Conditions: Atopic Dermatitis
Keywords: Atopic Dermatitis eczema tezepelumab dermatology dermatitis inflammation skin moderate dermatitis severe dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 251
Healthy volunteers: no

Brief summary:
This phase 2b study is designed to evaluate the safety and efficacy of tezepelumab as a monotherapy and explore its efficacy as adjunct therapy in subjects with moderate-to-severe atopic dermatitis (AD).

Detailed description:
All subjects will receive a subcutaneous (SC) dose of either investigational product or placebo as the first dose on day 1.

Subjects who are determined to be non-responders in Part A will receive tezepelumab SC every 2 weeks (Q2W) following completion of all week 16 study activities. Nonresponders are defined as those subjects who have not achieved at least a 50% improvement in Eczema Area and Severity Index (EASI) at week 16 compared to baseline (day 1).

Safety follow-up is 18 weeks after the end of treatment (EOT) visit (20 weeks after the final dose of investigational product).

Arms:
arm 1: Matching placebo administered via SC injection Q2W for a maximum of 52 weeks.

Participants defined as non-responders (those who do not achieve at least 50% improvement in EASI at Week 16 compared to baseline) will switch to receive tezepelumab 420 mg SC injection Q2W for the remainder of the study beginning with the Week 18 dose. arm 2: Tezepelumab 210 mg administered via SC injection once every 4 weeks (Q4W) from Week 4 for a maximum of 52 weeks.

All participants randomized to tezepelumab will receive 420 mg SC injection as their first dose. Participants will then receive a placebo at Week 2 to maintain blinding.

Participants defined as non-responders (those who do not achieve at least 50% improvement in EASI at Week 16 compared to baseline) will switch to receive tezepelumab 420 mg SC injection Q2W for the remainder of the study beginning with the Week 18 dose. arm 3: Tezepelumab 280 mg administered via SC injection Q2W from Week 2 for a maximum of 52 weeks.

All participants randomized to tezepelumab will receive 420 mg SC injection as their first dose. Participants will then receive their randomized dose of 280 mg Q2W from Week 2.

Participants defined as non-responders (those who did not achieve at least 50% improvement in EASI at Week 16 compared to baseline) will switch to receive tezepelumab 420 mg SC injection Q2W for the remainder of the study beginning with the Week 18 dose. arm 4: Tezepelumab 420 mg administered via SC injection Q2W for a maximum of 52 weeks. arm 5: Matching placebo administered via SC injection Q2W with topical corticosteroids (TCS) for a maximum of 52 weeks. arm 6: Tezepelumab 420 mg administered via SC injection Q2W with TCS for a maximum of 52 weeks.

Interventions: intervention 1: Tezepelumab intervention 2: Placebo
Intervention descriptions: intervention 1: Solution for injection intervention 2: Placebo solution for injection

Protocol document:
Prot_000.pdf: 
Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
Page 1 of 107 
CONFIDENTIAL 
 
 
Title Page 
Protocol Title: 
A Dose-Ranging, Double-Blind, 
Placebo-Controlled Study to Evaluate the Safety 
and Efficacy of Tezepelumab Alone or Combined 
With Topical Corticosteroids in 
Moderate-to-Severe Atopic Dermatitis 
Short Protocol Title: 
A Dose-Ranging, Placebo-Controlled, 
Double-Blind Study to Evaluate the Safety and 
Efficacy of Tezepelumab in Atopic Dermatitis 
Protocol Number: 
20170755 
Investigational Product: 
Tezepelumab 
Trade Name: 
 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
Telephone Number: 
1 (805) 447-1000 
Key 
Sponsor 
Contact 
Name: 
 
Address: 
One Amgen Center Drive, Thousand Oaks, CA 
Telephone Number: 
Email Address: 
EudraCT Number: 
2018-001997-52 
NCT Number: 
NCT03809663 
Protocol Date: 
Document Version 
Date 
Original 
20 July 2018 
Amendment 1 
20 November 2018 
Amendment 2 
04 September 2019 
Amendment 3 
25 August 2020 
Version/Date: 
Data Element 
Standards Version 
Date 
5.0 
15 March 2017 
 
 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.   
 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
Page 2 of 107 
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; Amgen’s general 
number in the US, 1-805-447-1000. 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
Page 3 of 107 
CONFIDENTIAL 
 
 
Investigator's Agreement: 
I have read the attached protocol entitled A Dose-Ranging, Double-Blind, 
Placebo-Controlled Study to Evaluate the Safety and Efficacy of Tezepelumab Alone or 
Combined With Topical Corticosteroids in Moderate-to-Severe Atopic Dermatitis, dated 
25 August 2020, 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 
subinvestigators (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:  20170755 
Date:  25 August 2020 
Page 4 of 107 
CONFIDENTIAL 
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Synopsis ................................................................................................... 9 
2. 
Study Schema and Schedule of Activities ............................................................. 15 
2.1 
Study Schema ........................................................................................... 15 
2.2 
Schedule of Activities ................................................................................ 16 
3. 
Introduction ........................................................................................................... 22 
3.1 
Study Rationale ......................................................................................... 22 
3.2 
Background ............................................................................................... 23 
3.2.1 
Disease ..................................................................................... 23 
3.2.2 
Amgen Investigational Product Background:  
Tezepelumab ............................................................................ 25 
3.3 
Benefit/Risk Assessment ........................................................................... 25 
4. 
Objectives, Endpoints and Hypotheses ................................................................. 27 
4.1 
Objectives and Endpoints .......................................................................... 27 
4.2 
Hypotheses ............................................................................................... 28 
5. 
Study Design ........................................................................................................ 29 
5.1 
Overall Design .......................................................................................... 29 
5.2 
Number of Subjects ................................................................................... 30 
5.2.1 
Replacement of Subjects ........................................................... 30 
5.2.2 
Number of Sites ......................................................................... 30 
5.3 
End of Study ............................................................................................. 30 
5.3.1 
End of Study Definition .............................................................. 30 
5.3.2 
Study Duration for Subjects ....................................................... 31 
5.4 
Justification for Investigational Product Dose ............................................ 31 
6. 
Study Population .................................................................................................. 32 
6.1 
Inclusion Criteria ....................................................................................... 32 
6.2 
Exclusion Criteria ...................................................................................... 33 
6.3 
Subject Enrollment .................................................................................... 35 
6.4 
Screen Failures ......................................................................................... 36 
7. 
Treatments ........................................................................................................... 36 
7.1 
Treatment Procedures............................................................................... 37 
7.1.1 
Investigational Products ............................................................ 37 
7.1.2 
Non-investigational Products ..................................................... 39 
7.1.3 
Medical Devices ........................................................................ 39 
7.1.4 
Other Protocol-required Therapies ............................................ 39 
7.1.5 
Other Treatment Procedures ..................................................... 39 
7.1.6 
Product Complaints ................................................................... 41 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
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CONFIDENTIAL 
 
 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 42 
7.2 
Method of Treatment Assignment ............................................................. 42 
7.3 
Blinding ..................................................................................................... 43 
7.3.1 
Study Center Personnel Access to Individual 
Treatment Assignments ............................................................ 43 
7.3.2 
Access to Individual Subject Treatment Assignments 
by Amgen or Designees ............................................................ 43 
7.4 
Dose Modification ...................................................................................... 44 
7.4.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 44 
7.4.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 44 
7.4.2.1 
Amgen Investigational Product:  
Tezepelumab .......................................................... 44 
7.4.2.2 
Non-Amgen/Amgen Non-Investigational 
Products .................................................................. 45 
7.4.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 45 
7.5 
Preparation/Handling/Storage/Accountability ............................................ 45 
7.6 
Treatment Compliance .............................................................................. 45 
7.7 
Treatment of Overdose ............................................................................. 45 
7.8 
Prior and Concomitant Treatment ............................................................. 46 
7.8.1 
Prior Treatment ......................................................................... 46 
7.8.2 
Concomitant Treatment ............................................................. 46 
8. 
Discontinuation Criteria ......................................................................................... 46 
8.1 
Discontinuation of Study Treatment........................................................... 46 
8.2 
Discontinuation From the Study ................................................................ 47 
8.2.1 
Reasons for Removal From Washout, Run-in, or 
Invasive Procedures .................................................................. 48 
8.2.2 
Reasons for Removal From Study ............................................. 48 
8.3 
Lost to Follow-up ....................................................................................... 48 
9. 
Study Assessments and Procedures .................................................................... 49 
9.1 
General Study Periods .............................................................................. 49 
9.1.1 
Screening, Enrollment, and Randomization ............................... 49 
9.1.2 
Treatment Period ....................................................................... 49 
9.1.3 
Safety Follow-up ........................................................................ 49 
9.1.4 
End of Study .............................................................................. 50 
9.2 
Description of General Study Assessments and Procedures ..................... 50 
9.2.1 
General Assessments ............................................................... 50 
9.2.1.1 
Informed Consent .................................................... 50 
9.2.1.2 
Demographics ......................................................... 50 
9.2.1.3 
Medical History ........................................................ 50 
9.2.1.4 
Physical Examination .............................................. 50 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
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CONFIDENTIAL 
 
 
9.2.1.5 
Physical Measurements .......................................... 50 
9.2.1.6 
Substance Use ........................................................ 51 
9.2.2 
Efficacy Assessments ................................................................ 51 
9.2.2.1 
Investigator’s Global Assessment ............................ 51 
9.2.2.2 
Eczema Area and Severity Index ............................ 51 
9.2.2.3 
Scoring of Atopic Dermatitis .................................... 51 
9.2.2.4 
Patient-reported Outcomes ..................................... 52 
9.2.3 
Safety Assessments .................................................................. 53 
9.2.3.1 
Adverse Events ....................................................... 53 
9.2.3.2 
Vital Signs ............................................................... 57 
9.2.3.3 
Electrocardiograms (ECGs) ..................................... 57 
9.2.3.4 
Suicidal Risk Monitoring .......................................... 57 
9.2.3.5 
Other Safety ............................................................ 57 
9.2.4 
Clinical Laboratory Assessments ............................................... 57 
9.2.4.1 
Tuberculosis Testing ............................................... 58 
9.2.4.2 
Pregnancy Testing .................................................. 58 
.................... 59 
9.2.5 
Pharmacokinetic Assessments .................................................. 59 
 ............................................... 60 
9.2.7 
Pharmacogenetic Assessments................................................. 60 
9.2.8 
Antibody Testing Procedures ..................................................... 60 
9.2.9 
Biomarker Development ............................................................ 61 
9.2.9.1 
Blood Biomarkers .................................................... 61 
9.2.9.2 
Skin RNA Transcript Profiling .................................. 61 
9.2.9.3 
DNA ........................................................................ 61 
9.2.10 
Clinical Outcome Assessments ................................................. 62 
9.2.10.1 
EQ-5D-3L ................................................................ 62 
9.2.11 
Optional Substudies .................................................................. 62 
9.2.12 
Other Assessments ................................................................... 62 
10. 
Statistical Considerations ...................................................................................... 62 
10.1 
Sample Size Determination ....................................................................... 62 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 63 
10.2.1 
Analysis Sets ............................................................................. 63 
10.2.1.1 
Full Analysis Set ...................................................... 63 
10.2.1.2 
Safety Analysis Set ................................................. 63 
10.2.1.3 
PK Analysis Set ....................................................... 63 
10.2.2 
Covariates ................................................................................. 63 
10.2.3 
Subgroups ................................................................................. 63 
10.2.4 
Handling of Missing and Incomplete Data .................................. 64 
10.3 
Statistical Analyses ................................................................................... 64 
10.3.1 
Planned Analyses ...................................................................... 64 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
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CONFIDENTIAL 
 
 
10.3.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 64 
10.3.1.2 
Primary Analysis ..................................................... 64 
10.3.1.3 
Exploratory Analysis for Part B ................................ 65 
10.3.1.4 
Final Analysis .......................................................... 65 
10.3.2 
Methods of Analyses ................................................................. 65 
10.3.2.1 
General Considerations ........................................... 65 
10.3.2.2 
Efficacy Analyses .................................................... 67 
10.3.2.3 
Safety Analyses ...................................................... 67 
10.3.2.4 
Other Analyses ........................................................ 68 
11. 
References ........................................................................................................... 69 
12. 
Appendices ........................................................................................................... 71 
Appendix 1.  List of Abbreviations and Definitions of Terms .................................. 72 
Appendix 2.  Clinical Laboratory Tests .................................................................. 75 
Appendix 3.  Study Governance Considerations ................................................... 77 
Regulatory and Ethical Considerations ...................................................... 77 
Informed Consent Process ........................................................................ 77 
Data Protection/Subject Confidentiality ..................................................... 79 
Publication Policy ...................................................................................... 80 
Investigator Signatory Obligations ............................................................. 81 
Data Quality Assurance ............................................................................. 81 
Source Documents .................................................................................... 82 
Study and Site Closure.............................................................................. 83 
Compensation ........................................................................................... 84 
Appendix 4.  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting ......................................................... 85 
Definition of Disease-related Event ........................................................... 85 
Definition of Adverse Event ....................................................................... 85 
Definition of Serious Adverse Event .......................................................... 86 
Definition of Adverse Device Effect ........................................................... 87 
Recording Adverse Events, Disease-related Events (if 
applicable), and Serious Adverse Events .................................. 88 
Evaluating Adverse Events and Serious Adverse Events .......................... 89 
Reporting of Serious Adverse Event .......................................................... 90 
Adverse Device Effects:  Recording, Evaluating and Reporting ................. 90 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information ................................................................................. 96 
Definition of Females of Childbearing Potential ......................................... 96 
Collection of Pregnancy Information .......................................................... 97 
Collection of Lactation Information ............................................................ 99 
Appendix 6.  Sample Storage and Destruction .................................................... 102 


Product:  Tezepelumab 
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Date:  25 August 2020 
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Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 104 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other 
Protocol-required Therapies Due to Potential 
Hepatotoxicity.......................................................................... 104 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity.......................................................................... 105 
Drug-induced Liver Injury Reporting and Additional 
Assessments ........................................................................... 106 
 
List of Tables 
Table 2-1.  Schedule of Activities for Part A and Part B (Screening Through 
Week 24) ................................................................................................ 17 
Table 2-2.  Schedule of Activities for Part A and Part B (Week 26 Through 
End of Study) .......................................................................................... 20 
Table 7-1.  Study Treatments ........................................................................................ 38 
Table 12-1.  Analyte Listing ........................................................................................... 76 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 105 
List of Figures 
Figure 2-1.  Study Schema for Part A ............................................................................ 15 
Figure 2-2.  Study Schema for Part B ............................................................................ 16 
Figure 10-1.  Alpha Split Between Two Doses of Interest .............................................. 66 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form .................. 91 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet .................................... 100 
 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
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CONFIDENTIAL 
 
 
1. 
Protocol Synopsis 
Protocol Title:  A Dose-Ranging, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety and Efficacy of Tezepelumab Alone or Combined With Topical Corticosteroids 
in Moderate-to-Severe Atopic Dermatitis 
Short Protocol Title:  A Dose-Ranging, Placebo-Controlled, Double-Blind Study to 
Evaluate the Safety and Efficacy of Tezepelumab in Atopic Dermatitis 
Study Phase:  2 
Indication:  Atopic Dermatitis (AD) 
Rationale 
Tezepelumab is being developed for the treatment of atopic dermatitis (AD).  Thymic 
stromal lymphopoietin (TSLP) is an epithelial cytokine shown to be elevated in skin 
lesions of patients with AD.  A previous phase 2a study (ALLEVIAD) demonstrated 
improvements in Investigator’s Global Assessment (IGA) and Eczema Area and Severity 
Index (EASI) scoring, but did not meet statistical significance in the primary endpoint.  A 
phase 1b study demonstrated improvement in IGA and EASI as secondary endpoints. 
Three dose levels of tezepelumab (420 mg subcutaneous injection [SC] every 2 weeks 
[Q2W], 280 mg SC Q2W, and 210 mg SC every 4 weeks [Q4W]) were selected based 
on exposure-response analysis of tezepelumab concentration and IGA response from 
the ALLEVIAD study.  These dose regimens will allow establishing exposure-response 
to aid in dose selection for future studies.  A first dose of 420 mg will allow faster 
achievement of steady state for the lower dose regimens (210 mg SC Q4W and 280 mg 
SC Q2W), and is also anticipated to improve symptoms of AD (eg, sleep and pruritus). 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
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CONFIDENTIAL 
 
 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary – Part A 
 
To evaluate the effect of tezepelumab 
compared with placebo, assessed using 
the Investigator’s Global Assessment 
(IGA) and Eczema Area and Severity 
Index (EASI) 
 
IGA score of 0 (clear) or 1 (almost clear) 
(IGA 0/1) at week 16 
 
75% reduction in EASI (EASI 75) at 
week 16 
Secondary – Part A 
 
To estimate the effect of tezepelumab 
compared with placebo on the efficacy 
measure of EASI 
 
50% and 90% reduction in EASI 
(EASI 50/90) at week 16 
 
To estimate the time needed to reach 
EASI 50/75/90 
 
Time at which EASI 50/75/90 is achieved 
from day 1 
 
To estimate the effect of tezepelumab 
compared with placebo on the efficacy 
measure of Scoring Atopic Dermatitis 
(SCORAD) 
 
SCORAD at week 16 
 
To estimate the effect of tezepelumab 
compared with placebo on the 
patient-reported outcome (PRO) measure 
of pruritus assessed using a numeric 
rating scale (NRS) 
 
Pruritus NRS at week 16 
 
To characterize the pharmacokinetics 
(PK) of tezepelumab 
 
Serum trough concentrations of 
tezepelumab at scheduled visits 
Safety – Part A and Part B 
 
To establish the safety and tolerability of 
tezepelumab compared with placebo 
 
Subject incidence of adverse events 
(including serious adverse events) 
 
Hypotheses 
Part A 
The primary hypothesis is that tezepelumab effectively increases the probability of an 
IGA 0/1 response and an EASI 75 response at week 16 in subjects with 
moderate-to-severe AD. 
Part B 
Part B is an estimation study; no hypotheses will be formally tested. 
Overall Design 
This phase 2b study is designed to evaluate the safety and efficacy of tezepelumab as a 
monotherapy and explore its efficacy as adjunct therapy in subjects with 
moderate-to-severe AD.  This study consists of Part A (the main study evaluating 
tezepelumab as a monotherapy) and Part B (a study evaluating tezepelumab as 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
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CONFIDENTIAL 
 
 
adjunctive therapy when combined with a topical corticosteroid [TCS] regimen).  In 
Part A, two futility analyses are planned when the 80th and 160th subjects are projected 
to complete week 16, respectively.  Upon a result of “not futile” for the first analysis and 
Part A has completed enrollment of 240 patients, enrollment of subjects in Part B of the 
study will commence.  A result of “futile” for either analysis in Part A will result in 
termination of both Part A and Part B of the study. 
Eligible subjects for both Part A and Part B will include adults with a clinical diagnosis of 
AD at least 2 years prior to screening, with AD that affects  10% of body surface area 
as assessed by EASI, an IGA score of ≥ 3, and an EASI score of  16. 
Part A and Part B of this study will consist of a 28-day screening period, a 52-week 
treatment period, and a 20-week safety follow-up period.  During the 28-day screening 
period, subjects must discontinue from all topical AD therapies, except for approved 
moisturizers (see Section 7.1.7), for at least the 7 consecutive days immediately prior to 
day 1.  During the study, approved moisturizers are allowed to be applied, with the 
exception of 8 hours prior to any scheduled visit. 
Part A is a dose-ranging, randomized, placebo-controlled, double-blind study designed 
to evaluate the safety and efficacy of tezepelumab as monotherapy in subjects with 
moderate-to-severe AD.  Following the screening period, eligible subjects will be 
randomized 1:1:1:1 to receive 420 mg SC Q2W, 280 mg SC Q2W, 210 mg SC Q4W, or 
placebo.  All subjects will receive a 420 mg SC dose (investigational product or placebo) 
as the first dose.  Subjects will then receive the appropriate dose of investigational 
product at the week 2 visit, depending on which treatment group they are randomized to.  
Depending on if they are randomized to Q2W or Q4W dosing, the dose at week 2 could 
be placebo or tezepelumab.  Non-responders are defined as those subjects who have 
not achieved at least a 50% improvement in EASI at week 16 compared to baseline 
(day 1).  Subjects who are determined to be non-responders in Part A will receive 
tezepelumab 420 mg SC Q2W for the remainder of the study, beginning with the week 
18 dose.  The randomized treatment assignments for the non-responders will remain 
blinded until the end of study. 
Part B is a randomized, placebo-controlled, double-blind study designed to evaluate the 
safety and efficacy of tezepelumab when administered with moderate class TCS in 
adults with moderate-to-severe AD.  Enrollment of subjects in Part B of the study will 
only commence if there is a result of “not futile” for the first interim analysis in Part A and 
Part A has completed enrollment of 240 patients.  Following the screening period, 


Product:  Tezepelumab 
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Date:  25 August 2020 
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CONFIDENTIAL 
 
 
eligible subjects will be randomized 2:1 to receive 420 mg SC Q2W or placebo; both 
groups in Part B will be allowed to use TCS after the day 1 visit.  Non-responders in  
Part B will not be switched to 420 mg SC Q2W at week 18 and will remain on their initial 
dose for the duration of the study. 
Number of Subjects 
Approximately 240 subjects will be enrolled in Part A of the study.  Approximately 
60 subjects will be enrolled in Part B of the study. 
Summary of Subject Eligibility Criteria 
Eligible subjects for both Part A and Part B will include adults with a clinical diagnosis of 
AD at least 2 years prior to screening, with AD that affects  10% of body surface area 
as assessed by EASI, an IGA score of  3, and an EASI score of  16. 
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.2. 
Treatments 
Study treatment include tezepelumab or placebo as outlined in the table below. 
Study 
Treatment 
Name 
Amgen Investigational Product:a 
Tezepelumab 
Placebo 
Dosage 
Formulation 
Each package will contain 3 vials. 
Placebo will be presented in identical 
containers and stored/packaged the 
same way as tezepelumab. 
Unit Dose 
Strength(s)/ 
Dosage 
Level(s) and 
Dosage 
Frequency 
Each subject will receive 3 injections 
per visit. 
For subjects randomized to 420 mg 
SC Q2W, 280 mg SC Q2W, and 
210 mg SC Q4W:  volumes for 
injections from vials provided will be 
detailed in the Investigational 
Product Instruction Manual (IPIM). 
Subjects randomized to Q4W dosing 
will receive placebo at intervening 
visits, such that all subjects receive 
an injection Q2W. 
Each subject will receive 3 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. 
Route of 
Administration 
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. 
In Part B of this study, subjects may commence TCS after day 1.  Subjects who use 
TCS during the study should follow the dosing regimen outlined in Section 7.1.5. 


Product:  Tezepelumab 
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Date:  25 August 2020 
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Procedures 
Key study procedures will include assessment of IGA, EASI, SCORAD, and other 
measures of AD disease severity.  Samples will be collected for PK analysis and 
biomarker development.  A safety follow-up will be conducted for 20 weeks after the final 
dose of study drug (18 weeks after the end of treatment [EOT] visit).  All adverse events 
observed by the investigator or reported by the subject that occur after the first dose of 
investigational product through the end of study/safety follow-up visit or for 20 weeks 
after the last administration of investigational product are to be collected/reported.  
Disease-related adverse events for this study include AD.  Serious adverse events 
observed by the investigator or reported by the subject after the signing of informed 
consent through the end of study/safety follow-up visit or for 20 weeks after the last 
administration of investigational product are reported using the Event CRF.   
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 9.2 and the Schedule of Activities in Table 2-1 and Table 2-2. 
Statistical Considerations 
In Part A of this study, a total of 240 subjects will be randomized in a 1:1:1:1 ratio to 
tezepelumab 420 mg SC Q2W, 280 mg SC Q2W, 210 mg SC Q4W, and placebo 
(approximately 60 in each group).  There is at least 85% power for each co-primary 
endpoint, assuming IGA 0/1 response rates of 10% and 40% for placebo and the highest 
tezepelumab dose group (420 mg SC Q2W), respectively, and assuming EASI response 
rates of 15% and 50%, respectively.  These assumed treatment effects are based on the 
results of other new agents in this indication (DUPIXENT, 2017).  These calculations 
used a 2-sided χ2 test at a significance level of 0.025 (to reflect the Bonferonni-based 
gatekeeping procedure described in Section 10.3.2.1) and assumed a 10% dropout rate. 
Part B of this study is exploratory.  A sample size of 60 subjects (40 in the tezepelumab 
420 mg SC Q2W group and 20 in the placebo group) was chosen as an adequate 
sample size to provide initial evidence of tezepelumab as a promising agent for adjunct 
therapy. 
Subject disposition, demographics, and baseline disease characteristics will be 
summarized descriptively by randomized treatment group.  For categorical endpoints, 
the descriptive statistics will contain frequency and percentage.  For continuous 
endpoints, the descriptive statistics will include the number of observations, mean, 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
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CONFIDENTIAL 
 
 
standard error, standard deviation, median, first quartile, third quartile, minimum, and 
maximum.   
For Part A, the treatment effect for the primary analysis of the primary endpoints will be 
tested using a Bonferonni-based gatekeeping procedure to control the family-wise 
2-sided type I error rate at 0.05.  The procedure splits the α of 0.05 equally to test in 
parallel tezepelumab 420 mg SC Q2W versus placebo, and tezepelumab 280 mg SC 
Q2W versus placebo for IGA 0/1 and EASI 75 sequentially within each parallel path.  If 
one of the parallel paths rejects the 2 hypotheses sequentially, and the other path has at 
least 1 hypothesis not rejected, then the unspent α of 0.025 from the successful path will 
be propagated to the unsuccessful path to retest the 2 hypotheses sequentially at a level 
of 0.05.   
For the primary endpoints of IGA 0/1 and EASI 75 at week 16, the treatment effect will 
be tested using a logistic regression model adjusting for covariates specified in 
Section 10.2.2.  From this model, odd ratios and 95% CIs will be reported comparing 
each tezepelumab dose group to placebo.  In addition, the percentage of subjects in 
each treatment group with a response and the difference in the percentage of subjects 
responding between each tezepelumab dose group and placebo will be summarized 
with a 95% confidence interval. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name:  Amgen Inc. 
 


Product:  Tezepelumab 
Protocol Number:  20170755 
 
Date:  25 August 2020 
Page 15 of 107 
CONFIDENTIAL 
 
 
2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
Figure 2-1.  Study Schema for Part A 
 
EASI = Eczema Area and Severity Index; EOS = End of Study; EOT = End of Treatment; IGA = Investigators’ Global Assessment; SC = subcutaneous;  
Q2W = every 2 weeks; Q4W = every 4 weeks 
a. All subjects will receive a 420 mg SC dose of either investigational product or placebo as the first dose on day 1. 
b. Subjects who are determined to be non-responders in Part A will receive tezepelumab 420 mg SC Q2W following completion of all week 16 study activities.  
Non-responders are defined as those subjects who have not achieved at least a 50% improvement in EASI at week 16 compared to baseline (day 1). 
c. Safety follow-up is 18 weeks after the EOT visit (20 weeks after the final dose of investigational product). 
Screening (up to 28 days + 7 days)
Day 1a
EOT
(week 52)
Treatment Period (52 weeks)
Safety Follow-up
Safety 
Follow-up Period
(18 weeksc)
Tezepelumab (N =  60) 
420 mg SC Q2Wa
Tezepelumab (N =  60) 
280 mg SC Q2Wa
Tezepelumab (N =  60) 
210 mg SC Q4Wa
Placeboa (N = 60)
Randomization
-28 to -1
Visits every 
2 weeks for 
52 weeks
Primary 
assessment of 
IGA 0/1 and EASI 
75 (week 16)
Non-Respondersb
Tezepelumab 420 mg 
SC Q2W
EOS
(week 70)


Product:  Tezepelumab 
Protocol Number:  20170755 
 
Date:  25 August 2020 
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CONFIDENTIAL 
 
 
Figure 2-2.  Study Schema for Part B 
Screening (up to 28 days
+ 7 days)
Day 1
EOT
(week 52)
Treatment Period (52 weeks)
Safety Follow-up
Safety 
Follow-up Period
(18 weeksa)
Tezepelumab (N =  40) 
420 mg SC Q2W+ TCS regimen
Placebo (N = 20) + TCS regimen
Randomization
-28 to -1
Visits every 
2 weeks for 
52 weeks
Exploratory 
assessment 
of IGA 0/1 
and EASI 75 
(week 16)
EOS
(week 70)
 
EASI = Eczema Area and Severity Index; EOS = End of Study; EOT = End of Treatment; IGA = Investigators’ Global Assessment; SC = subcutaneous; TCS = topical 
corticosteroids; Q2W = every 2 weeks 
a. Safety follow-up is 18 weeks after the EOT visit. 


Product:  Tezepelumab 
Protocol Number:  20170755 
 
Date:  25 August 2020 
Page 17 of 107 
CONFIDENTIAL 
 
 
2.2 
 Schedule of Activities 
Table 2-1.  Schedule of Activities for Part A and Part B (Screening Through Week 24) 
 
Screeninga 
(up to -28 d 
+ 7 d) 
Treatment Period (52 weeks)b, p 
Day 1 
Wk 2 
Wk 4 
Wk 6 
Wk 8 
Wk 10 
Wk 12 
Wk 14 
Wk 16 
Wk 18 
Wk 20 
Wk 22 Wk 24 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent for optional 
biomarker/pharmacogenetic 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verify eligibility criteria 
X 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical measurements 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and dermatology history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Substance use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease-related events 
X 
X 
X 
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 
X 
X 
LABORATORY ASSESSMENTS 
Serum or urine pregnancy teste 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Coagulation 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Hematology 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Chemistry 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
HIV, Hepatitis B and C screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (dipstick) 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Anti-tezepelumab-antibody 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum immunoglobulinsf 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Page 1 of 2 
Footnotes defined on last page of the table 


Product:  Tezepelumab 
Protocol Number:  20170755 
 
Date:  25 August 2020 
Page 18 of 107 
CONFIDENTIAL 
 
 
Table 2-1.  Schedule of Activities for Part A and Part B (Screening Through Week 24) 
 
Screeninga 
(up to -28 d 
+ 7 d) 
Treatment Period (52 weeks)b, p 
Day 1 
Wk 2 
Wk 4 
Wk 6 
Wk 8 
Wk 10 Wk 12 Wk 14 Wk 16 Wk 18 Wk 20 Wk 22 Wk 24 
PPD or Quantiferon GOLD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY-SPECIFIC ASSESSMENTS 
eDiary device distribution and 
training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electronic diaryg 
Completed in the morning at home on eDiary 
Assessment of EASI and IGA 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
SCORAD 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
EQ-5D-3L, POEM, DLQI, PGI-S 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Tracking of TCS use (Part B subjects 
only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PHARMACOKINETIC ASSESSMENTS 
PK samplingk 
 
X 
Xi 
Xi 
 
 
 
X 
 
X 
 
 
 
Xi 
PHARMACOGENETIC ASSESSMENTS 
Sample for DNA analysis (optional)l 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY TREATMENT 
Administration of tezepelumab or 
placebom 
 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 2 of 2 
AD = atopic dermatitis; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; Echo = echocardiogram;  
eCRF = electronic case report form; EOT = end of treatment; EQ-5D-3L = EuroQOL quality of life 5-dimensions 3-level version; HIV = human immunodeficiency virus; 
Ig = immunoglobulin; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; PD = pharmacodynamics; PGI-S = Patient’s Global Impression of 
Severity; PK = pharmacokinetics; PPD = purified protein derivate; POEM = Patient Oriented Eczema Measure; S. aureus = Staphylococcus aureus; 
SCORAD = Scoring Atopic Dermatitis;  
TCS = topical corticosteroids; Q4W = every 4 weeks; Wk = Week 
a The screening visit can occur up to 28 days + 7 days before the first dose of investigational product on day 1. 
b The window for visits is  3 days. 
c ECG must be collected prior to any blood draws. 


Product:  Tezepelumab 
Protocol Number:  20170755 
 
Date:  25 August 2020 
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CONFIDENTIAL 
 
 
d Vital signs will be taken pre-dose prior to administration of investigational product.  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. 
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 will be urine tests.  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.  
f This includes total serum IgE, IgA, IgG, and IgM.  All immunoglobulin results will be redacted from laboratory reports. 
g The eDiary includes Pruritus NRS. 
k PK samples at day 1 and weeks 2, 4, 12, 16, 24, 32, 40, 48, and 50 should be collected before dosing with investigational product (trough). 
l This is an optional assessment and requires an additional consent form.  The sample for DNA analysis will be obtained at the day 1 visit using the cell pellet from a 
plasma sample taken on the same day. 
m 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 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. 
n All subjects will receive a 420 mg SC dose of either study drug or placebo as their first dose. 
o 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. 
p All subjects who terminate the study early will complete an early termination visit consisting of all assessments included in the EOT (week 52) visit.  In addition, a 
safety follow-up visit will occur 18 weeks after the EOT visit. 


Product:  Tezepelumab 
Protocol Number:  20170755 
 
Date:  25 August 2020 
Page 20 of 107 
CONFIDENTIAL 
 
 
Table 2-2.  Schedule of Activities for Part A and Part B (Week 26 Through End of Study) 
 
Treatment Period (52 weeks)a 
EOTa/ETl 
 
EOSa 
Unscheduled 
Wk 
26 
Wk 
28 
Wk 
30 
Wk 
32 
Wk 
34 
Wk 
36 
Wk 
38 
Wk 
40 
Wk 
42 
Wk 
44 
Wk 
46 
Wk 
48 
Wk 50 
Wk 52 
Wk 
58 
Wk 70 
GENERAL AND SAFETY ASSESSMENTS 
Physical examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
12-lead ECGb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease-related events 
X 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
X 
X 
LABORATORY ASSESSMENTS 
Urine pregnancy testd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Coagulation 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
Hematology 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Chemistry 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Urinalysis (dipstick)e 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
Anti-tezepelumab-antibody 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Serum immunoglobulinsf 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
X 
PPD or Quantiferon GOLD 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
STUDY-SPECIFIC ASSESSMENTS 
Electronic diaryg 
Completed in the morning at home on eDiary 
X 
X 
Assessment of EASI and IGA 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
X 
 
SCORAD 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
EQ-5D-3L, POEM, DLQI, PGI-S 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
Tracking of TCS use (Part B subjects 
only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 1 of 2 
Footnotes defined on last page of the table 


Product:  Tezepelumab 
Protocol Number:  20170755 
 
Date:  25 August 2020 
Page 21 of 107 
CONFIDENTIAL 
 
 
Table 2-2.  Schedule of Activities for Part A and Part B (Week 26 Through End of Study) 
 
Treatment Period (52 weeks)a 
EOTa/ETl 
 
EOSa 
Unscheduled 
Wk 
26 
Wk 
28 
Wk 
30 
Wk 
32 
Wk 
34 
Wk 
36 
Wk 
38 
Wk 
40 
Wk 
42 
Wk 
44 
Wk 
46 
Wk 
48 
Wk 
50 
Wk 52 
Wk 
58 
Wk 70 
PHARMACOKINETIC ASSESSMENTS 
PK samplingj 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
STUDY TREATMENT 
Administration of tezepelumab or 
placebok 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Page 2 of 2 
DLQI = Dermatology Quality of Life Index; EASI = Eczema Area and Severity Index;  
ECG = electrocardiogram; Echo = echocardiogram; eCRF = electronic case report form; EOS = end of study; EOT = end of treatment; EQ-5D-3L = EuroQOL quality of 
life 5-dimensions 3-level version; ET = early termination; Ig = immunoglobulin; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; PGI-S = Patient’s 
Global Impression of Severity; PK = pharmacokinetics; POEM = Patient Oriented Eczema Measure; PPD = purified protein derivate; SCORAD = Scoring Atopic 
Dermatitis; TCS = topical corticosteroids; Wk = Week 
a The window for visits is  3 days. 
b ECG must be collected prior to any blood draws. 
c Vital signs will be taken pre-dose prior to administration of investigational product.  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. 
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 will be urine tests.  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 Urinalysis analyzed centrally only if dipstick locally is positive. 
f This includes total serum IgE, IgA, IgG, and IgM.  All immunoglobulin results will be redacted from laboratory reports. 
g The eDiary includes Pruritus NRS. 
j PK samples at day 1 and weeks 2, 4, 12, 16, 24, 32, 40, 48, and 50 should be collected before dosing with investigational product (trough). 
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 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. 
l All subjects who terminate the study early will complete an early termination visit consisting of all assessments included in the EOT (week 52) visit.  In addition, a 
safety follow-up visit will occur 18 weeks after the EOT visit. 
 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
Page 22 of 107 
CONFIDENTIAL 
 
 
3. 
Introduction 
3.1 
Study Rationale 
Tezepelumab is being developed for the treatment of atopic dermatitis (AD).  Thymic 
stromal lymphopoietin (TSLP) is an epithelial cytokine shown to be elevated in skin 
lesions of patients with AD.  A previous phase 2a study (ALLEVIAD) demonstrated 
improvements in Investigator’s Global Assessment (IGA) and Eczema Area and Severity 
Index (EASI) scoring, but did not meet statistical significance in the primary endpoint.  A 
phase 1b study demonstrated improvement in IGA and EASI as secondary endpoints. 
In the ALLEVIAD study, not achieving statistical significance for the primary endpoint 
may have been due to the patient population selected, key study design elements 
surrounding topical corticosteroid (TCS) use, and length of treatment.   
In the ALLEVIAD study, a small number of enrolled patients (20%) had severe disease 
and most had moderate AD (as determined by IGA score).  The current study requires a 
minimum of a 2-year history of AD and a higher EASI minimum score of 16, which may 
lead to a greater treatment effect and is consistent with other studies of biologic 
therapies for AD (Simpson et al, 2016).   
Patients were not required to be refractory to TCS at baseline (a requirement for the 
current study), and received TCS during the run-in and treatment periods.  The study 
design did not exclude responders after the 2-week run-in period, which may have 
contributed to the large placebo response observed.   
In the ALLEVIAD study, placebo-treated patients applied greater TCS amounts during 
treatment versus tezepelumab-treated patients.  In addition, all patients liberally applied 
high-strength TCS during the 2-week run-in period.  These 2 factors potentially 
decreased the differential effect due to tezepelumab treatment.  In the monotherapy 
design for Part A of the current study, subjects will wash out from TCS and are required 
to abstain from TCS use for 16 weeks.  This design has been used for other therapies 
and will allow for an evaluation of efficacy with less potential confounding 
(Simpson et al, 2016). 
Second, the 12-week treatment period in ALLEVIAD may not have been of sufficient 
duration to demonstrate efficacy in the AD population.  Dosing was through week 10, 
thus, steady-state exposures to tezepelumab were likely not attained.  In the current 
study, the longer treatment duration evaluation of the primary endpoint at week 16 will 
ensure that tezepelumab reaches steady-state concentrations.   


Product:  Tezepelumab 
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CONFIDENTIAL 
 
 
To explore whether clinical response continues to improve over time, treatment will 
continue up to 1 year, as tezepelumab is anticipated to be a chronic treatment regimen 
for a chronic disease.  Also, given the mechanism of action of TSLP, a longer treatment 
period may reveal greater improvements in AD symptoms beyond week 16.   
Part B of the current study is an exploratory study to investigate the clinical response of 
tezepelumab with TCS as adjunctive treatment.  Inclusion of this cohort will allow for an 
evaluation of the effects of tezepelumab in a more real-life scenario.  While TCS use 
was permitted in the ALLEVIAD study, the criteria for TCS use in Part B of the current 
study has been modified to provide guidance to the investigator for when and how to use 
TCS. 
Three dose levels of tezepelumab (420 mg subcutaneous injection [SC] every 2 weeks 
[Q2W], 280 mg SC Q2W, and 210 mg SC every 4 weeks [Q4W]) were selected based 
on exposure-response analysis of tezepelumab concentration and IGA response from 
the ALLEVIAD study.  These dose regimens will allow establishing exposure-response 
to aid in dose selection for future studies.  A first dose of 420 mg will allow faster 
achievement of steady state for the lower dose regimens (210 mg SC Q4W and 280 mg 
SC Q2W), and is also anticipated to improve symptoms of AD (eg, sleep and pruritus). 
3.2 
Background 
3.2.1 
Disease 
Atopic dermatitis is a chronic inflammatory skin disease (commonly referred to as 
eczema).  In its severe form, AD is characterized by widespread skin lesions that 
manifest as red, itchy, swollen, cracked, weeping lesions with crusting and/or scaling.  
There is frequently intractable pruritus, as well as enhanced susceptibility to bacterial, 
viral, and fungal skin infections.  Atopic dermatitis may affect up to 20% of children and 
up to 10% of adults (Hanifin and Reed, 2007; Silverberg and Hanifin, 2013; 
Silverberg et al, 2012).  Atopic dermatitis is associated with a substantial patient burden 
that typically includes poor quality of life, sleep disturbance, and reductions in work 
productivity (Kiebert et al, 2002).  Treatment recommendations for AD include liberal use 
of emollients, dry skin care protocols, and topical corticosteroids (TCS), which are 
commonly used in the clinical setting.  Unfortunately, TCS have inadequate efficacy in 
many patients with moderate-to-severe disease, and their long-term use is associated 
with important side effects, such as thinning and discoloration of the skin, increased risk 
of skin infection, contact dermatitis, decreased bone density, and slowing of growth in 


Product:  Tezepelumab 
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Date:  25 August 2020 
Page 24 of 107 
CONFIDENTIAL 
 
 
children depending on the extent of percutaneous administration (Chi et al, 2011; 
Ring et al, 2012). 
The immunopathology of AD varies depending on the type of skin lesions.  Acute lesions 
are characterized by a robust T helper 2 (Th2) immune response with production of 
interleukin (IL)-4, IL-5, and IL-13; and release of the epithelial cytokines IL-33, IL-25, and 
TSLP.  Chronic lesions are characterized by a mixed Th1 and Th2 response 
(Beck and Leung, 2000; Soumelis et al, 2002).   
Although TSLP is not detectable in the nonlesional skin of patients with AD, TSLP levels 
are elevated in both acute and chronic AD lesions (Soumelis et al, 2002).  Thymic 
stromal lymphopoietin increases the number and maturation status of human migratory 
Langerhans cells and, through dendritic cells, induces a Th2 cytokine profile in cluster of 
differentiation (CD) 4+ helper T cells (Ebner et al, 2007).  In a mouse model of AD, TSLP 
has been shown to directly stimulate antigen-specific CD4+ T cells to produce a 
Th2 cytokine profile following cutaneous allergen challenge (He et al, 2008).  The role of 
TSLP in the development of fibrosis in AD is not well understood, but TSLP is detectable 
in lung fibroblasts (Soumelis et al, 2002), and a recent study suggests that TSLP directly 
promotes fibrocytes to produce collagen and that neutralization of TSLP significantly 
reduces skin fibrosis (Oh et al, 2011).  As further evidence for the role of TSLP in the 
initiation and progression of AD, studies in mice overexpressing epidermal-specific TSLP 
demonstrate clinical and cellular features similar to human AD, including the 
development of eczematous lesions containing inflammatory cell infiltrates.  
Furthermore, in these studies, mice lacking T cells still develop AD-like disease, 
suggesting that TSLP can trigger AD-like skin inflammation in mice through direct 
activation of myeloid cells (Yoo et al, 2005). 
Although most patients develop AD before the age of 5 years, up to 20% of patients may 
not develop AD until adulthood (Bieber et al, 2002; Kim et al, 2016).  For many children, 
the onset of AD marks the beginning of a progression from AD to food allergy, allergic 
rhinitis, and eventually asthma, a phenomenon frequently described as the “atopic 
march” (Spergel and Paller, 2003).  Indeed, up to 70% of patients with severe AD will 
develop asthma (Zheng et al, 2011).  Numerous studies support a role for TSLP across 
the spectrum of atopic diseases and suggest that TSLP may function not only as an 
upstream regulator of inflammation in AD but as a modulator of disease progression 
within the atopic march.  Zhang et al used a mouse model to demonstrate that induced 
expression of TSLP in mouse epidermal keratinocytes not only triggers AD but also 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
Page 25 of 107 
CONFIDENTIAL 
 
 
induces experimental allergic asthma (Zhang et al, 2009).  In studies by Demehri and 
colleagues, mice overexpressing TSLP from skin keratinocytes not only developed 
AD-like skin inflammation but also were also susceptible to allergen-induced asthma.  
Furthermore, these authors demonstrated that epidermal-derived TSLP was sufficient to 
confer a severe asthma phenotype even in the absence of any skin defect 
(Demehri et al, 2009).  Taken together, these studies suggest that TSLP is both 
necessary and sufficient to trigger the atopic march in a mouse model.  In support of a 
key role for TSLP in the early development of AD, a prospective human birth cohort 
study revealed that high TSLP levels in skin at 2 months of age in addition to family 
history is a better predictor of AD development later in life compared to family history 
alone (Kim et al, 2016). 
3.2.2 
Amgen Investigational Product Background:  Tezepelumab 
Tezepelumab is a human recombinant monoclonal antibody of the immunoglobulin (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 AD. 
A detailed description of the chemistry, pharmacology, pharmacokinetics (PK), efficacy, 
and safety of tezepelumab is provided in the Investigator’s Brochure. 
3.3 
Benefit/Risk Assessment 
In order to evaluate the clinical benefit-risk balance, preclinical and clinical data as well 
as a review of the available information for humanized monoclonal antibodies that are 
approved for and are in development for the treatment of AD have been considered.  
The ALLEVIAD study demonstrated improvements in EASI and IGA scoring, but did not 
meet statistical significance in its primary endpoint.  A phase 1b study demonstrated 
improvement in IGA and EASI as secondary endpoints.  In summary, the benefits for 
tezepelumab over placebo in AD include reduction of IGA, EASI, Scoring Atopic 
Dermatitis (SCORAD), and other markers of AD disease severity. 
Tezepelumab has been well tolerated with no identified risks in studies to date. 
 
 
 
 
 


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The benefit/risk assessment for tezepelumab in AD based on the development through 
phase 2 is favorable.  The future benefit/risk assessment will largely be defined by 
results from the phase 3 program. 
More detailed information about the known and expected benefits and risks and safety 
profile of tezepelumab may be found in the Investigator’s Brochure. 


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4. 
Objectives, Endpoints and Hypotheses 
4.1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary – Part A 
 
To evaluate the effect of tezepelumab 
compared with placebo, assessed using 
the Investigator’s Global Assessment 
(IGA) and Eczema Area and Severity 
Index (EASI) 
 
IGA score of 0 (clear) or 1 (almost clear) 
(IGA 0/1) at week 16 
 
75% reduction in EASI (EASI 75) at 
week 16 
Secondary – Part A 
 
To estimate the effect of tezepelumab 
compared with placebo on the efficacy 
measure of EASI 
 
50% and 90% reduction in EASI 
(EASI 50/90) at week 16 
 
To estimate the time needed to reach 
EASI 50/75/90 
 
Time at which EASI 50/75/90 is achieved 
from day 1 
 
To estimate the effect of tezepelumab 
compared with placebo on the efficacy 
measure of Scoring Atopic Dermatitis 
(SCORAD) 
 
SCORAD at week 16 
 
To estimate the effect of tezepelumab 
compared with placebo on the patient-
reported outcome (PRO) measure of 
pruritus assessed using a numeric rating 
scale (NRS) 
 
Pruritus NRS at week 16 
 
To characterize the pharmacokinetics 
(PK) of tezepelumab 
 
Serum trough concentrations of 
tezepelumab at scheduled visits 
Safety – Part A and Part B 
 
To establish the safety and tolerability of 
tezepelumab compared with placebo 
 
Subject incidence of adverse events 
(including serious adverse events) 
 
Exploratory – Part A and Part B 
 
To estimate the long-term effect of 
tezepelumab on the efficacy measures of 
EASI, SCORAD, and Pruritus NRS 
 
IGA 0/1 at week 24, week 36, and 
week 52 
 
EASI 75 at week 24, week 36, and 
week 52 
 
EASI 50/90 at week 24, week 36, and 
week 52 
 
SCORAD at week 24, week 36, and 
week 52 
 
Pruritus NRS at week 24, week 36, and 
week 52 
 
To investigate potential biomarker 
development by biochemical analysis of 
blood or skin samples 
 
Serum biomarkers may include but are 
not limited to IgE, CCL17, and CCL22 
 
RNA transcriptional changes in blood and 
lesional versus nonlesional skin 


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Objectives 
Endpoints 
Exploratory – Part A and Part B (Continued) 
 
To explore the effect of tezepelumab on 
Patient Global Impression of Severity 
(PGI-S) 
 
Change from baseline in PGI-S at 
scheduled visits 
 
To evaluate the effect of tezepelumab on 
health-related quality of life (HRQoL) 
assessed using the Dermatology Life 
Quality Index (DLQI) 
 
Change from baseline in DLQI at 
scheduled visits 
 
To evaluate the immunogenicity of 
tezepelumab 
 
Anti-tezepelumab antibodies 
 
To investigate the effects of drug target 
genes and AD genes and/or subject 
response to tezepelumab 
 
Gene polymorphisms that may influence 
clinical response to study drug, such as 
filaggrin and TSLP 
Objectives 
Endpoints 
Exploratory – Part B 
 
To evaluate the effect of tezepelumab 
compared with placebo, assessed using 
the IGA and EASI 
 
IGA score of 0 (clear) or 1 (almost clear) 
(IGA 0/1) at week 16 
 
EASI 75 at week 16 
 
To estimate the effect of tezepelumab 
compared with placebo on the efficacy 
measure of EASI 
 
EASI 50/90 at week 16 
 
 
To estimate the time needed to reach 
EASI 50/75/90 
 
Time at which EASI 50/75/90 is achieved 
from day 1 
 
To estimate the effect of tezepelumab 
compared with placebo on the efficacy 
measure of SCORAD 
 
SCORAD at week 16 
 
To estimate the effect of tezepelumab 
compared with placebo on the PRO 
measure of pruritus assessed using an 
NRS 
 
Pruritus NRS at week 16 
 
To characterize the PK of tezepelumab 
 
Serum trough concentrations of 
tezepelumab at scheduled visits 
 
To establish the safety and tolerability of 
tezepelumab compared with placebo 
 
Subject incidence of adverse events 
(including serious adverse events) 
 
4.2 
Hypotheses 
Part A 
The primary hypothesis is that tezepelumab effectively increases the probability of an 
IGA 0/1 response and an EASI 75 response at week 16 in subjects with 
moderate-to-severe AD. 
Part B 
Part B is an estimation study; no hypotheses will be formally tested. 


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5. 
Study Design 
5.1 
Overall Design 
This phase 2b study is designed to evaluate the safety and efficacy of tezepelumab as a 
monotherapy and explore its efficacy as adjunct therapy in subjects with 
moderate-to-severe AD.  This study consists of Part A (the main study evaluating 
tezepelumab as a monotherapy) and Part B (a study evaluating tezepelumab as 
adjunctive therapy when combined with a TCS regimen).  In Part A, two futility analyses 
are planned when the 80th and 160th subjects are projected to complete week 16, 
respectively.  Upon a result of “not futile” for the first analysis and Part A has completed 
enrollment of 240 patients, enrollment of subjects in Part B of the study will commence.  
A result of “futile” for either analysis in Part A will result in termination of both Part A and 
Part B of the study. 
Eligible subjects for both Part A and Part B will include adults with a clinical diagnosis of 
AD at least 2 years prior to screening, with AD that affects  10% of body surface area 
as assessed by EASI, an IGA score of  3, and an EASI score of  16. 
Part A and Part B of this study will consist of a 28-day screening period, a 52-week 
treatment period, and a 20-week safety follow-up period.  During the 28-day screening 
period, subjects must discontinue from all topical AD therapies, except for approved 
moisturizers (see Section 7.1.7), for at least the 7 consecutive days immediately prior to 
day 1.  During the study, approved moisturizers are allowed to be applied, with the 
exception of 8 hours prior to any scheduled visit. 
Part A is a dose-ranging, randomized, placebo-controlled, double-blind study designed 
to evaluate the safety and efficacy of tezepelumab as monotherapy in subjects with 
moderate-to-severe AD.  Following the screening period, eligible subjects will be 
randomized 1:1:1:1 to receive 420 mg SC Q2W, 280 mg SC Q2W, 210 mg SC Q4W, or 
placebo.  All subjects will receive a 420 mg SC dose (investigational product or placebo) 
as the first dose.  Subjects will then receive the appropriate dose of investigational 
product at the week 2 visit, depending on which treatment group they are randomized to.  
Depending on if they are randomized to Q2W or Q4W dosing, the dose at week 2 could 
be placebo or tezepelumab.  Non-responders are defined as those subjects who have 
not achieved at least a 50% improvement in EASI at week 16 compared to baseline 
(day 1).  Subjects who are determined to be non-responders in Part A will receive 
tezepelumab 420 mg SC Q2W for the remainder of the study, beginning with the 


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week 18 dose.  The randomized treatment assignments for the non-responders will 
remain blinded until the end of study. 
Part B is a randomized, placebo-controlled, double-blind study designed to evaluate the 
safety and efficacy of tezepelumab when administered with moderate class TCS in 
adults with moderate-to-severe AD.  Enrollment of subjects in Part B of the study will 
only commence if there is a result of “not futile” for the first interim analysis in Part A and 
Part A has completed enrollment of 240 patients.  Following the screening period, 
eligible subjects will be randomized 2:1 to receive 420 mg SC Q2W or placebo; both 
groups in Part B will be allowed to use TCS after the day 1 visit.  Non-responders in Part 
B will not be switched to 420 mg SC Q2W at week 18 and will remain on their initial dose 
for the duration of the study. 
The overall study design is described by a study schema in Section 2.1.  The endpoints 
are defined in Section 4.1. 
5.2 
Number of Subjects 
Approximately 240 subjects will be enrolled in Part A of the study.  Approximately 
60 subjects will be enrolled in Part B of the study. 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 10.1. 
No groups/subgroups with specific needs are expected to be enrolled; no 
groups/subgroups are excluded from or underrepresented in the study. 
5.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
5.2.2 
Number of Sites 
Approximately 100 investigative study centers in North America, Europe, and the Asia 
Pacific region will be included in the study.  Study centers that do not enroll subjects 
within 6 months of site initiation may be closed. 
5.3 
End of Study 
5.3.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), whether the study concluded as planned in the protocol or was 
terminated early.   


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The primary completion date is the date when the last subject has completed the 
assessments for week 16 in Part A of this study. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject 
across all study centers 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. 
5.3.2 
Study Duration for Subjects 
In Part A, for an individual subject, the length of participation includes a screening period 
of up to 28 days, a double-blind treatment period of 52 weeks, and a safety follow-up 
that occurs for 20 weeks after the final dose of study drug (18 weeks after the end of 
treatment [EOT] visit). 
In Part B, for an individual subject, the length of participation includes a screening period 
of up to 28 days, a double-blind treatment period of 52 weeks, and a safety follow-up 
that occurs for 20 weeks after the final dose of study drug (18 weeks after the EOT visit). 
5.4 
Justification for Investigational Product Dose 
 
 
 
 
 
   
 
 
 
 
 
 
 
 


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6. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an Interactive Voice Response 
System (IVRS)/Interactive Web Response System (IWRS). 
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 enrolled.  
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, is not permitted.  Subjects who do not meet the entry 
requirements for enrollment are screen failures. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Appendix 3). 
6.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures 
102 
Age  18 to  75 years at screening 
103 
Clinical diagnosis of chronic AD (also known as atopic eczema) for at least 
2 years prior to screening and has confirmed AD (Hanifin and Rajka criteria for 
AD; Hanifin and Rajka, 1980) 
104 
AD that affects  10% body surface area as assessed by EASI at screening and 
on day 1 
105 
An IGA score of  3 at screening and on day 1 


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106 
An EASI score of  16 at screening and on day 1 
107 
Subject discontinued treatment with TCS, topical calcineurin inhibitors (TCI), and 
prescription moisturizers containing TCS or TCI for at least the 7 days 
immediately prior to the first dose of investigational product 
108 
Documented recent history (within 12 months before the screening visit) of 
inadequate response to treatment with topical TCS or subjects for whom topical 
treatments are otherwise medically inadvisable (ie, because of important side 
effects or safety risks) 
- 
Inadequate response is defined as failure to achieve and maintain remission or a 
low disease activity state (comparable to IGA 0 = clear to IGA 2 = mild) despite 
treatment with a daily regimen of TCS of medium or higher potency (with or 
without TCI as appropriate). 
6.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 
201 
Active dermatologic conditions, which might confound the diagnosis of AD or 
would interfere with the assessment of treatment, such as scabies, seborrheic 
dermatitis, cutaneous lymphoma, ichthyosis, psoriasis, allergic contact dermatitis, 
or irritant contact dermatitis 
202 
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 
203 
Diagnosis of a helminth parasitic infection within 6 months prior to screening that 
had not been treated with or had failed to respond to standard of care therapy 
204 
Documented medical history of chronic alcohol or drug abuse within 12 months 
prior to screening 
205 
History of anaphylaxis following any biologic therapy 
206 
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) 
207 
Subjects who, in the opinion of the investigator, have evidence of active 
tuberculosis (TB), either treated or untreated, or a positive 
QuantiFERON-tuberculosis Gold (QFT-G) test for TB during screening.  Subjects 
with an indeterminate QFT-G may be enrolled if they have ALL of the following: 
 
No symptoms of TB:  productive, prolonged cough (> 3 weeks); coughing up 
blood; fever; night sweats; unexplained appetite loss; unintentional weight 
loss 


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 
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 
208 
Positive hepatitis B surface antigen or hepatitis C antibody serology.  Subjects 
with a history of hepatitis B vaccination without a history of hepatitis B are 
allowed to enroll in the study. 
209 
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 Medical Conditions 
210 
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  
211 
History or evidence of severe depression, schizophrenia, previous suicide 
attempts, or suicidal ideation 
Prior/Concomitant Therapy 
212 
Subjects who are unwilling to abstain from the use of TCS, TCI, and prescription 
moisturizers (those that contain TCS and TCI) from screening through week 16 
(applies only to Part A subjects) 
213 
Subjects who have had side effects of topical medications including intolerance 
to treatment, hypersensitivity reactions, significant skin atrophy, or systemic 
effects as assessed by the investigator or by the subject’s treating physician 
(applies only to Part B subjects) 
214 
More than or equal to 30% of the total lesional surface is located on areas of thin 
skin that cannot be safely treated with medium or higher potency TCS (eg, face, 
neck, intertriginous areas, areas of skin atrophy) (applies only to Part B subjects) 
215 
Receipt of any approved biologic agent (eg, dupilumab) within 4 months or 
5 elimination half-lives (whichever is longer) prior to screening 
216 
Have used immunosuppressive/immunomodulating drugs (eg, systemic 
corticosteroids, cyclosporine, mycophenolate-mofetil, interferon (IFN)-gamma, 
Janus kinase inhibitors, azathioprine, methotrexate) within 4 weeks prior to 
screening, or any condition that, in the opinion of the investigator, is likely to 
require such treatment(s) during the first 4 weeks of study treatment. 
217 
Have had phototherapy for AD in the 2 months prior to day 1, and subjects 
unwilling to avoid phototherapy during the first 16 weeks of the study 
218 
If on allergen-specific immunotherapy, subjects must be on a maintenance dose 
and schedule for  28 days prior to screening.  Allergen-specific immunotherapy 
is defined as SC immunotherapy to aeroallergens and/or venom (Hymenoptera) 
as well as sublingual immunotherapy to aeroallergens 
219 
Vaccination with a live or attenuated vaccine within 28 days prior to day 1.  
Receipt of inactive/killed vaccinations (eg, inactive influenza) is allowed.  Note 


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that receipt of the Th2 cytokine inhibitor suplatast within 15 days prior to 
randomization and during the study is not allowed. 
220 
Major surgery within 8 weeks prior to screening or planned inpatient surgery or 
hospitalization during the study period 
Prior/Concurrent Clinical Study Experience 
224 
Currently receiving treatment in another investigational device or drug study, or 
less than 6 months since ending treatment on another investigational device or 
drug study(ies).  Other investigational procedures while participating in this study 
are excluded. 
Other Exclusions 
225 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 16 weeks after the last dose of 
investigational product.  (Females of childbearing potential should only be 
enrolled in the study after a negative highly sensitive serum pregnancy test). 
226 
Female subjects of childbearing potential who are sexually active with 
unsterilized male partners unwilling to use 1 highly effective method of 
contraception during treatment and for an additional 16 weeks after the last dose 
of investigational product.  Cessation of contraception after this point must be 
discussed with a responsible physician.  Females of childbearing potential are 
defined as those who are not surgically sterile (ie, had bilateral tubal ligation, 
bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined 
as 12 months with no menses without an alternative medical cause).  A highly 
effective method of contraception is defined as one that resulted in a low failure 
rate (ie, < 1% per year) when used consistently and correctly.  Refer to 
Appendix 5 for additional contraceptive information. 
230 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
231 
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. 
6.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the study center’s written institutional review board IRB/institutional 
ethics committee (IEC) approval of the protocol, informed consent form (ICF), and all 
other subject information and/or recruitment material, if applicable (see Appendix 3). 
The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB/IEC and Amgen approved informed consent before commencement of 
study-specific procedures. 


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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 (when informed consent 
is signed) receives a unique subject identification number before any study-related 
activities/procedures are performed.  The subject identification number will be assigned 
by IVRS/IWRS.  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.  
This number will not necessarily be the same as the randomization number assigned for 
the study. 
6.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, medical history, prior therapies, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) will 
not be rescreened.   
7. 
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. 


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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 7-1 below. 
7.1 
Treatment Procedures 
7.1.1 
Investigational Products 
The amount of investigational product, total volume, quantity, dose start date/time, and 
box number are to be recorded on each subject’s CRF. 
 


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Table 7-1.  Study Treatments 
Study Treatment 
Name 
Amgen Investigational Product:a 
Tezepelumab 
Placebo 
Dosage 
Formulation 
Each package will contain 3 vials. 
Placebo will be presented in identical containers, and 
stored/packaged the same as tezepelumab. 
Unit Dose 
Strength(s)/ 
Dosage Level(s) 
and Dosage 
Frequency 
Each subject will receive 3 injections per visit. 
For subjects randomized to 420 mg SC Q2W, 280 mg SC 
Q2W, and 210 mg SC Q4W:  volumes for injections from 
vials provided will be detailed in the Investigational Product 
Instruction Manual (IPIM). 
Subjects randomized to Q4W dosing will receive placebo at 
intervening visits, such that all subjects receive an injection 
Q2W. 
Each subject will receive 3 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. 
Route of 
Administration 
SC injection 
SC injection 
Accountability 
The amount of investigational product, total volume, quantity, 
dose start date/time, and box number of investigational 
product are to be recorded on each subject's CRF(s). 
The amount of investigational product, total volume, 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. 
CRF = case report form; 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. 


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7.1.2 
Non-investigational Products 
Not applicable. 
7.1.3 
Medical Devices 
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. 
7.1.4 
Other Protocol-required Therapies 
There are no other protocol-required therapies in this study. 
7.1.5 
Other Treatment Procedures 
During the 28-day screening period, subjects must discontinue from all AD therapies, 
except for approved moisturizers (see Section 7.1.7), for at least the 7 consecutive days 
immediately prior to day 1.  During the study, approved moisturizers are allowed to be 
applied, with the exception of 8 hours prior to any scheduled visit. 
Medications and procedures permitted at any time during the study for subjects enrolled 
in Part A and Part B include: 
 
Basic skin care (cleansing and bathing), emollients, bleach baths, topical 
anesthetics, and antihistamines (all for any duration) 
 
Medications used to treat chronic diseases such as diabetes, hypertension, and 
asthma 
Part A 
In Part A of the study, if needed to control intolerable AD symptoms, rescue treatment 
for AD may be provided at the discretion of the investigator.  Rescue is not allowed in 
the first 4 weeks of Part A.  Topical calcineurin inhibitors may be used for rescue, but are 
to be reserved for problem areas only (eg, face, neck, intertriginous and genital areas).  
Investigators are to attempt to limit the first step of rescue therapy to topical medications, 
and escalate to systemic medications only for subjects who do not respond adequately 
following at least 7 days of topical treatment.  If a subject receives rescue treatment with 
systemic corticosteroids or nonsteroidal systemic immunosuppressive drugs 


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(eg, cyclosporine, mycophenolate-mofetil, azathioprine), study treatment is to be 
immediately discontinued. 
All subjects are to complete the schedule of study visits and assessments whether or not 
they complete study treatment or receive rescue treatment for AD. 
Part A Rescue Guidance 
Subjects who use TCS are to apply medium potency TCS once daily to areas with 
active lesions.  Low potency TCS should be used once daily on areas of thin skin 
(eg, face, neck, intertriginous, genital areas, areas of skin atrophy) or for areas 
where continued treatment with medium potency TCS is considered unsafe.  
Triamcinolone acetonide 0.1% cream or fluocinolone acetonide 0.025% ointment are 
recommended as medium potency TCS therapy; hydrocortisone 1% cream is 
recommended as low potency TCS therapy.  After lesions are under control (clear or 
almost clear), subjects are to switch from medium potency to low potency TCS and 
treat once daily for 7 days, then cease TCS therapy. 
If the lesions return, subjects are to resume treatment with medium potency TCS, 
and are to use the step-down approach to low potency TCS described above.  For 
lesions that persist or worsen with once daily application of medium potency TCS, 
subjects may be treated (further rescued) with high or super-high potency TCS, 
unless higher potency TCS is considered unsafe. 
Part B 
Additionally, in Part B of the study, subjects are allowed to apply TCS following 
completion of all day 1 activities.  Subjects should bring their containers of TCS to the 
site at every visit to have the container weighed and the amount of TCS used since the 
previous visit recorded.   
Subjects who use TCS are to apply medium potency TCS once daily to areas with active 
lesions.  Low potency TCS should be used once daily on areas of thin skin (eg, face, 
neck, intertriginous, genital areas, areas of skin atrophy) or for areas where continued 
treatment with medium potency TCS is considered unsafe.  Triamcinolone acetonide 
0.1% cream or fluocinolone acetonide 0.025% ointment are recommended as medium 
potency TCS therapy; hydrocortisone 1% cream is recommended as low potency TCS 
therapy.  After lesions are under control (clear or almost clear), subjects are to switch 
from medium potency to low potency TCS and treat once daily for 7 days, then cease 
TCS therapy. 


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If the lesions return, subjects are to resume treatment with medium potency TCS, and 
are to use the step-down approach to low potency TCS described above.  For lesions 
that persist or worsen with once daily application of medium potency TCS, subjects may 
be treated (rescued) with high or super-high potency TCS, unless higher potency TCS is 
considered unsafe.   
In Part B, after all week 2 activities are completed, if needed to control intolerable 
symptoms, subjects may receive rescue treatment with any approved AD therapy (see 
Section 7.1.7 for excluded treatments).  If rescue with TCS is necessary, mometasone 
0.1% ointment is recommended as a high potency therapy; betamethasone dipropionate 
0.05% optimized ointment or clobetasol propionate 0.05% cream are recommended as 
super-high potency therapy.   
If a subject receives rescue treatment with systemic corticosteroids or nonsteroidal 
systemic immunosuppressive drugs (eg, cyclosporine, mycophenolate-mofetil, 
azathioprine) they must be discontinued from study treatment.  All subjects are to 
complete the schedule of study visits and assessments whether or not they complete 
study treatment or receive rescue treatment for AD. 
The use of TCI is to be reserved for problem areas (eg, face, neck, intertriginous and 
genital areas).  TCS and TCI are not to be used concomitantly to treat the same affected 
areas. 
7.1.6 
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 drug(s), device(s) or combination product(s) provisioned and/or 
repackaged/modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Any product complaint(s) associated with an investigational product(s), 
non-investigational product(s), device(s), or combination product(s) supplied by Amgen 
are to be reported according to the instructions provided in the IPIM. 


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7.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The use of other investigational procedures and products while participating in this study 
is prohibited.  The use of biologics, including dupilumab, is prohibited while participating 
in this study.  
Treatment with systemic immunosuppressive/immunomodulating drugs (eg, 
methotrexate, cyclosporine, azathioprine, mycophenolate-mofetil, tacrolimus, and 
interferon gamma), Ig and or blood product during the study period is prohibited. 
Vaccination with a live or attenuated vaccine is prohibited during the course of the study.   
Planned inpatient surgery or hospitalization during the study period is prohibited.   
Phototherapy is prohibited during the first 16 weeks of the study.   
In Part A of the study, treatment with TCS, TCI, and prescription moisturizers that 
contain TCS or TCI is prohibited.  Non-prescription moisturizers are allowed.  
Prescription moisturizers that have the same ingredients as available over-the-counter 
moisturizers are allowed for use. 
In Part B of the study, treatment with TCI, and prescription moisturizers that contain TCS 
or TCI is prohibited until the week 2 assessments are completed.  Non-prescription 
moisturizers are allowed.  Prescription moisturizers that have the same ingredients as 
available over-the-counter moisturizers are allowed for use.  Topical calcineurin 
inhibitors are only permitted for rescue.  Topical corticosteroids are only permitted after 
the completion of all day 1 activities.  After week 2, rescue with any approved AD 
therapy is allowed, however, study treatment will be discontinued for those subjects who 
use phototherapy, systemic corticosteroids, or injectable treatments as rescue therapy.  
Only those subjects using TCS and/or TCI as rescue will be permitted to continue 
concurrent therapy with study drug. 
7.2 
Method of Treatment Assignment 
In Part A, subjects will be randomized in a 1:1:1:1 allocation ratio, to tezepelumab 
420 mg SC Q2W, 280 mg SC Q2W, 210 mg SC Q4W, or placebo, respectively, in 
double-blind manner. 
In Part B, subjects will be randomized in a 2:1 allocation ratio to 420 mg SC Q2W or 
placebo, respectively, in a double-blind manner. 
The randomization will be performed by IVRS/IWRS. 


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The randomization date is to be documented in the subject’s medical record and on the 
enrollment case report form. 
7.3 
Blinding 
Both Part A and Part B of this study are double-blind.  Treatment assignment will be 
blinded to all subjects, study center personnel, and Amgen as described below. 
7.3.1 
Study Center Personnel Access to Individual Treatment 
Assignments 
A subject’s treatment assignment is to only be unblinded when knowledge of the 
treatment is essential for further clinical management of the subject on this study.  
Unblinding at the study center for any other reason will be considered a protocol 
deviation.  The Amgen Trial Manager must be notified before the blind is broken unless 
identification of the study treatment is required for a medical emergency in which the 
knowledge of the specific blinded study treatment will affect the immediate management 
of the subject’s condition.  In this case, the Amgen Trial Manager 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 and CRF, as applicable. 
A description of how responsible pharmacists and investigators will access treatment 
information (eg, via the IVR/IWR system), in the event that there is a need to break the 
blind, will be detailed in the IPIM. 
7.3.2 
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 except as specified (eg, Section 7.3.1). 
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 exposure-response analysis is performed, the exposure-response analysis team, 
including Clinical Pharmacology Modeling and Simulation and Global Biostatistics 


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Sciences, 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. 
7.4 
Dose Modification 
In Part A of this study, subjects who are determined to be non-responders will receive 
tezepelumab 420 mg SC Q2W for the remainder of the study, beginning with the 
week 18 dose.  Non-responders are defined as those subjects who have not achieved at 
least a 50% improvement in EASI at week 16 compared to baseline (day 1).  The 
randomized treatment assignments for the non-responders will remain blinded until the 
end of study. 
In Part B, there will be no dose modification. 
7.4.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
Not applicable. 
7.4.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.2.1 
Amgen Investigational Product:  Tezepelumab 
The reason for dose change of tezepelumab is to be recorded on each subject’s CRF(s). 
An individual subject may be discontinued at the discretion of the investigator and/or the 
sponsor due to clinically significant events. 
In Part A of the study, subjects who are determined to be non-responders will receive 
tezepelumab 420 mg SC Q2W for the remainder of the study, beginning with the 
week 18 dose.  Non-responders are defined as those subjects who have not achieved at 
least a 50% improvement in EASI at week 16 compared to baseline (day 1).  The 
randomized treatment assignments for the non-responders will remain blinded until the 
end of study. 
Subjects who receive rescue therapy with topical medications may continue treatment 
with study drug, per the instructions outlined in Section 7.1.5. 
If a subject receives rescue treatment with systemic corticosteroids or nonsteroidal 
systemic immunosuppressive drugs (eg, cyclosporine, mycophenolate-mofetil, 
azathioprine), study treatment is to be immediately discontinued.  All subjects are to 
complete the schedule of study visits and assessments whether or not they complete 
study treatment or receive rescue treatment for AD. 


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7.4.2.2 
Non-Amgen/Amgen Non-Investigational Products  
7.4.2.2.1 
Topical Corticosteroids 
Topical corticosteroid use is prohibited in Part A of this study.  If topical corticosteroid 
use is required during Part A, refer to rescue guidance in Section 7.1.5.  
In Part B of this study, subjects are allowed to initiate TCS use following completion of all 
day 1 activities.  Subjects who apply TCS are to follow the dosing regimen described in 
Section 7.1.5. 
Subjects will be monitored for signs of local or systemic TCS toxicity and will step down 
or stop treatment as directed by the Principal Investigator, who should direct the type 
and length of therapy.  Signs of local toxicity include skin thinning; signs of systemic 
toxicity include hyperglycemia. 
The reason for dose change of TCS is to be recorded on each subject’s CRF(s). 
7.4.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Appendix 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.  
7.5 
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. 
7.6 
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. 
7.7 
Treatment of Overdose 
A dose in excess of 420 mg tezepelumab administered within a 1-week period is 
considered an 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. 


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7.8 
Prior and Concomitant Treatment 
7.8.1 
Prior Treatment 
Prior therapies that were being taken from 5 years prior to screening through the first 
dose of investigational product should be collected.   
For prior therapies being taken for the disease under study (eg, steroids, topical 
medications), collect therapy name, indication, dose, unit, frequency, route, start date 
and stop date.  For all other prior therapies, collect therapy name, indication, dose, unit, 
frequency, route, and start date and stop date. 
7.8.2 
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 7.1.7. 
Concomitant therapies are to be collected from the first dose of investigational product 
through the end of study safety follow-up. 
For concomitant therapies being taken for the disease under study (eg, steroids, topical 
medications) collect therapy name, indication, dose, unit, frequency, route, start date 
and stop date.  For all other concomitant therapies, collect therapy name, indication, 
dose, unit, frequency, route, start date and stop date. 
Allowed concomitant treatments and directions pertaining to rescue therapy are outlined 
in Section 7.1.5. 
8. 
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 8.1, 8.2.1, and 8.2.2. 
8.1 
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 


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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 (see Table 2-1 
and Table 2-2) 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, disease-related events, and must document this decision in the subject’s 
medical records.  Subjects who receive systemic rescue therapies will be discontinued 
from study treatment but whenever safe and feasible, it is imperative that subjects 
remain on-study to ensure safety surveillance and/or collection of outcome data.  
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 Appendix 3. 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance  
 
Adverse event 
 
Subject request 
 
Pregnancy 
8.2 
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 
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 


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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 
Appendix 6 for further details).  Refer to the Schedule of Activities for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
8.2.1 
Reasons for Removal From Washout, Run-in, or Invasive 
Procedures 
Not applicable to this study. 
8.2.2 
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 
8.3 
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 center.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The study center 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.  
 
For subjects who are lost to follow-up, the investigator can search publicly available 
records [where 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. 


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9. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1 and Table 2-2).  
As protocol waivers or exemptions are not allowed if an enrolled 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 Schedule 
of Activities, is essential and required for study conduct. 
9.1 
General Study Periods 
9.1.1 
Screening, Enrollment, and 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 informed consent form, the study center will register the subject in the 
IVRS/IWRS and screen the subject in order to assess eligibility for participation.  The 
screening window for this study is up to 28 days (+ 7 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, 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 fail.  Screen fail subjects are not eligible for 
rescreening.  
9.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 2-1 and Table 2-2).  On-site study 
visits may be completed within a window of 3 days.  The date of the first dose of 
tezepelumab or placebo is defined as day 1.  All subsequent doses and study visits will 
be scheduled based on the day 1 date.  Administration of tezepelumab or placebo is to 
occur following completion of all other study activities for each visit. 
9.1.3 
Safety Follow-up 
A safety follow-up visit will be conducted 20 weeks after the final dose of study drug 
(18 weeks after the EOT visit).  All subjects who terminate the study early will complete 
an early termination visit consisting of all assessments included in the EOT (week 52) 


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visit and these subjects will complete a safety follow-up visit occur 18 weeks after the 
EOT visit. 
9.1.4 
End of Study 
The EOS visit will occur 18 weeks after the EOT visit (20 weeks after the final dose of 
study drug) and is the same as the safety follow-up visit. 
9.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
9.2.1 
General Assessments  
Study procedures and their timing are discussed in the Schedule of Activities (Table 2-1 
and Table 2-2). 
9.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed. 
9.2.1.2 
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 biomarker variability 
and PK of the protocol-required therapies.  
9.2.1.3 
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.  Record all findings on the 
medical history CRF.  In addition to the medical history above, AD history must date 
back to the original diagnosis.  The current severity will be collected for each condition 
that has not resolved. 
9.2.1.4 
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). 
9.2.1.5 
Physical Measurements 
Height in centimeters should be measured without shoes.  Weight in kilograms should 
be measured without shoes. 


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9.2.1.6 
Substance Use  
Obtain a detailed history of use of alcohol, tobacco, and caffeine. 
9.2.2 
Efficacy Assessments 
9.2.2.1 
Investigator’s Global Assessment 
The IGA allows investigators to assess overall disease severity at 1 given time point and 
consists of a 5-point severity scale from clear to severe disease (0 = clear; 1 = almost 
clear; 2 = mild disease; 3 = moderate disease; 4 = severe disease; 5 = very severe 
disease).  The IGA uses clinical characteristics of erythema, infiltration, papulation, 
oozing, and crusting as guidelines for the overall severity assessment 
(Breuer et al, 2004).  The IGA will be assessed at every visit according to the Schedule 
of Activities (Table 2-1 and Table 2-2).  Whenever possible, the IGA should be assessed 
by the same investigator at each visit to reduce inter-rater variability. 
9.2.2.2 
Eczema Area and Severity Index 
The EASI was designed by modifying the Psoriasis Area and Severity Index, which has 
been widely used in clinical trials and has been established as a well-accepted and 
standardized instrument for assessing therapeutic response in patients with psoriasis 
(Schmitt et al, 2007).  The EASI evaluates 4 natural anatomical regions for severity and 
extent of key disease signs and focuses on key acute and chronic signs of inflammation 
(ie, erythema, induration/papulation, excoriation, and lichenification).  The maximum 
score is 72, with higher values indicating more severe disease. 
The EASI will be assessed at every visit according to the Schedule of Activities 
(Table 2-1 and Table 2-2).  Whenever possible, the EASI should be assessed by the 
same investigator at each visit to reduce the inter-rater variability. 
9.2.2.3 
Scoring of Atopic Dermatitis 
The SCORAD is a clinical tool for assessing the severity (ie, extent, intensity) of AD.  
The tool evaluates the extent and intensity of the AD lesions, along with subjective 
symptoms (Kunz et al, 1997).  The maximum total score is 103, with higher values 
indicating more severe disease.  The SCORAD should be assessed by the same 
investigator at each visit, whenever possible, to reduce inter-rater variability.  The 
SCORAD will be conducted according to the Schedule of Activities (Table 2-1 and 
Table 2-2). 


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9.2.2.4 
Patient-reported Outcomes 
The electronic diary (eDiary), which includes the pruritus NRS, will be completed by the 
subject at home each morning during the treatment and follow-up periods.  The 
remaining PROs will be conducted at the study center at the visits specified in the 
Schedule of Activities (Table 2-1 and Table 2-2) and should be completed prior to other 
study assessments to avoid the possibility of introducing bias to subject responses. 
9.2.2.4.1 
Electronic Diary 
The electronic diary includes 1 item to capture subject-reported pruritus.  The diary will 
be completed by the subject at home each morning using an electronic device according 
to the Schedule of Activities (Table 2-1 and Table 2-2). 
9.2.2.4.1.1 
Pruritus Numeric Rating Scale 
Pruritus will be assessed using an NRS (0-10) with 0 = no itch and 10 = worst 
imaginable itch.  Subjects will complete the NRS as part of the daily diary each day in 
the morning according to the Schedule of Activities (Table 2-1 and Table 2-2). 
9.2.2.4.2 
Patient Oriented Eczema Measure 
The Patient Oriented Eczema Measure (POEM) is a 7-item validated questionnaire used 
in clinical practice and clinical trials to assess disease symptoms in children and adults 
(Charman, 2004).  It evaluates time spent in the past week with AD signs and 
symptoms:  individual items of itching, bleeding, oozing, cracked, flaking, and dry/rough 
skin, and their impact on sleep.  The POEM will be assessed at the study center, 
according to the Schedule of Activities (Table 2-1 and Table 2-2). 
9.2.2.4.3 
Dermatology Quality of Life Index 
The DLQI is a 10-item, subject-completed, HRQoL 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 will be completed by the subject at the study center 
according to the Schedule of Activities (Table 2-1 and Table 2-2). 
9.2.2.4.4 
Patient Global Impression of Severity 
The 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 


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(no symptoms to very severe symptoms.  The PGI-S will be completed by the subject at 
the study center according to the Schedule of Activities (Table 2-1 and Table 2-2). 
9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities. 
9.2.3.1 
Adverse Events 
All adverse events observed by the investigator or reported by the subject that occur 
after the first dose of investigational product through the end of study/safety follow-up 
visit or 20 weeks after the last administration of investigational product are to be 
collected/reported. 
All adverse events related to any study procedure/activities will be collected/reported 
after signing the informed consent form through the end of study/safety follow-up visit or 
20 weeks after the last dose of investigational product. 
9.2.3.1.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
9.2.3.1.1.1 
Disease-related Events 
Disease-related events are defined in Appendix 4. 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur after the first dose of investigational 
product(s)/study treatment/protocol-required therapies through the end of study are 
recorded using the Event CRF.   
All serious disease-related events will be recorded and reported to the sponsor or 
designee within 24 hours.  The investigator will submit any updated serious 
disease-related event data to the sponsor within 24 hours of it being available. 
Disease-related events assessed by the investigator to be more severe than expected 
and/or related to the investigational product(s)/study treatment/protocol-required 
therapies, and determined to be serious, must be reported on the Event CRF as serious 
adverse events and recorded and reported per Appendix 4 and Section 9.2.3.1.1.3. 
Disease-related events pre-defined for this study include AD.  
9.2.3.1.1.2 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0 and is described in 
Appendix 4. 


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The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product(s)/study treatment/protocol-required therapies through the end of study are 
reported using the Event CRF. 
9.2.3.1.1.3 
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 20 weeks after the last administration of investigational product are 
reported using the Event CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours, as indicated in Appendix 4.  The investigator will submit any 
updated serious adverse event data to the sponsor within 24 hours of it being available. 
The criteria for grade 4 in the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events.  It is left to the investigator’s judgment to report these 
grade 4 abnormalities as serious adverse events. 
9.2.3.1.1.4 
Serious Adverse Events After the Protocol-required Reporting 
Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  Per local requirements in some countries, 
investigators are required to report serious adverse events that they become aware of 
after end of study.  If serious adverse events are reported, the investigator is to report 
them to Amgen within 24 hours following the investigator’s knowledge 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.  
The method of recording, evaluating, and assessing causality of adverse events, 
adverse device effects, disease-related events, and serious adverse events and the 
procedures for completing and transmitting serious adverse event reports are provided 
in Appendix 4. 


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9.2.3.1.2 
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. 
9.2.3.1.3 
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 8.3).  
Further information on follow-up procedures is given in Appendix 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. 
9.2.3.1.4 
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, IRB/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an 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/IEC, if appropriate according to local requirements. 


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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 (SAT) as appropriate.  
Investigators will receive notification of related serious adverse events reports sent to 
regulatory authorities in accordance with local requirements. 
9.2.3.1.5 
Events of Interest 
An event of interest (EOI) is an event of scientific and medical interest towards improving 
the understanding of the investigational product.  An EOI may be serious or non-serious.  
For this study, EOIs include: 
9.2.3.1.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and female partners of 
male subjects will be collected after the start of study treatment and until 16 weeks after 
the final dose of study drug or the final study visit, whichever occurs later. 
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 Appendix 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, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Appendix 5. 


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9.2.3.2 
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. 
9.2.3.3 
Electrocardiograms (ECGs) 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  The ECG must 
include the following measurements:  Heart Rate, QRS, QT, QTc, and PR intervals.  The 
principal investigator (PI) (or designated study center physician or central reader) will 
review all ECGs.  Once signed, the original ECG tracing will be retained with the 
subject's source documents.  At the request of the sponsor, a copy of the original ECG 
will be made available to Amgen. 
9.2.3.4 
Suicidal Risk Monitoring 
Suicidal risk monitoring is not required for tezepelumab. 
9.2.3.5 
Other Safety 
There are no other safety considerations for this study. 
9.2.4 
Clinical Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities 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.  


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Where applicable, clinical sequelae (not the laboratory abnormality) are to be recorded 
as the adverse event. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities.  
Laboratory/analyte results that could unblind the study will not be reported to 
investigative study centers or other blinded personnel until the study has been 
unblinded.  Only eosinophils on complete blood count and differential are considered 
unblinding data for this study.  Additional details regarding potentially unblinding data 
and study personnel are provided in Section 7.3.2. 
9.2.4.1 
Tuberculosis Testing 
All subjects must receive either a purified protein derivate (PPD) or Quantiferon test at 
screening and ET/EOT. 
The PPD test must be read by a trained healthcare professional 48 to 72 hours after the 
test is placed.  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 central laboratory manual for instructions on sample collection, processing, and 
shipping of samples. 
9.2.4.2 
Pregnancy Testing 
A high sensitive serum pregnancy test should be completed at screening and a high 
sensitive urine test should be completed within 7 days of initiation of investigational 
product for females of childbearing potential.  Therefore, for this study, the initial 
pregnancy tests will occur at screening and at the day 1 visit (which is within 7 days of 
initiation of investigational product). 
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 
Worksheet, see Figure 12-2).  Refer to Appendix 5 for contraceptive requirements.  
Additional pregnancy testing should be performed monthly during treatment with 
protocol-required therapies, then at week 52 and week 70 during the safety follow-up 
period. 


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If a urine pregnancy test is positive, a confirmatory serum pregnancy test will be 
performed and entered into the electronic case report form (eCRF). 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
9.2.5 
Pharmacokinetic Assessments 
All subjects randomized to treatment with tezepelumab will have pharmacokinetic 
samples assessed. 


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Whole blood samples of approximately 5 mL will be collected for measurement of serum 
concentrations of tezepelumab as specified in the Schedule of Activities (Table 2-1 and 
Table 2-2).  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 study centers or blinded personnel until the study has been unblinded. 
9.2.7 
Pharmacogenetic Assessments 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of moderate-to-severe AD 
and/or to identify subjects who may have positive or negative response to investigational 
product or protocol-required therapies.  Samples collected for this part of the study are 
described in Section 9.2.9.3.  For subjects who consent to this/these analysis/analyses, 
DNA may be extracted.  The final disposition of samples is described in Appendix 6.  
9.2.8 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected according to the time points 
specified in the Schedule of Activities (Table 2-1 and Table 2-2).  Bioanalytical testing for 
anti-tezepelumab antibodies will be conducted only if there are unexpected PK findings 
or safety-related concerns in the study population that warrant further investigation.  
Samples that test positive for anti-tezepelumab antibodies may be further characterized.  
Additional blood samples may be obtained to rule out the presence of anti-tezepelumab 
antibodies during the study. 
Refer to the laboratory manual for detailed collection and handling instructions. 


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9.2.9 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
Biomarker development can be useful in developing markers to identify disease 
subtypes, guide therapy, and/or predict disease severity. 
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to tezepelumab to investigate and further understand 
moderate-to-severe AD. 
Blood samples and biopsies are to be collected according to the Schedule of Activities 
(Table 2-1 and Table 2-2).  Refer to the Laboratory Manual for detailed collection and 
sample handling procedures for biomarker assessment. 
9.2.9.1 
Blood Biomarkers 
Blood samples (serum/plasma and whole blood) will be collected as outlined in 
Table 2-1 and Table 2-2 for the assessment of changes in circulating biomarker levels 
that are elevated in subjects with AD.  Additional assays which may be performed on 
blood samples include measuring changes in mRNA transcripts after tezepelumab 
treatment. 
9.2.9.2 
Skin RNA Transcript Profiling 
Skin punch biopsy samples will be collected from a subset of consenting subjects 
according to the Schedule of Activities (Table 2-1 and Table 2-2) for RNA transcript 
analysis.  The purpose of these analyses will be to retrospectively evaluate transcript 
biomarkers predictive of subject response at baseline, prior to investigational product 
administration, as well as to potentially identify additional AD biomarkers. 
9.2.9.3 
DNA 
Whole blood will be collected at a single time point (day 1 visit) after subjects have been 
randomized into the study for extraction of DNA and analysis of polymorphisms 
associated with AD, TSLP, or tezepelumab response.  The collection of blood for DNA 
analysis is optional and subjects who do not wish to have the DNA test done will still be 
eligible for the study.  The completion of a separate Informed Consent Form 
(Pharmacogenetic ICF) related to DNA is required.  Subjects who elect to have the DNA 
test done may, at any time before the end of the study, request that the blood collected 
for DNA analysis be destroyed. 


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9.2.10 
Clinical Outcome Assessments 
9.2.10.1 
EQ-5D-3L 
The EuroQOL quality of life 5-dimensions 3-level version (EQ-5D-3L) is a standardized 
instrument for use as a measure of health-related quality of life (HRQoL) and was 
developed by EuroQol (Brooks, 1996).  It defines health in terms of 5 dimensions:  
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  Each 
dimension has 3 ordinal levels of severity:  1, no problem; 2, some problems; and 3, 
severe problems.  Overall health state is defined as a 5-digit number.  The EQ-5D-3L will 
be assessed at the study center, according to the Schedule of Activities (Table 2-1 and 
Table 2-2). 
9.2.11 
Optional Substudies 
Optional substudies include skin punch biopsies (biomarker) and the sample for DNA 
analysis (pharmacogenetics).  Obtain confirmation that the optional substudy ICF has 
been signed prior to performing any optional substudy procedures. 
9.2.12 
Other Assessments  
Not applicable to this study. 
10. 
Statistical Considerations 
10.1 
Sample Size Determination 
In Part A of this study, a total of 240 subjects will be randomized in a 1:1:1:1 ratio to 
tezepelumab 420 mg SC Q2W, 280 mg SC Q2W, 210 mg SC Q4W, and placebo 
(approximately 60 in each group).  There is at least 85% power for each co-primary 
endpoint, assuming IGA 0/1 response rates of 10% and 40% for placebo and the highest 
tezepelumab dose group (420 mg SC Q2W), respectively, and assuming EASI response 
rates of 15% and 50%, respectively.  These assumed treatment effects are based on the 
results of other new agents in this indication (DUPIXENT, 2017).  These calculations 
used a 2-sided χ2 test at a significance level of 0.025 (to reflect the Bonferonni-based 
gatekeeping procedure described in Section 10.3.2.1) and assumed a 10% dropout rate. 
Part B of this study is exploratory.  A sample size of 60 subjects (40 in the tezepelumab 
420 mg SC Q2W group and 20 in the placebo group) was chosen as an adequate 
sample size to provide initial evidence of tezepelumab as a promising agent for adjunct 
therapy.   


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10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
Part A and Part B of the study will be analyzed separately, therefore, the analysis sets 
described below will be created for each study part. 
10.2.1.1 
Full Analysis Set 
The full analysis set will include all randomized subjects.  Subjects will be analyzed 
according to their randomized treatment group.  Demographics, baseline disease 
characteristics, and efficacy analyses will be based on the full analysis set. 
10.2.1.2 
Safety Analysis Set 
The safety analysis set will consist of all randomized subjects who receive at least 
1 dose of investigational product.  Subjects will be analyzed according to the actual 
treatment received.  The safety analyses described in Section 10.3.2.3 will be based on 
the safety analysis set. 
10.2.1.3 
PK Analysis Set 
Subjects who receive investigational product and have a sufficient number of serum 
concentration measurements for computing PK parameters will be included in the PK 
analysis set and subjects will be analyzed according to the treatment they actually 
receive. 
10.2.2 
Covariates 
The analysis of the primary endpoints will be adjusted for the following baseline 
covariates: 
 
Baseline EASI (for EASI 75 at week 16) 
 
Baseline IGA (for IGA 0/1 at week 16) 
Additional covariates may be considered in exploratory analyses and will be described in 
the Statistical Analysis Plan (SAP). 
10.2.3 
Subgroups 
This study is not powered to draw conclusions from subgroup analyses.  However, 
exploratory subgroup analyses based on the covariates above will be conducted to 
examine the consistency of the treatment effect for the primary endpoints for Part A.  
Additional subgroups for Part A will be specified in the SAP.  Subgroup analyses are not 
planned for Part B. 


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10.2.4 
Handling of Missing and Incomplete Data 
Subjects missing data for the primary endpoints will be considered non-responders (ie, 
non-responder imputation).  The last observation carried forward and multiple imputation 
methods may also be considered in sensitivity analyses.  Similar methods will apply for 
the secondary endpoints EASI 50 and EASI 90 response.  For the change from baseline 
to week 16 secondary endpoints, subjects missing week 16 will have their last 
observation carried forward; multiple imputation and a completers analysis may also be 
considered in sensitivity analyses. 
10.3 
Statistical Analyses 
The SAP will be developed 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 
end of study, as defined in Section 5.3.1. 
10.3.1 
Planned Analyses 
10.3.1.1 
Interim Analysis and Early Stopping Guidelines 
For Part A, two interim analyses are planned when approximately 80 and 160 subjects 
complete their week 16 assessments, respectively.  
 
 
 
 
 
 
 
 
The interim analyses will be performed by an independent statistician.  The numerical 
results of the interim analyses will not be accessible to the study team.  The study team 
will only know whether the study will continue or will be terminated based on the results. 
For Part B, no interim analyses will be performed. 
10.3.1.2 
Primary Analysis 
The primary analysis will occur when the primary completion date described in 
Section 5.3.1 has been observed, and the data have been entered, cleaned, and locked.  
The objective for the primary analysis is to assess safety and efficacy through week 16 
for Part A only. 


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10.3.1.3 
Exploratory Analysis for Part B 
For Part B of this study, an exploratory analysis will occur when all subjects have 
completed the week 16 assessments, and the data have been entered, cleaned, and 
locked.  The objective for this exploratory analysis is to assess safety and efficacy 
through week 16 for Part B only. 
10.3.1.4 
Final Analysis 
The final analysis will occur when the end of study date described in Section 5.3.1 has 
been observed, and the data have been entered, cleaned, and locked.  The final 
analysis will analyze efficacy and safety over the entire study period for Part A and 
Part B.  For this analysis, Part A and Part B will be analyzed separately.  However, some 
additional analyses (eg, adverse event summaries) may combine Part A and Part B; if 
performed, these analyses will be described in the SAP. 
10.3.2 
Methods of Analyses 
10.3.2.1 
General Considerations 
Subject disposition, demographics, and baseline disease characteristics will be 
summarized descriptively by randomized treatment group.  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 Part A, the treatment effect for the primary analysis of the primary endpoints will be 
tested using a Bonferonni-based gatekeeping procedure to control the family-wise 
2-sided type I error rate at 0.05.  The procedure splits the  of 0.05 equally to test in 
parallel tezepelumab 420 mg SC Q2W versus placebo, and tezepelumab 280 mg SC 
Q2W versus placebo for IGA 0/1 and EASI 75 sequentially within each parallel path.  If 
one of the parallel paths rejects the 2 hypotheses sequentially, and the other path has at 
least 1 hypothesis not rejected, then the unspent  of 0.025 from the successful path will 
be propagated to the unsuccessful path to retest the 2 hypotheses sequentially at a level 
of 0.05.  This procedure is illustrated in Figure 10-1. 


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Figure 10-1.  Alpha Split Between Two Doses of Interest 
       Bonferroni 
         Parallel Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For all other endpoints in Part A and B, significance testing, if performed, will be 
considered descriptive. 
Hypothesis A1:  No treatment 
difference in IGA 0/1 between      
420 mg Q2W and Placebo         
(2-sided,  = 0.025)              
Hypothesis A2:  No treatment 
difference in IGA 0/1 between      
280 mg Q2W and Placebo         
(2-sided,  = 0.025)              
Hypothesis B1:  No treatment 
difference in EASI 75 between     
420 mg Q2W and Placebo         
(2-sided,  = 0.025)              
Hypothesis B2:  No treatment 
difference in EASI 75 between     
280 mg Q2W and Placebo         
(2-sided,  = 0.025)              
Hypothesis A2 Retested:       
No treatment difference in IGA 
0/1 between   
280 mg Q2W and Placebo         
(2-sided,  = 0.05)               
Hypothesis B2 Retested:       
No treatment difference in EASI 
75 between            
280 mg Q2W and Placebo         
(2-sided,  = 0.05)               
Hypothesis A1 Retested:       
No treatment difference in IGA 
0/1 between             
420 mg Q2W and Placebo         
(2-sided,  = 0.05)               
Hypothesis B1 Retested:       
No treatment difference in EASI 
75 between             
420 mg Q2W and Placebo         
(2-sided,  = 0.05)               
                        Null hypothesis is rejected                                     Null hypothesis is not rejected     


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10.3.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
For the primary endpoints of IGA 0/1 and EASI 75 at week 16, the 
treatment effect will be tested using a logistic regression model 
adjusting for covariates specified in Section 10.2.2.  From this model, 
odd ratios and 95% CIs will be reported comparing each tezepelumab 
dose group to placebo.  In addition, the percentage of subjects in each 
treatment group with a response and the difference in the percentage 
of subjects responding between each tezepelumab dose group and 
placebo will be summarized with a 95% confidence interval. 
Secondary 
The analysis of secondary endpoints will be descriptive and details will 
be provided in the SAP. 
Exploratory 
Details of the analysis of exploratory endpoints will be specified in the 
SAP. 
 
10.3.2.3 
Safety Analyses 
10.3.2.3.1 
Adverse Events and Disease-related Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product or other 
protocol-required therapies, and significant treatment-emergent adverse events will also 
be provided.  Subject incidence of disease-related events, if applicable, will be tabulated 
by system organ class and preferred term. 
10.3.2.3.2 
Laboratory Test Results 
Laboratory parameters will be summarized descriptively by treatment group and visit.  
Grade 0 through 4 toxicities, as defined by the CTCAE, version 5.0 (or most recent 
version) will be presented for each laboratory parameter when available. 
10.3.2.3.3 
Vital Signs 
Vital signs will be summarized by treatment group. 


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10.3.2.3.4 
Exposure to Investigational Product 
Exposure to investigational product will be summarized by treatment group.  The 
summary of study drug exposure will include descriptive statistics for the number of 
study drug doses administered, total amount of study drug exposure.  Additional details 
will be provided in the SAP. 
10.3.2.3.5 
Exposure to Other Protocol-required Therapy 
Descriptive statistics will be produced to describe the exposure to TCS following day 1 to 
end of study. 
10.3.2.3.6 
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 (WHODRUG) 
dictionary. 
10.3.2.4 
Other Analyses 
Not applicable. 


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11. 
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Beck LA, Leung DY.  Allergen sensitization through the skin induces systemic allergic 
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Bieber T, Leung DY, editors.  Atopic dermatitis.  New York:  Marcel Dekker, 2002. 
Breuer K, Braeutigan M, Kapp A, et al.  Influence of pimecrolimus cream 1% on different 
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Brooks R. EuroQol: the current state of play.  Health Policy.  1996; 37(1):  53-72. 
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Demehri S, Morimoto M, Holtzman MJ, Kopan R.  Skin-derived TSLP triggers 
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Hanifin JM, Reed ML.  Eczema Prevalence and Impact Working Group. A 
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18(2):82-91. 
Hanifin JM, Rajka G.  Diagnostic features of atopic dermatitis.  Acta Derm Venereol 
Suppl (Stockh).  1980; 92:44-47. 
He R, Oyoshi MK, Garibyan L, Kumar L, Ziegler SF, Geha RS.  TSLP acts on infiltrating 
effector T cells to drive allergic skin inflammation.  Proc Natl Acad Sci.  USU 2008; 105; 
33:11875-11880. 
Hijnen D, De Bruin-Weller M, Oosting B, et al.  Serum thymus and activation-regulated 
chemokine (TARC) and cutaneous T cell-attracting chemokine (CTACK) levels in allergic 
diseases: TARC and CTACK are disease-specific markers for atopic dermatitis.  J 
Allergy Clin Immunol.  2004; 113(2):334-340. 
Kiebert G, Sorensen SV, Revicki D, Fagan SC, Doyle JJ, Cohen J, et al.  Atopic 
dermatitis is associated with a decrement in health-related quality of life.  Int J Dermatol.  
2002; 41(3):151-158. 
Kim J, Kim BE, Lee J, et al.  Epidermal thymic stromal lymphopoietin predicts the 
development of atopic dermatitis during infancy.  J Allergy Clin Immunol.  2016; 
137(4):1282-1285. 


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Kunz B, Oranie AP, Labreze L et al.  Clinical validation and guidelines for the SCORAD 
index :  consensus report of the European Task Force on Atopic Dermatitis.  
Dermatology.  1997; 195(1):10-19. 
Novak N, Bieber T.  Allergic and nonallergic forms of atopic diseases.  J Allergy Clin 
Immunol.  2003; 112(2):252-262. 
Oh MH, Oh SY, Yu J, Myers AC, Leonard WJ, Liu YJ et al.  IL-13 induces skin fibrosis in 
atopic dermatitis by thymic stromal lymphopoietin.  J Immunol.  2011; 186:7232-7242. 
Ring J, Alomar A, Bieber T, Deleuran M, Fink-Wagner A, Gelmetti C, et al; European 
Dermatology Forum (EDF); European Academy of Dermatology and Venereology 
(EADV); European Federation of Allergy (EFA); European Task Force on Atopic 
Dermatitis (ETFAD); European Society of Pediatric Dermatology (ESPD); Global Allergy 
and Asthma European Network (GA2LEN). Guidelines for treatment of atopic eczema 
(atopic dermatitis) part I.  J Eur Acad Dermatol Venereol.  2012; 26(8):1045-1060. 
Schmitt J, Langan S, Williams HC; European Dermato-Epidemiology Network.  What are 
the Best Outcome Measurements for Atopic Eczema?  A Systematic Review.  J Allergy 
Clin Immunol.  2007; 120:1389-1398.  
Shimada Y, Takehara K, Sato S.  Both Th2 and Th1 chemokines (TARC/CCL17, 
MDC/CCL22, and Mig/CKCL9) are elevated in sera from patients with atopic dermatitis. 
J Dermatol Sci.  2004; 34(3):201-208. 
Silverberg JI, Hanifin JM.  Adult eczema prevalence and associations with asthma and 
other health and demographic factors:  A US population-based study.  J Allergy Clin 
Immunol.  2013; 132:1132-1138.   
Silverberg JI, Silverberg NB, Lee-Wong M.  Association between atopic dermatitis and 
obesity in adulthood.  Br J Dermatol.  2012; 166(3):  498-504. 
Simpson EL, Beiber T, Guttman-Yassky LA, Beck A, Blauvelt MJ, Cork JI, et al.  Two 
phase 3 trials of Dupilumab versus placebo in atopic dermatitis.  N Engl J Med.  2016; 
375(24):2335-2348. 
Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al.  Human 
epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP.  
Nat Immunol.  2002; 3(7):673-680. 
Spergel JM, AS Paller.  Atopic dermatitis and the atopic march.  J Allergy Clin Immunol.  
2003; 112(6 suppl):S118-S127. 
Tezepelumab Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
Yoo J, Omori M, Gyarmati D, Zhou B, Aye T, Brewer A, et al.  Spontaneous atopic 
dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene 
specifically in the skin.  J Exp Med.  2005; 4:541-549. 
Zhang Z, Hener P, Frossard N, Kato S, Metzger D, Li M, et al.  Thymic stromal 
lymphopoietin overproduced by keratinocytes in mouse skin aggravates experimental 
asthma.  PNAS.  2009; 106(5):1536-1541. 
Zheng T, Yu J, Oh MH, Zhu Z.  The Atopic March:  Progression from Atopic Dermatitis to 
Allergic Rhinitis and Asthma.  Allergy Asthma Immunol Res.  2011; 3(2):67-73. 


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12. 
Appendices 


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Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AD 
atopic dermatitis 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibody 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-7d 
area under the curve from day 0 to day 7 
AUC0-28d 
area under the curve from day 0 to day 28 
CBC 
complete blood count 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum observed serum concentration 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
drug induced liver injury  
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
EASI 50 
50% reduction from baseline in EASI score 
EASI 75 
75% reduction from baseline in EASI score 
EASI 90 
90% reduction from baseline in EASI score 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
Enrollment 
A subject is considered enrolled when the investigator decides 
that the subject has met all eligibility criteria at the screening visit 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the 
primary endpoint(s), 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 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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Abbreviation or Term 
Definition/Explanation 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
EOI 
event of interest 
EOT 
end of treatment 
EQ-5D-3L 
EuroQOL quality of life 5-dimensions 3-level version 
eSAE 
Electronic Serious Adverse Event 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
hormonal replacement therapy 
HRQoL 
Health-Related Quality of Life 
ICF 
informed consent form 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
ICH 
International Council for Harmonisation 
ID 
identification 
IFN 
interferon 
Ig 
immunoglobulin  
IGA 
Investigator’s Global Assessment 
IGA 0/1 
response of 0 (clear) or 1 (almost clear) skin on IGA scale 
IL 
interleukin 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Boards 
INR 
international normalized ratio 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
Interactive Voice Response 
System (IVRS) 
telecommunication technology that is linked to a central 
computer in real time as an interface to collect and process 
information   
Interactive Web Response 
System (IWRS) 
web based technology that is linked to a central computer in real 
time as an interface to collect and process information  
LDH 
lactate dehydrogenase 
LKM1 
liver kidney microsomal type 1 
NASH 
nonalcoholic steatohepatitis 
NRS 
numerical rating scale 
PD 
pharmacodynamics  
PGI-S 
Patient Global Impression of Severity 
PI 
principal investigator 


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Abbreviation or Term 
Definition/Explanation 
PK 
pharmacokinetics  
PRO 
patient-reported outcome 
POEM 
Patient Oriented Eczema Measure 
POR 
Proof of Receipts 
PPD 
purified protein derivate 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
QFT-G 
QuantiFERON-tuberculosis Gold 
Randomization 
A subject will undergo randomization upon meeting all eligibility 
criteria at the day 1 randomization visit 
S. aureus 
Staphylococcus aureus 
SAP 
statistical analysis plan 
SAT 
safety assessment team 
SC 
subcutaneous 
SCORAD 
Scoring of Atopic Dermatitis 
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. 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
tuberculosis  
TBL 
total bilirubin 
TCI 
topical calcineurin inhibitors 
TCS 
topical corticosteroids 
TSLP 
thymic stromal lymphopoietin 
ULN 
upper limit of normal 
WHODRUG 
World Health Organization Drug Dictionary 
 


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Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 12-1 will be performed by the central laboratory and/or by the 
local laboratory.  
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study treatment administration and/or response 
evaluation.  If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 6.1 to 6.2 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. 


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Table 12-1.  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 
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 
HLA typing 
Hep B surface 
antigen 
Hep C antibody 
HIVa 
Skin biopsyb 
IgE 
IgA 
IgG 
IgM 
Serum Pregnancy 
PPD or 
Quantiferon Gold 
Local Laboratory: 
Urine Pregnancy 
ALT = alanine aminotransferase; ALP = alkaline phosphatase; 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; I 
NR = international normalized ratio; LDH = lactate dehydrogenase; LDL = low density lipoprotein;  
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration;  
MCV = mean corpuscular volume; 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 HIV assessment is recommended. 
b Skin biopsy may be sent to a central lab for holding, then sent to a specialty lab for analysis. 
Laboratory/analyte results that could unblind the study will not be reported to 
investigative study centers or other blinded personnel until the study has been 
unblinded.  Only eosinophils on complete blood count and differential are considered 
unblinding data for this study and will not be reported to the site post-randomization. 


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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 (CIOMS) International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable 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)/Institutional Ethics Committee (IEC) 
by the investigator and reviewed and approved by the IRB/IEC.  A copy of the written 
approval of the protocol and informed consent form 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 study center. 
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 study center, 
deviations from the protocol or other adverse event reports received from Amgen, in 
accordance with local procedures 
 
Overall conduct of the study at the study center 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 
Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her study center.  Updates to the 
sample informed consent form are to be communicated formally in writing from the 


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Amgen Trial Manager to the investigator.  The written informed consent form 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 or their legally 
authorized representative (defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study) 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 (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
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 informed consent form 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 8. 


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Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(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 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9.) 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  The investigator or authorized designee will 
explain to each subject the objectives of the exploratory research.  Subjects will be told 
that they are free to refuse to participate and may withdraw their 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 
exploratory 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 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 informed consent forms) 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(ies), 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 (ICMJE) 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. 


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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 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 study center personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 


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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.  
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 & Development Compliance 
and Audit function (or designees).  Inspection of study center 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. 
CRFs must be completed in English.  TRADENAMES® (if used) for concomitant 
medications may be entered in the local language.  Consult the country-specific 
language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
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 study 
center. 
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, 


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and correspondence.  Source documents may also include data captured in the 
Interactive Voice Response System (IVRS)/Interactive Web Response System (IWRS) 
system (if used, such as subject identification (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. 
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, informed consent forms, 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 (POR), 
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 center 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 


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notify the IRB/IEC in writing of the study’s completion or early termination 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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Appendix 4.  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting 
Definition of Disease-related Event 
Disease-related Event Definition 
 
Disease-related events are events (serious or non-serious) anticipated to occur in 
the study population due to the underlying disease.  See Section 9.2.3.1.1.1 for the 
list of disease-related events.  All serious disease-related events will be recorded 
and reported to the sponsor or designee within 24 hours. 
 
Disease-related events that would qualify as an adverse event or serious adverse 
event: 
o An event based on the underlying disease that is worse than expected as 
assessed by the investigator for the subject’s condition or if the investigator 
believes there is a causal relationship between the investigational 
product(s)/study treatment/protocol-required therapies and disease worsening, 
this must be reported as an adverse event or serious adverse event. 
 
Disease-related events that do not qualify as adverse events or serious adverse 
events:  
o An event which is part of the normal course of disease under study (eg, 
disease progression in oncology or hospitalization due to disease progression) 
is to be reported as a disease-related event.   
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. 
 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram [ECG], 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. 


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Events Meeting the Adverse Event Definition 
 
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. 
 
 “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, 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.  
 
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. 
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 


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A Serious Adverse Event is defined as any untoward medical occurrence 
that, meets at least 1 of the following serious criteria: 
“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 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. 
Definition of Adverse Device Effect 
The detection and documentation procedures for adverse device effects described in 
this protocol apply to all Amgen medical devices provided for use in the study (see 
Section 7.1.3 for the list of Amgen medical devices). 
Adverse Device Effect Definition 
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include adverse events resulting 


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Adverse Device Effect Definition 
from insufficient or inadequate instructions for use, adverse events resulting from any 
malfunction of the device, or adverse events resulting from use error or from 
intentional misuse of the device. 
Recording Adverse Events, Disease-related Events (if applicable), and Serious 
Adverse Events 
Adverse Event, Disease-related Event (if applicable) and Serious Adverse Event 
Recording 
 
When an adverse event, disease-related 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/disease-related 
event/serious adverse event information in the Event case report form (CRF). 
o Additionally, the investigator is required to report a fatal disease-related event 
on the Event 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, or devices; 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 contact 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: 
The Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 which is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product, protocol-required therapies, device(s), and/or study-mandated procedures 
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 study center will 
report the information to Amgen using an Electronic Serious Adverse Event (eSAE) 
Contingency Form (paper form; see Figure 12-1) within 24 hours of the 
investigator’s knowledge of the event. 
 
The study center 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 study center, the EDC system will be taken 
off-line to prevent the entry of new data or changes to existing data. 
 
If a study center 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 study center can report this 
information on an Electronic Serious Adverse Event Contingency Form (paper 
form; see Figure 12-1). 
Adverse Device Effects:  Recording, Evaluating and Reporting 
 
Any adverse event resulting from an adverse device effect that occur during the 
study will be documented in the subject’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the Event CRF page. 
 
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by Amgen) at the time of the initial 
report and describes any corrective or remedial actions taken to prevent recurrence 
of the incident. 


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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form 
 
 


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Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and Lactation 
Information 
Study-specific contraception requirements for male and female subjects of childbearing 
potential are outlined in Section 6.2. 
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 
16 weeks 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 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 postmenopausal 
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 (IUD) 
 
Intrauterine hormonal-releasing system (IUS) 
 
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) 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhea method 
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 following the 
final administration of study drug. 
 
Information will be recorded on the Pregnancy Notification Worksheet (see 
Figure 12-2).  The worksheet 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 Worksheet 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 
following the final dose of the study drug.  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). 


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 
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 
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 Appendix 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 8.1 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 an additional 
16 weeks after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Worksheet.  The worksheet (see 
Figure 12-2) must be submitted to Amgen Global Patient Safety within 24 hours of 
the study center’s awareness of the pregnancy.  (Note:  Sites are not required to 
provide any information on the Pregnancy Notification Worksheet 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. 


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Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 16 weeks following the final 
administration of study drug. 
 
Information will be recorded on the Lactation Notification Worksheet (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 225. 
 
With the female subjects signed authorization for release of mother and infant 
health information, the investigator will collect mother and infant health information 
and complete the lactation questionnaire on any female subject who breastfeeds 
while taking protocol-required therapies through 16 weeks after discontinuing 
protocol-required therapies. 


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Figure 12-2.  Pregnancy and Lactation Notification Worksheet 
 


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Appendix 6.  Sample Storage and Destruction 
Any blood, biomarker, PK, DNA, or RNA sample collected according to the Schedule of 
Activities (Table 2-1 and Table 2-2) 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 study 
center 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 
moderate-to-severe atopic dermatitis (AD), the dose response and/or prediction of 
response to tezepelumab with or without TCS, 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 pharmacogenetic, biomarker development, 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 
(sample types [eg, blood, tumor]) 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 
Appendix 3 for subject confidentiality. 


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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 
 
Nonalcoholic fatty liver disease including steatohepatitis (NASH) 
 
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 12-2.  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 
> 3 x ULN  
at any time 
> 2 x ULN 
 
 
OR 
INR 
-- 
> 1.5 x ULN (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
> 5 x ULN but < 8 x ULN for ≥ 2 weeks 
> 5 x ULN but < 8 x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3 x 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 
> 3 x ULN (when baseline was < ULN) 
 
OR 
 
ALP 
> 8 x 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 tezepelumab is to be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Table 12-2) are never to be rechallenged. 


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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: 
 
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 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 Appendix 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 12-2 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 (total and direct), and INR within 24 hours  
 
In cases of TBL > 2 x 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 (CBC) with differential to assess for eosinophilia 
 
Serum total immunoglobulin G (IgG), anti-nuclear antibody (ANA), anti smooth 
muscle antibody, and liver kidney microsomal antibody -1 (LKM1) to assess for 
autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
Page 107 of 107 
CONFIDENTIAL 
 
 
 
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 
 
Viral serologies 
 
Creatine phosphokinase (CPK), haptoglobin, lactate dehydrogenase (LDH), and 
peripheral blood smear 
 
Appropriate liver imaging if clinically indicated 
 
Appropriate blood sampling for pharmacokinetic 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.  


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  25 August 2020 
Page 1 of 6 
Amendment no. 3 
Protocol Title:  A Dose-Ranging, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety and Efficacy of Tezepelumab Alone or Combined With Topical Corticosteroids in 
Moderate-to-Severe Atopic Dermatitis 
Amgen Protocol Number Tezepelumab 20170755 
 
Amendment Date: 
25 August 2020 
 
Rationale: 
The Protocol has been amended to update the safety language pertaining to the Pregnancy and 
Lactation information for female subjects and female partners. 
 
Female subjects and female partners of male subjects will now be required to refrain 
from becoming pregnant or breastfeeding until additional 16 weeks after the last dose of 
tezepelumab, instead of 14 weeks. 
 
Female subjects and female partners of male subjects’ pregnancies must also be 
reported for an additional 16 weeks after the subject’s last dose of tezepelumab, instead 
of 14 weeks. 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  04 September 2019 
Page 1 of 14 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Dose-ranging, Double-blind, Placebo Controlled Study to 
Evaluate the Safety and Efficacy of Tezepelumab Alone or Combined with Topical 
Corticosteroids in Moderate-to-Severe Atopic Dermatitis 
 
Amgen Protocol Number (Tezepelumab) 20170755 
 
Amendment Date: 
04 September 2019 
 
Rationale: 
The main purpose of this protocol amendment is two fold:  1) to address 
Amgen-mandated updates to the collection and reporting of disease-related events; and 
2) align the male contraception language in the protocol with the updated contraception 
guidance in the Tezepelumab Investigator’s Brochure. 
Other minor, protocol clarifications and inconsistencies were updated during this 
amendment. 
Approved 
 
 


Product:  Tezepelumab 
Protocol Number:  20170755 
Date:  20 November 2018 
Page 1 of 22 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Dose-Ranging, Double-Blind, Placebo Controlled Study to 
Evaluate the Safety and Efficacy of Tezepelumab Alone or Combined With Topical 
Corticosteroids in Moderate-to-Severe Atopic Dermatitis 
 
Amgen Protocol Number (Tezepelumab) 20170755 
 
Amendment Date: 
20 November 2018 
 
Rationale: 
The main purpose of this protocol amendment is to address regulatory questions from 
EU VHP EU VHP-No:  VHP1358 (VHP2018120) - RTQ submitted 06 Nov 2018 and to 
correct minor editorial changes and errors. 
The major changes to the protocol are outlined below: 
 
Updated the safety follow-up period in response to RTQ Amended protocol from 
VHP to address GNA #55 by extending follow up period to 20 weeks after last 
dose. 
 
Added additional descriptive statistics for continuous endpoints in response to 
RTQ Amended protocol from VHP to address GNA #38. 
 
Added PPD or Quantiferon GOLD testing at screening and EOT/ET visits as 
requested by VHP RTQ #5, 19, and 20. 
 
Updated inclusion criterion 107 as a recommendation from study sites and KOLs 
as restriction of moisturizer type would impact recruitment and not influence 
efficacy. 
 
Updated exclusion criterion 215 in response to RTQ Amended protocol from VHP 
to address GNA #23. 
 
Removed language regarding receiving treatment with systemic corticosteroids 
or nonsteroidal systemic immunosuppressive drugs after week 16 in response to 
RTQ Amended protocol from VHP to address GNA #26, 45, 52, 53. 
 
Updated interim analysis guidelines in response to RTQ Amended protocol from 
VHP to address GNA #54. 
 
Updated contraception guidance in response to RTQ Amended protocol from 
VHP to address GNA #46. 
Approved 
 
 

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