Clinical trial NCT04212169
Conditions: Atopic Dermatitis
Keywords: MEDI3506 Safety Efficacy Atopic Dermatitis Eczema
Sponsor: AstraZeneca
Start date: 2019-12-09; Completion date: 2022-09-20
Enrollment: 148 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a research study to determine the efficacy and safety of investigational drug MEDI3506 for the treatment of adult subjects with Atopic Dermatitis.

Detailed description:
This is a research study to determine the efficacy and safety of investigational drug MEDI3506 for the treatment of adult subjects with Atopic Dermatitis.

Each participant will be assigned randomly to a treatment arm, which could be different strengths of the active treatment or a placebo which does not contain active treatment. Both Participants and investigators will be masked to the treatment assignment.

Approximately 152 participants will take part in this study. There is a 4 weeks screening period to determine eligibility. After eligibility is confirmed, participants will receive investigational drug or placebo during the 16 weeks treatment period. This is then followed by an 8-week follow-up period.

Arms: arm 1: Participant will receive multiple doses of MEDI3506 at dose level 1. arm 2: Participant will receive multiple doses of MEDI3506 at dose level 2. arm 3: Participant will receive multiple doses of MEDI3506 at dose level 3. arm 4: Participant will receive multiple doses of Placebo
Interventions: intervention 1: MEDI3506 intervention 2: Placebo
Intervention descriptions: intervention 1: multiple doses intervention 2: multiple doses

Protocol documents:
Prot_000.pdf: 
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A Phase 2 Randomized, Double-blinded, Placebo-controlled Study 
to Evaluate the Efficacy and Safety of MEDI3506 in Adult 
Subjects with Moderate-to-severe Atopic Dermatitis
Sponsor Protocol Number: D9182C00001
Application Number:
IND number 141236
EudraCT number 2019-003304-12
Investigational Product:
MEDI3506
Sponsor:
AstraZeneca AB, SE-151 85, Södertälje, Sweden
Medical Monitor:
Contract Research Organization:
ICON
Protocol History, Date:
Original Protocol, 02Sep2019
Amendment 1, 01Oct2019
Amendment 2, 24Oct2019
Amendment 3, 13Jan2020
Amendment 4, 27Mar2020
Amendment 5, 03Jun2020
Amendment 6, 07Sep2020
Amendment 7, 29Oct2020
Amendment 8, 23Feb2021
Amendment 9, 15Jun2022
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorization from AstraZeneca.
PPD
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Disclosure
privileged or 
privileged or 
aZeneca.
aZeneca.


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PROTOCOL SYNOPSIS
TITLE
A Phase 2 Randomized, Double-blinded, Placebo-controlled Study to Evaluate the Efficacy and Safety of 
MEDI3506 in Adult Subjects with Moderate-to-severe Atopic Dermatitis
HYPOTHESES
Primary Hypothesis:
Atopic dermatitis (AD) disease severity will be decreased in adult subjects with moderate-to-severe AD 
administered MEDI3506 compared with placebo.
Secondary Hypotheses:
In adult subjects with moderate-to-severe AD:
•
AD disease severity and symptoms, as measured by additional endpoints, will be decreased in subjects 
administered MEDI3506 compared with placebo.
•
MEDI3506 will be safe and well tolerated compared with placebo.
•
The pharmacokinetic (PK) profile will support further clinical development of MEDI3506.
•
The immunogenicity profile will support further clinical development of MEDI3506.
OBJECTIVES AND ENDPOINTS
Type
Objective
Endpoint
Primary
Efficacy
To assess the effects of 
MEDI3506 compared with 
placebo on AD disease severity, 
in adult subjects with 
moderate-to-severe AD.
Percent change from baseline to Week 16 in EASI 
score.
Secondary
Efficacy
To further assess the effects of 
MEDI3506 compared with 
placebo on AD disease severity 
and symptoms, in adult subjects 
with moderate-to-severe AD.
•
EASI:
!
Percentage of subjects achieving a 90% 
reduction from baseline in EASI score 
(EASI 90) at Week 16.
!
Percentage of subjects achieving a 75% 
reduction from baseline in EASI score 
(EASI 75) at Week 16.
!
Percentage of subjects achieving a 50% 
reduction from baseline in EASI score 
(EASI 50) at Week 16.


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•
Percentage of subjects achieving an IGA of 
0 (clear) or 1 (almost clear) with at least a 
2 grade reduction from baseline score at 
Week 16.
•
Peak pruritus NRS: Percentage of subjects 
achieving a reduction of ≥3 from baseline to 
Week 16 in weekly mean of daily peak 
pruritus NRS.
•
Peak pruritus NRS: Change from baseline to 
Week 16 in weekly mean of daily peak 
pruritus NRS.
•
Skin pain NRS: Change from baseline to 
Week 16 in weekly mean of daily peak skin 
pain NRS.
•
SCORAD: Percent change from baseline to 
Week 16.
•
PGI-S at Week 16.
•
Change from baseline to Week 16 in:
!
% BSA affected by AD.
!
5-D itch.
!
POEM.
!
DLQI.
Safety
To assess the safety and 
tolerability of MEDI3506 
compared with placebo, in adult 
subjects with moderate-to-severe 
AD.
During the treatment and follow-up periods:
•
TEAEs and TESAEs.
•
Vital signs.
•
Safety laboratory analysis.
•
ECGs. The following parameters will be 
recorded for each ECG: 
!
Date and time of ECG.
!
Heart rate (beats/min).
!
QT (ms).
!
Overall evaluation (normal/abnormal).
•
Left ventricular ejection fraction as 
measured by echocardiogram.
PK
To evaluate the PK of 
MEDI3506 in adult subjects with 
moderate-to-severe AD.
Serum MEDI3506 concentration profiles during 
the treatment and follow-up periods.
Immunogenicity
To evaluate the immunogenicity 
of MEDI3506 in adult subjects 
with moderate-to-severe AD.
Incidence of ADA during treatment and follow-up 
periods.
Exploratory
Efficacy
To assess the effects of 
MEDI3506 compared with 
placebo on AD disease severity 
and symptoms over time to 
Week 24, in adult subjects with 
moderate-to-severe AD.
•
EASI:
!
Percentage of subjects achieving a 
90% reduction from baseline in EASI 
score (EASI 90) at Weeks 2, 4, 8, 12, 
20, and 24.


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!
Percentage of subjects achieving a 
75% reduction from baseline in EASI 
score (EASI 75) at Weeks 2, 4, 8, 12, 
20, and 24.
!
Percentage of subjects achieving a 
50% reduction from baseline in EASI 
score (EASI 50) at Weeks 2, 4, 8, 12, 
20, and 24.
!
Percent change from baseline to 
Weeks 2, 4, 8, 12, 20, and 24 in EASI 
score.
•
IGA: Percentage of subjects achieving an 
IGA of 0 (clear) or 1 (almost clear) with at 
least a 2 grade reduction from baseline score 
at Weeks 2, 4, 8 ,12, 20, and 24.
•
Peak pruritus NRS: Reduction of ≥3 from 
baseline to Weeks 2, 4, 8, 12, 20, and 24 in 
weekly mean of daily peak pruritus NRS.
•
Peak pruritus NRS: Reduction of ≥4 from 
baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 
in weekly mean of daily peak pruritus NRS.
•
Peak pruritus NRS: Change from baseline to 
Weeks 2, 4, 8, 12, 20, and 24 in the weekly 
mean of daily peak pruritus NRS.
•
Skin pain NRS: Change from baseline to 
Week 2, 4, 8, 12, 20, and 24 in weekly mean 
of daily peak skin pain NRS.
•
SCORAD: Percent change from baseline to 
Weeks 2, 4, 8, 12, 20, and 24.
•
PGI-S at Weeks 2, 4, 8, 12, 20, and 24.
•
Change from baseline to Weeks 2, 4, 8, 12, 
20, and 24 in:
!
% BSA affected by AD.
!
5-D itch.
!
POEM.
!
DLQI.


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Biomarkers
To evaluate the effect of 
MEDI3506 on blood biomarkers
that may either predict or reflect 
an efficacy response in adult 
subjects with moderate-to-severe 
AD.
•
Change from baseline to Week 16 in serum 
concentrations of:
!
sST2.
!
•
Change from baseline to Week 16 in whole 
blood PBMC subsets
•
Change from baseline to Weeks 1, 2, 4, 8, 
12, 16, 20, and 24 in serum biomarker 
levels, including but not limited to:
!
Eosinophils.
!
IL-5.
!
IL-13.
!
CCL17.
•
Change from baseline to Weeks 1, 2, 4, 16, 
20 and 24 in serum IL-33 bound to 
MEDI3506.
•
Change from baseline to Weeks 2, 8, 16, and 
24 in serum IgE levels.
•
Change from baseline to Week 16 in 
proinflammatory gene signatures in whole 
blood.
•
Change from baseline to Weeks 4, 16, and 
24 in plasma EDN levels.
Biomarkers
To evaluate the effect of 
MEDI3506 on skin biomarkers
that may either predict or reflect 
an efficacy response in adult 
subjects with moderate-to-severe 
AD.
•
Colonization of pathogenic bacteria (ie, 
Staphylococcus aureus) in lesional and 
non-lesional skin, from baseline to Week 16.
•
From baseline to Week 16 in lesional and 
non-lesional skin:
!
Proinflammatory gene signatures in 
tape strips and biopsies.
!
Gross inflammation evaluation.
Efficacy
To assess the effect of 
MEDI3506 compared with 
placebo on the need for rescue 
therapy, in adult subjects with 
moderate-to-severe AD.
•
Proportion of subjects requiring rescue 
therapy during the treatment and follow-up 
periods.
•
Time to first use of rescue therapy 
throughout the treatment and follow-up 
periods.
•
Incidence of skin infection TEAEs requiring 
systemic treatment during the treatment and 
follow-up periods.
Efficacy
To evaluate the effect of 
MEDI3506 compared with 
placebo on nasal symptom 
control, in a subset of adult 
subjects with moderate-to-severe 
AD and comorbid chronic 
inflammatory conditions of the 
nasal mucosa and/or paranasal 
sinuses.
Change from baseline to Week 16 and 24 in 
SNOT-22.
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3
Follow-up period: Safety, sustained efficacy, and the need for rescue therapy will be assessed in the 
follow-up period. Subjects will be required to apply moisturizers twice daily through to the end of the 
follow-up period at Visit 12 (Week 24), and will not be permitted to use TCSs and TCIs, except if 
medically necessary.
The primary analysis will occur once all subjects have either completed the Visit 10 (Week 16) assessments or 
have withdrawn from the study. The final analysis will occur when all subjects have completed the follow up 
period at Visit 12 (Week 24) or have withdrawn from the study.
TARGET SUBJECT POPULATION
Subjects aged 18 to 65 years inclusive with chronic, moderate-to-severe AD; with documented recent history of 
inadequate response to topical medications for AD, intolerance to treatment with topical medications for AD, or 
for whom topical medications are otherwise medically inadvisable.
TREATMENT GROUPS AND REGIMENS
At Visit 3 (Day 1), eligible subjects will be randomized to receive SC investigational product 
 
 as follows:
•
MEDI3506 
58 subjects),
•
MEDI3506 
 (18 subjects),
•
MEDI3506 
 (18 subjects),
•
Placebo 
 (6 subjects), or
•
Placebo 
 (52 subjects).
STATISTICAL METHODS
General Considerations:
The placebo 
 groups will be pooled for planned analyses, except where stated otherwise. 
Categorical data will be summarized by the number and percentage of subjects in each category. Continuous 
variables will be summarized by descriptive statistics including number of subjects, mean, standard deviation 
(SD), median, minimum, and maximum.
The study populations that will be used in the reporting of the study include the intent-to-treat (ITT), As-treated,
and PK populations. The ITT population will be used to summarize demographic and baseline characteristics, 
concomitant medications, and efficacy endpoints. The As-treated population will be used to summarize safety 
endpoints (adverse events [AEs], laboratory tests, electrocardiograms [ECGs], left ventricular ejection fraction, 
and vital signs), and will be used for other endpoints unless otherwise stated. The PK population will be used to 
summarize PK endpoints.
Sample Size:
A sample size of 144 subjects in an overall 3:1:1:3 ratio of MEDI3506 
:MEDI3506 
:MEDI3506 
: pooled placebo, will provide at least 90% power to detect a statistically significant difference in the 
percent change from baseline to Week 16 in Eczema Area and Severity Index (EASI) score between the highest 
dose of MEDI3506 and pooled placebo in a responder subgroup, assuming a 35% point difference between 
placebo and MEDI3506 at the highest dose, based on a SD of 40% points, a two-sided 10% alpha level, and 
50% of subjects in the responder subgroup. Based on identical assumptions, the sample size provides > 99% 
power to detect a statistically significant dose response in percent change from baseline to Week 16 in EASI 
score in all-comers.
The calculations for dose response assume that percent change from baseline to Week 16 in EASI score will 
increase monotonically with the administration of higher MEDI3506 doses. The power was calculated using a 
multiple comparison procedure with modelling techniques (MCP-Mod) with 4 candidate models for the dose 
response (linear, maximum effect attributable to the drug [Emax], and 2 Hill-Emax models). Randomization will 
be stratified by total immunoglobulin E (IgE) (< 150 kU/L or ≥150 kU/L) at screening.
To allow for the possibility that ≤5% of the subjects per treatment group may be ineligible for the ITT 
population, the total sample size will comprise approximately 152 subjects (58 for MEDI3506 
, 18 for 
MEDI3506 
, 18 for MEDI3506 
, and 58 for pooled placebo) randomized approximately to 
3:1:1:3 ratio overall to the treatment groups.
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Statistical Analyses:
Primary Efficacy Analysis
The primary efficacy endpoint is the percent change from baseline to Week 16 in EASI score. To assess the 
dose response at Week 16, percent change from baseline to Week 16 in EASI score will be analyzed using the 
mixed-effects model for repeated measures (MMRM) including data from visits up to Week 16. The model will 
include treatment group, randomization stratum (total IgE level < 150 kU/L or ≥150 kU/L), visit, and treatment 
group by visit interaction as categorical factors, with baseline EASI as a covariate and the baseline*visit 
interaction term. Visit will be a repeated factor within a subject and unstructured variance-covariance matrix 
will be used to describe the correlations between observations on a subject between visits. The coefficient of the 
treatment effects at Week 16 obtained from the MMRM will then be incorporated into an MCP-Mod, with 
4 candidate models (linear, Emax and 2 Hill-Emax models) to determine the dose response profile. The estimand of 
primary interest is the difference in mean percent change from baseline to Week 16 in EASI score between 
MEDI3506 and placebo in the ITT population. Data that are collected after withdrawal from the study or the 
use of rescue therapy will be treated as missing and excluded from the analysis.
Secondary Efficacy Analyses:
A key secondary efficacy endpoint is the percentage of subjects achieving an IGA response of 0 (clear) or 
1 (almost clear) and at least a 2 grade reduction from baseline at Week 16. IGA response at Week 16 will be 
analyzed for the ITT population using logistic regression including treatment group, randomization stratum 
(total serum IgE level < 150 kU/L or ≥150 kU/L), and baseline IGA as categorical factors. The coefficient of 
the treatment effects at Week 16 obtained from the logistic regression will then be used in an MCP-Mod 
analysis with 4 candidate models for the dose response (linear, Emax, and 2 Hill-Emax models). As part of the 
MCP-Mod model, the testing of the 4 candidate dose response models will be adjusted for multiplicity using a 
family-wise error rate of 0.10. If more than 1 candidate model shows a statistically significant dose response, 
the final model will be selected based on the Akaike Information Criteria obtained from each model.
A subject is defined as achieving a 50% reduction from baseline in Eczema Area and Severity Index score 
(EASI 50), a 75% reduction from baseline in Eczema Area and Severity Index score (EASI 75), or 
90% reduction from baseline in Eczema Area and Severity Index score (EASI 90) response if they have at least 
a 50%, 75%, or 90% reduction from baseline in EASI score, respectively. EASI 50, EASI 75, and EASI 90 
response at Week 16 will be analyzed using a logistic regression model including treatment group and 
randomization stratum (total serum IgE level < 150 kU/L or ≥150 kU/L) as categorical factors, and baseline 
EASI score as a covariate for each endpoint. In addition, the percentage of subjects achieving an EASI 75 
response at Week 16 will be analyzed for the ITT population using logistic regression followed by a dose 
response model similar to that described above for IGA response at Week 16.
Change from baseline to Week 16 in % body surface area affected by AD as assessed by EASI, 5-D itch, 
Patient-Oriented Eczema Measure, Dermatology Life Quality Index; and percent change from baseline to 
Week 16 in SCORing Atopic Dermatitis; will be summarized descriptively and analyzed for the ITT population 
using a MMRM, including data from visits up to Week 16. Details of the model for each endpoint are similar to 
those described above for the primary efficacy endpoint.
Daily peak pruritus Numerical Rating Scale (NRS) assessments will be summarized as weekly means. The 
weekly mean score will be set to missing if > 3 assessments are missed in that 7-day period. The percentage of 
subjects achieving a ≥3 point reduction from baseline to Week 16 in weekly mean of daily peak pruritus NRS 
will be analyzed using a logistic regression model including treatment group and randomization stratum (total 
serum IgE < 150 kU/L or ≥150 kU/L), and baseline weekly mean of daily peak pruritus score as a covariate.
Furthermore, change from baseline to Week 16 in the weekly mean of daily peak pruritus NRS will be analyzed 
using a MMRM, using a model similar to those described above for the primary efficacy endpoint.
Daily peak skin pain NRS assessments will be summarized as weekly means. The weekly mean score will be 
set to missing if > 3 assessments are missed in that 7-day period. Change from baseline to Week 16 in weekly 
mean peak skin pain NRS will be analyzed using a MMRM in a similar way as described above for the primary 
efficacy endpoint.
Patient Global Impression of Severity will be summarized with descriptive statistics including number of 
subjects, mean, SD, median, minimum, and maximum at each visit. In addition, the number and percentage of 
subjects in each category will be summarized by visit.
Safety:


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AEs will be coded using the Medical Dictionary for Regulatory Activities by system organ class and preferred 
term. Specific AEs will be counted once for each subject for calculating rates, but will be presented in total in 
subject listings. In addition, if the same AE occurs multiple times within a particular subject, the highest 
severity and level of causality will be reported. If any associations of interest between AEs and baseline 
characteristics are observed, additional stratified results may be presented.
Frequencies of abnormal laboratory measurements will be presented for each laboratory parameter. Also, 
laboratory parameters will be assessed by presenting tables containing information related to laboratory shifts 
from baseline relative to the normal range, as well as descriptively over time.
Vital signs, ECG parameters and left ventricular ejection fraction as measured by echocardiogram will be 
summarized descriptively.
Analysis of Immunogenicity and PK:
The incidence rate of positive antibodies to MEDI3506 and anti-drug antibody (ADA) titer will be reported by 
treatment group. Depending on the incidence of ADA, further analysis of ADAs effects may include assessment 
of the relationships between ADA titer and:
•
MEDI3506 exposure.
•
Biomarker endpoints.
•
Occurrence of AEs.
MEDI3506 serum concentrations will be tabulated and analyzed using descriptive statistics. Additional PK 
analyses may be conducted as appropriate. If the data allow, population PK analysis will be performed but will 
not be reported in the Clinical Study Report.
Primary and Final Analyses:
No formal interim analyses are planned for this study. The primary analysis will occur once all subjects have 
either completed the Visit 10 (Week 16) assessments or have withdrawn from the study and will include all 
available data. The final analysis will occur when all subjects have completed the follow-up period at Visit 12 
(Week 24) or have withdrawn from the study.


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS...................................................................................................... 2
TABLE OF CONTENTS.................................................................................................... 10
LIST OF ABBREVIATIONS ............................................................................................. 17
1
INTRODUCTION............................................................................................ 20
1.1
Disease Background ......................................................................................... 20
1.2
MEDI3506 Background.................................................................................... 20
1.3
Summary of Nonclinical Experience................................................................. 21
1.4
Summary of Clinical Experience....................................................................... 22
1.5
Rationale for Conducting the Study .................................................................. 23
1.6
Benefit-Risk and Ethical Assessment................................................................ 24
1.6.1
Coronavirus Disease 2019 (COVID-19)............................................................ 25
1.6.1.1
Vaccination Against COVID-19 ....................................................................... 27
1.7
Research Hypotheses ........................................................................................ 27
1.7.1
Primary Hypothesis .......................................................................................... 27
1.7.2
Secondary Hypotheses...................................................................................... 27
2
OBJECTIVES AND ENDPOINTS................................................................... 28
2.1
Primary Objective and Associated Endpoint ..................................................... 28
2.2
Secondary Objectives and Associated Endpoints............................................... 28
2.3
Exploratory Objectives and Associated Endpoints ............................................ 30
3
STUDY DESIGN ............................................................................................. 32
3.1
Description of the Study ................................................................................... 32
3.1.1
Overview.......................................................................................................... 32
3.1.2
Treatment Regimen........................................................................................... 34
3.1.3
Data and Safety Monitoring Board.................................................................... 34
3.2
Rationale for Dose, Population, and Endpoints ................................................. 34
3.2.1
Rationale for Dose and Dose Regimen.............................................................. 34
3.2.2
Rationale for Study Population ......................................................................... 36
3.2.3
Rationale for Endpoints .................................................................................... 37
3.2.3.1
Primary Endpoint.............................................................................................. 37
3.2.3.2
Secondary Endpoints ........................................................................................ 37
3.2.3.3
Exploratory Endpoints ...................................................................................... 37
4
MATERIALS AND METHODS ...................................................................... 38
4.1
Subjects............................................................................................................ 38
4.1.1
Number of Subjects .......................................................................................... 38
4.1.2
Inclusion Criteria .............................................................................................. 38
4.1.3
Exclusion Criteria ............................................................................................. 40
4.1.4
Subject Enrollment and Randomization ............................................................ 44
4.1.5
Withdrawal from the Study............................................................................... 45
4.1.6
Discontinuation of Investigational Product........................................................ 45


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4.1.7
Replacement of Subjects................................................................................... 46
4.1.8
Withdrawal of Informed Consent for Biological Sample Retention and 
Analyses ........................................................................................................... 46
4.2
Schedule of Study Procedures........................................................................... 46
4.2.1
Screening and TCS/TCI Wash Out Period......................................................... 47
4.2.2
Randomized Treatment Period.......................................................................... 49
4.2.3
Follow-up Period .............................................................................................. 54
4.3
Description of Study Procedures....................................................................... 55
4.3.1
Efficacy ............................................................................................................ 55
4.3.1.1
EASI Including Percentage BSA Affected by AD............................................. 55
4.3.1.2
IGA .................................................................................................................. 56
4.3.1.3
SCORAD.......................................................................................................... 56
4.3.1.4
Peak Pruritus NRS............................................................................................ 57
4.3.1.5
Skin Pain NRS.................................................................................................. 57
4.3.1.6
Moisturizer Use ................................................................................................ 57
4.3.1.7
5-D Itch ............................................................................................................ 57
4.3.1.8
Dermatology Life Quality Index ....................................................................... 57
4.3.1.9
Patient Global Impression of Severity............................................................... 57
4.3.1.10
Patient-Oriented Eczema Measure .................................................................... 58
4.3.1.11
SNOT-22.......................................................................................................... 58
4.3.1.12
ACQ-6.............................................................................................................. 58
4.3.2
Medical and Dermatology History, Physical Examinations, Weight, Height, 
Vital Signs, ECGs, and Echocardiograms ......................................................... 58
4.3.2.1
Medical and Dermatology History .................................................................... 59
4.3.2.2
Physical Examinations, Weight, and Height...................................................... 59
4.3.2.3
Vital Signs........................................................................................................ 59
4.3.2.4
ECGs................................................................................................................ 60
4.3.2.5
Echocardiograms .............................................................................................. 61
4.3.3
Clinical Laboratory Tests.................................................................................. 61
4.3.4
PK Evaluation and Methods.............................................................................. 62
4.3.5
Immunogenicity Evaluation and Methods ......................................................... 63
4.3.6
Genetic Evaluation and Methods....................................................................... 63
4.3.7
Biomarker Evaluation and Methods .................................................................. 63
4.3.7.1
Blood Biomarkers............................................................................................. 63
4.3.7.2
RNA PAXgene ................................................................................................. 64
4.3.7.3
Skin Punch Biopsies ......................................................................................... 64
4.3.7.4
RNA Transcript Profiling of RNA PAXgene and Skin Punch Biopsy Samples.. 64
4.3.7.5
S aureus Colonization....................................................................................... 64
4.3.7.6
Peripheral Blood Mononuclear Cells................................................................. 65
4.3.7.7
Adhesive skin tape patches ............................................................................... 65
4.3.8
Storage, Re-use, and Destruction of Biological Samples ................................... 65
4.3.9
Estimate of Volume of Blood to Be Collected................................................... 65
4.4
Study or Study Component Suspension or Termination..................................... 65
4.5
Investigational Products.................................................................................... 66
4.5.1
Identity of Investigational Products................................................................... 66
4.5.1.1
Investigational Product Handling ...................................................................... 67


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4.5.1.2
Investigational Product Inspection .................................................................... 67
4.5.1.3
Dose Preparation Steps ..................................................................................... 67
4.5.1.4
Treatment Administration................................................................................. 68
4.5.1.5
Monitoring Dose Administration....................................................................... 69
4.5.1.6
Reporting Product Complaints .......................................................................... 69
4.5.2
Labeling ........................................................................................................... 70
4.5.3
Storage ............................................................................................................. 70
4.5.4
Treatment Compliance...................................................................................... 70
4.5.5
Accountability .................................................................................................. 70
4.6
Treatment Assignment and Blinding ................................................................. 70
4.6.1
Methods for Assigning Treatment Groups......................................................... 70
4.6.2
Methods to Ensure Blinding.............................................................................. 71
4.6.3
Methods for Unblinding.................................................................................... 72
4.6.3.1
Unblinding in the Event of a Medical Emergency ............................................. 72
4.6.3.2
Unblinding for DSMB Purposes ....................................................................... 72
4.6.3.3
Unblinding for Primary Analysis Purposes........................................................ 72
4.7
Restrictions During the Study and Concomitant Treatment(s) ........................... 72
4.7.1
Permitted Concomitant Medications ................................................................. 72
4.7.2
Moisturizer Use ................................................................................................ 73
4.7.3
Prohibited Concomitant Medications and Therapies.......................................... 73
4.7.4
Prohibited Concomitant Medications as Rescue Therapy .................................. 74
4.7.5
COVID-19 Vaccination .................................................................................... 75
4.8
Statistical Evaluation ........................................................................................ 75
4.8.1
General Considerations..................................................................................... 75
4.8.2
Sample Size...................................................................................................... 76
4.8.3
Efficacy ............................................................................................................ 76
4.8.3.1
Primary Efficacy Analysis ................................................................................ 76
4.8.3.2
Additional Analyses of the Primary Endpoint ................................................... 77
4.8.3.3
Secondary Efficacy Analyses............................................................................ 78
4.8.3.4
Exploratory Analyses........................................................................................ 81
4.8.3.5
Subgroup Analyses ........................................................................................... 82
4.8.4
Safety ............................................................................................................... 82
4.8.4.1
Analysis of AEs................................................................................................ 82
4.8.4.2
Safety Laboratory Analysis............................................................................... 82
4.8.4.3
Analysis of Vital Signs, ECGs, and Echocardiograms....................................... 83
4.8.4.4
Subgroup Analyses ........................................................................................... 83
4.8.5
Analysis of Immunogenicity and PK................................................................. 83
4.8.6
Analysis of Biomarkers..................................................................................... 83
4.8.7
Primary and Final Analyses .............................................................................. 84
5
ASSESSMENT OF SAFETY ........................................................................... 84
5.1
Definition of Adverse Events............................................................................ 84
5.2
Definition of Serious Adverse Events ............................................................... 84
5.3
Definition of Adverse Events of Special Interest............................................... 85
5.4
Recording of Adverse Events............................................................................ 86
5.4.1
Time Period for Collection of Adverse Events .................................................. 86


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5.4.2
Follow-up of Unresolved Adverse Events......................................................... 86
5.4.3
Deaths .............................................................................................................. 86
5.4.4
Recording of Serious Hypersensitivity (Including Type 1 to 4 Hypersensitivity 
Reactions)......................................................................................................... 86
5.4.5
Recording of Injection Site Reactions ............................................................... 87
5.4.6
Recording of Cardiac Events (Including Angina or Myocardial Infarction, 
Congestive Heart Failure, Symptomatic Atherosclerotic Vascular Disease, or 
Pulmonale or Arrhythmia) ................................................................................ 87
5.4.7
Recording of Serious Infections (Including Opportunistic Infections and Viral 
Reactivations .................................................................................................... 87
5.4.8
Recording of Gastrointestinal Adverse Events .................................................. 87
5.4.9
Recording of Malignancy.................................................................................. 87
5.4.10
Adverse Events Based on Signs and Symptoms ................................................ 87
5.4.11
Adverse Events Based on Examination and Tests.............................................. 87
5.4.12
Hy’s Law.......................................................................................................... 88
5.5
Reporting of Serious Adverse Events................................................................ 88
5.6
Other Events Requiring Immediate Reporting................................................... 89
5.6.1
Overdose .......................................................................................................... 89
5.6.2
Pregnancy......................................................................................................... 89
5.6.2.1
Maternal Exposure............................................................................................ 89
5.6.2.2
Paternal Exposure............................................................................................. 90
5.6.3
Medication Error............................................................................................... 90
6
STUDY AND DATA MANAGEMENT........................................................... 91
6.1
Training of Study Site Personnel....................................................................... 91
6.2
Monitoring of the Study.................................................................................... 92
6.2.1
Source Data ...................................................................................................... 92
6.2.2
Study Agreements............................................................................................. 92
6.2.3
Archiving of Study Documents......................................................................... 93
6.3
Study Timetable and End of Study.................................................................... 93
6.4
Data Management............................................................................................. 93
6.5
Medical Monitor Coverage ............................................................................... 93
7
ETHICAL AND REGULATORY REQUIREMENTS...................................... 94
7.1
Subject Data Protection..................................................................................... 94
7.2
Ethics and Regulatory Review .......................................................................... 94
7.3
Informed Consent ............................................................................................. 95
7.4
Changes to the Protocol and ICF....................................................................... 95
7.5
Audits and Inspections...................................................................................... 95
8
REFERENCES................................................................................................. 97
9
CHANGES TO THE PROTOCOL ................................................................. 101
9.1
Protocol Amendment 9 ................................................................................... 101
9.2
Protocol Amendment 8 ................................................................................... 102


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9.3
Protocol Amendment 7 ................................................................................... 103
9.4
Protocol Amendment 6 ................................................................................... 104
9.5
Protocol Amendment 5 ................................................................................... 105
9.6
Protocol Amendment 4 ................................................................................... 107
9.7
Protocol Amendment 3 ................................................................................... 108
9.8
Protocol Amendment 2 ................................................................................... 110
9.9
Protocol Amendment 1 ................................................................................... 112


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LIST OF TABLES
Table 1
Primary Objective and Associated Endpoint ............................................ 28
Table 2
Secondary Objectives and Associated Endpoints...................................... 28
Table 3
Exploratory Objectives and Endpoints ..................................................... 30
Table 4
Predicted Maximum Dose Human Exposure comparison based on Phase 
1 Study .................................................................................................... 35
Table 5
Predicted Human Exposures and Safety Margins for the Phase 2 Clinical 
Study in AD............................................................................................. 36
Table 6
Schedule of Screening and TCS/TCI Wash Out Procedures ..................... 47
Table 7
Schedule of Treatment Period Study Procedures...................................... 50
Table 8
Schedule of Follow-up Procedures........................................................... 54
Table 9
Identification of Investigational Products................................................. 66
Table 10
Investigational Product Dose Preparation................................................. 68
Table 11
Study Populations.................................................................................... 76
Table 12
Summary of Non-substantial Revisions in Protocol Amendment 9......... 101
Table 13
Summary of Non-substantial Revisions in Protocol Amendment 8......... 102
Table 14
Summary of Substantial Revisions in Protocol Amendment 7................ 104
Table 15
Summary of Non-Substantial Revisions in Protocol Amendment 7........ 104
Table 16
Summary of Non-Substantial Revisions in Protocol Amendment 6........ 105
Table 17
Summary of Substantial Revisions in Protocol Amendment 5................ 105
Table 18
Summary of Non-Substantial Revisions in Protocol Amendment 5........ 105
Table 19
Summary of Non-Substantial Revisions in Protocol Amendment 5........ 106
Table 20
Summary of Substantial Revisions in Protocol Amendment 5................ 107
Table 21
Summary of Non-Substantial Revisions in Protocol Amendment 5........ 107
Table 22
Summary of Non-Substantial Revisions in Protocol Amendment 4........ 108
Table 23
Summary of Substantial Revisions in Protocol Amendment 3................ 109
Table 24
Summary of Non-substantial Revisions in Protocol Amendment 3......... 109
Table 25
Summary of Substantial Revisions in Protocol Amendment 2................ 110
Table 26
Summary of Non-substantial Revisions in Protocol Amendment 2......... 111
Table 27
Summary of Revisions in Protocol Amendment 1.................................. 112
Table A1
Highly Effective Methods of Contraception........................................... 114
Table G1
Classification of Representative TCSs ................................................... 130
Table H1
IGA ....................................................................................................... 132


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LIST OF FIGURES
Figure 1
Study Flow Diagram................................................................................ 34
LIST OF APPENDICES
Appendix A
Contraception Guidance......................................................................... 114
Appendix B
Additional Safety Guidance ................................................................... 115
Appendix C
National Institute of Allergy and Infectious Diseases and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis............ 118
Appendix D
Signs and Symptoms and Management of Acute Anaphylaxis ............... 119
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 121
Appendix F
Genetic Research................................................................................... 127
Appendix G
Classification of Topical Corticosteroids................................................ 130
Appendix H
Investigator’s Global Assessment .......................................................... 132


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ACQ
Asthma Control Questionnaire
AD
atopic dermatitis
ADA
anti-drug antibody(ies)
AE
adverse event
AESI
adverse event of special interest
ALT
alanine transaminase
ANCOVA
Analysis of covariance
anti-HBc
hepatitis B core antibody
anti-HBs
hepatitis B surface antibody
AST
aspartate transaminase
AUCB
area under the concentration-time curve
BSA
body surface area
CI
confidence interval
Cmax
maximum concentration
Cmax,ss
maximum concentration at steady-state
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CSR
Clinical Study Report
CYP450
Cytochrome P450
DBP
diastolic blood pressure
DLQI
Dermatology Life Quality Index
DSMB
Data and Safety Monitoring Board
EASI
Eczema Area and Severity Index
EASI 50
50% reduction from baseline in Eczema Area and Severity Index score
EASI 75
75% reduction from baseline in Eczema Area and Severity Index score
EASI 90
90% reduction from baseline in Eczema Area and Severity Index score
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eDiary
electronic diary
Emax
maximum effect attributable to the drug
FDA
Food and Drug Administration


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Abbreviation or 
Specialized Term
Definition
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HbA1c
hemoglobin A1c
HbsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
HL
Hy’s Law
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
Ig
immunoglobulin
IGA
Investigator’s Global Assessment
IGRA
interferon gamma release assay
IL
interleukin
IRB
Institutional Review Board
ITT
intent-to-treat
IXRS
interactive voice/web response system
IV
intravenous
LSLV
last subject last visit
mAb
monoclonal antibody
MCP-Mod
multiple comparison procedure with modelling techniques
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MMRM
mixed-effects model for repeated measures
NOAEL
no observed adverse effect level
NRS
Numerical Rating Scale
NT-proBNP
N-terminal prohormone of B-type natriuretic peptide
PBMC
Peripheral blood mononuclear cell
PD
pharmacodynamic(s)
PEI
Paul Ehrlich Institute
PGI-S
Patient Global Impression of Severity
PK
pharmacokinetic(s)
POEM
Patient-Oriented Eczema Measure


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Abbreviation or 
Specialized Term
Definition
PT
preferred term
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SBP
systolic blood pressure
SC
subcutaneous
SCORAD
SCORing Atopic Dermatitis
SD
standard deviation
SID
subject identification
SNOT
Sino-nasal Outcome Test
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
Q2W
every 2 weeks
Q4W
every 4 weeks
QW
every week
T2
Type 2
TB
tuberculosis
TBL
total bilirubin
TCI
topical calcineurin inhibitor
TCS
topical corticosteroid
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
ULN
upper limit of normal


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1
INTRODUCTION
1.1
Disease Background
Atopic dermatitis (AD) is a chronic inflammatory skin disease commonly referred to as 
eczema. In severe AD, there is widespread skin involvement. Affected skin may be red, itchy, 
swollen, cracked, weeping with crusting, and/or scaling. Pruritus is frequently intractable and 
with breakdown of barrier function there is an increased risk of bacterial, viral, and/or fungal 
skin infections. There may also be scarring in the form of lichenification, excoriation, 
papulation, or induration, due to chronic disease, the effects of treatment, or infective 
complications.
Up to 25% of children (DaVeiga, 2012) and 5% of adults (Barbarot et al, 2018) are affected 
by AD. Of the adults, 20% to 37% have moderate disease with 10% to 34% reported with 
severe disease (Kim et al, 2016; Pawankar, 2013). Patients with moderate-to-severe AD have 
a poor quality of life through a combination of symptoms, emotional stress from poor 
self-image, the burden of applying topical treatments regularly, sleep disturbance, and 
reductions in work productivity (Kiebert et al, 2002). Treatment recommendations for AD 
include liberal use of emollients, dry skin care protocols, topical corticosteroids (TCSs), and 
topical calcineurin inhibitors (TCIs).
For many patients with moderate-to-severe AD, TCS therapy has inadequate efficacy. In 
addition, long-term TCS use is associated with 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 children (Ring et al, 2012). A high proportion of patients have a partial 
or no clinical response to TCI therapy. Moreover, long-term safety of TCIs has not been 
established, and continuous, long-term use should be avoided (Elidel, 2017; Protopic, 2012). 
Off-label use of systemic immunomodulatory agents including cyclosporine, methotrexate, 
azathioprine, or mycophenolate mofetil is reserved for patients with poor AD control despite 
optimized use of first line topical therapies and phototherapy (Sidbury et al, 2014). Dupilumab 
(Dupixent®), an anti-interleukin (IL) 4Rα monoclonal antibody (mAb), is approved as an 
add-on therapy for adults and adolescents with moderate-to-severe AD whose disease is not 
adequately controlled with topical therapies. However, dupilumab also has limited efficacy in 
many patients. Consequently, there is an unmet need for new therapeutic agents for AD that 
improve outcomes in patients with moderate-to-severe disease.
1.2
MEDI3506 Background
MEDI3506 is briefly described below. Refer to the current Investigator’s Brochure (IB) for 
details.
MEDI3506 is a human immunoglobulin (Ig) G1 mAb that binds to human IL-33. MEDI3506 
neutralizes the pro-inflammatory actions of IL-33 by preventing binding of IL-33 to its 


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receptor ST2, which is expressed by a variety of inflammatory cells linked to AD 
pathophysiology. Nonclinical data support a role for anti-IL-33 therapy in AD. Blocking of 
IL-33 signaling through ST2 has a therapeutic effect in murine models of AD (Imai et al, 
2013; Peng et al, 2018). Clinical data also support a role for anti-IL-33 therapy in AD. An 
uncontrolled (ie, no placebo group), Phase 2a clinical study of a single intravenous (IV) dose 
of etokimab (ANB020; anti-IL-33 neutralizing antibody) showed efficacy of etokimab in 
adults with moderate-to-severe AD, indicating the potential of anti-IL-33 therapy for treating 
AD (Ogg, 2018). As both MEDI3506 and etokimab have a similar mechanism of action, the 
Phase 2a etokimab clinical study data provide support for investigating the therapeutic 
potential of MEDI3506 in AD. However, a Phase 2b, randomized, double-blinded, 
placebo-controlled clinical study of multiple doses of etokimab in adults with 
moderate-to-severe AD has, according to a preliminary report, not met its primary endpoint of 
statistically significant improvement in the Eczema Area and Severity Index (EASI) compared 
with placebo at Week 16 (AnaptysBio, 2019).
1.3
Summary of Nonclinical Experience
 
 
Nonclinical pharmacology studies demonstrated that MEDI3506 binds 
 
specifically and with high affinity. In addition, studies performed in vitro and in vivo have 
demonstrated the mechanism of action of MEDI3506.
 
 
 
 
 
The potential toxicity of MEDI3506 was evaluated in 2 repeat-dose studies.
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI


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Please refer to the IB for further details.
1.4
Summary of Clinical Experience
One Phase 1 clinical study of MEDI3506 (Study D9180C00001) has been completed to date.
Study D9180C00001 was a Phase 1, first time in human, randomized, blinded (investigator 
and subject blinded; sponsor unblinded), placebo-controlled clinical study to evaluate the 
safety, tolerability, PK, and immunogenicity of single and repeated doses of MEDI3506. The 
study had 3 parts. Part I involved single ascending dose administration of MEDI3506 either 
SC or IV to healthy adult subjects with a history of mild atopy, Part II involved multiple 
ascending dose administration of MEDI3506 SC to adult subjects with Global Initiative for 
Chronic Obstructive Lung Disease (GOLD) I to II chronic obstructive pulmonary disease 
(COPD), and Part III involved single dose administration of MEDI3506 IV to healthy adult 
Japanese subjects.
In healthy subjects with a history of mild atopy in Part I of the study, a similar proportion of 
subjects experienced at least 1 treatment-emergent adverse event (TEAE; ie, adverse events 
[AEs] occurring after the first dose of investigational product [MEDI3506 or placebo]) in the 
MEDI3506 and placebo groups. All reported TEAEs were Grade 1 or 2 (mild or moderate) in 
severity. There were no TEAEs leading to discontinuation of investigational product, 
treatment-emergent serious adverse events (TESAEs), or deaths.
In subjects with GOLD I to II COPD in Part II of the study, a similar proportion of subjects 
experienced at least 1 TEAE in the MEDI3506 and placebo groups. A majority of reported 
CCI
CCI


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TEAEs were Grade 1 or 2 in severity. One subject experienced a TEAE leading to 
discontinuation of investigational product, and 2 subjects experienced 2 TESAEs (1 TESAE in 
each subject). There was 1 death due to non-small cell lung cancer. The TEAE leading to 
discontinuation of investigational product, TESAEs, and death were considered not related to 
investigational product by the investigator.
In healthy Japanese subjects in Part III of the study, a similar proportion of subjects 
experienced at least 1 TEAE in the 300 mg IV MEDI3506 and placebo groups. All reported 
TEAEs were Grade 1 in severity. There were no TEAEs leading to discontinuation of 
investigational product, TESAEs, or deaths.
The MEDI3506 serum concentration versus time profiles from healthy subjects with a history 
of mild atopy showed linear and time-invariance first order absorption and first order 
elimination for single doses of 1 to 300 mg SC. There was no evidence of an antigen sink. For 
multiple every 2 weeks (Q2W) SC doses in subjects with GOLD I to II COPD, slight 
accumulation was observed, based on the trough concentration, following the first and third 
dose. The multiple and single dose half-lives were consistent.
Nine out of 88 subjects were anti-drug antibody (ADA)-positive at any time point. 
Treatment-emergent ADA were detected in 4 out of 66 subjects in the MEDI3506 groups. No 
subjects in the placebo groups (N = 22) had treatment-emergent ADA. TEAEs were similar in 
frequency and severity for ADA-positive and ADA-negative subjects. No impact of ADA on 
MEDI3506 PK was observed, except in 1 subject where the onset of treatment-emergent ADA 
coincided with a decrease in MEDI3506 serum concentration.
Please refer to the IB for further details.
1.5
Rationale for Conducting the Study
IL-33 is a cytokine constitutively expressed at endothelial and epithelial barrier surfaces and is 
released following injury. On release, IL-33 induces Type 2 (T2) inflammation, stimulating 
production of IL-5 and IL-13 cytokines and promoting eosinophil recruitment.
T2 inflammation is a characteristic feature of AD. Studies have found increased 
concentrations of IL-33 mRNA, and ST2 mRNA and protein, in the skin lesions of patients 
with AD and in the skin of mice induced to develop AD (Dickel et al, 2010; Savinko et al, 
2012). In addition, IL-33 impacts skin barrier integrity by downregulating the expression of 
filaggrin, a structural protein that plays a key role in AD skin barrier function (Salimi et al, 
2013; Seltmann et al, 2015). Genetic studies also support a role for IL-33 in the pathogenesis 
of AD. Single nucleotide polymorphisms in the IL-33 gene that result in loss of protein 
function have been linked to protection from allergic disorders (Smith et al, 2017). Genetic 
polymorphisms within the ST2 gene region are associated with AD (Shimizu et al, 2005).






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The study population is not considered to be particularly vulnerable to COVID-19, as study 
subjects are generally younger and without significant cardiac comorbidity. The incidence of 
asthma in the study population is expected to be higher than in the general population but mild 
in most cases.
Investigators should consider whether potential subjects who are considered to have particular 
significant risk factors for COVID-19 should be included during the pandemic, per Exclusion 
Criterion 10. Subjects older than 65 years are additionally excluded as they are at greater risk, 
per Inclusion Criterion 2.
Subjects who are suspected (or known) to have COVID-19 should not be included, per 
Exclusion Criterion 10. Subjects who, during the course of the study, are suspected of having 
contracted COVID-19 should not be brought into contact with other subjects. If it is not 
possible for a subject to attend a study visit, then the patient should be contacted by telephone 
for the assessment of AEs, changes in concomitant medications, and other assessments that 
may be performed entirely verbally. Polymerase chain reaction testing for severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2; the virus causing COVID-19) is not 
mandated for this study, as a subject with a negative result may become infected at any time 
after the sample was taken. Testing for COVID-19 may and should be performed, if required, 
by local / national guidelines.
It is recognized that depending on the location and facilities of a clinical site, study visit 
attendance may place subjects at risk of exposure to SARS-CoV-2. Furthermore, it is 
recognized that more general population level measures to reduce infection rates (eg, travel 
restrictions) may inhibit the ability of subjects to attend study visits. Necessary healthcare 
responses to the pandemic at sites (eg, additional infection control measures) may also inhibit 
the ability of a clinical site to effectively and properly conduct the study. Study visit 
attendance for dosing and for clinical assessments of treatment response are critical for the 
scientific value of the study.
Therefore, investigators should not enrol subjects unless they have reasonable confidence that 
throughout the duration of the study:
∀
Subjects will be able to attend study visits, whilst avoiding contact with concentrations of 
COVID-19 patients (eg, hospital entrances used by such patients) and
∀
The site will be able to effectively and safely conduct the study, considering relevant 
national and local factors.
The sponsor will conduct risk-based enrolment assessments on a country and site level, on a 
regular basis during the pandemic phase, and decisions will be documented.


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All site staff should wear personal protective equipment in accordance with local or national 
guidelines.
The primary endpoint will be analyzed using a mixed-effects model for repeated measures 
(MMRM) which, in the event of missing data, uses all data that are available. The sponsor will 
monitor the number of discontinuations, withdrawals, missed visits, and other missing data.
Given the limited additional risks to the study population related to COVID-19, from study 
participation, beyond those they would experience in everyday life, the mitigations described 
above are considered sufficient to ensure a favorable benefit-risk balance.
1.6.1.1
Vaccination Against COVID-19
There are no clinical data available to assess the interaction (if any) of MEDI3506 with any 
COVID-19 vaccine.
The sponsor accepts that vaccination against COVID-19, when and where it is available and 
subjects are eligible according to applicable guidelines, is in the subject’s best interest. 
Consequently, vaccination during the study is, in general, permitted and any delays in 
vaccination due to study participation should be minimized.
To help ensure the interpretability of safety data, receipt of COVID-19 vaccine (either first or 
subsequent dose) is prohibited within 30 days before randomization or within 7 days before or 
after any dose of investigational product (Section 4.7.3). Receipt of, at least, the first dose of 
COVID-19 vaccine more than 30 days before randomization, without significantly delaying 
enrollment, should be preferred but may not be possible, eg, not locally available at the time, 
subject not eligible at the time, express subject decision not to be vaccinated. Otherwise, 
vaccination may be performed at any time outside the prohibited 7-day window before or after 
any dose of investigational product. If the (approximate) date of a subsequent dose of 
COVID-19 vaccination is known, then enrollment of the subject should be timed so that the 
dose is not within 30 days prior to scheduled randomization. If this date is not known then 
enrollment into study should not be delayed. If an enrolled subject does (unexpectedly) 
receive COVID-19 vaccine within 30 days prior to scheduled randomization, the site should 
contact the AstraZeneca Study Physician for advice on how the situation should be managed.
1.7
Research Hypotheses
1.7.1
Primary Hypothesis
AD disease severity will be decreased in adult subjects with moderate-to-severe AD 
administered MEDI3506 compared with placebo.
1.7.2
Secondary Hypotheses
In adult subjects with moderate-to-severe AD:


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∀
AD disease severity and symptoms, as measured by additional endpoints, will be 
decreased in subjects administered MEDI3506 compared with placebo.
∀
MEDI3506 will be safe and well tolerated compared with placebo.
∀
The PK profile will support further clinical development of MEDI3506.
∀
The immunogenicity profile will support further clinical development of MEDI3506.
2
OBJECTIVES AND ENDPOINTS
2.1
Primary Objective and Associated Endpoint
Table 1
Primary Objective and Associated Endpoint
Type
Objective
Endpoint
Efficacy
To assess the effects of 
MEDI3506 compared with 
placebo on AD disease severity, in 
adult subjects with 
moderate-to-severe AD.
Percent change from baseline to Week 16 in EASI 
score.
AD = atopic dermatitis; EASI = Eczema Area and Severity Index.
2.2
Secondary Objectives and Associated Endpoints
Table 2
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
Efficacy
To further assess the effects of 
MEDI3506 compared with 
placebo on AD disease severity 
and symptoms, in adult subjects 
with moderate-to-severe AD.
•
EASI:
!
Percentage of subjects achieving a 90% 
reduction from baseline in EASI score 
(EASI 90) at Week 16.
!
Percentage of subjects achieving a 
75% reduction from baseline in EASI score 
(EASI 75) at Week 16.
!
Percentage of subjects achieving a 50% 
reduction from baseline in EASI score 
(EASI 50) at Week 16.
•
Percentage of subjects achieving an IGA of 
0 (clear) or 1 (almost clear) with at least a 
2 grade reduction from baseline score at 
Week 16.
•
Peak pruritus NRS: Percentage of subjects 
achieving a reduction of ≥3 from baseline to 
Week 16 in weekly mean of daily peak pruritus 
NRS.
•
Peak pruritus NRS: Change from baseline to 
Week 16 in weekly mean of daily peak pruritus 
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Table 2
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
•
Skin pain NRS: Change from baseline to 
Week 16 in weekly mean of daily peak skin pain 
NRS.
•
SCORAD: Percent change from baseline to 
Week 16.
•
PGI-S at Week 16.
•
Change from baseline to Week 16 in:
!
% BSA affected by AD.
!
5-D itch.
!
POEM.
!
DLQI.
Safety
To assess the safety and 
tolerability of MEDI3506 
compared with placebo, in adult 
subjects with moderate-to-severe 
AD.
During the treatment and follow-up periods:
•
TEAEs and TESAEs.
•
Vital signs.
•
Safety laboratory analysis.
•
ECGs. The following parameters will be 
recorded for each ECG:
!
Date and time of ECG.
!
Heart rate (beats/min).
!
QT (ms).
!
Overall evaluation (normal/abnormal).
•
Left ventricular ejection fraction as measured by 
echocardiogram.
PK
To evaluate the PK of MEDI3506 
in adult subjects with 
moderate-to-severe AD.
Serum MEDI3506 concentration profiles during the 
treatment and follow-up periods.
Immunogenicity
To evaluate the immunogenicity 
of MEDI3506 in adult subjects 
with moderate-to-severe AD.
Incidence of ADA during the treatment and follow-up 
periods.
AD = atopic dermatitis; ADA = anti-drug antibody(ies); BSA = body surface area; DLQI = Dermatology Life 
Quality Index; EASI = Eczema Area and Severity Index; EASI 50 = 50% reduction from baseline in Eczema 
Area and Severity Index score; EASI 75 = 75% reduction from baseline in Eczema Area and Severity Index 
score; EASI 90 = 90% reduction from baseline in Eczema Area and Severity Index score; 
ECG = electrocardiogram; IGA = Investigator’s Global Assessment; NRS = Numerical Rating Scale; 
PGI-S = Patient Global Impression of Severity; PK = pharmacokinetic(s); POEM = Patient-Oriented Eczema 
Measure; SCORAD = SCORing Atopic Dermatitis; TEAE = treatment-emergent adverse event; 
TESAE = treatment-emergent serious adverse event.


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2.3
Exploratory Objectives and Associated Endpoints
Table 3
Exploratory Objectives and Endpoints
Type
Objective
Endpoint
Efficacy
To assess the effects of 
MEDI3506 compared with 
placebo on AD disease severity 
and symptoms over time to 
Week 24, in adult subjects with 
moderate-to-severe AD.
•
EASI:
!
Percentage of subjects achieving a 90% 
reduction from baseline in EASI score 
(EASI 90) at Weeks 2, 4, 8, 12, 20, and 24.
!
Percentage of subjects achieving a 75% 
reduction from baseline in EASI score 
(EASI 75) at Weeks 2, 4, 8, 12, 20, and 24.
!
Percentage of subjects achieving a 50% 
reduction from baseline in EASI score 
(EASI 50) at Weeks 2, 4, 8, 12, 20, and 24.
!
Percent change from baseline to Weeks 2, 
4, 8, 12, 20, and 24 in EASI score.
•
IGA: Percentage of subjects achieving an IGA 
of 0 (clear) or 1 (almost clear) with at least a 
2 grade reduction from baseline score at 
Weeks 2, 4, 8 ,12, 20, and 24.
•
Peak pruritus NRS: Reduction of ≥3 from 
baseline to Weeks 2, 4, 8, 12, 20, and 24 in 
weekly mean of daily peak pruritus NRS.
•
Peak pruritus NRS: Reduction of ≥4 from 
baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in 
weekly mean of daily peak pruritus NRS.
•
Peak pruritus NRS: Change from baseline to 
Weeks 2, 4, 8, 12, 20, and 24 in the weekly 
mean of daily peak pruritus NRS.
•
Skin pain NRS: Change from baseline to 
Week 2, 4, 8, 12, 20, and 24 in weekly mean of 
daily peak skin pain NRS.
•
SCORAD: Percent change from baseline to 
Weeks 2, 4, 8, 12, 20, and 24.
•
PGI-S at Weeks 2, 4, 8, 12, 20, and 24.
•
Change from baseline to Weeks 2, 4, 8, 12, 20, 
and 24 in:
!
% BSA affected by AD.
!
5-D itch.
!
POEM.
!
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Table 3
Exploratory Objectives and Endpoints
Type
Objective
Endpoint
Biomarkers
To evaluate the effect of 
MEDI3506 on blood biomarkers
that may either predict or reflect 
an efficacy response in adult 
subjects with 
moderate-to-severe AD.
•
Change from baseline to Week 16 in serum 
concentrations of:
!
sST2.
!
•
Change from baseline to Week 16 in whole 
blood PBMC subsets
•
Change from baseline to Weeks 1, 2, 4, 8, 12, 
16, 20, and 24 in serum biomarker levels, 
including but not limited to:
!
Eosinophils.
!
IL-5.
!
IL-13.
!
CCL17.
•
Change from baseline to Weeks 1, 2, 4, 16, 20 
and 24 in serum IL-33 bound to MEDI3506
•
Change from baseline to Weeks 2, 8, 16, and 24 
in serum IgE levels.
•
Change from baseline to Week 16 in 
proinflammatory gene signatures in whole 
blood.
•
Change from baseline to Weeks 4, 16, and 24 in 
plasma EDN levels.
Biomarkers
To evaluate the effect of 
MEDI3506 on skin biomarkers
that may either predict or reflect 
an efficacy response in adult 
subjects with 
moderate-to-severe AD.
•
Colonization of pathogenic bacteria (ie, 
Staphylococcus aureus) in lesional and 
non-lesional skin, from baseline to Week 16.
•
From baseline to Week 16 in lesional and 
non-lesional skin:
!
Proinflammatory gene signatures in tape 
strips and biopsies.
!
Gross inflammation evaluation.
Efficacy
To assess the effect of 
MEDI3506 compared with 
placebo on the need for rescue 
therapy, in adult subjects with 
moderate-to-severe AD.
•
Proportion of subjects requiring rescue therapy 
during the treatment and follow-up periods.
•
Time to first use of rescue therapy throughout 
the treatment and follow-up periods.
•
Incidence of skin infection TEAEs requiring 
systemic treatment during the treatment and 
follow-up periods.
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Table 3
Exploratory Objectives and Endpoints
Type
Objective
Endpoint
Efficacy
To evaluate the effect of 
MEDI3506 compared with 
placebo on nasal symptom 
control, in a subset of adult 
subjects with 
moderate-to-severe AD who 
have comorbid chronic 
inflammatory conditions of the 
nasal mucosa and/or paranasal 
sinuses.
Change from baseline to Week 16 and 24 in 
SNOT-22.
Efficacy
To evaluate the effect of 
MEDI3506 on asthma symptom 
control compared with placebo, 
in a subset of adult subjects with 
moderate-to-severe AD who 
have comorbid asthma.
Change from baseline to Week 16 and 24 in ACQ-6.
 
 
 
 
 
 
 
 
ACQ = Asthma Control Questionnaire; AD = atopic dermatitis; BSA = body surface area; 
DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; EASI 50 = 50% reduction 
from baseline in Eczema Area and Severity Index score; EASI 75 = 75% reduction from baseline in Eczema 
Area and Severity Index score; EASI 90 = 90% reduction from baseline in Eczema Area and Severity Index 
score; EDN = eosinophil derived neurotoxin; Ig = immunoglobulin; IGA = Investigator’s Global Assessment; 
IL = interleukin; NRS = Numerical Rating Scale; PBMC = peripheral blood mononuclear cell; PGI-S = Patient 
Global Impression of Severity; POEM = Patient-Oriented Eczema Measure; SCORAD = SCORing Atopic 
Dermatitis; SNOT-22 = Sino-nasal Outcome Test; sST2 = soluble ST2; TEAE = treatment-emergent adverse 
event.
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
This is a Phase 2 randomized, double-blinded, placebo-controlled, parallel-group, 
proof-of-concept study to evaluate the efficacy, safety, PK, and immunogenicity of 
MEDI3506 in adult subjects with moderate-to-severe AD (Figure 1). Approximately 
152 subjects will receive 
 MEDI3506 SC; or placebo 
 SC, or 
placebo 
 SC; in a 3:1:1:1:2 ratio overall
 
The randomization ratio will change during the study 
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(Section 4.6.1). The randomization will be stratified based on total IgE (< 150 kU/L or 
≥150 kU/L) at screening. The study will be conducted at approximately 40 to 50 study sites in 
Australia, Europe, and North America.
Subjects will be enrolled in this study for approximately 7 months (28 weeks), comprising a 
screening and TCS/TCI wash out period of up to 4 weeks, a 16-week treatment period, and an 
8-week follow-up period (Figure 1):
1
Screening and TCS/TCI wash out period: Following the signing of informed consent, 
subjects will be assessed for study eligibility (Sections 4.1.2 and 4.1.3) at screening 
Visit 1 and, if eligible, invited to attend screening Visit 2, which must occur 7 or more 
days prior to randomization. Subjects who meet the eligibility (inclusion/exclusion) 
criteria will discontinue use of TCSs and TCIs at Visit 2. Subjects will be required to 
apply moisturizers twice daily for at least 7 days before randomization at Visit 3 (Day 1) 
with a minimum of 85% compliance.
2
Treatment period: To be randomized at Visit 3 (Day 1), subjects must meet all the 
eligibility criteria (Sections 4.1.2 and 4.1.3) before receiving investigational product by 
SC injection 
. Subjects will be required to apply moisturizers twice daily throughout 
the treatment period, and will not be permitted to use TCSs and TCIs, except if medically 
necessary (Section 4.7.4). 
 
and the primary endpoint assessment will occur at Visit 10 
(Week 16).
The first 72 subjects randomized will attend Visit 4a, whereas the remaining subjects will 
attend Visit 4b instead (Table 7).
Following provision of informed consent, skin punch biopsies at Visit 3 (Day 1) and 
Visit 10 (Week 16) will be collected from a subset of subjects (ie, approximately 
45 subjects in total). Subjects with comorbid chronic inflammatory conditions of the nasal 
mucosa and/or paranasal sinuses (eg, chronic rhinitis/rhinosinusitis, nasal polyps, allergic 
rhinitis) will complete the Sino-nasal Outcome Test (SNOT)-22 questionnaire. Similarly, 
subjects with comorbid asthma will complete the Asthma Control Questionnaire (ACQ)-6 
questionnaire.
3
Follow-up period: Safety, sustained efficacy, and the need for rescue therapy will be 
assessed in the follow-up period. Subjects will be required to apply moisturizers twice 
daily through to the end of the follow-up period at Visit 12 (Week 24), and will not be 
permitted to use TCSs and TCIs, except if medically necessary (Section 4.7.4).
Definitions for withdrawal criteria (Section 4.1.5) and subject completion of the study 
(Section 6.3) are provided.
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maximum concentration at steady-state (Cmax,ss; approximately 2.5-fold) and AUC 
(approximately 1.6-fold), compared with the highest dose administered (ie, single dose of 
 IV MEDI3506) in the Phase 1 clinical study (Study D9180C00001; Section 1.4). A 
dose of 
W is predicted to have a higher Cmax,ss, but the same AUC 
compared with the highest multiple dose administered (ie, 
 SC Q2W) in the same 
study (Table 4).
Table 4
Predicted Maximum Dose Human Exposure comparison based on 
Phase 1 Study
AUC0-4 weeks = area under the concentration time curve for 0 to 4 weeks at steady state; Cmax,ss = maximum 
concentration at steady state; SC = subcutaneous; 
.
The nature and severity of disease in the study population are not expected to significantly 
impact the overall exposure nor clearance. The published PK data for a monoclonal antibody 
licensed for use in AD indicate that the disease status (ie, healthy subjects vs subjects with 
AD) had no significant impact on exposure or clearance (Kovalenko et al, 2016). Hence, we 
anticipate that MEDI3506 exhibits similar PK profiles for both healthy subjects and subjects 
with AD.
Exposures (ie, mean Cmax,ss of 1,276 μg/mL, and area under the concentration-time curve for 0 
to 4 weeks at steady-state of 28,012 μg • day/mL) achieved at the 26-week NOAEL of 
150 mg/kg in cynomolgus monkeys (Section 1.3) are approximately 34- and 45-fold higher 
than predicted at the proposed highest dose of 
 in this Phase 2 clinical study 
(Table 5).
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with the aforementioned comorbidities will be included as subgroup populations for 
exploratory endpoints to investigate if these comorbidities might be improved by treatment 
with MEDI3506 (Silverberg and Simpson, 2013; Spergel, 2010).
3.2.3
Rationale for Endpoints
3.2.3.1
Primary Endpoint
The primary endpoint is percent change from baseline in EASI score. The EASI is a valid and 
reliable quantitative tool for assessing AD severity over time (Schmitt et al, 2013)
(Section 4.3.1.1).
3.2.3.2
Secondary Endpoints
The secondary efficacy endpoints will provide information to support the interpretation of the 
primary endpoint.
Clinical scientific experts advise that an EASI score ≥16 at randomization and an 
Investigator’s Global Assessment (IGA) score ≥3 reliably identify subjects with 
moderate-to-severe AD, so cut-off values for EASI and IGA were included as inclusion 
criteria (Section 4.1.2).
Standard safety, PK, and immunogenicity endpoints will be evaluated.
3.2.3.3
Exploratory Endpoints
Blood samples will be collected from subjects for the assessment of biomarkers that are 
relevant to disease pathology and/or the mechanism of action of MEDI3506.
Skin punch biopsies and skin tape strips will allow biomarker analyses directly from the target 
tissue.
Skin swabs will be collected from subjects to evaluate Staphylococcus aureus (S aureus) 
colonization. Levels of S aureus have been correlated with disease severity (Simpson et al, 
2018).
Many patients with AD have comorbid chronic rhinosinusitis. SNOT-22, a measure of nasal 
symptoms, will be performed and evaluated in subjects with comorbid chronic rhinosinusitis. 
Changes in SNOT-22 will be used to assess the impact of MEDI3506 on chronic 
rhinosinusitis.
Many patients with AD have comorbid asthma. The ACQ-6, a measure of asthma control, will 
be performed and evaluated in subjects with comorbid asthma to assess the impact of 
MEDI3506 on asthma symptoms.


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4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
Approximately 152 subjects are planned to be randomized in this study in 5 treatment groups, 
as follows:
∀
MEDI3506 
 (58 subjects).
∀
MEDI3506 
 (18 subjects).
∀
MEDI3506 
 (18 subjects).
∀
Placebo 
 (6 subjects).
∀
Placebo 
 (52 subjects).
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
Criteria to be Assessed at Screening Visit 1:
If any criterion cannot be fully assessed at screening Visit 1 (eg, due to awaiting information 
from the subject’s usual physician), the criterion must be fully assessed prior to 
randomization.
1
Written informed consent and any locally required authorization (eg, data privacy) prior 
to performing any protocol-related procedure, including screening.
2
Age 18 to 65 years inclusive at the time of consent.
3
Body mass index between 19.0 and 40.0 kg/m2 inclusive at screening Visit 1.
4
Documented history of chronic AD as defined using Hanifin and Rajka’s criteria (Hanifin 
and Rajka, 1980), for at least 1 year prior to screening Visit 1.
5
Meets at minimum 1 of the criteria, as follows:
(a) A documented history, within the 6 months prior to screening Visit 1, of an IGA 
score of ≥ 3, despite treatment with daily, medium or high potency TCSs 
(Appendix G) in the presence or absence of TCIs, applied for ≥ 4 weeks or for the 
maximum duration recommended by the product prescribing information, whichever 
is shorter, or
(b) A documented history, within the 6 months prior to screening Visit 1, of requiring 
intermittent or continuous systemic therapy,
(c) Subject intolerance to treatment with topical medications for AD, or
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(d) Topical medications are otherwise medically inadvisable (eg, due to important side 
effects or safety risks that outweigh the potential treatment benefits), as assessed by 
the investigator or by the physician who treats the subject’s AD.
Note, acceptable evidence of documented history includes:
(i)
Contemporaneous clinical notes that record ≥1 topical medication prescription 
and treatment outcome, from which an IGA score of ≥3 can be inferred.
(ii) Contemporaneous clinical notes that record ≥1 systemic medication 
prescription.
(iii) Investigator documentation based on communication with the physician who 
treats the subject’s AD.
Note, meeting (a) and/or (b) is considered to indicate a history of inadequate response to 
topical medications for AD.
6
Able and willing to comply with the requirements of the protocol including ability to 
read, write, be fluent in the translated language of all subject facing questionnaires used at 
site, and use electronic devices.
Criteria to be Assessed at Screening Visit 1, and Visit 3 (Day 1) Prior to Randomization:
7
AD that affects ≥10% of the body surface area (BSA) at both Visit 1 and Visit 3 (Day 1), 
as assessed by EASI.
8
An EASI score of ≥12 at Visit 1 and ≥16 at Visit 3 (Day 1).
9
An IGA score of ≥3 at both Visit 1 and Visit 3 (Day 1).
10 Female subjects, regardless of childbearing potential, must have negative pregnancy tests 
both at screening Visit 1 (serum pregnancy test) and pre-dose of investigational product at 
Visit 3 (Day 1; urine pregnancy test).
11 Female subjects of childbearing potential who are sexually active with a male partner 
must agree to use a highly effective method of contraception from screening until the end 
of the follow-up period at Visit 12 (Week 24) of the study. See Appendix A for 
definitions of childbearing potential and highly effective methods of contraception.
∀
In countries where spermicide is available, it is strongly recommended for the male 
partner of a female subject of childbearing potential to also use male condom plus 
spermicide throughout this period.
∀
In countries where spermicide is not available, it is strongly recommended for the 
male partner of a female subject of childbearing potential to also use male condom 
throughout this period.
Note there are no contraception requirements for female subjects who are not of 
childbearing potential. However, all female subjects should refrain from egg cell donation 
and breastfeeding throughout the study.


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Criteria to be Assessed at Visit 3 (Day 1) Prior to Randomization:
12 Female subjects of childbearing potential who are sexually active with a male partner 
must agree to use a highly effective method of contraception.
∀
In countries where spermicide is available, male subjects who are sexually active 
with a female partner of childbearing potential must agree to use a male condom with 
spermicide and another highly effective method of contraception during the treatment 
and follow-up periods from Visit 3 (Day 1) through to Visit 12 (Week 24) of the 
study.
∀
In countries where spermicide is not available, male subjects who are sexually active 
with a female partner of childbearing potential must agree to use a male condom and 
another highly effective method of contraception during the treatment and follow-up 
periods from Visit 3 (Day 1) through to Visit 12 (Week 24) of the study.
See Appendix A for definitions of childbearing potential and highly effective methods of 
contraception. Male subjects should also refrain from biologically fathering a child or 
donating sperm during the same period.
13 As confirmed from electronic diary (eDiary) entries, the subject has applied a stable dose 
of topical emollient (moisturizer) twice daily for ≥7 consecutive days immediately before 
baseline at Visit 3 (Day 1) with a minimum of 85% compliance.
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
Criteria to be Assessed at Screening Visit 1 and Visit 2:
If any criterion cannot be fully assessed at screening Visit 1 and Visit 2 (eg, laboratory results 
not yet available), the criterion must be fully assessed prior to randomization.
1
Subjects with a recent history of or who have a positive test for infective hepatitis, HIV, 
or unexplained jaundice, or subjects who have been treated for hepatitis B, hepatitis C, or 
HIV. For the hepatitis B testing (hepatitis B surface antigen [HbsAg], hepatitis B surface 
antibody [anti-HBs], and hepatitis B core antibody [anti-HBc]), any of the following 
would exclude the subject from the study:
(a) Subjects positive for HbsAg.
(b) Subjects positive for anti-HBc.
Subjects with a history of hepatitis B vaccination without a history of hepatitis B are 
permitted.
2
Evidence of active or latent tuberculosis (TB):
(a) Positive diagnostic TB test during screening Visit 1 defined as a positive interferon 
gamma release assay [IGRA] test).


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(b) Subjects with an indeterminate IGRA should undergo a repeat test and if still 
indeterminate may be enrolled only after being treated for TB and having a 
subsequent negative test.
(c) Subjects with a positive IGRA but no clinical history or suspicion of TB and no 
significant risk factors for TB may undergo a retest and be enrolled if that result is 
negative.
3
N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) level greater than the 
upper limit of the laboratory reference range at screening Visit 1; if the result is greater 
than the upper limit but this is clinically unexpected, the test may be repeated once.
4
A left ventricular ejection fraction < 45% measured by echocardiogram during screening, 
between the time of signing informed consent and prior to randomization.
5
A family history of heart failure defined as either of the following:
(a) ≥2 first degree relatives with clinically significant heart failure, or
(b) ≥1 first degree relative with heart failure known to be heritable (eg, hypertrophic 
cardiomyopathy), unless inheritance is excluded by genetic testing.
Criteria to be Assessed at Screening Visit 1, Visit 2, and Visit 3 (Day 1) Prior to 
Randomization:
6
Concurrent enrollment in another clinical study involving an investigational product.
7
Participated in a clinical study for a medical device within 3 months, prior to screening at 
Visit 1.
8
Subject is a participating investigator, sub-investigator, study coordinator, or employee of 
the participating site, or is a first-degree relative of the aforementioned.
9
Subject has been committed to an institution by virtue of an order issued either by the 
courts or by a public authority.
10 Any active medical or psychiatric condition, or other reason, prior to randomization, that, 
in the opinion of the investigator, would interfere with evaluation of the investigational 
product or interpretation of subject safety or study results. This includes but is not limited 
to:
(a) Diabetes mellitus, except for subjects with type 2 diabetes mellitus of ≤2 years’ 
duration who are well controlled (ie, hemoglobin A1c [HbA1c] < 8%) and are not 
using insulin.
(b) History of heart failure.
(c) Clinically significant or unstable ischemic heart disease, arrhythmia, or 
cardiomyopathy, including acute coronary syndrome within the last 6 months; or any 
history of myocardial infarction.
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(e) Systemic hypertension, unless ≤2 years’ duration and well controlled using a single 
medication.
(f) Pulmonary arterial hypertension.
(g) History of an underlying condition that predisposes the subject to infections (eg, 
history of splenectomy, known primary or secondary immune deficiency syndromes).
(h) History of ulcerative colitis, Crohn’s disease, or microscopic colitis diagnosed by 
either a gastroenterologist or by histopathology.
(i)
Obstructive sleep apnea.
(j)
History of treatment with cardiotoxic medications (eg, as part of cancer therapy) 
including thiazolidinediones.
(k) Significant risk factors for COVID-19, such that study participation is not in the best 
interests of the subject in the opinion of the investigator.
(l)
Known or clinically suspected COVID-19 infection within 3 months of 
randomization.
11 Any other clinically relevant abnormal findings from physical examination (including 
vital signs and electrocardiogram [ECG]) or from safety laboratory analysis (including 
hematology, coagulation, serum chemistry, or urinalysis) between informed consent and 
randomization, that in the opinion of the investigator or medical monitor might 
compromise the safety of the subject in the study or interfere with evaluation of the 
investigational product. Abnormal findings include, but are not limited to:
(a) Abnormal vital signs, after 10 minutes of supine rest (confirmed by 1 controlled 
measurement), defined as any of the following:
(i)
Systolic blood pressure (SBP) < 80 mmHg or ≥130 mmHg.
(ii) Diastolic blood pressure (DBP) < 50 mmHg or ≥90 mmHg.
(iii) Pulse < 45 or > 100 beats per minute.
(b) Signs of pulmonary edema or volume overload.
(c) Any clinically significant rhythm, conduction, or morphology abnormalities in the 
12-lead ECG including but not limited to QTc (Fridericia) (Vandenberk et al, 2016)
> 450 ms.
(d) Alanine transaminase (ALT) or aspartate transaminase (AST) > 2 × upper limit of 
normal (ULN).
(e) Total bilirubin (TBL) > 1.5 × ULN (unless due to Gilbert’s disease).
(f) Evidence of chronic liver disease.
12 A known history of severe reaction to any medication including biologic agents or human 
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13 Active dermatologic conditions that might confound the diagnosis of AD or would 
interfere with the assessment of the skin, for example scabies, seborrheic dermatitis, 
cutaneous lymphoma, or psoriasis.
14 Known active allergic or irritant contact dermatitis.
15 Known history of allergy or reaction to any component of the investigational product 
formulation, including hereditary fructose intolerance.
16 Pregnancy or intention to become pregnant during the course of the study, breastfeeding, 
or unwillingness to use a highly effective method of contraception throughout the study in 
female subjects of childbearing potential.
17 History of, or a reason to believe a subject has a history of, drug or alcohol abuse within 
the past 2 years prior to screening.
18 Major surgery within 8 weeks prior to screening at Visit 1, or planned inpatient surgery or 
hospitalization during the TCS/TCI wash out, treatment, or follow-up periods.
19 Donation of blood or blood products in excess of 500 mL within 3 months prior to 
screening Visit 1.
20 Current diagnosis of cancer.
21 History of cancer, except if treated with apparent success with curative therapy (response 
duration of > 5 years).
22 History of allogeneic bone marrow transplant.
23 History of herpes zoster within 3 months prior to randomization at Visit 3 (Day 1).
24 A helminth parasitic infection diagnosed within 6 months prior to randomization at 
Visit 3 (Day 1) that has not been treated, or has not responded to standard of care therapy.
25 Receiving any prohibited concomitant medications or therapies as specified in the 
protocol (Section 4.7.3), as follows:
(a) Identified any time from Visit 1 through to randomization Visit 3 (Day 1):
(i)
Systemic (oral or injectable) corticosteroids within 4 weeks of Visit 1.
(ii) Live or attenuated vaccines within 4 weeks of Visit 1. (Note: Vaccines with 
adenoviral vectors that are unable to replicate, eg, ChAdOx1, are not considered 
live attenuated).
(iii) Ig or blood products within 4 weeks of Visit 1.
(iv) If subjects are on a stable dose of moisturizers containing additives such as 
ceramide, hyaluronic acid, urea, or filaggrin degradation products commenced at 
least 4 weeks prior to Visit 1, this may continue otherwise initiation of such 
products during the study is prohibited.
(b) Identified at randomization Visit 3 (Day 1):
(i)
TCSs or TCIs; or any other topical anti-inflammatory treatment for AD (eg. 
Crisaborole) within 7 days of randomization.


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(ii) Any other immunosuppressive therapy within 3 months of randomization.
(iii) Any immunotherapy within 3 months of randomization, except for stable 
maintenance dose allergen-specific immunotherapy started, at least, 4 weeks 
prior to Visit 1 and expected to continue through to the end of the follow-up 
period.
(iv) Interferon gamma within 3 months of randomization.
(v) Investigational products within 4 months or 5 half-lives of randomization, 
whichever is longer.
(vi) Marketed biologics including dupilumab within 4 months or 5 half-lives of 
randomization, whichever is longer.
(vii)Use of tanning beds or phototherapy including NBUVB, UVB, UVA1, or PUVA 
within 4 weeks prior to randomization.
(viii)
Use of > 2 bleach baths per week within 4 weeks prior to randomization.
(ix) Vaccination against COVID-19 (either first or subsequent dose) within 30 days 
prior to randomization.
Criteria to be Assessed at Visit 3 (Day 1) Prior to Randomization:
26 History of a clinically significant non-skin infection within 4 weeks prior to Visit 3 
(Day 1; including unexplained diarrhea) or clinical suspicion of a non-skin infection at the 
time of dosing of investigational product. A clinically significant infection is defined as:
(a) A systemic infection, or
(b) An infection requiring treatment with a broad-spectrum antibiotic.
27 History of a skin infection that requires systemic antibiotics, antiviral medication, or 
antifungal medication for > 7 days within 4 weeks prior to Visit 3 (Day 1) or clinical 
suspicion of a skin-infection at time of dosing of investigational product.
4.1.4
Subject Enrollment and Randomization
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (ie, an interactive voice/web response system [IXRS]) and the 
screening evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The 
SID number will be used to identify the subject during the screening process and throughout 
study participation. At Visit 3 (Day 1), once a subject has been fully assessed as meeting the 
eligibility criteria, the central IXRS system will be used to randomize the subject 
(Section 4.6.1).
A log of all consented subjects will be maintained at the site and will document all screening 
failures (ie, subjects who are consented but do not meet study eligibility criteria and/or are not 
randomized), including the reason(s) for screening failure. Rescreening of subjects who fail to 


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meet the eligibility criteria is generally only permitted once, when there is a reasonable 
expectation that the subject will become eligible for the study. Permission to rescreen > 1 time 
may be granted by the medical monitor in the presence of extenuating circumstances. Prior to 
rescreening, subjects must be reconsented and receive a new SID number.
If acceptable documentation of previous inadequate response cannot be obtained, a subject 
may, at the investigator’s discretion, be prescribed a course of medium or high potency TCSs 
(Appendix G), in the presence or absence of TCIs, and be rescreened if the subject’s response 
is documented as inadequate.
4.1.5
Withdrawal from the Study
Subjects are free to withdraw their consent to participate in the study (investigational product 
and assessments) at any time, without prejudice to further treatment. Subjects who withdraw 
consent will be asked about the reason(s) and the presence of any AEs. If the subject is 
willing, the subject will be seen and assessed by the investigator. AEs will be followed up; the 
eDiary should be returned by the subject. If a subject withdraws from further participation in 
the study, then no further study visits or data collection should take place.
4.1.6
Discontinuation of Investigational Product
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question:
1
Withdrawal of consent to further treatment with investigational product.
2
Lost to follow-up.
3
Any anaphylactic reaction to investigational product requiring epinephrine administration.
4
Any TESAE that is considered related to investigational product by the investigator.
5
Any TESAE that is in the Cardiac Disorders system organ class, regardless of whether or 
not the event is considered related to investigational product by the investigator.
6
Confirmed diagnosis of new onset of heart failure during the study, regardless of severity 
or whether or not the event is considered related to investigational product by the 
investigator. For a subject with suspected new onset of heart failure, the subject should 
not be administered investigational product unless and until the diagnosis is refuted.
7
Any other AE that, in the opinion of the investigator or the sponsor, warrants 
discontinuation of further dosing of investigational product.
8
Pregnancy.
9
Following randomization, the subject meets ≥ 1 of the exclusion criteria (Section 4.1.3) or 
fails to meet all of the inclusion criteria (Section 4.1.2) for study participation.
10 Receipt of prohibited medications (as defined in Section 4.7.3) except for:
(a) TCS and TCI as rescue therapy (as defined in Section 4.7.4).


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(b) Where the principal investigator and the medical monitor agree that nature, duration, 
etc of the receipt of prohibited medication does not justify discontinuation and the 
subject may continue receiving investigational product. 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for protocol-specified assessments including follow-up of any AEs unless consent is 
withdrawn from further study participation, the subject is lost to follow-up, or the subject is 
enrolled in another clinical study.
4.1.7
Replacement of Subjects
Randomized subjects will not be replaced.
4.1.8
Withdrawal of Informed Consent for Biological Sample Retention and 
Analyses
AstraZeneca ensures that biological samples will be destroyed at the end of a specified period 
as described in the informed consent.
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, 
AstraZeneca is not obliged to destroy the results of this research.
Collection of the non-optional biological samples is an integral part of the study; therefore, if 
a subject withdraws consent to the use of the samples the subject is withdrawn from further 
study participation.
The principal investigator:
∀
Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca. AstraZeneca will ensure the organization(s) holding 
the samples is/are informed about the withdrawn consent immediately and that samples 
are disposed of/destroyed, the action documented, and the signed document returned to 
the study site.
∀
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action is documented and that the 
subject and AstraZeneca are informed about the sample disposal.
4.2
Schedule of Study Procedures
Disease severity assessments including EASI, IGA, and SCORing Atopic Dermatitis 
(SCORAD) should be performed by the same investigator for each subject, whenever 
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Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, the blood draws should occur last. The timing of the first 2 assessments should be such 
that it allows the blood draw (eg, PK blood sample) to occur at the proper nominal time.
4.2.1
Screening and TCS/TCI Wash Out Period
Table 6 shows all procedures to be conducted at the screening and TCS/TCI wash out visits.
Table 6
Schedule of Screening and TCS/TCI Wash Out Procedures
Study Period
Screening
TCS/TCI Wash Out
Visit Number
Visit 1
Visit 2
Procedure/Study Day
Day -28 to -12 a
Day -11 to -8 a
Study Week
Week -4 to -2
Week -1
Written informed consent/assignment of SID number
X
Written informed consent for future use and/or DNA 
analysis (optional)
X
Verify eligibility criteria
X
X
Efficacy assessments:
EASI including % BSA affected by AD, and IGA
X
X
DLQI, 5-D itch, PGI-S, and POEM
X
SNOT-22 and ACQ-6 b
X
eDiary
Daily for 
≥7 consecutive days 
immediately before 
baseline (Visit 3)
Preparation for future efficacy assessments:
Select area of non-lesional skin for SCORAD 
assessments in treatment and follow-up periods
X
Provision of and training on use of eDiary for daily 
recording of peak pruritus NRS, skin pain NRS, and 
moisturizer use
X
Assess adherence to the completion of daily eDiary 
entries for peak pruritus NRS, skin pain NRS, and 
moisturizer use
X
Safety assessments:
Assessment of AEs/SAEs
X
X
Concomitant medications
X
X
Physical examination (full)
X
Weight and height
X


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Table 6
Schedule of Screening and TCS/TCI Wash Out Procedures
Study Period
Screening
TCS/TCI Wash Out
Visit Number
Visit 1
Visit 2
Procedure/Study Day
Day -28 to -12 a
Day -11 to -8 a
Study Week
Week -4 to -2
Week -1
Demography; medical and dermatology history
X
12-lead ECG
X
Vital signs
X
Echocardiogram
X e
Urine collection for:
Urinalysis
X
Blood collection for:
Serum chemistry
X
Hematology
X
HbA1c
X
NT-proBNP c
X
IgE (serum)
X
EDN (plasma)
X
Serum pregnancy test (all female subjects)
X
FSH (if needed to confirm post-menopausal status in 
female subjects aged < 50 years)
X
Hepatitis B (HbsAg, anti-HBs, anti-HBc) and C 
antibodies; HIV-1 and HIV-2 antibodies
X
IGRA (TB test) d
X
Coagulation
X
Discontinue use of TCSs/TCIs
X
Application of stable dose of topical emollient 
(moisturizer)
Twice daily for 
≥7 consecutive days 
immediately before 
baseline (Visit 3) f


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Table 6
Schedule of Screening and TCS/TCI Wash Out Procedures
Study Period
Screening
TCS/TCI Wash Out
Visit Number
Visit 1
Visit 2
Procedure/Study Day
Day -28 to -12 a
Day -11 to -8 a
Study Week
Week -4 to -2
Week -1
AD = atopic dermatitis; ACQ = Asthma Control Questionnaire; AE = adverse event; anti-HBc = hepatitis B 
core antibody; anti-HBs = hepatitis B surface antibody; BSA = body surface area; DLQI = Dermatology Life 
Quality Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; EDN = eosinophil 
derived neurotoxin; eDiary = electronic diary; FSH = follicle-stimulating hormone; HbA1c = hemoglobin 
A1c; HbsAg = hepatitis B surface antigen; Ig = immunoglobulin; IGA = Investigator’s Global Assessment; 
IGRA = interferon gamma release assay; NRS = Numerical Rating Scale; NT-proBNP = N-terminal 
prohormone of B-type natriuretic peptide; PGI-S = Patient Global Impression of Severity; 
POEM = Patient-Oriented Eczema Measure; SAE = serious adverse event; SCORAD = SCORing Atopic 
Dermatitis; SID = subject identification; SNOT = Sino-nasal Outcome Test; TB = tuberculosis; TCI = topical 
calcineurin inhibitor; TCS = topical corticosteroid.
a
Visit 2 must occur a minimum of 7 days prior to randomization. If inclusion criterion 13 is (or will) not 
be met at or on Visit 3 then (if considered appropriate by the investigator and may lead to the criterion 
being met) Visit 3 may be delayed so as occur up to 14 days after Visit 2 ie, retrospectively Visits 1 and 
2 may be as early as Days -31 and -14 respectively.
b
SNOT-22 and ACQ-6 will be administered to a subset of subjects as described in Sections 4.3.1.11 and 
4.3.1.12, respectively.
c
If the NT-proBNP result is greater than the upper limit but this is clinically unexpected the test may be 
repeated once.
d
See exclusion criterion 2.
e
Echocardiogram may be performed at any time after informed consent is signed. Echocardiogram results 
must be available prior to randomization at Visit 3 (Day 1).
f
Minimum of 85% compliance.
4.2.2
Randomized Treatment Period
Table 7 shows all procedures to be conducted during the treatment period. 


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Table 7
Schedule of Treatment Period Study Procedures
Study Period
Treatment Period
Visit Number
Visit 3 a
Visit 4a b
TC
Visit 4b b
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
 
 
 
 
 
Efficacy assessments:
EASI including % BSA affected by 
AD, IGA, and SCORAD a
X c
X
X
X
X
X
X
DLQI, 5-D itch, PGI-S, and POEM
X
X
X
X
X
X
SNOT-22 and ACQ-6 d
X
X
X
X
X
eDiary
Daily throughout treatment period
Assess adherence to the completion 
of daily eDiary entries for peak 
pruritus NRS, skin pain NRS, and 
moisturizer use
X
X
X
X
X
X
X
X
X
Safety assessments:
Assessment of TEAEs/TESAEs
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
Physical examination (abbreviated)
X e
X
X
X
X e
Weight
X
12-lead ECG f
X
X
X
X
X
X
Vital signs g
X
X
X
X
X
X
X
Echocardiogram
X h
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Table 7
Schedule of Treatment Period Study Procedures
Study Period
Treatment Period
Visit Number
Visit 3 a
Visit 4a b
TC
Visit 4b b
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
 
 
 
 
 
NT-proBNP and echocardiogram
As required, for subjects who might be experiencing heart failure, or as soon as possible after heart 
failure might have occurred
Verify eligibility criteria
X
Randomization
X c
Urine collection for:
Urinalysis
X
X
X
X
X
X
Pregnancy test (all female subjects)
X
X
X
X
X
Blood collection for:
Serum chemistry i
X
X
X
X
X
X
X
Hematology i
X
X
X
X
X
X
X
NT-proBNP i
X
X
X
PK (serum) i
X
X
X
X
X
X
X
X
sST2 and 
 
 
ADA (serum) i
X
X
X
X
X
IgE (serum) i
X
X
X
X
EDN (plasma) i
X
X
X
IL-33 (serum) i
X
X
X
X
X
CCI
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C
C


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Table 7
Schedule of Treatment Period Study Procedures
Study Period
Treatment Period
Visit Number
Visit 3 a
Visit 4a b
TC
Visit 4b b
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
 
 
 
 
 
Additional exploratory biomarkers 
(serum) i
X
X
X
X
X
X
X
 
 
 
RNA PAXgene for quantifying 
proinflammatory gene signatures 
(whole blood) i
X
X
DNA analysis (optional) j
X
PBMCs (CPT tube) i
X
X
Lesional and non-lesional skin swabs for 
Staphylococcus aureus i
X
X
Skin punch biopsies k
X
X
Adhesive skin tape patches
X
X
Application of stable dose of topical 
emollient (moisturizer)
Twice daily throughout treatment period
 
 
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Table 7
Schedule of Treatment Period Study Procedures
Study Period
Treatment Period
Visit Number
Visit 3 a
Visit 4a b
TC
Visit 4b b
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
 
 
 
 
 
ACQ = Asthma Control Questionnaire; AD = atopic dermatitis; ADA = anti-drug antibody(ies); BSA = body surface area; CPT = Cell Preparation Tubes; 
DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; eDiary = electronic diary; EDN = eosinophil 
derived neurotoxin; Ig = immunoglobulin; IGA = Investigator’s Global Assessment; IL = interleukin; NRS = Numerical Rating Scale; NT-
proBNP = N-terminal prohormone of B-type natriuretic peptide; PBMC = peripheral blood mononuclear cell; PGI-S = Patient Global Impression of Severity; 
POEM = Patient-Oriented Eczema Measure; PK = pharmacokinetic(s); SC = subcutaneous; SCORAD = SCORing Atopic Dermatitis; SNOT = Sino-nasal 
Outcome Test; sST2 = soluble ST2; TC = telephone contact; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event.
a
Specifications for moisturizer use prior to visits when SCORAD will be assessed are described in Section 4.3.1.3.
b
Visit 4a only applies to the first 72 subjects randomized, subsequent subjects will attend Visit 4b instead, as described in Section 3.1.1.
c
Subjects must be assessed on IGA, EASI, and SCORAD rating scales prior to randomization to ensure the subjects still qualify for the study.
d
SNOT-22 and ACQ-6 will be administered to a subset of subjects only as described in Sections 4.3.1.11 and 4.3.1.12, respectively.
e
At the visits specified, the physical examination will include an alopecia areata assessment as described in Section 4.3.2.2.
f
Detailed procedures including the frequency and timing of ECGs by visit are described in Section 4.3.2.4.
g
Detailed procedures and the timing of vital signs are described in Section 4.3.2.3.
h
Echocardiogram may be performed at any time at or between Visit 9 (Week 12) and Visit 10 (Week 16) inclusive.
i
Prior to administration of investigational product on days when investigational product is administered.
j
Blood samples will be collected on Day 1 or on any other day during the treatment period.
k
Skin punch biopsies will be collected from a subset of subjects as described in Section 4.3.7.3.
l
If a suspected anaphylactic reaction occurs during or within a 24-hour period after administration of investigational product, blood samples for serum 
tryptase will be collected as soon as possible after the event, at 60 ± 30 minutes after the event, at discharge, and between 2 and 4 weeks post-discharge. 
Immediate care of the subject and treatment of the reaction must take priority over collecting blood samples. Additional details on anaphylactic reactions 
are provided in Appendix C and Appendix D.
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4.2.3
Follow-up Period
Table 8 shows all procedures to be conducted during the follow-up period.
Table 8
Schedule of Follow-up Procedures
Study Period
Follow-up
Visit Number
Visit 11
Visit 12
Unscheduled/ 
Early 
Discontinuation 
Visit
Efficacy assessments:
EASI including % BSA affected by AD, 
IGA, and SCORAD a
X
X
X
DLQI, 5-D itch, PGI-S, and POEM
X
X
X
SNOT-22 and ACQ-6 b
X
X
eDiary
Daily throughout follow-up period
Assess adherence to the completion of 
daily eDiary entries for peak pruritus 
NRS, skin pain NRS, and moisturizer use
X
X
X
Safety assessments:
Assessment of TEAEs/TESAEs
X
X
X
Concomitant medications
X
X
X
Physical examination (abbreviated)
X
X
12-lead ECG
X
X
Vital signs
X
X
NT-proBNP and echocardiogram
As required, for subjects who might be experiencing heart 
failure, or as soon as possible after heart failure might have 
occurred
Urine collection for:
Urinalysis
X
X
X
Pregnancy test (all female subjects)
X
X
X
Blood collection for:
Serum chemistry
X
X
X
Hematology
X
X
X
NT-proBNP
X
X
PK (serum)
X
X
X
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Table 8
Schedule of Follow-up Procedures
Study Period
Follow-up
Visit Number
Visit 11
Visit 12
Unscheduled/ 
Early 
Discontinuation 
Visit
sST2 and 
ADA (serum)
X
X
RNA PAXgene for quantifying 
proinflammatory gene signatures (whole 
blood)
IgE (serum)
X
EDN (plasma)
X
IL-33 (serum)
X
X
Additional exploratory biomarkers 
(serum)
X
X
Lesional and non-lesional skin swabs for 
Staphylococcus aureus
Application of stable dose of topical emollient 
(moisturizer)
Twice daily throughout follow-up period
Assessment of SC injection sites
X
ACQ = Asthma Control Questionnaire; AD = atopic dermatitis; ADA = anti-drug antibody(ies); BSA = body 
surface area; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; 
ECG = electrocardiogram; eDiary = electronic diary; EDN = eosinophil derived neurotoxin; 
Ig = immunoglobulin; IGA = Investigator’s Global Assessment; IL = interleukin; NRS = Numerical Rating 
Scale; NT-proBNP = N-terminal prohormone of B-type natriuretic peptide; PGI-S = Patient Global Impression 
of Severity; POEM = Patient-Oriented Eczema Measure; PK = pharmacokinetic(s); SC = subcutaneous; 
SCORAD = SCORing Atopic Dermatitis; SNOT = Sino-nasal Outcome Test; sST2 = soluble ST2; 
TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event.
a
Specifications for moisturizer use prior to visits when SCORAD will be assessed are described in 
Section 4.3.1.3.
b
SNOT-22 and ACQ-6 will be administered to a subset of subjects only as described in Sections 4.3.1.11
and 4.3.1.12, respectively.
4.3
Description of Study Procedures
4.3.1
Efficacy
4.3.1.1
EASI Including Percentage BSA Affected by AD
The EASI was designed by modifying the Psoriasis Area and Severity Index, which has been 
widely used in clinical studies and has been established as a well-accepted and standardized 
instrument for assessing therapeutic response in patients with psoriasis (Schmitt et al, 2013). 
The EASI is a one-dimensional scoring system, measuring only the clinical signs of AD not 
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including the symptoms. The EASI evaluates 4 anatomic regions for severity and extent of 
key disease signs and focuses on the acute and chronic signs of inflammation (ie, erythema, 
edema, papulation, excoriation, and lichenification). The maximum score is 72, with higher 
values indicating more severe disease.
The EASI including percentage BSA affected by AD will be assessed according to the 
schedule of study procedures (Table 6, Table 7, and Table 8). The EASI will be completed by 
the investigator on an electronic device supplied to the site, which will calculate the domain 
and total scores for the subject. Additional instructions for the investigator are described in 
Section 4.2. The percentage of subjects achieving a 75% reduction from baseline in Eczema 
Area and Severity Index score (EASI 75), 50% reduction from baseline in Eczema Area and 
Severity Index score (EASI 50), and 90% reduction from baseline in Eczema Area and 
Severity Index score (EASI 90) will be calculated from the EASI scores. The percentage BSA 
affected by AD is a component of EASI and will be analyzed separately from the composite 
EASI score.
4.3.1.2
IGA
The IGA allows investigators to assess overall AD disease severity at 1 given time point and 
consists of a 5-point severity scale from clear to very severe disease (0 = clear, 1 = almost 
clear, 2 = mild disease, 3 = moderate disease, and 4 = severe disease; Appendix H). The IGA 
uses clinical characteristics of erythema, infiltration, papulation, oozing, and crusting as 
guidelines for the overall severity assessment.
The IGA will be assessed according to the schedule of study procedures (Table 6, Table 7, and 
Table 8), and will be completed by the investigator on an electronic device supplied to the 
site. Additional instructions for the investigator are described in Section 4.2.
4.3.1.3
SCORAD
SCORAD is a clinical tool for assessing the severity of AD that evaluates the extent and 
intensity of AD lesions, in addition to subjective symptoms (Kunz et al, 1997). The maximum 
total score is 103, with higher values indicating more severe disease.
A suitable area of non-lesional skin will be designated at screening for SCORAD assessments 
of skin dryness at Visit 1. To allow for the assessment of skin dryness, moisturizers should not 
be applied to the designated area for ≥8 hours before visits when SCORAD will be assessed. 
This should be explained to subjects at Visit 1.
SCORAD will be assessed according to the schedule of study procedures (Table 7 and 
Table 8). SCORAD will be completed on an electronic device supplied to the site, which will 
calculate the domain and total scores for the subject. Additional instructions for the 
investigator are described in Section 4.2.


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4.3.1.4
Peak Pruritus NRS
Peak pruritus (ie, worst itch experienced in the previous 24 hours) will be assessed using an 
Numerical Rating Scale (NRS; 0 to 10) with 0 = no itch and 10 = worst imaginable itch 
(Yosipovitch et al, 2019). Subjects will complete the pruritus NRS using an eDiary each 
morning according to the schedule of study procedures (Table 6, Table 7, and Table 8).
4.3.1.5
Skin Pain NRS
Skin pain (ie, worst skin pain experienced in the previous 24 hours) will be assessed using an 
NRS (0 to 10) with 0 = no pain and 10 = worst imaginable pain (Humphrey et al, 2017; 
Vakharia et al, 2017). Subjects will complete the pain NRS using an eDiary each morning 
according to the schedule of study procedures (Table 6, Table 7, and Table 8).
4.3.1.6
Moisturizer Use
Subjects will record their moisturizer use using an eDiary each morning according to the 
schedule of study procedures (Table 6, Table 7, and Table 8). The records of the subjects will 
be used to monitor compliance with daily moisturizer use.
4.3.1.7
5-D Itch
5-D itch is a questionnaire typically completed in < 5 minutes designed to assess itch or 
pruritus, with a recall period of 2 weeks. 5-D itch takes into account the multidimensional 
nature of pruritus and its impact on quality of life, and is capable of detecting changes over 
time (Elman et al, 2010). Subjects will complete the 5-D itch on an electronic device supplied 
to the site according to the schedule of study procedures (Table 6, Table 7, and Table 8).
4.3.1.8
Dermatology Life Quality Index
The Dermatology Life Quality Index (DLQI) is a 10-item, patient-completed, health-related 
quality of life assessment of dermatology conditions with a recall period of 1 week (Finlay 
and Khan, 1994). The DLQI captures perceptions of dermatology-related symptoms and 
feelings; 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 with 0 = not at all ⁄not 
relevant, 1 = a little, 2 = a lot, and 3 = very much (Basra et al, 2008). The DLQI can be 
completed in approximately 5 minutes.
Subjects will complete the DLQI on an electronic device supplied to the site according to the 
schedule of study procedures (Table 6, Table 7, and Table 8).
4.3.1.9
Patient Global Impression of Severity
The Patient Global Impression of Severity (PGI-S) is a tool that allows patients to rate the 
severity of a condition. The PGI-S will comprise a single question of, “Please select the 
response below that best describes the severity of your overall symptoms over the past 7 
days.” with response options of “No symptoms”, “Very mild”, “Mild”, “Moderate”, “Severe” 


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or “Very severe”. Subjects will complete the PGI-S on an electronic device supplied to the site 
according to the schedule of study procedures (Table 6, Table 7, and Table 8).
4.3.1.10
Patient-Oriented Eczema Measure
The Patient-Oriented Eczema Measure (POEM) is a 7-item questionnaire for assessing disease 
symptoms including dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping 
occurring in the past week with a scoring system of 0 (absent disease) to 28 (severe disease) 
(Charman et al, 2004). Subjects will complete POEM on an electronic device supplied to the 
site according to the schedule of study procedures (Table 6, Table 7, and Table 8).
4.3.1.11
SNOT-22
The SNOT-22 is a validated questionnaire for assessing the impact of chronic rhinosinusitis 
on quality of life (Hopkins et al, 2009). The SNOT-22 contains a list of 22 symptoms and 
social/emotional consequences of a patient’s nasal disorder, and measures how severe each 
symptom is and the social/emotional consequences of symptoms over a 2-week period on a 
scale from 0 (no problem) to 5 (problem as bad as it can be). A total score is summed.
The SNOT-22 will be administered to subjects who have comorbid chronic inflammatory 
conditions of the nasal mucosa and/or paranasal sinuses (eg, chronic rhinitis/rhinosinusitis, 
nasal polyps, allergic rhinitis). Subjects will complete the SNOT-22 on an electronic device 
supplied to the site according to the schedule of study procedures (Table 6, Table 7, and 
Table 8).
4.3.1.12
ACQ-6
The ACQ was the first questionnaire developed and validated to measure asthma control 
(Yosipovitch et al, 2019). The ACQ includes 6 questions regarding symptoms at night, in the 
morning, limitation of normal daily activities, dyspnea, wheezing, and beta-2 agonist use. 
Subjects are asked to recall how their asthma has been during the previous week and to 
answer questions using a 7-point scale with 0 = no impairment and 6 = maximum 
impairment). ACQ-6 does not include spirometry and is the equally weighted mean of 
6 questions.
The ACQ-6 will be administered to subjects who have a medical history of comorbid asthma.
Subjects will complete the ACQ-6 on an electronic device supplied to the site according to the 
schedule of study procedures (Table 6, Table 7, and Table 8).
4.3.2
Medical and Dermatology History, Physical Examinations, Weight, 
Height, Vital Signs, ECGs, and Echocardiograms
In addition to the medical and dermatology history, physical examinations, weight, height, 
vital signs, ECG and echocardiogram assessments described below, additional assessments 
may be performed at the investigator’s discretion.


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4.3.2.1
Medical and Dermatology History
Complete medical history will include history of and current medical conditions, past or 
present cardiovascular disorders, respiratory, gastrointestinal, renal, hepatic, neurological, 
endocrine, lymphatic, hematologic, immunologic, psychiatric, genitourinary, drug and 
surgical history, or any other diseases or disorders (including COVID-19 and COVID-19 
vaccination).
The subject’s dermatology history will also be collected including questions related to the 
subject’s dermatology history, duration of AD, and AD medications (both past and current).
Medical and dermatology history will be assessed according to the schedule of study 
procedures (Table 6).
4.3.2.2
Physical Examinations, Weight, and Height
Full and abbreviated physical examinations will be performed by a licensed healthcare 
provider (eg, physician, physician’s assistant, or licensed nurse practitioner). Full physical 
examinations will include, but are not limited to, assessment of general appearance, head, 
ears, eyes, nose, throat, neck, skin, as well as cardiovascular, respiratory, abdominal, and 
nervous systems. Abbreviated physical examinations will include assessment of 
cardiovascular, respiratory, and nervous systems. Each clinically significant abnormal finding 
will be recorded in the medical history, and each treatment-emergent abnormality including 
injection site reactions identified by assessing SC injection sites will be recorded as a TEAE. 
Physical examinations, weight, and height will be performed according to the schedule of 
study procedures (Table 6, Table 7, and Table 8).
In addition, subjects will be assessed for the presence or absence of current alopecia areata at 
Visit 3 (Day 1) and Visit 10 (Day 113; Table 7). In subjects who had current alopecia areata at 
Visit 3 (Day 1), the presence or absence of an improvement in alopecia areata will be recorded 
at Visit 10 (Day 113).
4.3.2.3
Vital Signs
The nominal timing of vital signs, ECGs, and blood draws is described (Section 4.2). The 
subject should be in a resting supine position for at least 10 minutes prior to the collection of 
vital signs, as follows:
∀
Oral or tympanic temperature.
∀
DBP
∀
SBP
∀
Heart (pulse) rate
∀
Respiratory rate.


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For the first 2 doses of investigational product, subjects are to remain at the site for ≥2 hours 
or until stable, whichever is later. In addition, vital signs will be taken before and immediately 
after administration of investigational product, and at 30, 60, and 120 minutes (± 5 minutes) 
thereafter or until stable, whichever is later. For the final 2 doses of investigational product, 
subjects are to remain at the site for ≥1 hour or until stable, whichever is later. In addition, 
vital signs will be taken before and immediately after administration of investigational 
product, and at 30 and 60 minutes (± 5 minutes) thereafter. Following the observation period, 
subject discharge will be at the discretion of the investigator. Vital signs will be recorded at 
visits according to the schedule of study procedures (Table 6, Table 7, and Table 8).
4.3.2.4
ECGs
The nominal timing of vital signs, ECGs, and blood draws is described (Section 4.2). The 
subject should be in a resting supine position for at least 10 minutes prior to the collection of 
ECGs. At baseline, pre-dose of investigational product at Visit 3 (Day 1), triplicate ECGs will 
be performed (all 3 ECGs within a 5-minute time period, at least 1 minute apart). The mean 
value of each parameter from the triplicate will be used as the baseline value. ECGs taken at 
all other times will be single assessments. ECGs will be recorded at visits according to the 
schedule of study procedures (Table 6, Table 7, and Table 8).
ECGs will be recorded with 12-lead digital ECG devices at a speed of 25 mm/second with 
amplitude recording of 10 mm/mV. Where possible the same make and model ECG device 
should be used for recording all ECGs for a particular subject. At least 3 full complexes must 
be recorded. Date and time settings should be checked regularly and following time changes 
for daylight savings time. Skin preparation should be thorough and electrode positions should 
be according to standard 12-lead ECG placements.
ECG device software will be used to assess ECG parameters. All ECGs must be reviewed by 
the principal investigator or a qualified designee before the subject is permitted to leave the 
clinic. Abnormalities and obvious changes in ECG parameters from baseline will be assessed 
by the principal investigator for clinical significance.
ECG variables will be collected, as follows:
∀
Heart (pulse) rate.
∀
RR interval.
∀
QRS interval.
∀
PR interval.
∀
QT interval.


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4.3.2.5
Echocardiograms
A transthoracic echocardiogram to assess left ventricular ejection fraction will be performed 
and read locally according to the schedule of study procedures (Table 6, Table 7, and Table 8).
4.3.3
Clinical Laboratory Tests
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study. Clinical laboratory safety tests will be performed in a 
central clinical laboratory. Urine pregnancy tests may be performed at the site using a licensed 
test (dipstick). Clinically significant abnormal laboratory results should be repeated as soon as 
possible (preferably within 24 to 48 hours).
The following clinical laboratory tests will be performed (see Table 6, Table 7, and Table 8
for the schedule of study procedures):
Serum Chemistry
•
Potassium
•
IgA, IgG, IgM, total Ig
•
Sodium
•
Creatinine
•
AST
•
Blood urea nitrogen
•
ALT
•
Albumin
•
ALP
•
Total protein
•
TBL (if result is > 1.5 ULN, indirect and direct 
bilirubin will be measured)
•
Uric acid
•
GGT
ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; 
GGT = gamma-glutamyl transferase; Ig = immunoglobulin; TBL = total bilirubin; ULN = upper limit of normal.
Note for serum chemistry: Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed 
concurrently.
Hematology
•
WBC count with differential a
•
Platelet count
•
RBC count
•
Hemoglobin
•
Hematocrit
RBC = red blood cell; WBC = white blood cell.
Note for hematology: Blinding procedures for eosinophil, basophil, and monocyte data are described in 
Section 4.6.2.
a
Whole blood samples will be collected concurrently for both hematology and exploratory biomarker 
(Section 4.3.7.1) assessments of eosinophils.
Urinalysis
•
Color
•
Glucose
•
Appearance
•
Ketones
•
Specific gravity
•
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•
pH
•
Bilirubin
•
Protein
•
Leukocytes 
•
Microscopy including WBCs, RBCs, and casts
RBC = red blood cell; WBC = white blood cell.
Pregnancy Test (Female Subjects Only)
∀
Serum beta-human chorionic gonadotropin.
∀
Urine human chorionic gonadotropin.
Other Safety Tests
∀
Follicle-stimulating hormone (if needed to confirm post-menopausal status in female 
subjects aged < 50 years).
∀
HbA1c.
∀
Hepatitis B antibodies (HbsAg, anti-HBs, and anti-HBc) and hepatitis C virus antibody.
∀
HIV-1 and HIV-2 antibodies.
∀
IGRA (TB test). See Exclusion Criterion 2.
∀
Coagulation.
∀
Serum tryptase will only be taken in the event of suspected anaphylaxis (Appendix C and 
Appendix D).
∀
NT-proBNP.
Other Laboratory Tests
∀
Total IgE.
∀
∀
EDN
4.3.4
PK Evaluation and Methods
The nominal timing of vital signs, ECGs, and blood draws is described (Section 4.2). The time 
of the first SC injection will be recorded for each subject as the timings will be required for 
analyzing the PK data. Serum will be collected to evaluate the PK of MEDI3506 according to 
the schedule of study procedures (Table 7 and Table 8). MEDI3506 concentration in serum 
will be measured utilizing a validated assay method.
Instructions for sample collection, processing, storage, and shipment can be found in a 
separate laboratory manual provided to sites.
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4.3.5
Immunogenicity Evaluation and Methods
Blood samples will be collected according to the schedule of study procedures (Table 7 and 
Table 8) to evaluate potential serum ADA responses to MEDI3506. Evaluations will be 
performed using a validated immunoassay. Tiered analyses will be performed to include 
screening, confirmatory, and titer assay components, and the positive-negative cut points will 
be statistically determined from drug-naïve samples. Samples may be utilized for further 
characterization of the ADA response, including possible assessment of neutralizing antibody. 
Serum samples collected for ADA will be stored for 15 years following the issue of Clinical 
Study Report (CSR), and they may be utilized for further characterization of the antibody 
response.
Instructions for sample collection, processing, storage, and shipment can be found in a 
separate laboratory manual provided to the sites.
4.3.6
Genetic Evaluation and Methods
 
 
On Day 1, a sample for DNA analysis will be taken. Participation in additional genetic 
research (ie, DNA analysis) is optional for subjects. The objectives, plan, and procedures for 
optional genetic research are described (Appendix F).
4.3.7
Biomarker Evaluation and Methods
The subject’s consent to the use of donated biological samples is mandatory.
Biological samples (eg, serum) will be collected and may be analyzed for exploratory 
biomarkers to assess correlations with disease activity, effects of investigational product, 
clinical outcomes, and toxicity. The results of this biomarker research will be reported either 
in the CSR itself or as an addendum, or separately in a scientific report or publication. The 
results of this biomarker research may be pooled with biomarker data from other studies with 
the investigational product to generate hypotheses to be tested in future research.
4.3.7.1
Blood Biomarkers
Blood samples for exploratory biomarker analyses will be collected at visits according to the 
schedule of study procedures (Table 7 and Table 8). Whole blood samples will be collected 
concurrently for both hematology (Section 4.3.3) and exploratory biomarker assessments of 
eosinophils. Plasma samples will be collected to evaluate EDN levels. Serum samples will be 
collected for all other exploratory biomarker analyses. A qualified immunoassay method will 
be used to analyze the biomarker samples.
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4.3.7.2
RNA PAXgene
Whole blood for RNA PAXgene will be collected according to the schedule of study 
procedures (Table 7 and Table 8). RNA PAXgene will be used for the collection, transport, 
and storage of whole blood, and the stabilization of intracellular RNA. RNA transcript 
profiling analyses (Section 4.3.7.4) will be performed on RNA PAXgene samples.
4.3.7.3
Skin Punch Biopsies
Following provision of informed consent, skin punch biopsy samples will be collected from a 
subset of subjects according to the schedule of study procedures (Table 7).
Local anesthesia may be used in accordance with local practices. Skin punch biopsy samples 
will be collected from areas of lesional and non-lesional skin that are close in distance 
(≤5 cm) to each other. If possible, a 3 mm skin punch should be used. For the evaluation of 
the proinflammatory gene signature endpoint, RNA transcript profiling (Section 4.3.7.4) 
analyses will be performed on skin punch biopsy samples. For the evaluation of gross 
inflammation, hematoxylin and eosin staining analyses will be performed on skin punch 
biopsy samples. 
At Visit 10, lesional and non-lesional skin biopsy samples should be taken from areas close in 
distance to where the lesional and non-lesional samples, respectively, were taken at Visit 3.
4.3.7.4
RNA Transcript Profiling of RNA PAXgene and Skin Punch Biopsy Samples
Intracellular RNA will be isolated and purified from whole blood RNA PAXgene 
(Section 4.3.7.2) and skin punch biopsy (Section 4.3.7.3) samples. Proinflammatory gene 
signatures will be quantified from the RNA. The expression levels of genes associated with 
disease activity, specific cell types, and signaling, including the IL-33/ST2 pathway will be 
quantified. The analyses will retrospectively evaluate transcript biomarkers predictive of 
subject response at baseline, prior to investigational product administration, as well as 
potentially identify additional biomarkers. In addition, these biomarker measurements will aid 
in the determination of which biological pathways are affected by treatment with MEDI3506.
4.3.7.5
S aureus Colonization
S. aureus has the potential to exacerbate AD skin disease through colonization, 
super-infection of the skin, and production of inflammation-inducing toxins. Skin swabs will 
be collected from subjects to assess S. aureus colonization and infection according to the 
schedule of study procedures (Table 7 and Table 8). Swabs will be rotated across non-lesional 
and lesional skin that are close in distance (≤5 cm) to each other. S. aureus colonization and 
infection will be characterized to determine whether differential benefit is observed among 
subjects in relation to S. aureus abundance, and if S. aureus colonization and infection are 
impacted by MEDI3506 treatment.


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4.3.7.6
Peripheral Blood Mononuclear Cells
Whole blood will be collected to isolate peripheral blood mononuclear cells (PBMCs) 
according to the schedule of study procedures (Table 7). This exploratory biomarker may help 
identify a responder population based on the investigation of immune cell subset ratios at 
baseline and/or after MEDI3506 intervention. 
4.3.7.7
Adhesive skin tape patches
Adhesive skin tape patches will be used to collect skin samples from all subjects for gene 
expression analysis according to the schedule of study procedures (Table 7). The worst target 
lesion and a non-lesional site (≤5 cm from the worst target lesional site) will be selected at 
baseline, both of which must not overlap with the selected sites for skin punch biopsies. Those 
two sites will then be used at both timepoints. This exploratory analysis may help identify a 
responder population based on transcript biomarkers, as well as to potentially identify 
additional pharmacodynamic biomarkers related to responders and non-responders to the 
investigational product.
Information regarding the handling/shipping of specimens will be provided in a separate 
manual.
4.3.8
Storage, Re-use, and Destruction of Biological Samples
Samples will usually be stored for a maximum of 15 years from the date of LSLV, after which 
they will be destroyed. If required, ADA samples might be stored for longer than 15 years 
based on the requirements described (Section 4.3.5).
4.3.9
Estimate of Volume of Blood to Be Collected
The estimated total volume of blood to be collected from each subject at each visit from 
screening through to the end of study will range from 25 to 55 mL. If repeats of any blood 
tests are required, the volume of blood collection will increase accordingly. The total blood 
volume to be collected throughout the study for each subject will not exceed 400 mL.
4.4
Study or Study Component Suspension or Termination
AstraZeneca reserves the right to temporarily suspend or permanently terminate this study or 
component of the study (eg, study site) at any time. The reasons for temporarily suspending or 
permanently terminating the study may include but are not limited to the following: 
1
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects.
2
Subject enrollment is unsatisfactory.
3
Non-compliance that might significantly jeopardize the validity or integrity of the study.
4
Sponsor decision to terminate development of the investigational product for this 
indication.


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If AstraZeneca determines that temporary suspension or permanent termination of the study or 
component of the study is required, AstraZeneca will discuss the reasons for taking such 
action with all participating investigators (or head of the medical institution, where 
applicable). When feasible, AstraZeneca will provide advance notice to all participating 
investigators (or head of the medical institution, where applicable) of the impending action.
If the study or component of the study is suspended or terminated for safety reasons, 
AstraZeneca will promptly inform all investigators, heads of the medical institutions (where 
applicable), and/or institutions conducting the study. AstraZeneca will also promptly inform 
the relevant regulatory authorities of the suspension/termination along with the reasons for 
such action. Where required by applicable regulations, the investigator or head of the medical 
institution must inform the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) promptly and provide the reason(s) for the suspension/termination. If the study or 
component of the study is suspended for safety reasons and it is deemed appropriate by 
AstraZeneca to resume the study or component of the study, approval from the relevant 
regulatory authorities (and IRBs/IECs when applicable) will be obtained prior to resuming the 
study.
4.5
Investigational Products
4.5.1
Identity of Investigational Products
AstraZeneca will provide the investigators with investigational product (MEDI3506 or 
placebo; Table 9) using designated distribution centers.
Table 9
Identification of Investigational Products
Investigational Product
Manufacturer
Concentration and Formulation as 
Supplied
MEDI3506
AstraZeneca
2R vial with nominal 1 mL of 150 mg/mL 
MEDI3506 containing 20 mM L-histidine / 
L-histidine-hydrochloride, 220 mM 
L-arginine-hydrochloride, 0.03% (w/v) 
polysorbate 80, pH 5.5.
Placebo
AstraZeneca
3-cc vial with nominal 1 mL solution of 
20 mM L-histidine / L-histidine-
hydrochloride, 240 mM sucrose, 0.02% (w/v) 
polysorbate 80, pH 6.0
w/v = weight/volume.
Both MEDI3506 and placebo will be packaged into single vial kits with a unique number that 
is printed on all labels within the kit (ie, the outer carton label and the label of the vial within 
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4.5.1.1
Investigational Product Handling
The MEDI3506 doses will be prepared by the site’s designated unblinded investigational 
product manager using aseptic technique. MEDI3506 does not contain preservatives and 
therefore, any unused portion will be discarded.
The unblinded investigational product manager will select the appropriate kits allocated by the 
IXRS to prepare the subject’s dose. The unblinded investigational product manager must 
ensure that only the unblinded team members have access to the areas of the pharmacy where 
the investigational product is being stored and prepared.
4.5.1.2
Investigational Product Inspection
Each vial allocated for dose preparation should be inspected. MEDI3506 is supplied as a clear 
to opalescent sterile liquid in a 2R glass vial at a concentration of 150 mg/mL. Placebo is 
supplied as a clear to opalescent sterile liquid in a 3cc glass vial.
If there are any defects noted with the investigational product, the investigator and site 
monitor should be notified immediately. Refer to the Product Complaint section 
(Section 4.5.1.6) for further instructions.
4.5.1.3
Dose Preparation Steps
No incompatibilities between MEDI3506 and plastics passing compatibility tests (ie, 
polypropylene and polycarbonate syringes) have been observed.
MEDI3506 and placebo do not contain preservatives and any unused portion must be 
discarded. Preparation of investigational product is to be performed aseptically. Total in-use 
storage time from needle puncture of the investigational product vial to start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C (36°F to 46°F). If 
storage time exceeds these limits, a new dose must be prepared from new vials assigned by the 
IXRS.
Preparation of SC Doses
A vial should be used only 1 time to prepare a single dose.
To prepare the subject’s dose, the unblinded investigational product manager will select 
investigational product for administration according to the kit identification numbers assigned 
by the IXRS. A summary of the investigational product volumes required and syringes to 
prepare for SC dose administration in each treatment group is provided (Table 10).


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Table 10
Investigational Product Dose Preparation
 
 
 
 
 
 
 
 
 
a
Do not mix MEDI3506 and placebo in the same syringe.
The dose preparation steps are, as follows:
1
Prepare the IXRS assigned MEDI3506 and/or placebo vials for the particular treatment 
group as per Table 10.
2
Withdraw the required volume of MEDI3506 or placebo from each vial using a separate, 
appropriately sized syringe and a separate 18-20-gauge 1-1.5 inch needle.
3
Remove the 18-20-gauge needle. Replace with a capped 27-gauge 0.5 inch needle until 
administration.
4.5.1.4
Treatment Administration
Female subjects, regardless of childbearing potential, must have a negative urine pregnancy 
test prior to receiving each dose of investigational product.
MEDI3506 and placebo are not identical in appearance or viscosity. The syringes should be 
kept out of sight of all blinded persons, including the subject, to maintain the blind.
Investigational product will be administered SC by unblinded site personnel via a 27-gauge 
0.5-inch needle to the abdomen, back of the arms, or thigh. For multiple injections at the same 
visit, there should be an approximately 1-inch (2.5 cm) distance between injection sites in the 
same anatomical region. The unblinded site personnel administering the dose will wipe the 
skin surface of the administration sites with alcohol and allow the skin surface to air dry. The 
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skin will be pinched to isolate the SC tissue from the muscle. The needle will be fully inserted 
at a 45-degree angle into the SC tissue. The investigational product will be slowly injected (at 
least 5 seconds’ duration is recommended). The area should not be massaged after injection.
It is advised that the site of injection be rotated so that the subject receives investigational 
product injections in different anatomical regions from one visit to the next. In cases when 
rotation of the injection site is not feasible and/or the subject prefers not to rotate injection 
sites, the reason for not rotating the injection site should be documented in the source 
documents.
Each injection site must be documented on the electronic case report form (eCRF) and in the 
source documents at each treatment visit.
4.5.1.5
Monitoring Dose Administration
Post dose of investigational product, vital signs will be periodically assessed (Section 4.3.2.3), 
and SC injection sites will be assessed for injection site reactions (Section 4.3.2.2).
As with any biologic product, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat anaphylaxis 
(Appendix C and Appendix D).
4.5.1.6
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the sponsor 
Product Complaint Department by the site with further notification to the site monitor. All 
defects will be communicated to the sponsor and investigated further with the Product 
Complaint Department. During the investigation of the product complaint, all investigational 
product must be stored at labeled conditions unless otherwise instructed.
Sponsor contact information for reporting product complaints:
Email: productcomplaints@medimmune.com
Phone:+1-301-398-2105
Mail: MedImmune
Attn: Product Complaint Department
One MedImmune Way,
Gaithersburg, MD USA 20878


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4.5.2
Labeling
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice and local regulatory guidelines. Label text will be translated into local 
languages, as required.
4.5.3
Storage
Store investigational product at 2°C to 8°C (36°F to 46°F).
4.5.4
Treatment Compliance
Investigational product is administered by unblinded study site personnel, who will monitor 
compliance.
4.5.5
Accountability
The site’s designated unblinded investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies 
of investigational product accountability records will be returned to AstraZeneca. All unused 
investigational product will be disposed of following site procedures and upon authorization 
by AstraZeneca, or will be returned to an AstraZeneca-authorized depot if a site is unable to 
dispose of unused investigational product.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An IXRS will be used for randomization to a treatment group and assignment of blinded 
investigational product kit numbers. A subject is considered randomized into the study when 
the investigator notifies the IXRS that the subject meets eligibility criteria and the IXRS 
provides the assignment of blinded investigational product kit numbers for the subject.
The first 72 subjects in the study will be randomized using a 3:3:3:1:2 ratio to receive 
 
MEDI3506 SC; or placebo 
 SC, or placebo 
 SC. The remaining 
subjects will be randomized using a 1:1 ratio to receive 600 mg MEDI3506 SC or placebo 
4 mL SC. Randomization may be paused briefly to enable this change. The version of the 
Informed Consent Form (ICF) used will be dependent on the randomization ratio in operation 
at the time (Section 7.3).
The randomization will be stratified based on total IgE (< 150 kU/L or ≥150 kU/L) at 
screening. 
The procedure for using the IXRS is, as follows:
∀
The investigator or designee contacts the IXRS and provides the SID number and the 
subject’s baseline characteristic(s) used to verify that it is the same subject.
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∀
The correct amount of kits of MEDI3506 and/or placebo will be assigned to the subject.
∀
Confirmation of this information is sent to the unblinded investigational product manager 
who prepares the investigational product to be dispensed to the subject per the response 
system and records the appropriate information in the investigational product 
accountability log.
∀
Blinded study personnel will receive a notification containing a dose tracking number, 
that will not disclose how many kits are assigned to the subject.
Investigational product (MEDI3506 or placebo) must be administered the same day the 
investigational product is assigned. If there is a delay in the administration of investigational 
product such that it will not be administered within the specified timeframe, the site monitor 
must be notified immediately.
4.6.2
Methods to Ensure Blinding
This is a double-blinded study in which MEDI3506 and placebo are not identical in 
appearance or viscosity. Neither the subject nor any of the investigator or sponsor staff who 
are involved in the treatment or clinical evaluation of the subjects will be aware of the 
treatment received (ICH E9; see Section 4.6.3.3 for unblinding related to planned analyses). 
Since MEDI3506 and placebo are not identical, investigational product will be handled by an 
unblinded investigational product manager at the site and will be administered by an 
unblinded study team member who will not be involved in the management of study subjects. 
An independent investigational product monitor will also be unblinded to perform 
investigational product accountability. In the event that the treatment allocation for a subject 
becomes known to the investigator or other study staff involved in the management of study 
subjects, AstraZeneca must be notified immediately. If the treatment allocation for a subject 
needs to be known to treat an individual subject for an AE (Section 4.6.3.1), the investigator 
must notify AstraZeneca immediately. The site will maintain a written plan detailing which 
staff members are blinded/unblinded and the process of investigational product preparation 
and administration used to maintain the blind.
MEDI3506 could reduce eosinophil counts in blood over time. As a precaution, eosinophil, 
basophil, and monocyte data from the hematology laboratory tests (Section 4.3.3) will not be 
communicated to blinded sponsor or site personnel during the treatment and follow-up 
periods.
To facilitate the in-stream analysis of PK and ADA samples, the randomization schedule may 
be provided to limited personnel who have responsibility for analysing the samples. These 
unblinded sample analysts will not have any other involvement with the conduct of the study.


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4.6.3
Methods for Unblinding
4.6.3.1
Unblinding in the Event of a Medical Emergency
In the event of a medical emergency, the investigator may unblind an individual subject’s 
investigational product allocation. Instructions for unblinding an individual subject’s 
investigational product allocation are contained in the IXRS manual. In general, unblinding 
should only occur if management of the medical emergency would be different based on the 
subject having received MEDI3506. In the majority of cases, the management of a medical 
emergency would be the same whether or not investigational product was received by the 
subject. If this were the case, the investigational product allocation should not be unblinded. In 
the event there is unblinding, the investigator should promptly document and explain to 
AstraZeneca the reason for any premature unblinding.
AstraZeneca retains the right to unblind the treatment allocation for serious adverse events 
(SAEs) that are unexpected and are suspected to be causally related to an investigational 
product and that potentially require expedited reporting to regulatory authorities.
4.6.3.2
Unblinding for DSMB Purposes
If unblinding is required by the DSMB (Section 3.1.3), details of the methods for unblinding 
(sponsor will remain blinded) will be provided in a separate DSMB charter.
4.6.3.3
Unblinding for Primary Analysis Purposes
The primary analysis (Section 4.8.7) will be performed after all subjects have completed 
Visit 10 (Week 16) or have withdrawn from the study. The sponsor staff will be unblinded 
following database lock for the primary analysis. Investigators and site staff will not be made 
aware of unblinded treatment assignments for individual subjects who are in the follow-up 
period until these subjects have completed the study.
4.7
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the final study visit. Any concomitant medication(s), including herbal 
preparations, taken during the study will be recorded in the eCRF.
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for prohibited medications and therapies 
(Section 4.7.3). Specifically, subjects should receive full supportive care during the study, 
including treatment with antibiotics, anti-emetics, anti-diarrheals, and analgesics, and other 
care as deemed appropriate, and in accordance with their institutional guidelines.


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4.7.2
Moisturizer Use
Subjects will be required to apply stable doses of moisturizers twice daily for at least 7 days 
before randomization at Visit 3 (Day 1) with a minimum of 85% compliance, through to the 
end of the follow-up period at Visit 12 (Week 24; Table 6, Table 7, and Table 8). Moisturizers 
should not be applied to the area of non-lesional skin designated for SCORAD assessments 
for ≥8 hours before visits when SCORAD will be assessed (Section 4.3.1.3). Use of certain 
moisturizers is not permitted (Section 4.7.3)
4.7.3
Prohibited Concomitant Medications and Therapies
Subjects are not permitted to receive any of the following (for the time periods stated):
∀
Systemic (oral or injectable) corticosteroids within 4 weeks of Visit 1 until the end of the 
follow-up period.
∀
TCSs and TCIs, and any other topical anti-inflammatory treatment for AD (eg, 
crisaborole) throughout the treatment and follow-up periods, except if medically 
necessary (Section 4.7.4).
∀
Any other immunosuppressive therapy within 3 months of randomization until the end of 
the follow-up period.
∀
Any immunotherapy within 3 months of randomization, except for stable maintenance 
dose allergen-specific immunotherapy started 4 weeks prior to Visit 1 until the end of 
follow-up period.
∀
Interferon gamma within 3 months of randomization until the end of the follow-up period.
∀
Investigational products other than MEDI3506 within 4 months or 5 half-lives, whichever 
is longer, of randomization until the end of the follow-up period.
∀
Marketed biologics including dupilumab within 4 months or 5 half-lives, whichever is 
longer, prior to randomization until the end of the follow-up period.
∀
Ig or blood products within 4 weeks of Visit 1 until the end of the follow-up period.
∀
Live or attenuated vaccines within 4 weeks of Visit 1 until the end of the follow-up 
period. (Note: Vaccines with adenoviral vectors that are unable to replicate, eg, 
ChAdOx1, are not considered live attenuated).
∀
Vaccination against COVID-19 (either first or subsequent dose) within 30 days before 
randomization or within 7 days before or after any dose of investigational product.
∀
Use of tanning beds or phototherapy including NBUVB, UVB, UVA1, or PUVA within 
4 weeks prior to randomization until the end of the follow-up period.
∀
> 2 bleach baths per week within 4 weeks prior to randomization until the end of the 
follow-up period.
∀
Moisturizers containing additives including ceramide, hyaluronic acid, urea, or filaggrin 
degradation products from Visit 1 until the end of the follow-up period. Subjects may 
continue using stable doses of such moisturizers throughout the study if initiated at least 
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Other than the permitted medications described in Section 4.7.1, use of concomitant 
medications or therapies from screening through to the early discontinuation visit/end of study
is discouraged. Medications or therapies that are not prohibited and neither compromise 
subject safety nor affect study data, as judged by the investigator, will be permitted.
The activity of cytochrome P450 (CYP450) enzymes can be altered by increased levels of 
certain cytokines (eg, IL-1, IL-6, IL-10, tumor necrosis factor alpha, interferon) during 
chronic inflammation (Huang et al, 2010). Thus, MEDI3506, through its downstream 
mechanism of action, has the potential to normalize the formation of CYP450 enzymes 
indirectly, through the alteration of local and systemic cytokine levels. However, a role for 
IL-33 in the regulation of CYP450 enzymes has not been reported. As a precaution, upon 
initiation or discontinuation of MEDI3506, in patients who are receiving concomitant drugs 
that have a narrow therapeutic index and are CYP450 substrates (eg, warfarin), the 
investigator should consider whether (increased) monitoring is indicated.
4.7.4
Prohibited Concomitant Medications as Rescue Therapy
As this is a study of the effects of MEDI3506 in patients with AD not using TCS or TCI, 
inappropriate use of TCS, TCI or other prohibited concomitant medications as rescue therapy 
could undermine the validity/integrity of the trial. For example, use of rescue medication by a 
patient, before sufficient time has passed since first dose, to allow the opportunity for the 
investigational product to demonstrate beneficial effects on AD severity, may lead to those 
beneficial effects being undetected. Therefore, the following restrictions on the use of rescue 
therapy must be observed to ensure appropriate use.
If medically necessary for intolerable AD symptoms that occur throughout the study, rescue 
therapy with otherwise prohibited concomitant medications or therapies (Section 4.7.3) may 
be prescribed to subjects. In all other circumstances, rescue therapy should be restricted to 
subjects at or after Visit 7 (Day 29), who have:
∀
A worsening of EASI by ≥50% from baseline, or
∀
A clinically significant, disproportionate worsening of pruritus sustained for at least 
7 days, that remains intolerable for the subject despite use of permitted medications 
(Section 4.7.1) and therapies for managing symptoms.
Rescue therapy should only be prescribed after assessment of the subject in the clinic, either at 
a scheduled or unscheduled visit. A justification for each subject who commences rescue 
therapy must be documented by the investigator in the clinical notes.
Rescue therapy should initially be restricted to topical therapies (ie, TCSs or TCIs, or any 
other topical anti-inflammatory treatment [eg, crisaborole]). TCSs should be prescribed at the 
lowest potency appropriate for the situation. TCIs should be reserved for problem areas only 
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reserved for subjects who do not adequately respond to topical rescue therapy after ≥7 days of 
treatment.
Subjects who receive topical rescue therapy only may continue to receive investigational 
product provided no discontinuation criteria (Section 4.1.6) are met. Investigational product 
will be immediately discontinued in subjects who receive systemic rescue therapy, which is a 
prohibited medication (Section 4.7.3). All subjects should complete the schedule of study 
visits and assessments whether or not they continue treatment with investigational product, 
and whether or not they receive systemic rescue therapy. Investigators should make every 
attempt to conduct efficacy and safety assessments immediately before administration of any 
systemic rescue therapy. If it is not possible for the subject to complete the remaining visits, 
then the subject should complete the early discontinuation visit as outlined in the schedule of 
study procedures (Table 8).
4.7.5
COVID-19 Vaccination
If a subject receives a COVID-19 vaccination it should be recorded as a concomitant 
medication. Data regarding the date, dose, brand name, site of administration and lot number 
(if known) of each vaccine dose (eg, 10Feb2021; first dose; Pfizer-BioNTech COVID-19 
Vaccine; left deltoid; Lot xxx) should be recorded in the patient’s case notes.
Any AEs suspected to be due to the vaccination should be captured in the AE form including 
the causality assessment related to COVID-19 vaccine.
4.8
Statistical Evaluation
4.8.1
General Considerations
Unless specified otherwise, baseline is defined as the last assessment prior to dosing on Day 1 
(Visit 3). The placebo 
 groups will be pooled for planned analyses, except where 
stated otherwise. Tabular summaries will be presented by treatment group. Categorical data 
will be summarized by the number and percentage of subjects in each category. Continuous 
variables will be summarized by descriptive statistics including number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum.
The study populations that will be used in the reporting of the study include the intent-to-treat 
(ITT), As-treated, and PK populations (Table 11). The ITT population will be used to 
summarize demographic and baseline characteristics, concomitant medications, and efficacy 
endpoints. The As-treated population will be used to summarize safety endpoints (AEs, 
laboratory tests, ECGs, left ventricular ejection fraction, and vital signs), and will be used for 
other endpoints unless otherwise stated. The PK population will be used to summarize PK 
endpoints.
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Table 11
Study Populations
Population
Description
ITT
Subjects who are randomized and receive any investigational product. Subjects will be 
analyzed according to their randomized treatment group.
As-treated
Subjects who are randomized and receive any investigational product. Subjects will be 
analyzed according to the treatment they actually receive.
PK
Subjects who receive at least 1 dose of MEDI3506 and have at least 1 detectable serum 
concentration measurement post first dose of treatment. Subjects will be analyzed 
according to the treatment they actually receive.
ITT = intent-to-treat; PK = pharmacokinetic(s).
Additional details of statistical analyses will be described in the Statistical Analysis Plan 
(SAP).
4.8.2
Sample Size
A sample size of 144 subjects in an overall 3:1:1:3 ratio of MEDI3506 
:MEDI3506 
:MEDI3506 
:pooled placebo, will provide at least 90% power to detect a 
statistically significant difference in the percent change from baseline to Week 16 in EASI 
score between the highest dose of MEDI3506 and pooled placebo in a responder subgroup, 
assuming a 35% point difference between placebo and MEDI3506 at the highest dose, based 
on a SD of 40% points, a two-sided 10% alpha level, and 50% of subjects in the responder 
subgroup. Based on identical assumptions, the sample size provides > 99% power to detect a 
statistically significant dose response in percent change from baseline to Week 16 in EASI 
score in all-comers.
The calculations for dose response assume that percent change from baseline to Week 16 in 
EASI score will increase monotonically with the administration of higher MEDI3506 doses. 
The power was calculated using a multiple comparison procedure with modelling techniques 
(MCP-Mod) (Bretz et al, 2005) with 4 candidate models for the dose response (linear, 
maximum effect attributable to the drug [Emax], and 2 Hill-Emax models). Randomization will 
be stratified by total IgE (< 150 kU/L or ≥150 kU/L) at screening.
To allow for the possibility that ≤5% of the subjects per treatment group may be ineligible for 
the ITT population, the total sample size will comprise approximately 152 subjects (58 for 
MEDI3506 
, 18 for MEDI3506 
, 18 for MEDI3506 
, and 58 for pooled 
placebo) randomized approximately to 3:1:1:3 ratio overall to the treatment groups.
4.8.3
Efficacy
4.8.3.1
Primary Efficacy Analysis
Percent Change in EASI Score
The primary efficacy endpoint is the percent change from baseline to Week 16 in EASI score.
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To assess dose response at Week 16, percent change from baseline to Week 16 in EASI score 
will be analyzed using an MMRM including data from visits up to Week 16. The model will 
include treatment group, randomization stratum (total serum IgE < 150 kU/L or ≥ 150 kU/L), 
visit, and treatment group by visit interaction as categorical factors, with baseline EASI score 
as a covariate and the baseline*visit interaction term. Visit will be a repeated factor within a 
subject and an unstructured variance-covariance matrix will be used to describe the 
correlations between observations on a subject between visits. If the unstructured 
variance-covariance matrix will not fit, then suitable alternatives will be considered, with 
details provided in the SAP. The coefficient of the treatment effects at Week 16 obtained from 
the MMRM will then be incorporated into an MCP-Mod (Pinheiro et al, 2014), with 
4 candidate models (linear, Emax, and 2 Hill-Emax models) to determine the dose response 
profile. As part of the MCP-Mod model, the testing of the 4 candidate dose response models 
will be adjusted for multiplicity using a family-wise error rate of 0.10. If more than 1 
candidate model shows a statistically significant dose response, the final model will be 
selected based on the Akaike Information Criteria obtained from each model.
The estimand of primary interest is the difference in mean percent change from baseline to 
Week 16 in EASI score between MEDI3506 and placebo in the ITT population. Data that are 
collected after withdrawal from the study, or the use of rescue therapy will be treated as 
missing and excluded from the analysis. From the final model obtained from the MCP-Mod 
dose response analysis, the adjusted difference in mean percent change from baseline in EASI 
score between the placebo group and each MEDI3506 group at Week 16 will be estimated 
along with the 90% confidence interval (CI) and two-sided p-value. In addition, an estimate of
the adjusted difference in mean percent change from baseline in EASI at each visit for each 
treatment group will be summarized together with a two-sided 90% CI, and p-value.
4.8.3.2
Additional Analyses of the Primary Endpoint
Percent Change in EASI Score
A supplementary analysis using the ITT population will be done using all available data from 
subjects irrespective of whether or not they completed treatment, including data collected after 
subjects received rescue therapy. A MMRM followed by a MCP-Mod dose response model 
will be used for the analysis as described above for the analysis of the primary efficacy 
endpoint (Section 4.8.3.1).
A second supplementary analysis will be performed using the ITT population. Data from 
assessments performed after prohibited medications (eg, rescue therapies) are received will be 
excluded and a last observation carried forward approach will be applied for the missing data. 
An ANCOVA followed by a MCP-Mod dose response model including treatment group and 
randomization stratum (total serum IgE level < 150 kU/L or ≥150 kU/L) as categorical factors 
and baseline EASI score as covariate, with 4 candidate models for the dose response (linear, 
Emax, and 2 Hill-Emax models) will be used for the analysis. The results will be presented in a 


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similar way as described above for the efficacy analysis for the primary endpoint 
(Section 4.8.3.1).
A third supplementary analysis for percent change in EASI score will be performed using a 
MMRM as described above (Section 4.8.3.1), including data from visits up to Week 24. The 
ITT population will be used for the analysis and data from visits after subjects receive rescue 
therapy will be excluded from the analysis. From the final model obtained from the fitted 
MMRM, the adjusted difference in mean percent change from baseline in EASI score between 
the placebo and each MEDI3506 group at Week 16 will be estimated along with the 90% CI
and two-sided p-value.
4.8.3.3
Secondary Efficacy Analyses
IGA Response at Week 16
A key secondary efficacy endpoint is the percentage of subjects achieving an IGA response of 
0 (clear) or 1 (almost clear) and at least a 2 grade reduction from baseline at Week 16.
IGA response at Week 16 will be analyzed for the ITT population using logistic regression
including treatment group, randomization stratum (total serum IgE level < 150 kU/L or 
≥150 kU/L), and baseline IGA as categorical factors. The coefficient of the treatment effects 
at Week 16 obtained from the logistic regression will then be used in an MCP-Mod analysis
with 4 candidate models for the dose response (linear, Emax, and 2 Hill-Emax models). As part 
of the MCP-Mod model, the testing of the 4 candidate dose response models will be adjusted 
for multiplicity using a family-wise error rate of 0.10. If more than 1 candidate model shows a 
statistically significant dose response, the final model will be selected based on the Akaike 
Information Criteria obtained from each model.
The composite estimand of primary interest is the difference in IGA response rate at Week 16 
between MEDI3506 and placebo in the ITT population. Subjects who withdraw from the 
study or require rescue therapy will be considered as non-responders. From the final model 
obtained from the MCP-Mod dose response analysis, the difference in IGA response rate 
between the placebo and each MEDI3506 group will be estimated along with the 90% CI. For 
each MEDI3506 group versus placebo, the results will be presented as the difference in 
response rates, the 90% CI for the difference in response rates, and two-sided p-value.
Additional Analyses of the IGA Response at Week 16
A supplementary analysis using the ITT population will be done using all available data from 
subjects irrespective of whether or not they completed treatment, including data from subjects 
who received rescue therapy. Subjects who discontinue investigational product or withdraw 
from the study before Week 16 will be considered as non-responders.


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A second supplementary analysis will be performed using the ITT population. Data from 
assessments performed after prohibited medications are received will be excluded and a last 
observation carried forward approach will be applied for missing data. The logistic regression 
and MCP-Mod dose response model used for the 2 supplementary analyses and the 
presentation of results will be similar as described above for the secondary efficacy analysis 
for IGA.
A third supplementary analysis will be performed using a generalized estimating equation 
model for repeated measures including treatment group, randomization stratum (total serum 
IgE < 150 kU/L or ≥ 150 kU/L), baseline IGA value, visit, and visit by treatment group 
interaction as covariates. The analysis will be conducted including data from visits up to
Week 24. The model will use a logistic link function and an independence working correlation 
matrix. If the assumed working correlation matrix will not fit, then suitable alternatives will be 
considered, with details provided in the SAP. From the model obtained, estimates of the 
treatment effect at Week 16 together with the associated standard errors, 90% CIs, and 
p-values will be provided.
Percentage of Subjects Achieving EASI 50, EASI 75, and EASI 90 at Week 16
A subject is defined as achieving an EASI 50, EASI 75, or EASI 90 response if they have at 
least a 50%, 75%, or 90% reduction from baseline in EASI score, respectively.
EASI 50, EASI 75 and EASI 90 response at Week 16 will be analyzed using a logistic 
regression model including treatment group and randomization stratum (total serum IgE level 
< 150 kU/L or ≥150 kU/L) as categorical factors, and baseline EASI score as a covariate for 
each endpoint. The composite estimand will be the difference between MEDI3506 and 
placebo in EASI 50, EASI 75, or EASI 90 response rate at Week 16 in the ITT population. 
Subjects who discontinue investigational product, withdraw from the study, or require rescue 
therapy will be considered as non-responders. For each MEDI3506 group compared with 
placebo, differences in response rates, 90% CIs for the differences in response rates (Ge et al, 
2011), and two-sided p-values will be reported for each endpoint. If the number of responders 
is < 5 in any MEDI3506 group, the logistic regression model will not be used. Instead, the 
90% CI and p-value for the difference in response rates will be calculated using an 
unconditional exact method (Chan and Zhang, 1999).
Additional Analyses of the EASI 75 response at Week 16
The percentage of subjects achieving an EASI 75 response at Week 16 will be analyzed for 
the ITT population using a logistic regression and MCP-Mod dose response model similar to 
that described above for IGA response at Week 16. Results obtained from the analysis will 
also be described in a similar way as described for the IGA response.


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Change from Baseline to Week 16 in % BSA Affected by AD
Change from baseline to Week 16 in % BSA affected by AD, as assessed by EASI, will be 
analyzed for the ITT population using a mixed effects model for repeated measures, including 
data from visits up to Week 16. Data from visits after subjects receive rescue therapy will be 
excluded from the analysis. Details of the model are similar to those described above for the 
percent change from baseline to Week 16 in EASI score (Section 4.8.3.1).
Percent Change from Baseline to Week 16 in SCORAD
Percent change from baseline to Week 16 in SCORAD will be analyzed for the ITT 
population using a MMRM, including data from visits up to Week 16. Data from visits after 
subjects receive rescue therapy will be excluded from the analysis. Details of the model are 
similar to those described for percent of change from baseline to Week 16 in EASI score 
(Section 4.8.3.1).
Analysis of Peak Pruritus NRS at Week 16
Daily peak pruritus NRS assessments will be summarized as weekly means. The weekly mean 
score will be set to missing if > 3 assessments are missed in that 7-day period.
The percentage of subjects achieving a ≥3 point reduction from baseline to Week 16 in 
weekly mean of daily peak pruritus NRS will be analyzed using a logistic regression model 
including treatment group and randomization stratum (total serum IgE < 150 kU/L or 
≥150 kU/L), and baseline weekly mean of daily peak pruritus score as a covariate. Other 
details of the model are similar to those described above for the analyses of the secondary 
efficacy endpoint of EASI 50.
Furthermore, change from baseline to Week 16 in the weekly mean of daily peak pruritus 
NRS will be analyzed using a MMRM. Data from visits after subjects receive rescue therapy 
will be excluded from the analysis. Details of the model are similar to those described for 
percent change from baseline to Week 16 in EASI score (Section 4.8.3.1).
Analysis of Skin Pain NRS at Week 16
Daily peak skin pain NRS assessments will be summarized as weekly means. The weekly 
mean score will be set to missing if > 3 assessments are missed in that 7-day period.
Change from baseline to Week 16 in weekly mean peak skin pain NRS will be analyzed using 
a MMRM. Data from visits after subjects receive rescue therapy will be excluded from the 
analysis. Details of the model are similar to those described for percent change from baseline 
to Week 16 in EASI score (Section 4.8.3.1).


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Analysis of 5-D Itch, POEM, and DLQI at Week 16
Change from baseline to Week 16 in 5-D itch, POEM, and DLQI will be summarized 
descriptively, and analyzed using a mixed effects model for repeated measures. Data from 
visits after subjects receive rescue therapy will be excluded from the analysis. Details of the 
model are similar to those described for percent change from baseline to Week 16 in EASI 
score (Section 4.8.3.1).
Analysis of PGI-S at Week 16
The PGI-S is on a 3-point categorical response scale (mild, moderate, or severe). PGI-S will 
be summarized with descriptive statistics including number of subjects, mean, SD, median, 
minimum, and maximum at each visit. In addition, the number and percentage of subjects in 
each category will be summarized by visit.
4.8.3.4
Exploratory Analyses
The number and percentage of subjects achieving EASI 50 by Weeks 2, 4, 8, 12, 20, and 24 
will be summarized by visit. Similar summary statistics will be provided for the percentage of 
subjects achieving EASI 75 and EASI 90. Furthermore, analyses using a generalized 
estimating equation model for repeated measures will be performed separately for each 
endpoint. Details of the model are similar to those described for the additional analysis of the 
IGA response at Week 16 (Section 4.8.3.3).
Percent change from baseline to Weeks 2, 4, 8, 12, 20, and 24 in EASI score will be 
summarized descriptively by visit, and analyzed using a MMRM including data from visits up 
to Week 24 as described for the primary efficacy endpoint of percent change from baseline to 
Week 16 in EASI score (Section 4.8.3.1).
The number and percentage of subjects achieving an IGA response at Weeks 2, 4, 8, 12, 20, 
and 24 will be summarized by visit, and analyzed using the generalized estimating equation 
model as described for IGA response at Week 16 (Section 4.8.3.3).
For peak pruritus NRS, the number and percentage of subjects achieving reduction of ≥3 
from baseline to Weeks 2, 4, 8, 12, 20, and 24 in weekly mean of daily peak pruritus NRS will 
be summarized by visit and analyzed using the generalized estimating equation model as 
described above for IGA response. The number and percentage of subjects achieving 
reduction of ≥4 from baseline to Weeks 2, 4, 8, 12, 20, and 24 in weekly mean of daily peak 
pruritus NRS will be summarized and analyzed similarly.
Change from baseline to Weeks 2, 4, 8, 12, 20, and 24 in the weekly mean of daily peak 
pruritus NRS and change from baseline to Weeks 2, 4, 8, 12, 20, and 24 in weekly mean of 
daily peak skin pain NRS will be summarized by visit and analyzed using a MMRM as 
described for the primary efficacy endpoint (Section 4.8.3.1).


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Percent change from baseline to Weeks 2, 4, 8, 12, 20, and 24 in SCORAD will be 
summarized descriptively by visit, and analyzed using a mixed effects model for repeated 
measures as described for the primary efficacy endpoint (Section 4.8.3.1).
PGI-S at Weeks 2, 4, 8, 12, 20, and 24 will be summarized by visit with descriptive statistics 
including number of subjects, mean, SD, median, minimum, and maximum. In addition, the 
number and percentage of subjects in each category will also be summarized by visit.
Change from baseline to Weeks 2, 4, 8, 12, 20, and 24 in percent BSA affected by AD, 
5-D itch, POEM, and DLQI will be summarized descriptively by visit, and analyzed using a 
MMRM as described for the primary efficacy endpoint (Section 4.8.3.1).
The number and percentage of subjects requiring rescue therapy during the treatment and 
follow-up periods will be summarized by visit. Summary descriptive statistics (including 
number, mean, median, SD, minimum, and maximum) will be provided for time to first use of 
rescue therapy either during the treatment or follow-up period. Additional analyses that may 
be conducted for these endpoints will be described in the SAP.
Change from baseline to Week 16, and to Week 24, in SNOT-22 and ACQ-6 will be 
summarized using descriptive statistics including number of subjects, mean, median, SD, 
minimum, and maximum.
Additional details of the exploratory endpoint analyses will be described in the SAP.
4.8.3.5
Subgroup Analyses
Subgroup analyses may be performed, and will be described in the SAP as required.
4.8.4
Safety
4.8.4.1
Analysis of AEs
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) by 
system organ class (SOC) and preferred term (PT). Specific AEs will be counted once for 
each subject for calculating rates, but will be presented in total in subject listings. In addition, 
if the same AE occurs multiple times within a particular subject, the highest severity and level 
of causality will be reported. If any associations of interest between AEs and baseline 
characteristics are observed, additional stratified results may be presented. TEAEs will be 
summarized overall and by MedDRA SOC and PT, by severity, and relationship to 
investigational product. In addition, summaries of deaths, SAEs, and treatment 
discontinuations due to AEs will be provided.
4.8.4.2
Safety Laboratory Analysis
Laboratory parameters will be assessed at baseline and throughout the study (Table 6, Table 7, 
and Table 8). Frequencies of abnormal laboratory measurements will be presented for each 


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laboratory parameter. Also, laboratory parameters will be assessed by presenting tables 
containing information related to laboratory shifts from baseline relative to the normal range, 
as well as descriptively over time.
4.8.4.3
Analysis of Vital Signs, ECGs, and Echocardiograms
Vital signs, ECG parameters and left ventricular ejection fraction as measured by 
echocardiogram will be summarized descriptively.
4.8.4.4
Subgroup Analyses
Subgroup analyses may be performed, and will be described in the SAP as required.
4.8.5
Analysis of Immunogenicity and PK
The incidence rate of positive antibodies to MEDI3506 and ADA titer will be reported by 
treatment group. Depending on the incidence of ADA, further analysis of ADA effects may 
include the assessment of the relationship between ADA titer and:
∀
MEDI3506 exposure.
∀
Biomarker endpoints.
∀
Occurrence of AEs.
MEDI3506 serum concentrations will be tabulated and analyzed using descriptive statistics. 
Additional PK analyses may be conducted as appropriate. If the data allow, population PK 
analysis will be performed but will not be reported in the CSR.
4.8.6
Analysis of Biomarkers
Change from baseline to Week 16 in the concentrations of sST2 will be summarized 
descriptively by visit and analyzed using an ANCOVA model. The model will include 
treatment group and randomization stratum (total serum IgE < 150 kU/L or ≥ 150 kU/L) as 
categorical factors, with baseline sST2 as a covariate. 
Change from baseline to Weeks 1, 2, 4, 8, 12, 16, 20, and 24 in eosinophils and change from 
baseline to Weeks 1, 2, 4, 16, 20, and 24 in IL-33 bound to MEDI3506 will be summarized 
descriptively by visit and treatment group. Change from baseline to Weeks 2, 8, 16, and 24 in 
IgE biomarker levels and change from baseline to Weeks 4, 16, and 24 in eosinophil derived 
neurotoxin levels will also be summarized by visit. In addition, descriptive plots will be 
provided to assess the association between primary efficacy endpoints and the changes in 
biomarker levels at each visit. Change from baseline to Week 16 in colonization of bacteria in 
lesional and non-lesional skin will be summarized using descriptive statistics. Additional 
analyses that may be conducted for these endpoints will be described in the SAP.
Analyses of biomarker endpoints will be further described in the SAP.


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4.8.7
Primary and Final Analyses
No formal interim analyses are planned for this study.
The primary analysis will occur once all subjects have either completed the Visit 10 
(Week 16) assessments or have withdrawn from the study and will include all available data. 
Details on unblinding for primary analysis purposes are described (Section 4.6.3.3).
The final analysis will occur when all subjects have completed the follow-up period at 
Visit 12 (Week 24) or have withdrawn from the study.
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or non-serious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.
5.2
Definition of Serious Adverse Events
An SAE is any AE that fulfils 1 or more of the following criteria:
∀
Results in death.
∀
Is immediately life-threatening.
∀
Requires inpatient hospitalization or prolongation of existing hospitalization.
∀
Results in persistent or significant disability/incapacity.
∀
Is a congenital anomaly/birth defect in offspring of the subject.
∀
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above.


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Medical or scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in this situation. Examples of medically important events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalizations, or development of drug dependency or drug abuse.
AEs for malignant tumours reported during a study should generally be assessed as SAEs. If 
no other seriousness criteria apply, the “important medical event” criterion (Appendix B) 
should be used. However, in certain situations medical judgment on an individual event basis 
should be applied to clarify that the malignant tumor event should be assessed and reported as 
a non-serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfill the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as non-serious; examples include Stage 1 
basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.
5.3
Definition of Adverse Events of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the investigational product and may require close monitoring and rapid 
communication by the investigator to AstraZeneca. An AESI may be serious or non-serious. 
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational product.
The following AESIs will be particularly monitored in this study (see the Safety Handling 
Plan for instructions and timing on completing any additional information required for 
specific types of events related to the categories noted below):
∀
Hepatic function abnormality meeting the definition of Hy’s Law (HL) as described in 
Section 5.4.12.
∀
Serious hypersensitivity (including Type 1 to 4 hypersensitivity reactions), for example 
anaphylaxis and severe allergic reactions, and immune complex disease.
∀
Injection site reactions.
∀
Cardiac events (including angina or myocardial infarction, congestive heart failure, 
symptomatic atherosclerotic vascular disease, cor pulmonale, or arrhythmia).
∀
Serious infections (including opportunistic infections and viral reactivations), for example 
VZ/HSV, EBV/CMV, and TB.
∀
Gastrointestinal adverse events.
∀
Malignancy.


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5.4
Recording of Adverse Events
AEs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. AEs will be assessed by the investigator for severity, relationship 
to the investigational product, possible etiologies, and whether the event meets criteria of an 
SAE and therefore requires immediate notification to AstraZeneca (see Section 5.5). See 
Section 5.2 for the definition of SAEs and Appendix B for guidelines for assessment of 
severity and relationship.
If an AE evolves into a condition that meets the regulatory definition of “serious” it will be 
reported on the SAE Report Form.
5.4.1
Time Period for Collection of Adverse Events
AEs and SAEs will be collected from time of signature of informed consent at Visit 1, 
throughout the treatment period and including the follow-up period through Visit 12 
(Week 24) or date of last contact.
5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically indicated, 
but without further recording in the eCRF. AstraZeneca retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.
5.4.3
Deaths
All deaths that occur during the study, including the protocol-defined follow-up period must 
be reported as follows:
•
The AE causing the death must be reported as an SAE within 24 hours. The report should 
assign main and contributory causes of death.
•
Deaths with an unknown cause should always be reported as an SAE. A post-mortem 
(autopsy) may be helpful in the assessment of the cause of death, and if performed a copy 
of the post-mortem results should be forwarded to AstraZeneca representative(s) within 
the usual timeframes (refer to Section 5.5 for additional information).
5.4.4
Recording of Serious Hypersensitivity (Including Type 1 to 4 
Hypersensitivity Reactions)
For AESIs of serious hypersensitivity, narrative information will be recorded including the 
rationale for considering the event to be, or not to be, anaphylaxis (Appendix C).


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5.4.5
Recording of Injection Site Reactions
For AESIs of injection site reactions, the sign or symptom, and diameter of area will be 
recorded.
5.4.6
Recording of Cardiac Events (Including Angina or Myocardial 
Infarction, Congestive Heart Failure, Symptomatic Atherosclerotic 
Vascular Disease, or Pulmonale or Arrhythmia)
For subjects with AESIs of cardiac events suggestive of new onset and/or progression of heart 
failure, left ventricular ejection fraction measured by echocardiogram and NT-proBNP will be 
recorded.
5.4.7
Recording of Serious Infections (Including Opportunistic Infections 
and Viral Reactivations
No additional information will be recorded beyond standard.
5.4.8
Recording of Gastrointestinal Adverse Events
No additional information will be recorded beyond standard.
5.4.9
Recording of Malignancy
No additional information will be recorded beyond standard.
5.4.10
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: “Have you had any health problems since the previous visit/you were 
last asked?”, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
5.4.11
Adverse Events Based on Examination and Tests
The results from the protocol-mandated laboratory tests and vital signs will be summarized in 
the CSR. An abnormal laboratory finding (including echocardiogram or ECG finding) that 
requires medical intervention by the investigator, or a finding judged by the investigator as 
medically significant, should be reported as an AE. If clinical sequelae are associated with a 
laboratory abnormality, the diagnosis or medical condition should be reported (eg, renal 
failure, hematuria) not the laboratory abnormality (eg, elevated creatinine, urine red blood cell 
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If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
5.4.12
Hy’s Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with TBL ≥2 × ULN may need to be
reported as SAEs. Please refer to Appendix E for further instruction on cases of increases in 
liver biochemistry and evaluation of HL.
5.5
Reporting of Serious Adverse Events
Prompt notification (within 24 hours) by the investigator to the sponsor of an SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of subjects and the 
safety of a study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB/IEC, and investigators.
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSARs) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then 
file it along with the IB or and will notify the IRB/IEC, if appropriate according to local 
requirements.
Once the investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to inform the designated sponsor 
representative(s).
If the EDC system is not available, then the investigator or other study site personnel reports 
an SAE to the appropriate sponsor representative by telephone. The sponsor representative 
will advise the investigator/study site personnel how to proceed.


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The reference document for definition of expectedness/listedness is Section 5.6 Reference 
Safety Information for Assessment of Expectedness of Serious Adverse Reactions in the IB.
5.6
Other Events Requiring Immediate Reporting
5.6.1
Overdose
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the IB, unless otherwise specified in this protocol.
∀
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.
∀
An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca investigational product occurs during the course of the 
study, then the investigator or other site personnel should inform appropriate sponsor 
representatives immediately, but no later than 24 hours after becoming aware of the event.
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 5.5. 
For other overdoses (ie, those not associated with an AE or SAE), reporting must occur within 
30 days.
5.6.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the sponsor except if the 
pregnancy is discovered before the subject has received any investigational product.
5.6.2.1
Maternal Exposure
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomalies/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital anomaly) should be followed up and documented even if the 
subject was discontinued from the study.


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If any pregnancy occurs during the course of the study, then the investigator or other site 
personnel will inform the appropriate sponsor representatives within 1 calendar day, ie, 
immediately but no later than 24 hours after becoming aware of the event.
The designated study representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s patient safety data entry site within 1 or 5 calendar 
days for SAEs (see Section 5.5) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The pregnancy reporting module in the eCRF is used to report the pregnancy and the 
pregnancy outcome module is used to report the outcome of the pregnancy.
5.6.2.2
Paternal Exposure
Pregnancy of the subject’s partners is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly), occurring from the date of the first dose until the end of the 
follow-up period (Visit 12 [Week 24]) or date of last contact should, if possible, be followed 
up and documented.
5.6.3
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca investigational product that either causes harm to the 
subject or has the potential to cause harm to the subject.
A medication error is not lack of efficacy of the investigational product, but rather a human-
or process-related failure while the investigational product is in control of the study site staff 
or subject.
Medication error includes situations where an error:
∀
Occurred.
∀
Was identified and intercepted before the subject received the investigational product.
∀
Did not occur, but circumstances were recognized that could have led to an error.
Examples of events to be reported in clinical studies as medication errors:
∀
Drug name confusion (ie, instead of receiving the investigational product, the subject 
received a medication that has a similar-sounding name).
∀
Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the subject.


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∀
Investigational product not administered as indicated, for example, wrong route or wrong 
site of administration.
∀
Investigational product not taken as indicated, eg, tablet dissolved in water when it should 
be taken as a solid tablet.
∀
Investigational product not stored as instructed, eg, kept in the refrigerator when it should 
be at room temperature.
∀
Wrong subject received the investigational product (excluding IXRS errors).
∀
Wrong investigational product administered to subject (excluding IXRS errors).
Examples of events that do not require reporting as medication errors in clinical studies:
∀
Errors related to or resulting from IXRS- including those which lead to 1 of the above 
listed events that would otherwise have been a medication error.
∀
Subject accidentally missed investigational product dose(s), eg, forgot to take medication.
∀
Accidental overdose (will be captured as an overdose).
∀
Subject failed to return unused investigational product or empty packaging.
∀
Errors related to background and rescue therapy, or standard of care medication in open 
label studies, even if an AstraZeneca product.
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 5.5) and within 30 days for all other medication errors. 
Medication errors should be reported using a Medication Error Report Form.
6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the protocol and related documents with the investigational 
staff and also train them in any study-specific procedures and system(s) utilized.
The principal investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.


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The principal investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).
6.2
Monitoring of the Study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:
∀
Provide information and support to the investigator(s).
∀
Confirm that facilities remain acceptable.
∀
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed.
∀
Perform source data verification (a comparison of the data in the eCRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (eg, clinic charts).
∀
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The AstraZeneca representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct.
Investigational product accountability (Section 4.6.2) and any other unblinded monitoring 
activities will be conducted by an additional unblinded monitor.
6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The principal investigator at each/the center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this protocol and the Clinical Study Agreement, the terms of protocol 
shall prevail with respect to the conduct of the study and the treatment of subjects and in all 
other respects, not relating to study conduct or treatment of subjects, the terms of the Clinical 
Study Agreement shall prevail.
Agreements between AstraZeneca and the principal investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled.


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6.2.3
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through their last protocol-specified visit/assessment (including telephone contact) 
regardless of the number of doses of investigational product that was received.
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Sections 4.1.5 and 4.1.6).
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit (including telephone contact) for the last subject in the study (ie, LSLV).
6.4
Data Management 
Data management will be performed by AstraZeneca Data Management staff or other party
according to the Data Management Plan.
An EDC system will be used for data collection and query handling. The investigator will 
ensure that data are recorded in the eCRFs as specified in the study protocol and in accordance 
with the eCRF instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the principal investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the principal investigator is not available, the treating physician or 
health care provider can contact a medical monitor through this system, which is managed by 
a third-party vendor.


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7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Subject Data Protection
Each subject will be assigned a SID to ensure that personally identifiable information is kept 
separate from the study data. Subject data that are relevant to the trial, eg, demographic 
information, physical or mental health condition, diagnosis, comorbidities, laboratory test 
results, etc. will only be collected with the subject’s informed consent. The ICF will 
incorporate (or, in some cases, be accompanied by a separate document incorporating) 
wording that describes how subject data will be collected, used, and distributed in compliance 
with relevant data protection and privacy legislation.
Extra precautions will be taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the subject. AstraZeneca will not provide individual genotype results 
to subjects, any insurance company, any employer, their family members, general physician or 
any other third party, unless required to do so by law.
7.2
Ethics and Regulatory Review
The IRB/IEC responsible for each site must review and approve the final study protocol, 
including the final version of the ICF and any other written information and/or materials to be 
provided to the subjects. The IRB/IEC must also approve all advertising used to recruit 
subjects for the study. The investigator is responsible for submitting these documents to the 
applicable IRB/IEC, and distributing them to the study site staff.
The opinion of the IRB/IEC must be given in writing. The investigator must provide a copy of 
the written approval to AstraZeneca before enrollment of any subject into the study.
AstraZeneca should approve any substantive modifications to the ICF that are needed to meet 
local requirements.
If required by local regulations, the protocol must be re-approved by the IRB/IEC annually.
Before the study is initiated, AstraZeneca will ensure that the national regulatory authority in 
each country has been notified and their approval has been obtained, as required. AstraZeneca 
will provide safety updates/reports according to local requirements, including SUSARs where 
relevant, to regulatory authorities, IRB/IEC, and principal investigators.
Each principal investigator is responsible for providing reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the investigational product to the 
IRB/IEC. AstraZeneca will provide this information to the principal investigator so that he/she 
can meet these reporting requirements.


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7.3
Informed Consent
Informed consent of each subject will be obtained through a written and verbal explanation 
process that addresses all elements required by ICH/GCP. AstraZeneca will develop a core 
ICF for use by all investigators in the clinical study. AstraZeneca must approve any 
modifications to the ICF that are needed to meet local requirements.
The principal investigator(s) at each center will:
∀
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk, and benefit of the study.
∀
Ensure each subject is notified that they are free to discontinue from the study at any time.
∀
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided.
∀
Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study.
∀
Ensure the original, signed ICF(s) is/are stored in the investigator’s study file.
∀
Ensure a copy of the signed ICF is given to the subject.
∀
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the ICF that is approved by an IRB/IEC.
∀
Ensure that the ICF version used is appropriate for the randomization ratio in operation at 
the time. Subjects who have provided informed consent but are still in screening (ie, have 
not been randomized) when the randomization ratios change (Section 4.6.1) should be 
reconsented to the appropriate ICF version.
7.4
Changes to the Protocol and ICF
Study procedures will not be changed without the mutual agreement of the coordinating 
investigator and AstraZeneca. Any changes must be documented in a study protocol 
amendment. 
For a substantial change to the protocol, AstraZeneca will distribute amended versions of the 
protocol to the principal investigator(s). Before implementation, amended protocols must be 
approved by relevant IRB/IEC (see Section 7.2) and reviewed as per local regulatory authority 
requirements. The IRB/IEC must also approve revisions to the ICF, advertising, and any other 
written information and/or materials resulting from the change to the protocol.
Any non-substantial changes will be communicated to or approved by each IRB/IEC.
7.5
Audits and Inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the center, including source data verification. The purpose of 


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an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines of the 
ICH, and any applicable regulatory requirements. The investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the site.


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8
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Table 12
Summary of Non-substantial Revisions in Protocol Amendment 9
Section of the Protocol Affected
Reason for Amendment
4.3.5 (Immunogenicity Evaluation and Methods)
Updated the duration of storage for ADA samples 
from 2 years after marketing approval to 15 years 
following the issue of CSR, to be consistent with 
standard AstraZeneca processes and to allow easier 
tracking of sample lifecycle.
4.3.6 (Genetic Evaluation and Methods)
Text added to differentiate between the genetic 
samples collected during the study.
4.8.3.2 (Additional Analyses of the Primary 
Endpoint)
Use of ANCOVA added for the second 
supplementary analysis to be consistent with other 
MCP-Mod analyses. 
4.8.6 (Analysis of Biomarkers)
Correction of statistical method used to analyse sST2 
data from a mixed effects model for repeated 
measures to an ANCOVA model; the model was 
changed to ANCOVA due to the removal of some 
timepoints.
4.8.6 (Analysis of Biomarkers)
Removal of reference to how 
, 
PBMC, IL-5, IL-13, CCL17, proinflammatory gene 
signatures, and gross inflammation data will be 
summarised as these data will be explored and 
reported separately to the CSR.
5.6.2.1 (Maternal Exposure), 5.6.2.2 (Paternal 
Exposure)
Congenital abnormality changed to congenital 
anomaly to meet regulatory requirements on good 
pharmacovigilance practices.
9.2
Protocol Amendment 8
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 8. The principal reason for this amendment is to update guidance on permitted 
vaccines in response to recent emergency use authorizations or approvals of vaccines against 
COVID-19.
All changes to the protocol are considered to be non-substantial (Table 13) and are 
summarized below.
Table 13
Summary of Non-substantial Revisions in Protocol Amendment 8
Section of the Protocol Affected
Reason for Amendment
Synopsis, 3.1.1 (Overview), Table 6 (Schedule of 
Screening and TCS/TCI Wash Out Procedures)
To extend the maximum duration of the screening 
period in response to investigator feedback that 
obtaining echocardiograms in the previously allowed 
period was challenging in the COVID-19 
environment.
CCI


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Table 13
Summary of Non-substantial Revisions in Protocol Amendment 8
Section of the Protocol Affected
Reason for Amendment
1.6.1.1 (Vaccination Against COVID-19)
New section added to inform investigators of the 
sponsor’s approach to COVID-19 vaccination in 
Study D9181C00001, to provide clarification to 
investigators and to help ensure interpretability of 
safety data.
4.1.2 (Inclusion Criteria)
To lower the EASI threshold score at Screening 
Visit 1 so that subjects that worsen during the 
TCS/TCI wash out period could become eligible at 
Visit 3 prior to randomization, in order to improve 
recruitment.
4.1.3 (Exclusion Criteria)
4.7.3 (Prohibited Concomitant Medications and 
Therapies)
To clarify adenoviral vector vaccines are not 
considered live attenuated and to add certain 
restrictions on when vaccines against COVID-19 may 
be administered.
4.3.2.1 (Medical and Dermatology History)
4.7.5 COVID-19 Vaccination
To clarify the need for recording of history of 
COVID-19 and receipt of COVID-19 vaccination.
Synopsis, 3.1.1 (Overview), 4.1.2 (Inclusion Criteria), 
Table 6 (Schedule of Screening and TCS/TCI Wash 
Out Procedures), 4.7.2 (Moisturizer Use)
To alter required moisturizer use requirements prior 
to randomization to better approximate real-world 
use.
4.1.3 (Exclusion Criteria), Table 6 (Schedule of 
Screening and TCS/TCI Wash Out Procedures), 4.3.3 
(Clinical Laboratory Tests)
To permit retesting of subjects with a positive IGRA 
test result, following investigator feedback. A 
negative IGRA test result is still required for 
eligibility.
4.1.3 (Exclusion Criteria)
To permit retesting of subjects with a NT-proBNP 
result greater than the upper limit of the laboratory 
reference range if this is clinically unexpected. An 
acceptable NT-proBNP result is still required.
Table 6 (Schedule of Screening and TCS/TCI Wash 
Out Procedures)
To allow for investigators to slightly delay 
randomization to maximize subject eligibility.
Table 6 (Schedule of Screening and TCS/TCI Wash 
Out Procedures), Table 7 (Schedule of Treatment 
Period Study Procedures), Table 8 (Schedule of 
Follow-up Procedures)
Clarification that all female subjects should have a 
pregnancy test.
4.6.2 (Methods to Ensure Blinding)
To facilitate in-stream analysis of PK and ADA 
samples.
ADA = anti-drug antibody(ies); COVID-19 = coronavirus disease 2019; EASI = Eczema Area and Severity 
Index; IGRA = interferon gamma release assay; NT-proBNP = N-terminal prohormone of B-type natriuretic 
peptide; PK = pharmacokinetic(s); TCI = topical calcineurin inhibitor; TCS = topical corticosteroid.
9.3
Protocol Amendment 7
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 7. The principal reason for this amendment is to remove the interim analysis and 
add an additional PK sampling timepoint.


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Changes to the protocol considered to be substantial (Table 14) and non-substantial (Table 15) 
are summarized below.
Table 14
Summary of Substantial Revisions in Protocol Amendment 7
Section of the Protocol Affected
Reason for Amendment
Synopsis, Table 7 (Schedule of Treatment Period 
Study Procedures) and Section 3.1.1 (Overview)
An additional PK sampling timepoint has been added 
for the 73rd and subsequent randomized subjects. 
This is to better characterize the pharmacokinetics 
(absorption phase) of MEDI3506 with the current 
formulation. The additional timepoint requires an 
additional visit to site early after the first dose, this 
(in addition to the clinical experience gained by that 
point) leaves the telephone call with the subject on 
Day 2 unnecessary and so it has been removed for 
applicable subjects.
Table 15
Summary of Non-Substantial Revisions in Protocol Amendment 7
Section of the Protocol Affected
Reason for Amendment
Section 4.1.3 (Exclusion Criteria)
Correction of typographical error leading to subjects 
who test positive for HIV but have not been treated, 
not being explicitly excluded.
Synopsis, Section 3.1.1 (Overview and Figure 1 
[Study Flow Diagram]), Section 4.6.3.3 (Unblinding 
for Interim Analysis Purposes, entirely removed), 
Section 4.6.3.4 (Unblinding for Primary Analysis 
Purposes, this is now Section 4.6.3.3), Section 4.8.2 
(Sample Size), and Section 4.8.7 (Interim, Primary, 
and Final Analyses, renamed)
The interim analysis was intended and expected to 
usefully serve internal administrative purposes. 
However, it is no longer expected to do so. Hence, 
the interim analysis and all references to it have been 
removed.
Table 7 (Schedule of Treatment Period Study 
Procedures)
Correction of an omission of a footnote from certain 
procedures.
Section 1.4 (Summary of Clinical Experience), 
Section 1.5 (Rationale for Conducting Study), and 
Section 1.6 (Risk-Benefit and Ethical Assessment)
Text updated in line with the fact that the Phase 1 
study of MEDI3506 (Study D9180C00001) is now 
fully complete. However, no new or additional safety 
data have been added.
9.4
Protocol Amendment 6
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 6. The principal reason for this amendment is to allow for the collection of 
adhesive skin tape patches for exploratory purposes.
All changes to the protocol are considered to be non-substantial (Table 16) and are 
summarized below.


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Table 16
Summary of Non-Substantial Revisions in Protocol Amendment 6
Section of the Protocol Affected
Reason for Amendment
Synopsis, Table 3 (Exploratory Objectives and 
Endpoints), Table 7 (Schedule of Treatment Period 
Study Procedures), Section 3.2.3.3 (Exploratory 
Endpoints) and Section 4.3.7.7 (Adhesive Skin Tape 
Patches)
Addition of one new exploratory biomarker at two 
timepoints as it may help identify a responder 
population based on skin transcriptomics.
Section 4.3.1.9 (Patient Global Impression of 
Severity)
In error a different wording of the question and 
responses was deployed in the study to the one stated 
in the original protocol. This error was discovered 
during the clinical conduct of the study. To ensure all 
responses are comparable and hence maintain the 
integrity of the study the protocol has been updated.
9.5
Protocol Amendment 5
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 5. The principal reason for this amendment is to provide a harmonised global 
protocol by incorporating changes from local amendments for Germany and the UK (feedback
from the Paul Ehrlich Institute and the UK Medicines and Healthcare products Regulatory 
Agency, respectively). Changes are summarized by country/region.
Changes from Global Protocol Amendment 4
Changes include those detailed in Table 17 and Table 18.
Table 17
Summary of Substantial Revisions in Protocol Amendment 5
Section of the Protocol Affected
Reason for Amendment
1.6.1 (COVID-19), Section 4.1.2 (Inclusion Criteria) 
and Section 4.1.3 (Exclusion Criteria)
Addition of safety mitigations related to COVID-19 
and description of benefit-risk balance.
COVID-19 = coronavirus disease 2019.
Table 18
Summary of Non-Substantial Revisions in Protocol Amendment 5
Section of the Protocol Affected
Reason for Amendment
Synopsis and 4.8.7 (Interim, Primary and Final 
Analyses)
Added clarification regarding the purpose of the 
interim analysis and study continuation after the 
analysis.
3.2.1 (Rationale for Dose and Dose Regimen)
Added further information on pharmacokinetic 
predictions.
4.1.3 (Exclusion Criteria)
Clarified that hereditary fructose intolerance is 
exclusionary, to address concerns from the PEI.
Reduction in exclusionary threshold for total 
bilirubin.


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Table 18
Summary of Non-Substantial Revisions in Protocol Amendment 5
Section of the Protocol Affected
Reason for Amendment
4.1.6 (Discontinuation of Investigational Product)
Clarified that incorrect randomization or use of 
prohibited medications should lead to discontinuation 
of investigational product except in defined 
circumstances, to address concerns from the PEI.
4.6.3.3 (Unblinding for Interim Analysis Purposes)
Clarified restrictions and requirements necessary to 
ensure the integrity of the trial to address concerns 
from the PEI and MHRA.
4.7.3 (Prohibited Concomitant Medications and 
Therapies)
Addition of possibility of indirect drug-drug 
interaction and related mitigation.
4.7.4 (Prohibited Concomitant Medications as Rescue 
Therapy)
•
Added justification for restrictions on use of 
rescue therapy.
•
Revised wording regarding use of rescue 
therapy before Visit 7 (Day 29), to address 
concerns from the PEI.
4.8.2 (Sample Size)
Added justification for sample size and timepoint of 
interim analysis.
5.5 (Reporting of Serious Adverse Events)
Clarified the required timelines.
4.8.7 (Interim, Primary, and Final Analyses)
Clarified that the study will be continued and 
completed regardless of interim analysis results.
MHRA = Medicines and Healthcare products Regulatory Agency; PEI = Paul Erlich Institute.
Changes from UK Local Protocol Amendment 3
Changes include those detailed in Table 19 and Table 22.
Table 19
Summary of Non-Substantial Revisions in Protocol Amendment 5
Section of the Protocol Affected
Reason for Amendment
Synopsis and 4.8.7 (Interim, Primary and Final 
Analyses)
Added clarification regarding the purpose of the 
interim analysis and study continuation after the 
analysis.
3.2.1 (Rationale for Dose and Dose Regimen)
Added further information on pharmacokinetic 
predictions.
4.1.3 (Exclusion Criteria)
Clarified that hereditary fructose intolerance is 
exclusionary, to address concerns from the PEI.
4.1.6 (Discontinuation of Investigational Product)
Clarified that incorrect randomization or use of 
prohibited medications should lead to discontinuation 
of investigational product except in defined 
circumstances, to address concerns from the PEI.
4.7.4 (Prohibited Concomitant Medications as Rescue 
Therapy)
•
Added justification for restrictions on use of 
rescue therapy.
•
Revised wording regarding use of rescue 
therapy before Visit 7 (Day 29), to address 
concerns from the PEI.


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Section of the Protocol Affected
Reason for Amendment
4.8.2 (Sample Size)
Added justification for sample size and timepoint of 
interim analysis.
4.8.7 (Interim, Primary, and Final Analyses)
Clarified that the study will be continued and 
completed regardless of interim analysis results.
PEI = Paul Erlich Institute
Changes from Germany Local Protocol Amendment 2
Changes include those detailed in Table 20, Table 21, Table 22, Table 23 and Table 24.
Table 20
Summary of Substantial Revisions in Protocol Amendment 5
Section of the Protocol Affected
Reason for Amendment
1.6.1 (COVID-19), Section 4.1.2 (Inclusion Criteria) 
and Section 4.1.3 (Exclusion Criteria)
Addition of safety mitigations related to COVID-19 
and description of benefit-risk balance.
COVID-19 = coronavirus disease 2019.
Table 21
Summary of Non-Substantial Revisions in Protocol Amendment 5
Section of the Protocol Affected
Reason for Amendment
4.1.3 (Exclusion Criteria)
Reduction in exclusionary threshold for total 
bilirubin.
4.7.3 (Prohibited Concomitant Medications and 
Therapies)
Addition of possibility of indirect drug-drug 
interaction and related mitigation.
5.5 (Reporting of Serious Adverse Events)
Clarified the required timelines.
9.6
Protocol Amendment 4
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 4. The principal reason for this amendment is to allow for countries where 
spermicide is not available and to correct a miscalculation in the number of subjects in each 
treatment group.
All changes to the protocol are considered to be non-substantial (Table 22) and are 
summarized below.


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Table 22
Summary of Non-Substantial Revisions in Protocol Amendment 4
Section of the Protocol Affected
Reason for Amendment
Protocol synopsis, Section 3.1.2 (Treatment 
Regimen), Section 4.1.1 (Number of Subjects), 
Section 4.8.2 (Sample Size)
Correction of a miscalculation in subject numbers for 
each treatment group, given the change in 
randomization ratio during the study introduced in 
Protocol Amendment 3. For each dose level of 
MEDI3506 and for the placebo groups combined the 
change is only 1 subject. The total sample size 
remains unchanged.
Protocol synopsis, Table 3 (Exploratory Objectives 
and Endpoints), Table 6 (Schedule of Treatment 
Period Study Procedures), Table 7 (Schedule of 
Follow-up Procedures), Section 4.3.7.6 (Peripheral 
Blood Mononuclear Cells) and Section 4.8.6 
(Analysis of Biomarkers)
•
Removal of certain timepoints from certain 
exploratory biomarkers (in schedule of 
assessments, endpoints and analysis) as no 
longer considered useful and to lower patient 
burden.
•
Addition of one new exploratory biomarker at 
two timepoints as it may help identify a 
responder population based on investigation of 
immune cell subset ratios in treated subjects. 
Section 4.1.2 (Inclusion Criteria)
Amended to allow for participating countries where 
spermicide is not available. This change has no 
impact in countries where it is available.
Section 4.1.3 (Exclusion Criteria) and Section 4.7.3 
(Prohibited Concomitant Medications and Therapies)
Clarified that for all prohibited medications where the 
minimum washout period is a specified number of 
months or a specified number of half-lives, the 
minimum washout is whichever is longer.
Section 4.3.7.1 (Blood Biomarkers)
Clarification added regarding plasma sample 
collection.
Section 4.3.7.3 (Skin Punch Biopsies)
Reduced the size of skin punch biopsy needle to align 
with other protocols using skin punch biopsies.
Section 4.3.7.6 (Peripheral blood mononuclear cells)
New subsection added to describe collection of 
peripheral blood mononuclear cells
9.7
Protocol Amendment 3
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 3. The principal reasons for this amendment are to introduce updates based on a 
preliminary report of a Phase 2b clinical study of etokimab that was not previously available, 
and to introduce changes suggested in the “Study May Proceed Letter” from the Food and 
Drug Administration (FDA).
Changes to the protocol considered to be substantial (Table 23) and non-substantial (Table 24) 
are summarized below.


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Table 23
Summary of Substantial Revisions in Protocol Amendment 3
Section of the Protocol Affected
Reason for Amendment
 
 
 
 
 
 
 
 
 
 
 
Protocol Synopsis (Study Design, Treatment Groups 
and Regimens, and Statistical Methods), Section 3.1.1 
(Overview and Figure 1 Study Flow Diagram), 
Section 3.1.2 (Treatment Regimen), Section 4.1.1 
(Number of Subjects), Section 4.6.1 (Methods for 
Assigning Treatment Groups), Section 4.6.3.3 
(Unblinding for Interim Analysis Purposes), 
Section 4.8.2 (Sample Size), Section 7.3 (Informed 
Consent), and Section 8 (References)
To introduce updates based on a preliminary report of 
a Phase 2b clinical study of etokimab that was not 
previously available:
•
Increased the total number of subjects in the 
study.
•
Modified the randomization ratios.
•
Increased the number of study sites.
•
Modified the number of subjects in each 
treatment group.
•
Revised the description of the statistical 
analyses.
Section 1.2 (MEDI3506 Background) and Section 1.5 
(Rationale for Conducting the Study)
Added text describing the preliminary report of a 
Phase 2b clinical study of etokimab that was not 
previously available to justify the substantial 
revisions made in Protocol Amendment 3.
AD = atopic dermatitis; IL = interleukin.
Table 24
Summary of Non-substantial Revisions in Protocol Amendment 3
Section of the Protocol Affected
Reason for Amendment
Protocol Synopsis (Objectives and Endpoints), 
Section 2.3 (Table 3 Exploratory Objectives and 
Endpoints), Section 4.2.2 (Table 6 Schedule of 
Treatment Period Study Procedures), Section 4.2.3 
(Table 7 Schedule of Follow-up Procedures), 
Section 4.3.9 (Estimate of Volume of Blood to Be 
Collected), and Section 4.8.6 (Analysis of 
Biomarkers)
Upon further consideration after authoring the 
original protocol:
•
Added exploratory plasma EDN endpoint to 
introduce an assessment for measuring activated 
eosinophils.
•
Revised proinflammatory gene signatures in 
whole blood exploratory endpoint to clarify the 
text.
Protocol Synopsis (Statistical Methods), 
Section 4.8.3.1 (Primary Efficacy Analysis), and 
Section 4.8.3.3 (Secondary Efficacy Analyses) 
Upon further consideration after authoring the 
original protocol, minor revisions were introduced to 
clarify the text.
Section 4.1.2 (Inclusion criteria)
Revised inclusion criterion 5b to remove 
corticosteroids “(b) A documented history, within the 
6 months prior to screening Visit 1, of requiring 
intermittent or continuous systemic therapy,”
Section 4.1.3 (Exclusion Criteria)
Added an exclusion criterion (Criterion 9) that is a 
German legal requirement that was inadvertently not 
included in the original protocol.
CCI


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Table 24
Summary of Non-substantial Revisions in Protocol Amendment 3
Section of the Protocol Affected
Reason for Amendment
Section 4.1.6 (Discontinuation of Investigational 
Product)
Revised criteria to introduce changes suggested in the 
“Study may proceed” letter from the FDA.
Section 4.2.3 (Table 7 Schedule of Follow-up 
Procedures)
Added assessment of SC injection sites at the 
unscheduled/early discontinuation visit to introduce a 
change suggested in the “Study may proceed” letter 
from the FDA.
Section 4.3.3 (Clinical Laboratory Tests)
Added serum chemistry assessment of GGT to 
introduce a change suggested in the “Study may 
proceed” letter from the FDA.
Section 4.8.7 (Interim, Primary and Final Analyses)
Added clarification of the interim analysis “No 
adjustments to the study design are planned based on 
the results of the interim analysis since….’ To make 
it clear that the randomization ratio adjustment is not 
linked to the interim analysis.
EDN = eosinophil derived neurotoxin; FDA = Food and Drug Administration; GGT = gamma-glutamyl 
transferase; SC = subcutaneous.
9.8
Protocol Amendment 2
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 2. The principal reason for this amendment is to address feedback from the FDA.
Changes to the protocol considered to be substantial (Table 25) and non-substantial (Table 26) 
are summarized below.
Table 25
Summary of Substantial Revisions in Protocol Amendment 2
Section of the Protocol Affected
Reason for Amendment
Synopsis
Updates were made to the synopsis to maintain 
consistency with the safety endpoint alteration in the 
main protocol body.
Section 2.2 (Table 2 Secondary Objectives and 
Associated Endpoints), Section 4.8.1 (General 
Considerations), Section 4.8.4.3 (Analysis of Vital 
Signs, ECGs, and Echocardiograms), Section 5.4.11 
(Adverse Events Based on Examination and Tests)
Left ventricular ejection fraction added to safety 
endpoints to capture data collected by 
echocardiogram assessments that were added to 
address safety concerns from the FDA.


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Table 25
Summary of Substantial Revisions in Protocol Amendment 2
Section of the Protocol Affected
Reason for Amendment
Section 4.1.3 (Exclusion Criteria)
•
Subjects with the following were excluded to 
address safety concerns from the FDA:
!
Elevated NT-proBNP.
!
Decreased left ventricular ejection fraction.
!
Family history of heart failure.
!
History of myocardial infarction.
!
Systemic hypertension.
!
History of treatment with cardiotoxic 
medications.
•
Exclusion criterion for diabetes mellitus was 
more tightly defined to address safety concerns 
from the FDA.
Section 4.2.1 (Table 5 Schedule of Screening and 
TCS/TCI Wash Out Procedures), Section 4.2.2 
(Table 6 Schedule of Treatment Period Study 
Procedures) and Section 4.2.3 (Table 7 Schedule of 
Follow-up Procedures)
•
To address safety concerns from the FDA:
!
HbA1c added to screening Visit 1.
!
NT-proBNP added to screening Visit 1, 
Visit 8 (Week 8), Visit 9 (Week 12), 
Visit 10 (Week 16), Visit 12 (Week 24), 
and for any unscheduled/early 
discontinuation visit.
!
Echocardiogram added to TCS/TCI 
washout Visit 2, and Visit 9 (Week 12).
Section 4.3.2 (Medical and Dermatology History, 
Physical Examinations, Weight, Height, Vital Signs, 
ECGs, and Echocardiograms), Section 4.3.2.5 
(Echocardiograms) and Section 4.3.3 (Clinical 
Laboratory Tests)
New subsection added to describe study procedure 
for echocardiogram, and echocardiogram removed 
from clinical laboratory tests section for clarity.
FDA = Food and Drug Administration; TCI = topical calcineurin inhibitor; TCS = topical corticosteroid; 
NT-proBNP = N-terminal prohormone of B-type natriuretic peptide.
Table 26
Summary of Non-substantial Revisions in Protocol Amendment 2
Section of the Protocol Affected
Reason for Amendment
Section 4.1.6 (Discontinuation of Investigational 
Product)
Reworded criterion on suspected new onset and/or 
progression of heart failure to clarify the default 
action is to discontinue investigational product.
Section 4.3.3 (Clinical Laboratory Tests)
Clarification that abnormal laboratory results that are 
not considered clinically significant are not required 
to be repeated.


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9.9
Protocol Amendment 1
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1. The principal reasons for this amendment are to correct errors inadvertently 
introduced in the original protocol and to introduce updates based on new information not 
available when drafting the original protocol.
Changes to the protocol considered to be non-substantial are summarized in Table 27.
Table 27
Summary of Revisions in Protocol Amendment 1
Section of the Protocol Affected
Reason for Amendment
Protocol Synopsis (Objectives and Endpoints), 
Section 2.3 (Table 3 Exploratory Objectives and 
Endpoints), Section 4.3.7.3 (Skin Punch Biopsies), 
and Section 4.8.6 (Analysis of Biomarkers)
Upon further consideration after authoring the 
original protocol, gross inflammation evaluation in 
lesional and non-lesional skin was added as an 
exploratory biomarker endpoint to add a standard 
assessment to the study.
Protocol Synopsis (Objectives and Endpoints), 
Section 2.3 (Table 3 Exploratory Objectives and 
Endpoints), and Section 4.8.6 (Analysis of 
Biomarkers)
Upon further consideration after authoring the 
original protocol, IL-33 bound to MEDI3506 was 
added as an exploratory biomarker endpoint to 
provide an assessment for confirming the new 
MEDI3506 formulation is able to bind to its IL-33 
target.
Section 4.1.3 (Exclusion Criteria)
The formatting of bullet (c) of exclusion criterion 1 
was changed to correct a formatting error 
inadvertently introduced in the original protocol.
Section 4.2.1 (Table 5 Schedule of Screening and 
TCS/TCI Wash Out Procedures)
Assessment of adherence to the completion of daily 
eDiary entries was added to Visit 2, to correct an 
error inadvertently introduced in the original 
protocol.
Section 4.2.2 (Table 6 Schedule of Treatment Period 
Study Procedures)
•
The baseline echocardiogram assessment 
planned for Visit 3 (Day 1) was removed to 
correct an error inadvertently introduced in the 
original protocol.
•
Upon further consideration after authoring the 
original protocol, an ADA assessment was 
added to Visit 7 (Day 29) to: 
!
Further support PK modeling.
!
Provide an additional opportunity for 
monitoring ADA between visits.
Section 4.2.2 (Table 6 Schedule of Treatment Period 
Study Procedures), Section 4.3.3 (Clinical Laboratory 
Tests), and Appendix D (Appendix D 2.3 Specific 
Measures to Consider after Epinephrine Injections, 
Where Appropriate)
The requirements for and the timing of the collection 
of serum tryptase samples changed based on new 
information that the stability period of the samples 
will be shorter than originally anticipated.


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Table 27
Summary of Revisions in Protocol Amendment 1
Section of the Protocol Affected
Reason for Amendment
Section 4.2.3 (Table 7 Schedule of Follow-up 
Procedures)
•
To correct errors inadvertently introduced in the 
original protocol:
!
Added urinalysis and serum chemistry 
assessments to Visit 11 (Day 141)
!
Added ECG assessment to the 
unscheduled/early discontinuation visit.
Section 4.3.3 (Clinical Laboratory Tests)
Revised description of pregnancy test specifications 
to correct an error inadvertently introduced in the 
original protocol.
Section 5.4.6 (Recording of Cardiac Events 
[Including Angina or Myocardial Infarction, 
Congestive Heart Failure, Symptomatic 
Atherosclerotic Vascular Disease, or Pulmonale or 
Arrhythmia])
Added how left ventricular ejection fraction is 
planned to be measured to clarify the text.
Section 4.5.1.4 (Treatment Administration)
Added a clause describing which female subjects 
must have negative urine pregnancy tests, to clarify 
the text.
Appendix E (Appendix E 7 Laboratory Tests)
Removed non-mandatory IgM anti-HCV test as the 
test is no longer recommended by the sponsor and the 
central laboratory is unable to provide the test.
ADA = anti-drug antibody(ies); ECG = electrocardiogram; eDiary = electronic diary; HCV = hepatitis C virus; 
Ig = immunoglobulin; IL = interleukin; PK = pharmacokinetic(s); TCI = topical calcineurin inhibitor; 
TCS = topical corticosteroid.


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Appendix A
Contraception Guidance
Women are considered to be of childbearing potential unless they meet either of the criteria, 
as follows:
∀
Surgically sterilized (including bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy), or
∀
Post-menopausal.
For women aged < 50 years, post-menopausal is defined as having both:
∀
A history of ≥12 months amenorrhea, without an alternative cause, following cessation of 
exogenous sex-hormonal treatment and,
∀
A follicle-stimulating hormone level in the post-menopausal range.
For women aged ≥50 years, post-menopausal is defined as having a history of ≥12 months 
amenorrhea, without an alternative cause, following cessation of exogenous sex-hormonal 
treatment.
A highly effective method of contraception is defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly. The acceptable methods of 
contraception are described in Table A1.
Periodic abstinence, the rhythm method, and withdrawal are NOT acceptable methods of 
contraception.
Table A1
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
•
Intrauterine device
•
Intrauterine hormone-releasing system (IUS) a
•
Bilateral tubal occlusion
•
Vasectomized partner b
•
Sexual abstinence c
Combined (estrogen and progestogen containing 
hormonal contraception)
!
Oral (combined pill)
!
Injectable
!
Transdermal (patch)
Progestogen-only hormonal contraception
!
Desogestrel
a
This is also considered a hormonal method.
b
With appropriate post-vasectomy medical testing of surgical success (ie, absence of sperm in ejaculate).
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the subject.


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Appendix B
Additional Safety Guidance
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from an adverse event 
(AE) as it occurred or it is suspected that use or continued use of the product would result in 
the subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent 1 or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
Examples of such events are:
∀
Angioedema not severe enough to require intubation but requiring intravenous (IV) 
hydrocortisone treatment.
∀
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine.
∀
Intensive treatment in an emergency room or at home for allergic bronchospasm.
∀
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion) or convulsions 
that do not result in hospitalization.
∀
Development of drug dependency or drug abuse.
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. The determination of severity should be made by the investigator based upon 
medical judgment and the severity categories of Grade 1 to 5 as defined below.


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Grade 1
An event of mild intensity that is usually transient and may 
require only minimal treatment or therapeutic intervention. The 
event does not generally interfere with usual activities of daily 
living.
Grade 2
An event of moderate intensity that is usually alleviated with 
additional specific therapeutic intervention. The event interferes 
with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject.
Grade 3
A severe event that requires intensive therapeutic intervention. 
The event interrupts usual activities of daily living, or 
significantly affects the clinical status of the subject.
Grade 4
An event, and/or its immediate sequelae, that is associated with
an imminent risk of death.
Grade 5
      Death as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 
non-serious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE.
Assessment of Relationship
A Guide to Interpreting the Causality Question
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product. The following factors should be considered when deciding if there is a 
“reasonable possibility” that an AE may have been caused by the investigational product.
∀
Time Course. Exposure to suspect investigational product. Has the subject actually 
received the suspect investigational product? Did the AE occur in a reasonable temporal 
relationship to the administration of the suspect investigational product?
∀
Consistency with known investigational product profile. Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or products of the same pharmacological class? OR could the AE be anticipated from its 
pharmacological properties?
∀
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect investigational product?


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∀
No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, or other host or environmental factors.
∀
Re-challenge experience. Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? AstraZeneca would not normally recommend or 
support a re-challenge.
∀
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship?
In difficult cases, other factors could be considered such as:
∀
Is this a recognized feature of overdose of the investigational product?
∀
Is there a known mechanism?
Causality of “related” is made if following a review of the relevant data, there is evidence for 
a “reasonable possibility” of a causal relationship for the individual case. The expression 
“reasonable possibility” of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as “not related.”
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
Relationship to Protocol Procedures
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-emergent 
SAEs. A protocol-related SAE may occur as a result of a procedure or intervention required 
during the study (eg, blood collection, washout of an existing medication). The following 
guidelines should be used by investigators to assess the relationship of SAEs to the protocol:
Protocol related:
The event occurred due to a procedure/intervention that was described 
in the protocol for which there is no alternative etiology present in the 
subject’s medical record.
Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record).


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Appendix C
National Institute of Allergy and Infectious Diseases and 
Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
National Institute of Allergy and Infectious Diseases (NAID) and Food Allergy and 
Anaphylaxis Network (FAAN) define anaphylaxis as a serious allergic reaction that is rapid in 
onset and may cause death. They recognize 3 categories of anaphylaxis, with criteria 
designated to capture from 80% of cases (category 1) to > 95% of all cases of anaphylaxis (for 
all 3 categories). 
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST 1 OF THE FOLLOWING:
(a) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia).
(b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence).
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula).
(b) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia).
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting).
3
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
(a) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline.
For the purpose of AE reporting, the above criteria should be used to guide retrospective 
judgment as to whether an event was true anaphylaxis. Guidance on the recognition of 
possible anaphylaxis at the time of the event is provided (Appendix D).


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Appendix D
Signs and Symptoms and Management of Acute Anaphylaxis
Appropriate drugs, such as epinephrine, antihistamines, corticosteroids, etc, and medical 
equipment to treat anaphylactic reactions must be immediately available at study sites, and 
study personnel should be trained to recognize and treat anaphylaxis. Local or national 
guidelines for the recognition and management of acute anaphylaxis should be followed 
where available. Where not available, guidance is provided below.
D 1
Signs and Symptoms of Acute Anaphylaxis
Anaphylaxis is an acute and potentially lethal multi-system allergic reaction in which some or 
all of the following signs and symptoms occur:
∀
Diffuse erythema.
∀
Pruritus.
∀
Urticaria and/or angioedema.
∀
Bronchospasm.
∀
Laryngeal edema.
∀
Hypotension.
∀
Cardiac arrhythmias.
∀
Feeling of impending doom.
∀
Unconsciousness.
∀
Shock.
Other earlier or concomitant signs and symptoms can include:
∀
Itchy nose, eyes, pharynx, genitalia, palms, and soles.
∀
Rhinorrhea.
∀
Change in voice.
∀
Metallic taste.
∀
Nausea, vomiting, diarrhea, abdominal cramps, and bloating.
∀
Lightheadedness.
∀
Headache.
∀
Uterine cramps.
∀
Generalized warmth.
D 2
Management of Acute Anaphylaxis
D 2.1
Immediate Intervention
1
Assessment of airway, breathing, circulation, and adequacy of mentation.


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2
Administer epinephrine intramuscularly every 5 to 15 minutes, in appropriate doses, as 
necessary, depending on the presenting signs and symptoms of anaphylaxis, to control 
signs and symptoms and prevent progression to more severe symptoms such as 
respiratory distress, hypotension, shock and unconsciousness.
D 2.2
Possibly Appropriate, Subsequent Measures Depending on Response to 
Epinephrine
1
Place patient in recumbent position and elevate lower extremities.
2
Establish and maintain airway.
3
Administer oxygen.
4
Establish venous access.
5
Normal saline IV for fluid replacement.
D 2.3
Specific Measures to Consider after Epinephrine Injections, Where 
Appropriate
1
Consider epinephrine infusion.
2
Consider H1 and H2 antihistamines.
3
Consider nebulized beta-2 agonist [eg, albuterol (salbutamol)] for bronchospasm resistant 
to epinephrine.
4
Consider systemic corticosteroids.
5
Consider vasopressor (e.g. dopamine).
6
Consider glucagon for patient taking b-blocker.
7
Consider atropine for symptomatic bradycardia.
8
Consider transportation to an emergency department or an intensive care facility.
9
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged 
resuscitation efforts are encouraged, if necessary.
If a suspected anaphylactic reaction occurs during or within a 24-hour period after 
administration of investigational product, blood samples for serum tryptase should be 
collected as soon as possible after the event, at 60 ± 30 minutes after the event, at discharge, 
and between 2 and 4 weeks post-discharge. Immediate care of the subject and treatment of the 
reaction must take priority over collecting blood samples.
Adapted from Kemp SF, Lockey RF, Simons FE; World Allergy Organization ad hoc 
Committee on Epinephrine in Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. 
A statement of the World Allergy Organization. Allergy. 2008;63(8):1061-70.


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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 1
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. Specific guidance 
on managing liver abnormalities can be found in Section 5.4.12 of the protocol.
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated alanine transaminase (ALT) from a central laboratory 
and/or elevated total bilirubin (TBL) from a local laboratory.
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than drug-induced liver injury (DILI) caused by the investigational product. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
E 2
Definitions
E 2.1
Potential Hy’s Law
Aspartate transaminase (AST) or ALT ≥ 3 × upper limit of normal (ULN) together with TBL 
≥2 × ULN at any point during the study following the start of investigational product
irrespective of an increase in alkaline phosphatase (ALP).
E 2.2
Hy’s Law
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than 
the investigational product, can be found to explain the combination of increases; eg, elevated 
ALP indicating cholestasis, viral hepatitis, or another drug.


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For PHL and HL, the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
E 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL, it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:
∀
ALT ≥ 3 × ULN.
∀
AST ≥ 3 × ULN.
∀
TBL ≥ 2 × ULN.
When a subject meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the investigator (also sent to sponsor study 
representative).
The investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the investigator will:
∀
Request a repeat of the test (new blood draw) by the central laboratory without delay.
∀
Complete the appropriate unscheduled laboratory case report form (CRF) module(s) with 
the original local laboratory test result.
When the identification criteria are met from central or local laboratory results the investigator 
will without delay:
∀
Determine whether the subject meets PHL criteria (see Section E 2) by reviewing 
laboratory reports from all previous visits (including both central and local laboratory 
results).
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria Not Met
If the subject does not meet PHL criteria the investigator will:
∀
Inform the study representative that the subject has not met PHL criteria.
∀
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the study protocol.


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E 4.2
Potential Hy’s Law Criteria Met
If the subject does meet PHL criteria the investigator will:
∀
Notify the sponsor study representative who will then inform the study team.
∀
Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criteria ‘Important medical event’ and causality assessment ‘yes/related’ 
according to clinical study protocol process for SAE reporting.
The medical monitor contacts the investigator, to provide guidance, discuss and agree on an 
approach for the study subjects’ follow-up (including any further laboratory testing) and the 
continuous review of data. Subsequent to this contact the investigator will:
∀
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated. 
Complete follow-up SAE Form as required.
∀
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the medical monitor. This includes deciding which the tests available in the HL lab 
kit should be used.
∀
Complete the relevant CRF Modules as information becomes available.
E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the medical 
monitor will contact the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
investigational product, to ensure timely analysis and reporting to health authorities per local 
requirements from the date PHL criteria were met. The medical monitor and global safety 
physician will also be involved in this review together with other subject matter experts as 
appropriate.
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for an SAE:
∀
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF.


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∀
If the alternative explanation is an AE/SAE, update the previously submitted PHL SAE 
and AE CRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the sponsor’s standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the investigational product:
∀
Send the updated SAE (report term “Hy’s Law”) according to the sponsor’s standard 
processes.
#
The “Medically Important” serious criterion should be used if no other serious 
criteria apply.
#
As there is no alternative explanation for the HL case, a causality assessment of 
“related” should be assigned.
If, there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:
∀
Provide any further update to the previously submitted SAE of PHL (report term now 
“Hy’s Law case”), ensuring causality assessment is related to the investigational product 
and seriousness criteria are medically important, according to the clinical study protocol 
process for SAE reporting.
∀
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following clinical study protocol process for SAE reporting, according to the outcome of 
the review and amend the reported term if an alternative explanation for the liver 
biochemistry elevations is determined.
E 6
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a subject meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
∀
Was the alternative cause for the previous occurrence of PHL criteria being met found to 
be the disease under study eg, chronic or progressing malignant disease, severe infection, 
or liver disease.


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If No: follow the process described in Section E 4.2, for reporting PHL as an SAE.
If Yes: Determine if there has been a significant change in the subject’s condition compared 
with when PHL criteria were previously met:
∀
If there is no significant change no action is required.
∀
If there is a significant change follow the process described in Section E 4.2, for reporting 
PHL as an SAE.
A “significant” change in the subject’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator; this 
may be in consultation with the medical monitor if there is any uncertainty.
E 7
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory when using a central laboratory. For studies using a local 
laboratory, the list may be modified based on clinical judgment. If required, for additional 
assistance on which tests could be used to evaluate other potential causes of liver dysfunction, 
consult with the Hepatic Safety Knowledge Group. Any test results need to be recorded.
Hy’s Law Lab Kit for Central Laboratories
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgG anti-HCV
HCV RNA
IgM anti-HEV
HEV RNA


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Other viral infections
IgM and IgG anti-CMV
IgM and IgG anti-HSV
IgM and IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
REFERENCES
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry (issued July 2009) 'Drug-induced liver injury: Premarketing 
clinical evaluation'


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Appendix F
Genetic Research
F 1
Rationale and Objectives
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments, or medications.
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
F 2
Genetic Research Plan and Procedures
F 2.1
Selection of Genetic Research Population
Study Selection Record
All subjects will be asked to participate in this genetic research. Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit. The subject will 
not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria described 
in the main body of the protocol and:
∀
Provide informed consent for the genetic sampling and analyses.
Exclusion Criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:
∀
Previous allogeneic bone marrow transplant.
∀
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection.
F 2.2
Discontinuation of Subjects from this Genetic Research
Specific reasons for discontinuing a subject from this genetic research are:
∀
Withdrawal of consent for genetic research: Subjects may withdraw from this genetic 
research at any time, independent of any decision concerning participation in other 


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aspects of the main study. Voluntary discontinuation will not prejudice further treatment. 
Procedures for discontinuation are outlined in Section 4.1.8 of the protocol.
F 2.3
Collection of Samples for Genetic Research
The blood sample for genetic research will be obtained from the subjects at Visit 3 in the 
treatment period. Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding subjects who may withdraw due to an AE, such subjects 
would be important to include in any genetic analysis. If for any reason the sample is not 
drawn at Visit 3, it may be taken at any visit until the last study visit. Only 1 sample should be 
collected per subject for genetics during the study. Samples will be collected, labelled, stored, 
and shipped as detailed in the Laboratory Manual.
F 2.4
Coding and Storage of DNA Samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality. Samples will be stored for a maximum of 
15 years, from the date of last subject last visit, after which they will be destroyed. DNA is a 
finite resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable by the second, unique number only. This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organization. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organizations working with the DNA).
The link between the subject enrollment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organizations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit 
and to trace samples for destruction in the case of withdrawal of consent.
F 2.5
Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 7 of the protocol.
F 2.6
Informed Consent
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component. To participate 
in the genetic component of the study the subject must sign and date both the consent form for 


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the main study and the genetic component of the study. Copies of both signed and dated 
consent forms must be given to the subject and the original filed at the study center. The 
principal investigator(s) is responsible for ensuring that consent is given freely and that the 
subject understands that they may freely discontinue from the genetic aspect of the study at 
any time.
F 2.7
Subject Data Protection
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, a global safety physician or an investigator might know a subject’s 
identity and also have access to his or her genetic data. Also, regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate.
F 2.8
Data Management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples.
The results from this genetic research may be reported in a separate report from the Clinical 
Study Report or published in scientific journals.
AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as Hospitals, Academic Organization, or Health Insurance Companies. This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease. The researchers can 
only use this information for health-related research purposes. Researchers may see summary 
results but they will not be able to see individual subject data or any personal identifiers.
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
F 2.9
Statistical Methods and Determination of Sample Size
The number of subjects that will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan for genetic research will be prepared where appropriate.


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Appendix G
Classification of Topical Corticosteroids
Topical corticosteroids (TCSs) are grouped into 7 classes based on vasoconstriction assays, 
with Class I TCSs the most potent and Class VII TCSs the least potent (Table G1). If a TCS 
not included in the table below is desired, the investigator should contact the medical monitor 
to confirm classification. These groups may vary depending on the formulation and 
concentration and should be considered approximate. In general, ointments are more potent 
than creams or lotions. Potency is also increased when TCSs are used under occlusive 
dressings or in intertriginous areas.
Table G1
Classification of Representative TCSs
Potency
Class
TCS
Formulation
Strength (%)
Very high
I
Augmented betamethasone dipropionate
O
0.05
Clobetasol propionate
C, F, or O
0.05
Diflorasone diacetate
O
0.05
Halobetasol propionate
C or O
0.05
High
II
Amcinonide
C, L, or O
0.1
Augmented betamethasone dipropionate
C
0.05
Betamethasone dipropionate
C, F, O, or S
0.05
Desoximetasone
C or O
0.25
Desoximetasone
G
0.05
Diflorasone diacetate
C
0.05
Fluocinonide
C, G, O, or S
0.05
Halcinonide
C or O
0.1
Mometasone furoate
O
0.1
Triamcinolone acetonide
C or O
0.5
Medium
IV
Betamethasone valerate
C, F, L, or O
0.1
Clocortolone pivalate
C
0.1
Desoximetasone
C
0.05
Fluocinolone acetonide
C or O
0.025
Flurandrenolide
C or O
0.05
Fluticasone propionate
O
0.005
Mometasone furoate
C
0.1
Triamcinolone acetonide
C or O
0.1
Lower-
medium
V
Hydrocortisone butyrate
C, O, or S
0.1
Hydrocortisone probutate
C
0.1
Hydrocortisone valerate
C or O
0.2
Prednicarbate
C
0.1
Low
VI
Alclometasone dipropionate
C or O
0.05
Desonide
C, G, F, or O
0.05
Fluocinolone acetonide
C or S
0.01
Lowest
VII
Dexamethasone
C
0.1
Hydrocortisone
C, L, O, or S
0.25, 0.5, or 1
Hydrocortisone acetate
C or O
0.5-1
C = cream; F = foam; G = gel; L = lotion; O = ointment; S = solution; TCS = topical corticosteroid.


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REFERENCES
Eichenfield et al 2014, J Am Acad Dermatol 71(1):116-132.
Paller AS, Mancini AJ. Eczematous eruptions in childhood. In: Paller AS, Mancini AJ. 
Hurwitz Clinical Pediatric Dermatology. St. Louis, MO: Elsevier Inc; 2011 chapter 3, p.49.


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Appendix H
Investigator’s Global Assessment
The Investigator’s Global Assessment is not standardized, so the version provided should be 
used (Table H1).
Table H1
IGA
Score
Disease Severity
Standard IGA Scale
IGA Morphological Descriptors
0
Clear
No inflammatory signs of AD.
No erythema and no elevation 
(papulation/infiltration).
1
Almost clear
Just perceptible erythema, and just 
perceptible papulation/infiltration.
Barely perceptible erythema and/or 
minimal lesion elevation 
(papulation/infiltration) that is not 
widespread.
2
Mild disease
Mild erythema and mild 
papulation/infiltration.
Visible detectable, light pink 
erythema and very slight elevation 
(papulation/infiltration).
3
Moderate disease
Moderate erythema and moderate 
papulation/infiltration.
Dull red, clearly distinguishable 
erythema and clearly perceptible but 
not extensive elevation 
(papulation/infiltration).
4
Severe disease
severe erythema and severe 
papulation/infiltration.
Deep/dark erythema, marked and 
extensive elevation 
(papulation/infiltration).
AD = atopic dermatitis; IGA = Investigator’s Global Assessment.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d9182c00001-csp-amendment-9
Document Title:
D9182C00001 Clinical Study Protocol Amendment 9
Document ID:
Doc ID-004360626
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
21-Jun-2022 07:01 UTC
Hitesh Pandya
Author Approval
20-Jun-2022 09:18 UTC
Joanna Kiraga
Content Approval
20-Jun-2022 07:24 UTC
Rachel Moate
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: 
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Statistical Analysis Plan
A Phase 2 Randomized, Double-blinded, 
Placebo-controlled Study to Evaluate the 
Efficacy and Safety of MEDI3506 in Adult 
Subjects with Moderate-to-severe Atopic 
Dermatitis
Protocol Number: D9182C00001
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Disclosure


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TABLE OF CONTENTS
1
INTRODUCTION ......................................................................................................7
2
STUDY OVERVIEW .................................................................................................7
2.1
Study Objectives...............................................................................................7
2 . 1 . 1
Primary Study Objective(s) ......................................................7
2 . 1 . 2
Secondary Study Objectives.....................................................7
2 . 1 . 3
Exploratory Study Objectives...................................................7
2.2
Study Design.....................................................................................................8
2.3
Treatment Assignment, Blinding and Analysis Datasets....................................9
2 . 3 . 1
Analysis Datasets...................................................................10
2.4
Sample Size ....................................................................................................10
3
STATISTICAL METHODS......................................................................................11
3.1
General Considerations ...................................................................................11
3 . 1 . 1
General Computation Rules....................................................11
3.1.1.1
Absolute and Percent Change from Baseline ..........................11
3 . 1 . 2
Visit Windows .......................................................................11
3.2
Analysis Populations.......................................................................................14
3.3
Study Subjects ................................................................................................15
3 . 3 . 1
Subject Disposition and Completion Status ............................15
3 . 3 . 2
Important Protocol Deviations................................................16
3 . 3 . 3
Demographics and Baseline Characteristics............................16
3 . 3 . 4
Investigational Product Exposure ...........................................17
3 . 3 . 5
Prior and Concomitant Medications .......................................17
3 . 3 . 6
Prohibited and Rescue Concomitant Medications ...................18
3.4
Efficacy Analyses ...........................................................................................18
3 . 4 . 1
Primary Efficacy Endpoint(s) and Analyses ...........................18
3.4.1.1
Primary Efficacy Endpoint(s).................................................18
3.4.1.2
Handling of Dropouts and Missing Data.................................19
3.4.1.3
Primary Efficacy Analysis......................................................19
3.4.1.4
Additional Analyses of the Primary Efficacy Endpoint(s).......20
3.4.1.5
Subgroup Analyses ................................................................21
3 . 4 . 2
Secondary Efficacy Endpoints and Analyses ..........................22
3.4.2.1
Secondary Efficacy Endpoints................................................22
3.4.2.2
Handling of Dropouts and Missing Data.................................26
3.4.2.3
Secondary Efficacy Analyses .................................................26
3.4.2.4
Subgroup Analyses ................................................................31
3 . 4 . 3
Other Efficacy Analyses.........................................................32


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3.4.3.1
Number and percentage of subjects achieving EASI 90, 
EASI 75, and EASI 50, at Weeks 2, 4, 8, 12, 16, 
20, and 24 ................................................................32
3.4.3.2
Percentage change from baseline to Weeks 2, 4, 8, 12, 16, 
20, and 24 in EASI score..........................................32
3.4.3.3
Percentage of subjects achieving IGA 0/1 and ≥2 grade 
reduction from baseline at Weeks 2, 4, 8, 12, 16, 
20, and 24 ................................................................33
3.4.3.4
Change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 
in %BSA affected by AD .........................................33
3.4.3.5
Peak pruritus NRS: reduction of ≥3 from baseline to Weeks 
2, 4, 8, 12, 16, 20, and 24 .........................................33
3.4.3.6
Peak pruritus NRS: reduction of ≥4 from baseline to Weeks 
2, 4, 8, 12, 16, 20, and 24 .........................................33
3.4.3.7
Peak pruritus NRS: change from baseline to Weeks 2, 4, 8, 
12, 16, 20, and 24.....................................................33
3.4.3.8
Skin pain NRS: change from baseline to Weeks 2, 4, 8, 12, 
16, 20, and 24 ..........................................................33
3.4.3.9
SCORAD: Percent change from baseline to Weeks 2, 4, 8, 
12, 16, 20 and 24......................................................34
3.4.3.10
PGI-S at Weeks 2, 4, 8, 12, 16, 20 and 24 ................34
3.4.3.11
Change from baseline to Weeks 2, 4, 8, 12, 16, 20, 
and 24 in 5-D itch ....................................................34
3.4.3.12
Change from baseline to Weeks 2, 4, 8, 12, 16, 20, 
and 24 in POEM ......................................................34
3.4.3.13
Change from baseline to Weeks 2, 4, 8, 12, 16, 20, 
and 24 in DLQI........................................................34
3.4.3.14
Change from baseline to Weeks 16 and 24 in 
SNOT-22 .................................................................34
3.4.3.15
Change from baseline to Weeks 16 and 24 in 
ACQ-6.....................................................................34
3.4.3.16
Subjects requiring rescue therapy during the 
treatment and follow-up period ................................35
3.4.3.17
Time to first use of rescue therapy............................35
3.4.3.18
Incidence of skin infection TEAEs...........................35
3.5
Biomarker Analyses........................................................................................35
3 . 5 . 1
Blood Concentration of sST2 and 
.........35
3 . 5 . 2
Peripheral Blood Mononuclear Cell (PBMC) subset...............36
3 . 5 . 3
Blood biomarker levels of Eosinophils, IL-33 bound to 
MEDI3506, IL-5, IL-13 and CCL17.......................................36
3 . 5 . 4
Serum IgE levels and Plasma Eosinophil Derived 
Neurotoxin (EDN) levels........................................................36
CCI




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List of Abbreviations
Abbreviation or 
Specialized Term
Definition
ACQ
Asthma Control Questionnaire
AD
atopic dermatitis
ADA
anti-drug antibody(ies)
AE
adverse event
AESI
adverse event of special interest
ALT
alanine transaminase
ANCOVA
analysis of covariance
AST
aspartate transaminase
BSA
body surface area
CI
confidence interval
CSR
Clinical Study Report
DLQI
Dermatology Life Quality Index
EASI
Eczema Area and Severity Index
EASI 50
50% reduction from baseline in Eczema Area and Severity Index score
EASI 75
75% reduction from baseline in Eczema Area and Severity Index score
EASI 90
90% reduction from baseline in Eczema Area and Severity Index score
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EDN
Eosinophil Derived Neurotoxin
Emax
maximum effect attributable to the drug
GEE
Generalized Estimating Equation
ICH
International Council for Harmonisation
IGA
Investigator’s Global Assessment
IL
interleukin
IPD
Important protocol deviation
ITT
intent-to-treat
IXRS
interactive voice/web response system
IV
intravenous
mAb
monoclonal antibody
MCP-Mod
multiple comparison procedure with modelling techniques
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effects model for repeated measures
NRS
Numerical Rating Scale
NT-proBNP
N-terminal prohormone of B-type natriuretic peptide
PD
pharmacodynamic(s)
PDP
protocol deviation plan 
PGI-S
Patient Global Impression of Severity


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Abbreviation or 
Specialized Term
Definition
PK
pharmacokinetic(s)
POEM
Patient-Oriented Eczema Measure
PT
preferred term
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous
SCORAD
SCORing Atopic Dermatitis
SD
standard deviation
SNOT
Sino-nasal Outcome Test
SOC
system organ class
TBL
total bilirubin
TCI
topical calcineurin inhibitor
TCS
topical corticosteroid
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
TS
Translational Science
ULN
upper limit of normal
Q4W
every 4 weeks


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1
INTRODUCTION
This document describes the statistical analysis for protocol D9182C00001, a Phase 2 proof-
of-concept clinical study which aims to evaluate the efficacy and safety of MEDI3506 in 
subjects with moderate to severe Atopic Dermatitis (AD).    
2
STUDY OVERVIEW
2.1 Study Objectives
2 . 1 . 1    Primary Study Objective(s)
The primary objective of the study is to assess the effects of MEDI3506 compared with 
placebo on AD disease severity, in adult subjects with moderate-to-severe AD.
2 . 1 . 2    Secondary Study Objectives
The secondary objectives are: 
!
To further assess the effects of MEDI3506 compared with placebo on AD disease 
severity and symptoms, in adult subjects with moderate-to-severe AD
!
To assess the safety and tolerability of MEDI3506 compared with placebo, in adult 
subjects with moderate-to-severe AD
!
To evaluate the PK of MEDI3506, in adult subjects with moderate-to-severe AD  
!
To evaluate the immunogenicity of MEDI3506, in adult subjects with moderate-to-severe 
AD. 
2 . 1 . 3      Exploratory Study Objectives
The exploratory objectives are as follows: 
!
To assess the effects of MEDI3506 compared with placebo on AD disease severity and 
symptoms over time to Week 24, in adult subjects with moderate-to-severe AD
!
To evaluate the effect of MEDI3506 on blood biomarkers that may either predict or 
reflect an efficacy response in adult subjects with moderate-to-severe AD
!
To evaluate the effect of MEDI3506 on skin biomarkers that may either predict or reflect 
an efficacy response in adult subjects with moderate-to-severe AD


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!
To assess the effect of MEDI3506 compared with placebo on the need for rescue therapy, 
in adult subjects with moderate-to-severe AD
!
To evaluate the effect of MEDI3506 compared with placebo on nasal symptom control, 
in a subset of adult subjects with moderate-to-severe AD and comorbid chronic 
inflammatory conditions of the nasal mucosa and/or paranasal sinuses
!
To evaluate the effect of MEDI3506 on asthma symptom control compared with placebo, 
in a subset of adult subjects with moderate-to-severe AD and comorbid asthma. 
!
To evaluate genetic markers that may predict an efficacy response in adult subjects with 
moderate-to-severe AD treated with MEDI3506 compared with placebo. 
2.2 Study Design
This is a Phase 2 randomized, double-blinded, placebo-controlled, parallel-group, 
proof-of-concept study to evaluate the efficacy, safety, PK, and immunogenicity of 
MEDI3506 in adult subjects with moderate-to-severe AD. Approximately 152 subjects will 
receive 
 MEDI3506 SC; or pooled placebo SC; in a 3:1:1:3 ratio overall, 
 The 
randomization ratio will change during the study. The first 72 subjects in the study will be 
randomized using a 3:3:3:1:2 ratio to receive 
MEDI3506 SC; or placebo 
 SC, or placebo 
 SC. The remaining subjects will be randomized using a 1:1 ratio 
to receive 
 MEDI3506 SC or placebo 
 SC. The randomization will be stratified 
based on total IgE (< 150 kU/L or ≥150 kU/L) at screening.
Subjects will be enrolled in this study for approximately 6.8 months (28 weeks), comprising 
a screening and TCS/TCI wash out period of up to 4 weeks, a 16-week treatment period, and 
an 8-week follow-up period (Figure 1). Subjects will not be permitted to use TCSs and TCIs 
during these periods, except if medically necessary. The final dose of investigational product 
will be administered at Visit 9 (Week 12) and the primary endpoint assessment will occur at 
Visit 10 (Week 16).   
Figure 1:
Study Flow Diagram
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The final analysis will occur when all subjects have completed the follow up period at Visit 
12 (Week 24) or have withdrawn from the study.  
2 . 3 . 1    Analysis Datasets
The primary analysis datasets contain all data (efficacy, safety, ADA, and PK) from all 
randomized subjects through Visit 10 (Week 16), and all available safety data as of the data 
cut-off date.
The final analysis datasets contain all data collected in this study, including data in the 
primary datasets and data from the subjects who were ongoing in the study at the time when 
the primary datasets were locked.
2.4 Sample Size
A sample size of 144 subjects in an overall 3:1:1:3 ratio of MEDI3506 
: MEDI3506 
: MEDI3506 
: pooled placebo will provide at least 90% power to detect a 
statistically significant difference in the percent change from baseline to Week 16 in EASI 
score between the highest dose of MEDI3506 and pooled placebo in a responder subgroup, 
assuming a 35% point difference between placebo and MEDI3506 at the highest dose, based 
on a SD of 40% points, a two–sided 10% alpha level and 50% of subjects in the responder 
subgroup. Based on identical assumptions, the sample size provides > 99% power to detect a 
statistically significant dose response in percent change from baseline to Week 16 in EASI 
score in all-comers.
The calculations for dose-response assume that percent change from baseline to Week 16 in 
EASI score will increase monotonically with the administration of higher MEDI3506 doses. 
The power was calculated using a multiple comparison procedure with modelling techniques 
(MCP-Mod) (Bretz et al, 2005) with 4 candidate models for the dose response (linear, 
maximum effect attributable to the drug [Emax], and 2 Hill-Emax models). Randomization will 
be stratified by total IgE (< 150 kU/L or ≥150 kU/L) at screening. The sample size 
calculations were performed using the R statistical computing software.
To allow for the possibility that ≤5% of the subjects per treatment group (for MEDI3506 
 
 and placebo) may be ineligible for the ITT population, the total sample size will comprise 
approximately 152 subjects (58 MEDI3506 
, 18 for MEDI3506 
, 18 for 
MEDI3506 
, and 58 for pooled placebo) randomized approximately to 3:1:1:3 ratio 
overall to the treatment groups.
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3
STATISTICAL METHODS
3.1 General Considerations
In general, unless specified otherwise, baseline is defined as the last non-missing assessment 
prior to dosing. If the baseline is missing following the above definition, baseline evaluations 
will not be imputed and will be considered as missing. All safety analyses will be performed 
on the As-treated population. All PK analyses will be conducted using the PK-population. 
Immunogenicity evaluation will be based on the As-treated population. All other analyses will 
be performed on the ITT population unless stated otherwise. All data will be provided in data 
listings sorted by treatment group and subject number. The placebo 
 groups will 
be pooled for planned analyses, except where stated otherwise. All tabular summaries will be 
presented by treatment group. Categorical data will be summarized by the number and 
percentage of subjects in each category. Continuous variables will be summarized by 
descriptive statistics including number of subjects, mean, standard deviation (SD), median, 
minimum, and maximum. All statistical tests will be two-sided at an alpha = 0.1 significance 
level unless stated otherwise.
Day 1 is the first dosing date. Prior to Day 1, study days will be calculated as (sample collection 
date – Day 1). After Day 1, study days will be calculated as (sample collection date – Day 1 + 
1).
3 . 1 . 1    General Computation Rules
3.1.1.1 Absolute and Percent Change from Baseline
Absolute change from baseline will be computed as (visit value – baseline value). Percent 
change from baseline will be computed as (visit value – baseline value)*100/baseline value.
If either a visit value or the baseline value is missing, then the absolute change from baseline 
value and the percent change from baseline will also be set to missing. If a visit value is 
non-zero while the baseline value is zero, then the absolute change from baseline will be 
computed but the percent change from baseline will be set to missing. If a visit value is zero 
and the baseline value is zero, the percent change will also be zero.
3 . 1 . 2    Visit Windows
Visit windows will be used for all scheduled assessments to allow for by-visit analyses, since 
not all assessments are performed on the scheduled day. The analysis visit windows will be 
calculated by bisecting the scheduled visit days. The lower limit of each window will be the 
mean of the two adjacent planned study days, rounded up to the nearest integer. The upper 
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limit of each window will be the mean of the two adjacent planned study days, rounded down 
to the nearest integer. 
The visit result will be missing if no assessment was reported within the specified visit window 
around the scheduled date. If multiple readings are recorded within a single visit window, then 
rules will be applied, as follows:
•
If there are 2 or more observations within the same visit window, the non-missing
observation closest to the scheduled visit will be used in the analysis.
•
If 2 observations are equidistant from the scheduled visit, the non-missing observation
with the earlier collection date or time will be used in the analysis.
•
If two observations are collected on the same date, the non-missing observation with the
earlier collection time will be used in the analysis.
•
Additional rules for cases not covered by the 2 rules above will be documented in the
Analysis Conventions Document.
For EASI, IGA and SCORAD, adjusted protocol-defined visit windows will be usedas 
defined in
Table 1.


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Table 1
Adjusted Protocol-defined Visit Windows for EASI, IGA, and 
SCORAD
Visit Number
Name/Week Number
Scheduled Study Day in the Protocol
Visit Windows
1
Screening a
-28 to -12
Study Day ≤-12
2
TCS/TCI Wash Out a
-11 to -8
-11 ≤Study Day ≤-8
3
Week 0 (Day 1) a
1
-7 ≤Study Day ≤1
5
Week 1
8
2 ≤Study Day ≤11
6
Week 2
15
12 ≤Study Day ≤22
7
Week 4
29
23 ≤Study Day ≤43
8
Week 8
57
44 ≤Study Day ≤71
9
Week 12
85
72 ≤Study Day ≤99
10
Week 16
113
100 ≤Study Day ≤127
11
Week 20
141
128 ≤Study Day ≤155
12
Week 24
169
Study Day ≥ 156
a
The Screening and Week 0 (Day 1) visit windows are applicable only when the visit is present for 
descriptive statistics in the summary tables for EASI, IGA, and SCORAD. For analyses, baseline is defined 
as the last assessment value prior to dosing unless stated otherwise.
For the patient-reported questionnaires collected by electronic PRO, the data will be 
summarized based on the visit windows provided (Table 2).


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Table 2
Visit Windows for PRO Data
Questionnaire
Collection Frequency and Scheduled Visits
Visit Windows
Pruritus NRS
!
Daily
Not Applicable
Skin pain NRS
!
Daily
Not Applicable
Moisturizer use
!
Daily
Not Applicable
5-D Pruritus Scale
!
Initial assessment at site: Day 1
!
At site: Weeks 2, 4, 8, 12, 16, 20 and 24
Day 1: Study Day ≤1
Week 2: 2 ≤Study Day ≤22
Week 4: 23 ≤Study Day ≤43
Week 8: 44 ≤Study Day ≤71
Week 12: 72 ≤Study Day ≤99
Week 16: 100 ≤Study Day ≤128
Week 20: 128 ≤Study Day ≤155
Week 24: Study Day ≥156
DLQI
!
Initial assessment at site: Day 1
!
At site: Weeks 2, 4, 8, 12, 16, 20 and 24
Same as 5-D Pruritus Scale
PGI-S
!
Initial assessment at site: Day 1
!
At site: Weeks 2, 4, 8, 12, 16, 20 and 24
Same as 5-D Pruritus Scale
POEM
!
Initial assessment at site: Day 1
!
At site: Weeks 2, 4, 8, 12, 16, 20 and 24
Same as 5-D Pruritus Scale
ACQ
!
Initial assessment at site: Day 1
!
At site: Weeks 4, 8, 12, 16 and 24
Day 1: Study Day ≤1
Week 4: 2 ≤Study Day ≤43
Week 8: 44 ≤Study Day ≤71
Week 12: 72 ≤Study Day ≤99
Week 16: 100 ≤Study Day ≤141
Week 24: Study Day ≥142
SNOT-22
!
Initial assessment at site: Day 1
!
At site: Weeks 4, 8, 12, 16 and 24
Same as ACQ
3.2 Analysis Populations
There are 3 analysis populations defined for this study (Table 3). A summary of the analysis 
populations by treatment group will be provided.
Table 3
Analysis Populations
Population
Description
ITT
Subjects who are randomized and receive any investigational product. Subjects will be 
analyzed according to their randomized treatment group.
As-treated
Subjects who are randomized and receive any investigational product. Subjects will be 
analyzed according to the treatment they actually receive. 


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Table 3
Analysis Populations
Population
Description
PK
Subjects who receive at least 1 dose of MEDI3506 and have at least 1 detectable serum 
concentration measurement post first dose of treatment. Subjects will be analyzed 
according to the treatment they actually receive. 
ITT = intent-to-treat; PK = pharmacokinetic(s).
3.3 Study Subjects
3 . 3 . 1    Subject Disposition and Completion Status
Summaries of subject eligibility, randomization, treatment received, and subjects randomized 
but not treated will be provided. In addition, subject disposition throughout the study and by 
visit with respect to treatment completion and follow-up completion will be provided. The 
summaries will be presented by treatment group and for all subjects combined. The 
denominators for this summary will include all subjects who were randomized into the study.
The number and percentage of subjects with one or more disruptions due to COVID-19 
pandemic will be presented by treatment group. A listing of all subjects affected by the 
COVID-19 related study disruption by unique subject number identifier and by 
investigational site, and a description of how the individual’s participation was altered, will 
be produced. COVID-19 related study disruptions can be:
1. Visit related (if visit is impacted by global/country situation, then contact mode will be
specified);
2. Study drug related (if study drug action taken (except “Drug Withdrawn”) was impacted
by global/country situation; study drug administration or location was impacted by
global/country situation; who performed a study drug administration);
3. Concomitant medication related (if when treatment was stopped due to any
global/country related situations ie: epidemic/pandemic, healthcare crisis etc.);
4. Discontinuation of study drug due to COVID-19 pandemic (if study drug action taken
“Drug Withdrawn” was impacted by global/country situation);
5. Withdrawal from study (if primary reason for ending study is related to global/country
situation).


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3 . 3 . 2    Important Protocol Deviations
Important protocol deviations (IPDs) are a subset of protocol deviations that may 
significantly impact the completeness, accuracy, and/or reliability of the study data or that 
may significantly affect a subject’s rights, safety, or wellbeing (ICH E3 guidance). The 
category of IPDs for the study are:
1. Did not fulfil eligibility criteria
2. Developed discontinuation criteria but continued
3. Received incorrect investigational treatment/dose
4. Received prohibited concomitant medication
5. Protocol-required procedure not adhered to
6. Other reason
Details of the definition of IPDs will be provided in the protocol deviation plan (PDP), which 
will be developed for the study. The method for identifying IPDs will be documented in the 
PDP. The list of identified IPDs will be reviewed by the study statistician, medical monitor, 
study physician, lead data manager and study manager. All blinded IPDs will be agreed prior 
to study unblinding by blinded study personnel. The review will take place at the time of 
primary analysis and final analysis for the study. Unblinding IPDs (ie. those that relate to 
study medication/dosing and which could potentially unblind a reviewer to subject’s 
treatment group) will be agreed by unblinded personnel. The finalized list of IPDs will be 
approved by the study statistician, medical monitor and study physician.
The number and percentage of subjects with at least one IPD, including and excluding 
COVID-19 related IPDs, will be summarized following the IPD categories for each study 
intervention group and overall. A listing of all identified IPDs will also be provided. All 
issues reported due to COVID-19 pandemic, regardless of whether the type of issue is 
considered an IPD or not, will be listed separately.
3 . 3 . 3    Demographics and Baseline Characteristics
Demographic information related to sex, age, race, weight, height, and body mass index (BMI) 
will be presented by treatment group and for all subjects combined. A summary of baseline 
disease characteristics will include, but will not be limited to:


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1. Stratification factor – Total immunoglobulin (Ig)E (< 150kU/L vs ≥150 kU/L)
2. Total serum IgE level (kU/L)
3. EASI score
4. EASI Score (≤ 25 points vs > 25 points)
5. Body surface area affected by AD (%)
6. Investigator’s Global Assessment (IGA) score
7. SCORAD
8. DLQI
9. 5-D itch
10. PGI-S
11. POEM
12. Peripheral blood eosinophil count (cells/μL)
13. Peripheral blood eosinophil count (cells/μL) (<300 vs ≥ 300)
14. Plasma EDN level (ng/mL)
15. Staphylococcus aureus (< median vs ≥ median) (lesional and non-lesional skin
separately) (at final analysis only)
16. TCS use at Screening (Low Potency TCS vs Medium to High Potency TCS vs No TCS)
17. Systemic therapy use in past 6 months (Yes vs No)
18. Topical medication use not tolerated or medically inadvisable (Yes vs No)
Medical history and AD history will be summarized by treatment group and for all subjects 
combined.
3 . 3 . 4    Investigational Product Exposure
Exposure to investigational product will be summarized by treatment group for the As-treated 
population. The summary of investigational product exposure will include descriptive statistics 
for the number of investigational product doses administered, total amount of investigational 
product exposure (in mg), and dose intensity for the entire study period. Also, total amount of 
investigational product administered by visit (in mg) will be summarized using descriptive 
statistics as well as for dose intensity. Dose intensity is defined as a percent of actual dose 
received versus total protocol planned dose.
3 . 3 . 5    Prior and Concomitant Medications
Prior and concomitant medications (including atopic dermatitis medications) will be coded 
using the WHODrug-Global-B3 Drug Dictionary. All prior and concomitant medications will 
be presented in a data listing. Prior medications include those medications that were stopped 
prior to the first dose of the investigational product. Concomitant medications exclude 
medications that were stopped prior to the first dose of investigational product. Summaries will 
be provided by preferred term and treatment group, as follows:
•
Prior atopic dermatitis medications


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•
Prior other medications (ie. non-AD medications)
•
Concomitant atopic dermatitis medications
•
Concomitant other medications (ie. non-AD medications)
3 . 3 . 6    Prohibited and Rescue Concomitant Medications
If a subject receives prohibited or rescue AD therapy, which may impact their efficacy 
assessments, they should discontinue investigational product. Prohibited and rescue AD 
therapy will be identified prior to unblinding. All prohibited and rescue AD therapies identified 
will be reviewed and a list of medications deemed to influence the disease will be made before 
unblinding, the list will be approved by the medical monitor. 
For the purpose of analyses, prohibited and rescue concomitant medications and therapies will 
be summarized. Cumulative summary of prohibited and rescue medication use by visit will 
also be provided. In addition, the cumulative distribution plot of the proportion of subjects 
receiving rescue therapy will be provided. A listing of all subjects who received prohibited 
rescue therapies will be provided specifying the prohibited therapy and the timing of use.
3.4 Efficacy Analyses
3 . 4 . 1    Primary Efficacy Endpoint(s) and Analyses
3.4.1.1 Primary Efficacy Endpoint(s)
The primary efficacy endpoint is the percent change from baseline to Week 16 in EASI 
score. The EASI is a one-dimensional scoring system, measuring only the clinical signs of 
AD not including the symptoms. The EASI evaluates 4 anatomic regions for severity and 
extent of key disease signs and focuses on the acute and chronic signs of inflammation (ie, 
erythema, edema, papulation, excoriation, and lichenification). The maximum score is 72, 
with higher values indicating more severe disease. 
EASI score is calculated as described (Table 4) (Hanifin et al, 2001).


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Table 4
EASI Score Calculation
Body Region
Severity
Area
Score
Head/Neck (H)
The average degree of severity 
of each sign (erythema [E],
induration/papulation [I], 
excoriation [EX], and 
lichenification [L]) is defined 
on a 4-point ordinal scale with 
half-steps (0.5, 1.5, and 2.5):
0 = none
0.5
1 = mild
1.5
2 = moderate
2.5
3 = severe
The area is defined on 
a 7-point ordinal scale:
0 = no eruption
1 = < 10%
2 = 10%-29%
3 = 30%-49%
4 = 50%-69%
5 = 70%-89%
6 = 90%-100%
(E + I + Ex + L) × Area × 0.1
Upper limbs (UL)
(E + I + Ex + L) × Area × 0.2
Trunk (T)
(E + I + Ex + L) × Area × 0.3
Lower limbs (LL)
(E + I + Ex + L) × Area × 0.4
EASI Score
NA
NA
Sum of scores for H, UL, T, 
and LL
NA = not applicable.
3.4.1.2 Handling of Dropouts and Missing Data
If any component of EASI is missing, the calculation of the score will be set to missing. For 
subjects who receive prohibited or rescue concomitant medications and therapies, the data 
obtained after the use of this therapy will be treated as missing and excluded from the 
primary analysis. In addition, sensitivity analyses will be performed in which the last 
response value recorded on the day of, or prior to, use of prohibited concomitant medications 
and therapies, and prohibited rescue therapies, will be carried forward.
3.4.1.3 Primary Efficacy Analysis
EASI score will be summarized with descriptive statistics (number of subjects with a valid 
value, mean, standard deviation, median, minimum, and maximum) by treatment group and 
visit. In addition, the change from baseline will be summarized with descriptive statistics for 
each post-baseline visit.
To assess dose response at Week 16, percent change from baseline to Week 16 in EASI score 
will be analyzed using a mixed-effects model for repeated measures (MMRM) including data 
from visits up to Week 16. The model will include treatment group, randomization stratum 
(total serum IgE < 150 kU/L or ≥ 150 kU/L), visit, and treatment group by visit interaction as 
categorical factors, with baseline EASI score as a covariate and the baseline*visit interaction 
term. Visit will be a repeated factor within a subject and an unstructured variance-covariance 


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matrix will be used to describe the correlations between observations on a subject between 
visits. If the unstructured variance-covariance matrix will not fit, then an alternative such as 
compound symmetry or first order auto-regressive will be used. The coefficient of the 
treatment effects at Week 16 obtained from the MMRM will then be incorporated into an 
MCP-Mod (Pinheiro et al, 2014), with 4 candidate models (linear, Emax, and 2 Hill-Emax
models) to determine the dose response profile. Details of the candidate models are provided 
in Appendix 1. As part of the MCP-Mod model, the testing of the 4 candidate dose response 
models will be adjusted for multiplicity using a family-wise error rate of 0.10. If more than 1 
candidate model shows a statistically significant dose response, the final model will be 
selected based on the Akaike Information Criteria obtained from each model.
The estimand of primary interest is the difference in mean percent change from baseline to 
Week 16 in EASI score between MEDI3506 and placebo in the ITT population. Data that are 
collected after withdrawal from the study or the use of rescue therapy will be treated as 
missing and excluded from the analysis. Data collected from subjects who discontinue the 
investigational product and did not use any rescue therapy afterwards will be included in the 
analysis. From the final model obtained from the MCP-Mod dose response analysis, the 
adjusted difference in mean percent change from baseline in EASI score between the placebo 
group and each MEDI3506 group at Week 16 will be estimated along with the 90% 
confidence interval (CI) and two-sided p-value. In addition, an estimate of the adjusted 
difference in mean percent change from baseline in EASI at each visit for each treatment 
group compared to placebo arm will be summarized together with a two-sided 90% CI, and 
p-value.
3.4.1.4 Additional Analyses of the Primary Efficacy Endpoint(s)
The following additional analyses will be performed to assess the sensitivity of the 
assumptions of the statistical methods used in the primary efficacy analysis. Firstly, a 
supplementary analysis using the ITT population will be done using all available data from 
subjects irrespective of whether or not they completed treatment, including data collected 
after subjects received rescue therapy. An MMRM followed by a MCP-Mod dose response 
model will be used for the analysis and the results from the fitted dose response model and 
the MMRM will be presented in a similar way as described above for the analysis of the 
primary efficacy endpoint (Section 3.4.1.3).  
A second supplementary analysis will be performed using the ITT population. Data from 
assessments performed after prohibited or rescue therapies are received will be excluded and 
a last observation carried forward (LOCF) approach will be applied for the missing data. An 
ANCOVA followed by a MCP-Mod dose response model including treatment group and 


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randomization stratum (total serum IgE level < 150 kU/L or ≥150 kU/L) as categorical 
factors and baseline EASI score as covariate, with 4 candidate models for the dose response 
(linear, Emax, and 2 Hill-Emax models) will be used for the analysis. The results from the fitted 
dose response model and the ANCOVA will be presented in a similar way as described 
above for the efficacy analysis for the primary endpoint (Section 3.4.1.3).
A third supplementary analysis will be performed using the ITT population, excluding data 
from subjects 
 whose treatment allocations were accidentally 
unblinded at the site. All other details of this analysis are the same as those for the primary 
analysis (Section 3.4.1.3).
A fourth supplementary analysis for percent change in EASI score will be performed using a 
MMRM as described above (Section 3.4.1.3), including data from visits up to Week 24. The 
ITT population will be used for the analysis and data from visits after subjects receive rescue 
therapy will be excluded from the analysis. From the final model obtained from the fitted 
MMRM, the adjusted difference in mean percent change from baseline in EASI score 
between the placebo and each MEDI3506 group at each visit will be estimated along with the 
90% CI and two-sided p-value. A plot of the adjusted mean percent change from baseline (±
SE) in EASI by visit will be provided.
In addition, similar summary (MMRM) will be provided for each of the four components of 
EASI (ie. erythema, papulation, excoriation and lichenification).    
3.4.1.5 Subgroup Analyses
The consistency of the overall treatment effect on the primary endpoint will be assessed in 
subgroups of subjects. A MMRM, as described in Section 3.4.1.3, including data from up to 
Week 16, will be used for each subgroup. The analyses will be performed for subgroups, as 
follows:
•
Total serum IgE level at baseline (< 150 kU/L vs ≥ 150 kU/L).
•
Baseline IGA score (3 vs 4).
•
Baseline EASI (≤25 points vs > 25 points).
•
S aureus in lesional skin at baseline ( < median vs ≥ median) (at final analysis only).
•
S aureus in non-lesional skin at baseline (< median vs ≥ median) (at final analysis only).
•
Age (18 to 35 years of age vs 36 to 75 years of age).
•
Age at onset of AD (< 18 years of age vs ≥ 18 years of age).
•
Parent having a history of AD (presence vs absence).
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•
Sex (male vs female).
•
Race (White vs non-White).
•
Region (North America vs Europe/Australia).
•
Blood eosinophil count at baseline (< 300 cells/μL vs ≥ 300 cells/μL).
•
Aeroallergens (presence vs absence).
•
Food allergies (presence vs absence).
•
Contact allergies (presence vs absence).
•
Asthma comorbidity (presence vs absence).
The MMRM will be fitted separately to each subgroup. The analysis for each subgroup will 
be performed if the subgroup has at least 20% of subjects in the ITT population.
3 . 4 . 2    Secondary Efficacy Endpoints and Analyses
3.4.2.1 Secondary Efficacy Endpoints
Secondary efficacy endpoints will be measured up to Week 16 for on-therapy effects and at 
time points beyond the end of treatment for off-therapy effects.
IGA
The IGA consists of a 5-point severity scale from clear to severe disease (0 = clear, 1 = almost 
clear, 2 = mild disease, 3 = moderate disease, and 4 = severe disease). The secondary efficacy 
IGA endpoint is the percentage of subjects achieving both an IGA score of 0 (clear) or 1 
(almost clear) and a reduction from baseline of ≥2 points at Week 16.
EASI including Percentage BSA Affected by AD
Secondary efficacy endpoints based on EASI include, as follows:
•
Percentage of subjects achieving a 90% reduction from baseline in EASI score (EASI 90)
at Week 16
•
Percentage of subjects achieving a 75% reduction from baseline in EASI score (EASI 75)
at Week 16
•
Percentage of subjects achieving a 50% reduction from baseline in EASI score (EASI 50)
at Week 16
•
Change from baseline to Week 16 in the percentage of BSA affected by AD, as assessed
by EASI.


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Pruritus NRS
Pruritus will be assessed using an NRS (0 to 10) with 0 = no itch and 10 = worst imaginable 
itch. Daily peak pruritus NRS assessments will be summarized as weekly means. The weekly 
mean score will be set to missing if > 3 assessments are missed in that 7-day period. Baseline 
will be defined as an average of the last 7 days prior to study drug being administered. If more 
than 3 days have missing data in the baseline period, the baseline period will be shifted back 
to the last 7-day period which includes at least 4 non-missing days. 
The secondary efficacy endpoints based on pruritus NRS include:
•
Change from baseline to Week 16 in weekly mean of daily peak pruritus NRS, and
•
Percentage of subjects achieving a reduction of ≥3 from baseline to Week 16 in weekly
mean of daily peak pruritus NRS.
Skin Pain NRS
Skin pain (ie, worst skin pain experienced in the previous 24 hours) will be assessed using an 
NRS (0 to 10) with 0 = no pain and 10 = worst imaginable pain. Daily peak skin pain NRS 
assessments will be summarized as weekly means. The weekly mean score will be set to 
missing if > 3 assessments are missed in that 7-day period. Baseline will be defined as an 
average of the last 7 days prior to investigational product being administered. If more than 3 
days have missing data in the baseline period, the baseline period will be shifted back to the 
last 7-day period which includes at least 4 non-missing days.
The secondary efficacy endpoint based on skin pain NRS is change from baseline to Week 
16 in weekly mean of daily peak skin pain NRS. 
SCORAD
The secondary efficacy endpoint based on SCORAD is the percent change from baseline to 
Week 16 in SCORAD, which is calculated as presented in Table 5 (European Task Force on 
Atopic Dermatitis, 1993).


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Table 5
SCORAD Calculation
Component
Definition
Grading
Score
Extent (A)
!
head and neck
!
upper limbs
(anterior/posterior)
!
lower limbs
(anterior/posterior)
!
anterior trunk
!
back
!
genitals
!
hand (right/left)
!
head and neck: 9%
!
upper limbs: 9% each
!
lower limbs: 18% each
!
anterior trunk: 18%
!
back: 18%
!
genitals: 1%
!
hand: 1% each
Sum of each extent item 
score to give a total extent 
score A (range 0-102)
Intensity (B)
!
erythema
!
edema/papulation
!
oozing/crusts
!
excoriations
!
lichenification
!
dryness
Each intensity item is 
defined on a 4-point ordinal 
scale:
0 = absent
1 = mild
2 = moderate
3 = severe
Sum of each intensity item 
score to give a total 
intensity score B (range 0-
18)
Subjective 
Symptoms (C)
!
pruritus
!
sleep loss
Each symptom has an NRS 
(0-10) where 0 is no 
pruritus/sleep loss and 10 is 
the worst imaginable 
pruritus/sleep loss.
Sum of each subjective 
symptom score to give a 
total symptom score C 
(range 0-20)
Objective 
SCORAD Score
NA
NA
(A/5) + (7×B/2)
SCORAD Score
NA
NA
(A/5) + (7×B/2) + C
NA = not applicable.
Patient Global Impression of Severity (PGI-S)
The PGI-S is a tool that allows patients to rate the severity of a condition. The PGI-S 
comprises a single question of, “Would you describe your AD or eczema as no symptoms, 
very mild, mild, moderate, severe or very severe?” The secondary efficacy endpoint based on 
this is PGI-S score at Week 16.
5-D Pruritus Score
A secondary efficacy endpoint includes change from baseline to Week 16 in 5-D pruritus score. 
5-D pruritus score is calculated as presented in Table (Elman et al, 2010).


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Table 6
5-D Pruritus Score Calculation
Domain
Definition
5-D Pruritus Score
Duration
Single-item domain score (range 1-5)
Range 1-5
Degree
Single-item domain score (range 1-5)
Range 1-5
Direction
Single-item domain score (range 1-5)
Range 1-5
Disability
Four items that assess the impact of itching on daily 
activities
!
sleep (range 1-5)
!
leisure/social (range 1-5)
!
housework/errands (range 1-5)
!
work/school (range 1-5)
Highest score on any of the four 
items
Distribution
Sixteen affected body parts (sum 0-16)
!
1 = sum of 0-2
!
2 = sum of 3-5
!
3 = sum of 6-10
!
4 = sum of 11-13
!
5 = sum of 14-16
5-D Pruritus
NA
Sum of five domains
NA =  not applicable.
Patient-Oriented Eczema Measure (POEM)
The Patient-Oriented Eczema Measure (POEM) is a 7-item questionnaire for assessing 
disease symptoms including dryness, itching, flaking, cracking, sleep loss, bleeding, and 
weeping occurring in the past week. Each item is scored on a 5-point scale with 0 = no days, 
1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = every day. The total POEM score is 
calculated by summing the score of each item resulting in a maximum of 28 and a minimum 
of 0, with higher values indicating severe disease (Charman et al, 2004). The secondary 
efficacy endpoint based on this questionnaire is the change from baseline to Week 16.   
Dermatology Life Quality Index 
The Dermatology Life Quality Index (DLQI) is a 10-item, patient-completed, health-related 
quality of life assessment of dermatology conditions with a recall period of 1 week. The 
DLQI captures perceptions of dermatology-related symptoms and feelings; 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 with 0 = not at all ⁄not relevant, 1 = a little, 2 = a 
lot, and 3 = very much (Basra et al, 2008). The DLQI score is calculated by summing the 
score of each item resulting in a maximum of 30 and a minimum of 0. The higher the score, 
the more quality of life is impaired. The secondary efficacy endpoint based on DLQI is 
change from baseline in DLQI score to Week 16. 


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3.4.2.2 Handling of Dropouts and Missing Data
If any component of SCORAD, 5-D Pruritus Score, POEM, DLQI or EASI score is missing, 
the calculation of the score will be set to missing.
For the analysis of efficacy responder endpoints, including the proportion of subjects achieving 
both IGA score of 0 (clear) or 1 (almost clear) and a reduction from baseline of ≥2 points, 
EASI 50, EASI 75, EASI 90 and peak pruritus NRS responders, subjects who discontinue 
investigational product, withdraw from the study, or require rescue therapy will be considered 
as non-responders. For the EASI 75 and IGA endpoints, additional sensitivity analyses will be 
performed using the last non-missing post-baseline value carried forward approach to assess 
the impact of including efficacy data beyond the use of rescue therapies. For subjects who 
receive rescue therapies, the last response value recorded on the day of, or prior to, the subject 
received a prohibited rescue therapy will be carried forward.
The continuous efficacy endpoints, including, percent change from baseline to Week 16 in 
SCORAD, change from baseline to Week 16 in peak pruritus NRS, skin pain NRS, 5-D 
pruritus (itch) score, percentage of BSA affected by AD, POEM, and DLQI will be analyzed 
using MMRM. All data points for subjects in the ITT population will be included in the 
analysis, up to and including the day the rescue therapy is used.
3.4.2.3 Secondary Efficacy Analyses
IGA Score 0 or 1 with ≥ 2 Grade Reduction from Baseline to Week 16
The percentage of subjects achieving an IGA score of 0 (clear) or 1 (almost clear) and a 
reduction from baseline of ≥2 points at Week 16 will be analyzed using a logistic regression 
model including treatment group, randomization stratum (total serum IgE level < 150 kU/L or 
≥150 kU/L), and baseline IGA as categorical factors. The coefficient of the treatment effects 
at Week 16 obtained from the logistic regression will then be used in an MCP-Mod analysis 
with 4 candidate models for the dose response (linear, Emax, and 2 Hill-Emax models). Details 
of the candidate models are provided in Appendix 1. As part of the MCP-Mod model, the 
testing of the 4 candidate dose response models will be adjusted for multiplicity using a 
family-wise error rate of 0.10. If more than 1 candidate model shows a statistically significant 
dose response, the final model will be selected based on the Akaike Information Criteria 
obtained from each model.
The composite estimand of primary interest is the difference in IGA response rate at Week 16 
between MEDI3506 and placebo in the ITT population. Subjects who withdraw from the study 
or require rescue therapy will be considered as non-responders. From the final model obtained 


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from the MCP-Mod dose response analysis, the difference in IGA response rate between the 
placebo and each MEDI3506 group will be estimated along with the 90% CI. For each 
MEDI3506 group versus placebo, the results will be presented as the difference in response 
rates, the 90% CI for the difference in response rates, and two-sided p-value.
A plot showing the percentage of subjects achieving IGA response in each treatment group 
by visit will be provided. In addition, barplot of IGA response rate at Week 16 in each 
treatment group will be provided.   
Supplementary analyses will be performed to assess the sensitivity of the assumptions of the 
statistical methods used in the primary analysis for the IGA endpoint. 
A logistic regression model of IGA response rate at Week 16 will be performed based on the 
ITT population. The model will include treatment group and randomization stratum (total 
serum IgE level < 150 kU/L or ≥150 kU/L) as categorical factors, and baseline IGA score as 
a covariate. Subjects who discontinue investigational product, withdraw from the study, or 
require rescue therapy will be considered as non-responders. For each MEDI3506 group 
compared with placebo, differences in response rates, 90% CIs for the differences in 
response rates (Ge et al, 2011), and two-sided p-values will be reported. If the number of 
responders is < 5 in any MEDI3506 group, the logistic regression model will not be used. 
Instead, the 90% CI and p-value for the difference in response rates will be calculated using 
an unconditional exact method (Chan and Zhang, 1999).  
An analysis based on the ITT population will be done using all available data from subjects 
irrespective of whether or not they completed treatment, including data from subjects who 
received rescue therapy. Subjects who discontinue investigational product or withdraw from 
the study before Week 16 will be considered as non-responders. The analysis will be 
performed using the same MCP-Mod as described for as described above for the secondary 
efficacy analysis for IGA. In addition, a logistic regression analysis similar to that described 
above, will also be performed for this ITT population for all observed cases.   
Another supplementary analysis will be performed using the ITT population in which data 
from assessments performed after rescue therapies are received are excluded and a last 
observation carried forward approach applied for missing data. The logistic regression and 
MCP-Mod dose response model used for this analysis and the presentation of results will be 
similar as described above for the secondary efficacy analysis for IGA. In addition, a logistic 
regression analysis like that described above, will also be performed for this ITT population 
with LOCF.


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Another supplementary analysis will be performed using the ITT population excluding data 
from subjects 
  whose treatment allocations were 
accidentally unblinded at the site. The analysis will be performed using the same MCP-Mod 
as described above for the secondary efficacy analysis for IGA.
Furthermore, an analysis will be performed using a generalized estimating equation (GEE) 
model for repeated measures including treatment group, randomization stratum (total serum 
IgE < 150 kU/L or ≥ 150 kU/L), baseline IGA value, visit, and visit by treatment group 
interaction as covariates. The analysis will be conducted including data from visits up to 
Week 24. The model will use a logistic link function and an independence working correlation 
matrix. If the assumed working correlation matrix will not fit, then suitable alternatives 
including exchangeable, unstructured, and autoregressive matrixes will be explored. From the 
model obtained, estimates of the treatment effect at each visit together with the associated 
standard errors, 90% CIs, and p-values will be provided. 
Percentage of Subjects Achieving EASI 50, EASI 75, or EASI 90 at 
Week 16
The percentage of subjects achieving EASI 50, EASI 75, or EASI 90 at Week 16 will be 
analyzed separately a logistic regression model including treatment group and randomization 
stratum (total serum IgE level < 150 kU/L or ≥150 kU/L) as categorical factors, and baseline 
EASI score as a covariate for each endpoint. The composite estimand will be the difference 
between MEDI3506 and placebo in EASI 50, EASI 75, or EASI 90 response rate at Week 16 
in the ITT population. Subjects who discontinue investigational product, withdraw from the 
study, or require rescue therapy will be considered as non-responders. For each MEDI3506 
group compared with placebo, differences in response rates, 90% CIs for the differences in 
response rates (Ge et al, 2011), and two-sided p-values will be reported for each endpoint. If 
the number of responders is < 5 in any MEDI3506 group, the logistic regression model will 
not be used. Instead, the 90% CI and p-value for the difference in response rates will be 
calculated using an unconditional exact method (Chan and Zhang, 1999).
As a supportive analysis for EASI 75, the percentage of subjects achieving an EASI 75 
response at Week 16 will be analyzed for the ITT population using an MCP-Mod dose response 
model similar to that described above for IGA response. Results obtained from the analysis 
will also be described in a similar way as described for the IGA response.
Barplot of the percentage of subjects achieving EASI 50, EASI 75, or EASI 90 at Week 16 
will be provided. A plot showing the percentage of subjects achieving an EASI 50 response 
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in each treatment group by visit will also be provided. Similar plot will be provided for EASI 
75 and EASI 90.
Change from Baseline to Week 16 in % BSA Affected by AD
The endpoint of change from baseline in % BSA affected by AD, as assessed by EASI, will 
be summarized descriptively and analyzed for the ITT population using a MMRM. Data from 
visits after subjects receive rescue therapy will be excluded from the analysis. Details of the 
model are similar to those described for percent change from baseline to Week 16 in EASI 
score (Section 3.4.1.3).
A plot of the adjusted mean change from baseline (± standard error) in %BSA by visit will be 
provided.
Peak Pruritus NRS at Week 16
The endpoint change from baseline to Week 16 in weekly mean of daily peak pruritus NRS 
will be summarized descriptively and analyzed using a MMRM. Data from visits after 
subjects receive rescue therapy will be excluded from the analysis. Details of the model are 
similar to those described for percent change from baseline to Week 16 in EASI score 
(Section 3.4.1.3)
The endpoint percentage of subjects achieving a ≥3 point reduction from baseline to 
Week 16 in weekly mean of daily peak pruritus NRS will be analyzed using a logistic 
regression model including treatment group and randomization stratum (total serum IgE 
< 150 kU/L or ≥150 kU/L), and baseline weekly mean of daily peak pruritus score as a 
covariate. Other details of the model are similar to those described above for the analyses of 
the secondary efficacy endpoint of EASI 50.
Skin pain NRS at Week 16
Change from baseline to Week 16 in weekly mean peak skin pain NRS will be summarized 
descriptively and analyzed using a MMRM. Data from visits after subjects receive rescue 
therapy will be excluded from the analysis. Details of the model are similar to those 
described for percent change from baseline to Week 16 in EASI score (Section 3.4.1.3).
Percent Change from Baseline to Week 16 in SCORAD
The endpoint of percent change from baseline to Week 16 in SCORAD will be analyzed using 
a MMRM, including data from visits up to Week 16. Data from visits after subjects receive 


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rescue therapy will be excluded from the analysis. Details of the model are similar to those 
described for percent change from baseline to Week 16 in EASI score (Section 3.4.1.3).
A cumulative distribution plot of percent change from baseline in SCORAD will be presented.
In addition, descriptive summary of the total SCORAD score at each visit will be provided by 
treatment group. In addition, similar summary will be provided for each of the components of 
SCORAD (extent, intensity, pruritus, sleep loss, objective). In addition, summary of change 
from baseline will be provided by visit for the total SCORAD score and separately for each of 
the components.
PGI-S at Week 16
The PGI-S will be summarized with descriptive statistics including number of subjects, mean, 
SD, median, minimum, and maximum at each visit. In addition, the number and percentage of 
subjects in each category will be summarized by visit.
Change from Baseline to Week 16 in 5-D Itch 
The endpoint change from baseline to Week 16 in 5-D itch will be summarized descriptively 
and analyzed using a MMRM, including data up to Week 16. Data from visits after subjects 
receive rescue therapy will be excluded from the analysis. Details of the model are similar to 
those described for percent change from baseline to Week 16 in EASI score (Section 3.4.1.3).
In addition, descriptive summary of the total 5-D itch score at each visit will be provided by 
treatment group. Similar summary will be provided for each of the domains of 5-D itch 
(duration, degree, direction, disability, distribution). In addition, summary of change from 
baseline will be provided by visit for the total 5-D itch score and separately for each of the 
domains. 
Change from Baseline to Week 16 in POEM
The endpoint change from baseline to Week 16 in POEM will be summarized descriptively 
and analyzed using a MMRM, including data up to Week 16. Data from visits after subjects 
receive rescue therapy will be excluded from the analysis. Details of the model are similar to 
those described for percent change from baseline to Week 16 in EASI score (Section 3.4.1.3).
Change from Baseline to Week 16 in DLQI
The endpoint change from baseline to Week 16 in DLQI will be summarized descriptively 
and analyzed using a MMRM, including data up to Week 16. Data from visits after subjects 


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receive rescue therapy will be excluded from the analysis. Details of the model are similar to 
those described for percent change from baseline to Week 16 in EASI score (Section 3.4.1.3).
In addition, descriptive summary of the total DLQI score at each visit will be provided by 
treatment group. Similar summary will be provided for each of the components of DLQI (daily 
activities, leisure, personal relationship, work or school, symptoms and feelings, treatment side 
effects). In addition, summary of change from baseline will be provided by visit for the total 
DLQI score and separately for each of the components. 
3.4.2.4 Subgroup Analyses
The consistency of the detected overall treatment effect on the IGA response at Week 16 will 
be assessed in a subgroup of subjects. A logistic regression model including treatment group, 
randomization stratum (total serum IgE level < 150 kU/L or ≥150 kU/L), and baseline IGA 
as categorical factors, will be used in a similar way as described in Section 3.4.2.3 for the
following subgroup populations of interest: 
•
Total serum IgE level (< 150 kU/L vs ≥ 150 kU/L).
•
IGA score (3 vs 4).
•
Baseline EASI (≤25 points vs > 25 points).
•
S aureus in lesional skin ( < median vs ≥ median) (at final analysis only).
•
S aureus in non-lesional skin (< median vs ≥ median) (at final analysis only).
•
Age (18 to 35 years of age vs 36 to 75 years of age).
•
Age at onset of AD (< 18 years of age vs ≥ 18 years of age).
•
Parent having a history of AD (presence vs absence).
•
Sex (male vs female).
•
Race (White vs non-White).
•
Region (North America vs Europe/Australia).
•
Blood eosinophil count (< 300 cells/μL vs ≥ 300 cells/μL).
•
Aeroallergens (presence vs absence).
•
Food allergies (presence vs absence).
•
Contact allergies (presence vs absence).
•
Asthma comorbidity (presence vs absence).


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The logistic regression will be fitted separately to each subgroup. The analysis for each 
subgroup will be performed if the subgroup has at least 20% of subjects in the ITT 
population. 
Similarly, the consistency of the detected overall treatment effect on the percentage of subjects 
achieving EASI 75 at Week 16 will be assessed in subgroup of subjects described above using 
a similar logistic regression model as described previously (Section 3.4.2.3). 
3 . 4 . 3    Other Efficacy Analyses
Descriptions of the exploratory efficacy endpoints are provided (Section 3.4.2.1), except for 
SNOT-22 and ACQ-6, provided below.
The SNOT-22 is a validated questionnaire for assessing the impact of chronic rhinosinusitis 
on quality of life. The SNOT-22 contains a list of 22 symptoms and social/emotional 
consequences of a patient’s nasal disorder, and measures how severe each symptom is and 
the social/emotional consequences of symptoms over a 2-week period on a scale from 0 (no 
problem) to 5 (problem as bad as it can be). A total score is summed.
The ACQ-6 is a questionnaire developed and validated to measure asthma control. The ACQ 
includes 6 questions regarding symptoms at night, in the morning, limitation of normal daily 
activities, dyspnea, wheezing, and beta-2 agonist use. Subjects are asked to recall how their 
asthma has been during the previous week and to answer questions using a 7-point scale with 
0 = no impairment and 6 = maximum impairment). ACQ-6 does not include spirometry and 
is the equally weighted mean of 6 questions.
3.4.3.1 Number and percentage of subjects achieving EASI 90, EASI 75, and EASI 50, 
at Weeks 2, 4, 8, 12, 16, 20, and 24
The number and percentage of subjects achieving EASI 90, EASI 75, and EASI 50 by Weeks 
2, 4, 8, 12, 16, 20, and 24 will be summarized by visit separately for each endpoint. Analyses 
using a GEE model for repeated measures will be performed separately for each endpoint and 
will include all data up to Week 24. Details of the model are similar to those described for 
the additional analysis of the IGA response at Week 16 (Section 3.4.2.3).
3.4.3.2 Percentage change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in EASI 
score
The percent change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in EASI score will be 
summarized descriptively by visit and analyzed using a MMRM including data from visits up 
to Week 24 in a similar way as described for percent change from baseline to Week 16 in 
EASI score (Section 3.4.1.3).


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3.4.3.3 Percentage of subjects achieving IGA 0/1 and ≥2 grade reduction from baseline
at Weeks 2, 4, 8, 12, 16, 20, and 24 
The number and percentage of subjects achieving an IGA response at Weeks 2, 4, 8, 12, 16, 
20, and 24 will be summarized by visit, and analyzed using the GEE model as described for 
IGA response at Week 16 (Section 3.4.2.3).
3.4.3.4 Change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in %BSA affected by 
AD
Change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in percent BSA affected by AD 
will be summarized descriptively by visit, and analyzed using a MMRM as described for 
percent change from baseline to Week 16 in EASI score (Section 3.4.1.3).
3.4.3.5 Peak pruritus NRS: reduction of ≥3 from baseline to Weeks 2, 4, 8, 12, 16, 20, 
and 24
The number and percentage of subjects achieving reduction of ≥3 from baseline to Weeks 2, 
4, 8, 12, 20, and 24 in weekly mean of daily peak pruritus NRS will be summarized by visit 
and analyzed using the GEE model as described above for IGA response at Week 16 
(Section 3.4.2.3).
3.4.3.6 Peak pruritus NRS: reduction of ≥4 from baseline to Weeks 2, 4, 8, 12, 16, 20, 
and 24
The number and percentage of subjects achieving reduction of ≥4 from baseline to Weeks 2, 
4, 8, 12, 16, 20, and 24 in weekly mean of daily peak pruritus NRS will be summarized by 
visit and analyzed using the GEE model as described above for IGA response at Week 16 
(Section 3.4.2.3).
3.4.3.7 Peak pruritus NRS: change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24
Change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in the weekly mean of daily peak 
pruritus NRS will be summarized descriptively by visit and analyzed using a MMRM as 
described for percent change from baseline to Week 16 in EASI score (Section 3.4.2.3)
3.4.3.8 Skin pain NRS: change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24
Change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in the weekly mean of daily peak 
skin pain NRS will be summarized by visit and analyzed using a MMRM as described for 
percent change from baseline to Week 16 in EASI score (Section 3.4.2.3).


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3.4.3.9 SCORAD: Percent change from baseline to Weeks 2, 4, 8, 12, 16, 20 and 24 
Percent change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in SCORAD will be 
summarized descriptively by visit and analyzed using a MMRM as described for the percent 
change from baseline to Week 16 in EASI score (Section 3.4.2.3).
3.4.3.10
PGI-S at Weeks 2, 4, 8, 12, 16, 20 and 24
PGI-S at Weeks 2, 4, 8, 12, 16, 20, and 24 will be summarized by visit with descriptive 
statistics including number of subjects, mean, SD, median, minimum, and maximum. In 
addition, the number and percentage of subjects in each category will also be summarized by 
visit.
3.4.3.11
Change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in 5-D itch
Change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in 5-D itch will be summarized by 
visit and analyzed using a MMRM as described for percent change from baseline to Week 16 
in EASI score (Section 3.4.2.3).
3.4.3.12
Change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in POEM
Change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in POEM will be summarized by 
visit and analyzed using a MMRM as described for percent change from baseline to Week 16 
in EASI score (Section 3.4.2.3).
3.4.3.13
Change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in DLQI
Change from baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 in DLQI will be summarized by 
visit and analyzed using a MMRM as described for percent change from baseline to Week 16 
in EASI score (Section 3.4.2.3).
3.4.3.14
Change from baseline to Weeks 16 and 24 in SNOT-22
Change from baseline to Week 16 and to Week 24 in SNOT-22 will be summarized 
separately by treatment group using descriptive statistics including number of subjects, mean, 
median, SD, minimum, and maximum.
3.4.3.15
Change from baseline to Weeks 16 and 24 in ACQ-6
Change from baseline to Week 16 and to Week 24 in ACQ-6 will be summarized separately 
by treatment group using descriptive statistics including number of subjects, mean, median, 
SD, minimum, and maximum.


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3.4.3.16
Subjects requiring rescue therapy during the treatment and follow-up 
period
The number and percentage of subjects requiring rescue therapy during the treatment period 
will be summarized by visit. Similarly, the number and percentage of subjects requiring 
rescue therapy during the treatment period and the follow-up period will also be summarized. 
In addition, a plot of the cumulative proportion of subjects receiving rescue therapy during 
the treatment and follow-up periods will be provided. 
3.4.3.17
Time to first use of rescue therapy
Summary descriptive statistics (including number, minimum, maximum, median, 25th and 
75th percentiles) will be provided for time to first use of rescue therapy either during the 
treatment or follow-up period. In addition, Kaplan-Meier analysis of the time to first use of 
rescue therapy will also be performed. 
3.4.3.18
Incidence of skin infection TEAEs
The incidence of skin infection TEAEs requiring systemic treatment during the treatment and 
follow-up periods will be summarized descriptively by treatment group.
3.5 Biomarker Analyses
3 . 5 . 1    Blood Concentration of sST2 and 
The blood concentration of soluble ST2 (sST2) will be summarized by visit using descriptive 
statistics (number, mean, geometric mean, SD, median, coefficient of variation, minimum, 
and maximum). Change from (or ratio to) baseline to Week 16 in the concentrations of sST2 
will be summarized descriptively by visit as described above. The concentration values will 
be log-transformed and analysis of change from baseline to Week 16 of the log-transformed 
data will be performed using an ANCOVA model. The model will include treatment group 
and randomization stratum (total serum IgE < 150 kU/L or ≥ 150 kU/L) as categorical 
factors, with baseline sST2 as a covariate. The restricted maximum likelihood (REML) 
approach will be used for the estimation of the variance and covariance parameters of the 
linear mixed model. No imputation will be made for missing data. The results obtained will 
be back-transformed to the original scale. The estimated adjusted mean ratio to baseline (± 
standard error) for each treatment group will be provided. Also, the ratio of the adjusted 
mean ratio of each MEDI3506 group to placebo will be provided along with the 90% CI and 
p-value. The change from baseline to Week 16 in blood concentration of 
 will be explored and reported separately to the CSR.  
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3 . 5 . 2    Peripheral Blood Mononuclear Cell (PBMC) subset
The change from baseline in levels of PBMC subsets in whole blood at Week 16 may be 
explored and reported separately to the CSR.
3 . 5 . 3    Blood biomarker levels of Eosinophils, IL-33 bound to MEDI3506, IL-
5, IL-13 and CCL17
Blood biomarker levels of eosinophils and IL-33 bound to MEDI3506 will be summarized 
descriptively (number, mean, geometric mean, median, coefficient of variation, minimum, 
and maximum) by visit for each treatment group. Change from (or ratio to) baseline to 
Weeks 1, 2, 4, 8, 12, 16, 20, and 24 in eosinophils and change from baseline to Weeks 1, 2, 4, 
16, 20 and 24 in IL-33 bound to MEDI3506 will also be summarized descriptively by visit 
and treatment group for each biomarker. In addition, for IL-33 bound to MEDI3506, the 
levels will be log-transformed and analysis of change from baseline to Week 24 of the log-
transformed data will be performed using a MMRM as described for the percent change from 
baseline to Week 16 in EASI score (Section 3.4.1.3). The results obtained from the model 
will be back-transformed to the original scale. The estimated adjusted mean ratio to baseline 
(± standard error) for each treatment group will be provided. Also, the ratio of the adjusted 
mean ratio of each MEDI3506 group to placebo will be provided along with the 90% CI and 
p-value. The mean (± standard error) change from baseline through to Week 16 and to Week 
24 for IL-33 bound to MEDI3506 of the log-transformed data will be plotted for each 
treatment group separately for each biomarker. For eosinophils, the analysis will be done on 
the original scale, that is, no log-transformation will be performed for this biomarker. The 
change from baseline up to Week 24 in levels of IL-5, IL-13 and CCL17 will be explored and 
reported separately to the CSR.     
3 . 5 . 4    Serum IgE levels and Plasma Eosinophil Derived Neurotoxin (EDN) 
levels
Descriptive summary statistics (number, geometric mean, median, coefficient of variation, 
minimum, and maximum) will be provided separately for serum IgE levels and plasma EDN 
levels by visit and treatment group. Change from baseline to Weeks 2, 8, 16, and 24 in serum 
IgE levels and to Weeks 4, 16, and 24 in plasma EDN levels will be summarized 
descriptively by visit for each treatment group. In addition, the IgE levels and EDN levels 
will be log-transformed and similar analysis described in Section 3.5.1   above will be 
performed on the log-transformed data. Also, a plot of mean change (± standard error) from 
baseline through to Week 24 of log-transformed IgE levels and EDN levels will be provided. 




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subject, the highest severity and level of relationship observed will be reported. The number 
and percentages of participants will also be summarized by SOC and PT for participants with 
COVID-19 related AEs and SAEs. All treatment-emergent adverse events (TEAEs) will be 
summarized overall, as well as categorized by MedDRA SOC and PT. A TEAE is any new 
sign, symptom, disease, or other untoward medical event that begins or worsens after the first 
dose of investigational product up to the FU visit.
Summaries of adverse events will be presented by subjects who are COVID-19 positive or 
negative where a subject is COVID-19 positive if they have a TEAE in the MedDRA 
COVID-19 SMQ. Summaries will include TEAEs, TEAEs by MedDRA preferred term and 
SOC, SAEs, and adverse events of special interest (AESI).
3 . 6 . 2    Adverse Events of Special Interest
The following are AESIs have been defined in the study protocol: 
•
Hepatic function abnormality meeting the definition of Hy’s Law (HL), which is defined 
as any increase in alanine transaminase (ALT) or aspartate transaminase (AST) to greater 
than 3 × upper limit of normal (ULN) and concurrent increase in total bilirubin (TBL) to
greater than 2 × ULN.
•
Serious hypersensitivity (including Type 1 to 4 hypersensitivity reactions), including 
anaphylaxis and severe allergic reactions, and immune complex disease.
•
Injection site reactions.
•
Cardiac events (including angina or myocardial infarction, congestive heart failure, 
symptomatic atherosclerotic vascular disease, cor pulmonale, or arrhythmia).
•
Serious infections (including opportunistic infections and viral reactivations), for 
example VZ/HSV, EBV/CMV, and TB.
•
Gastrointestinal adverse events.
•
Malignancy.
AEs will be assigned to a specific category based on investigator’s judgement, using a 
checkbox on the AE CRF page. In addition, an AESI search strategy provided by Patient 
Safety will also be used to identify AESIs programmatically. 
Subjects who meet the following criteria will be summarized by treatment group and separate 
listings of subjects will be presented:


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•
ALT/AST > 3 × ULN and any bilirubin > 2 × ULN
•
ALT/AST > 5 × ULN for more than 2 weeks
•
ALT/AST > 8 × ULN
All other AESIs will be summarized by treatment group and included in separate listings. In 
addition, the injection site reaction AE will be summarized by the placebo groups.  
3 . 6 . 3    Deaths and Treatment Discontinuations due to Adverse Events
The number and percent of subjects with deaths and treatment discontinuation due to TEAEs 
will be summarized by treatment group, and separate listings of subjects will be presented. 
3 . 6 . 4    Clinical Laboratory Evaluation
Hematology, urinalysis and serum chemistry parameters will be assessed at baseline as well 
as throughout the study. These laboratory parameters and change from baseline will be 
summarized descriptively by treatment group and visit. Also, the laboratory measurements 
will be presented as the number and percentage of subjects above or below the normal range 
for each laboratory test and shifts from baseline relative to the normal range for each   
treatment group. For laboratory values reported as lower than the limit of quantification 
(LLOQ), a value equal to half the limit of quantification will be imputed in the summaries. 
For each hematology and chemistry parameters, boxplots showing the distribution of each 
parameter by treatment arm and visit will be provided.  All laboratory parameters will be 
provided in the by-subject listings as reported and values outside of the normal range will be 
flagged. 
3 . 6 . 5    Vital Signs                                                                                              
Vitals signs will be summarized by treatment group and visit. Change from baseline to 
post-dose evaluations for vital signs will be summarized in a similar way. 
3 . 6 . 6    ECGs and Left Ventricular Ejection Fraction
An electrocardiogram (ECG) will be performed to confirm that MEDI3506 does not affect 
cardiac electrophysiological intervals.
The computerized triplicate 12-lead ECG results and QT intervals (msec) will be summarized 
descriptively by treatment group and visit for each of the ECG variables collected (heart rate, 
RR interval, QRS interval, PR interval, QT interval (using both Fridericia’s correction: 
QTcF[msec] = QT[msec]/(RR[sec]1/3) and Bazett’s correction: QTcB[msec] = 


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QT[msec]/(RR[sec]1/2))). For the triplicate 12-lead ECG, an average of 3 reads will be used.
Changes from baseline will be summarized by treatment group and visit into 3 categories: 
increase ≤ 30 msec, 30 msec < increase ≤ 60 msec, and increase > 60 msec. Shift tables for 
QTc intervals (QTc ≤ 450 msec, 450 < QTc ≤ 480 msec, 480 msec < QTc ≤ 500 msec, QTc > 
500 msec) will be presented to compare the baseline ECG evaluation and the post-dose 
evaluations. In addition, descriptive summary of qualitative ECG results by visit will be 
provided.
Left ventricular ejection fraction, as measured by echocardiogram, will be summarized 
descriptively by treatment group and visit.  
3 . 6 . 7    Other safety tests
NT-proBNP results will be summarized descriptively by treatment group at each visit and 
change from baseline summarized for each post-baseline visit. The summary based on the 
number and percentage of participants above or below the normal range will be produced as 
well as shifts from baseline relative to the normal range. A boxplot showing the distribution 
of NT-proBNP by treatment arm and visit will be provided. NT-proBNP results will be 
provided in the by-subject listings as reported and values outside of the normal range will be 
flagged.
3.7 Immunogenicity
Anti-drug antibodies (ADA) in serum will be assessed at baseline prior to MEDI3506 
administration, and at multiple time points post MEDI3506 administration during the treatment 
and follow-up period of the study. Blood samples for determination of ADA in serum will be 
assayed by bioanalytical test sites operated by, or on behalf of, AstraZeneca, using an 
appropriately validated bioanalytical method. Tiered analyses will be performed to include
screening, confirmatory, and titer assay components. ADA results from each sample will be 
reported as either positive or negative. If the sample is positive, the ADA titre will be reported 
as well.
ADA detection at subject level:
!
A subject is considered ADA positive if a collected sample is tested positive at any 
time during the study, including baseline and/or post-baseline.
!
A subject is considered ADA negative if collected samples are tested negative at all 
timepoints, including baseline and post-baseline. 
Treatment-related ADA development at subject level:


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!
Treatment-emergent ADA positive (TE-ADA positive) is defined as the sum of 
treatment-induced ADA positive (ADA negative at baseline and post-baseline ADA 
positive) and treatment-boosted ADA positive (ADA positive at baseline and boosted 
(≥4 fold) the pre-existing titre during the study period). 
!
Treatment-emergent ADA negative (TE-ADA negative) is defined as ADA positive 
but not fulfilling the definition of TE-ADA positive. 
The following ADA responses variables will also be evaluated:
!
Participants who are ADA positive at baseline
!
Participants who are ADA positive at any post-baseline visit
!
Participants who are ADA positive post-baseline and positive at baseline
!
Participants who are ADA positive post-baseline and not detected (or missing) at 
baseline
!
Participants with ADA negative post-baseline and positive at baseline
!
Participants who are ADA positive at any time during the study, including baseline 
and/or post-baseline (also generally referred to as ADA prevalence). 
!
Participants who are TE-ADA positive, also known as ADA incidence. 
!
Participants who are ADA persistently positive, defined as ADA positive at ≥ 2 post-
baseline assessments (with ≥ 16 weeks between first and last positive) or ADA 
positive at last post-baseline assessment. 
!
Participants who are ADA transiently positive, defined as negative at last post-
baseline assessment and positive at only one post-baseline assessment or at ≥ 2 post-
baseline assessments (with < 16 weeks between first and last positive). 
For the ADA status across the study, the number and percentage of subjects with ADA 
responses will be summarized together with corresponding titre summaries by treatment 
group, according to the ADA categories defined above. For the time-course evaluation, the 
number of subjects with positive ADA result and ADA titres will be summarized at baseline 
and at all scheduled visits by treatment group. A listing of individual ADA results of all 
subjects will be provided. 
For ADA summaries at a single time point the corresponding titre summary will be based on 
the titre of the positive sample for that particular visit, but for summaries across visits, the 
corresponding titre summaries will be based on the maximum titre of all positive samples for 
each subject. All valid assay results from subjects who receive any investigational product 
will be included in the ADA summaries. Blood samples collected at early discontinuation 
visit will be summarized at the closest nominal time point that does not already have a value.


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To evaluate the effect of ADA on PK, descriptive statistics of MEDI3506 concentrations
over time will be presented by ADA category (TE-ADA positive, ADA negative, TE-ADA
negative).
Summaries of adverse events will be presented by ADA category (TE-ADA positive, ADA 
negative and TE-ADA negative). Summaries will include TEAEs, TEAEs by MedDRA 
preferred term and SOC, SAEs, and AESI. Also, the relationship between ADA category 
(TE-ADA positive, ADA negative and TE-ADA negative) and the percent change from 
baseline in EASI will be summarized.
3.8 Pharmacokinetics
Pharmacokinetic analysis will be based on the PK analysis set. Drug concentration data for 
MEDI3506 for all randomized subjects will be provided. Descriptive statistics of MEDI3506 
serum concentrations by treatment group and visit and also over time by ADA category  (TE-
ADA negative, TE-ADA positive, ADA negative) will be reported. Individual serum 
MEDI3506 concentration over time plots will be provided. Spaghetti plots of individual 
serum MEDI3506 concentrations over time by dose and by ADA category (TE-ADA 
negative, TE-ADA positive, ADA negative) will be provided. 
4
INTERIM ANALYSIS
There is no planned interim analysis.
5
EXPLORATORY ANALYSIS FOR RESPONDER SUBGROUP 
IDENTIFICATION
Exploratory analysis will be conducted post hoc to identify subgroup of patients that may 
have received enhanced benefits when treated with MEDI3506 vs placebo. The analysis will 
be based on a list of biomarkers that will be provided by the Translational Science group 
before the database lock for the primary analysis of the study. A post-hoc analysis plan will 
be developed prior to the conduct of the analysis and it will provide more details about the 
methods and analysis to be conducted. The results will not be reported in the CSR, and might 
be reported separately from the CSR.             




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!
Included a section on exploratory 
analysis that will be performed post 
hoc 
!
To align with Protocol Amendment #3
3.0
08JUN2022
!
Removed interim analysis
!
Added visit window calculation and 
updated visit window tables
!
Updated IPD categories
!
Added COVID-19 PD listings and 
summaries
!
Added additional analyses excluding 
unblinded subjects (sections 3.4.1.4 
and 3.4.2.3)
!
Corrected MCP-Mod analysis of 
%change in EASI with LOCF to 
remove MMRM 
!
PGI-S categories updated to 6
!
Removed PGI-S MMRM analysis 
from section 3.4.2.2
!
Updated IGA and EASI 75 MCP-
Mod analyses to use coefficients from 
logistic regression 
!
Appendix I- corrected IGA MCP-
Mod analysis and added EASI75
!
Updated biomarker section
!
Removed section 3.5.9 Responder 
subgroup identification 
!
Added equations for QTcB and QTcF
!
Added additional ADA categories to 
section 3.7 
!
Updated PK section (3.8)
!
Changed S aureus subgroups to use 
median
!
Added AESI search strategy in 
section 3.6.2
!
Changed screening window to 4 
weeks
!
Added Plasma EDN to baseline 
disease characteristic list and 
removed serum IgE (pos vs neg)
!
Updated section 3.4.1.5 to remove 
sentences on subgroups
!
Corrected SCORAD calculation
!
Added extra biomarker endpoints to 
be reported separately to CSR
!
Updated clinical lab evaluation 
section
!
Added Other safety tests section to 
include NT-proBNP analysis
!
Added ADA safety and efficacy 
tables
!
Added COVID-19 pos/neg safety 
analysis
!
To align with Protocol Amendment 
#7, #8
!
Clarification of how to calculate visit 
windows
!
To align with other Medi3506 studies
!
To align with Protocol Amendment #5
!
Sensitivity analysis for unblinded 
subjects
!
Correction of method
!
To match what is being collected
!
Analysis not needed (not really 
continuous) 
!
Correction of method
!
Correction of method
!
Scope has changed
!
Information is covered in section 5
!
Was missing
!
To align with AZ process
!
To align with AZ process
!
Data is going to be continuous
!
Requested by patient safety
!
To align with PA #8
!
Update of list
!
Covered in section 5 already
!
Correction of error
!
To align with endpoints in protocol
!
To remove lab toxicities as analysis 
not needed
!
Analysis was missing
!
To evaluate safety profile
!
To evaluate impact of COVID-19 on 
the safety profile


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!
Removed IL-5, IL-13 and CCL17 
biomarker analyses from CSR
!
Removed PBMC analyses from CSR
!
Added comorbid asthma subgroup to 
3.4.1.5 and 3.4.2.4
!
Data will not be available, will be 
reported separately to CSR
!
Results may be reported separately to 
CSR
!
Genetic association between IL33 and 
asthma is strong so might be a 
difference in efficacy


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Appendix 1
Determination of dose-response profile using MCP-Mod
To determine dose-response profile using MCP-Mod, the candidate models first need to be 
defined. For this study, four candidate models will be used for the MCP-Mod models and 
these are: Linear, Emax and 2 Hill-Emax models. The description of the function of each model 
and the parameters are specified below: 
 Linear Model:                (, ) =  + 
 Emax Model:                   (, ) =  + 

  
 Hill-Emax Model:          (, ) =  + 


  
where d denotes the dose parameter; E0 is the placebo effect; δ is the slope parameter for the 
linear model; Emax is the asymptotic maximum effect; ED50 is the dose giving half of the 
asymptotic maximum effect; h is the hill parameter which determines the steepness of the 
model as the ED50.
For the percent change from baseline to Week 16 in EASI endpoint, the models are defined 
as follows: 
fmodels=Mods(linear = NULL, emax = 150, sigEmax = rbind(c(150,3), c(450,3)),   
                        doses = c(
), placEff=0, maxEff=35, direction = c("decreasing")).
where maxEff is the maximum effect over placebo.
For the percentage of subjects achieving IGA response at Week 16 endpoint, the models are 
defined as follows on the logit scale:
fmodels=Mods(linear = NULL, emax = 150, sigEmax = rbind(c(150,3), c(450,3)),   
                        doses = c(
), placEff=logit(10), maxEff=logit(30)-logit(10), 
direction=c("increasing"))
where logit(x) is log(x/(1-x)). 
For the percentage of subjects achieving EASI 75 response at Week 16 endpoint, the models 
are defined as follows:
fmodels=Mods(linear = NULL, emax = 150, sigEmax = rbind(c(150,3), c(450,3)),   
                        doses = c(
), placEff=logit(15), maxEff=logit(35)-logit(15),                     
                     direction=c("increasing")).
CCI
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Once the models are defined, then the MCP-Mod analysis is performed. For the percent 
change from baseline to Week 16 in EASI endpoint, the MCP-Mod analysis is performed as 
follows: 
MM=MCPMod(dose=doses, EstEffects, S= vCov, models = fmodels, type = "general”,   
placAdj=FALSE, Delta=35, alpha=0.1, alternative=c(“two.sided”)).
    where 

“doses” denotes the vector of doses,

“EstEffects” denotes the vector of estimated coefficient obtained from the
MMRM,

“vCov” denotes the estimated variance-covariance matrix,

“fmodels” is the specified candidate models,

“type=“general” ” indicates that the estimates and their covariance matrix are
specified,

“placAdj =FALSE” indicates that the estimated specified are not placebo-
adjusted,

“Delta” is the target effect size over placebo,

“alpha” is the significance level for the multiple contrasts.
For the percentage of subjects achieving IGA response at Week 16 endpoint, the MCP-Mod 
analysis is performed as follows: 
MM=MCPMod(dose=doses, EstEffects , S= vCov, models = fmodels, type = "general”, 
placAdj=FALSE, Delta=logit(30)-logit(10), alpha=0.1, alternative=c(“two.sided”)).
where 

“EstEffects” denotes the vector of estimated coefficient obtained from the fitted
logistic regression model,

“vCov” denotes the estimated variance-covariance matrix.

All the other parameters are the same as those described above for the EASI
endpoint.


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For the percentage of subjects achieving EASI 75 response at Week 16 endpoint, the MCP-
Mod analysis is performed as follows: 
MM=MCPMod(dose=doses, EstEffects , S= vCov, models = fmodels, type = "general”, 
                           placAdj=FALSE, Delta=logit(35)-logit(15), alpha=0.1,   
                     alternative=c(“two.sided”))
where the parameters are the same as those described for the IGA endpoint.
The IGA and EASI 75 results are then back transformed from the logit scale to percentages.


SIGNATURE PAGE
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Document Name: d9182c00001-sap-v3
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