Conditions: Atopic Dermatitis Eczema
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 119
Healthy volunteers: no

Brief summary:
This is a Phase 2a safety and efficacy study of EVO101 for the treatment of adults with atopic dermatitis

Detailed description:
This is a Phase 2a safety and efficacy study of EVO101 Topical Cream, 0.1%, applied twice daily for 8 weeks in adults with mild-to moderate atopic dermatitis.

Arms:
arm 1: Active Treatment, BID, 8 weeks arm 2: Vehicle Treatment, BID, 8 weeks

Interventions: intervention 1: EVO101
Intervention descriptions: intervention 1: Topical Cream

Protocol document:
SAP_002.pdf: 
Statistical Analysis Plan 
 
CONFIDENTIAL 
 
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A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF 
EVO101 IN ADULT SUBJECTS WITH ATOPIC DERMATITIS 
 
Sponsor 
 
Evommune, Inc. 
Product/Compound/Device 
EVO101 Topical Cream, 0.1% 
Phase of the study 
2a 
 
 
 






Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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Contents 
1 
Abbreviations ................................................................................................................................ 6 
2 
Document Version History ............................................................................................................ 8 
3 
Introduction ................................................................................................................................... 9 
4 
Study Objectives and Endpoints ................................................................................................. 10 
5 
Overall Study Design .................................................................................................................. 11 
6 
Determination of Sample Size .................................................................................................... 12 
7 
Data Sets to be Analyzed ........................................................................................................... 12 
8 
Statistical and Analytical Plans ................................................................................................... 13 
8.1 
Changes from the Protocol  ................................................................................................ 13 
8.2 
Pre-Analysis Review ........................................................................................................... 13 
8.3 
Hypothesis and Statistical Methods .................................................................................... 14 
8.3.1 
Definitions ....................................................................................................................... 14 
8.3.2 
Summary Statistics ......................................................................................................... 15 
8.3.3 
Patient/Subject Data Listings .......................................................................................... 16 
8.3.4 
Demographic and Other Baseline Characteristics .......................................................... 17 
8.3.5 
Primary Efficacy Analysis ............................................................................................... 18 
8.3.6 
Secondary and Exploratory Analyses ............................................................................. 19 
8.3.7 
Exposure to Treatment ................................................................................................... 21 
8.3.8 
Concomitant Medications and Therapy .......................................................................... 22 
8.3.9 
Adverse Events .............................................................................................................. 23 
8.3.10 
Other Safety Assessments ......................................................................................... 24 
8.4 
Level of Significance, Multiple Comparisons and Multiplicity ............................................. 27 
8.5 
Multicenter Studies ............................................................................................................. 27 
8.6 
Adjustment for Covariates .................................................................................................. 27 
8.7 
Examination of Subgroups ................................................................................................. 27 
8.8 
Handling of Dropouts and Missing Data ............................................................................. 27 
8.9 
Interim Analysis .................................................................................................................. 28 
8.10 
Data Monitoring Committee ................................................................................................ 28 
8.11 
References ......................................................................................................................... 28 
9 
Tables, Listings and Figures Overview ....................................................................................... 29 
9.1 
Tables to be Produced for the Clinical Study Report .......................................................... 29 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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9.2 
Listings of Individual Subject Data and Other Information to be Produced for the Clinical 
Study Report ................................................................................................................................... 31 
10 
Appendices ................................................................................................................................. 33 
10.1 
Definitions and Derivations of the efficacy assessment scores .......................................... 33 
10.2 
SAS code for multiple imputation of primary endpoint ........................................................ 35 
10.3 
SAS code for pooled proportions of secondary binary endpoints ....................................... 37 
 
 
 
 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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1 
Abbreviations 
AD 
Atopic Dermatitis 
AE 
Adverse Event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AST 
Aspartate aminotransferase 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
CMH 
Cochrane Mantel- Haenszel 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
EASI 
Eczema Area and Severity Index 
ECG 
Electrocardiogram  
F 
Fahrenheit 
IC 
Informed Consent 
IGA 
Investigator's Global Assessment scale 
ITT 
Intent-to-treat  
LSR 
Local Skin Reactions  
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration  
MCV 
Mean Corpuscular Volume  
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numeric Rating Scale 
PD 
Protocol Deviation 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term 
RBC 
Red Blood Cells 
SAF 
Safety 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TLR 
Toll-like receptor 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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WBC 
White Blood Cells 
WHO 
World Health Organization 
 
 
 
 






Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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4 
Study Objectives and Endpoints 
Objective 
Endpoint 
Primary 
 
The primary objective is to assess 
the safety, tolerability, and 
preliminary efficacy of EVO101 
Topical Cream, 0.1%, applied twice 
daily, in adults with AD. 
Safety will be assessed through: 
• 
Incidence of treatment-emergent adverse events 
(TEAEs) 
• 
Incidence of local skin reactions (LSRs) 
• 
Changes in clinical laboratory tests (Chemistry, 
Hematology and Urinalysis) from baseline to 
Week 8 and incidence of abnormal laboratory 
tests. 
• 
Changes in vital signs from baseline over time (to 
Week 2, 4 and 8) and incidence of anormal vital 
signs.  
• 
Changes in Electrocardiogram (ECG) parameters 
from baseline to Week 8 and incidence of 
abnormal overall ECG evaluation.  
• 
Incidence of abnormal physical examinations. 
 
Efficacy will be assessed through: 
• 
Mean percentage change from Baseline in EASI 
score at Week 8 
 
Secondary 
 
Efficacy 
 
 
• 
IGA response (≥2 point change from baseline) at 
Week 8. 
• 
Change from Baseline in IGA at Week 8. 
• 
Mean change from Baseline in BSA affected at 
Week 8 
Pharmacokinetics 
 
The secondary Pharmacokinetics 
objective of this study will be to 
assess the pharmacokinetics of 
EVO101 Topical Cream, 0.1%, 
applied twice daily, in adults with AD 
• 
Plasma levels of EVO101 at Baseline, Week 2 
and 8 








Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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- 
Subjects not meeting the eligibility criteria 
- 
Subjects not completing the study 
- 
Protocol deviations  
- 
Subjects with no documented dose of study drug 
- 
Study medication compliance 
- 
Concomitant medication violations 
- 
Main evaluable efficacy assessments by visit (evaluable data for: EASI, IGA, BSA and 
pruritus-NRS by visit) 
- 
Preliminary subjects’ classifications of analysis populations, as far as possible 
 
8.3 
Hypothesis and Statistical Methods 
8.3.1 
Definitions 
Baseline 
Baseline value refers to the last non-missing assessment made before 
or up to the date of the first study drug application at the screening or 
baseline visit.  
If not possible to obtain a baseline value from the specified visits the 
unscheduled assessment will be included in the derivation of baseline 
value. 
Baseline pruritus score is derived based on the prior 7 days of subject 
diary data, of which at least 4 of the 7 days must be completed.    
Date of first study drug 
application 
The date of first study drug application will be taken from ePRO. 
In case ePRO is not available, then the first available date will be taken 
from the drug accountability. 
Relative day 
The relative day of an event is derived as: 
Relative day = (Start date) - (Date of first study drug application) + 1 
For events occurring or starting before the date of first study drug 
application the relative day is derived as: 
Relative day = (Start date) - (Date of first study drug application) 
In this way, there will be no Day 0. Day 1 is the same day as the day of 
first study drug application, and Day -1 is the day before. 
Relative day will be calculated only for the completed dates. 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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Treatment-emergent 
adverse event (AE) 
Treatment-emergent is defined as any AE with an onset on or after the 
date of the first study drug application: 
TEAE if: (Start AE date) ≥ (Date of first study drug application) 
Derivation of the flag when missing or partial AE dates is specified in 
section 8.8. 
 
AEs reported on the same day as first drug administration, associated 
with abnormal physical examination findings and vital signs, will be 
identified and manually reviewed by the medical monitor to confirm if 
the AE(s) will be considered as a treatment-emergent event. 
Additionally, AE(s) reported same day as first drug administration 
associated with a skin reaction and indicated in the reported term (pre-
dose or pre-administration) will not be considered as treatment-
emergent. 
Change from baseline to 
specific visit 
Change from baseline to specific visit will be calculated as: 
Change to visit X = Value at visit X – Baseline value 
Percentage of change 
from baseline to specific 
visit 
Percentage of change from baseline to specific visit will be calculated 
as: 
Percentage of change to visit X =  
[(Value at visit X – Baseline value) / (Baseline value)] x 100  
 
 
8.3.2 
Summary Statistics 
Appropriate descriptive statistics will be produced by treatment group according to the nature of the 
variable. 
For continuous data, number of subjects, mean, standard deviation, median and range (minimum and 
maximum) will be presented. 
For categorical data, frequency distributions and percentages for each category will be presented. 
Percentages will be given with 1 decimal place.  
The number of subjects with missing data will be presented under the “Missing” category. Missing 
values will not be included in the denominator count when computing percentages. When continuous 
data are summarized, only the non-missing values will be used for computing summary statistics. 
Summary statistics will be presented by treatment group and visit, as applicable. 
 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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8.3.3 
Patient/Subject Data Listings 
Data collected in the CRF will generally be listed in Appendix 16.2 (see Section 9.2). CRF check 
questions (e.g., reminders) will not be listed. 
Listings will be sorted by randomized treatment group, actual treatment group, subject ID, visit and 
assessment time as applicable.  
 
 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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8.3.4 
Demographic and Other Baseline Characteristics 
The following summaries will be given by treatment group and in total. and will be based on the ITT 
population. For parameters where assessments are made at baseline and at other visits, baseline data 
will be presented together with the rest of the data in by-visit displays in the corresponding efficacy or 
safety section. 
 
Subject disposition: 
§ 
Study disposition and discontinuation and reasons for withdrawal: number and percentage of 
subjects randomized, treated, completing and discontinued the study and reason for 
discontinuation 
§ 
Subject disposition in analysis data sets and reasons for exclusion: number and percentage 
of subjects in ITT, PP, PK and SAF population and reason for not inclusion in each 
population.  
§ 
Screen failures and reasons: All subjects who signed the informed consent (IC) and reason 
for screen failure. 
 
Protocol deviations: 
Protocol deviations (PDs) collected during the study will be classified by type and significance. 
Significant/Major PDs will be summarized presenting the number and percentage of subjects with at 
least one and the total number of deviations by type and deviation term. If a subject has more than 
one deviation by term, the subject will be only counted once and in addition the number of deviations 
will also be shown. The calculation of percentages will be based on the number of subjects within each 
treatment arm.  
All PDs will be listed including the severity, type, and deviation term. 
 
Demographic characteristics: 
The following characteristics will be summarized as indicated in section 0 depending on the nature of 
the variable: 
§ 
Age (years) 
§ 
Age group: <65 years and ≥65 years 
§ 
Gender: Male and female 
§ 
Race: White, Asian, Black or African American, American Indian or Alaska Native and Native 
Hawaiian or Other Pacific Islander 
§ 
Ethnicity: Hispanic or latino, Not hispanic or latino, Not reported and Unknown 
§ 
Height (m) 






Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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Derivations of the following assessments are described in appendix 10.1. 
The following summaries and analyses will be conducted: 
EASI: 
§ 
Summary statistics at baseline, Week 2, Week 4 and Week 8 will be provided by each 
treatment group as well as for the change and percentage change from baseline. These 
analyses will also be conducted using the PP population. 
§ 
Number and percentage of subjects with EASI-75 at Week 2, Week 4 and Week 8 (defined as 
a subject with a percentage change from baseline <= - 75). These analyses will also be 
conducted using the PP population. 
§ 
Number and percentage of subjects with EASI-90 at Week 2, Week 4 and Week 8 (defined as 
a subject with a percentage change from baseline <= - 90).  
§ 
A listing with the visit, date of the assessment, score, change and percentage from baseline 
and the flags of EASI-75 and EASI-90. 
 
IGA: 
§ 
Summary statistics at baseline, Week 2, Week 4 and Week 8 will be provided by each 
treatment group. 
§ 
Number and percentage of subjects with IGA response (≥2 points change from baseline (i.e., 
a change from baseline ≤ -2) at Week 8 and comparisons between treatments will be 
conducted in the ITT and PP populations.  
§ 
Number and percentage of subjects with IGA success (subjects with a score of 0 to 1 who 
have an improvement of ≥ 2 points, that means a change from baseline ≤ -2) from Baseline at 
Week 8 and comparison between treatments. 
§ 
A listing with the visit, date of the assessment, score, change from baseline and the flags of 
IGA response and IGA score of 0 to 1 who have an improvement of ≥ 2 points achievement. 
  
BSA: 
§ 
Summary statistics at baseline, Week 2, Week 4 and Week 8 will be provided by each 
treatment group as well as for the change and the percentage change from baseline. 
§ 
Comparison between treatments for the change and percentage change from baseline to each 
visit. 
§ 
A listing with the visit, date of the assessment, value, change and percentage change from 
baseline. 
 
Pruritus-NRS: 
§ 
For the assessment of pruritus-NRS: 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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o 
Day 1 through Day 7 values will be based on the single assessments performed on 
each subject on that day. 
o 
Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7 and Week 8 
values will be based on the average pruritus-NRS score of the 7 days prior to the visit 
date.  Subjects with less than 4 values in the 7 days prior to the visit date will have 
that visit value considered missing. 
§ 
Summary statistics at baseline, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Week 1, 
Week 2, Week 3, Week 4, Week 5, Week 6, Week 7 and Week 8 will be provided by each 
treatment group as well as the change and percentage of change from baseline. 
§ 
Comparison between treatments in the change and percentage change from baseline to each 
visit will be conducted in the ITT and PP populations. 
§ 
Number and percentage of subjects achieving a 4-point improvement in the pruritus-NRS 
score from Baseline to Week 8 in subjects who had an average maximum pruritus-NRS score 
of at least 4 at Baseline.  Comparisons between treatments will be made in the ITT and PP 
populations. 
§ 
A listing with the visit, date of the assessment, score, change and percentage from baseline 
and the flags of 4-point improvement achievement. 
 
Pharmacokinetics: 
Plasma levels of EVO101 will be evaluated by: 
§ 
Summary statistics at baseline, Week 2, and Week 8 will be provided for the active treatment 
group. 
§ 
A listing with the visit, date of the assessment and value. 
 
8.3.7 
Exposure to Treatment 
The extent of exposure to study drug in each treatment group will be summarized by total number of 
days of exposure, total number of applications, number of missed applications and number and 
percentage of subjects who are compliant. A subject will be considered compliant with the dosing 
regimen if the subject applied 80% to 120% of the expected number of applications while enrolled in 
the study. The compliance categories will be: <80%, [80%-120%] and >120%. Compliance will be 
summarized additionally as a quantitative variable. 
Extent of exposure to study drug will be derived as: 
Exposure (days) = (last study drug application date) – (first study drug application date) + 1 
Compliance will be derived as: 
Actual compliance (%) = (total number of applications / total number of expected applications as per 
protocol) x 100 








Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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Vital Signs 
For all vital signs parameters [systolic and diastolic blood pressure (mmHg), pulse rate (beats/min), 
respiratory rate (breaths/min), temperature (ºF)] summary statistics will be provided at the following 
visits: Baseline, Week 2, Week 4 and Week 8. Additionally, Weight will be provided at baseline and 
Week 8. 
For these parameters, the following summaries will be provided at each time-point: 
§ 
A summary table showing the values and the changes from baseline 
§ 
A summary table showing the number and percentage of subjects reporting “normal”, 
“abnormal, not clinically significant” and “abnormal, clinically significant” results 
§ 
A shift table presenting the number and the percentage of subjects in each bivariate category 
(baseline versus each post-baseline visit) 
§ 
Listing by subject including the parameter, visit, date of the assessment, the value, change 
from baseline and Normal/abnormal classification. 
 
Clinical Laboratory Measurements 
Analysis of clinical laboratory data will be performed for Hematology, Biochemistry and Urinalysis tests 
at the following visits: Baseline and Week 8.  
The following laboratory tests will be summarized: 
§ 
Hematology: hematocrit, hemoglobin, red blood cells (RBC) count, white blood cells (WBC), 
percentage of Neutrophils, Lymphocytes, Monocytes, Eosinophils and Basophils, Mean 
Corpuscular Hemoglobin (MCH), Mean Corpuscular Hemoglobin Concentration (MCHC), 
Mean Corpuscular Volume (MCV), RBC morphology, Platelet count and Absolute of 
Neutrophils, Lymphocytes, Monocytes, Eosinophils and Basophils. 
§ 
Clinical chemistry: sodium, potassium, chloride, calcium, phosphorus, bicarbonate, uric acid, 
blood urea nitrogen, creatinine, total protein, albumin, total and direct bilirubin, Aspartate 
aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP) and 
non-fasting Glucose. 
§ 
Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, leukocytes 
esterase, microscopic examination and urobilinogen. 
For those parameters, the following summaries will be provided at each time-point: 
§ 
A summary table showing the values and the changes from baseline 
§ 
A summary table showing the number and percentage of subjects reporting “normal”, 
“abnormal, not clinically significant” and “abnormal, clinically significant” results 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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§ 
A shift table presenting the number and the percentage of subjects in each bivariate category 
(baseline versus each post-baseline visit) 
§ 
3 listings (hematology, chemistry and urinalysis) by subject including the parameter, visit, date 
of the assessment, value, change form baseline and Normal/abnormal classification. 
  
Cardiac Assessments 
For all ECG parameters [ECG Mean Heart Rate (beats/min), RR interval (msec), PR interval (msec), 
QRS duration (msec), QT interval (msec), QTcB interval (msec) and QTcF interval (msec)] summary 
statistics will be given at the following visits: Baseline and Week 8.  
For those parameters, the following summaries will be provided at each time-point: 
§ 
A summary table showing the values and the changes from baseline. 
§ 
A summary table showing the number and percentage of subjects reporting “normal”, 
“abnormal, not clinically significant” and “abnormal, clinically significant” results for the overall 
interpretation. 
§ 
A shift table presenting the number and the percentage of subjects in each bivariate category 
(baseline versus each post-baseline visit) for the overall interpretation. 
§ 
Listing by subject including the parameter, visit, date of the assessment, the value, change 
from baseline, Normal/abnormal classification and any comments reported related to the 
result. 
 
Physical Examination  
For all body systems (general appearance, dermatological other than Atopic Dermatitis, head, ears, 
eyes, nose, throat, respiratory, cardiovascular, abdominal, neurological, musculoskeletal and 
lymphatic body system) collected in the physical examination)] summary statistics will be given at the 
following visits: Baseline and Week 8.  
For those parameters, the following summaries will be provided at each time-point: 
§ 
A summary table showing the number and percentage of subjects reporting “normal”, 
“abnormal, not clinically significant” and “abnormal, clinically significant” results for the overall 
interpretation. 
§ 
A shift table presenting the number and the percentage of subjects in each bivariate category 
(baseline versus each post-baseline visit) for the overall interpretation. 
§ 
Listing by subject including the parameter, visit, date of the assessment, the value, change 
from baseline, Normal/abnormal classification and any comments reported related to the 
result. 
 
COVID-19 and pregnancy tests 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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Listing by subject including the test, visit, date of the assessment and the result will be provided for 
Covid-19 and pregnancy tests. 
 
8.4 
Level of Significance, Multiple Comparisons and Multiplicity 
. 
For secondary efficacy endpoints, no adjustments for multiplicity will be applied. 
8.5 
Multicenter Studies 
Not applicable. 
8.6 
Adjustment for Covariates 
Covariates used for adjustment in the efficacy models are specified in the corresponding efficacy 
sections (8.3.5, 8.3.6). 
8.7 
Examination of Subgroups 
Not applicable. 
 
8.8 
Handling of Dropouts and Missing Data 
Adverse event 
The following rules will be followed to determine treatment-emergent flag: 
AE start date 
AE stop date 
TEAE rule 
Known 
Known, Partial 
or Missing 
if AE start date < first study drug application date, then not TEAE 
if AE start date ≥ first study drug application date, then TEAE 
 
Partial 
(missing day)  
Known 
if AE stop date < first study drug application date, then not TEAE 
if AE stop date ≥ first study drug application date and month 
and/or year of AE start date < first study drug application month 
and/or year, then not TEAE 
if AE stop date ≥ first study drug application date and month 
and/or year of AE start date ≥ first study drug application month 
and/or year, then TEAE 
 
Partial (missing 
day or missing 
month and day) 
If month and/or year of AE start date < first study drug application 
month and/or year, then not TEAE 
If month and/or year of AE start date >= first study drug 
application month and/or year, then TEAE 
 


Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
Template Ref: STL-BIS03-00-01 SAP Template v 6.0 effective 11-Mar-2021 
Page 28 of 37 
This template is an appendix to SOP-BIS03 SAP 
Filing instructions: File original in TMF section 11.01.01 
 
 
Prior and concomitant medications 
The following rules will be followed when partial or missing medication start and end dates: 
Medication 
start date 
Medication 
stop date 
Prior and concomitant rule 
Known, Partial 
(missing day or 
missing month 
and day) or 
Missing 
Known 
if stop date < first study drug application date, then prior 
if stop date ≥ first study drug application date, then concomitant 
Partial (missing 
day or missing 
month and day) 
It's imputed stop date as latest possible date (only for the 
prior/concomitant calculation purpose): 
- if day missing then the day will be imputed to the last day of 
the month 
- if day and month missing then they will be imputed to 
December 31th 
After this imputation the rule will be: 
if stop date < first study drug application, then prior 
if stop date ≥ first study drug application, then concomitant 
Missing 
if ongoing ticked as "Yes" then medication as concomitant 
if ongoing not ticked then: 
if start/imputed start date < first study drug application, then 
prior 
if start/imputed start date ≥ first study drug application, then 
concomitant 
 
 
 
Efficacy endpoints 
Handling of efficacy data is defined in sections 8.3.5 and 8.3.6. 
8.9 
Interim Analysis 
No Interim analysis is planned for this study. 
8.10 Data Monitoring Committee 
No data monitoring is planned for this study. 
8.11 References 
Not applicable. 






Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
Template Ref: STL-BIS03-00-01 SAP Template v 6.0 effective 11-Mar-2021 
Page 31 of 37 
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Filing instructions: File original in TMF section 11.01.01 
14.3.4.3 Hematology: Shift table from baseline versus each post-baseline visit 
of Normal/Abnormal values 
SAF 
 
14.3.4.4 Chemistry: Absolute values and changes from baseline 
SAF 
 
14.3.4.5 Chemistry: Number of subjects (%) with abnormal values by visit 
SAF 
 
14.3.4.6 Chemistry: Shift table from baseline versus each post-baseline visit of 
Normal/Abnormal values 
SAF 
 
14.3.4.7 Urinalysis: Absolute values and changes from baseline 
SAF 
 
14.3.4.8 Urinalysis: Number of subjects (%) with abnormal values by visit 
SAF 
 
14.3.4.9 Urinalysis: Shift table from baseline versus each post-baseline visit of 
Normal/Abnormal values 
SAF 
 
14.3.5.1 ECG: Absolute values and changes from baseline 
SAF 
 
14.3.5.2 ECG: Number of subjects (%) with abnormal values by visit 
SAF 
 
14.3.5.3 ECG: Shift table from baseline versus each post-baseline visit of 
Normal/Abnormal values 
SAF 
 
14.3.6.1 Physical examination: Number of subjects (%) with abnormal values 
by visit 
SAF 
 
14.3.6.2 Physical examination: Shift table from baseline versus each post-
baseline visit of Normal/Abnormal values 
SAF 
 
14.3.7.1 Exposure and compliance data 
SAF 
X 
 
9.2 
Listings of Individual Subject Data and Other Information to be Produced for the 
Clinical Study Report  
Title 
Population 
Key/Top 
Line 
Results 
16.1.7 Randomization Scheme  
RND  
X 
16.2.1.1 Study discontinuation and reasons for withdrawal  
ITT 
X 
16.2.1.2 Screening failures including reasons for failure  
All 
 
16.2.2 Protocol deviations  
ITT 
 
16.2.3 Patient disposition in analysis data sets and primary reasons for 
withdrawal  
ITT 
X 
16.2.4.1 Demographic data  
ITT 
X 
16.2.4.2 Medical/Surgical history  
ITT 
 
16.2.4.3 Prior medication and therapy  
SAF 
 
16.2.4.4 Concomitant medication and therapy  
SAF 
 
16.2.5.1 Extent of study drug administration compliance  
SAF 
X 
16.2.6.1 EASI by visit  
ITT 
X 
16.2.6.2 IGA by visit  
ITT 
X 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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Page 32 of 37 
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Filing instructions: File original in TMF section 11.01.01 
16.2.6.3 BSA by visit  
ITT 
X 
16.2.6.4 Pruritus-NRS by visit  
ITT 
X 
16.2.6.5 Pharmacokinetic: Plasma levels of EVO101 by visit 
PK 
 
16.2.7.1 Adverse events 
SAF 
X 
16.2.7.2 Serious adverse events 
SAF 
 
16.2.7.3 Deaths  
SAF 
 
16.2.7.4 Local skin reactions 
SAF 
 
16.2.8.1 Hematology  
SAF 
 
16.2.8.2 Clinical Chemistry  
SAF 
 
16.2.8.3 Urinalysis  
SAF 
 
16.2.8.4 Covid-19 and Pregnancy tests by visit 
SAF 
 
16.2.9 Vital Signs  
SAF 
 
16.2.10 ECG values and interpretation  
SAF 
 
16.2.11 Physical Examination by Body System  
SAF 
 
 
 
 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
Template Ref: STL-BIS03-00-01 SAP Template v 6.0 effective 11-Mar-2021 
Page 33 of 37 
This template is an appendix to SOP-BIS03 SAP 
Filing instructions: File original in TMF section 11.01.01 
10 Appendices 
10.1 Definitions and Derivations of the efficacy assessment scores 
Assessment 
Derivation 
EASI 
EASI is used to assess the severity and extent of AD; it is a composite index with 
scores ranging from 0 to 72, with higher values indicating more severe and/or 
extensive disease.  
Four (4) body regions are analyzed: head and neck, trunk, upper extremities and 
lower extremities. The severity of disease in each region is evaluated using 5 
clinical symptoms: Erythema, Edema/Papulation, Excoriation and Lichenification. 
The grade of the severity of each symptom uses a 0-3 scale: 0-None, 1-Mild, 2-
Moderate and 3-Severe. An average score will be calculated.  However, 0.5 will 
be not permitted: if a sign is present, it should be at least mild (1). Additionally, for 
each of the 4 regions of the body, the region area score will be recorded on a 
scale of 0 to 6: 0-0%, 1-[1-9%], 2-[10-29%], 3-[30-49%], 4-[50-69], 5-[70-89%]  
and 6-[90-100%]. Area score is the total percentage of skin affected with eczema 
for each body region. 
 
The severity score is calculated for each region of the body as the sum of the 
severity of the 4 different signs. For example:  
 
Severity score (Head and neck) = severity(Erythema) + 
severity(Edema/Papulation) + severity(Excoriation) + severity(Lichenification) 
 
Then for each region, the area score and the severity score will be multiplied.   
The following additional multiplies will also be used: 
- Head and neck: severity score x area score x 0.1 
- Trunk: severity score x area score x 0.3 
- Upper extremities: severity score x area score x 0.2 
- Lower extremities: severity score x area score x 0.4 
 
The final EASI will be the sum of the total scores for each region.   The range of 
the score is from 0 to 72. 
All calculations defined above are automatically conducted in the eCRF. 
 
The value of EASI to be used for the analysis will be the corresponding EASI 
score in the visit schedule: Week 2, 4 and 8. The baseline value is defined in 
section 8.3.1. 
 
Note: If any severity score of a sign and/or region area score is missing, the EASI 
score will be not possible to calculate, and this will be considered as missing. 
  


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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Filing instructions: File original in TMF section 11.01.01 
IGA 
The investigator global assessment will be on a scale of 0 to 4: 0-Clear, 1-Almost 
clear, 2-Mild, 3-Moderate and 4-Severe. 
 
Note: No additional calculation will be needed for this assessment.  
 
The value of the IGA score to be used for the analysis will be the corresponding 
IGA score in the visit schedule: Week 2, 4 and 8. The baseline value is defined in 
section 8.3.1. 
  
BSA 
The BSA assessment estimates the extent of disease or skin involvement with 
respect to AD and is expressed as a percentage of total body surface. BSA will be 
determined by the Investigator or designee using the subject palm = 1% rule. 
Note: No additional calculation will be needed for this assessment.  
 
The value of BSA percentage to be used for the analysis will be the 
corresponding BSA percentage in the visit schedule: Week 2, 4 and 8. The 
baseline value is defined in section 8.3.1Error! Reference source not found.. 
Pruritus-NRS 
Pruritus will be assessed using a Pruritus Numerical Rating Scale (NRS). The 
Pruritus NRS is an 11-point scale used by subjects to rate their worst itch severity 
over the past 24 hours with 0 indicating “No itch” and 10 indicating “Worst itch 
imaginable.” Subject assessments will be captured daily using an electronic diary.  
The value at each visit (Baseline, Week 1, Week 2, Week 3 Week 4, Week 5, 
Week 6, Week 7 Week 8) will be calculated as the mean of the values of the 7 
previous days up to the corresponding visit.  If there are less than 4 values in the 
prior 7 days, the value for that visit day will be set to missing. 
 
Values at each day (Day 1 through Day 7) will be the corresponding value 
collected in the day specified. 
The baseline value is defined in section 8.3.1. 
If more than one assessment is reported in the same day, then it will be taken 
that one with the worst severity following a conservative approach. 
 
In the case of early withdrawals, a time window will be used for the efficacy assessments mentioned 
above, to reassign values to the correct visits using the days from baseline as follows. 
 
Visit 
Target day 
Visit Window (days on treatment) 
Visit 2 
14 
Days from Baseline ≤ 21 
Visit 4 
28 
21 < Days from Baseline ≤ 42 
Visit 8 
56 
42 < Days from Baseline 
 
 
 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
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Page 35 of 37 
This template is an appendix to SOP-BIS03 SAP 
Filing instructions: File original in TMF section 11.01.01 
10.2 SAS code for multiple imputation of primary endpoint 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
       
 
       
 
       
 
        
       
 
 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
Template Ref: STL-BIS03-00-01 SAP Template v 6.0 effective 11-Mar-2021 
Page 36 of 37 
This template is an appendix to SOP-BIS03 SAP 
Filing instructions: File original in TMF section 11.01.01 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Protocol title: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF EVO101 IN 
ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Sponsor code: EVO101-AD001 
 code: EPQ1001 
Version number: Final 1.0 
Date: 17-AUG-2023 
 
CONFIDENTIAL 
 
Template Ref: STL-BIS03-00-01 SAP Template v 6.0 effective 11-Mar-2021 
Page 37 of 37 
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Filing instructions: File original in TMF section 11.01.01 
10.3 SAS code for pooled proportions of secondary binary endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 =
 
 
 
 
 
 
 
 
 
 

Prot_001.pdf: 
Evommune, Inc. 
EVO101 Topical Cream 
EVO101-AD001 
Protocol: 11 May 2023 
1 
Confidential 
 
A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY  
AND EFFICACY STUDY OF EVO101 IN ADULT SUBJECTS  
WITH ATOPIC DERMATITIS 
Protocol Number 
EVO101-AD001 
Protocol Final Date 
20 April 2022 
Amendment 1 Date 
10 June 2022 
Amendment 2 Date 
06 January 2023 
Amendment 3 Date 
11 May 2023 
Study Drug 
EVO101 Topical Cream, 0.1%  
IND Number 
155054 
Sponsor 
Evommune, Inc. 
1841 Page Mill Road 
Palo Alto, CA 94304 
USA 
CONFIDENTIAL INFORMATION 
The information contained herein is confidential and the proprietary property of 
Evommune. Any use or disclosure of such information without the prior written 
authorization of Evommune is expressly prohibited. 
 


Evommune, Inc. 
EVO101 Topical Cream 
EVO101-AD001 
Protocol: 11 May 2023 
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PROTOCOL AMENDMENT 3.0 SUMMARY OF CHANGES 
Changes to the protocol, introduced in Amendment 3.0, are summarized in the following table. 
Section(s) 
Modification 
Rationale 
Synopsis 
Comparisons between active and 
vehicle treated arms will be conducted 
using a one-sided test instead of a two-
sided test.  
For consistency between the protocol 
and Statistical Analysis Plan (SAP)  
15.1, 15.4, 15.8 
Comparisons between active and 
vehicle treated arms will be conducted 
using a one-sided test instead of a two-
sided test. 
For consistency between the protocol 
and SAP  
 


Evommune, Inc. 
EVO101 Topical Cream 
EVO101-AD001 
Protocol: 11 May 2023 
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PROTOCOL AMENDMENT 2.0 SUMMARY OF CHANGES 
Changes to the protocol, introduced in Amendment 2.0, are summarized in the following table. 
Section 
Modification 
Rationale 
Title Page 
Updated Sponsor Address 
New headquarters established for 
Evommune (Sponsor)  
6 
Updated Schedule of Assessments 
For consistency between Table 3 and 
Section 13.1.4.1  
13.1.4.1 
Provided additional direction on 
recording local skin responses as 
adverse events where appropriate  
Clarification for study sites  
15.2 
Removed “and received study drug” 
from the intent-to-treat (ITT) 
population definition 
For consistency between the protocol 
and Statistical Analysis Plan (SAP)  
15.5.1 
Removed “and received study drug” 
from the ITT population definition 
For consistency between the protocol 
and SAP  
 
 


Evommune, Inc. 
EVO101 Topical Cream 
EVO101-AD001 
Protocol: 11 May 2023 
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PROTOCOL AMENDMENT 1.0 SUMMARY OF CHANGES 
Changes to the protocol, introduced in Amendment 1.0, are summarized in the following table. 
Section 
Modification 
Rationale 
1.1 
Updated description of inhibitory 
properties of EVO101, primarily as an 
inhibitor of interleukin 1 receptor-
associated kinase 4; removed 
characterization as an inhibitor of 
tropomyosin receptor kinase A (TrkA) 
For a more accurate characterization of 
the primary pharmacology of EVO101 
1.2.1 
Removed subsection (formerly 1.2.1.2) 
that described TrkA 
For consistency with the primary 
pharmacology of EVO101 
1.2.1.3 
Updated summary of genotoxicity 
assessment and included results of the 
Comet test in rats 
To provide the most current safety 
information for EVO101 
1.2.1.4.1 
Made minor corrections to the 
summary of results from Study 
EVO101-HV001 
To align with final data summarized in 
the clinical study report 
Procedures in 
Case of 
Emergency 
Updated Table 1: Emergency Contact 
Information  
New general contact number for the 
CRO will be used for this study 
13.1.4.1 
Clarified that all local skin responses 
should be recorded as adverse events 
FDA request 
 




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Protocol: 11 May 2023 
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INVESTIGATOR SIGNATURE PAGE 
A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY OF 
EVO101 IN ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Protocol Number: 
EVO101-AD001 
Protocol Final Date: 
20 April 2022 
Amendment 1 Date: 
10 June 2022 
Amendment 2 Date: 
06 January 2023 
Amendment 3 Date: 
11 May 2023 
 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in the protocol, according to current Good Clinical Practice and local 
laws and regulations, including those of the United States (US) Food and Drug Administration 
(FDA) and according to the regulations of the country where the study is being conducted. 
I will ensure that all sub-Investigators and other staff members associated with this study have 
read and understand all aspects of this protocol.  
I have read and understand all study related information provided to me.  
The objectives and conduct of this protocol as well as the results deriving from this study will be 
treated confidentially and will not be made available to third parties without prior authorization 
by Evommune. All rights of publication of the results reside with Evommune unless other 
agreements were made in a separate contract.  
 
 
_____________________________________ 
_______________________ 
Investigator’s Signature 
Date 
 
 
_____________________________________ 
Investigator’s Name (print) 
 




Evommune, Inc. 
EVO101 Topical Cream 
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Protocol: 11 May 2023 
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SYNOPSIS  
Name of Sponsor/Company: Evommune, Inc. 
Name of Investigational Product: EVO101 Topical Cream, 0.1% 
Protocol Number:  
EVO101-AD001 
Phase: 2a 
Country: USA 
Title of Study: A RANDOMIZED, VEHICLE-CONTROLLED, SAFETY AND EFFICACY STUDY 
OF EVO101 IN ADULT SUBJECTS WITH ATOPIC DERMATITIS 
Objectives:  
Primary: Assess the safety, tolerability, and preliminary efficacy of EVO101 Topical Cream, 0.1%, 
applied twice daily in adults with atopic dermatitis (AD). 
Secondary: The secondary objective of this study will be to assess the pharmacokinetics of EVO101 
Topical Cream 0.1%, applied twice daily in adults with AD. 
Study Design: Randomized, Double-Blind, Parallel Group, Vehicle Controlled 
Number of subjects (planned): 118 
Diagnosis and main criteria for inclusion: Adults with mild to moderate AD 
Investigational product, dosage, and mode of administration: EVO101 Topical Cream, 0.1% twice 
a day (BID) 
Duration of treatment: 8 weeks 
Reference therapy, dosage, and mode of administration: EVO101 Topical Cream, Vehicle BID 
Criteria for evaluation: 
Efficacy: Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI), Body 
Surface Area (BSA), Pruritus-Numerical Rating Scale (NRS) 
Safety: Adverse Event (AEs), Local Skin Response (LSRs), Physical Exam, Serum Chemistry, 
Hematology and Urinalysis, ECG 
Pharmacokinetics: Plasma drug concentrations 
Statistical methods: 
Sample size justification: 
The assumed true standard deviation of the percentage change from Baseline to Week 8 in the EASI 
score is 50%. Based on the use of a one-sided test at the alpha=0.05 level of significance, a total 
sample size of 118 subjects (59 subjects/treatment arm) will provide greater than 90% power to detect 
a mean between-group difference of 30 percentage points. 
Primary efficacy analysis: 
The primary efficacy analysis will be conducted in the intent-to-treat population (all randomized 
subject) using an analysis of variance (ANOVA) model with the percentage change from Baseline to 
Week 8 in EASI as the dependent variable and treatment group and the randomization stratification 
variable as factors. The two arms will be compared using a one-sided test at the alpha=0.05 level of 
significance. 
Secondary efficacy analyses: 
All secondary endpoints defined as the percentage change from Baseline will be analyzed using the 
same type of ANOVA model as specified for the primary analysis. All change from Baseline 


Evommune, Inc. 
EVO101 Topical Cream 
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Protocol: 11 May 2023 
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secondary endpoints will be analyzed using analysis of covariance (ANCOVA) models with treatment 
group and the randomization stratification variable as factors and with the baseline value of the 
corresponding endpoint as a covariate. Secondary endpoints that are defined as proportion variables 
will be analyzed using Pearson’s chi-square test or (if more than 25% of expected cell frequencies are 
less than 5) Fisher’s exact test. All secondary analyses will be conducted using one-sided tests at the 
alpha=0.05 level of significance, with no adjustments for multiplicity. 
 
 
 


Evommune, Inc. 
EVO101 Topical Cream 
EVO101-AD001 
Protocol: 11 May 2023 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT 3.0 SUMMARY OF CHANGES ....................................................2 
PROTOCOL AMENDMENT 2.0 SUMMARY OF CHANGES ....................................................3 
PROTOCOL AMENDMENT 1.0 SUMMARY OF CHANGES ....................................................4 
SPONSOR SIGNATURE PAGE ....................................................................................................5 
INVESTIGATOR SIGNATURE PAGE .........................................................................................6 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................7 
SYNOPSIS .......................................................................................................................................8 
1. 
INTRODUCTION ......................................................................................................16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ..........................................................................................20 
1.3. 
Study Rationale ...........................................................................................................21 
2. 
STUDY OBJECTIVES ..............................................................................................22 
2.1. 
Primary Objective .......................................................................................................22 
2.2. 
Secondary Objectives .................................................................................................22 
3. 
STUDY ENDPOINTS ................................................................................................23 
3.1. 
Efficacy Endpoints ......................................................................................................23 
3.2. 
Pharmacokinetic Endpoints ........................................................................................23 
4. 
INVESTIGATIONAL PLAN .....................................................................................24 
4.1. 
Overall Study Design ..................................................................................................24 
4.2. 
Study Population and Number of Subjects .................................................................24 
4.3. 
Duration of the Study ..................................................................................................24 
5. 
STUDY DESIGN SCHEMATIC ...............................................................................25 
6. 
SCHEDULE OF ASSESSMENTS .............................................................................26 
7. 
SELECTION OF SUBJECTS ....................................................................................27 
7.1. 
Inclusion Criteria ........................................................................................................27 
7.2. 
Exclusion Criteria .......................................................................................................28 


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8. 
STUDY DRUG ...........................................................................................................29 
8.1. 
Description of Study Drug ..........................................................................................29 
8.2. 
Study Drug Packaging and Labelling .........................................................................29 
8.3. 
Study Drug Storage .....................................................................................................29 
8.4. 
Randomization and Blinding ......................................................................................29 
8.5. 
Study Drug Administration and Application ..............................................................29 
8.6. 
Study Drug Dispensing and Return ............................................................................30 
8.7. 
Study Drug Compliance .............................................................................................30 
8.8. 
Study Drug Accountability and Disposal ...................................................................30 
9. 
CONCOMITANT MEDICATIONS AND PROCEDURES ......................................31 
9.1. 
Permitted Treatments and Procedures ........................................................................31 
9.2. 
Prohibited Treatments and Procedures .......................................................................31 
10. 
STUDY PROCEDURES BY VISIT ..........................................................................32 
10.1. 
Screening Period .........................................................................................................32 
10.2. 
Baseline (Day 1) .........................................................................................................32 
10.3. 
Week 2 ........................................................................................................................33 
10.4. 
Week 4 ........................................................................................................................33 
10.5. 
Week 8 (Study Exit/Early Withdrawal) ......................................................................34 
10.6. 
Unscheduled Visit .......................................................................................................34 
11. 
ASSESSMENT OF EFFICACY ................................................................................35 
11.1. 
Investigator Global Assessment (vIGATM) .................................................................35 
11.2. 
Eczema Severity and Area Index (EASI) ...................................................................35 
11.3. 
Body Surface Area (BSA) Involvement .....................................................................36 
11.4. 
Pruritus-NRS Scale .....................................................................................................36 
12. 
BASELINE DEMOGRAPHICS, ATOPIC DERMATITIS AND MEDICAL 
HISTORY ...................................................................................................................37 
12.1. 
Demographics and Other Baseline Characteristics .....................................................37 
12.1.1. 
Atopic Dermatitis Prior Medications History .............................................................37 
12.1.2. 
Other Atopic Diseases History ...................................................................................37 
12.2. 
Medical History ..........................................................................................................37 
13. 
ASSESSMENT OF SAFETY .....................................................................................38 
13.1. 
Safety Parameters .......................................................................................................38 
13.1.1. 
Vital Signs ..................................................................................................................38 


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13.1.2. 
Physical Examination .................................................................................................38 
13.1.3. 
Electrocardiogram (ECG) ...........................................................................................38 
13.1.4. 
Laboratory Assessments .............................................................................................38 
13.1.4.1. 
Local Skin Reactions (LSRs) ......................................................................................39 
13.2. 
Adverse and Serious Adverse Events .........................................................................40 
13.2.1. 
Definition of Adverse Events .....................................................................................40 
13.2.1.1. 
Adverse Event (AE) ....................................................................................................40 
13.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................40 
13.2.2. 
Reporting of Adverse Events ......................................................................................41 
13.2.3. 
Reporting of Serious Adverse Events .........................................................................42 
13.2.4. 
Relationship to Study Drug ........................................................................................43 
13.3. 
Pregnancy Testing ......................................................................................................43 
13.4. 
Pharmacokinetic Sampling .........................................................................................43 
14. 
STUDY DISCONTINUATIONS ...............................................................................44 
14.1. 
Discontinuation of the Study ......................................................................................44 
14.2. 
Early Withdrawal of Study Subjects ...........................................................................44 
14.3. 
Study Drug Discontinuation .......................................................................................45 
15. 
STATISTICAL CONSIDERATIONS .......................................................................46 
15.1. 
General Statistical Methodology ................................................................................46 
15.2. 
Populations Analyzed .................................................................................................46 
15.3. 
Exposure and Compliance ..........................................................................................47 
15.4. 
Efficacy Measures ......................................................................................................47 
15.4.1. 
Primary Efficacy Analysis ..........................................................................................47 
15.4.2. 
Secondary Efficacy Analyses .....................................................................................47 
15.5. 
Adverse Events ...........................................................................................................47 
15.5.1. 
Local Skin Reactions ..................................................................................................48 
15.6. 
Other Safety Data .......................................................................................................48 
15.7. 
Pharmacokinetic Analysis ..........................................................................................48 
15.8. 
Sample Size Determination ........................................................................................48 
16. 
ACCESS TO SOURCE AND STUDY RELATED DOCUMENTS .........................49 
16.1. 
Study Monitoring ........................................................................................................49 
16.2. 
Audits and Inspections ................................................................................................49 
17. 
ETHICS ......................................................................................................................50 


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17.1. 
Ethics Review .............................................................................................................50 
17.2. 
Ethical Conduct of the Study ......................................................................................50 
17.3. 
Written Informed Consent ..........................................................................................50 
17.4. 
Compliance with the Protocol and Protocol Amendments .........................................50 
17.5. 
Study Documentation and the Case Report Form ......................................................51 
18. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................52 
19. 
DATA HANDLING AND RECORD KEEPING ......................................................53 
19.1. 
Inspection of Records .................................................................................................53 
19.2. 
Retention of Records ..................................................................................................53 
20. 
PUBLICATION POLICY ..........................................................................................54 
21. 
LIST OF REFERENCES ............................................................................................55 
22. 
APPENDICES ............................................................................................................57 
Appendix 1. Subject AD Mapping Image ...................................................................................57 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................7 
Table 2: 
Estimated Safety Margins Based on Animal to Human Dose Multiples ....................19 
Table 3: 
Schedule of Assessments ............................................................................................26 
Table 4: 
vIGA ...........................................................................................................................35 
Table 5: 
Subject Assessed Local Skin Reactions .....................................................................40 
Table 6: 
Investigator Assessed Local Skin Reactions ..............................................................40 
 
LIST OF FIGURES 
Figure 1: 
IRAK4 Functions Downstream of TLR and IL-1 Family Cytokine Receptors ..........17 
 


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LIST OF ABBREVIATIONS  
The abbreviations listed below are a non-exhaustive list of those commonly used in Evommune, 
Inc., study documents. Not all acronyms listed below are used within this document. 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
AD 
atopic dermatitis 
AUC0-24 
area under the plasma concentration-time curve over the last 24-h dosing 
interval 
BID 
twice a day 
BSA 
body surface area 
C 
Celsius 
CFR 
code of federal regulations 
CNS 
central nervous system 
eCRF 
electronic case report form 
CRO 
clinical research organization 
Cmax 
maximum plasma concentration 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
DNCB 
dinitrochlorobenzene  
DP 
drug product 
DRF 
dose range-finding 
DS 
drug substance 
EASI 
eczema area and severity index 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
good clinical practices 
GLP 
good laboratory practices 
HED 
human equivalent dose 
ICF 
informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
International ethics committee 
IGA 
investigator global assessment  
IL 
interleukins 


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Abbreviation or Specialist Term 
Explanation 
IND 
Investigational New Drug 
IR 
infrared (spectrophotometry) 
IRAK4 
interleukin 1 receptor associated kinase 4 
IRB 
institutional review board 
ITT 
intent-to-treat 
IWRS 
interactive web-based randomization system 
kg 
kilogram 
LSR 
local skin response 
MedDRA 
medical dictionary for regulatory activities 
mg 
milligram 
mL 
milliliter 
mmHg 
millimeters of mercury 
MyD88 
myeloid differentiation primary response gene 88 
NF-kB 
nuclear factor-kappa B 
ng 
nanograms 
NGF 
nerve growth factor 
NOAEL 
no-observed-adverse-event-level 
NRS 
numerical rating scale 
PK 
pharmacokinetics 
ppm 
parts per million 
PI 
principal investigator 
RBC 
red blood cell 
SAE 
serious adverse event(s) 
SD 
standard deviation 
Th 
T helper type 
TLR 
toll-like receptor 
TEAE 
treatment emergent adverse event 
TRPV1 
Transient Receptor Membrane Potential cation channel subfamily V 
member 1 
US 
United States 
VEGF 
vascular endothelial growth factor 


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1. 
INTRODUCTION 
1.1. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.3. 
Study Rationale 
Study EVO101-AD001 is planned as a randomized, double-blinded, parallel group proof-of-
concept trial in which safety, preliminary efficacy and pharmacokinetics will be assessed. 
Approximately 118 adult subjects with mild-to-moderate AD will be randomized and apply 
study drug or vehicle to their affected areas twice daily for 8 weeks. This dosing regimen has 
been selected because it was found to be well-tolerated in a previous study, EVO101-HV001, 
conducted in adult healthy volunteers.  
 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of this study will be to assess the safety, tolerability, and preliminary 
efficacy of EVO101 Topical Cream, 0.1%, applied twice daily, in adults with AD. 
2.2. 
Secondary Objectives 
The secondary objective of this study will be to assess the pharmacokinetics of EVO101 Topical 
Cream, 0.1%, applied twice daily, in adults with AD.  
 


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3. 
STUDY ENDPOINTS 
3.1. 
Efficacy Endpoints 
The primary efficacy endpoint for this trial will be:  
• Mean percentage change from Baseline in EASI score at Week 8 
Secondary efficacy endpoints for this study will be:  
• IGA response (≥2 point change from baseline) at Week 8 
• Change from Baseline in IGA at Week 8 
• Mean change from Baseline in BSA affected at Week 8 
Exploratory efficacy endpoints for this study will be: 
• EASI-75 and EASI-90 from Baseline to Week 2, 4 and 8 
• Mean change from Baseline in EASI at Weeks 2 and 4 
• Proportion of subjects achieving an IGA score of 0 to 1 who have an improvement of 
≥ 2 points from Baseline at Week 8 
• Change from Baseline in IGA score at Weeks 2, 4 and 8 
• Mean change from Baseline in the pruritus-NRS score at Weeks, 2, 4 and 8 
• Mean and percentage change from Baseline in the pruritus-NRS score at Week 8 
• Proportion of subjects achieving a 4-point improvement in the pruritus-NRS score 
from Baseline to Week 8 
• Mean change from Baseline in BSA affected at Weeks, 2, 4 and 8 
3.2. 
Pharmacokinetic Endpoints 
Plasma levels of EVO101 at Baseline, Week 2 and 8. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
The study is a randomized, double-blinded, vehicle controlled, parallel group study, designed to 
assess the safety, tolerability, and preliminary efficacy of EVO101 Topical Cream, 0.1%, in 
subjects with mild-to-moderate AD.  
Approximately 118 adult subjects, ≥18 years of age will be enrolled into this trial. The duration 
of the study for each subject is expected to be approximately 12 weeks (up to 4 weeks screening, 
8 weeks treatment). 
Subjects will be in generally good health and have a clinical diagnosis of mild-to-moderate AD 
for at least one year, an IGA score of 2 or 3, an EASI of 5-20, and an affected BSA of 4-12%. 
Subjects must be willing to discontinue any therapies for AD and refrain from using any topical 
or systemic agents for AD, other than the investigational product, during the trial. Subjects will 
be randomized (1:1), at Baseline, to one of two treatment arms: EVO101 Topical Cream, 0.1%, 
or vehicle cream. The randomization will be stratified by baseline IGA score (IGA 2, IGA 3).  At 
most 40% of randomized subjects can be in the IGA 2 stratum. 
Subjects will be instructed to apply a thin layer of study drug to the affected areas, twice daily, 
during their trial participation.  
Subjects will participate in the trial for 8 weeks in duration and be seen for in-clinic visits at 
Screening (up to 30 days prior to Baseline), Baseline, Week 2, Week 4 and Week 8 (Study Exit).  
Efficacy will be assessed using the IGA for AD (scored from 0-4), EASI, percentage BSA 
affected, and pruritus (using an 11-point pruritus-NRS; assessing the worst itch in the last 
24-hours, by the subject, daily).  
Safety will be assessed through physical exam, serum chemistries, hematology, urinalysis, 
ECGs, AEs, and local skin reactions.  
Pharmacokinetic samples will be collected at Baseline, Week 2 and Week 8. 
4.2. 
Study Population and Number of Subjects 
Approximately 118 subjects with AD that are ≥18 years of age will be enrolled. 
4.3. 
Duration of the Study 
The duration of the study for each subject is expected to be approximately 12 weeks (up to 
4 weeks screening, 8 weeks treatment). 
 


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5. 
STUDY DESIGN SCHEMATIC 
 


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6. 
SCHEDULE OF ASSESSMENTS 
Table 3: 
Schedule of Assessments 
Visit 
Screening 
Day -30 to -1 
Baseline 
Day 1 
Week 2 
Week 4 
Week 8 
Study Exit/ 
Early 
Withdrawal 
Unscheduled 
Visit 
Visit Window 
 
 
+/- 1 day 
+/- 2 days  
+/- 4 days 
 
Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Physical Exam 
X 
X 
 
 
X 
X2 
Height and Weight 
X 
 
 
 
 
 
Serum Chemistry, 
Hematology, Urinalysis 
X 
 
 
 
X 
X2 
Urine Pregnancy Test 
X 
X 
X 
X 
X 
X2 
Vital Signs 
X 
X 
X 
X 
X 
X2 
COVID-19 Test4 
X 
 
 
 
 
X2 
12-lead ECG 
X 
 
 
 
X 
X2 
Adverse Events 
X 
X1 
X 
X 
X 
X2 
Local Skin Reactions 
 
X1 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X2 
IGA 
X 
X 
X 
X 
X 
 
BSA 
X 
X 
X 
X 
X 
 
EASI 
X 
X 
X 
X 
X 
 
Pruritus-NRS (e-diary) 
X3 
X 
X 
X 
X 
 
Pharmacokinetic Sample 
 
X 
X 
 
X 
 
Dispense Study Drug 
 
X 
X 
X 
 
X2 
Study Drug Compliance  
 
 
X 
X 
X 
 
1 
LSRs collected pre-application and 15 minutes following application on Baseline/Day 1 (see Section 13.1.4.1 for details on 
LSR assessment).  
2 
Perform these procedures only if clinically indicated 
3 
Subjects are to rate pruritus severity daily, for 7 days prior to Baseline using e-diary. 
4 
COVID test to be performed within Day -4 to -1 or at the Baseline visit. 
 
 


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7. 
SELECTION OF SUBJECTS 
Subject selection criteria are outlined below. Any questions on the eligibility of a subject for this 
study must be referred to the Sponsor or their designee, prior to enrollment. No exceptions to 
inclusion or exclusion criteria will be made. 
7.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for study participation: 
1. 
Signed informed consent. 
2. 
Willing and able to comply with the study visit schedule, procedures, and questionnaires. 
3. 
Male or non-pregnant, non-lactating, females, age ≥18 years. 
4. 
Chronic AD (according to the American Academy of Dermatology Consensus Criteria) 
that has been present for ≥1 year before the Screening visit. 
5. 
Investigator's Global Assessment score of 2 to 3 at Screening and Baseline. 
6. 
EASI of 5-20 at screening and baseline. 
7. 
BSA of AD involvement, excluding the face and intertriginous areas, of 4% to 12% at 
Screening and Baseline. 
8. 
Application of a stable dose of non-medicated topical moisturizer twice daily for ≥7 days 
prior to the Baseline visit and willing to maintain stable dosing during study participation 
9. 
Completed electronic diary entries for pruritus for a minimum of 4 of 7 days preceding 
randomization at the Baseline visit.  
10. Willing to use effective contraceptive method, if applicable, during study participation 
and for 30 days following the end of treatment. 
For women of childbearing potential: agree to remain abstinent (refrain from 
heterosexual intercourse) or use a highly effective contraceptive method during the 
treatment period and for at least 30 days after the last application of study drug.  
A woman of childbearing potential is defined as a postmenarcheal female, who has not 
reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause) and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  
The following are highly effective contraceptive methods: combined (estrogen and 
progestogen containing) hormonal contraception (oral, intravaginal, transdermal) 
associated with inhibition of ovulation, progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of ovulation, intrauterine device (IUD), 
intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized 
partner, or sexual abstinence. The reliability of sexual abstinence should be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. Females must 
agree not to donate ova during the study and for 30 days after the end of study visit.  


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Male subjects must agree to use an effective barrier method of contraception during the 
study and for a minimum of 30 days following the last application of study drug if 
sexually active with a female of child-bearing potential. Males must agree not to donate 
sperm during the study and for 30 days after the end of study visit. 
7.2. 
Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for study participation: 
1. 
Significant AD flare, in the opinion of the Investigator, within 4 weeks prior to Baseline. 
2. 
Use of biologic therapy (e.g., dupilumab) within 12 weeks or 5 half-lives prior to 
Baseline. 
3. 
Use of topical treatments such as corticosteroids, calcineurin inhibitors or 
phosphodiesterase-4 inhibitors within 2 weeks prior to the Baseline visit.  
4. 
Use of systemic antibiotics within 2 weeks of Baseline.  
5. 
Use of prescription moisturizers within 7 days of the Baseline visit.  
6. 
Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks of the 
Screening visit.  
7. 
Presence of skin comorbidities or other condition that may interfere with study 
assessments.  
8. 
Active participation in an experimental therapy study or who received experimental 
therapy within 30 days or 5 half-lives (whichever is longer) before Baseline. 
9. 
Screening clinical chemistry or hematology laboratory value that is considered clinically 
significant, in the opinion of the Investigator. 
10. Abnormal findings on screening ECG, deemed clinically significant by the Investigator. 
11. Positive COVID-19 test within 3 days of Baseline visit or as part of the Baseline visit. 
Patients can be rescreened after recovering from COVID clinically, and a negative 
COVID PCR or antigen test must be done, after discussion with the sponsor’s Medical 
Monitor.  
12. COVID vaccination (last dose) within 2 weeks of start of Screening. 
13. Systemic immunosuppressive or immunomodulating drugs (e.g., systemic 
corticosteroids, cyclosporine, mycophenolate-mofetil, IFN-γ, Janus kinase inhibitors, 
azathioprine, methotrexate, etc.) or phototherapy and photochemotherapy (PUVA) within 
4 weeks prior to the Baseline visit. 
14. Prior use of EVO101 Topical Cream. 
15. Known hypersensitivity or severe reaction to the study drug or any of its excipients. 
16. Subjects who are a poor medical risk because of other systemic diseases or active 
uncontrolled infections, or any other condition which, in the judgment of the Investigator, 
would put the subject at unacceptable risk for participation in the study. 
 




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Study site staff will use the Subject AD Mapping Image (Appendix 1) to identify and map all 
AD affected areas for each respective subject enrolled. A copy of the diagram will be given to 
each subject to use as a guide when applying study drug at home. Patients must apply study drug 
to the same affected areas throughout the study, even though their AD disease may improve or 
clear during the study. Subjects will be instructed to apply study drug to any new AD lesions, 
should they occur. The original diagram will be retained as a source document.  
The first dose of the study drug will be applied at the study site for instructional purposes and 
will be recorded in the dosing diary as the first dose. Subjects will apply the study drug twice 
daily, in the morning and evening for a total of 8 weeks. Missed doses should be applied 
provided there is at least a 4-hour window until the next scheduled dose.  
8.6. 
Study Drug Dispensing and Return 
It is the responsibility of the Investigator to ensure that study drug is only used on study subjects 
enrolled in this study. Study drug must only be dispensed from official study sites by authorized 
personnel according to the protocol and local regulations.  
Subjects should return their used and unused study drug at their next study site visit for study 
drug accountability purposes. Subjects may be re-dispensed unused study medication.  
Subjects are to return all their study drug (used or unused) to the study site at the end of study 
participation. Study staff will record tubes dispensed and returned, by subject in any source 
documents and the eCRF.  
Each subject is to be instructed on the importance of returning study drug to the study site at their 
final study visit. Subjects who fail to return their study drug will be directed to return it as soon 
as possible. 
8.7. 
Study Drug Compliance 
Treatment compliance will be assessed by the subject, daily, using an e-diary. A subject 
deviating significantly (less than 80% compliant) from the twice daily dosing regimen will be 
counseled or terminated from the trial, at the discretion of the Investigator. Study site staff will 
monitor subject compliance regularly.  
8.8. 
Study Drug Accountability and Disposal 
The Investigator or designee will be responsible for documenting drug accountability at the site. 
Study drug accountability records will document the receipt, dispensing and return of study drug 
and provide a complete account of all used and unused drug product.  
Study drug accountability records will be reviewed by the Sponsor or designee. Following final 
accountability, instructions will be provided to the site regarding study drug return and 
destruction.  


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9. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
All medications, including over-the-counter drugs, vitamins, antacids, and skin care products, 
taken during screening and throughout the study will be recorded in the eCRF.  
Medication entries should be specific to the generic name (if a combination drug, then marketed 
product name) and will include the dose, unit, and frequency of administration and/or treatment, 
route of administration, start date, discontinuation date, and indication.  
The Investigator should examine the acceptability of all concomitant procedures, medications, 
topical preparations, and dietary supplements not explicitly prohibited in this study.  
In order to ensure that appropriate concomitant therapy is administered, subjects will be 
instructed to consult with the Investigator prior to taking any medication (either self-
administered non-prescription drugs or prescription therapy prescribed by another physician). 
9.1. 
Permitted Treatments and Procedures 
The use of concomitant medications for the treatment of an AE is permitted during this study.  
Moisturizer Use: 
• Non-medicated moisturizer must be used during trial participation, twice daily (may be 
applied at the time of study drug application), to all non-affected areas. 
• Sunscreens may be used on all areas provided the application occurs at least 15 minutes 
following study drug application.  
• Subjects are asked to avoid the use of moisturizers and sunscreens prior to the study visit 
but may use these products following study visits.  
Concomitant medications for mild-to-moderate asthma, allergic rhinitis and allergies are 
permitted. Concomitant medications for the treatment of any other diseases except those 
prohibited concomitant medications listed in Section 10.2 are permitted. The medical monitor 
may be consulted if needed for questions on permitted and prohibited treatments and procedures.  
9.2. 
Prohibited Treatments and Procedures 
Subjects should not undergo any elective medical procedure without prior consultation with the 
Investigator. Elective out-patient procedures (e.g., minor outpatient surgery) that might require 
hospitalization or anesthesia must be deferred until after the study.  
The following medications and treatments are prohibited during the study:  
• Any prescription or over-the-counter product intended to treat AD.  
• Use of tanning booth. 
• Excessive sun exposure. 
The medical monitor may be consulted if needed for questions on permitted and prohibited 
treatments and procedures. 


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10. 
STUDY PROCEDURES BY VISIT 
The procedures required for subject evaluation at each study visit are outlined below and in the 
study Schedule of Visits and Procedures. The timing of each study day is relative to the day of 
initial dosing/application (Baseline/Day 1). Visit windows are provided, where allowed, to allow 
study sites flexibility in maintaining the study visit schedule for participating subjects. 
10.1. 
Screening Period 
The screening evaluation period may take up to 30 days in order to provide adequate washout 
time for subjects taking certain medications. The purpose of the Screening visit is to ensure that 
appropriate subjects are entered into the study and remain stable during the pre-treatment period. 
Questions on subject eligibility will be referred to the Sponsor or their designee. Screen failures 
may not be re-screened unless approved by the Sponsor.  
• Obtain written informed consent.  
• Collect demographic information. 
• Complete medical history. 
• Review inclusion/exclusion criteria. 
• Query subject for prior and concomitant medication use. 
• Perform a physical examination. 
• Record height and weight. 
• Measure vital signs. 
• COVID-19 test. 
• 12-lead ECG. 
• Draw blood samples for laboratory tests and urine for urinalysis and urine pregnancy 
test. 
• Collect IGA, BSA and EASI. 
• Upload and instruct on e-diary for pruritus-NRS. 
• Collect AEs 
• Schedule next visit. 
10.2. 
Baseline (Day 1) 
• Collect concomitant medication information. 
• Measure vital signs. 
• Medical history: update medical history if appropriate.  
• Perform a physical examination. 
• Conduct urine pregnancy test.  


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• Draw blood sample for pharmacokinetic analysis. 
• Collect IGA, BSA and EASI. 
• Collect AEs. 
• Collect LSRs pre and post study drug application. 
• Confirm pruritus-NRS diary data is complete. 
• Confirm subject eligibility and enrollment. 
• Instruct subject on study medication application and e-diary completion. 
• Apply first application in clinic and record in diary. 
• Dispense study drug and Subject AD Mapping Image. 
• Schedule next visit. 
10.3. 
Week 2 
• Collect AEs 
• Collect concomitant medication information. 
• Measure vital signs. 
• Conduct urine pregnancy test.  
• Draw blood sample for pharmacokinetic analysis. 
• Collect IGA, BSA and EASI. 
• Collect LSRs. 
• Confirm compliance with pruritus-NRS diary.  
• Confirm compliance with study drug application. 
• Dispense study drug. 
• Schedule next visit. 
10.4. 
Week 4 
• Collect AEs 
• Collect concomitant medication information. 
• Measure vital signs. 
• Conduct urine pregnancy test.  
• Collect IGA, BSA and EASI. 
• Collect LSRs. 
• Confirm compliance with pruritus-NRS diary. 


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• Confirm compliance with study drug application. 
• Dispense study drug. 
• Schedule next visit. 
10.5. 
Week 8 (Study Exit/Early Withdrawal) 
• Perform physical exam. 
• Collect AEs. 
• Collect concomitant medication information. 
• Measure vital signs. 
• Collect ECG. 
• Draw blood samples for laboratory tests and urine for urinalysis and urine pregnancy 
test. 
• Draw blood sample for pharmacokinetic analysis. 
• Collect IGA, BSA and EASI. 
• Collect LSRs. 
• Confirm compliance with pruritus-NRS diary. 
• Confirm compliance with study drug application. 
• Close e-diary and exit subject from study. 
10.6. 
Unscheduled Visit 
Additional visits may be scheduled as necessary to ensure the safety and well-being of subjects 
who experience AEs. Physical exam and laboratory evaluations, if necessary, should be 
conducted. Laboratory evaluations should be collected and analyzed using the central laboratory 
for this study. Data will be recorded in the eCRF. 


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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Investigator Global Assessment (vIGATM) 
The IGA is a static assessment and rates the severity of the subject’s AD and is a 5-point scale 
ranging from 0 (clear) to 4 (severe). A score is selected using descriptors that best describe the 
overall appearance of the lesions at a given time point. It is not necessary that all characteristics 
under the morphological description be present. A single assessor should be assigned to each 
individual subject for as many visits as possible, to avoid inter-assessor variability in scoring. 
Assessors must be trained and certified by the Sponsor prior to conducting this assessment. The 
IGA must be conducted prior to conducting EASI and BSA assessments.  
The IGA score is selected using the descriptors below that best describe the overall appearance 
of the lesions at a given time point.  
Table 4: 
vIGA 
Score 
Clinical Definition1,2 
0-Clear 
No inflammatory signs of atopic dermatitis (no erythema, no 
induration/papulation, no lichenification, no oozing/crusting). Post-inflammatory 
hyperpigmentation and/or hypopigmentation may be present. 
1-Almost clear 
Barely perceptible erythema, barely perceptible induration/papulation, and/or 
minimal lichenification. No oozing or crusting. 
2-Mild 
Slight but definite erythema (pink), slight but definite induration/papulation, 
and/or slight but definite lichenification. No oozing or crusting. 
3-Moderate 
Clearly perceptible erythema (dull red), clearly perceptible induration/papulation, 
and/or clearly perceptible lichenification. Oozing and crusting may be present. 
4-Severe 
Marked erythema (deep or bright red), marked induration/papulation, and/or 
marked lichenification. Disease is widespread in extent. Oozing or crusting may 
be present. 
1 In indeterminate cases, please use extent to differentiate between scores.  
2 Excoriations should not be considered when assessing disease severity 
Copyright ©2017 Eli Lilly and Company – Used with the permission of Eli Lilly and Company under a Creative 
Commons Attribution-NoDerivatives 4.0 International License - https://creativecommons.org/licenses/by-nd/4.0/ 
11.2. 
Eczema Severity and Area Index (EASI) 
EASI is used to assess the severity and extent of AD; it is a composite index with scores ranging 
from 0 to 72, with the higher values indicating more severe and/or extensive disease. Assessors 
must be trained and certified by the Sponsor prior to conducting this assessment.  


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11.3. 
Body Surface Area (BSA) Involvement  
The BSA assessment estimates the extent of disease or skin involvement with respect to AD and 
is expressed as a percentage of total body surface. BSA will be determined by the Investigator or 
designee using the subject palm = 1% rule. Assessors must be trained and certified by the 
Sponsor prior to conducting this assessment. 
11.4. 
Pruritus-NRS Scale 
Pruritus will be assessed using a Pruritus Numerical Rating Scale (NRS). The Pruritus NRS is an 
11-point scale used by subjects to rate their worst itch severity over the past 24 hours with 0 
indicating “No itch” and 10 indicating “Worst itch imaginable.” Subject assessments will be 
captured daily using an electronic diary.  
Subjects will be provided with an electronic diary at least 7 days prior to the baseline visit and 
instructed to enter their pruritus scores daily subjects may be provided the electronic diary at the 
first Screening visit. Pruritus diary compliance will be checked by the study site staff and 
subjects will be counseled for non-compliance. At least 4 of the 7 days prior to the baseline visit, 
the diary must be completed in order for the subject to be eligible for study participation.  


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12. 
BASELINE DEMOGRAPHICS, ATOPIC DERMATITIS AND 
MEDICAL HISTORY  
12.1. 
Demographics and Other Baseline Characteristics  
At the screening visit, demographic information including age, gender, race and ethnicity will be 
collected and recorded in the eCRF for each subject. 
12.1.1. 
Atopic Dermatitis Prior Medications History  
All prior AD medications will be collected.  
12.1.2. 
Other Atopic Diseases History  
Prior and concomitant atopic disease history will be collected including asthma, allergic rhinitis, 
food allergies, chronic rhinosinusitis with or without polyposis, and eosinophilic esophagitis.  
12.2. 
Medical History 
A complete medical history will be collected as part of the screening assessment and include all 
clinically relevant past or coexisting medical conditions (including COVID-19 infection and 
vaccination) or surgeries. The medical history will be updated prior to treatment at Baseline 
should new findings be present since the screening visit. Findings will be recorded in the eCRF. 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety Parameters 
13.1.1. 
Vital Signs 
Vital signs, including body temperature, respiratory rate (breath per minute), pulse (beats per 
minute), and blood pressure (mmHg), will be obtained with the subject in the seated position, 
after sitting for at least 5 minutes. Any abnormal findings which are new or worsened in severity 
and clinically significant, in the opinion of the Investigator, will be recorded as an AE. Vital sign 
measurements will be recorded in the eCRF.  
13.1.2. 
Physical Examination 
A complete physical examination will be conducted at screening and cover general appearance, 
dermatological, head, ears, eyes, nose, throat, respiratory, cardiovascular, abdominal, 
neurological, musculoskeletal, and lymphatic body systems. A symptom directed physical exam 
may be performed at each subsequent visit, if needed, to assess the subject. Height and weight 
will be recorded as part of the screening physical exam and only the subject’s weight will be 
recorded with the end of study physical exam. Findings will be recorded in the eCRF.  
13.1.3. 
Electrocardiogram (ECG) 
12-lead ECG measurements will be obtained in all subjects. The subject should rest quietly for at 
least 5 minutes in a supine position prior to ECG collection. The ECG should be obtained either 
prior to the time of blood collection, or at least 15 minutes afterwards.  
At screening, the Investigator will use the machine-read ECG to determine subject eligibility. 
The medical monitor may be consulted if needed for interpretation of ECGs. 
All study sites will be supplied with standardized, validated digital 12-lead ECG (12 lead at 
25 mm/sec reporting rhythm, ventricular rate, the RR interval, the PR interval, QRS duration, 
QT, QTcF and QTcB intervals) equipment capable of recording, storing, and printing producing 
high resolution 12-lead ECG. Study sites will be trained on the use of the equipment prior to 
study start.  
Machine-read ECG recordings will be collected and analyzed centrally. Data will be transferred 
electronically to the database. Additional details regarding subject preparation, ECG 
procurement and data transmission may be provided in a separate study manual.  
13.1.4. 
Laboratory Assessments 
Laboratory tests will be collected to evaluate safety in all study subjects and analyzed using a 
central laboratory. Laboratory samples will be collected per the Schedule of Visits and 
Procedures, and as clinically indicated. Laboratory samples are to be shipped on the same day as 
collected. Laboratory tests are described below.  
COVID-19: molecular (RT-PCR) test or antigen test for COVID-19 infection. 
Hematology: hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell count and 
differential (%), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 


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concentration (MCHC), mean corpuscular volume, RBC morphology, platelet count, absolute 
neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils, and absolute 
basophils. 
Chemistry: sodium, potassium, chloride, calcium, phosphorus, bicarbonate, uric acid, blood urea 
nitrogen (BUN), creatinine, total protein, albumin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, bilirubin (total and direct), and non-fasting 
glucose. 
Urine pregnancy testing (beta human chorionic gonadotropin [β-hCG]): performed in all females 
unless post-menopausal/sterile.  
Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, urobilinogen, 
leukocyte esterase. A microscopic examination of urine will be performed if clinically indicated 
in the opinion of the Investigator based on the findings of the urinalysis or clinical signs and 
symptoms. Any clinically significant laboratory result is to be recorded as an AE after study drug 
dosing. 
Screening laboratory values must be reviewed by the Investigator prior to subject enrollment. 
Subjects will be screen failed for clinically significant laboratory values. Screening laboratory 
tests may be repeated one time in order to confirm out of range results or clinical significance at 
the discretion of the investigator. Subjects with a positive test result for COVID-19 may be 
rescreened for the trial eligibility.  
The central laboratory should be used for any laboratory testing required for a subject during 
study participation, including laboratory testing needed for unscheduled visits. Clinically 
significant laboratory results must be recorded on the AE eCRF, preferably as a diagnosis rather 
than individual test results. Any subject who has a clinically significant laboratory test result will 
be evaluated by the PI and will be treated and/or followed up at the discretion of the PI until the 
value returns to clinically acceptable levels. 
13.1.4.1. Local Skin Reactions (LSRs) 
A static assessment of local skin reactions will be conducted in all subjects at each study visit. 
LSRs include burning/stinging, pruritus, edema, erythema, dryness and scaling. Each LSR will 
be scored as 0 (None), 1 (Mild), 2 (Moderate) or 3 (Severe). 
Burning/stinging and pruritus will be assessed by the subject and edema/swelling, erythema, 
dryness, and scaling will be assessed by the Investigator/designee. Subjects will be read the 
definition of each subject-assessed LSR and asked to select the appropriate definition. The 
corresponding grade will be assigned by the site and entered in the eCRF. 
At the Baseline visit, LSRs are collected prior to study drug application and approximately 
15 minutes (+30 minutes) following the first application of study drug.  
When assessing the LSRs, the underlying disease involving the skin should be considered in the 
overall score.  Local skin reaction assessments subsequent to study drug application, that are 
greater than the Baseline visit pre-application assessment score are to be recorded as an AE.  The 
stop date for the AE is the date that the score is less than or equal to the pre-application Baseline 
Day 1 visit score.  


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Table 5: 
Subject Assessed Local Skin Reactions 
Score 
Grade 
Burning/Stinging 
Pruritus 
0 
None 
No stinging/burning 
No pruritus 
1 
Mild 
Slightly warm, tingling sensation; not 
really bothersome 
Occasional, slight itching/scratching 
2 
Moderate 
Definite warm; tingling/stinging 
sensation that is somewhat bothersome 
Intermittent itching/scratching which does 
not disturb sleep 
3 
Severe 
Hot, tingling/stinging sensation that has 
caused definite discomfort 
Bothersome itching/scratching which 
disturbs sleep 
Table 6: 
Investigator Assessed Local Skin Reactions 
Score 
Grade 
Edema 
Erythema 
Dryness 
Scaling 
0 
None 
No edema 
No erythema 
present 
None 
None 
1 
Mild 
Slight, barely 
perceptible edema 
Slight erythema: 
very light-pink 
Perceptible dryness 
with no flakes or 
fissure formation 
Slight diffuse 
scaling 
2 
Moderate 
Distinct presence 
of edema 
Dull red, clearly 
distinguishable 
Easily noted 
dryness and flakes 
but no fissure 
formation 
Diffuse scaling 
3 
Severe 
Marked, intense 
edema 
Deep/dark red 
Easily noted 
dryness with flakes 
and fissure 
formation 
Prominent, dense 
scaling 
13.2. 
Adverse and Serious Adverse Events 
13.2.1. 
Definition of Adverse Events 
13.2.1.1. Adverse Event (AE) 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether or 
not considered casually related to the product. In clinical studies, an AE can include an 
undesirable medical condition occurring at any time, including baseline or washout periods, even 
if no study treatment has been administered. 
13.2.1.2. Serious Adverse Event (SAE) 
An AE or suspected AE reaction is considered serious if, in the view of either the Investigator or 
Sponsor, it results in any of the following outcomes: 
• Death; 
• Immediately life-threatening; 


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An AE or suspected AE is considered “life threatening” if, in view of either the 
Investigator or Sponsor, its occurrence places the study subject at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might have 
caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
Any hospital admission will be considered an in-patient hospitalization, regardless of 
duration. An emergency room visit without hospital admission will not be recorded as an 
SAE under this criterion, nor will hospitalization for a procedure scheduled before 
signing of informed consent. However, unexpected complications and/or prolongation of 
hospitalization that occur during elective surgery should be recorded as AEs and assessed 
for seriousness. Admission to the hospital for a pre-planned procedure or social or 
situational reasons (e.g., no place to stay, lives too far away to come for hospital visits) 
will not be considered in-patient hospitalizations. 
• Persistent or significant disability or incapacity. 
• Congenital abnormality or birth defect. 
• It is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the study subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in in-patient 
hospitalizations, or the development of drug dependency. 
13.2.2. 
Reporting of Adverse Events 
AEs spontaneously reported by the subject and/or in response to an open question from the study 
personnel or revealed by observation will be recorded during the study at the investigational site.  
Non-serious AEs should be recorded on the eCRF from the time the subject has signed informed 
consent through the last study visit, unless otherwise specified. Any changes in the subject’s 
status between signing informed consent, up to the time administration of the first dose of study 
drug will be recorded as a pre-treatment AE. Any AE occurring after administration of the first 
dose of study drug will be considered a treatment emergent AE (TEAE). 
The AE term should be reported in standard medical terminology when possible.  
Any subject who has an AE (whether serious or non-serious) or clinically significant test value 
will be evaluated by the PI and will be treated and/or followed up until the symptoms or values 
return to normal or to clinically acceptable levels, as judged by the PI.  
Unless a diagnosis is available, signs and symptoms must be reported as individual AEs in the 
eCRF; a diagnosis is preferred. 


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For each AE, the investigator will evaluate and report the onset date, resolution date, intensity, 
causality, action taken, serious outcome (if applicable), and whether or not it caused the subject 
to discontinue the study. 
Intensity will be assessed according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 5.0, 2017. The NCI Common 
Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for 
AE reporting. A grading (severity) scale is provided for each AE term. Grade refers to the 
severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of 
severity for each AE based on this general guideline:  
• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.  
• Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL).  
• Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.  
• Grade 4 Life-threatening consequences; urgent intervention indicated.  
• Grade 5 Death related to AE. 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 13.2.1.2. An AE of severe intensity 
may not be considered serious significance (e.g., ‘severe’ headache). Seriousness of AEs is based 
on the outcome/action of an AE. 
13.2.3. 
Reporting of Serious Adverse Events 
SAEs must be reported to the Sponsor or designee within 24 hours of awareness of the event 
from the time the subject has signed informed consent through the last study visit, unless 
otherwise specified, using a SAE Reporting Form, provided for this study. In particular, if the 
SAE is fatal or life-threatening, notification to the Sponsor or designee, must be made 
immediately, irrespective of the extent of information available. In all cases, the PI should 
continue to monitor the clinical situation and report all material facts relating to the progression 
or outcome of the SAE. The Investigator may be required to provide supplementary information 
as requested by the Sponsor or its designee. 
When reporting SAEs, the following additional points should be considered: 
• When the diagnosis of an SAE is known or suspected, the PI should report the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms; 
signs, symptoms and tests that support the diagnosis should be provided. 
• Death should not be reported as an SAE, but as an outcome of a specific SAE, unless 
the event preceding the death is unknown. If an autopsy was performed, the autopsy 
report should be provided. 


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The Sponsor will process and evaluate all SAEs as soon as the reports are received. For each 
SAE received, the Sponsor will make a determination as to whether the criteria for expedited 
reporting to relevant regulatory authorities have been met.  
The Sponsor will assess the expectedness of each SAE to the study treatment. The current 
Investigator’s Brochure will be used as the reference document to assess expectedness of the 
event to study drug. 
13.2.4. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated or Related). The Investigator should decide 
whether, in his or her medical judgment, there is a reasonable possibility that the event may have 
been caused by the investigational product. If no valid reason exists for suggesting a relationship, 
then the AE should be classified as “unrelated.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 
product and the occurrence of the AE, then the AE should be considered “related.” 
The relationship of the AE to the study treatment will be based on the following two definitions: 
Not related: An AE is defined as “not related” if the AE is not judged to be associated with the 
study drug and is attributable to another cause. 
Related: An AE is defined as “related” where a causal relationship between the event and the 
study drug is a reasonable possibility (possibly or probably related). A reasonable causal 
relationship is meant to convey that there are facts (e.g., evidence such as dechallenge/ 
rechallenge) or other clinical arguments to suggest a causal relationship between the AE and 
study treatment. 
13.3. 
Pregnancy Testing 
Should a subject become pregnant during study participation, study drug dosing will be 
discontinued, and the subject will be withdrawn from study. The Investigator must perform 
medical assessments as clinically indicated and continue to follow the subject for at least 
4 weeks after delivery. Details for both the mother and baby must be obtained. Pregnancy is not 
itself an AE or SAE; however, maternal/fetal complications or abnormalities must be recorded as 
AEs or SAEs. The Investigator must complete a study-specific pregnancy form upon 
confirmation of a pregnancy. Pregnancy reporting forms will be provided to the study site.  
13.4. 
Pharmacokinetic Sampling 
Blood samples for pharmacokinetic (PK) anlaysis will be collected in all subjects. The 
procedural instructions will be provided in a separate pharmacokinetic instruction manual.  


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14. 
STUDY DISCONTINUATIONS 
14.1. 
Discontinuation of the Study 
The Sponsor has the right to terminate or to stop the study at any time. Should this be necessary, 
both the Sponsor and the Investigator will ensure that proper study discontinuation procedures 
are completed. The entire study will be stopped if: 
• Evidence has emerged that, in the collective opinion of the Investigator with the 
concurrence of the Sponsor or the sole opinion of the Sponsor, makes the 
continuation of the study unnecessary or unethical. 
• The stated objectives of the study are achieved. 
• The Sponsor discontinues the development of the study drug. 
Regardless of the reason for withdrawal, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented. 
14.2. 
Early Withdrawal of Study Subjects 
The Investigator will make every reasonable effort to keep each subject in the study; however, a 
subject may voluntarily withdraw from study participation at any time. If the subject withdraws 
consent and discontinues from the study, the Investigator will attempt to schedule an Early 
Withdrawal Visit as soon as possible, determine the reason for discontinuation, and record the 
reason in the subject’s study records and in the eCRF.  
If at any time during the study, the Investigator determines that it is not in the best interest of the 
subject to continue, the subject will be discontinued from participation. The Investigator may 
discontinue a subject at any time if medically necessary. The Investigator may discontinue a 
subject’s participation if the subject has failed to follow study procedures or, to keep follow-up 
appointments. Prior to discontinuing a subject from study participation, the Investigator will 
discuss his/her intentions with the Sponsor’s Medical Monitor or designee. Appropriate 
documentation in the subject’s study record and eCRF regarding the reason for discontinuation 
must be completed. 
All subjects who fail to return to the study site for the required follow-up visits will be contacted 
by phone to determine the cause(s) why the subject failed to return for the necessary visit or 
elected to discontinue from the study. If a subject is unreachable by telephone after a minimum 
of two documented attempts (one attempt on two different days), a registered letter will be sent 
requesting that subject contact the site regarding study follow-up.  
Subjects will be discontinued early from the study if any of the following occur: 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
• Any clinical AE, laboratory abnormality, or inter-current illness which, in the opinion 
of the Investigator, indicates that continued treatment and/or participation in the study 
is not in the best interest of the subject. 
• Death. 


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• Serious protocol violation, including persistent non-compliance, subjects requiring 
prohibited medications or procedures allowing subjects to receive the appropriate 
medical attention. In such cases, the Investigator must contact the Sponsor or 
designee, as the final decision to withdraw the subject will be taken by the Sponsor. 
• Discontinuation of the study by the Sponsor. 
14.3. 
Study Drug Discontinuation  
Subjects who discontinue or have their study drug discontinued prematurely should continue to 
have all protocol-specified safety assessments and end of study procedures collected.  
The Investigator should stop study drug treatment in the following instances: 
• Inter-current illness that would, in the judgment of the Investigator, affect 
assessments of clinical status to a significant degree. 
• Any AE which is clinically significant, is deemed persistent, is probably or definitely 
related to study drug in the judgment of the Investigator.  
• Unacceptable toxicity. 
 


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15. 
STATISTICAL CONSIDERATIONS 
15.1. 
General Statistical Methodology 
A statistical analysis plan (SAP), describing all statistical analyses will be provided as a separate 
document. The SAP will be finalized prior to unblinding of the study treatments. 
All statistical processing will be performed using SAS® unless otherwise stated. No interim 
analyses are planned. All statistical tests will be one-sided and will be performed at the 0.05 level 
of significance.  
Descriptive statistics will be used to provide an overview of the efficacy and safety results. 
For categorical parameters, the number and percentage of subjects in each category will be 
presented. For continuous parameters, descriptive statistics will include n (number of subjects), 
mean, standard deviation (SD), median, minimum, and maximum. Appropriate inferential 
statistics will be used for the primary and secondary efficacy variables. 
The primary method of handling missing efficacy data will be based on MCMC; additional 
details, including details on sensitivity analyses will be provided in the SAP.  
The pruritus-NRS weekly mean will be calculated as follows: The mean of each subject’s 
baseline and post-baseline pruritus-NRS scores will be computed for each week based on the 
previous 7 days. The weekly mean will be calculated if a subject has responses for pruritus-NRS 
on at least 4 of the 7 days of the week. If the subject has 3 or fewer pruritus-NRS responses, the 
mean value for that item will be considered missing. All pruritus-NRS efficacy endpoint analyses 
will be conducted on the weekly mean.  
Demographic data will be summarized by treatment group using descriptive statistics. Subjects’ 
baseline characteristics related to efficacy analyses will be compared with descriptive statistics 
among treatment groups to ensure comparable results. 
The number of subjects in each analysis set will be summarized. Reasons for study withdrawal 
during the blinded study will be summarized using frequencies and percentages by treatment 
group. 
15.2. 
Populations Analyzed 
All subjects who are randomized will be included in the intent-to-treat (ITT) population.  
Per-protocol (PP) population: All subjects in the ITT population who complete the Week 8 
evaluation without any significant protocol violations 
PK population: All subjects who had blood collected for PK analysis will be included in the PK 
population.  
All subjects who are randomized and receive at least one confirmed dose of study drug will be 
included in the safety population. 
The primary efficacy analysis and the analysis of all secondary endpoints will be performed 
using the ITT population Additional supportive efficacy analyses will be performed using the PP 
population. In all efficacy analysis, subjects will be included in the treatment arm to which they 


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were randomized. Safety analyses will be performed using the safety population. In all safety 
analyses, subjects will be analyzed based on the treatment that was received. 
15.3. 
Exposure and Compliance 
The extent of exposure to study drug in each treatment group will be summarized by total 
number of days of exposure, total number of applications, number of missed applications and 
number and percentage of subjects who are compliant. A subject will be considered compliant 
with the dosing regimen if the subject applied 80% to 120% of the expected number of 
applications while enrolled in the study.  
15.4. 
Efficacy Measures 
15.4.1. 
Primary Efficacy Analysis 
The primary efficacy analysis will be conducted with an analysis of variance (ANOVA) model 
with the percentage change from Baseline to Week 8 in EASI score as the dependent variable 
and treatment group and the randomization stratification variable as factors. The two arms will 
be compared using a one-sided test at the alpha=0.05 level of significance. 
15.4.2. 
Secondary Efficacy Analyses 
All secondary endpoints defined as the percentage change from baseline will be analyzed using 
the same type of ANOVA model as specified for the primary analysis. All change from baseline 
secondary endpoints will be analyzed using analysis of covariance (ANCOVA) models with 
treatment group and the randomization stratification variable as factors and with the baseline 
value of the corresponding endpoint as a covariate. Secondary endpoints that are defined as 
proportion variables will be analyzed using Pearson’s chi-square test or (if more than 25% of 
expected cell frequencies are less than 5) Fisher’s exact test. All secondary analyses will be 
conducted using one-sided tests at the alpha=0.05 level of significance, with no adjustments for 
multiplicity. 
15.5. 
Adverse Events 
All AEs that occur during the study will be recorded and classified on the basis of Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. TEAEs are defined as AEs with an 
onset on or after the date of the first study drug application. AEs noted prior to the first study 
drug administration that worsen after baseline will also be reported as AEs and included in the 
summaries.  
All information pertaining to an AE noted during the study will be listed by subject, detailing the 
verbatim term given by the Investigator or designee, preferred term, system organ class, onset 
date, resolution date, severity, seriousness, action taken, outcome and drug relatedness. The 
event onset will also be shown relative (in number of days) to date of first application.  
Treatment-emergent AEs will be summarized by treatment group, the number of subjects 
reporting a TEAE, system organ class, preferred term, severity, relationship to study drug 
(causality) and seriousness. When summarizing AEs by severity and relationship, each subject 
will be counted once within a system organ class or a preferred term by using the event with the 
highest severity and greatest relationship within each classification.  


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Serious AEs will be summarized by treatment group, severity and relationship to study drug, and 
individual SAEs will be listed by subject. In addition, a list of subjects who prematurely 
discontinue from the study due to an AE will be provided. 
15.5.1. 
Local Skin Reactions 
Local Skin Reaction assessments (LSRs) include burning/stinging, pruritus, edema/swelling, 
erythema, dryness, and scaling. LSRs will be scored as 0 (None), 1 (Mild), 2 (Moderate) or 3 
(Severe).  
LSRs will be summarized by visit using descriptive statistics. A by-subject listing of subjects 
with any LSR scored as 3 will be presented. 
15.6. 
Other Safety Data 
Laboratory test results will be summarized descriptively at baseline and Week 8. Additionally, 
shifts from baseline to Week 8 in laboratory test results based on normal ranges will be 
summarized with descriptive statistics. Individual laboratory test results will be presented in a 
by-subject listing. Any clinically significant laboratory abnormalities will be captured as AEs. 
Vital signs will be presented by treatment group as observed values and changes from baseline 
using descriptive statistics. 
Medical histories will be coded using the MedDRA dictionary and presented in a by-subject 
listing. 
Concomitant medications will be coded using the WHO-Drug dictionary. Concomitant 
medications will be summarized by treatment, drug class and preferred term.  
Physical examination data will be presented in a by-subject listing.  
Descriptive statistics by treatment group and visit will be provided for the following ECG 
parameters: heart rate (HR), RR duration, QRS duration, PR duration, QT duration and QTcF 
and QTcB duration.  
15.7. 
Pharmacokinetic Analysis 
Plasma concentration data will be tabulated and summarized (geometric mean, arithmetic mean, 
minimum, maximum, SD, and % coefficient of variation) by treatment group for each visit at 
which samples were taken.  
15.8. 
Sample Size Determination 
The assumed true standard deviation of the percentage change from Baseline to Week 8 in the 
EASI score is 50%. Based on the use of a one-sided test at the alpha=0.05 level of significance, a 
total sample size of 118 subjects (59 subjects/treatment arm) will provide greater than 90% 
power to detect a mean between-group difference of 30 percentage points. 


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16. 
ACCESS TO SOURCE AND STUDY RELATED DOCUMENTS 
16.1. 
Study Monitoring 
The Sponsor or designee will ensure that all study sites are qualified to participate and enroll 
subjects in this trial and will ensure that the facilities are adequate to conduct the trial and site 
staff are trained on the protocol. The study will be discussed with the investigator(s) and other 
personnel with regard to their responsibilities, protocol adherence, and the responsibilities of the 
Sponsor or its representatives.  
During the study, the Sponsor or its designee will have regular contact with the study site 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 recorded in the case report forms, and that investigational product 
accountability checks are being performed. 
• Perform source data verification. This includes a comparison of the data in the case 
report forms with the subject’s medical records at the hospital or practice, and other 
records relevant to the study. This will require direct access to all original records for 
each subject (e.g., clinic charts). 
• Record and report any protocol deviations not previously identified.  
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm all 
SAEs have been forwarded to the Sponsor or its designee and, as appropriate, 
forwarded to the institutional review board (IRB). 
Subject confidentiality will be always maintained. The monitor will be available between visits if 
the investigator(s) or other staff needs information or advice. The Investigator agrees to 
cooperate with the study monitor to ensure that any problems detected during the monitoring 
visits are resolved. 
16.2. 
Audits and Inspections 
Authorized representatives of the Sponsor or its designee, a regulatory authority, an Independent 
Ethics Committee (IEC) or an IRB may visit the site to perform audits or inspections, including 
source data verification. The purpose of a Sponsor’s 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, Good Clinical Practice guidelines of the International Council for Harmonisation, 
and any applicable regulatory requirements. The investigator should contact the Sponsor or its 
designee immediately if contacted by a regulatory agency about an inspection. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form (ICF), must 
be approved or given a favorable opinion in writing by an IRB or IEC, as appropriate. The 
investigator must submit written approval to the Sponsor or its designee before he or she can 
enroll any subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol, in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. The Sponsor or its designee will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
17.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable with all 
local regulatory requirements. 
17.3. 
Written Informed Consent 
The Principal Investigator(s) at each study site will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risk, and benefit of the 
study. Subjects must also be notified that they are free to discontinue from the study at any time. 
The subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the subject. 
17.4. 
Compliance with the Protocol and Protocol Amendments 
The study shall be conducted as described in this protocol. All revisions to the protocol must be 
prepared by the Sponsor. The Investigator will not implement any deviation or change to the 
protocol without prior review and documented approval/favorable opinion from the IRB/EC of 
an Amendment, except where necessary to eliminate an immediate hazard(s) to study subjects. 
Any significant deviation must be documented and submitted to the IRB/EC; the Sponsor or 
designee; and, if required, Regulatory Authority(ies). 


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Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to the Sponsor and/or designee. 
17.5. 
Study Documentation and the Case Report Form 
The Investigator is responsible for ensuring that data are properly recorded in the eCRFs and on 
related documents. All entries must be supported by the subject’s medical records or source 
notes. The Investigator who has signed the protocol signature page is to ensure that the 
observations and findings are recorded correctly and completely. 
All Investigator observations/assessments must be reported in the eCRF. The original reports and 
any traces and films must be reviewed, signed, and dated and retained by the Investigator for 
future reference. 
An Investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
with the investigational product or entered as a control in the investigation. Data reported in the 
eCRFs that are derived from source documents must be consistent with the source documents or 
the discrepancies must be explained. 
The Investigator must certify that the data are complete and accurate at the time the subject ends 
the study or as instructed by the Sponsor or designee by applying an electronic signature to the 
eCRF study completion page.  
 
 


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18. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
the Sponsor may conduct a quality assurance audit.  
 
 


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19. 
DATA HANDLING AND RECORD KEEPING 
19.1. 
Inspection of Records 
The Sponsor or its designee will be allowed to conduct site visits to the investigation facilities for 
the purpose of monitoring any aspect of the study. The Investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability records, subject charts 
and study source documents, and other records relative to study conduct. 
19.2. 
Retention of Records 
The Investigator must retain study drug disposition records, copies of eCRFs and all study-
related source documents for the maximum period required by applicable regulations and 
guidelines, or Institution procedures, or for the period specified by the Sponsor, whichever is 
longer. The Investigator must contact the Sponsor prior to destroying any records associated with 
the study. Following the study close-out visit, data will be provided to the Investigator to store 
with the Investigator’s study file for archiving purposes. 


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20. 
PUBLICATION POLICY 
Publication rights are addressed in the Investigator and/or CRO agreements, as applicable. 


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21. 
LIST OF REFERENCES 
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receptor-induced inflammation through the transcription factor IRF5 in primary human 
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Dinarello CA. (2018). Overview of the IL-1 family in innate inflammation and acquired 
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Dou H, Song Y, Liu X, et al. (2014). A novel benzenediamine derivate rescued mice from 
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Fraczek J, Kim TW, Xiao H, et al. (2008). The kinase activity of IL-1 receptor-associated kinase 
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Gottlieb A. Bermekimab is a rapid and effective treatment for atopic dermatitis, including 
marked reduction in pruritis. Presented at: 28th European Academy of Dermatology and 
Venereology Congress; Oct. 9-13, 2019; Madrid. 
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Therapeutics in Adult Healthy Volunteers. July 2005. FDA website. 
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Hanel KH, Pfaff CM, Cornelissen C, et al. (2016). Control of the Physical and Antimicrobial 
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Hulshof L, Hack DP, Hasnoe QCJ, et al. (2019). A minimally invasive tool to study immune 
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630. https://doi.org/10.1111/bjd.16994  
Imai Y. (2019). Interleukin-33 in atopic dermatitis. J Dermatol Sci, 96(1), 2-7. 
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Jensen LE. (2010). Targeting the IL-1 family members in skin inflammation. Curr Opin Investig 
Drugs, 11(11), 1211-1220. https://www.ncbi.nlm.nih.gov/pubmed/21157640  
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Kim TW, Staschke K, Bulek K, et al. (2007). A critical role for IRAK4 kinase activity in Toll-
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26(8), 1020-1022. https://doi.org/10.1111/j.1468-3083.2011.04133.x  
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Picard C, von Bernuth H, Ghandil P, et al. (2010). Clinical features and outcome of patients with 
IRAK-4 and MyD88 deficiency. Medicine (Baltimore), 89(6), 403-425. 
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22. 
APPENDICES 
Appendix 1. 
Subject AD Mapping Image