been shown to lower 
blood eosinophils, total immunoglobulin (Ig) E, and Th2 pathway activity 
(interleukin [IL]-5, IL-13).  
 
 
 
 
. 
There is strong preclinical and clinical evidence that TSLP plays a role in Th2-mediated 
pathways, and TSLP is a reasonable target for the treatment of CSU.  Thymic stromal 
lymphopoietin has been shown to promote mast cell development and is critical in mast 
cell biology.  A study of human skin mast cell function demonstrated TSLP receptor 
expression prevented apoptosis of human skin mast cells (Hazzan et al, 2019).  
Compared to healthy controls, the number of TSLP-positive cells is increased in both 
lesioned and non-lesioned skin of patients with CSU (Kay et al, 2015).  Mast cell 
numbers are also known to be increased up to 3-fold in the lesioned and non-lesioned 
skin of CSU patients (Kay et al, 2015).  In the skin, the production and release of TSLP 
is restricted to epidermal keratinocytes and mast cells (He and Geha, 2010).  In addition, 

Product:  Tezepelumab  
Protocol Number:  20190194  
Date:  26 April 2022 
Page 25 of 110 
CONFIDENTIAL  
 
 
TSLP is well known to act as an alarmin, and its expression and release from epithelial 
cells is induced in response to a broad array of stimuli, including mechanical injury, 
infection, and inflammatory cytokines (Allakhverdi et al, 2007; He and Geha, 2010; Roan 
et al, 2019). 
Combined these findings support the therapeutic targeting TSLP by inhibition with 
tezepelumab as a strong potential candidate for treatment in patients with CSU.  
This study will evaluate the safety and efficacy in the treatment of tezepelumab in 
patients with CSU.  Qualified subjects will have documented symptoms of CSU despite 
treatment with H1-antihistamines.  The target population will be composed of subjects 
who are anti-IgE naïve, and subjects previously exposed to anti-IgE therapy.  
Omalizumab is the only approved anti-IgE therapy for CSU.  Subjects who had 
inadequate responses or were intolerant to anti-IgE therapy, or discontinued 
omalizumab for other reasons may be included in the group of subjects previously 
exposed to anti-IgE therapy.  Two dose levels of tezepelumab (420 mg subcutaneous 
[SC] injection every 2 weeks [Q2W] and 210 mg SC every 4 weeks [Q4W]) were 
selected based on tezepelumab exposure, safety and response analysis of tezepelumab 
concentration, and response data collected in previous clinical trials in an asthma 
allergen challenge study, as well as phase 2b asthma and phase 2a atopic dermatitis 
clinical studies.  An omalizumab treatment group will used for contextualization of study 
results.  These subjects will serve as a positive control. 
2.2 
Background 
2.2.1 
Disease 
Chronic spontaneous urticaria is a common skin disease that is characterized by the 
spontaneous appearance of wheals, angioedema, or both for  6 weeks as a result of 
known (ie, the presence of mast cell-activating autoantibodies) or unknown causes 
(Zuberbier et al, 2018; Bernstein et al, 2014).  
Chronic spontaneous urticaria is highly prevalent, affecting up to 1% of the population.  It 
primarily affects women (Vestergaard et al, 2017).  It is a self-limiting disorder, persisting 
for 2 to 5 years in the majority of cases, although 20% of patients suffer for more than 
5 years (Nebiolo et al, 2009).  Beyond the visual impact of wheals and angioedema, 
quality of life (QoL) is substantially reduced in patients due to pruritus, interference with 
sleep, daily activities, social interaction, work productivity, and emotional well-being 
(Maurer et al, 2011).  

Product:  Tezepelumab  
Protocol Number:  20190194  
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The underlying pathophysiology for CSU involves mast cell and basophil degranulation 
with release of histamine, leukotrienes, prostaglandins, and other inflammatory 
mediators.  Functional autoantibodies against the high-affinity IgE receptor have been 
detected in approximately one-third of patients, suggesting an autoimmune component 
to CSU.  In addition, cytokines that promote a Th2 profile of inflammation such as IL-33, 
IL-25, and TSLP have been shown to be increased in CSU skin lesions, suggesting that 
innate pathways may play a role in the pathogenesis of CSU, perhaps by enhancing 
survival of mast cells in the lesioned skin (Kay et al, 2015). 
According to the EAACI/GA2LEN/EDF/WAO guideline for the management of urticaria, 
the goal of treatment is complete symptom control.  Therapies aim to reduce the effect of 
mast cell mediators such as histamine, platelet-activating factor, cytokines, and others 
on target structures of the skin, including blood vessels (vasodilation and extravasation) 
and sensory nerves (itch).  The guideline uses a stepwise treatment algorithm 
(Figure 2-1).  First-line treatment consists of approved doses of second generation 
H1-antihistamines (sgAH).  If there is inadequate response to treatment, higher doses 
(up to 4x approved doses) of sgAH are recommended.  After that, omalizumab, a 
humanized anti-IgE monoclonal antibody, is recommended.  Although omalizumab has 
provided advancement in treatment, 20 to 40 of patients do not respond to treatment.  
Those who don’t respond to omalizumab may be treated with cyclosporine although it is 
not approved for CSU and many patients must discontinue treatment due to adverse 
events.  Additional treatment options are needed for patients with CSU. 

Product:  Tezepelumab  
Protocol Number:  20190194  
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Figure 2-1.  EAACI/GA2LEN/EDF/WAO Guideline for the Management of Urticaria 
 
sgAH  second generation antihistamines  
Source:  Zuberbier et al, 2018 
2.2.2 
Amgen Investigational Product Background:  Tezepelumab 
Tezepelumab is a human recombinant monoclonal antibody of the Ig G2 subclass that 
specifically binds human TSLP, blocking the interaction between TSLP and its 
high-affinity receptor complex.  Targeting TSLP may serve to inhibit multiple biologic 
pathways involved in CSU.  
A detailed description of the chemistry, pharmacology, pharmacokinetics (PK), efficacy, 
and safety of tezepelumab is provided in the Investigator’s Brochure. 
2.2.3 
Non-Amgen Investigational Product Background:  Xolair 
(omalizumab) 
Omalizumab is a humanized anti-IgE monoclonal antibody that binds to the Fc region of 
free IgE and prevents it from binding to its high-affinity receptor on mast cells and 
basophils.  As described in a boxed warning in its US prescribing information, 
omalizumab has been associated with anaphylaxis presented as bronchospasm, 
hypotension, syncope, urticaria, and/or angioedema of the throat or tongue, as early as 
after the first dose, but also beyond 1 year after beginning regularly administered 
treatment (Xolair prescribing information). 

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Refer to the regional manufacturer package insert for additional information. 
2.3 
Risk Assessment 
To date, tezepelumab has been well tolerated with no identified risks from studies in 
healthy volunteers, or patients with asthma, chronic obstructive pulmonary disease, and 
moderate to severe atopic dermatitis. 
Hypersensitivity (including anaphylaxis, serious allergic reactions, and immune complex 
disease) is an important potential risk for tezepelumab and is considered a key safety 
risk.  No serious allergic reactions nor anaphylactic reactions considered related to 
tezepelumab have been reported in the clinical program.  The subject incidence of 
positive posttreatment antidrug antibodies observed in the phase 2 dose-ranging asthma 
study was low and was higher in subjects who received placebo (4.3%) than in subjects 
treated with tezepelumab (1.7%).  No subjects developed neutralizing antibodies in that 
study.  As part of the current study, subjects can be randomized to receive treatment 
with omalizumab (Xolair), which has been associated with anaphylaxis and has a 
boxed warning in its US prescribing information (Xolair prescribing information).  For 
these reasons, all visits where investigational product is administered, subjects will be 
observed for a period of time of 2 hours or at the discretion of the investigator as defined 
in Section 6.1. 
Serious infections are also an important potential risk associated with tezepelumab and 
are considered a key safety risk.  The mechanism of action of tezepelumab suggests 
potential inhibitory effects on immune responses mediated by Th2 cells, leading to the 
possibility of suppression of the host’s protective immune response and impairing host 
defense against certain infections (eg, bacterial infections, parasitic [helminth] infections, 
and opportunistic infections).  However, there is no clear preclinical or clinical evidence 
supporting such a role, and no safety signals related to infections have been detected in 
the tezepelumab program. 
Injection site reactions are considered a potential risk for tezepelumab.  Injection site 
reactions were balanced between the treatment groups and placebo in the phase 2b 
severe asthma study and no event was considered serious. 
Data from preclinical, clinical, and literature sources does not currently support 
malignancy being considered a risk with tezepelumab; however, it is categorized as an 
adverse event of special interest.  
 
 

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  Thymic stromal lymphopoietin literature 
data (ie, information on class effects, knockout mouse models, and human genetic 
mutations) does not indicate a potential carcinogenic concern associated with long-term 
tezepelumab treatment; however, malignancies will be carefully monitored in this study. 
Tezepelumab binds to human TSLP and prevents its interaction with the TSLP receptor 
complex.  There are no data on CSU and the risk of coronavirus disease 2019 
(COVID-19).  Subjects will be closely monitored and the potential impact of 
COVID-19 on these participants will be carefully considered. 
The benefit/risk assessment for tezepelumab in CSU based on the development for 
atopic dermatitis and asthma through phase 2 is anticipated to be favorable.  The future 
benefit/risk assessment will largely be defined by results from the phase 3 program. 
The above benefit risk assessment supports the conduct of this clinical trial.  Reference 
should be made to the Investigator’s Brochure for further data on tezepelumab. 
3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the effect of 
tezepelumab on improvement in 
the Urticaria Activity Score over 
7 days (UAS7) 
 
Change from baseline in UAS7 at 
week 16 
The first estimand of the primary objective consists of: 
 
Target population – Adults with chronic spontaneous urticaria (CSU) who are 
symptomatic (inadequately controlled) despite treatment with second generation 
H1-antihistamines (sgAH) 
 
Endpoint – Change from baseline in UAS7 score at week 16 
 
Intercurrent events –  Use of protocol-excluded medications due to CSU 
(regardless of discontinuation of IP):  treatment failure will be considered and the 
composite strategy will be applied where subject’s post-baseline effect will be 
similar as the baseline starting from the protocol-excluded medication use until the 
end of study; Use of protocol-excluded medications not due to CSU (regardless of 
discontinuation of IP): 
 
Discontinuation of investigational product due to reasons other than 
protocol-excluded medication use:  treatment policy will be applied, where data will 
be used as collected from these subjects regardless of whether subjects complete 
16 weeks of study treatment.   
 
Summary measure – Difference of mean change from baseline in UAS7 score 
at week 16 between tezepelumab 420 mg subcutaneous (SC) every 2 weeks 

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(Q2W) or 210 mg SC every 4 weeks (Q4W) and placebo (tezepelumab 420 mg 
SC Q2W or 210 mg SC Q4W minus placebo). 
In summary, the first estimand of the primary endpoint is the difference of mean 
change from baseline in UAS7 score at week 16 between tezepelumab 420 mg SC 
Q2W or 210 mg SC Q4W and placebo, in adults with CSU who are symptomatic 
(inadequately controlled) despite treatment with sgAH, regardless of whether subjects 
complete 16 weeks of study treatment. 
The second estimand of the primary endpoint consists of the same definitions of 
endpoint, intercurrent event, and the summary measures in the target population of 
adults with CSU who are symptomatic (inadequately controlled) despite treatment with 
sgAH and are also anti-immunoglobulin (Ig) E naïve.  
The third estimand of the primary endpoint consists of the same definitions of 
endpoint, intercurrent event, and summary measures in the target population of adults 
with CSU who are symptomatic (inadequately controlled) despite treatment with sgAH 
and are anti-IgE experienced (intolerant, inadequate responder, or have discontinued 
for other reason). 
Secondary 
 
To evaluate the effect of 
tezepelumab on improvement in 
itch using the Itch Severity Score 
over 7 days (ISS7) 
 
Change from baseline in ISS7 at 
week 16 
 
To evaluate the effect of 
tezepelumab on improvement in 
hives using the Hives Severity 
Score over 7 days (HSS7) 
 
Change from baseline in HSS7 
score at week 16 
 
To evaluate the effect of 
tezepelumab on subjects 
achieving minimal residual 
disease using the UAS7 
 
UAS7  6 at week 16 
 
To evaluate the effect of 
tezepelumab on subjects 
achieving the minimal important 
difference (MID) on change from 
baseline in the UAS7  
 
Change from baseline in 
UAS7  -10 at week 16 
 
To evaluate the effect of 
tezepelumab compared with 
placebo in CSU subjects using 
the UAS7 
 
Complete response in UAS7 
defined as UAS7  0 at week 16 
 
To evaluate the effect of 
tezepelumab on complete 
resolution of itch using the ISS7 
 
ISS7  0 at week 16 
 
To evaluate the effect of 
tezepelumab on subjects 
achieving the MID on change from 
baseline in the ISS7  
 
Change from baseline in 
ISS7  -5 at week 16 

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 
To evaluate the effect of 
tezepelumab on the complete 
resolution of hives using the HSS7 
 
HSS7  0 at week 16 
 
To evaluate the effect of 
tezepelumab on subjects 
achieving the MID on change from 
baseline in the HSS7 
 
Change from baseline in 
HSS7  -5.5 at week 16 
 
To evaluate the effect of 
tezepelumab on sleep 
interference and quality (falling 
asleep, nighttime awakenings, 
restfulness upon awakening)  
 
Change from baseline in sleep 
interference score at week 16 
 
Change from baseline in the sleep 
interference and quality diary 
items at week 16 
 
To evaluate the effect of 
tezepelumab on improvement in 
urticaria disease control using the 
Urticaria Control Test (UCT) 
 
Change from baseline UCT score 
at week 16 
 
 
To evaluate the effect of 
tezepelumab on angioedema 
using the Angioedema Activity 
Score over 7 days (AAS7) 
 
Change from baseline in AAS7 at 
week 16 
 
To evaluate the effect of 
tezepelumab on the cumulative 
time period that treated subjects 
are angioedema occurrence-free 
using the AAS7 
 
Cumulative weeks that subjects 
achieve AAS7  0 responses 
between baseline and week 16 
 
To evaluate the effect of 
tezepelumab on subject 
urticaria-specific quality of life 
(QoL) using the Chronic Urticaria 
Quality of Life Questionnaire 
(CU-Q2oL) 
 
Change from baseline in the 
CU-Q2oL at week 16 
 
To evaluate the effect of 
tezepelumab on subject QoL 
using the Dermatology Life Quality 
Index (DLQI) 
 
Change from baseline in DLQI at 
week 16  
 
To evaluate the effect of 
tezepelumab on subject 
angioedema-specific QoL using 
the Angioedema Quality of Life 
Questionnaire (AE-QoL) 
 
Change from baseline in the 
AE-QoL at week 16 
 
To evaluate the effect of 
tezepelumab on improvement in 
angioedema disease control using 
the Angioedema Control Test 
(AECT) 
 
Change from baseline in the 
AECT score at week 16  

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Exploratory 
 
To evaluate the effect of 
tezepelumab on improvement in 
CSU  
 
Achieving minimal disease 
activity, MID score, time to MID, 
complete response and the 
change from baseline of defined 
CSU disease activity on all 
primary and secondary endpoints 
(UAS7, ISS7, HSS7, AAS7) at all 
measured timepoints other than 
week 16 
 
To evaluate the effect of 
tezepelumab on the cumulative 
time period that treated subjects 
are urticaria symptom-free  
 
Cumulative weeks that subjects 
achieve UAS7  0, ISS7  0, or 
HSS7  0 responses between 
baseline and week 16 
 
To evaluate the effect of 
tezepelumab on the cumulative 
time period that treated subjects 
have minimal disease using the 
UAS7 
 
Cumulative weeks that subjects 
achieve UAS7  6 between 
baseline and week 16 
 
To evaluate the effect of 
tezepelumab on QoL as 
 
Achieving minimal disease activity 
and the change from baseline of 
defined CSU QoL measures 
 
To evaluate the effect of 
tezepelumab on subjects 
achieving complete control of 
angioedema disease using the 
AECT 
 
Complete control in AECT 
(AECT  16) at week 16 
 
To evaluate the effect of 
tezepelumab on the improvement 
in productivity and activity 
impairment using the Work 
Productivity and Activity 
Impairment Questionnaire:  
Chronic Urticaria (WPAI-CU) 
 
Change from baseline in 
WPAI-CU score at week 16 
 
To evaluate the effect of 
tezepelumab on H1-antihistamine 
rescue medication utilization 
 
Cumulative frequency of 
H1-antihistamine rescue 
medication utilization from 
baseline to week 16 
 
To characterize the 
pharmacokinetics (PK) of 
tezepelumab  
 
Serum concentrations of 
tezepelumab at scheduled visits 
 
To evaluate the safety and 
tolerability of tezepelumab  
 
Subject incidence of adverse 
events (including serious adverse 
events)  

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measured by all patient-reported 
outcomes (PROs)  
(DLQI, CU-Q2oL AECT, AE-QoL, 
WPAI-CU) at all other measured 
timepoints other than week 16 
 
To evaluate the effect of 
tezepelumab on sleep  
 
Change from baseline in sleep 
interference and sleep quality 
items at all measured timepoints 
other than week 16 
 
To evaluate the effect of 
tezepelumab on subjects 
achieving the MID on the DLQI 
 
Achieving MID defined as change 
from baseline in DLQI  -2.24 at 
week 16 and all other measured 
timepoints 
 
Time to achieve the MID 
 
To evaluate the effect of 
tezepelumab on subjects 
achieving the MID on the 
CU-Q2oL 
 
Achieving MID defined as change 
from baseline in CU-Q2oL  -15 at 
week 16 and all other measured 
timepoints 
 
Time to achieve the MID 
 
To evaluate the effect of 
tezepelumab on subjects 
achieving the MID on the AE-QoL 
 
Change from baseline in 
AE-QoL  -6 at week 16 and all 
other measured timepoints 
 
Time to achieve the MID 
 
To evaluate the effect of 
tezepelumab on the improvement 
in urticaria disease control using 
the UCT 
 
Change from baseline UCT score 
at all measured timepoints other 
than week 16 
 
UCT  12 at week 16 and all other 
measured timepoints 
 
UCT  16 at week 16 and all other 
measured timepoints 
 
To evaluate the effect of 
tezepelumab on subjects 
achieving the MID on the UCT 
 
Improvement from baseline in 
UCT  3 at week 16 and all other 
measured timepoints 
 
Time to achieve the MID on the 
UCT 
 
To evaluate the effect of 
tezepelumab on subjects 
achieving well controlled disease 
using the AECT  
 
AECT  10 at week 16 and all 
other measured timepoints 
 
To evaluate the effect of 
tezepelumab on the improvement 
in Patient Global Impression of 
Severity (PGI-S) 
 
Response of PGI-S at 
week 16 and all other measured 
timepoints 
 
To evaluate the effect of 
tezepelumab on the Patient 
Global Impression of Change 
(PGI-C) 
 
PGI-C at week 16 and all other 
measured timepoints 

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 
To evaluate the effect on 
tezepelumab on time to achieve 
disease control using the UAS7, 
ISS7, and HSS7 
 
Time to achieve UAS7  0, 
ISS7  0, and HSS7  0 
 
Time to achieve minimal disease 
defined as UAS7  6  
 
To evaluate the duration of 
tezepelumab effect after 
discontinuation of investigational 
product 
 
Complete response on UAS7 after 
discontinuation of investigational 
product at weeks 24 and 32 
 
Minimum residual disease, 
defined as all subjects with 
UAS7  6, after discontinuation of 
investigational product at 
weeks 24 and 32 
 
Complete response on ISS7 or 
HSS7 after discontinuation of 
investigational product at 
weeks 24 and 32 
 
To evaluate the effect of 
tezepelumab on H1-antihistamine 
rescue medication utilization 
 
Receiving H1-antihistamine 
rescue medication 
 
To evaluate the immunogenicity of 
tezepelumab 
 
Incidence of anti-tezepelumab 
antibodies at all measured 
timepoints  
 
4. 
Study Design 
4.1 
Overall Design 
This phase 2b study is designed to evaluate the efficacy and safety of tezepelumab in 
adult subjects with CSU.  Eligible subjects include adults with a clinical diagnosis of CSU 
for  6 months at the time of screening who remain symptomatic despite treatment with 
sgAH (up to 4x the approved dose) and are anti-IgE naïve or subjects who are also 
previous users of anti-IgE therapies (symptomatic despite treatment with sgAH and are 
intolerant, inadequate responder, or were discontinued for other reason).  The study 
duration is approximately 38 weeks and includes an up to 42-day screening period, a 
16-week treatment period, and 16-week safety follow-up period.  The screening period 

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consists of 2 visits and allows a maximum of 42 days before enrollment/randomization.  
At screening visit 1, the majority of screening eligibility criteria will be reviewed, and 
subjects will be asked to complete the Urticaria Control Test (UCT).  At screening visit 2 
(a minimum of 14 days before randomization), subjects will receive the electronic diary 
(eDiary).  In addition, at screening visit 2, subjects will also begin a sgAH stabilization 
period of at least 14 days, and will be required to complete a daily Urticaria Activity 
Score (UAS) recording, daily Angioedema Activity Score (AAS) recording, and adverse 
event related to study procedures collection.  Starting from screening visit 2, subjects 
must maintain a stable dose of sgAH during the 14 days sgAH stabilization period and 
continue throughout the duration of the study until the end of study (EOS) visit.  Subjects 
who do not meet all of the screening criteria will be considered screen failures.  For 
eligible subjects, investigational product dosing will occur on day 1 and weeks 2, 4, 6, 8, 
10, 12, and 14.  Primary and secondary objectives will be evaluated at the week 16 visit.  
After week 16, subjects will continue in the safety follow-up period for 16 weeks.   
Figure 4-1.  Screening and Enrollment 
 
Note:  Subjects may proceed to screening visit 2 if serologic elements related to eligibility from screening 
visit 1 are not yet available. 
Up to 2 interim analyses will be performed:  1) the first interim analysis for futility will 
be performed after the first 60 enrolled subjects in the anti-IgE naïve stratum have 
had the opportunity to complete the week 16 assessments or early terminate from the 
study, and 2) the second interim analysis for administrative decision making will 
be performed after 120 subjects in the anti-IgE naïve stratum have had the 
opportunity to complete the week 16 assessments or early terminate from the study.   
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 

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4.2 
Number of Subjects 
Approximately 159 subjects will be enrolled to the anti-IgE naïve stratum and the 
anti-IgE experienced stratum with an approximate 3:1 ratio:  120 CSU subjects who are 
symptomatic despite treatment with sgAH and are anti-IgE naïve, and approximately 
39 subjects who are symptomatic despite treatment with sgAH and were previously 
treated with anti-IgE therapies.  Subjects will be randomized to either placebo, 
omalizumab, or 1 of 2 doses of tezepelumab in the anti-IgE naïve stratum, and placebo 
or 1 of 2 doses of tezepelumab in the anti-IgE experienced stratum.   
Subjects in this clinical investigation shall be referred to as “subjects.”  For the sample 
size justification, see Section 9.2. 
4.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
4.2.2 
Number of Sites 
Approximately 80 investigative sites in Europe, the Americas, and Asia will be included 
in the study.  Sites that do not enroll subjects within 6 months of site initiation may be 
closed. 
4.3 
Justification for Investigational Product Dose 
The tezepelumab dose of 210 mg Q4W has been shown to have efficacy in the 
treatment of asthma and an impact on mast cell related biomarkers including IL-5 (60% 
reduction), eosinophils (50% reduction), and IgE (20%).  Although the impact of 
tezepelumab on CSU endpoints has not been previously evaluated, since in CSU like in 
asthma, eosinophils, mast cells, and IgE play an important role in the pathophysiology, 
this dose of tezepelumab has the potential to show efficacy.  Reports suggest higher 
active TSLP and cytokine levels in lesioned skin in CSU; hence, this study is also 
evaluating a higher dose (420 mg Q2W) (Kay et al, 2015).  The tezepelumab 420 mg 
Q2W dose has exposure levels higher than what was observed at 280 mg Q2W 
(PATHWAY highest dose in the phase 2b asthma and phase 2a atopic dermatitis 
studies) and trough concentrations close to 700 mg intravenously Q4W in the asthma 
allergen challenge study, which demonstrated improvement in physiologic 
measurements in subjects with mild atopic asthma (Gauvreau et al, 2014).  
Tezepelumab 420 mg Q2W will allow for the further evaluation of tezepelumab efficacy 
and impact on skin mast cells at higher nonoverlapping drug concentrations with 210 mg 
Q4W.  Inclusion of the 420 mg Q2W dose will also allow for exposure-response analysis 
to further inform dose selection for future CSU studies.   

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Preclinical data supporting the safety of a tezepelumab 420 mg SC Q2W dose are 
based on a no-observed adverse effect level for 6-month toxicology studies of 
300 mg/kg SC weekly, 
 
.  Additionally, predicted steady state 
exposures (Cmax and AUC) from the tezepelumab 420 mg SC Q2W dosing regimen are 
also within the range of the exposures in previous tezepelumab clinical studies which 
were deemed safe. 
4.3.1 
Justification for Non-Amgen Investigational Product Dose 
The maximum approved dose for omalizumab in the treatment of chronic idiopathic 
urticaria is 300 mg SC Q4W, thus, that is the dose that will be evaluated in this study.  
The omalizumab group will be used as the internal active control for the evaluation of 
treatment effect of tezepelumab.  Per urticaria treatment guidelines, use of omalizumab 
is third line after higher off-label antihistamine use has failed to provide an adequate 
response (Zuberbier et al, 2018). 
4.4 
End of Study 
4.4.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or received an intervention to collect final data for the primary 
endpoint(s).  The primary completion date for this study is the date when the last 
subject has completed the assessments for week 16. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination [ET] of the study), then the primary completion will be the 
date when the last subject is assessed or received an intervention for evaluation in the 
study (ie, last subject last visit). 
End of Study:  The EOS date is defined as the date when the last subject across all 
sites is assessed or receives an intervention for evaluation in the study (ie, last subject 
last visit), following any additional parts in the study (eg, long-term follow-up), as 
applicable.  The EOS date is the date when the last subject has an opportunity to 
complete the assessments for week 32. 

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4.4.2 
Study Duration for Subjects 
For an individual subject, the length of participation includes a 2-visit screening period of 
a maximum of 42 days, including an H1-antihistamine stabilization period of at least 
14 days, a 16-week treatment period, and an EOS visit that occurs 18 weeks after the 
final dose of study drug (16 weeks after the end of treatment [EOT] visit). 
4.5 
Patient Input on Study Design 
Patient input was not obtained. 
5. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidates (eg, date of 
screening).  This log may be completed and updated via an Interactive Response 
Technology (IRT). 
Eligibility criteria will be evaluated during screening.  Each subject should meet all the 
inclusion criteria and none of the exclusion criteria for this study in order to be 
randomized.  Under no circumstances can there be exceptions to this rule.  Prospective 
approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions will not be provided.  Subjects who consent to participate 
in the study but are not subsequently randomized are considered screen failures. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.3). 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject has been informed about study procedures and medications and has 
provided informed consent prior to initiation of any study-specific 
activities/procedures 
102 
Subject is able to communicate with the investigator, and understands and 
complies with the requirements of the study 
103 
Age  18 to  80 years of age at screening  
104 
Chronic spontaneous urticaria diagnosis for  6 months at the time of screening 
visit 1 
105 
CSU inadequately controlled by sgAH at enrollment, as defined by all of the 
following: 
 
The presence of itch and hives for  6 consecutive weeks at any time prior to 
screening visit 2 
 
Failure to respond to an sgAH (up to 4 times the approved dose) 

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 
Urticaria Activity Score over 7 days (UAS7) (range 0-42)  16 and Hives 
Severity Score over 7 days (HSS7) (range 0-21)  8 during the 7 days prior to 
enrollment 
106 
Subject must have been on a sgAH at approved or increased doses (up to 4x the 
approved dose) for treatment of CSU for at least 3 consecutive days immediately 
prior to the day -14 screening visit (screening visit 2) and must have documented 
current use on the day of screening visit 1 
107 
This is only applicable for anti-IgE experienced subjects.  Subject with CSU who 
discontinued, is intolerant to, or was an inadequate responder to anti-IgE 
therapies despite being treated with omalizumab 300 mg Q4W for 6 months or 
higher doses of omalizumab  2 months (or per local country treatment 
standards) or another anti-IgE therapy.   
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 
201 
Urticaria is solely due to inducible urticaria 
202 
Active dermatologic diseases (or conditions) other than chronic urticaria, with 
urticaria wheals or angioedema symptoms such as urticarial vasculitis, erythema 
multiforme, cutaneous mastocytosis (urticaria pigmentosa) and hereditary or 
acquired angioedema (eg, due to C1 inhibitor deficiency) 
203 
Any other active skin disease associated with chronic itching that might influence, 
in the investigator’s opinion, the study evaluations and results (eg, atopic 
dermatitis, dermatitis herpetiformis, senile pruritus, etc.) 
204 
History of a clinically significant infection within 28 days prior to day 1 that, in the 
opinion of the investigator or medical monitor, might compromise the safety of 
the subject in the study, interfere with evaluation of the investigational product, or 
reduce the subject’s ability to participate in the study.  Clinically significant 
infections are defined as either of the following:  
- 
1) a systemic infection; or  
- 
2) a serious skin infection requiring parenteral antibiotic, antiviral, or 
antifungal medication 
205 
Diagnosis of a helminth parasitic infection within 6 months prior to screening 
visit 1 that had not been treated with or had failed to respond to standard of care 
therapy 
206 
Documented medical history of chronic alcohol or drug abuse within 12 months 
prior to screening visit 1 
207 
Evidence of active liver disease at screening, including jaundice or aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), or alkaline 
phosphatase greater than twice the upper limit of normal (ULN) 
208 
Subjects who, in the opinion of the investigator, have evidence of active 
tuberculosis (TB), either treated or untreated, or a positive purified protein 
derivative (PPD) or QuantiFERON-tuberculosis Gold Plus (QFT-Plus) test for TB 
during screening.  Subjects with an indeterminate QFT-Plus may be enrolled if 
they have ALL of the following: 

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 
No symptoms of TB:  productive, prolonged cough ( 3 weeks); coughing up 
blood; fever; night sweats; unexplained appetite loss; unintentional weight 
loss 
 
No evidence of active TB on chest radiograph within 3 months prior to the 
first dose of investigational product.  Note:  Chest radiograph is not part of 
screening procedure and will be the responsibility of the Investigator as this is 
outside the scope of this protocol 
Note:  If required, QFT-plus test can be repeated.  Subjects with the repeated 
indeterminate QFT-plus should be excluded from the study. 
209 
History of malignancy, except for basal cell carcinoma or in situ carcinoma of the 
cervix treated with apparent success with curative therapy  12 months prior to 
screening or other malignancies treated with apparent success with curative 
therapy  5 years prior to screening visit 1 
210 
Subject is unable to complete an electronic patient diary or complete 
questionnaires, or does not meet the required level of compliance with the eDiary 
during the 14 days sgAH stabilization period 
 
Completion of UAS (daily) for  11 of 14 days prior to randomization, or 
 
Completion of AAS (daily) for  11 of 14 days prior to randomization 
Other Medical Conditions 
211 
Medical examination or laboratory findings that suggest the possibility of 
decompensation of co-existing conditions for the duration of the study.  Any items 
that are cause for uncertainty must be reviewed and approved by the Medical 
Monitor 
212 
History or evidence of severe depression, schizophrenia, previous suicide 
attempts, or suicidal ideation 
Prior/Concomitant Therapy 
213 
Treatment with any biologic products (eg, omalizumab, ligelizumab) within 
4 months or 5 half-lives (whichever is longer) prior to screening visit 1 
214 
Routine (daily or every other day for 5 or more consecutive days) use of systemic 
corticosteroids within 30 days prior to screening visit 1 
215 
Routine (daily or every other day for 5 or more consecutive days) use of systemic 
hydroxychloroquine within 30 days prior to screening visit 1 
216 
Routine (daily or every other day for 5 or more consecutive days) use of 
methotrexate, cyclosporine A, cyclophosphamide, tacrolimus, azathioprine, and 
mycophenolate mofetil within 30 days prior to screening visit 1 
217 
Undergone plasmapheresis within 30 days prior to screening visit 1 
218 
Major surgery within 8 weeks prior to screening visit 1 or planned inpatient 
surgery or hospitalization during the study period 
219 
Receipt of Ig or blood products within 30 days prior to screening visit 1 
220 
Regular (daily or every other day) treatment with oral doxepin within 14 days 
prior to screening visit 1 
221 
Vaccination with a live or attenuated vaccine within 30 days prior to screening 
visit 1.  Receipt of COVID-19 vaccines and inactive/killed vaccinations 

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(eg, inactive influenza) are allowed, provided the vaccinations are not 
administered within 7 days before or after any study dosing visit 
222 
Known hypersensitivity, including severe hypersensitivity reactions and/or history 
of anaphylactic shock, to omalizumab or any ingredient of Xolair 
223 
History of or known hypersensitivity, including severe hypersensitivity reactions, 
and/or history of anaphylactic shock, to any biologic therapy, to any of the 
products or components to be administered during dosing or to products of 
similar chemical classes (ie, to murine, chimeric, or human antibodies) 
Prior/Concurrent Clinical Study Experience 
224 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending the previous non-biologic clinical study, or less 
than 4 months or 5 half-lives (whichever is longer) since ending the treatment on 
another biologic clinical study.   
Diagnostic Assessments 
225 
Any clinically meaningful abnormal finding in physical examination, vital signs, 
hematology, clinical chemistry, or urinalysis during the run-in period, which in the 
opinion of the investigator, may put the subject at risk because of participation in 
the study, or may influence the results of the study, or the subject’s ability to 
complete the entire duration of the study 
226 
Positive hepatitis B surface antigen and Hepatitis B core antibody (if a country 
requirement), or hepatitis C antibody serology.  Subjects with a history of 
hepatitis B vaccination without a history of hepatitis B can enroll in the study. 
227 
Positive human immunodeficiency virus (HIV) test at screening or the subject is 
taking antiretroviral medications, as determined by medical history, prior 
medications, and/or the subject’s verbal report 
Other Exclusions 
228 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for 16 weeks after the last dose of any 
protocol-required therapy.  Females of childbearing potential should only be 
enrolled in the study after a negative highly sensitive serum pregnancy test 
229 
Female subjects of childbearing potential unwilling to use 1 highly effective 
method of contraception during treatment and for 16 weeks after the last dose of 
any protocol-required therapy.  Refer to Section 11.5 for additional contraceptive 
information 
230 
Female subjects of childbearing potential with a positive pregnancy test 
assessed at screening and/or day 1 by a serum pregnancy test.  
231 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures 
(eg, patient-reported outcome [PRO] Assessments) to the best of the subject and 
investigator’s knowledge 
232 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion 

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5.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval of the protocol, informed consent form (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.3). 
The subject or subject’s legally acceptable representative must personally sign and date 
the IRB/IEC approved informed consent before commencement of study-specific 
procedures.  
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (at the time of signing 
the informed consent) receives a unique subject identification number before any 
study-related activities/procedures are performed.  The subject identification number will 
be assigned by IRT.  This number will be used to identify the subject throughout the 
clinical study and must be used on all study documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study. 
The sponsor will monitor the study population baseline characteristics during enrollment.  
If necessary, the sponsor may restrict enrollment of certain populations in order to 
ensure the appropriate distributions of subject characteristics. 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently randomized into the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened once.  Refer to Section 8.1.1. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen failure.  Screen failure subjects may be eligible for 

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rescreening once.  Subjects who fail to meet inclusion criterion 105 relating to disease 
severity at baseline as reported in the eDiary after the 2-week sgAH stabilization period 
(UAS7 score [range:  0 to 42]  16 and HSS7 [range:  0 to 21]  8 during the 7 days prior 
to randomization) will not be eligible for rescreening.  
5.5 
Antihistamine Stabilization Period  
A minimum of 14 days sgAH stabilization period is required prior to randomization.  Each 
subject should  maintain a stable dose of the sgAH (up to 4x approved dose) prescribed 
by their treating physician for at least 14 days prior to determination of eligibility for 
enrollment as described in Section 6.4.1.   
Subjects who do not meet the inclusion criteria 105 of UAS7 and HSS7 at baseline 
after the sgAH stabilization period and/or satisfy the daily eDiary completion compliance 
criteria for UAS and AAS (Exclusion #210) will not be eligible to enroll into the study.   
Subjects should maintain a stable dose of sgAH as the background medication from 
screening visit 2 throughout the study treatment and follow-up period, up to the EOS 
visit.   
Rescue medication is permitted up to 4x the approved dose of the same sgAH used as 
the background medication, if necessary, for worsening of urticaria symptoms (eg, daily 
UAS maximum score of 6, angioedema). 
6. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Table 6-1 below.  Information on 

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preparation, handling, storage, accountability, destruction, or return of the investigational 
product during the study are provided in the IPIM. 
6.1 
Treatment(s) Administered 
6.1.1 
Investigational Products 
The quantity of investigational product administered, dose start date/time, and box 
number are to be recorded on each subject’s CRF.  The site’s unblinded 
pharmacist/administrator will prepare the appropriate dose of the investigational product 
(tezepelumab, omalizumab, or placebo) as per the randomization schedule for each 
subject.  The unblinded administrator will provide the appropriate treatment for each 
subject. 

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Table 6-1.  Study Treatments 
Study Treatment 
Name 
Amgen Investigational Product:a 
Tezepelumab 
Placebo 
Non-Amgen Investigational Product:b 
Omalizumab (Xolair)  
Dosage Formulation 
 mg/mL in 
mM acetate,  
weight/volume L-proline, 
 
weight/volume polysorbate 80, pH 
 
 weight/volume sodium carboxy 
methyl cellulose in 
 mM acetate, 
 mM L-proline,
 weight/volume 
polysorbate 80, pH
150 mg/mL in a pre-filled syringe (PFS) 
(Xolair) 
Unit Dose 
Strength(s)/ 
Dosage Level(s) and 
Dosage Frequency 
Each subject will receive 2 injections per 
visit. 
For subjects randomized to 210 mg 
Q4W and 420 mg Q2W, volumes for 
injections from vials will be detailed in 
the IPIM. 
Subjects randomized to Q4W dosing will 
receive placebo at intervening visits, 
such that all subjects receive an injection 
Q2W. 
Each subject will receive 2 injections per 
visit. 
For subjects randomized to placebo, 
volumes for injections from vials 
provided will be detailed in the IPIM.  
Subjects will receive placebo dosing 
Q2W. 
Each subject will receive 2 injections per 
visit. 
For subjects randomized to 300 mg 
Q4W, volumes for injections from PFS 
will be detailed in the IPIM. 
Subjects randomized to Q4W dosing will 
receive placebo at intervening visits, 
such that all subjects receive an injection 
Q2W. 
Route of 
Administration 
SC injection 
SC injection 
SC injection 
Accountability 
The quantity, dose start date/time, and 
box number of investigational product 
are to be recorded on each subject's 
CRF(s). 
The quantity, dose start date/time, and 
box number of investigational product 
are to be recorded on each subject's 
CRF(s). 
The quantity, dose start date/time, and 
box number of investigational product 
are to be recorded on each subject's 
CRF(s). 
Dosing Instructions 
Investigational product will be 
administered by qualified study center 
personnel as the final activity for each 
study visit.  The window for study visits 
is  3 days. 
Injection sites are to be rotated. 
Subjects will be observed for 2 hours 
post-treatment at the day 1 and week 
2 visits.  For all other visits where 
investigational product is administered, 
subjects will be observed for a period of 
time at the discretion of the Investigator. 
Investigational product will be 
administered by qualified study center 
personnel as the final activity for each 
study visit.  The window for study visits 
is  3 days. 
Injection sites are to be rotated. 
Subjects will be observed for 2 hours 
post-treatment at the day 1 and week 
2 visits.  For all other visits where 
investigational product is administered, 
subjects will be observed for a period of 
time at the discretion of the Investigator. 
Investigational product will be 
administered by qualified study center 
personnel as the final activity for each 
study visit.  The window for study visits 
is  3 days. 
Injection sites are to be rotated. 
Subjects will be observed for 2 hours 
post-treatment at the day 1 and week 
2 visits.  For all other visits where 
investigational product is administered, 
subjects will be observed for a period of 
time at the discretion of the Investigator. 
CRF  case report form; IPIM  Investigational Product Instruction Manual; PFS  prefilled syringe; SC  subcutaneous; Q2W  every 2 weeks; Q4W  every 4 weeks 
a Tezepelumab will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug distribution procedures. 
b Omalizumab will be manufactured and packaged by Novartis Pharmaceuticals Corporation and/or Genentech, Inc. and distributed using Amgen (or designee) clinical 
study drug distribution procedures.  

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6.1.2 
Non-Amgen Investigational Products 
Not applicable. 
6.1.3 
Medical Devices 
The following non-Amgen investigational combination product provided by Amgen for 
use in this study is Omalizumab (Xolair) with prefilled syringe (Table 6-1).  
Non-Amgen investigational combination product Xolair with prefilled syringe is a 
single-use, disposable, handheld, mechanical “spring-based” device for fixed dose 
subcutaneous injection of 150 mg/mL.  
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices.   
6.1.4 
Other Protocol-required Therapies 
A stable dose of sgAH is required daily throughout the entire duration of the study from 
screening visit 2 to the EOS visit.  See Section 6.1.5.1. 
6.1.5 
Other Treatment Procedures 
6.1.5.1 
Background Medication 
The study background medication of one type of sgAH is required from screening visit 
2 (start of the 14 day sgAH stabilization period), throughout the study until the EOS visit. 
The type of sgAH and dose for each individual subject should be directed by subject’s 
physician.  
Subjects should maintain a stable dose of a sgAH (either 1x, 2x, 3x or 4x approved 
dose) as they entered at screening visit 2.  The type of sgAH and dose must not be 
changed while they are on the study.   
Examples of an acceptable approved sgAH include 1 tablet daily of the following:  
cetirizine 10 mg, desloratadine 5 mg, ebastine 10 mg, fexofenadine 120 mg, 
levocetirizine 5 mg, loratadine 10 mg, and rupatadine 10 mg (van den Elzen et al, 2017).  
The investigator should instruct the subject to notify the study site of any new 
medications he/she takes after enrollment into the study.  All medications and 
procedures administered after the subject was enrolled into the study must be recorded 

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on the respective CRF pages.  The therapy name, indication, dose, unit, frequency, 
route, start date, and stop date should be recorded.  Background sgAH medication will 
be sourced locally.  Subjects will record daily use in the eDiary. 
6.1.5.2 
Rescue Medication 
The same sgAH that the subject is on at screening visit 2 will be allowed as a rescue 
medication at up to 4x the approved dose.  A switch of the rescue medication for an 
individual subject is not permitted.  Subjects should be directed to use rescue medication 
dosing only if there is worsening of urticaria symptoms (eg, a daily UAS score of 6 or 
angioedema).  All sgAH rescue medication will be sourced locally.  Use of rescue 
medication (number of tablets taken over the past 24 hours) will be recorded daily in the 
subject’s eDiary.  The dose per day of rescue medication will be calculated as the 
additional daily number of tablets.  The dose per week will be calculated as the sum of 
the dose per day (daily dose plus rescue medication), over 7 days. 
All subjects are to be encouraged to complete the schedule of study visits and 
assessments whether or not they complete study treatment or receive rescue treatment. 
6.1.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material. 
This includes any investigational product(s), device(s) or combination product(s) 
provisioned and/or repackaged/modified by Amgen. 
Any product complaint(s) associated with an investigational product(s), 
non-investigational products(s), devices(s), or combination product(s) supplied by 
Amgen are to be reported according to the instructions provided in the IPIM. 
6.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Initiation of the following classes of treatments is NOT allowed after the start of 
screening (visit 1).  
 
anti-IgE therapy 
 
systemic corticosteroids 
 
systemic hydroxychloroquine 

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 
methotrexate, cyclosporine A, cyclophosphamide, tacrolimus, azathioprine, and 
mycophenolate mofetil 
 
H2 antagonists (H2 blockers) 
 
leukotriene receptor antagonists (LTRAs) 
Note:  For LTRAs and H2 blockers, if they are used for the conditions other than 
CSU and a stable dose was maintained at least 4 weeks prior to visit 1, and no 
dose change during the study, they are not prohibited from use. 
 
intravenous or intramuscular IgG 
 
plasmapheresis 
 
doxepin (oral) 
 
live attenuated vaccines 
Each concomitant drug must be individually assessed against all exclusion criteria.  If in 
doubt, the investigator should contact the sponsor or delegate before randomizing a 
subject or allowing a new medication to be started. 
If the prohibited treatment was inadvertently used during the study for an indication other 
than CSU, the subject must immediately discontinue use of the prohibited treatment if 
he/she wishes to continue in the study.  Medication should be assessed for adherence to 
the indication and other inclusion/exclusion criteria. 
Systemic corticosteroids (SCS) and anti-inflammatory medications are not 
recommended for the treatment for CSU, and are prohibited medications for this study.   
If a subject uses SCS during the treatment period, the event will be handled as an 
intercurrent event.  The subject may continue IP treatment if no safety concerns judged 
by the investigator and the sponsor.  Any marketed or investigational biologics (eg, 
dupilumab and omalizumab) are not allowed within 4 months or 5 half-lives (whichever is 
longer) prior to visit 1, during study period and 4 months or 5 half-lives (whichever is 
longer) after last dose of investigational product. 
All subjects are to complete the schedule of study visits and assessments whether or not 
they complete study treatment or receive rescue medication. 
6.2 
Dose Modification 
6.2.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
There are no dose-cohort study escalation/de-escalation and/or stopping rules in this 
study. 

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6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
6.2.2.1 
Amgen Investigational Product:  Tezepelumab 
The reason for dose change of tezepelumab is to be recorded on each subject’s CRF(s).  
No dose changes are permitted for tezepelumab. 
An individual subject may be discontinued at the discretion of the investigator and/or the 
sponsor due to clinically significant events. 
Subjects who receive rescue medications may continue treatment with study drug, per 
the instructions outlined in Section 6.1.5.2.   
6.2.2.2 
Non-Amgen Investigational Product(s):  Omalizumab 
The reason for dose change of omalizumab is to be recorded on each subject’s CRF(s).  
No dose changes are permitted for omalizumab.  
Anaphylaxis, presenting as bronchospasm, hypotension, syncope, urticaria, and/or 
angioedema of the throat or tongue, has been reported to occur after administration of 
omalizumab.  Anaphylaxis has occurred after the first dose of omalizumab but also has 
occurred beyond 1 year after beginning treatment.  Closely observe patients for an 
appropriate period of time after omalizumab administration and be prepared to manage 
anaphylaxis and have them seek immediate medical care should symptoms occur.  
Additional information on risks associated with omalizumab will be found in the local 
medical health authority approved product information.  
Subjects experiencing a severe hypersensitivity reaction to study drug must discontinue 
treatment. 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.7 for details regarding drug-induced liver injury (DILI) guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.  
6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product during the study are provided in the IPIM. 
6.4 
Measures to Minimize Bias:  Randomization and Blinding 
6.4.1 
Method of Treatment Assignment 
After meeting all randomization requirements described in Section 4.1, subjects who are 
symptomatic despite treatment with a sgAH and are anti-IgE naïve will be randomized in 

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a 1:1:1:1 allocation ratio to 1 of 2 tezepelumab treatment groups, omalizumab, and 
placebo, respectively.  Subjects who are symptomatic despite treatment with a sgAH 
and are anti-IgE experienced (intolerant, inadequate responder, or discontinued for other 
reason), will be randomized in a 1:1:1 ratio to 1 of 2 tezepelumab treatment groups and 
placebo, respectively. 
The randomization will be stratified by: 
1. 
anti-IgE naïve versus anti-IgE experienced 
2. 
 
3. 
disease severity (UAS7 at baseline  28 versus  28) 
The randomization will be performed by the IRT system.  The randomization number will 
be provided to the site through an IRT.  
 
 
  
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF. 
6.4.2 
Blinding 
Treatment assignment will be blinded to all subjects, site personnel (with the exception 
of the pharmacist and study drug administrator), and Amgen as described below.   
6.4.2.1 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment is to only be unblinded by the investigator when 
knowledge of the treatment is essential for the further management of the subject on this 
study or may potentially impact the safety of the subject.  Unblinding at the study site, by 
anyone other than the unblinded pharmacist and the unblinded study drug administrator, 
for any other reason will be considered a protocol deviation.  It is encouraged that the 
Amgen Trial Manager and the Amgen Medical Monitor be notified before the blind is 
broken unless the investigator believes that identification of the study treatment is 
required for a medical emergency.  If this is not possible, the Amgen Trial Manager and 
Amgen Medical Monitor must be notified within 24 hours after breaking the blind.  The 
date and reason that the blind was broken must be recorded in the source 
documentation.  An unblinded pharmacist and unblinded study drug administrator will 
have access to the treatment based on the randomization list from the IRT.  A 
description of how responsible investigators will access treatment information, in the 
event that there is a need to break the blind will be detailed in the IPIM. 

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6.4.2.2 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information is not to be 
distributed to the study team, investigators, or subjects prior to the study being formally 
unblinded (eg, the formal unblinding may occur at the final analysis rather than during 
the primary analysis) except as specified (eg, Section 6.4.2.1). 
Pre-identified members of the team may be unblinded following the Primary Analysis; 
however, the investigators, subjects, and members of the study team who interact with 
sites or are involved in decision making on the conduct of the study will not have access 
to unblinding information until the study is formally unblinded at the Final Analysis.  Any 
member of the clinical study team that is unblinded at the Primary Analysis must be 
replaced by a blinded team member. 
Staff from Clinical Supply Chain, Biological Sample Management, Clinical Pharmacology 
Modeling and Simulation, Computational Biology, Clinical Immunology, Clinical 
Biomarkers and Diagnostics, and Global Biostatistical Sciences departments who are 
responsible for tracking, assaying, or analyzing biological samples during the conduct of 
this study are considered unblinded to the treatment assignments in this study.  These 
individuals will not to have access to subject level clinical data apart from the samples 
they are assaying and analyzing during the course of the study. 
If interim analysis and/or exposure-response analysis is performed, the interim analysis 
team and/or exposure-response analysis team, including Clinical Pharmacology 
Modeling and Simulation, Global Biostatistics Sciences, and Biostatistical programming, 
who are independent of the study team, may be unblinded.  The analysis plan and data 
integrity document for the exposure-response analysis will detail the analyses and 
describe the timing for unblinding according to Amgen’s standard operating procedure. 
6.5 
Treatment Compliance 
Subjects will receive the SC doses of investigational product at the study centers.  The 
doses will be administered by qualified study personnel for the duration of the study.  All 
efforts should be made to administer investigational product within the defined study 
windows.  In the case of an out of window visit, investigational product can be 
administered within 1 week of the target visit day (ie, calculated from the day 1 visit).  If 
investigational product cannot be administered within 1 week of the target visit date, the 
dose is considered missed.  If a subject arrives for a visit and investigational product was 

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administered within  1 week prior, the dose should not be administered, but all other 
study procedures should be conducted and administration of investigational product 
should occur as soon as possible at least 1 week after the previous administration. 
6.6 
Treatment of Overdose 
There is currently no specific treatment in the event of overdose of tezepelumab and the 
effects of overdose of this product are not known.  An overdose with associated adverse 
events is recorded as the adverse event diagnosis/symptoms on the relevant adverse 
event modules in the Event CRF. 
6.7 
Prior and Concomitant Treatment 
6.7.1 
Prior Treatment 
Prior therapies that were being taken/used from 5 years prior to screening through the 
first dose of investigational product will be collected. 
For all prior therapies, therapy name, indication, dose, unit, frequency, route, start date 
and stop date, specifically prior CSU therapies, should be collected.   
6.7.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.1.7. 
Concomitant therapies are to be collected from the first dose of investigational product 
through the EOS.  Therapy name, indication, dose, unit, frequency, route, start date and 
stop date should be collected.   
Allowed concomitant treatments and directions pertaining to rescue therapy are outlined 
in Section 6.1.5.2. 
7. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 7.1, 7.2.1, and 7.2.2. 

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7.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (SoA) 
(Table 1-1) including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints, adverse events, 
and must document this decision in the subject’s medical records.  Subjects who have 
discontinued investigational product and/or other protocol-required therapies or 
procedures should not be automatically removed from the study.  Whenever safe and 
feasible, it is imperative that subjects remain on-study to ensure safety surveillance 
and/or collection of outcome data. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 11.3. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance 
 
Adverse event 
 
Subject request 
 
Pregnancy or breastfeeding 
 
Disease flare requiring treatment not allowed in the protocol 
7.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 

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unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records. 
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 11.6 for further details).  Refer to the SoA (Table 1-1) for data to be collected at 
the time of study discontinuation and follow-up and for any further evaluations that need 
to be completed. 
7.2.1 
Reasons for Removal From Washout Period, Run-in Period, or 
Invasive Procedures 
Not applicable to this study. 
7.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  

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 
For subjects who are lost to follow-up, the investigator can search publicly available 
records where legally permitted to ascertain survival status.  This ensures that the 
data set(s) produced as an outcome of the study is/are as comprehensive as 
possible. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the SoA (see Table 1-1).   
As protocol waivers or exemptions are not allowed if a randomized subject is 
subsequently determined to be ineligible for the study, this must be discussed with the 
sponsor immediately upon occurrence or awareness to determine if the subject is to 
continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
Telemedicine and home healthcare visits may be implemented at randomization/day 1 
onward, where circumstances outside the subject’s, site’s, and sponsor’s control (eg, 
pandemic) result in study visits being unable to be conducted.  The sponsor must 
authorize use of these approaches in advance of each visit and this approach may only 
be used where allowable by local health authorities, ethics committees, and healthcare 
provider guidelines (eg, hospital policies).  The minimum possible number of visits 
should occur outside the clinic, and visits should return to “in-clinic” at the earliest 
possible opportunity. 
8.1 
General Study Periods 
8.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 
signed the ICF, the site will register the subject in the IRT and screen the subject in 
order to assess eligibility for participation.  The screening window is a maximum of 
42 days. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, (see Section 5.4) as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen failure.  Screen failure subjects may be eligible for 
rescreening once.  Subjects who fail to meet inclusion criteria related to disease severity 

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at baseline as reported in the eDiary after the 2 week sgAH stabilization period 
(UAS7 score [range:  0 to 42]  16 and HSS7 [range:  0 to 21]  8 during the 7 days prior 
to randomization) will not be eligible for rescreening.  
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 42-day 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  If the rescreening period begins more than 30 days 
after the original signing of the ICF, all screening procedures, including informed 
consent, must be repeated. 
8.1.2 
Treatment Period 
Visits will occur per the SoA (Table 1-1).  The window for study visits is  3 days.  The 
date of the first dose of investigational product is defined as day 1.  All subsequent 
doses and study visits will be scheduled based on the day 1 date.  Administration of 
investigational product is to occur following completion of all other study activities for 
each visit. 
8.1.3 
Safety Follow-up 
The safety follow-up period begins after the week 16 visit and continues through week 
32.  Safety follow-up visits will occur at weeks 24 and week 32/EOS (Table 1-2).  All 
subjects who terminate the study early will complete an ET visit consisting of all 
assessments included in the EOT (week 16) visit.  In addition, safety follow-up visits will 
occur at 8 weeks and 16 weeks after the EOT visit.  In the event a patient is unable to 
have a safety follow-up visit, the site will attempt to contact the subject by telephone to 
obtain safety information. 
8.1.4 
End of Study 
The EOS visit will occur 16 weeks after the EOT visit at week 16 (at week 32/18 weeks 
after the final dose of investigational product) (Table 1-2). 
8.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
timepoints. 
8.2.1 
General Assessments  
8.2.1.1 
Informed Consent 
All subjects must sign and personally date the IRB/IEC approved informed consent 
before any study-specific procedures are performed. 

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8.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact on biomarkers variability 
and PK of the protocol-required therapies.  
8.2.1.3 
Medical History 
The investigator or designee will collect a complete medical history that started within 
5 years prior to enrollment through informed consent.  Medical history will include 
information on the subject's concurrent medical conditions, specifically CSU history and 
medication use.  Record all findings on the medical history CRF.  In addition to the 
medical history above, CSU history, including information on prior use of anti-IgE 
therapy for subjects in the anti-IgE experienced stratum, must date back to the original 
diagnosis.   
8.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
8.2.1.5 
Physical Measurements 
Height in centimeters should be measured without shoes.  Weight in kilograms should 
be measured without shoes. 
8.2.1.6 
Substance Abuse History  
Obtain a detailed history of prior and/or concurrent use of drugs, alcohol, tobacco, and 
caffeine. 
8.2.2 
Efficacy Assessments 
8.2.2.1 
Patient-Reported Outcomes (PRO) 
At each timepoint, as indicated in Table 1-1, PROs are to be assessed prior to any other 
assessments. 
8.2.2.1.1 
Electronic Diary (eDiary) 
The eDiary, which includes certain PRO measures, will be completed by the subject at 
home each morning using an electronic device according to the SoA (Table 1-1) and 
should be completed prior to other study assessments to avoid the possibility of 
introducing bias to subject responses.  Use of daily standard sgAH and any need for 
rescue medication dosing, including the number of additional tablets should also be 

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recorded daily in the subject’s eDiary.  The subject should bring the eDiary to each study 
visit.   
8.2.2.1.2 
Urticaria Activity Score (UAS) 
The UAS is a CSU-specific PRO measure mainly used to assess CSU activity/severity 
and treatment response.  It contains 2 components:  the Hives Severity Score (HSS) 
for number of wheals (ie, hives) and Itch Severity Score (ISS) for itch intensity, which 
are scored from 0 (no wheals, no itch) to 3 (many wheals, severe itch).  Subjects are 
asked to document both scores daily with a recall period over past 24-hours, and the 
summed result of daily HSS and ISS gives a daily UAS score (range:  0 to 
6 points/day).  The daily UAS score summed over a 7-day period gives a weekly UAS 
score (UAS7) (range:  of 0 to 42 points) (Mathias et al, 2012a).   
0 
Itch and hive free — indicative of no symptoms of CSU and considered a full 
treatment response 
1–6 
Well-controlled urticaria — indicates a good response to treatment 
7–15 
Mild urticaria — indicates also a lower response level 
16–27 
Moderate activity urticaria — entry criteria for clinical trials in CSU 
28–42 
Severe activity urticaria 
The HSS component of the UAS assigns a score of 0, 1, 2, or 3 points for no wheals, 
 20 wheals, 20 to 50 wheals, and  50 wheals per day, respectively (Hawro et al, 2018).  
The minimal important difference (MID) for UAS7 is between 9.5 and 10.5 points 
(equivalent to 10 points).  The UAS is the current standard for measuring signs and 
symptoms, as well as disease activity in CSU and is used in clinical care and trials 
(Zuberbier et al, 2018; Hawro et al, 2018).  Once daily UAS is recommended by 
treatment guidelines (Zuberbier et al, 2018) and is what will be used in this study. 
8.2.2.1.3 
Angioedema Activity Score (AAS) 
The AAS is a prospective 5-item PRO measure used to determine angioedema activity 
(Weller et al, 2013).  Subjects document, as part of the daily diary, each morning, the 
presence or absence of angioedema during the past 24 hours.  If angioedema was 
present, subjects score 5 key factors (duration, physical discomfort, impact on daily 
activities, impact on appearance, and overall severity) each with 0 to 3 points.  The AAS 
daily score ranges from 0 to 15 points.  The daily AAS scores are summed for 7 days to 
form the Angioedema Activity Score over 7 days (AAS7).  The MID for AAS7 is 8 points 

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(Weller et al, 2013).  The AAS will be measured once daily according to the SoA 
(Table 1-1). 
8.2.2.1.4 
Sleep Related Outcomes 
The sleep related outcomes consist of 4 daily items:  1 sleep interference score and 
3 items on sleep quality.  The sleep interference score is part of the Urticaria Patient 
Daily Diary, which has been validated in adults and adolescents with chronic idiopathic 
urticaria and CSU (Mathias et al, 2012b; Mathias et al, 2010).  Sleep interference will be 
assessed by the subject, once daily in the morning and recorded in the eDiary.  Subjects 
will score sleep interference on a scale of 0 to 3 (Mathias et al, 2010), where: 
0  no interference 
1  mild, little interference with sleep 
2  moderate, woke up occasionally, some interference with sleep 
3  substantial, woke up often, severe interference with sleep. 
The sleep quality items consist of 3 questions:  falling asleep, wakefulness, and feeling 
rested in the morning.  These are adapted from the chronic urticaria quality of life 
questionnaire (CU-Q2oL) sleep items (Baiardini et al, 2011; Baiardini et al, 2005).   
Details on the questions are as follows: 
1. How much difficulty did you have falling asleep last night because of your urticaria? 
Response options range from 0 to 3, where: 
0  No difficulty 
1  A little difficulty 
2  Moderate difficulty 
3  A lot of difficulty 
2. How often did you wake up during the night because of your urticaria? 
Response options range from 0 to 3, where: 
0  Not at all 
1  Rarely 
2  Occasionally 
3  Quite often 
3. To what degree did you wake up this morning feeling rested? 
Response options range from 0 to 3, where: 
0  Not at all 

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1  Slightly 
2  Moderately 
3  Very much 
Each diary item will be summed to generate a weekly score (range:  0 to 21).  The order 
of item 3 response will be reversed in the analysis so that a higher score indicates 
poorer sleep quality/greater sleep interference. 
8.2.2.1.5 
Patient Global Impression of Severity (PGI-S) 
The Patient Global Impression of Severity (PGI-S) is a single item designed to capture 
the subject’s perception of overall symptom severity at the time of completion on a 
5-point categorical response scale (no symptoms to very severe symptoms).  The PGI-S 
will be completed by the subject at the study center according to the SoA (Table 1-1). 
8.2.2.1.6 
Patient Global Impression of Change (PGI-C) 
The Patient Global Impression of Change (PGI-C) is a single item designed to capture 
the subject’s perception of overall response to treatment at the time of completion.  The 
assessment uses a 7-point rating scale:  1  very much improved, 2  much improved, 
3  minimally improved, 4  no change, 5  minimally worse, 6  much worse, and 
7  very much worse.  The PGI-C will be completed by the subject at the study center 
according to the SoA (Table 1-1). 
8.2.2.1.7 
Urticaria Control Test (UCT) 
The UCT is a retrospective, simple validated scoring system that evaluates the physical 
symptoms of chronic urticaria (itch, hives and/or angioedema) and the effectiveness of 
treatment over 4 weeks (Weller et al, 2012).  The UCT is designed to assess disease 
control in patients with CSU.  The questions cover severity of physical symptoms, how 
much symptoms have affected QoL, how often treatment has been inadequate to control 
symptoms, and how well symptoms have been under control.  It consists of 4 questions 
with 5 answer options each that are scored from 0 to 4.  The UCT score is the sum of all 
4 questions with a lowest and highest possible value of 0 (no control) and 16 (complete 
control), respectively.  A score of  12 indicates well-controlled urticaria, while a score of 
 11 points toward poor disease control (Weller et al, 2012).  The minimal clinical 
change, which can be regarded as meaningful to patients, is determined to be 3 points 
(Weller et al, 2017).  The UCT will be completed by the subject at the study center 
according to the SoA (Table 1-1). 

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8.2.2.1.8 
Angioedema Control Test (AECT) 
This PRO measure is only applicable for subjects with angioedema.  The Angioedema 
Control Test (AECT) is a simple retrospective, questionnaire evaluating disease control 
that consists of questions in the domains of signs and symptoms, QoL, anxiety/fear, and 
effectiveness of therapy (Weller et al, 2020a).  Subjects answer the 4 questions with 
5 answer options based on their symptoms over the last 3 months.  The results of the 
validation of the AECT have been validated (Weller et al, 2020b).  Angioedema control 
test scores range from 0 to 16 points.  A cutoff value of  10 points is used to identify 
well-controlled disease and  10 points is used to identify poorly controlled disease 
(Weller et al, 2020b).  The MID has not been established (Weller et al, 2020a).  The 
AECT will be completed by the subject at the study center according to the SoA 
(Table 1-1). 
8.2.2.1.9 
Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) 
The CU-Q2oL is a 23-item, self-reported urticaria-specific measure which evaluates 
6 dimensions of QoL:  pruritus (2 items), impact on life activities (6 items), sleep 
problems (5 items), limitations (3 items), looks (5 items), and swelling (2 items).  
Subjects are asked how bothered they have been by each symptom in the previous 
2 weeks.  Each item is assessed on a 5-point Likert scale (1  never to 5  very much).  
The total score is transformed to a linear scale of 0 to 100, with a higher CU-Q2oL score 
indicating a higher QoL impairment (Baiardini et al, 2011; Baiardini et al, 2005).  A study 
by Kulthanan et al suggests that the minimal clinically important difference in CU-Q2oL 
corresponds to a reduction of 15 points (Kulthanan et al, 2016).  The CU-Q2OL will be 
completed by the subject at the study center according to the SoA (Table 1-1). 
8.2.2.1.10 
Angioedema Quality of Life Questionnaire (AE-QoL) 
This PRO measure is only applicable for subjects with angioedema.  The Angioedema 
Quality of Life Questionnaire (AE-QoL) is the first validated angioedema QoL 
questionnaire (Weller et al, 2012) and is only completed if the subject has angioedema.  
It consists of 17 questions in 4 domains (functioning, fatigue/mood, fear/shame, and 
food) and has a recall period of 4 weeks.  Each question has 5 answer options, with 
higher numbers indicating a more adverse impact.  The total score is calculated and 
then transformed to a linear scale of 0 to 100, with a higher score indicating worse 
impairment in QoL.  The minimal clinically important difference is 6 points (Weller et al, 
2016).  This questionnaire is to be completed by those subjects with recurrent 

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angioedema as determined by baseline AAS7 score and AE-QoL will be measured at 
the study center according to the SoA (Table 1-1). 
8.2.2.1.11 
Dermatology Life Quality Index (DLQI) 
The Dermatology Life Quality Index (DLQI) is a 10-item, subject-completed, 
health-related QoL assessment with content specific to those with dermatology 
conditions.  The recall period is 1 week (Finlay and Kahn, 1994).  The DLQI content 
captures respondent perceptions of dermatology-related symptoms and feelings 
(embracement), impacts on daily activities, leisure, work or school, personal 
relationships, and the side effects of treatment.  Each item is scored on a 4-point Likert 
scale:  0  not at all/not relevant; 1  a little; 2  a lot; and 3  very much 
(Basra et al, 2008).  The DLQI is validated in CSU and the established MID is 
2.24 (Shijkar et al, 2005).  The DLQI will be completed by the subject at the study center 
according to the SoA (Table 1-1). 
8.2.2.1.12 
Work Productivity and Activity Impairment Questionnaire:  Chronic 
Urticaria (WPAI-CU) 
The Work Productivity and Activity Impairment Questionnaire:  Chronic Urticaria 
(WPAI-CU) is a questionnaire that assesses the impact of an intervention on work 
productivity.  It evaluates presenteeism, work productivity loss, and activity impairment 
over the past 7 days (Reilly et al, 1993).  The WPAI-CU will be completed by the subject 
at the study center according to the SoA (Table 1-1). 
8.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the SoA see (Table 1-1). 
8.2.3.1 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Subject must be in a supine position in a rested 
and calm state for at least 5 minutes before blood pressure assessments are conducted.  
If the subject is unable to be in the supine position, the subject should be in most 
recumbent position as possible.  The position selected for a subject should be the same 
that is used throughout the study and documented on the vital sign CRF.  The 
temperature location selected for a subject should be the same that is used throughout 
the study and documented on the vital signs CRF.  Record all measurements on the vital 
signs CRF. 

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8.2.3.2 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause of death should be obtained. 
8.2.4 
Adverse Events and Serious Adverse Events  
Treatment-emergent adverse events are events categorized as adverse events starting 
or worsening on or after the first dose of investigational product as determined by “did 
the event start before the first dose of investigational product” equal to “No” or missing 
on the events CRF and up to the EOS date. 
8.2.4.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.2.4.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the Amgen Standard 
Grading Scale, and is described in Section 11.4.  The investigator is responsible for 
ensuring that any adverse events related to study procedures that were observed by the 
investigator or reported by the subject that occur after screening visit 2 through the 
EOS/safety follow-up or 18 weeks after the last administration of investigational product 
are collected and reported using the Event CRF.  In addition, the investigator is 
responsible for ensuring that all adverse events observed by the investigator or reported 
by the subject that occur after the first dose of investigational product are collected and 
reported using the Event CRF. 
8.2.4.1.2 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through the EOS visit are reported using the Event CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s knowledge of the event, as indicated in 
Section 11.4.  The investigator will submit any updated serious adverse event data to the 
sponsor within 24 hours of it being available.  It is important to distinguish between 
serious and severe AEs.  Severity is a measure of intensity whereas seriousness is 
defined by the criteria in Appendix 4 (Section 11.4).  An AE of severe intensity need not 
necessarily be considered serious unless it meets the criteria shown in Appendix 
4 (Section 11.4). 

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8.2.4.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
If the investigator becomes aware of serious adverse events after the protocol-required 
reporting period is complete, these serious adverse events will be reported to Amgen 
(regardless of causality).  The investigator will report serious adverse events to Amgen 
within 24 hours following the investigator’s awareness of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.  
If further safety related data is needed to fulfill any regulatory reporting requirements for 
a reportable event, then additional information may need to be collected from the 
subject’s records after the subject ends the study. 
The method of recording, evaluating, and assessing causality of adverse events, and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Section 11.4. 
8.2.4.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
8.2.4.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3).  
Further information on follow-up procedures is given in Section 11.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 

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8.2.4.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment 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 treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Aggregate 
analyses may also be unblinded by the Safety Assessment Team, as appropriate.  
Investigators will receive notification of related serious adverse events reports sent to 
regulatory authorities in accordance with local requirements. 
8.2.4.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
8.2.4.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects or the female partner of a 
male subject, will be collected after the start of study treatment and through 16 weeks 
after the last dose of any protocol required therapy.   
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 

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Section 11.5.  Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Section 11.5. 
8.2.4.7 
Adverse Events of Interest 
An adverse event of interest is an event of scientific and medical interest towards 
improving the understanding of the investigational product.  An adverse event of interest 
may be serious or non-serious.  For this study, adverse events of interest include: 
 
Hypersensitivity (including anaphylactic reactions and immune complex 
disease [Type III hypersensitivity reactions]) 
 
Malignancy 
 
Severe infections  
 
Helminth infections 
 
Injection site reactions 
 
Guillain-Barre syndrome 
Please refer to the section of the important Key Safety Information or additional 
information regarding adverse events of interest in the current active Investigator’s 
Brochure. 
8.2.5 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
SoA (Table 1-1) for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine whether an abnormal value in an individual study subject represents a 
clinically significant change from the subject’s baseline values.  In general, abnormal 
laboratory findings without clinical significance (based on the investigator's judgment) 
are not to be recorded as adverse events.  However, laboratory value changes that 
require treatment or adjustment in current therapy are considered adverse events.  
Where applicable, clinical sequelae (not the laboratory abnormality) are to be recorded 
as the adverse event. 
All protocol-required laboratory assessments, as defined in Section 11.2, must be 
conducted in accordance with the laboratory manual and the SoA (Table 1-1).   
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.  Total 

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IgE, and eosinophils on complete blood count and differential are considered unblinding 
data for this study.  Pharmacokinetic and anti-drug antibody (ADA) testing and results 
should always be blinded until end of study.  Additional details regarding potentially 
unblinding data and study personnel are provided in Section 6.4.2.2. 
8.2.5.1 
Tuberculosis Testing 
All subjects must receive either a purified protein derivative (PPD) or QuantiFERON test 
at screening and EOT/ET. 
The PPD test must be read by a trained healthcare professional 48 to 72 hours after the 
test is placed.  The PPD reader must be identified on the delegation of authority for this 
responsibility. 
If a subject does not receive a PPD test, they must have QuantiFERON testing.  Refer to 
the laboratory manual for instructions on sample collection, processing, and shipping of 
samples. 
8.2.5.2 
Pregnancy Testing 
A highly sensitive serum pregnancy test should be completed at screening and a highly 
sensitive urine test should be completed at the day 1 visit for females of childbearing 
potential.   
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Form, see Figure 11-2).  Refer to Section 11.5 for contraceptive requirements.  
Additional pregnancy testing should be performed Q4W during treatment with 
protocol-required therapies and at weeks 24 and 32 (18 weeks after the last dose of 
protocol-required therapies).  
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
8.2.6 
SARS-CoV-2 Serology (Antibody) Testing 
For subjects who received COVID-19 (SARS-CoV-2) vaccination, a 
SARS-CoV-2 serology (antibody) test will be done approximately 4 weeks after the last 
dose of vaccination and at a scheduled visit.  Instructions for sample collection, 
processing, storage, and shipment will be included in a separate laboratory manual 
provided to the sites.   

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8.2.7 
Pharmacokinetic Assessments 
All subjects randomized to treatment with tezepelumab will have PK samples assessed.  
Whole blood samples of approximately 5 mL will be collected for measurement of serum 
concentrations of tezepelumab as specified in the SoA (Table 1-1).  A maximum of 
2 samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the sponsor.  Instructions for the collection 
and handling of biological samples will be provided by the sponsor.  The actual date and 
time (24-hour clock time) of each sample will be recorded. 
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
8.2.8 
Pharmacodynamic Assessments 
Venous blood samples will be collected for measurement of 
, 
and 
 at time points specified in the SoA (Table 1-1). 
8.2.10 
Anti-drug Antibody Testing Procedures 
Blood sample(s) for anti-drug antibody testing are to be collected according to the time 
points specified in the SoA (Table 1-1).  Antibody testing will only be conducted if there 
is unexplained loss of exposure to tezepelumab or a potentially antibody-related safety 
concern.  Samples testing positive for binding antibodies may be further characterized. 
Refer to the laboratory manual for detailed collection and handling instructions. 

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9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
The primary hypothesis is: 
Tezepelumab effectively decreases UAS7 scores at week 16 from baseline 
compared to placebo in the overall population consisting of the anti-IgE naïve 
stratum and the anti-IgE experienced stratum. 
The secondary hypothesis is: 
Tezepelumab effectively decreases UAS7 scores at week 16 from baseline 
compared to placebo within the anti-IgE naïve stratum. 
For primary endpoint, tezepelumab 420 mg SC Q2W and 210 mg SC Q4W compared 
to placebo in the overall and the anti-IgE naïve population will be tested sequentially 
using the Bonferroni procedure to control for the type 1 error rate adjusting for 
covariates specified in Section 9.3.2. 
The remaining comparisons for the effects of tezepelumab over placebo on 
secondary/exploratory endpoints will be tested without adjusting for multiple tests.  
Nominal p-values will be provided. 
9.2 
Sample Size Determination 
A sample size of approximately 159 subjects will be enrolled to anti-IgE naïve 
stratum and anti-IgE experienced stratum to 1 of 2 doses of tezepelumab, 
omalizumab (ie, anti-IgE naïve stratum only), and placebo.  For the anti-IgE naïve 
stratum, 120 subjects will be randomized in a ratio of 1:1:1:1 (30 each for tezepelumab 
420 mg SC Q2W, tezepelumab 210 mg SC Q4W, omalizumab 300 mg SC, and 
placebo), where the omalizumab group serves as the active control.  For the anti-IgE 
experienced stratum, approximately 39 subjects will be randomized in a ratio of 

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1:1:1 (approximately 13 each for tezepelumab 420 mg SC Q2W, tezepelumab 210 mg 
SC Q4W, and placebo).  
The treatment effect comparison on the primary endpoint for the primary hypothesis will 
be made between placebo and one of the 2 tezepelumab treatment groups 
respectively in the overall CSU population.  
 
 
 
 
 
 
 
 
 
The secondary hypothesis of treatment effect comparison on the primary endpoint will 
be made between each of the 2 tezepelumab treatment groups versus the placebo 
group within anti-IgE naïve stratum.  In the anti-IgE naïve stratum, 
 
 
 
 
 
 
 
 
. 
9.3 
Analysis Sets, Subgroups, and Covariates 
9.3.1 
Analysis Sets 
9.3.1.1 
All Subjects Randomized 
All subjects randomized will be used in analysis of disposition information according to 
their randomized treatment group.   
9.3.1.2 
Full Analysis Set (FAS) 
The full analysis set (FAS) will consist of all randomized subjects who received at least 
1 dose of investigational product.  The FAS will be used in demographic information, 

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baseline disease characteristics and efficacy analyses unless otherwise specified, and 
analyzed as a randomized treatment group as intent-to-treat (ITT) concept. 
9.3.1.3 
Safety Analysis Set (SAS) 
The SAS will consist of all randomized subjects who received at least 1 dose of 
investigational product and analyzed as treated.  All safety analyses will be based on the 
SAS. 
9.3.1.4 
Pharmacokinetic Analysis Set 
Subjects who received tezepelumab and have at least 1 sample with a measurable 
serum concentration for computing PK parameters will be included in the PK analysis 
set. 
9.3.2 
Covariates 
The analysis of the primary endpoint will be adjusted for the following as appropriate: 
 
Anti-IgE naïve versus anti-IgE experienced 
 
Baseline score of endpoint 
The analysis of other endpoints will be adjusted for the following covariates as 
appropriate: 
 
Baseline score of endpoint 
 
Stratification factors: 
o Anti-IgE naïve versus anti-IgE experienced  
o Disease severity (UAS7 at baseline  28 versus  28) 
Additional covariates may be considered and will be described in the statistical analysis 
plan (SAP). 
9.3.3 
Subgroups 
Two types of subgroup analyses will be conducted:  1) to explore the internal 
consistency of the detected overall treatment effect on the primary efficacy variable; and 
2) to explore a treatment effect in the prespecified subpopulation (anti-IgE naïve stratum 
and anti-IgE experienced stratum) on the primary endpoint.  The treatment effect on 
the primary endpoint will be tested only in the anti-IgE naïve stratum. 
To explore the consistency of treatment effect, subgroup analyses by age, gender, race, 
baseline disease characteristics, type of background medication, comorbidities, region, 
and baseline biomarkers may be performed as appropriate.  The detailed list of variables 
and cutoff for subgroup analyses will be described in the SAP.  The study is not powered 
to draw conclusions from the first type of subgroup analysis.  The second subgroup 

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analysis will be conducted as secondary hypotheses on the primary endpoint as 
described in Section 9.4.2.2 below.  
9.3.4 
Handling of Missing and Incomplete Data 
Missing data for continuous efficacy endpoints will be analyzed using a repeated 
measure model.  Missing data in binary efficacy endpoints may be addressed through 
multiple imputation of the continuous versions of the endpoints or may be considered as 
nonresponder in efficacy analysis. 
9.4 
Statistical Analyses 
The details of the statistical analyses will be developed in a separate SAP and finalized 
before database lock.  Below is a summary of the timing and methods for the planned 
statistical analyses.  To preserve study integrity, the final analysis will be conducted and 
reported following the EOS, as defined in Section 4.4.1. 
9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis and Early Stopping Guidelines 
Up to 2 interim analyses will be performed:  1) the first interim analysis for futility will 
be performed after the first 60 enrolled subjects in the anti-IgE naïve stratum have 
had the opportunity to complete the week 16 assessments or early terminate from the 
study, and 2) the second interim analysis for administrative decision making will 
be performed after 120 subjects in the anti-IgE naïve stratum have had the 
opportunity to complete the week 16 assessments or early terminate from the study.   
The interim analysis will be performed by the internal interim analysis team including 
Global Biostatistics Sciences and Biostatistical programming, who are independent of 
the study team.  The detailed process, decision criteria and analysis methods will be 
described in the interim analysis charter and a separate statistical analysis plan. 
9.4.1.2 
Primary Analysis 
The primary analysis will occur when all subjects have had the opportunity to complete 
the week 16 assessments or have early terminated from the study. 
9.4.1.3 
Final Analysis 
The final analysis will occur after the last subject either completes the week 32 follow-up 
and ends the study or early terminates from the study. 

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9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Subject disposition, demographics, and baseline disease characteristics will be 
summarized descriptively by randomized treatment group based on the FAS, or all 
randomized subjects.  For categorical endpoints, the descriptive statistics will contain 
frequency and percentage.  For continuous endpoints, the descriptive statistics will 
include the number of observations, mean, standard error, standard deviation, median, 
first quartile, third quartile, minimum, and maximum.   

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9.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary endpoint of change from baseline in UAS7 at week 16 will 
be analyzed using a repeated measure model.  The repeated 
measure model will include treatment, study week, and 
treatment-by-week interaction, baseline UAS7 score and stratification 
factor (prior anti-IgE status ).  Multiple imputation and baseline 
observation carried forward (BOCF) may be considered for sensitivity 
analysis for missing data. 
Secondary 
The binary secondary endpoint of response rate (eg, UAS7, 
HSS7, ISS7, AAS7) will be analyzed with generalized estimating 
equations (GEE).  The GEE model will include treatment, study 
week, and treatment by week interaction, baseline score, and 
stratification factor (prior anti-IgE status).  Multiple nonresponder 
imputation may be considered for sensitivity analysis.  The 
continuous secondary endpoints of change from baseline in ISS7, 
HSS7, AAS7, UCT, CU-Q2oL, DLQI, AE-QoL, AECT, WPAI-CU, and 
sleep related outcomes will be analyzed using a repeated measure 
model that includes terms for treatment, study week, and 
treatment-by-week interaction, baseline continuous value of the 
endpoint and stratification factors (prior anti-IgE therapy status).  
Cumulative frequency of H1-antihistamine rescue medication use and 
cumulative number of weeks with complete response will be analyzed 
using a generalized linear model that includes terms for treatment, 
prior anti-IgE therapy status, and baseline disease severity. 
Exploratory 
Exploratory endpoints will be described in the SAP finalized before 
database lock 
The efficacy analyses of primary, secondary, and some exploratory endpoints will be 
performed for all FAS subjects, then for anti-IgE naïve and anti-IgE experienced 
subjects, respectively, by excluding the stratification factor of prior anti-IgE treatment 
status from the model. 
9.4.2.3 
Safety Analyses 
9.4.2.3.1 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Tables of fatal adverse events, serious adverse events, adverse events 
leading to withdrawal from investigational product or other protocol-required therapies, 

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and significant treatment-emergent adverse events will also be provided.  Subject 
adverse events of interest, will be tabulated by system organ class and preferred term. 
9.4.2.3.2 
Laboratory Test Results 
Laboratory parameters will be summarized descriptively by treatment group.  Mild, 
moderate, or severe, as defined by the Amgen Standard Grading Scale will be 
presented for each laboratory parameter, when available. 
9.4.2.3.3 
Vital Signs 
The analyses of vital signs will include summary statistics over time by treatment group.  
Shifts in vital sign values between the baseline and the worst on-study value will be 
tabulated by treatment group. 
9.4.2.3.4 
Physical Measurements 
Height and weight will be summarized descriptively as baseline summaries. 
9.4.2.3.5 
Exposure to Investigational Product 
Exposure to investigational product will be summarized by treatment group.  Additional 
details will be provided in the SAP. 
9.4.2.3.6 
Exposure to Non-investigational Product 
Descriptive statistics will be produced to describe the exposure to omalizumab by 
treatment group.  Additional details may be provided in the SAP. 
9.4.2.3.7 
Exposure to Other Protocol-required Therapy 
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group. 
9.4.2.3.8 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized for 
each treatment group as coded by the World Health Organization Drug Dictionary 
(WHODRUG).  The use of study medication not allowed in the study will be summarized 
and analyzed.  Details of the analysis will be described in the SAP. 

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10. 
References 
Allakhverdi Z, Jessup HK, Yoon B-RP, et al,  Thymic stromal lymphopoietin is released 
by human epithelial cells in response to microbes, trauma, or inflammation and 
potentially activates mast cells.  J Exp Med.  2007;204:253-258. 
Baiardini I, Braido F, Bindslev-Jensen C, et al,  Recommendations for assessing patient-
reported outcomes and health-related quality of life in patients with urticaria:  a GA(2) 
LEN taskforce position paper.  Allergy.  2011;66(7):840-844. 
Baiardini I, Pasquali M, Braido F, et al,  A new tool to evaluate the impact of chronic 
urticaria on quality of life:  chronic urticaria quality of life questionnaire (CU-Q2oL).  
Allergy.  2005;60:1073-1078. 
Basra MK, Fenech R, Gatt RM, et al,  The Dermatology Life Quality Index 1994-2007:  a 
comprehensive review of validation data and clinical results.  Br J Dermatol.  2008; 
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Bernstein JA, Lang DM, Khan DA, et al,  The diagnosis and management of acute and 
chronic urticaria:  2014 update.  J Allergy Clin Immunol.  2014;133(5):1270-1277. 
Finlay AY, Khan GK.  Dermatology Life Quality Index (DLQI) – a simple practical 
measure for routine clinical use.  Clin Exp Dermatol.  1994; 19(3):210-216. 
Gauvreau GM, O’Byrne PM, Boulet L-P, et al,  Effects of an anti-TSLP antibody on 
allergen-induced asthmatic responses.  N Engl J Med.  2014;370:2102-2110. 
Hawro T, Ohanyan T, Schoepke N, et al,  Comparison of interpretability of the available 
urticaria activity scores.  Allergy.  2018;73(1):251-255. 
Hazzan T, Eberle J, Worm M, Babina M.  Thymic stromal lymphopoietin interferes with 
the apoptosis of human skin mast cells by a dual strategy involving STAT5/Mcl-1 and 
JNK/Bcl-xL.  Cells.  2019;8(8):829. 
He R, Geha RS.  Thymic stomal lymphopoietin.  Ann N Y Acad Sci.  2010;1183:13-24. 
Jariwala SP, Moday H, de Asis ML, et al,  The Urticaria Severity Score:  a sensitive 
questionnaire/index for monitoring response to therapy in patients with chronic urticaria.  
Ann Allergy Asthma Immunol.  2009;102:475-482. 
Kaur D, Brightling C.  OX40/OX40 ligand interactions in T-cell regulation and asthma.  
Chest.  2012;141(2):494-499. 
Kay AB, Clark P, Maurer M, Ying S.  Elevations in T-helper-2-initiating cytokines 
(interleukin-33, interleukin-25 and thymic stromal lymphopoietin) in lesional skin from 
chronic spontaneous (‘idiopathic’) urticaria.  Br J Dermatol.  2015;172(5):1294-1302. 
Kulthanan K, Chularojanamontri L, Tuchinda P, et al,  Minimal clinical important 
difference (MCID) of the Thai Chronic Urticaria Quality of Life Questionnaire (Cu-Q2oL).  
Asian Pac J Allergy Immunol.  2016;34:137-145. 
Mathias SD, Crosby RD, Zazzali JL, Maurer M, Saini SS.  Evaluating the minimally 
important difference of the urticaria activity score and other measures of disease activity 
in patients with chronic idiopathic urticaria.  Ann Allergy Asthma Immunol.  
2012a;108:20-24. 
Mathias SD, Tschosik EA, Zazzali JL.  Adaptation and validation of the urticaria patient 
daily diary for adolescents.  Allergy Asthma Proc.  2012b;33(2):186-190. 

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Mathias SD, Dreskin SC, Kaplan A, Saini SS, Spector S, Rosén KE.  Development of a 
daily diary for patients with chronic idiopathic urticaria.  Ann Allergy Asthma Immunol.  
2010;105(2):142-148. 
Maurer M, Weller K, Bindslev-Jensen C, et al,  Unmet clinical needs in chronic 
spontaneous urticaria.  A GA2 LEN task force report.  Allergy.  2011;66:317-330. 
Nebiolo F, Bergia R, Bommarito L, et al,  Effect of arterial hypertension on chronic 
urticaria duration.  Ann Allergy Asthma Immunol.  2009;103(5):407-410. 
Reilly MC, Zbrozek AS, Dukes E.  The validity and reproducibility of a work productivity 
and activity impairment measure.  Pharmacoeconomics.  1993;4(5):353-365. 
Roan F, Obata-Ninomiya K, Ziegler SF.  Epithelial cell-derived cytokines:  more than just 
signaling the alarm.  J Clin Invest.  2019;129:1441-1451. 
Shijkar R, Harding G, Leahy M.  Minimal important difference (MID) of the Dermatology 
Life Quality Index (DLQI):  results from patients with chronic idiopathic urticaria.  Health 
Qual Life Outcomes.  2005;20:36. 
Tezepelumab Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
Van den Elzen MT, van Os-Medendorp H, van den Brink I, et al,  Effectiveness and 
safety of antihistamines up to fourfold or higher in treatment of chronic spontaneous 
urticaria.  Clin Transl Allergy.  2017;7:4. 
Vestergaard C, Toubi E, Maurer M, et al,  Treatment of chronic spontaneous urticaria 
with an inadequate response to H1-antihistamines:  an expert opinion.  Eur J Dermatol.  
2017;27(1):10-19. 
Watson B, Gauvreau GM.  Thymic stromal lymphopoietin:  a central regulator of allergic 
asthma.  Expert Opin Ther Targets.  2014;18(7):771-785. 
Weller K, Altrichter S, Krause K, et al,  Development of the Angioedema Control Test 
(AECT) – a patient-reported outcome measure that assesses disease control in patients 
with recurrent angioedema.  Allergy.  2020;75(5):1165-1177. 
Weller K, Donoso T, Magerl M, et al,  Validation of the Angioedema Control Test (AECT) 
– a patient-reported outcome instrument for assessing angioedema control.  J Allergy 
Clin Immunol Pract.  2020;8(6):2050-2057.e4. 
Weller K, Siebenhaar F, Hawro T, et al,  Clinical measures of chronic urticaria.  Immunol 
Allergy Clin North Am.  2017;37:35-49. 
Weller K, Magerl M, Peveling-Oberhag A, et al,  The Angioedema Quality of Life 
Questionnaire (AE-QoL) – assessment of sensitivity to change and minimal clinically 
important difference.  Allergy.  2016;71(8):1203-1209. 
Weller K, Groffik A, Magerl M, et al,  Development, validation, and initial results of the 
Angioedema Activity Score.  Allergy.  2013;68:1185-1192. 
Weller K, Groffik A, Magerl M, et al,  Development and construct validation of the 
angioedema quality of life questionnaire.  Allergy.  2012;67:1289-1298. 
Xolair (omalizumab) [package insert].  South San Francisco CA:  Genentech, USA, Inc; 
May 2019.  Available at:  https://www.gene.com/download/pdf/xolair_prescribing.pdf.  
Accessed 28 May 2020. 
Zuberbier T, Aberer W, Asero R, et al,  The EAACI/GA2LEN/EDF/WAO guideline for the 
definition, classification, diagnosis and management of urticaria.  Allergy.  2018;73:1393-
1414. 

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11. 
Appendices 
 

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11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AAS 
Angioedema Activity Score 
AAS7 
Angioedema Activity Score over 7 days 
AECT 
Angioedema Control Test 
AE-QoL 
Angioedema Quality of Life Questionnaire 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-7d 
area under the concentration-time curve from day 0 to day 7 
AUC0-28d 
area under the concentration-time curve from day 0 to day 28 
BIL 
bilirubin 
BOCF 
baseline observation carried forward 
CFR 
U.S. Code of Federal Regulations 
Cmax 
maximum observed serum concentration 
CMH 
Cochran-Mantel-Haenszel  
COVID-19 
coronavirus disease 2019  
CRF 
case report form 
CRO 
contract research organization 
CSU 
chronic spontaneous urticaria 
CU-Q2oL 
Chronic urticaria Quality of Life Questionnaire 
DILI 
drug induced liver injury 
DLQI 
Dermatology Life Quality Index 
eDiary 
electronic diary 
EDC 
electronic data capture 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
End of Follow-up 
defined as when the last subject completes the last protocol-
specified assessment in the study   
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or 
received an intervention to collect final data for the primary 
endpoint(s), for the purposes of conducting the primary analysis, 
whether the study concluded as planned in the protocol or was 
terminated early  
End of Study (end of trial) 
defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit), following any additional parts in the 
study (eg, long-term follow-up), as applicable 

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End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
Enrollment 
A subject is considered enrolled once the subject is randomized 
and has received investigational product 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
Exposure-Response  
Analysis 
mechanism-based modeling & simulation and statistical 
analyses based on individual pharmacokinetic (PK) exposure 
(eg, population pharmacokinetic modeling) and response, which 
may include biomarkers, pharmacodynamic (PD) effects, 
efficacy and safety endpoints. 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration  
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equations 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
HSS 
Hives Severity Score  
HSS7 
Hives Severity Score over 7 days 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IL 
interleukin 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IRT 
interactive response technology that is linked to a central 
computer in real time as an interface to collect and process 
information 
ISS 
Itch Severity Score 
ISS7 
Itch Severity Score over 7 days 
ITT 
Intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MID 
minimal important difference 
NCT 
National Clinical Trials 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
pharmacokinetics 

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PPD 
purified protein derivative 
PRO 
patient-reported outcome 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
QFT-Plus 
QuantiFERON-tuberculosis Gold Plus 
QoL 
quality of life 
Randomization 
A subject will undergo randomization upon meeting all eligibility 
criteria at the day 1 randomization visit  
SAP 
statistical analysis plan 
SAS 
Safety Analysis Set 
sgAH 
second generation antihistamines 
Source Data 
information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value. 
SC 
subcutaneous 
SoA 
schedule of activities 
Study day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TB 
tuberculosis 
TBL 
total bilirubin 
Th2 
T helper 2 
TSLP 
thymic stromal lymphopoietin 
UAS 
Urticaria Activity Score 
UAS7 
Urticaria Activity Score over 7 days 
UCT 
Urticaria Control Test 
ULN 
upper limit of normal 
WHODRUG 
World Health Organization Drug Dictionary 
WPAI-CU 
Work Productivity and Activity Impairment Questionnaire:  
Chronic Urticaria 
 

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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 11-1 will be performed by the central laboratory and/or by the 
local laboratory.  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 5.1 and 5.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Table 11-1.  Analyte Listing 
Central 
Laboratory:  
Chemistry 
Central 
Laboratory:  
Coagulation 
Central 
Laboratory:  
Urinalysis 
Central 
Laboratory:  
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Adjusted 
calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
Cholesterol 
HDL 
LDL 
Triglycerides 
PT/INR 
PTT/APTT 
 
Specific gravity 
pH 
Blood 
Protein  
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
RBC 
Nucleated RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
WBC 
Differential 
• Total neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
• Myeloblasts 
• Promyelocytes 
• Myelocytes 
• Metamyelocytes 
• Atypical 
lymphocytes 
 
 
Central 
Laboratory:  
Antibodies 
 
Hep B surface 
antigen 
Hep B core 
antigena 
Hep C antibody 
HIVb 
 
IgE 
Serum pregnancy 
PPD or 
QuantiFERON 
Gold Plus 
 
SARS-CoV-2 anti
body 
 
Local Laboratory: 
Urine Pregnancy  
ALP  alkaline phosphatase; ALT  alanine aminotransferase; APTT  activated partial thromboplastin time; 
AST  aspartate aminotransferase; BUN  blood urea nitrogen;
 HDL  high 
density lipoprotein; Hep  hepatitis; HIV  human immunodeficiency virus; HLA  human leukocyte antigen; 
IgE  immunoglobulin E; INR  international normalized ratio; LDH  lactate dehydrogenase; LDL  low 
density lipoprotein; MCH  mean corpuscular hemoglobin; MCHC  mean corpuscular hemoglobin 
concentration; MCV  mean corpuscular volume; PPD  purified protein derivative; PT  prothrombin time; 
RBC  red blood cell count; RDW  Red cell distribution width; SGOT  serum glutamic-oxaloacetic 
transaminase; SGPT - serum glutamic-pyruvic transaminase; WBC  white blood cell count 
a If a country requirement. 
b HIV assessment is recommended. 

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Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.  

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11.3 
Appendix 3.  Study Governance Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure, and other relevant documents (eg, subject recruitment advertisements) must 
be submitted to an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
by the investigator and reviewed and approved by the IRB/IEC.  A copy of the written 
approval of the protocol and ICF must be received by Amgen before recruitment of 
subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Recruitment Procedures 
Recruitment and retention of patients is fundamental to a successful study.  We will 
implement modern innovative methods such as reaching out to social networks and 
patient advocacy groups.  

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Informed Consent Process 
An initial sample ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the sample ICF are to be 
communicated formally in writing from the Amgen Trial Manager to the investigator.  The 
written ICF is to be prepared in the language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered, and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects will then 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 
requirements, where applicable, and the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the ICF. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the ICF is to be signed and personally dated by the subject or a legally 
acceptable representative and by the person who conducted the informed consent 
discussion.  Subject withdrawal of consent or discontinuation from study treatment 
and/or procedures must also be documented in the subject’s medical records; refer to 
Section 7. 

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Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
The original signed ICF is to be retained in accordance with institutional policy, and a 
copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.  
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood.  (Refer to ICH GCP guideline, Section 4.8.9.) 
A subject who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional future research.  The investigator or authorized designee will 
explain to each subject the objectives of the future research.  Subjects will be told that 
they are free to refuse to participate and may withdraw their specimens at any time and 
for any reason during the storage period.  A separate signature will be required to 
document a subject’s agreement to allow any remaining specimens to be used for future 
research.  Subjects who decline to participate will not provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the Case Report Form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in 
confidence by the investigator, except as described below. 

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In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above.  Acquisition of funding, collection of 
data, or general supervision of the research group, alone, does not justify authorship.  All 
persons designated as authors must qualify for authorship, and all those who qualify are 
to be listed.  Each author must have participated sufficiently in the work to take public 

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responsibility for appropriate portions of the content.  All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
A recognized expert in the therapeutic area 
 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An Investigator contributing a high number of eligible subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  

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The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 
Compliance and Audit function (or designees).  Inspection of site facilities (eg, 
pharmacy, protocol-required therapy storage areas, laboratories) and review of 
study-related records will occur to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the 
interactive response technology (IRT) system (if used, such as subject ID and 
randomization number) and CRF entries if the CRF is the site of the original recording 
(ie, there is no other written or electronic record of data, such as paper questionnaires 
for a clinical outcome assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 

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The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
 
Subject files containing completed CRFs, ICFs, and subject identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination (ET) and send 
a copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
 

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11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device or procedure. 
 
Note:  Treatment-emergent adverse events will be defined in the statistical 
analysis plan (SAP). 
 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, that are considered 
clinically significant in the medical and scientific judgment of the investigator (ie, 
not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as adverse event or serious adverse event if they fulfill the definition of an 
adverse event or serious adverse event.  Also, “lack of efficacy” or “failure of 
expected pharmacological action” also constitutes an adverse event or serious 
adverse event. 
 
Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 

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Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that, 
meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are an adverse 
event.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event is to be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not 
considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse 
event reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 1 of 

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the other outcomes listed in the above definition.  These events are typically to be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of 
the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Event case report form (CRF). 
 
The investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Severity (or toxicity defined below); 
o Assessment of relatedness to investigational product, other protocol-required 
therapies; and 
o Action taken. 
 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event CRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to sponsor/responsible contract research organization (CRO) in 
lieu of completion of the Event CRF page. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 

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Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on:   
Grade 
Definition 
MILD 
Aware of sign or symptom, but easily tolerated 
MODERATE 
Discomfort enough to cause interference with usual activity 
SEVEREa 
Incapacitating with inability to work or do usual activity 
a An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in the 
definition of a serious adverse event, NOT when it is rated as severe. 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product protocol-required therapies and/or study-mandated procedure and each 
occurrence of each adverse event/serious adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 

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Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Amgen with a copy of any post-mortem findings 
including histopathology. 
 
New or updated information will be recorded in the originally completed Event 
CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen 
within 24 hours of receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the electronic 
data capture (EDC) system via the Safety Report Form.  
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using an electronic Serious Adverse Contingency Report 
Form (see Figure 11-1) within 24 hours of the investigator’s knowledge of the 
event. 
 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line 
to prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC has been taken off-line, then the site can report this information on a paper 
Serious Adverse Event Report Form (see Figure 11-1). 
 

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Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form 
 

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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for females of childbearing potential pediatric 
are outlined in Section 5.2. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to the fetus if they become pregnant during treatment and for 
a period of relevant systemic exposure after the last dose of protocol-required therapies. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and/or for an increased length of time.  In addition, male 
subjects may also be required to use contraception.  The investigator must discuss 
these contraceptive changes with the subject. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  1) 
review of subject’s medical records; 2) subject’s medical examination; or 3) subject’s 
medical history interview. 
 
Premenarchal female 
 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 

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Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
Note:  Failure rate of < 1% per year when used consistently and correctly. 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system  
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 16 weeks after the last 
dose of any protocol-required therapy. 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 11-2).  
The form must be submitted to Amgen Global Patient Safety within 24 hours of 
learning of a subject’s pregnancy.  (Note:  Sites are not required to provide any 
information on the Pregnancy Notification Form that violates the country or regions 
local privacy laws). 
 
After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female subject who 
becomes pregnant while taking protocol-required therapies through 16 weeks after 
the last dose of protocol-required therapy.  This information will be forwarded to 
Amgen Global Patient Safety.  Generally, infant follow-up will be conducted up to 
12 months after the birth of the child (if applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 

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complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 11.4.  While the 
investigator is not obligated to actively seek this information in former study subjects, 
he or she may learn of a serious adverse event through spontaneous reporting.  
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 7.1 for details). 
Male Subjects with Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
 
In the event a male subject fathers a child during treatment, and for 16 weeks after 
discontinuing protocol-required therapies, the information will be recorded on the 
Pregnancy Notification Form.  The form (see Figure 11-2) must be submitted to 
Amgen Global Patient Safety within 24 hours of the site’s awareness of the 
pregnancy.  (Note:  Sites are not required to provide any information on the 
Pregnancy Notification Form that violates the country or regions local privacy laws). 
 
The investigator will attempt to obtain a signed authorization for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 
After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies and for 16 weeks after the last dose of any 
protocol-required therapy.   
 
Information will be recorded on the Lactation Notification Form (see below) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 228. 
 
With the female subjects signed authorization for release of mother and infant health 
information, the investigator will collect mother and infant health information and 

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complete the lactation questionnaire on any female subject who breastfeeds while 
taking protocol-required therapies through 16 weeks after discontinuing protocol-
required therapies. 
Figure 11-2.  Pregnancy and Lactation Notification Forms 
 

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11.6 
Appendix 6.  Sample Storage and Destruction 
Any blood eg, biomarker, pharmacokinetics (PK), pharmacogenetic sample collected 
according to the SoA (Table 1-1) can be analyzed for any of the tests outlined in the 
protocol and for any tests necessary to minimize risks to study subjects.  This includes 
testing to ensure analytical methods produce reliable and valid data throughout the 
course of the study.  This can also include, but is not limited to, investigation of 
unexpected results, incurred sample reanalysis, and analyses for method transfer and 
comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
inflammatory conditions, the dose response and/or prediction of response to 
tezepelumab, characterize antibody response, and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of 
 or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood or tissue samples and any other components from the cells can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 

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request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
 

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11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR, and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Non-alcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed for possible 
drug-induced liver injury (DILI) according to recommendations in the last section of this 
appendix.  

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Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix). 
Table 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x ULN  
at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
 8x ULN at any time 
 5x ULN but  8x ULN for  2 weeks 
 5x ULN but  8x ULN and unable to 
adhere to enhanced monitoring schedule 
 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
 3x ULN (when baseline was  ULN) 
 
OR 
 
ALP 
 8x ULN at any time 
-- 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase; 
INR  international normalized ratio; TBL  total bilirubin; ULN  upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then Amgen investigational product and 
other protocol-required therapies, as appropriate is to be permanently discontinued.  
Subjects who clearly meet the criteria for permanent discontinuation (as described in 
Table 11-2) are never to be rechallenged. 
Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following: 

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 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
 
The appropriate Case Report Form (CRF) (eg, Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 11.4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 11-2 or who experience AST or ALT elevations  3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
are to undergo a period of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.   
Assessments that are to be performed during this period include:   
 
Repeat AST, ALT, ALP, bilirubin (BIL) (total and direct), and INR within 24 hours  
 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count with differential to assess for eosinophilia 
 
Serum total immunoglobulin (Ig) G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 
 
A more detailed history of:   
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, hypersensitivity-
type reactions, fatigue, nausea, vomiting, and fever 
o Prior and/or concurrent use of alcohol, recreational drugs, and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 

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 
Viral serologies 
 
Creatine phosphokinase, haptoglobin, lactate dehydrogenase, and peripheral blood 
smear 
 
Appropriate liver imaging if clinically indicated 
 
Appropriate blood sampling for pharmacokinetic (PK) analysis if this has not already 
been collected 
 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs.  
 

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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0   
 
Amendment 2 
Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled, Multicenter, 
Dose-Ranging, Phase 2b Study to Evaluate Efficacy and Safety of Tezepelumab 
for the Treatment of Chronic Spontaneous Urticaria 
 
Amgen Protocol Number:  20190194 
EudraCT Number:  2020-002759-39 
NCT Number:  NCT04833855 
 
Amendment Date: 
26 April 2022 
 
Rationale: 
This protocol is being amended mainly to reduce the number of anti-immunoglobin E 
(IgE) experienced subjects since there are limited sources of these subjects.  Applicable 
sections of the protocol are being modified to clarify that approximately 39 subjects will 
be randomized to the anti-IgE experienced strata.  In addition, interim analysis 2 is being 
added for administrative decision making purposes.  This interim analysis will be 
performed when the 120 subjects in the anti-IgE naïve stratum complete week 16.  
 
 
 
  
  Changes 
including, but not limited to, the following were incorporated into the protocol: 
 
Added language to study rationale to include the tezepelumab brand name, 
TEZSPIRE, and to clarify that the U.S. Food and Drug Administration (FDA) has 
approved tezepelumab as an add-on maintenance treatment for adult and pediatric 
patients aged 12 years and older with severe asthma  
 
Updated number of subjects (ie, in synopsis, number of subjects, and sample size 
determination sections) recruited for the anti-IgE experienced cohort to 
approximately 39 subjects (approximately 13 per arm) due to limited source of 
subjects 

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Page 2 of 46 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0   
 
Updated objectives and endpoints language (ie, in synopsis and objectives and 
endpoints sections) to modify the summary measure language of the first estimand 
of the primary objective, to delete exploratory endpoints measured at end of 
treatment (EOT) and language on time to first event of subjects receiving H1 
antihistamine recue medication, and to relocate the key secondary objective and 
endpoint to be part of the secondary objectives and endpoints.  This change is being 
made in response to regulatory advice regarding Hives Severity Scores over 7 days 
(HSS)7 and Itch Severity Score over 7 days (ISS7) assessments.  In addition, 
Urticaria Activity Score over 7 days (UAS7) ≤ 6 and minimal import difference (MID) 
are also clinical meaningful endpoints. 
 
Updated exclusion criteria 221 to clarify that coronavirus disease 2019 (COVID-19) 
vaccines are allowed provided that the vaccination is not administered within 7 days 
before or after any study dosing visit 
 
Updated language in urticaria activity score (UAS) section to clarify that subjects are 
required to document both Hives Severity Scores (HSS) and Itch Severity Scores 
(ISS) daily with a recall period over 24 hours, and to define that a weekly UAS score 
represents the sum over a period of 7 days   
 
Updated statistical considerations sections to accommodate changes in number of 
subjects, and to relocate the key secondary endpoints to the secondary endpoints 
section, as well as changes to the multiple testing strategy 
 
Administrative and editorial changes have been made throughout the protocol for 
clarification 

Product:  Tezepelumab 
Protocol Number:  20190194 
Date:  30 September 2021 
Page 1 of 34 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 1 
Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled, Multicenter, 
Dose-Ranging, Phase 2b Study to Evaluate Efficacy and Safety of Tezepelumab for the 
Treatment of Chronic Spontaneous Urticaria 
Amgen Protocol Number (tezepelumab) 20190194 
EudraCT Number:  2020-002759-39 
Amendment Date: 
01 September 2021 
Superseding Amendment 
Date: 
30 September 2021 
Rationale: 
The following changes were made to the protocol, dated September 01st, 2021, to incorporate 
regulatory authority recommendations, to align with international treatment guidelines, to reduce 
patient burden and improve study experience by reducing the frequency of select eDiary data 
collection and eliminate USS, and to clarify/correct other items in the protocol.  
Target patient population changes include: 
 
Updated overall design (Section 4.1) to clarify second generation H1-antihistamines (sgAH) 
requirements. 
 
Updated inclusion criterion 105 to clarify which subjects are considered inadequately 
controlled by sgAH. 
 
Updated exclusion criterion 210 to clarify the sgAH stabilization period. 
 
Updated antihistamine stabilization period (Section 5.5) to clarify sgAH requirements. 
 
Updated background medication (Section 6.1.5.1) and rescue medication (Section 6.1.5.2) 
to clarify sgAH requirements 
Patient Reported Outcomes (PRO) changes include: 
 
Updated schedule of activities (Section 1.3) to reduce the frequency of chronic urticaria 
quality of life questionnaire, dermatology life quality index assessment, and work productivity 
and activity impairment questionnaire (chronic urticaria). 
 
Removed the urticaria severity score (Section 8.2.2.1.11), and from the schedule of activities 
(Section 1.3), objectives and endpoints (Section 3), and throughout the protocol.   
Reduction of washout period for prior use of biologics changes include: 
 
Updated exclusion criterion 213 to 4 months or 5 half-lives (whichever is longer) prior to 
screening visit 1 based on the half-life of biological products. 
 
Updated exclusion criterion 224 to clarify timeframe for non-biologic clinical studies, and 
biological clinical studies or treatment based on the half-life of biological products. 
Systemic corticosteroid changes include: 

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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Updated excluded treatments, medical devices, and/or procedures (Section 6.1.7) to clarify 
the use of systemic corticosteroids. 
Leukotriene receptor antagonist and H2-blocker changes include: 
 
Updated excluded treatments, medical devices, and/or procedures (Section 6.1.7) to 
exclude H2 antagonists and leukotriene receptor antagonists as classes of treatment during 
the study. 
Statistical changes include: 
 
Updated primary objectives and endpoints (Section 3) to clarify the definition of intercurrent 
events under the first estimand of primary and key secondary objectives. 
 
Updated primary objectives and endpoints (Section 3) to add a secondary objective 
evaluating the effect of tezepelumab on subjects achieving complete control of angioedema 
disease. 
 
Updated objectives and endpoints (Section 3) to clarify the minimal residual disease 
endpoints. 
 
Updated adverse events (Section 8.2.4.1.1) to replace common terminology criteria for 
adverse events with Amgen’s standard grading scale for AE intensity. 
 
Updated covariates (Section 9.3.2) to clarify the analysis of the primary and key secondary 
endpoints using the baseline score of endpoint. 
 
Updated handling of missing and incomplete data (Section 9.3.4) to clarify addressing 
missing data in binary efficacy endpoints. 
 
Updated efficacy analyses (Section 9.4.2.2) to clarify statistical analysis methods to be used 
for primary, key secondary, and secondary endpoints. 
Other changes include: 
 
Updated exclusion criterion 208 to clarify QFT-plus test requirements. 
 
Updated exclusion criterion 226 to clarify Hepatitis B core antibody testing, only where 
required by local country or region. 
 
Updated laboratory test results (Section 9.4.2.3.2) to utilize Amgen’s standard grading scale 
for AE intensity. 
 
Updated assessment of severity for evaluating adverse events and serious adverse events 
(Appendix 4, Section 11.4) to replace common terminology criteria for adverse events with 
Amgen’s standard grading scale for AE intensity. 
 
Updated template safety language. 
 
Administration, typographical and formatting changes were made throughout the protocol.  
On 30 September 2021, the protocol Amendment 1 was superseded to rectify the error in study 
schema 

Product:  Tezeplumab 
Protocol Number:  20190194 
Date:  01 September 2021 
Page 1 of 33 
Amendment 1 
Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled, Multicenter, 
Dose-Ranging, Phase 2b Study to Evaluate Efficacy and Safety of Tezepelumab for the 
Treatment of Chronic Spontaneous Urticaria 
Amgen Protocol Number (tezepelumab) 20190194 
EudraCT Number:  2020-002759-39 
 
Amendment Date: 
01 September 2021 
 
Rationale: 
The following changes were made to the protocol, dated September 01st, 2021, to incorporate 
regulatory authority recommendations, to align with international treatment guidelines, to reduce 
patient burden and improve study experience by reducing the frequency of select eDiary data 
collection and eliminate USS, and to clarify/correct other items in the protocol.  
Target patient population changes include: 
 
Updated overall design (section 4.1) to clarify second generation H1-antihistamines 
(sgAH) requirements. 
 
Updated inclusion criterion #105 to clarify which subjects are considered inadequately 
controlled by sgAH. 
 
Updated exclusion criterion #210 to clarify the sgAH stabilization period. 
 
Updated antihistamine stabilization period (section 5.5) to clarify sgAH requirements. 
 
Updated background medication (section 6.1.5.1) and rescue medication 
(section 6.1.5.2) to clarify sgAH requirements. 

Product:  Tezeplumab 
Protocol Number:  20190194 
Date:  01 September 2021 
Page 2 of 33 
Patient Reported Outcomes (PRO) changes include: 
 
Updated schedule of activities (section 1.3) to reduce the frequency of chronic urticaria 
quality of life questionnaire, dermatology life quality index assessment, and work 
productivity and activity impairment questionnaire (chronic urticaria). 
 
Removed the urticaria severity score (section 8.2.2.1.11), and from the schedule of 
activities (section 1.3), objectives and endpoints (section 3), and throughout the protocol.   
Reduction of washout period for prior use of biologics changes include: 
 
Updated exclusion criterion #213 to 4 months or 5 half-lives (whichever is longer) prior to 
screening visit 1 based on the half-life of biological products. 
 
Updated exclusion criterion #224 to clarify timeframe for non-biologic clinical studies, 
and biological clinical studies or treatment based on the half-life of biological products. 
Systemic corticosteroid changes include: 
 
Updated excluded treatments, medical devices, and/or procedures (section 6.1.7) to 
clarify the use of systemic corticosteroids. 
Leukotriene receptor antagonist and H2-blocker changes include: 
 
Updated excluded treatments, medical devices, and/or procedures (section 6.1.7) to 
exclude H2 antagonists and leukotriene receptor antagonists as classes of treatment 
during the study. 
Statistical changes include: 
 
Updated primary objectives and endpoints (section 3) to clarify the definition of 
intercurrent events under the first estimand of primary and key secondary objectives. 
 
Updated primary objectives and endpoints (section 3) to add a secondary objective 
evaluating the effect of tezepelumab on subjects achieving complete control of 
angioedema disease. 
 
Updated objectives and endpoints (section 3) to clarify the minimal residual disease 
endpoints. 

Product:  Tezeplumab 
Protocol Number:  20190194 
Date:  01 September 2021 
Page 3 of 33 
 
Updated adverse events (section 8.2.4.1.1) to replace common terminology criteria for 
adverse events with Amgen’s standard grading scale for AE intensity. 
 
Updated covariates (section 9.3.2) to clarify the analysis of the primary and key 
secondary endpoints using the baseline score of endpoint. 
 
Updated handling of missing and incomplete data (section 9.3.4) to clarify addressing 
missing data in binary efficacy endpoints. 
 
Updated efficacy analyses (section 9.4.2.2) to clarify statistical analysis methods to be 
used for primary, key secondary, and secondary endpoints. 
Other changes include: 
 
Updated exclusion criterion #208 to clarify QFT-plus test requirements. 
 
Updated exclusion criterion #226 to clarify Hepatitis B core antibody testing, only where 
required by local country or region. 
 
Updated laboratory test results (section 9.4.2.3.2) to utilize Amgen’s standard grading 
scale for AE intensity. 
 
Updated assessment of severity for evaluating adverse events and serious adverse 
events (Appendix 4, section 11.4) to replace common terminology criteria for adverse 
events with Amgen’s standard grading scale for AE intensity. 
 
Updated template safety language. 
 
Administration, typographical and formatting changes were made throughout the 
protocol.