Conditions: Atopic Dermatitis
Keywords: Mild Atopic Dermatitis Moderate Atopic Dermatitis Severe Atopic Dermatitis Mild Eczema Moderate Eczema Severe Eczema
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 421
Healthy volunteers: no

Brief summary:
The purpose of this research study is to determine whether the study drug, EDP1815, is safe and effective in the treatment of atopic dermatitis compared with placebo. The study will look at different doses of the study drug, and whether there are differences when the drug is given once daily or twice daily.

Detailed description:
Atopic dermatitis (atopic eczema) is a very common type of skin disease. It typically causes red, dry, and itchy skin and may have a significant impact on quality of life. Rashes may appear on the arms and behind the knees, or anywhere else on the body. While there are existing therapies, there is currently no cure for atopic dermatitis.

This is a randomized, double blind, placebo controlled, parallel group, Phase 2 study to evaluate the efficacy and safety of EDP1815 in adult participants 18 to ≤75 years of age with mild, moderate, and severe atopic dermatitis (AD).

Participants will be screened within 28 days prior to the first dose of study intervention to confirm study eligibility. Subjects must have mild, moderate, or severe AD involving at least 5% Body Surface Area (BSA); an Investigator Global Assessment (IGA) score of 2, 3, or 4; and an Eczema Area Severity Index (EASI) of at least 6 at screening and Day 1.

All participants must agree to use a background therapy (per protocol) twice daily for at least 14 days prior to Day 1 in order to be considered eligible for the study.

Approximately 405 participants will be randomized to receive either EDP1815 or placebo (295 to EDP1815: 110 to placebo) and treated for 16 weeks. Participants in Cohorts 1, 2, \& 3 will be randomized in a 3:1 ratio (225 to EDP1815: 75 to placebo). Participants in Cohort 4 will be randomized in a 2:1 ratio (70 to EDP1815: 35 to placebo). Cohorts 1, 2 \& 3 will be run concurrently, and Cohort 4 recruitment will commence after enrollment for Cohorts 1, 2, \& 3 are completed.

Randomization will be stratified by baseline disease severity (mild \[IGA = 2\], moderate \[IGA = 3\] or severe \[IGA = 4\] AD). The investigational product will be administered either once or twice daily for 16 weeks. Background emollient (moisturizer) therapy must continue at least twice daily for the duration of the treatment and follow-up periods. Topical rescue therapy is allowed during the treatment period per protocol.

The primary efficacy endpoint is achievement of an EASI-50 response at Week 16. Secondary efficacy endpoints will look at EASI, IGA, BSA, SCORAD, DLQI, Pruritus-NRS, Sleep Disturbance-NRS, POEM, and the need for rescue therapy at Weeks 4, 8, 12 and 16 (unless otherwise specified in the protocol). Safety and efficacy assessments will be conducted at the investigator site by a clinical assessor blinded to treatment assignment. Scheduled clinic study visits for all subjects will occur at Screening, Day 1, Week 2, Week 4, Week 8, Week 12, Week 16 (end of treatment) and Week 20 (post-treatment follow-up). Participants discontinuing early from the study will undergo a 28-day follow-up period, where possible.

At the end of the 16-week study treatment, qualified participants completing the study will have the option to enter an open label study.

Arms:
arm 1: 100 participants with mild, moderate or severe Atopic Dermatitis 75 participants on EDP1815 and 25 participants on matching placebo administered as 2 capsules (1.6 x 10\^11 total cells) once daily for 16 weeks arm 2: 100 participants with mild, moderate or severe Atopic Dermatitis 75 participants on EDP1815 and 25 participants on matching placebo administered as 2 capsules (6.4 x 10\^11 total cells) once daily for 16 weeks arm 3: 100 participants with mild, moderate or severe Atopic Dermatitis 75 participants on EDP1815 and 25 participants on matching placebo administered as 1 capsule (3.2 x 10\^11 cells) twice daily (6.4 x 10\^11 total cells) for 16 weeks arm 4: 105 participants with mild, moderate or severe Atopic Dermatitis 70 participants on EDP1815 and 35 participants on matching placebo administered at 1 capsule (8.0x10\^10 total cells) once daily for 16 weeks

Interventions: intervention 1: EDP1815 intervention 2: Placebo
Intervention descriptions: intervention 1: EDP1815 is an orally administered, pharmaceutical preparation of a single strain of bacteria intervention 2: Placebo oral capsule

Protocol document:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
NCT05121480 
 
 
A PHASE 2, MULTICENTER, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTIPLE-COHORT STUDY 
INVESTIGATING THE EFFECT OF EDP1815 IN 
PARTICIPANTS FOR THE TREATMENT OF MILD, 
MODERATE AND SEVERE ATOPIC DERMATITIS 
 
PROTOCOL EDP1815-207 
Version 5.0 / 24 April 2022 


 
 
PROTOCOL EDP1815-207 
A PHASE 2, MULTICENTER, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTIPLE-COHORT STUDY 
INVESTIGATING THE EFFECT OF EDP1815 IN 
PARTICIPANTS FOR THE TREATMENT OF MILD, 
MODERATE AND SEVERE ATOPIC DERMATITIS 
PHASE 2 
EudraCT Number: 2021-001805-63 
IND Number: 27698 
Sponsor 
EVELO Biosciences, Inc. 
Cambridge, MA, 02139 
USA 
Protocol/Amendment number 
Date 
Type of 
amendment 
Protocol 5.0  
25 April 2022 
Global 
 
 






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Table of Contents 
LIST OF ABBREVIATIONS .................................................................................................... 9 
PROTOCOL SUMMARY ....................................................................................................... 11 
1. 
INTRODUCTION ........................................................................................................... 13 
1.1. Atopic Dermatitis ............................................................................................................. 13 
1.2. Previous Experience with EDP1815 and Rationale for Treating Atopic Dermatitis ....... 14 
2. 
STUDY OBJECTIVE(S) ................................................................................................. 17 
2.1. Primary Objectives ........................................................................................................... 17 
2.2. Secondary Objectives ....................................................................................................... 17 
2.3. Exploratory Objectives .................................................................................................... 18 
3. 
STUDY VARIABLES ..................................................................................................... 19 
3.1. Efficacy Variable(s) ......................................................................................................... 19 
3.1.1. 
Primary Efficacy Variable(s) ............................................................................... 19 
3.1.2. 
Secondary Efficacy Variable(s) ........................................................................... 19 
3.2. Pharmacokinetic and Pharmacodynamic Variable(s) ...................................................... 20 
3.3. Safety Variables ............................................................................................................... 20 
3.4. Exploratory Variables ...................................................................................................... 20 
4. 
STUDY DESIGN ............................................................................................................. 22 
4.1. Study Description ............................................................................................................. 22 
4.2. Study Duration per Participant ......................................................................................... 22 
4.3. Planned Number of Participants ...................................................................................... 23 
4.4. Anticipated Regions and Countries ................................................................................. 23 
4.5. Schedule of Study Assessments ....................................................................................... 24 
4.6. Schematic Study Diagram ................................................................................................ 28 
4.7. Rationale for study design and selection of dose ............................................................. 29 
4.7.1. 
Placebo Rationale ................................................................................................ 29 
4.7.2. 
Dose Rationale ..................................................................................................... 29 
5. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS .......................................... 31 
5.1. Inclusion criteria .............................................................................................................. 31 
5.2. Exclusion criteria ............................................................................................................. 32 
5.3. Screen Failures ................................................................................................................. 34 
5.3.3. 
Rescreening .......................................................................................................... 34 
5.4. Discontinuation from Treatment and/or Withdrawal ....................................................... 34 
5.4.1. 
Withdrawal from the Study ................................................................................. 36 
5.4.2. 
Lost to Follow-Up ................................................................................................ 36 
6. 
STUDY TREATMENT(S) .............................................................................................. 37 
6.1. Investigational Medicinal Product(s) ............................................................................... 37 
6.2. Investigational Medicinal Product(s) to be Administered ............................................... 37 




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8.2. Validated Investigator’s Global Assessment ................................................................... 53 
8.3. SCORing Atopic Dermatitis ............................................................................................ 53 
8.4. Patient Oriented Eczema Measure ................................................................................... 54 
8.5. Dermatology Life Quality Index ...................................................................................... 54 
8.6. Peak Pruritus Numerical Rating Scale (PP-NRS) ............................................................ 54 
8.7. Sleep Disturbance Numerical Rating Scale (SD-NRS) ................................................... 54 
8.8. Body Surface Area ........................................................................................................... 54 
8.9. 12-Item Short Form Health Survey .................................................................................. 54 
8.10. 
Hospital Anxiety and Depression Scale ................................................................. 55 
8.11. 
Atopic Dermatitis Control Tool ............................................................................. 55 
9. 
SAFETY ASSESSMENTS .............................................................................................. 56 
9.1. Adverse Events ................................................................................................................ 56 
9.1.1. 
Adverse Events of Special Interest ...................................................................... 56 
9.2. Adverse Drug Reactions .................................................................................................. 56 
9.3. Serious Adverse Events ................................................................................................... 56 
9.4. Reporting and Recording AEs ......................................................................................... 57 
9.4.1. 
Assessment of AEs .............................................................................................. 58 
9.4.2. 
Assessment of Severity ........................................................................................ 58 
9.4.3. 
Assessment of Causality ...................................................................................... 59 
9.4.4. 
Description of Adverse Events ............................................................................ 59 
9.4.4.1. 
Rule for Repetition of an AE ..................................................................... 59 
9.5. Reporting Serious Adverse Events .................................................................................. 60 
9.5.5. 
Follow Up of Adverse Events .............................................................................. 60 
9.6. Pregnancy ......................................................................................................................... 60 
9.7. Overdose .......................................................................................................................... 61 
9.8. Safety Signal Detection .................................................................................................... 61 
9.9. Study Halting Criteria ...................................................................................................... 61 
9.10. 
Laboratory Measurements ..................................................................................... 62 
9.10.1. 
Review of Laboratory Measurements .................................................................. 63 
9.10.2. 
Blood Volumes .................................................................................................... 63 
9.11. 
Biomarkers ............................................................................................................. 63 
9.11.1. 
Genetic Testing .................................................................................................... 63 
9.11.2. 
Immune Protein Markers ..................................................................................... 64 
9.11.3. 
Transcription Analysis ......................................................................................... 64 
9.11.4. 
Microbiome Sample ............................................................................................. 64 
9.12. 
Other Safety Measurements ................................................................................... 64 
9.12.1. 
Vital Signs, Height and Weight ........................................................................... 64 
9.12.2. 
Physical Examination .......................................................................................... 64 


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9.12.3. 
12-Lead Electrocardiogram ................................................................................. 65 
9.13. 
Non-Safety Measurements ..................................................................................... 65 
9.13.1. 
Digital Photography ............................................................................................. 65 
10. STUDY MANAGEMENT AND ADMINISTRATION ................................................. 66 
10.1. 
Adherence to protocol ............................................................................................ 66 
10.2. 
Monitoring ............................................................................................................. 66 
10.2.1. 
Definition of Source Data .................................................................................... 66 
10.2.2. 
Source Data Verification ..................................................................................... 67 
10.3. 
Data Management .................................................................................................. 67 
10.3.1. 
Data Quality Assurance ....................................................................................... 67 
10.3.2. 
Case Report Form Completion ............................................................................ 68 
10.3.3. 
Data Entry and Reconciliation ............................................................................. 68 
10.3.4. 
Participant Screening & Enrollment Log/Participant Identification Code List ... 68 
10.4. 
Termination of the Study ....................................................................................... 69 
10.5. 
Archiving and Data Retention ............................................................................... 69 
10.6. 
Audit and Inspection .............................................................................................. 69 
10.7. 
Good Clinical Practice ........................................................................................... 70 
11. STATISTICS ................................................................................................................... 71 
11.1. 
Definition of Analysis Sets .................................................................................... 71 
11.1.1. 
Participant Analysis Sets ..................................................................................... 71 
11.1.2. 
Defined Data Point Sets ....................................................................................... 71 
11.2. 
General Statistical Considerations ......................................................................... 72 
11.3. 
Estimands and Intercurrent Events ........................................................................ 74 
11.3.1. 
Primary Estimand and Supplementary Estimands of the Primary Objective ...... 74 
11.3.2. 
Secondary Estimands ........................................................................................... 76 
11.3.3. 
Exploratory Efficacy Estimands .......................................................................... 77 
11.3.4. 
Safety Estimands ................................................................................................. 79 
11.4. 
Planned Analyses ................................................................................................... 79 
11.4.1. 
Analysis of Primary Estimand ............................................................................. 79 
11.4.2. 
Analysis of Supplementary Estimands on the Primary Objective ....................... 80 
11.4.3. 
Cohort 4 Sensitivity Analysis of the Primary Estimand ...................................... 80 
11.4.4. 
Analysis of Secondary Estimands ....................................................................... 80 
11.4.5. 
Analysis of Exploratory Estimands ..................................................................... 81 
11.4.6. 
Analysis of Safety Estimands .............................................................................. 82 
11.4.7. 
Other Analyses ..................................................................................................... 82 
11.5. 
Handling of Protocol Deviations ........................................................................... 82 
11.6. 
Handling of Dropouts or Missing Data .................................................................. 82 
11.7. 
Planned Interim Analysis and Data Monitoring .................................................... 82 


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11.8. 
Determination of Sample Size ............................................................................... 83 
12. ETHICS AND REGULATORY REQUIREMENTS ...................................................... 85 
12.1. 
Informed Consent................................................................................................... 85 
12.2. 
Participant Identification Cards ............................................................................. 85 
12.3. 
Institutional Review Boards and Independent Ethics Committees ........................ 85 
12.4. 
Participant Privacy ................................................................................................. 86 
12.5. 
Protocol Amendments ............................................................................................ 87 
12.6. 
Insurance ................................................................................................................ 87 
12.7. 
Financial Disclosures ............................................................................................. 87 
12.8. 
Publications ............................................................................................................ 87 
12.8.1. 
Dissemination of Clinical Study Data ................................................................. 87 
13. REFERENCES ................................................................................................................ 88 
14. APPENDICES ................................................................................................................. 91 
14.1. 
Hanifin and Rajka (1980) Criteria for Diagnosis of Atopic Dermatitis ................. 91 
14.2. 
Classification of Potency of Topical Corticosteroids ............................................ 92 
14.3. 
Contraceptive Guidance and Collection of Pregnancy Information ...................... 93 
14.4. 
EDP1815 COVID-19 Risk Assessment ................................................................. 96 
14.5. 
Toxicity Grading Scale ........................................................................................ 101 
15. DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 103 
16. SPONSOR DECLARATION ........................................................................................ 104 
17. PROTOCOL AMENDMENTS ..................................................................................... 105 
                                                                                                      
LIST OF TABLES 
Table 4-1:Schedule of Assessments......................................................................................... 24 
Table 6-1: IMP to be Administered ......................................................................................... 38 
Table 11-1: 
Intercurrent Event Strategies for the Primary and Supplementary 
Estimands ......................................................................................................... 75 
Table 11-2: Secondary Estimand Details ................................................................................. 77 
Table 11-3: Exploratory Estimand Details .............................................................................. 78 
Table 11-4: Safety Endpoint Details ........................................................................................ 79 
Table 14-1: 
Highly Effective Contraceptive Methods ........................................................ 94 
        
LIST OF FIGURES 
Figure 4-1: Schematic Diagram ............................................................................................... 28 
  


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LIST OF ABBREVIATIONS 
AD 
Atopic Dermatitis 
ADCT 
Atopic Dermatitis Control Tool 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
APP 
Application 
AST 
Aspartate Aminotransferase 
BSA 
Body Surface Area 
CDMS 
Clinical Data Management System 
CI 
Confidence Intervals 
CPM 
Clinical Project Manager 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DLQI 
Dermatology Life Quality Index 
DNA 
Deoxyribonucleic Acid 
DPS 
Data Point Set 
EC1 or EC2 
Enteric Coating 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA/EMEA 
European Medicines Agency 
EASI 
Eczema Area and Severity Index 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 


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IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LS 
Least Squares Mean Estimate 
mL 
Milliliter 
MMRM 
Mixed Model for Repeated Measures 
OLE 
Open Label Extension 
PBMC 
Peripheral Blood Mononuclear Cell 
PP-NRS 
Peak Pruritus Numerical Rating Scale 
RNA 
Ribonucleic Acid 
SD-NRS 
Sleep Disturbance Numerical Rating Scale 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SF-12 
12-Item Short Form Health Survey 
SLS 
Sodium Lauryl Sulfate 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
TMF 
Trial Master File 
ULN 
Upper Limit of Normal 
vIGA or IGA 
Validated Investigator Global Assessment 
WGS 
Whole Genome Sequencing 
WOCBP 
Woman of Child-Bearing Potential 


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PROTOCOL SUMMARY 
 
Study Objectives: The primary objective is to show superiority of EDP1815 over placebo in the 
treatment of atopic dermatitis.  The secondary objectives are to further evaluate the efficacy, safety 
and tolerability of EDP1815.  Exploratory objectives aim to evaluate the best daily dose and 
frequency of dosing for EDP1815 in the treatment of atopic dermatitis, the time to onset of clinical 
response to EDP1815 and the effect of EDP1815 treatment on blood biomarkers. 
 
Primary endpoint: The Eczema Area and Severity Index (EASI) will be utilized to measure the 
extent and severity of a participant’s atopic dermatitis.  The percentage of participants achieving 
EASI-50 (percentage of participants with a ≥ 50% reduction in EASI score from baseline) at Week 
16 will be utilized to evaluate the efficacy of EDP1815 over placebo. Participants requiring use of 
topical corticosteroid rescue therapy less than 28 days before the Week 16 visit or who withdraw 
from the study prior to the Week 16 visit for reasons considered related to study treatment will be 
considered as non-responders.  
 
Secondary endpoints:  The EASI Score will also be utilized to measure other aspects of clinical 
benefit of EDP1815 in the treatment of atopic dermatitis.  In addition to EASI, the Validated 
Investigator’s Global Assessment (vIGA), the body surface area (BSA) of skin affected by atopic 
dermatitis, the SCORing Atopic Dermatitis (SCORAD), the use of Rescue Medications, the 
Dermatology Life Quality Index (DLQI), the Peak Pruritus Numerical Rating Scale (PP-NRS), the 
Sleep Disturbance Numerical Rating Scale (SD-NRS) and the Patient Oriented Eczema Measure 
(POEM) will be measured throughout the study.  
 
The severity and frequency of Adverse Events will be used to evaluate the safety and tolerability 
of EDP1815. 
 
Exploratory endpoints: A number of exploratory endpoints will be evaluated to determine further 
aspects of treatment efficacy including time to achieve clinical response and patient reported health 
outcomes.  Changes in eosinophils, immune protein markers and immune cell RNA profile will be 
used to evaluate the effect of EDP1815 treatment on biomarkers in blood. A fecal sample will be 
used for microbiome profiling. Human Leukocyte Antigen (HLA) typing will be performed in 
those participants who consent to assess the correlation with clinical outcomes.  
 
Brief Study Design: This study will evaluate EDP1815 in participants with mild, moderate, and 
severe atopic dermatitis, to compare efficacy, safety, and tolerability to placebo. The 
Investigational Medicinal Product (IMP) is EDP1815 or matching placebo. The study will be 
blinded to the participants, Investigator, and Sponsor.   
 
Approximately 405 participants will be randomized to receive either EDP1815 or placebo (295 to 
EDP1815: 110 to placebo) and treated for 16 weeks.  Following end-of-treatment assessments, 
participants may enter a 4-week post-treatment follow-up period or may elect to participate in an 
Open Label Extension (OLE) Protocol for EDP1815, if available.  Cohorts 1, 2 & 3 will be run 
concurrently, and Cohort 4 recruitment will commence after enrollment for Cohorts 1, 2, & 3 are 
completed. 
 


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Participants will be dosed with EDP1815 or matching placebo administered as the following: 
 
• 
Cohort 1: 1.6x1011 total cells of EDP1815 or matching placebo administered as 2 capsules 
once daily. 
 
• 
Cohort 2: 6.4x1011 total cells of EDP1815 or matching placebo administered as 2 capsules 
once daily. 
 
• Cohort 3: 6.4x1011 total cells of EDP1815 or matching placebo administered as 1 capsule 
of 3.2x1011 cells twice daily. 
 
• 
Cohort 4: 8.0x1010 total cells of EDP1815 or matching placebo administered as 1 capsule 
once daily. 
 
Participants in Cohorts 1, 2, & 3 will be randomized in a 3:1 ratio (225 to EDP1815: 75 to placebo). 
Participants in Cohort 4 will be randomized in a 2:1 ratio (70 to EDP1815: 35 to placebo). 
Randomization to Cohort 4 will not start before randomization to Cohorts 1, 2 & 3 have completed. 
  
An interim analysis may be performed just before the end of recruitment to Cohorts 1, 2 & 3 to 
check the assumptions used for the sample size calculation and to ensure that there is no imbalance 
between treatment groups caused by incomplete randomization blocks.  
 
The data collected for Cohorts 1, 2 & 3 may also be locked and analyzed prior to the completion 
of Cohort 4. 
 
Study Duration: The maximum study duration is up to 24 weeks for all participants.  Following 
informed consent, participants will have up to a 4-week screening period, followed by a 16-week 
treatment period and a post treatment follow-up visit 4 weeks later. Should a participant elect to 
participate in the Open Label Extension (OLE protocol), their study duration during this study 
would be a maximum of 20 weeks. 
 
 
 
 


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1. INTRODUCTION 
 
1.1. 
Atopic Dermatitis 
Atopic dermatitis (AD), also known as (atopic) eczema, is a chronic, highly symptomatic relapsing 
inflammatory skin disease, affecting up to 30% of children and 10% of adults (Bieber, Atopic 
Dermatitis, 2010).  While AD often begins in infancy or childhood, it may become chronic and 
persist into adulthood (Katoh, 2019). Depending on factors such as severity of skin lesions or body 
surface area coverage, the disease can be classified clinically as mild, moderate, or severe. 
 
Patients with AD typically have highly symptomatic skin lesions that may present acutely with 
erythema, exudates, papulovesicles, scales and crusts, often symmetrically distributed on the body 
(Katoh, 2019).  The disease typically follows a variable course with acute flares, often triggered 
by external factors, which cause a worsening of skin disease and symptoms. More chronic lesions 
are associated with thickened lichenified skin which may be accompanied by pigmentary changes 
and further excoriations (Bieber, Atopic Dermatitis, 2010). The primary symptom at both stages 
of disease is typically pruritus (itch). Such signs and symptoms are associated with a substantial 
patient burden that typically includes sleep disturbance, mood disturbance and mental health 
problems (Simpson, 2012), poor quality of life, and social functioning (Kiebert, 2002). 
 
AD, like other atopic disease, is characterized by a T helper type 2 (Th2) cell-mediated 
inflammation, with up-regulation of Th2 cytokines including IL-4, IL-5, and IL-13 (Indra, 2013). 
In turn, this leads to increased IgE production by B-cells, which can trigger release of cytokines 
and chemical mediators such as histamine from mast cells and Langerhans cells. In addition, 
thymic stromal lymphoprotein is thought to be a critical cytokine in the triggering and maintenance 
of AD (Indra, 2013), and is associated with migration of Th2 cells into the skin lesion (Katoh, 
2019). The resulting systemic inflammation drives the disease pathology and patient symptoms, 
with the resultant scratching of pruritic lesions further worsening the skin lesions and the skin 
barrier function, further driving the disease process. Therefore, targeting systemic inflammation 
improves disease signs and symptoms – for example systemic corticosteroids typically lead to 
rapid clinical improvements, but generally are not acceptable as a long-term treatment due to 
associated side-effects (Lee, 2016). 
 
In general, treatment of AD is aimed at a combination of resolution of skin disease and 
improvement of symptoms such as itch (acute therapy), and also prevention of further flares 
(maintenance therapy). Emollients, also known as moisturizers, are the first-line and baseline 
therapy for all severities of disease, and act by treating the defective skin barrier and providing 
cutaneous hydration (Lee, 2016). There are a number of other topical treatments including topical 
corticosteroids (TCS) and topical calcineurin inhibitors (TCI) (Katoh, 2019). Unfortunately, there 
are associated problems with such treatments including adverse effects, limitations in efficacy, and 
low patient acceptability and tolerability, particularly when used as chronic treatment options. 
 
In the US, there are currently no licensed oral treatments for atopic dermatitis; while in the 
European Union, only ciclosporin is licensed as an oral treatment. Due to its associated risks and 
side-effects, such as renal failure, ciclosporin is generally only recommended for short-term use 
(Katoh, 2019). Other anti-inflammatory treatments, such as methotrexate or azathioprine, are 
therefore used off license in order to reduce the Th2-driven systemic inflammation. These systemic 


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treatments all have associated risks and side-effects and are therefore not suitable for a large 
population of patients, including many of those with mild and moderate disease. Finally, for 
patients with moderate-to-severe disease, Dupixent (dupilumab) is now licensed as a biologic 
injectable treatment and is currently used to treat a small proportion of patients with such disease 
severity. 
 
A 2016 patient survey (National Eczema Association, 2016) highlights and summarizes what it is 
like for patient living with atopic dermatitis: 
• 84% are “very” or “extremely” bothered by dry skin, 83% by itch, and 63% by rash/redness 
• 75% stated AD interferes with their job and house chores, 71% say it interferes with 
hobbies, and 65% don’t feel as healthy because of AD 
• Nearly half of people with moderate to severe AD report their disease “interferes with their 
social life, intimate relations, and relationships with their spouse and children” 
• 1 in 3 takes one or more hours per day to treat their AD 
• More than half are dissatisfied overall with each of the following treatments that they are 
using or have used: topical steroids, topical calcineurin inhibitors, phototherapy, and oral 
medications 
 
The conclusion from this study was that there is a “lack of safe and effective treatments” for AD, 
allowing for “unchecked symptoms [which] contribute to the range of health issues”. This sums 
up the unmet need for and importance of further oral treatments for AD. 
 
1.2. 
Previous Experience with EDP1815 and Rationale for Treating Atopic 
Dermatitis 
Evelo Biosciences, Inc. (Evelo) is developing orally administered biologic medicines based on a 
new understanding of how immunity and inflammation are controlled. Evelo’s medicines are 
selected for their ability to modulate the small intestinal axis (SINTAX™). This is the network of 
anatomical and functional connections that has evolved to link the small intestine and the rest of 
the body. It links small intestinal mucosal immunology with systemic inflammation and is 
accessible with oral SINTAX medicines. 
 
The inflammatory control mechanisms of SINTAX down-regulate multiple inflammatory 
pathways including those which have been validated with targeted antibody therapies, but without 
the side effects seen with antibody therapeutics or broadly acting oral kinase inhibitors. This occurs 
via specific interactions between the oral SINTAX therapy and small intestine enterocytes and 
immune cells. These interactions drive the development of an immune-regulatory subset of 
lymphocytes that travel from the gut to the systemic circulation, via the mesenteric lymph nodes. 
Here, these circulating cells mediate their effects on peripheral inflammation at the target sites 
(e.g., atopic dermatitis skin). 
 
EDP1815 is a pharmaceutical preparation of a single strain of Prevotella histicola, originally 
isolated from a duodenal biopsy. The drug substance is essentially non-viable and non-replicating, 
with a cell viability of <0.02%. It has not been genetically modified. It does not colonize the gut 
nor alter the microbiome and has no detectable systemic exposure following oral dosing to date – 
i.e., it is gut-restricted. 
 


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Prevotella as a genus are gram-negative, obligate anaerobic bacteria that are natural human 
commensals found in the oral cavity and gastrointestinal (GI) tract. Strains of Prevotella have been 
found in all human populations tested to date, at abundances ranging from <1% to nearly 50% of 
total fecal microbial load (Vandeputte, Kathagen, & D'hoe, 2017). 
 
In vitro studies of EDP1815 in human and mouse cellular assays and in vivo models support its 
use in the treatment of immunoinflammatory diseases, including atopic dermatitis. Oral 
administration of EDP1815 to mice led to striking therapeutic effects on delayed-type 
hypersensitivity (DTH), imiquimod-induced skin inflammation, fluorescein isothiocyanate (FITC) 
cutaneous hypersensitivity, collagen-induced arthritis (CIA) (Marietta, Murray, & Luckey, 2016) 
and experimental acute encephalomyelitis (EAE) (Mangalam, Shahi, & Luckey, 017) in-vivo 
models. EDP1815 was shown to down-regulate key Th2-related cytokines including IL-4 and IL-
31. No potentially related adverse effects were seen in the animals used in these experiments with 
daily dosing for up to 3 weeks, or alternate day dosing for over 7 weeks. Ex vivo 
immunophenotyping in these models shows increased regulatory T cell numbers and regulatory 
dendritic cells (DCs) in spleen and mesenteric lymph nodes, as well as decreases in pro-
inflammatory cytokines such as IL-23 p40, IL-17, and IL-13. EDP1815 does not suppress the 
expression of Type1 interferons in these ex vivo experiments, suggesting that the broad spectrum 
of anti-inflammatory effects is achieved without damaging mechanisms of immune surveillance 
critical for avoiding cancers and pathogens. Treatment also led to enhancement of gut intestinal 
barrier integrity, which is often disrupted in patients with inflammatory diseases. The effects on 
immune parameters have been observed both within and outside of the GI tract, which 
demonstrates that host-microbe interactions in the gut can affect the immune response in peripheral 
tissues.  
 
This pre-clinical data therefore supported advancing EDP1815 into the treatment of atopic 
dermatitis, due to the resolution of systemic inflammation including in models of Th2-driven 
disease, and the reduction of Th2-dervied cytokines that are known to drive the pathophysiology 
of atopic dermatitis. 
 
Clinical data is accumulating that supports both the role of the small intestinal axis in humans and 
that it can be harnessed by EDP1815 as a potent modulator of systemic inflammation, in Th1, Th2 
and Th17 inflammation. As of September 2021, a total of 623 adult participants have been exposed 
to EDP1815 or placebo.  A total of 458 participants received EDP1815: 54 healthy volunteers, 234 
patients with mild to moderate psoriasis, 48 patients with mild to moderate AD and 122 patients 
with COVID-19 infection. A total of 165 subjects received placebo: 16 healthy volunteers, 117 
patients with mild to moderate psoriasis, 24 patients with mild to moderate AD and 8 patients with 
COVID 19 infection.  To date, EDP1815 is well tolerated with a safety profile comparable to 
placebo – there are no AEs of special interest and no related serious adverse events have been seen. 
 
In the phase 1b study EDP1815-101, 16 participants in cohort 7 were treated with EDP1815 
capsules at a dose of 8.0 x 1011 cells once daily for 8 weeks, with a further 8 participants given 
matching placebo. Clinically meaningful and significant responses were observed at the end of the 
treatment period, in terms of the changes in EASI, vIGA*BSA and SCORAD, as well as within 
the patient-reported outcomes, which also found improvements in itch and sleep scores.  
 


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The available evidence to date has found EDP1815 to be very well tolerated with evidence for 
proof of concept as an effective treatment for atopic dermatitis. A well tolerated oral therapy could 
offer significant benefit in atopic dermatitis for all severities of disease.  
 


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2. STUDY OBJECTIVE(S) 
 
2.1. 
Primary Objectives 
The study will compare four treatment regimens of EDP1815 with placebo in participants with 
atopic dermatitis who are using twice daily topical emollients.  
 
The primary comparison of interest is the odds ratio for achievement of an EASI-50 response at 
Week 16. The primary trial objective is to show superiority of EDP1815 over placebo. 
 
The primary comparison will be made using a treatment policy strategy with respect to study 
medication but without regard to treatment compliance or any changes in background therapy.  A 
composite strategy will be used with respect to use of topical corticosteroid rescue therapy with 
any participants who use these less than 28 days prior to the Week 16 assessment being considered 
as non-responders. A composite strategy will also be used for participants who withdraw from the 
study prior to the Week 16 visit for reasons relating to study medication (e.g., related adverse 
event, lack of efficacy, requirement of for alternative therapy) also being considered as non-
responders. A ‘while on treatment’ strategy will be used for participants who withdraw from the 
study prior to Week 16 for reasons considered unrelated to study medication, with the achievement 
of response at Week 16 being considered missing.  
 
A number of supportive analyses to check the robustness of the primary estimand approach will 
be performed. These will consider  
• Topical corticosteroid rescue therapy in the window of 2-4 weeks prior to study 
medication as having no effect and using the composite strategy only for use less than 14 
days prior to the Week 16 visit 
• Using a ‘while on treatment’ strategy for rescue medications with any Week 16 data 
collected less than 28 days after rescue medication use being considered missing. 
• Using a ‘while on treatment’ strategy for discontinuation of the study for any reason before 
Week 16. 
• Using a principal stratum strategy excluding participants who are non-compliant with 
respect to study medication or emollient use (<75% compliance), use a prohibited 
background therapy, take at least one dose of the incorrect study medication or who are 
unblinded prior to the end of the study. 
• Using an alternative composite strategy for topical corticosteroid rescue therapy, with all 
participants who use any topical corticosteroid therapy at any time between Day 1 and 
Week 16 considered as non-responders at the Week 16 visit. 
 
2.2. 
Secondary Objectives 
The secondary objectives of this study are the following:  
 
1. To evaluate the clinical benefit of EDP1815 in the treatment of atopic dermatitis. 
 
2. To evaluate the safety and tolerability of EDP1815. 
 


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These objectives will be evaluated using a treatment policy approach with respect to study 
medication and a composite approach with respect to use of topical corticosteroid rescue therapy 
within 4 weeks.  Full details can be found in Section 11 Statistics.  
 
2.3. 
Exploratory Objectives 
The exploratory objectives of this study are the following: 
 
1. To evaluate the time to onset of clinical response to EDP1815. 
 
2. To evaluate the most effective dose and dosing frequency of EDP1815 in the treatment of 
atopic dermatitis. 
 
3. To evaluate the effect of EDP1815 on patient reported outcomes. 
 
4. To evaluate the effect of early use of rescue therapy on Week 16 responder status. 
 
5. To evaluate the relationship of EDP1815 treatment with biomarkers such as immune 
protein markers, eosinophils, and immune cell RNA profile in blood. 
 
6.  To evaluate correlation of genetic markers and EDP1815 treatment outcomes.  
 
7. To evaluate correlation of gut microbiome and EDP1815 treatment outcomes. 
 
 


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3. STUDY VARIABLES 
 
3.1. 
Efficacy Variable(s) 
3.1.1. 
Primary Efficacy Variable(s) 
The primary efficacy endpoint is achievement of an EASI-50 response at Week 16.  
 
3.1.2. 
Secondary Efficacy Variable(s) 
The following secondary endpoints will be evaluated at Weeks 4, 8, 12 and 16 (unless otherwise 
specified) to evaluate the maximum clinical benefit of EDP1815 in the treatment of atopic 
dermatitis: 
 
• Percentage of Participants Achieving EASI-50 [Time Frame: Week 4, 8 and 12] 
• Percentage of Participants Achieving EASI-75  
• Percentage of Participants Achieving EASI-90  
• Mean absolute change and percentage change from baseline in EASI Score  
 
• Percentage of Participants Achieving Investigator's Global Assessment (vIGA) of 0 or 1 
with a ≥2 Point Improvement from baseline  
• Percentage of Participants Achieving vIGA of 0 or 1 
• Percentage of Participants Achieving vIGA of 0 [Time Frame: Week 16] 
• Mean absolute change and percentage change from baseline in vIGA*BSA  
• Mean absolute change and percentage change from baseline in BSA 
• Percentage of Participants Achieving BSA-50 
• Percentage of Participants Achieving BSA-75 
• Percentage of Participants Achieving BSA reduction to 3% BSA or less 
 
• Mean absolute change and percentage change from baseline in SCORing Atopic Dermatitis 
(SCORAD)  
• Percentage of Participants Achieving SCORAD-50  
• Percentage of Participants Achieving SCORAD-75  
 
• Mean absolute change and percentage change from baseline in DLQI  
• Percentage of Participants achieving a reduction of ≥4 in the DLQI, of those with a score 
of ≥4 at baseline [Time Frame: Week 16] 
 
• Mean absolute change from baseline in worst Pruritus-NRS  
• Percentage of Participants achieving a reduction of ≥2 in the worst Pruritus-NRS, of those 
with a score of ≥2 at baseline  
• Percentage of Participants achieving a reduction of ≥4 in the worst Pruritus-NRS, of those 
with a score of ≥4 at baseline [Time Frame: Week 16] 
 
• Mean absolute change from baseline in SD-NRS score  
• Percentage of Participants achieving a reduction of ≥2 in SD-NRS score, of those with a 
score of ≥2 at baseline [Time Frame: Week 16] 
 


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• Mean absolute change and percentage change from baseline in Patient Oriented Eczema 
Measure (POEM)  
• Percentage of Participants achieving a reduction of ≥4 in the POEM score, of those with a 
score of ≥4 at baseline [Time Frame: Week 16] 
 
• Number of courses of rescue therapy per Participant  
• Number of days of treatment with rescue therapy per Participant  
• Proportion of participants not requiring rescue therapy  
 
For secondary estimands, a treatment policy approach will be used with respect to study 
medication and a composite approach will be used for data collected within 28 days of rescue 
medication use and withdrawal from the study for reasons related to study treatment. 
 
3.2. 
Pharmacokinetic and Pharmacodynamic Variable(s) 
EDP1815 has no systemic absorption and therefore no systemic exposure. Therefore, no samples 
for pharmacokinetic analysis will be performed in this study.  
 
3.3. 
Safety Variables 
The severity and frequency of adverse events will be used to evaluate the safety and tolerability of 
EDP1815.  Vitals signs, weight, physical examinations, clinical laboratory tests, ECG and use of 
concomitant medications will also be used to evaluate the safety and tolerability of EDP1815. 
 
3.4. 
Exploratory Variables 
The following endpoints will be used to evaluate the time to onset of clinical response to EDP1815: 
• Time to first achievement of EASI-50 
• Time to first achievement of sustained* EASI-50 
• Time to first achievement of IGA of 0 or 1 with a 2-point improvement from baseline 
• Time to first achievement of a ≥2 point in improvement in PP-NRS score, in participants 
with a score of ≥2 at baseline 
• Time in days to first sustained** ≥2 point in improvement in PP-NRS score, in participants 
with a score of ≥2 at baseline 
• Time to first achievement of a ≥4 point in improvement in PP-NRS score, in participants 
with a score of ≥4 at baseline 
• Time in days to first sustained** ≥4 point in improvement in PP-NRS score, in participants 
with a score of ≥4 at baseline 
• Time to first achievement of a ≥2 point in improvement in SD-NRS score, in participants 
with a score of ≥2 at baseline 
• Time in days to first sustained** ≥2 point in improvement in SD-NRS score, in participants 
with a score of ≥2 at baseline 
* Sustained EASI-50 response is defined as one which is present on at least two consecutive visits. 
** Sustained PP-NRS or SD-NRS response is one which is present at all days where the diary is 
completed in a minimum of a 14-day period 
 
The following endpoints will be used to evaluate other aspects of the efficacy of EDP1815 as a 
treatment for atopic dermatitis at Weeks 4, 12 and 16 unless otherwise specified: 


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• Percentage of Participants Achieving Investigator's Global Assessment (vIGA) of 0 or 1 
with a ≥2 Point Improvement from screening  
• Mean absolute change and percentage change from Screening in EASI Score   
• Percentage of Participants developing skin infections requiring topical or systemic 
antibiotic treatment [Time Frame: Week 16] 
• Changes from baseline in SF-12 MCS and PCS scores 
• Changes from baseline in HADS anxiety and depression scores 
• Changes from baseline in ADCT scores 
• Daily changes from baseline in the PP-NRS and SD-NRS [Timescale: Days 2 to 140] 
 
To evaluate the effect of early use of topical corticosteroid rescue therapy on Week 16 responder 
status, the subgroup of participants with no rescue use at any time before Week 16 will be 
compared to subgroups of participants with rescue therapy use within only the first 4, 8, 12 and 14 
weeks of treatment and to participants with rescue therapy use within the 2 weeks and 4 weeks 
prior to the Week 16 visit.  For these subgroups, the following endpoints will be summarized: 
• Percentage of Participants Achieving EASI-50, EASI-75 and EASI-90 
• Percentage of Participants Achieving IGA 0 or 1, with and without a 2-point improvement 
from Baseline 
• Percentage of Participants Achieving BSA-50, and BSA-75 
 
The following endpoints will be used to evaluate the effect of EDP1815 treatment on biomarkers 
in blood at Weeks 2, 16 and 20 (unless otherwise specified): 
• Changes from baseline in eosinophils  
• Changes from baseline in serum immune protein markers including IgE [Time Frame: 
Week 16] 
• Changes from baseline in immune cell RNA profile  


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4. STUDY DESIGN 
 
4.1. 
Study Description 
This is a randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety and 
tolerability of EDP1815 as compared to placebo in participants with mild, moderate and severe 
atopic dermatitis. 
 
This study will consist of 4 cohorts with a possible interim analysis prior to end of recruitment in 
Cohorts 1, 2 & 3.  The purpose of this interim analysis is to check the assumptions around placebo 
response rate. 
 
Approximately 100 participants will be randomly allocated to each of Cohorts 1, 2, & 3.  These 
cohorts will run concurrently. Within each cohort, participants will then be randomized to 
treatment in a 3:1 ratio (75 to EDP1815, 25 to placebo).  Therefore, across Cohorts 1, 2, & 3, 
approximately 225 participants will be randomly assigned to receive EDP1815, and 75 participants 
will be randomized to matching placebo for 16 weeks. Following end-of-treatment assessments, 
participants may enter a 4-week post-treatment follow-up period or may elect to participate in an 
Open Label Extension (OLE) protocol for EDP1815, if available. 
 
• 
Cohort 1: 1.6x1011 total cells of EDP1815 or matching placebo administered as 2 capsules 
once daily. 
 
• 
Cohort 2: 6.4x1011 total cells of EDP1815 or matching placebo administered as 2 capsules 
once daily. 
 
• 
Cohort 3: 6.4x1011 total cells of EDP1815 or matching placebo administered as 1 capsule 
of 3.2x1011 cells twice daily. 
 
Cohort 4 will run after enrollment is completed in Cohorts 1, 2, & 3.  Approximately 105 
participants in this cohort will be randomized to treatment in a 2:1 ratio (70 to EDP1815, 35 to 
placebo).  Participants will be treated for 16 weeks. Following end-of-treatment assessments, 
participants may enter a 4-week post-treatment follow-up period or may elect to participate in an 
Open Label Extension (OLE) protocol for EDP1815, if available. 
 
• 
Cohort 4: 8.0x1010 total cells of EDP1815 or matching placebo administered as 1 capsule 
once daily. 
 
4.2. 
Study Duration per Participant 
All cohorts will consist of:  
 
• Up to a 4-week Screening Period 
 
• A 16-week Treatment Period 
 
• A 4-week Post-Treatment Follow-up Period 


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Total participant duration is up a maximum of 24 weeks from screening to safety follow-up, unless 
they elect to participate in the OLE protocol, and their maximum participation in this study would 
be 20 weeks.   
 
The end of the study is defined as the date of the last visit of the last participant (LPLV). 
 
4.3. 
Planned Number of Participants 
This study will be conducted as a multi-center study at approximately 60 centers globally. 
Approximately 405 total participants will be randomized and treated with EDP1815 or matching 
placebo.   
 
4.4. 
Anticipated Regions and Countries 
This study may be conducted as a multi-regional study at centers located in North America, Europe 
and Asia Pacific. 








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i 
A single ECG tracing is to be obtained on the day of the visit approximately 5 minutes after the participant has rested. If, in the opinion of the Investigator, 
there appear to be clinically significant findings, repeat tracings should be obtained, as necessary. 
j 
Blood pressure, heart rate, respiratory rate, and temperature will be measured after approximately 5 minutes after the participant has rested.  
k 
Participant to be randomized after all Day 1 activities are completed and patient is still eligible to participate in the study. 
l 
The first IMP dose will be given at the Day 1 visit after all procedures are completed following randomization. Subsequent doses are taken daily in the 
morning at approximately the same time ±2 hours where possible.  On study visit days, dosing may occur at home prior to the study visit, even if dosing 
falls outside the dosing window. Participants should refrain from consuming acidic drinks 1 hour either side of dosing and from eating 2 hours before 
dosing and 1 hour after dosing.  
m  
Digital photographs should be taken of the upper and lower body (upper & lower anterior and upper & lower posterior) as half body shots.  Additional 
close-up photographs of up to six specific body areas (i.e., limbs, trunk and back) will also be taken.  The same sites photographed at Day 1 should be 
followed throughout the study for each participant. 
n 
AD Investigator rating scales. Participants will be asked to withhold all emollients, sunscreens, or moisturizers on the day of these study visits until all 
study assessments are completed. 
o 
The Pruritus-NRS (worst itch) will be asked daily from the Screening Visit to the Week 20 Visit via a participant diary. 
p 
The Sleep Disturbance-NRS (SD-NRS) will be asked daily starting at the Screening Visit to the Week 20 Visit via a participant diary. 
q 
Adverse Events (AE) and Serious Adverse Events (SAE) will be captured from the time the participant signs the informed consent. 
r 
Study staff will review the patient diary with participants at each visit. Diaries will be reviewed for completeness and accuracy, and participants will be 
coached as needed on compliance with the protocol. 
s 
Patients will be asked if they have enough emollient to last them until the next study visit.  
** 
A fecal sample is not required for any participant that enrolls under Protocol Version 5.0.




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4.7. 
Rationale for study design and selection of dose 
 
4.7.1. 
Placebo Rationale 
EDP1815-207 will utilize a matching placebo control in each cohort in order to fulfill the double-
blind design of the study, so that neither the investigator nor subject has knowledge of the treatment 
being administered. The purpose of this study design is to control for the placebo effect, control 
for variables caused by knowledge of treatment assignment, control for other factors that can 
influence study outcomes, and finally to allow for a more complete understanding of the risk-
benefit profile of the active study drug.  A position statement from the International Eczema 
Council (Leshem, et al., 2019) has given clear guidance on the design of studies in atopic 
dermatitis, including supporting and giving a scientific rationale for the use of placebo-control in 
studies in this condition. Placebo-controlled studies are the recommended standard. In addition, in 
this study, we are minimizing the proportion of placebo subjects by using a 3:1 randomization ratio 
(Cohorts 1-3) between active and placebo, and then pooling the placebo subjects together for 
comparison.  In Cohort 4, a 2:1 randomization ratio will be used together with a strategy that allows 
for a proportion of placebo participants from Cohorts 1-3 to be borrowed using a matching 
algorithm to increase power while also minimizing the proportion of placebo participants.  
 
4.7.2. 
Dose Rationale 
The study is designed to evaluate the efficacy of EDP1815 in the treatment of atopic dermatitis at 
three different doses across two regimens, 8.0x1010 total cells QD, 1.6x 1011 total cells QD, 3.2x1011 
total cells BID and 6.4x1011 total cells QD. 
 
The pharmacological site of action of EDP1815 is within the epithelium of the small intestine 
where EDP1815 interacts with immune and epithelial cells.  These interactions modify the 
systemic immune system and promote inflammation resolution throughout the body.  The 
preclinical and clinical data generated to date suggest this is a broad effect working across Th1, 
Th2 and Th17 pathologies.  As the intent is to generate a maximal inflammation-resolving 
phenotype regardless of inflammation pathology, the dose response is expected to be common 
across indications, and therefore we aim to cross compare to previous studies to support this 
hypothesis. A full dose-ranging study is currently being carried out in a phase 2 study (EDP-1815-
201) in psoriasis patients.  
 
Evelo’s Phase 1 Study EDP1815-101 evaluated EDP1815 for the treatment of atopic dermatitis 
with an oral dose of 8.0x1011 cells delivered as ten capsules once a day for 8 weeks.  This dose was 
safe and well tolerated and clinical benefit was observed with an improvement of 50-65% over 
placebo by Week 8 in EASI, SCORAD, and vIGA*BSA endpoints. In addition, doses of 1.6x1011 
and 8.0x1011 total cells given for 28 days have been investigated in this study for the treatment of 
psoriasis. Similar clinical benefit was observed at both dose levels. A Phase 2 dose ranging study 
in psoriasis (EDP1815-201) was conducted in approximately 225 participants for 16 weeks, at 
doses of 8.0x1010, 3.2x1011, and 8.0x1011 total cells. No evidence of dose response was seen in this 
study.  Further information on these studies is detailed in the EDP1815 Investigator’s Brochure 
(IB).  
 
The doses selected for evaluation in EDP1815-207 represent commercially acceptable dosing 
regimens in terms of capsule load and frequency for patients. The doses of 8.0x1010 total cells and 


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1.6x1011 total cells are comparable with data being generated in the lower dose cohorts of 
EDP1815-201, whilst the dose of 6.4x1011 total cells approximates to that administered in 
EDP1815-101, cohort 7. This latter total daily dose is being tested as both a once daily and twice 
daily regimen, to explore whether this leads to a change in the efficacy profile of EDP1815 in 
atopic dermatitis. 
 
 


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5. SELECTION AND WITHDRAWAL OF PARTICIPANTS 
Participants with a confirmed diagnosis of mild, moderate or severe atopic dermatitis will be 
treated in this study only if they meet all inclusion and no exclusion criteria during screening. Any 
participant who signs the informed consent form will be considered enrolled in the study.  Study 
screening procedures will begin after participants sign the informed consent.  
 
5.1. 
Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met: 
 
1. Must have given written informed consent (signed and dated) and any authorizations 
required by local law and be able to comply with all study requirements. 
 
2. Males or females aged ≥ 18 and ≤ 75 years old at the time of informed consent. 
 
3. A diagnosis of atopic dermatitis (AD) meeting Hanifin and Rajka criteria for AD at 
screening (Appendix 14.1) with patient- or clinician- reported disease duration of at least 
6 months. 
 
4. Have severity of atopic dermatitis meeting the below criteria at both Screening and Day 1: 
i. An IGA of 2, 3 or 4 on the vIGA scale, and; 
ii. A BSA of ≥5%, and; 
iii. An EASI score of ≥6. 
 
A cap will be set for each of the three IGA severity grades. When this cap is reached, Sponsor 
will notify sites that participants with severity score at Screening and/or Day 1 matching the 
closed stratum should be considered ineligible according to Inclusion Criterion 4i.  
 
5. All participants must agree to use a bland additive-free, sodium lauryl sulfate (SLS)-free, 
and fragrance-free emollient cream, gel or ointment twice daily (or more, as needed) for at 
least 14 consecutive days immediately prior to randomization and must continue this 
treatment twice daily throughout the trial. See Section 6.9.1.1. Background Therapy. 
 
6. Meet the following contraception criteria: 
i. Male participants: 
i. A male participant must agree to use contraception as detailed in Appendix 14.3 of 
this protocol during their participation in this study and for a period of 90 days after 
the last dose and refrain from donating sperm during this period. 
ii. Female participants: 
i. A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least 1 of the following conditions applies: 
1. Not a WOCBP as defined in Appendix 14.3 or 
2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 14.3 
during their participation in this study, 28 days prior to the first dose and for at 
least 1 complete menstrual cycle (≥30 days) after the last dose. 
 
Agrees to not increase their usual sun exposure significantly during the study. 


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5.2. 
Exclusion criteria 
Participants are not permitted to enroll in the study if any of the following criteria is met: 
 
1. Atopic dermatitis limited to the hands and/or feet and/or scalp. 
 
2. Have been in a clinical trial for EDP1815 prior to signing of ICF. 
 
3. History of active skin infection within 14 days prior to randomization. 
 
4. Evidence of dermatologic conditions that may, in the opinion of the investigator, interfere 
with AD evaluation or the assessment of treatment response. 
 
5. Use of phototherapy or tanning beds; systemic medications/treatments that could affect AD 
or its symptoms including immunosuppressive therapy (e.g., oral or injectable 
corticosteroids, methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, JAK 
inhibitors, tacrolimus, and/or leukotriene inhibitor) within 4 weeks of randomization. 
 
6. Previously received any biologic agent for AD and either was: 
a. Unresponsive to biologic agent, or 
b. Responsive to biologic agent and received this therapy within 3 months or 5 half-
lives prior to randomization, whichever is longer. 
 
7. Treatment with topical agents that could affect atopic dermatitis, including topical 
corticosteroids, topical calcineurin inhibitors (e.g., tacrolimus or pimecrolimus), or topical 
PDE-4 inhibitor (e.g., crisaborole) within 14 days prior to randomization. 
 
8.  Received any investigational or licensed biologic agent for conditions other than AD: 
a. Any cell-depleting agent, including rituximab, within 6 months prior to 
randomization, or until lymphocyte cell counts return to normal, whichever is 
longer. 
b. Any other biologic agent, within 3 months or 5 half-lives prior to randomization, 
whichever is longer. 
 
9. Gastrointestinal tract disease (e.g., short-bowel syndrome, diarrhea-predominant irritable 
bowel syndrome) that could interfere with GI delivery and transit time. 
 
10. Active inflammatory bowel disease. 
 
11. Ongoing acute or chronic infectious disease. Patients with hepatitis B, hepatitis C, and HIV 
may be enrolled provided that the disease is adequately controlled and/or is in remission.  
 
12. Has received live or live-attenuated vaccination within 6 weeks prior to Screening or 
intends to have such a vaccination during the study.  Non-live and non-replicating vaccines 
are permitted. 
 


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13. Clinically significant abnormalities in screening laboratory values that in the opinion of the 
Investigator would make a participant unsuitable for inclusion in the study. One retest is 
permitted within the 28-day screening window. 
 
14. Screening Labs: For women, serum creatinine ≥125 μmol/L (1.414 mg/dL); for men, serum 
creatinine ≥135 μmol/L (1.527 mg/dL).   
 
15. Screening Labs: ALT or AST >2 × ULN.  
 
16. History of clinically significant acute cardiac or cerebrovascular event within 6 months of 
signing ICF (includes stroke, transient ischemic attack, and coronary heart disease [angina 
pectoris, myocardial infarction, heart failure, revascularization procedures]). 
 
17. History of active substance (drug and/or alcohol) abuse within the prior 12 months.  This 
does not include the current or prior use of cannabis. 
 
18. In the opinion of the Investigator, evidence of clinically important cardiac conduction 
abnormalities as judged by the screening ECG. 
 
19. Hypersensitivity to P histicola or to any of the excipients. 
 
20. Active mental or psychiatric disorder, which, in the opinion of the Investigator or Sponsor, 
would make the participant unsuitable for inclusion or could interfere with the participant 
participating in or completing the study. 
 
21. Recent major surgery within 3 months of signing the ICF, or major surgery planned during 
the study. 
 
22. Malignancy within 5 years of signing the ICF, except for basal or squamous cell carcinoma 
of the skin or carcinoma in situ of the cervix that has been successfully treated. 
 
23. Treatment with another investigational drug or device within 3 months or 5 half-lives of 
investigational agent prior to randomization, whichever is longer. 
 
24. Treatment with supplements containing high doses of probiotics and prebiotics as usually 
found in capsules/tablets/powders, within 14 days prior to randomization and throughout 
the study period. Note that probiotic and prebiotic foods that contain low doses are allowed 
(e.g., yoghurt, kefir, kombucha). 
 
25. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator. 
 
26. Have any serious conditions that would be anticipated to require the use of systemic 
corticosteroids or otherwise interfere with study participation or require active frequent 
monitoring (e.g., unstable chronic asthma). 
 


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27. Have any other conditions, which, in the opinion of the Investigator or Sponsor, would 
make the participant unsuitable for inclusion or could interfere with the participant 
participating in or completing the study. 
 
5.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention/entered in the study due to failure to 
meet eligibility criteria or failing to randomize for any reason. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes informed consent, 
demography, screen failure details, eligibility criteria, and any AEs and SAEs. 
 
5.3.3. 
Rescreening 
Participants who fail to satisfy inclusion and exclusion criteria at Screening may be rescreened one 
additional time with the agreement of the Medical Monitor before re-screening.   
 
A participant that is re-screened will be assigned a new participant identifier (ID).  Additional 
information on rescreening will be provided in the appropriate specific user manual. 
 
5.4. 
Discontinuation from Treatment and/or Withdrawal 
Participants may discontinue from treatment and withdraw their participation from the study at 
any time and for any reason without prejudice to their future medical care by the Investigator or at 
the study site. Every effort should be made to keep participants in the study. The reasons for 
participants discontinuing treatment and withdrawing from the study will be recorded in the source 
files and on the eCRF.  
 
Interruption of treatment is defined as a temporary stopping of IMP that resumes during the 
treatment period, due to an AE or any other reason. The maximum permitted interruption at one 
time is 7 days and the participants should not interrupt IMP for more than 14 days in total. 
 
Early discontinuation of treatment is defined as permanent stopping of IMP before the Week 16 
visit. Investigators will strive to ensure that a participant who has interrupted treatment for a 
particular reason will not discontinue IMP unless discontinuation is medically imperative in the 
Investigator’s judgment. However, a dose interruption of more than 7 days or multiple dose 
interruptions totaling more than 14 days will result in mandatory discontinuation of IMP and early 
termination of the participant.  
 
Early withdrawal from the study is defined as failing to complete the 16-week treatment and the 
4-week follow-up period unless the participant transitions to the Open Label Extension (OLE) 
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A participant will discontinue IMP and be withdrawn from the study for any of the following 
reasons: 
 
1. The participant experiences treatment failure, demonstrated by the participant commencing 
phototherapy, an oral agent, biological, or intermediate or high-potency topical therapy 
other than those permitted as rescue therapy. 
 
2. The participant has a serious or intolerable AE that in the Investigator’s opinion requires 
discontinuation from IMP and withdrawal from the study.   
 
NB: Dosing may be interrupted at the Investigator’s discretion due to AE or intercurrent 
illness for a period of up to 7 days, following which the participant may resume treatment 
if the Investigator considers it safe to do so.  The participant should discontinue treatment 
permanently if the same AE which caused dose interruption occurs a second time requiring 
another dose interruption and is believed to be related to treatment. 
 
3. The participant has symptoms or an intercurrent illness not consistent with the protocol 
requirements or that justifies withdrawal. 
 
4. The participant is lost to follow-up. 
 
5. Other reasons (e.g., pregnancy, development of contraindications to use of IMP). 
 
6. The participant withdraws consent, or the Investigator or Sponsor decides to discontinue the 
participant’s participation in the study. 
 
A participant may discontinue IMP and be withdrawn from the study for any of the following 
reasons: 
 
1. The participant is noncompliant with the protocol. 
 
2. The participant has laboratory safety results that reveal clinically significant hematological 
or biochemical changes from the baseline values. 
 
3. If the participant is required to start therapy for a concurrent condition that may affect the 
study endpoints, e.g., a disease modifying agent for asthma. 
 
Investigators should contact the Medical Monitor, whenever possible, to discuss the treatment 
discontinuation and withdrawal of a participant in advance of this decision. 
 
Investigators should attempt to obtain information on participants in the case of treatment 
discontinuation and withdrawal.  All results of these evaluations and observations, together with a 
narrative description of the reason(s) for removing the participant, must be recorded in the source 
documents. The CRF must document the primary reason for treatment discontinuation and 
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5.4.1. 
Withdrawal from the Study 
Participants may withdraw from the study at any time at their own request or they may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. The Investigator will also withdraw a participant if Evelo terminates the 
study. 
 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.    
 
If a participant withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the source and eCRF.  
 
The participant randomization number accounts for an expected drop-out rate of approximately 
20%.  
 
The drop-out rate within each treatment group will be estimated during the interim analysis.  
Should 1 or more treatment groups be found to have a drop-out rate of 25% or more, additional 
participants will be randomized. 
  
5.4.2. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if s/he repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
 
The following actions must be taken if a participant fails to return to the study site for a required 
study visit: 
 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 
 
• Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 2 telephone calls and, if 
necessary, a written message to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the eCRF (date and 
summary of the phone call and copy of the written message in the source documents). 
 
If the participant continues to be unreachable, s/he will be considered to have withdrawn from the 
study. 
 
 


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6. STUDY TREATMENT(S) 
 
6.1. 
Investigational Medicinal Product(s) 
Investigational Medicinal Product (IMP) is defined as any investigational treatment(s), marketed 
product(s), placebo, or medical device(s) intended to be administered to a study participant 
according to the study protocol. 
 
All IMP in this study will be administered orally. EDP1815 will be supplied as capsules that are 
enteric-coated to release the contents upon gastric emptying. EDP1815 enteric-coated capsules 
contain lyophilized Prevotella histicola, mannitol, magnesium stearate, colloidal silicon dioxide, 
hydroxypropyl methylcellulose, methacrylic acid-ethyl acrylate copolymer, talc, triethyl citrate, 
titanium dioxide, and iron oxide.  
 
EDP1815 capsules will be manufactured in the following dose strengths and associated enteric 
coating thickness (EC).  The thickness of the capsule enteric coating for Cohort 4 is thinner (EC2) 
than the capsule enteric coating for Cohorts 1, 2, & 3 (EC1): 
 
Cohort 1:   
8.0x1010 total cells per capsule (EC1) 
Cohort 2 & 3:  3.2x1011 total cells per capsule (EC1) 
Cohort 4:   
8.0x1010 total cells per capsule (EC2) 
 
The drug substance used in Cohorts 1 and the 4 is manufactured by a different process than used 
in Cohorts 2 and 3. The drug substance in Cohorts 2 and 3 was manufactured using an optimized 
process to yield a higher concentration of microbe per capsule. It has been demonstrated to be 
similar to the drug substance in DTH mouse and healthy-volunteer human models. All IMP, 
regardless of manufacturing processes, is identical in appearance. Further information is detailed 
in the EDP1815 IB. The drug product is manufactured by 
 
.   
 
The matching placebo is identical in appearance but does not contain P histicola or any other 
bacteria. The coated placebo capsules are composed of microcrystalline cellulose, magnesium 
stearate, hydroxypropyl methylcellulose, methacrylic acid-ethyl acrylate copolymer, talc, triethyl 
citrate, titanium dioxide, and iron oxide.  The matching placebo capsules are manufactured by 
  
 
6.2. 
Investigational Medicinal Product(s) to be Administered 
The study IMP (EDP1815 or placebo) will be administered as capsules for 16 weeks in total.   
 
Study IMP is to be taken with water at approximately the same times each day (±2 hours, whenever 
possible). With twice daily dosing, administration should be in the morning and evening, with the 
doses separated by approximately 12 hours (±2 hours, whenever possible).  
 
Participants should refrain from consuming acidic drinks (such as cola/soda, coffee, sports and 
energy drinks, flavored waters and citrus juices) 1 hour either side of dosing and from eating 2 
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The Investigator (or designee) will instruct the participant to store the IMP following the 
instructions on the label. 
 
6.6. 
IMP Accountability 
An Interactive Response Technology (IRT) system will be used to record IMP dispensing and 
return information on a by-participant basis during the study. Details of any IMP lost, damaged 
(due to breakage or wastage), not used, partially used, disposed of at the study site, or returned to 
the Sponsor or designee must also be recorded. All supplies and pharmacy documentation must be 
made available throughout the study for the Sponsor (or designee) to review. 
 
Participants will utilize an electronic diary (eDiary) to record their IMP intake on a daily basis 
(Section 6.6.1 eDiary). 
 
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned or destroyed. 
 
The Investigator may assign some of the Investigator’s duties for IMP accountability at the study 
site to an appropriate pharmacist/designee. 
 
The Investigator must ensure that the IMP is used only in accordance with the protocol. 
 
All used (including empty containers)/partially used, unused, damaged, and/or expired IMP must 
be reconciled and returned to the Sponsor or designee or it may be destroyed at the site according 
to applicable laws and regulations, and Sponsor SOPs, if applicable.  Investigational medicinal 
product intended for the study cannot be used for any other purpose than that described in this 
protocol. 
 
6.6.1. eDiary 
The primary purpose of the diary is to enhance participant compliance with the protocol.  All 
participants will be provided with a paper participant diary at the Screening Visit to record their 
emollient use and daily PP-NRS and SD-NRS scores prior to the Day 1 Visit.  The participants 
will then utilize an electronic diary (eDiary) commencing upon completion of the Day 1 Visit 
through the Week 20 Follow-Up Visit.  The eDiary will be an application (app) that will be 
downloaded to the participant’s mobile smartphone, and for those participants that do not have a 
mobile smartphone or do not wish to download an app to their phone, they will receive an eDiary 
device specifically designated for the purpose of collecting information as described below.  
Participants will be asked to capture the following information in their eDiary: 
• Study IMP 
o Confirmation of dosing 
o Date and time of dosing  
o Number of capsules taken, with reasons not taken, if applicable. 
• Background Therapy (Emollient(s)) 
o Frequency of usage (number of times a day) 
• Rescue Therapy Usage 
o Confirmation of usage 
• Daily Peak Pruritus Numerical Rating Scale (PP-NRS) 


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o Evaluation of worst itch over previous 24-hour period 
• Daily Sleep Disturbance Numerical Rating Scale (SD-NRS) 
o Evaluation of worst sleep over previous 24-hour period 
 
Study staff will review the eDiary entries with participants at each visit.  eDiaries will be reviewed 
for completeness and accuracy, and participants will be coached as needed on compliance with the 
protocol.   
 
At the Week 20 Follow-Up Visit, the study staff will assist the participants to uninstall the eDiary 
application on their mobile smartphone devices and/or collect any eDiary devices that were 
distributed to the participants. 
 
6.7. 
Drug Compliance 
Participants will use the eDiary to capture compliance with their study IMP.  At specified visits 
per the Schedule of Activities (SOA), the study site staff will check numbers of used/unused 
capsules against diary entries and remind the participant of the need to self-administer the capsules 
as directed, and to store the IMP according to label instructions. 
 
Prior to the specified study visits per the SOA, study site staff will call participants to remind them 
to bring all empty IMP wallets and cartons in the original containers to the study site for their visit. 
If a participant is found to be persistently noncompliant, the Sponsor, in conjunction with the 
Investigator, will decide as to whether the participant should be withdrawn from the study. 
 
6.8. 
Dose Modification 
Dose adjustments, including dose interruptions, and/or decreasing the dose frequency may be 
allowed for safety or tolerability after consultation with the Medical Monitor.  The maximum 
permitted interruption at one time is 7 days and the participants should not interrupt IMP for more 
than 14 days in total. 
 
6.9. 
Concomitant Medications and Treatments 
Throughout the study, the participant may be prescribed concomitant medications or treatments 
deemed necessary to provide adequate supportive care at the discretion of the Investigator provided 
that the medications are licensed.  However, it is the responsibility of the Investigator to ensure 
that details regarding the medication are recorded in full in the eCRF. 
 
All concomitant medications and/or treatments received by a participant should be recorded on the 
appropriate source document and eCRF with the following minimum requirements: 
• Drug trade name 
• Total daily dose 
• Dates of administration   
• Reason for use (indication) 
• Dosage information (including dose and frequency)   
 
This will include all prescription drugs, herbal products, vitamins, minerals, over-the-counter 
(OTC) medications, and vaccines.  Any changes in concomitant medications also will be recorded 


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in the participant’s eCRF.  The participant’s dosing diary may contain information relevant to the 
documentation of changes in concomitant medication. 
 
6.9.1. Permitted Concomitant Medications and Treatments 
The following concomitant medications are permitted for use during the study: 
• Concomitant medications for conditions other than AD may continue throughout the trial, 
if not meeting any exclusion criteria, and should continue without change in dosage or 
formulation whenever possible. 
• New therapy/treatments, not expected to have any impact on AD, but deemed necessary 
for the welfare of the participant during the study, are permitted. If there is doubt about 
their impact on AD or ability to continue in the study, then this should be discussed with 
the Medical Monitor. 
• Topical and oral antibiotics (For suspected skin infection, see Section 6.9.1.2 Rescue 
Therapy) 
• All participants must use an emollient twice daily for at least 14 consecutive days prior to 
Day 1 and throughout the study (Section 6.9.1.1 Background Therapy). 
• Topical and oral antibiotics, antiviral, or antifungal therapy. 
• Oral antihistamines. 
• Nasal, inhaled and ophthalmic corticosteroids. 
• Non-replicating / Non-live vaccines (Section 6.9.3 Immunizations). 
 
6.9.1.1. Background Therapy 
All participants must use an emollient twice daily to all body areas for at least 14 consecutive days 
immediately prior to randomization.  This must be a bland emollient which is additive-free, SLS-
free, and fragrance-free and may be in cream, gel or ointment formulation. Whenever possible, the 
same brand and formulation of emollient should be used throughout the study by a participant. 
Participants are not allowed to use emollients containing additives (e.g., urea, ceramide, 
nicotinamide). Participants should continue this background emollient treatment twice daily until 
the Week 20 Follow-up Visit but if a daily dose is missed, this will not be a protocol deviation.  
On the day of the study visits, the participant will be asked to withhold the application of the 
emollient, and where safe, sunscreen and any other topical products until after all study 
assessments have been performed. 
 
Participants will be considered to have acceptable compliance with respect to emollient use if they 
administer at least 75% of the expected applications during the study. Participants need to meet 
this criterion within the 14 days prior to randomization in order to be randomized (i.e., 21 
applications of emollient out of the previous 28 applications (14 days) immediately prior to Day 
1). Otherwise, participants may be considered for re-screening. 
 
If a participant is found to be persistently noncompliant, the Sponsor, in conjunction with the 
Investigator, will decide as to whether the participant should be withdrawn from the study. 
 
Background therapy between Screening and Randomization will be recorded via a paper diary.  
Participants will record their background therapy via the participant eDiary from Day 1 to the 
Week 20 Follow-Up Visit (Section 6.6.1 eDiary). 
 


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Please contact the Medical Monitor to discuss any questions on the use of background therapies. 
 
6.9.1.2. Rescue Therapy 
If required, Investigators may prescribe / recommend prescription of rescue therapy for 
participants experiencing unacceptable worsening of atopic dermatitis. Additionally, individuals 
with uncontrolled atopic dermatitis could be at risk for a secondary skin infection.  These 
participants may be prescribed an antimicrobial therapy to treat the infection as detailed below. 
Rescue therapy use is allowed throughout the entire study. There is no limit on the number of times 
that topical rescue therapy can be prescribed, although Investigators and participants may wish to 
consider whether the study is suitable for them if repeated courses are required. 
 
Rescue therapy, including antimicrobial rescue therapy, should be prescribed as detailed below, 
and any specific deviations should first be discussed with the Medical Monitor. Participants 
rescued by such topical therapy will continue to take IMP and use of rescue therapy will be 
documented in the participant eDiary (Section 6.6.1 eDiary). Of note, Investigators should make 
every attempt to conduct the following assessments immediately prior to administering any rescue 
therapy, by use of an unscheduled visit, if needed: 
• EASI  
• vIGA 
• PP-NRS 
• AEs 
• Concomitant Medications 
 
For non-sensitive body sites: 
• Moderate potency (grade IV and V – Appendix 14.2) topical corticosteroids, twice daily 
for up to 7 days 
 
For sensitive sites e.g., head and neck: 
• Topical tacrolimus (0.1%), topical pimecrolimus (1%) or grade VII topical corticosteroid, 
twice daily for up to 7 days 
 
If topical rescue therapy fails to control symptoms adequately, then the participant should be 
considered for alternative systemic therapy or phototherapy by the Investigator/their practitioner, 
at which point they will be classified as a treatment failure and IMP will be discontinued. 
 
For possible skin infection: 
• Topical: 
o Appropriate courses of topical antimicrobial therapies, such as fucidic acid cream 
(e.g., Fucidin), are acceptable for use for skin infections, as required 
o If requiring concomitant moderate potency steroid therapy, fucidic acid with 
betamethasone 0.1% (as the valerate ester), (e.g., Fucibet cream) twice daily for up 
to 7 days 
• Oral: 
o Appropriate course(s) of oral antibiotic(s) may be prescribed as per clinical need 
 


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6.9.2. 
Prohibited Concomitant Medications and Treatments 
 
6.9.2.1. Prohibited Concomitant Medications  
The following concomitant medications are prohibited during the study: 
• Live (attenuated) vaccinations: not permitted at any point during the study (Section 6.9.3 
Immunizations). 
 
6.9.2.2. Discontinuation of Prohibited Concomitant Medications 
Use of any of the following concomitant medications during the study require the concomitant 
medication to be immediately discontinued where possible. If the prohibited medication cannot be 
discontinued for any reason, then the IMP should be discontinued: 
• Emollients containing additives including SLS 
• Topical Corticosteroids or Topical Calcineurin Inhibitors (unless used as Rescue Therapy, 
Section 6.9.1.2 Rescue Therapy) 
• Topical PDE-4 Inhibitors  
• Bleach baths 
• Tanning beds 
• Leukotriene Receptor Antagonists 
• Allergen Immunotherapy 
 
6.9.2.3. Prohibited Concomitant Medications Requiring IMP Discontinuation 
Introduction of any of the following concomitant medications during the study will be classified 
as a treatment failure and require IMP discontinuation: 
• Phototherapy treatment 
• Systemic treatments that may lead to clinical improvements in atopic dermatitis, e.g., oral 
or injectable corticosteroids, methotrexate, azathioprine, cyclosporine, mycophenolate 
mofetil, JAK-inhibitors, biologic therapy, and other systemic immunosuppressive therapy 
(note single dose intra-articular or intra-lesional corticosteroid therapy is permitted). 
 
6.9.3. 
Immunizations 
Non-replicating / Non-live vaccines are permitted during the study.  This includes all SARS-CoV-
2 (COVID) non-live vaccines and non-replicating vaccines.  However, the first dose of IMP should 
not be taken within a 7-day window of administration of the vaccine. 
 
Live (attenuated) vaccinations are not permitted at any point during the study. This includes 
vaccines for measles, mumps, rubella, vaccinia, varicella, zoster (which contains the same virus as 
varicella vaccine but in much higher amount), yellow fever, rotavirus, and influenza (intranasal).  
The non-intranasal seasonal flu vaccine is permitted, as is the recombinant zoster vaccine (non-
live). 
 
6.10. Blinding 
Cohort assignments will not be blinded however, assignment to IMP within a cohort will be 
blinded. All IMP within a cohort (EDP1815 and matching placebo) will be supplied in identical 
packaging, color, smell, and appearance to enable double-blinded conditions that ensure all 
Investigators, study site staff, participants, and clinical monitors will remain blinded throughout 
the study.  The IRT system will assign IMP to participants at the time of randomization.  Only 


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personnel supporting the IRT system, the independent randomization team, and clinical supplies 
will be unblinded and will have access to treatment assignments; all other parties involved in the 
study will be fully blinded.  
 
For the interim analysis just before the end of recruitment to Cohorts 1, 2 & 3, unblinded aggregate 
results will be produced by an unblinded team (external to Evelo) and reviewed by senior Evelo 
personnel who are not participating in study conduct to allow decision making on increasing the 
sample size. These will not be shared with any study site staff, participants, or any members of the 
study team who will be involved in the collection, review or analysis of individual study data. 
 
6.10.1. Breaking the Blind 
A participant’s treatment assignment will not be unblinded for the Investigator or study site staff 
until end of study unless medical treatment of the participant depends on knowing the study 
treatment the participant received. In the rare event that unblinding is needed because of a medical 
emergency, the Investigator may unblind an individual participant’s treatment allocation through 
the IRT. In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a participant’s study treatment assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. If the Investigator decides that 
unblinding is warranted, the Investigator should make every effort to contact the Medical Monitor 
prior to unblinding a participant’s study treatment assignment unless this could delay emergency 
treatment of the participant. If a participant’s study treatment assignment is unblinded, the Medical 
Monitor must be notified within 24 hours after breaking the blind. Reasons for treatment 
unblinding must be clearly explained and justified in the source and eCRF. The date on which the 
code was broken together with the identity of the person responsible must also be documented. 
 
Participants who are unblinded will be allowed to continue their participation in the study; 
however, any data collected after the unblinding occurred may be excluded from one or more of 
the defined data point sets. 
 
The Clinical Safety Team at 
will be unblinded to study treatment to facilitate appropriate 
identification and reporting of SUSARs to Competent Authorities and the relevant IECs/IRBs. 
 
6.11. Randomization  
An IRT will be used for assigning eligible participants to a cohort (as applicable) based on a 
predetermined production randomization and/or packaging schedule. The randomization schedule 
will be produced by the IRT vendor. The IRT will generate individual assignments for participant 
kits of IMP, as appropriate, according to the visit schedule. 
 
To randomize a participant, the Investigator or designee will contact the IRT and provide brief 
details about the participant to be randomized. The IRT will assign a participant randomization 
number. The IRT will allocate kit numbers to the participant based on the participant number 
during the course of the study. The kit number may be incorporated into the CRF. 
 
The randomization schedule will be stratified by vIGA at Day 1 to ensure that the cohorts and 
treatment groups within Cohorts 1, 2, and 3 are balanced with respect to disease severity. The 
randomization schedule for Cohort 4 will also be stratified by vIGA at Day 1. In order to match as 


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closely as possible the severity of Cohorts 1, 2 & 3. Cohort 4 may also limit the numbers of 
participants recruited to each strata to match the proportions of each vIGA strata in Cohorts 1, 2 
& 3. 
 


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7. STUDY PROCEDURES BY VISIT  
 
No study procedures should be performed prior to the signing of the informed consent form (ICF).   
 
Visit windows are consecutive calendar days and the target visit dates are calculated from the Day 
1 visit.  
 
The Schedule of Activity (SOA) is presented in Table 4-1.  An overview of each of the study 
assessments is presented in the subsections below.  If a visit is not completed per protocol, it will 
be considered a missed visit.  The site should still contact the participant by telephone to ensure 
that there have not been any adverse reactions.  
 
7.1. 
Screening Visit 
At the time of Screening, each site will sequentially assign a unique identifier to each participant 
which will be used for the duration of the study.   
 
The following procedures will be performed at the Screening Visit to determine the participant’s 
eligibility for the study: 
• Obtain written informed consent from participant 
• Assess inclusion and exclusion criteria 
• Collect demographics including year of birth, age, gender, race, and ethnicity. 
• Obtain medical history including onset year of AD and the participant’s smoking status 
• Perform full physical examination 
• Measure vital signs (blood pressure, heart rate, respiratory rate and temperature) including 
height and weight 
• Perform 12-lead electrocardiogram (ECG) 
• Collect blood for screening labs  
• Collect urine for screening urinalysis 
• Perform serum pregnancy test for women of child-bearing potential (WOCBP) 
• Determine the Investigator’s Global Assessment (vIGA) Score 
• Perform EASI rating scale and determine BSA involvement (%) 
• Review and document concomitant medications and therapies 
• Assess and document adverse events (AEs) that occur after participant signs informed 
consent form (ICF) 
• After the participant has completed all screening activities, provide them the Patient Skin 
Care Instructions for emollient, as well as paper diaries for recording emollient use and the 
PP-NRS and SD-NRS scores. 
 
7.2. 
Day 1 Visit 
All participants must use an emollient twice daily for at least 14 consecutive days prior to 
randomization with a minimum compliance of 75% total applications (minimum of 21 out of the 
28 applications in the 14 days prior to day 1). On the day of the Day 1 Visit, the participant will 
be asked to withhold the application of the emollient, and where safe, sunscreen and any other 
topical products until after all study assessments have been performed (Section 6.9.1.1 
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The Day 1 Visit will take place within 28 days of the Screening Visit.  The following procedures 
will be performed: 
• Review inclusion and exclusion criteria 
• Perform full physical examination 
• Measure vital signs including weight 
• Collect blood for safety labs as well as serum immune protein markers and inflammatory 
markers 
• Collect urine for urinalysis 
• Perform urine pregnancy test for WOCBP 
• Take digital photographs of the upper and lower body (anterior and posterior) as half body 
shots.  Additional photographs of up to six specific body areas, i.e., limbs, trunk and back 
(excluding scalp, genitals and any identifying features) may also be taken.   
• Perform AD rating scales - vIGA, EASI (and BSA), and SCORAD 
• Perform patient reported clinical rating scales – HADS, POEM, DLQI, ADCT, and SF-12 
• Review and document concomitant medications and therapies including emollient use 
• Assess and document adverse events (AEs)  
• OPTIONAL: If participant consented to genetic testing, collect appropriate blood sample  
 
Randomization Procedures 
• Randomize the participant in IRT after all Day 1 activities are completed and the participant 
is still deemed eligible to participate 
• Administer the first dose of IMP 
• Dispense IMP to cover the first 4 weeks of the treatment period  
• Assist participant in mobile app installation on their smartphone device and provide 
instructions on completion of eDiary 
 
7.3. 
Week 2 Visit 
This visit will take place 14 days (±3 days) after the Day 1 Visit. Participants may dose at home 
on the day of the visit. Prior to the visit, the participant will be asked to withhold the application 
of the emollient, and where safe, sunscreen and any other topical products until after all study 
assessments have been performed.  See Section 6.9.1.1 Background Therapy. 
 
The following procedures will be performed: 
• Perform brief physical examination 
• Measure vital signs  
• Collect blood for safety labs as well as inflammatory markers 
• Collect urine for urinalysis 
• Perform AD rating scales - vIGA, EASI (and BSA), and SCORAD 
• Perform patient reported clinical rating scales – POEM, and DLQI 
• Review and document concomitant medications and therapies including emollient use 
• Assess and document adverse events (AEs)  
• Confirm patient is taking IMP per protocol and is recording this via the eDiary 
• Dispense IMP to cover the next 4 weeks of the treatment period  
 


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7.4. 
Week 4 Visit 
This visit will take place 28 days (±3 days) after the Day 1 Visit. Participants may dose at home 
on the day of the visit. Prior to the visit, the participant will be asked to withhold the application 
of the emollient, and where safe, sunscreen and any other topical products until after all study 
assessments have been performed.  See Section 6.9.1.1 Background Therapy. 
 
The following procedures will be performed: 
• Perform brief physical examination 
• Measure vital signs including weight 
• Perform 12-lead ECG 
• Collect blood for safety labs  
• Collect urine for urinalysis 
• Perform urine pregnancy test for WOCPB 
• Take digital photographs of the same body locations taken at the Day 1 Visit 
• Perform AD rating scales, including vIGA, EASI (and BSA), and SCORAD 
• Perform patient reported clinical rating scales – HADS, POEM, DLQI, ADCT, and SF-12 
• Review and document concomitant medications and therapies including emollient use 
• Assess and document adverse events (AEs)  
• Confirm patient is taking IMP per protocol and is recording this via the eDiary 
• Collect empty and unused study wallets/cartons dispensed at the Day 1 Visit 
• Dispense IMP to cover the next 4 weeks of the treatment period  
 
7.5. 
Week 8 Visit 
This visit will take place 56 days (±3 days) after the Day 1 Visit. Participants may dose at home 
on the day of the visit. Prior to the visit, the participant will be asked to withhold the application 
of the emollient, and where safe, sunscreen and any other topical products until after all study 
assessments have been performed.  See Section 6.9.1.1 Background Therapy. 
 
The following procedures will be performed: 
• Perform brief physical examination 
• Measure vital signs  
• Collect blood for safety labs  
• Perform urine pregnancy test for WOCBP 
• Perform AD rating scales, including vIGA, EASI (and BSA), and SCORAD 
• Perform patient reported clinical rating scales – POEM, and DLQI 
• Review and document concomitant medications and therapies including emollient use 
• Assess and document adverse events (AEs)  
• Confirm patient is taking IMP per protocol and is recording this via the eDiary 
• Dispense IMP to cover the last 4 weeks of the treatment period  
 
7.6. 
Week 12 Visit 
This visit will take place 84 days (±3 days) after the Day 1 Visit. Participants may dose at home 
on the day of the visit. Prior to the visit, the participant will be asked to withhold the application 
of the emollient, and where safe, sunscreen and any other topical products until after all study 
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The following procedures will be performed: 
• Perform brief physical examination 
• Measure vital signs  
• Collect blood for safety labs  
• Perform urine pregnancy test for WOCBP 
• Take digital photographs of the same body locations taken at the Day 1 Visit 
• Perform AD rating scales, including vIGA, EASI (and BSA), and SCORAD 
• Perform patient reported clinical rating scales – HADS, POEM, DLQI, ADCT and SF-12 
• Review and document concomitant medications and therapies including emollient use 
• Assess and document adverse events (AEs)  
• Confirm patient is taking IMP per protocol and is recording this via the eDiary 
 
7.7. 
Week 16 Visit 
This visit will take place 113 days (±3 days) after the Day 1 Visit. Participants may dose at home 
on the day of the visit. Prior to the visit, the participant will be asked to withhold the application 
of the emollient, and where safe, sunscreen and any other topical products until after all study 
assessments have been performed. See Section 6.9.1.1 Background Therapy. 
 
The following procedures will be performed: 
• Perform full physical examination 
• Measure vital signs including weight 
• Perform 12-lead ECG 
• Collect blood for safety labs as well as serum immune protein markers and inflammatory 
markers  
• Collect urine for urinalysis 
• Perform urine pregnancy test for WOCBP 
• Take digital photographs of the same body locations taken at the Day 1 Visit 
• Perform AD rating scales, including vIGA, EASI (and BSA), and SCORAD 
• Perform patient reported clinical rating scales – HADS, POEM, DLQI, ADCT and SF-12 
• Review and document concomitant medications and therapies including emollient use 
• Assess and document adverse events (AEs)  
• Confirm patient took IMP per protocol and recorded this via the eDiary 
• Collect all remaining empty and unused study wallets/cartons dispensed at the Week 2, 
Week 4 and Week 8 Visits 
 
Open Label Extension Option 
Participants who complete the 16 weeks of double-blind treatment may have the option to enter an 
Open Label Extension (OLE) protocol at the Week 16 Visit, if available.  A separate consent form 
must be signed prior to the Week 16 Visit, however, only those participants that complete all 16 
weeks on study IMP (active or placebo) will be allowed to participate in the OLE. 
 
Participants who do not enroll into the OLE will enter a 4-week follow-up period and complete 
the Week 20 Visit per the SOA. 
 


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7.8. 
Week 20 Follow--Up Visit 
This visit will take place 141 days (+3 days) after the Day 1 Visit. Prior to the visit, the participant 
will be asked to withhold the application of the emollient until after all study assessments have 
been performed.  See Section 6.9.1.1 Background Therapy. 
 
The following procedures will be performed: 
• Perform brief physical examination 
• Measure vital signs including weight 
• Perform 12-lead ECG 
• Collect blood for safety labs as well as inflammatory markers  
• Collect urine for urinalysis 
• Perform urine pregnancy test for WOCBP 
• Take digital photographs of the same body locations taken at the Day 1 Visit 
• Perform AD rating scales, including vIGA, EASI (and BSA), and SCORAD 
• Perform patient reported clinical rating scales – HADS, POEM, DLQI, ADCT, and SF-12 
• Review and document concomitant medications and therapies including emollient use 
• Assess and document adverse events (AEs) 
• Assist the participant to uninstall the mobile application from their smartphone device 
 
7.9. 
Early Termination Visit 
Participants who withdraw prematurely from the study should have an early termination visit using 
the Early Termination Visit schedule within 14 days of asking to withdraw consent or within 72 
hours of starting any AD therapy if their withdrawal was due to treatment failure.  The participant 
will also be asked to have a final telephone call 28 days (+3 days) after taking their last dose of 
IMP for safety assessments. The date of this telephone call will be considered the end of study date 
for these participants.  
 
7.10. Unscheduled Visits 
Unscheduled visits are visits that fall outside of the scheduled visits indicated in the SOA.  These 
visits and the findings are to be recorded on the appropriate eCRFs.   
 
If an unscheduled visit occurs due to the participant requiring rescue therapy, every attempt should 
be made to conduct efficacy and safety assessments (e.g., EASI, BSA, vIGA, AEs, and 
concomitant medications) immediately before prescribing/administering any rescue therapy 
[Section 6.9.1.2 Rescue Therapy]. 
 
7.11. COVID-19 Pandemic 
Parts or all of this study are expected to run during the COVID-19 pandemic.  As a result, a 
thorough risk analysis has been carried out.  In addition, a number of mitigation steps have been 
considered, for example, the scenarios of individual self-isolation or local/national lockdown. 
 
7.11.1. EDP1815 and Risk of COVID-19 Infection 
EDP1815 does not broadly impair either innate or adaptive immune responses, as detailed in a full 
risk-assessment in Appendix 14.4.  Anti-viral responses such as cytotoxic T-cell production of 
interferon-gamma, innate anti-viral production of interferon-alpha and interferon-beta, and the 


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generation of high-affinity antibodies are all preserved pre-clinically after treatment with 
EDP1815. There is no pre-clinical or clinical evidence of EDP1815 causing immunosuppression. 
 
EDP1815 was investigated as a treatment of patients hospitalized with Covid-19 infection (study 
reference: EDP1815-204 and EDP1815-205), but no safety or efficacy data have yet been reported 
from these studies.  
 
7.11.2. EDP1815 and COVID-19 Vaccination 
As detailed in Section 6.9.3 Immunizations of this protocol, live and live-attenuated vaccines 
should not be given with EDP1815. Non-live and non-replicating vaccines are permitted, and it is 
not expected that the safety of participants will be impacted by their co-administration. The 
efficacy of the vaccines co-administered with EDP1815 has not been tested. 
 
7.11.3. EDP1815-207 and COVID-19 Infection 
Self-isolation or a positive COVID-19 test in a well subject may not be a reason in itself to stop 
dosing, as EDP1815 is not expected to increase the risks associated with COVID-19. If a study 
participant is diagnosed with COVID-19 infection (diagnosed clinically or by laboratory tests), the 
participant may continue study treatment if the Investigator considers that there is a positive 
individual risk/benefit balance. This should be discussed with the Medical Monitor. 
 
7.11.3.1. COVID-19 Mitigation Steps 
If a participant with COVID-19 must self-isolate or quarantine while on study, and a study visit 
coincides with this self-isolation or quarantine, the study visit will be missed and the reason the 
visit was not done recorded in the source documents with COVID-19 isolation / lockdown as the 
reason for the visit not completed.   
 
In lieu of the study visits, the participant may receive a telephone call to assess adverse reactions, 
ascertain study IMP status (i.e., did the participant self-interrupt taking IMP) and emollient usage, 
and collect information on any concomitant medications, including any rescue therapy.  
Information should be recorded in the participant’s source documents and entered into the EDC, 
as applicable.  
 
The Week 16 study visit should not be missed wherever possible; these visits, therefore, may be 
conducted outside of the protocol study window.  Please contact the Medical Monitor to discuss 
further.   
 
7.12. Missed Visits and Procedures 
Missed visits and any procedures not performed (not attempted) for reasons other than screen 
failure, illness, injury or progressive disability (i.e., subject is physically unable to perform test) 
will be reported as protocol deviations.  
 
A major protocol deviation will be recorded for missed visits and any procedures not performed 
(not attempted) for Day 1 and Week 16 visits, regardless the reason the visit was missed.   
 


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Procedures or visits not performed due to screen failure, illness, injury or disability, including 
procedures that were attempted but failed (i.e., blood samples unable to be drawn after multiple 
attempts) will not be reported as protocol deviations.  
 
 
 


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8. EFFICACY ASSESSMENTS 
 
Assessments will be performed at designated time-points throughout the study for efficacy 
evaluations. In addition to the assessments below, participants will provide information on their 
demographics and smoking history, past medical history (including diagnosis of atopic dermatitis), 
as well as concomitant medication usage. 
 
All efficacy assessments will be completed at the study site utilizing a site tablet at the specified 
visits as indicated on the SOA.  The site staff will assist the participant in completing those 
assessments that are considered patient reported outcomes (PRO). The same reviewer should 
conduct the skin assessments wherever possible for a single participant, and if not possible, at a 
minimum, the same reviewer performs the Day 1 and Week 16 assessments for that participant.   
 
The Investigators and site staff will be provided with further details on how to perform the 
following assessments and how to calculate each of the scores (if applicable).   
 
8.1. 
Eczema Area and Severity Index 
The Eczema Area and Severity Index (EASI) is a validated measure of eczema severity, which 
considers a combination of the body surface area affected across 4 body regions, and the severity 
of the clinical signs of erythema, oedema/induration, excoriation and lichenification (Eczema, 
n.d.). The EASI score ranges from 0 – 72 (EASI, 2017 Jan). EASI-50, EASI-75, EASI-90 
responses are defined as at least 50%, 75% and 90% decrease from baseline EASI score 
respectively. 
 
EASI is the core outcome for measuring the clinical signs of AD in all AD trials, as selected by 
the Harmonising Outcome Measures for Eczema (HOME) group. The EASI score will be assessed 
to determine the treatment effect of EDP1815 compared to placebo.   
 
8.2. 
Validated Investigator’s Global Assessment 
The Validated Investigator Global Assessment scale for Atopic Dermatitis (vIGA) will be used to 
describe the overall appearance of lesions at a given time-point (Simpson E, 2020 Sep). There is a 
standardised grading system based on an overall assessment of the degree of erythema, 
papulation/induration, lichenification, and oozing/crusting. In indeterminate cases, extent will be 
used to differentiate between scores – but otherwise extent is not used in the scoring system. The 
vIGA score ranges from 0 (Clear skin) to 4 (Severe disease). 
 
8.3. 
SCORing Atopic Dermatitis 
The SCORing Atopic Dermatitis (SCORAD) is a clinical tool which is also used to assess the 
extent and severity of eczema, to assess treatment effects. There is an investigator-rated area score 
which uses the rule of nines to assess disease extent, and a disease intensity score comprising 
erythema, swelling, oozing/crusting, excoriation, lichenification, and dryness. Additionally, there 
is a subjective symptoms component which considers itch and sleeplessness scored using a visual 
analogue scale. These scores combine to give a SCORAD score between 0 – 103 (Dermatitis, 
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8.4. 
Patient Oriented Eczema Measure 
The Patient Oriented Eczema Measure (POEM) is a simple PRO assessment tool for monitoring 
disease severity.  It includes a series of 7 questions, measuring itch, sleep, bleeding, 
weeping/oozing, cracking, flaking, and dryness/roughness over the last week, and is scored by the 
participant.  Each of the 7 questions is scored from 0 (no days) to 4 (every day), giving a POEM 
score range from 0 to 28, with higher scores representing higher disease severity (Charman, 2004 
and Charman, 2013). The minimally clinically important difference threshold is a change of ≥3.4 
points on average (Schram, et al., 2011). For the purposes of changes within an individual 
participant, a response will therefore be considered to be a ≥4-point change from baseline. 
 
8.5. 
Dermatology Life Quality Index 
This is a validated patient reported outcomes instrument comprised of 10 questions to assess how 
a participant’s skin disease has affected their quality of life over the past week (Finlay AY, 1994). 
The DLQI score ranges from 0 to 30, with higher scores indicating greater impairment of quality 
of life. A DLQI score of 0 or 1 is considered as having no effect on a patient’s quality of life, and 
a 4-point change from baseline is considered the minimal clinically important difference threshold 
(Basra, 2015). 
 
8.6. 
Peak Pruritus Numerical Rating Scale (PP-NRS)  
The Peak Pruritus Numerical Rating Scale (PP-NRS) is a scale from 0 (“no itch”) to 10 (“worse 
imaginable itch”) for participants to rate their worst itch that they have experienced over the 
previous 24 hours (Phan, 2011).  The PP-NRS will be completed daily question via a daily 
questionnaire from the Screening Visit to the Week 16 visit. A ≥2-4-point change from baseline is 
considered the minimally clinically important difference threshold (Yosipovitch, et al., 2019). 
 
8.7. 
Sleep Disturbance Numerical Rating Scale (SD-NRS)  
The Sleep Disturbance Numerical Rating Scale (SD-NRS) is a scale from 0 (“best possible sleep”) 
to 10 (“worse possible sleep”) for participants to rate their worst sleep that they have experienced 
over the previous 24 hours. The SD-NRS will be completed via a daily questionnaire from the 
Screening Visit to the Week 16 visit. A ≥2 point change from baseline is considered the minimally 
clinically important difference threshold (Dias-Barbosa, Matos, & Vernon, 2020). 
 
8.8. 
Body Surface Area 
The Body Surface Area (BSA) is a measure of the extent of atopic dermatitis at a given time. It is 
calculated by estimating the number of participant’s handprints of active atopic dermatitis are 
present where one handprint (including digits) represents 1% body surface area. The BSA provides 
another assessment of disease severity by looking at coverage of body surface and is sometimes 
assessed as a product of the vIGA*BSA as a further marker of disease severity and response to 
treatment (Suh, 2020). 
 
8.9. 
12-Item Short Form Health Survey 
The 12-Item Short Form Health Survey (SF-12) is a PRO instrument consisting of twelve questions 
used to measure non-disease related outcomes in 8 health domains, including vitality, physical 
functioning, bodily pain, general health perceptions, physical role functioning, emotional role 
functioning, social functioning, and mental health. The score (ranging from 0 to 100) is presented 
in two components: a mental composite scale (MCS) and physical composite scale (PCS).  The 


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higher the score, the better the physical and mental health functioning. The SF-12 scores have been 
shown to correlate with those of the 36-Item Short Form Health Survey (SF-36) (Ware J, 1996). 
 
8.10. Hospital Anxiety and Depression Scale 
The Hospital Anxiety and Depression Scale (HADS) is a PRO instrument used to measure anxiety 
and depression over the past week.  It is comprised of 7 questions for anxiety and 7 questions for 
depression and each are scored using a 4-point Likert scale (e.g., 0-3). Scores for each domain 
therefore range from 0-21, where 8-10 is mild, 11-14 is moderate and 15-21 is severe anxiety or 
depression (Snaith, 2003). 
 
8.11. Atopic Dermatitis Control Tool 
The Atopic Dermatitis Control Tool (ADCT) is a 6-question PRO instrument used to detect change 
of disease activity in a person over time.  There are six main areas that assess the multi-dimensional 
aspects of disease control over the course of a week, scored between 0-4, with a minimum score 
of 0 and a maximum score of 24.  A higher score indicates lower AD control.  A change of 5 points 
is the threshold for meaningful within person change, where a decrease of 5 or more points 
indicates clinically relevant improvement of AD control and an increase of 5 or more points 
indicates a clinically relevant worsening of AD control (Pariser, 2020). 
 
 
 


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9. SAFETY ASSESSMENTS 
 
The adverse event (AE) definitions and reporting procedures provided in this protocol comply with 
all applicable regulations and International Conference on Harmonization (ICH) guidelines. The 
Investigator will carefully monitor each subject throughout the study for possible adverse events.  
 
9.1. 
Adverse Events 
An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with a 
study, use of a drug product or device whether or not considered related to the drug product or 
device.  
 
Signs or symptoms of the condition/disease for which the IMP is being studied should be recorded 
as AEs only if their nature changes considerably or their frequency or intensity increases in a 
clinically significant manner as compared to the clinical profile known to the investigator from the 
participant’s history or from Day 1. 
 
9.1.1. 
Adverse Events of Special Interest 
There are no prespecified AEs of special interest (AESI) for this study. 
 
9.2. 
Adverse Drug Reactions 
Adverse drug reactions (ADR) (also known as suspected unexpected adverse drug reactions or 
SUSARs) are all noxious and unintended responses to a medicinal product related to any dose. 
The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out. Therefore, a subset of AEs can be classified as suspected ADRs or SUSARs, 
if there is a causal relationship to the medicinal product. 
 
9.3. 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an adverse event that meets any of the following 
criteria:  
 
• Results in death. 
 
• Is life threatening; that is, poses an immediate risk of death as the event occurred. 
− This serious criterion applies even if the participant, in the view of the Investigator or 
Sponsor, is at immediate risk of death from the AE as it occurs.  It does not apply if an AE 
hypothetically might have caused death if it were more severe. 
 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
− A participant admitted to a hospital, even if he/she is released on the same day, meets the 
criteria for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization criteria. 
However, emergency room visits that do not result in admission to the hospital would not 
qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious (e.g., life threatening adverse experience, important medical event). 


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− Hospitalizations for reasons not associated with the occurrence of an AE (e.g., preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner) do not qualify for reporting.  
◦ 
For example, if a participant has a condition recorded on his/her medical history and 
later has a preplanned surgery for this condition, it is not appropriate to record the 
surgery or hospitalization as an SAE, since there is no AE upon which to assess the 
serious criteria.  
◦ 
Please note that, if the pre-existing condition has worsened or manifested in an unusual 
or uncharacteristic manner, this would then qualify as an AE and, if necessary, the 
seriousness of the event would need to be determined. 
 
• Results in persistent or significant disability or incapacity. 
− This serious criterion applies if the “disability” caused by the reported AE results in a 
substantial disruption of the participant’s ability to carry out normal life functions. 
 
• Results in a congenital anomaly or birth defect in the offspring of the participant (whether the 
participant is male or female). 
 
• Is an important medical event that, based upon appropriate medical judgment, may jeopardize 
the participant and may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the definition of serious. 
− Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
9.4. 
Reporting and Recording AEs 
The Investigator will carefully monitor each participant throughout the study for possible AEs.  In 
order to ensure complete safety data collection, all AEs occurring during the study (i.e., after the 
signing of the Informed Consent form), including the pre-treatment period required by the 
protocol, must be reported in the CRF even if no IMP was taken but specific study procedures 
were conducted. This includes all AEs not present prior to the initial visit and all AEs that recurred 
or worsened after the initial visit.   
 
All AEs will be collected and reported in the electronic data capture (EDC) system and compiled 
into reports for periodic reviewing by the Medical Monitor. The Medical Monitor shall promptly 
review all information relevant to the safety of the investigational product, including all serious 
adverse events (SAEs). Special attention will be paid to those that result in permanent 
discontinuation of the investigational product being studied, whether serious or non-serious. 
  
If the investigator learns of any SAE, including a death, at any time after a participant has been 
discharged from the study, and he/she considers the event to be reasonably related to the IMP or 
study participation, the investigator must promptly notify the sponsor (or designee). 
 
Serious AEs that occur more than 30 days after the last dose of IMP need not be reported unless 
the investigator considers them related to the IMP. 
 


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9.4.1. 
Assessment of AEs 
Adverse events will be solicited in a consistent manner at every study visit. Participants will be 
asked uniform open-ended questions to elicit any medically related changes in their well-being. 
They will also be asked if they have been hospitalized, had any accidents, used any new 
medications, changed concomitant medication regimens (prescription or OTC medications), 
noticed any changes in bowel habits or had unplanned visits to their general practitioner since the 
last visit.  
 
In addition to participant observations, AEs identified from any study data (e.g., laboratory values, 
physical examination findings, ECG changes) or identified from review of other documents (e.g., 
participant diaries) that are relevant to participant safety will be documented on the AE page in the 
CRF. 
 
If the participants reports an adverse event, the following will be recorded in the source and on the 
eCRF:  
1. Description of the event  
2. Date and time of onset and resolution (duration)  
3. Record grading as per appropriate toxicity scale 
4. Seriousness (does the event meet the above definition for an SAE) 
5. Causality, relation to investigational product  
6. Action taken regarding investigational product  
7. Outcome 
8. If any Concomitant Medications were given 
9. Whether the AE resulted in participant withdrawal from the study 
10. Investigator-specified assessment if the AE is related to a recent/current COVID 
infection 
11. If a COVID positive PCR test received within the last 14 days 
 
Signs or symptoms of a participant’s atopic dermatitis should be recorded as AEs only if their 
nature changes considerably or their frequency or intensity increases in a clinically significant 
manner as compared to the clinical profile known to the Investigator from the participant’s history.   
 
9.4.2. 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the participant’s 
daily activities or their health. The intensity of the AE will be rated in accordance with the CTCAE 
Version 5.0.  Adverse events related to temperature and abnormal laboratory results that are not 
found in the CTCAE Version 5.0 will be rated in accordance with the FDA Guidance for Industry 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials [Appendix 14.5 Toxicity Grading Scale]. 
 
Changes in the severity of an AE should be documented to allow an assessment of the duration of 
the event at each level of intensity to be performed. Adverse events characterized as intermittent 
do not require documentation of onset and duration of each episode. 
 


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9.4.3. 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to IMP is part of the documentation process. 
Regardless of the investigator's assessment of an AE's relationship to IMP, the AE must be 
reported.  
 
The relationship or association of the IMP in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
 
Unrelated:  
 
There is no association between the IMP and the reported events. 
 
Possible: 
Treatment with the IMP may have caused or contributed to the AE, i.e., the 
event follows a reasonable temporal sequence from the time of drug 
administration or follows a known response pattern to the IMP but could also 
have been produced by another factor. 
 
Probable: 
A reasonable temporal sequence of the event with drug administration exists 
and, based upon the known pharmacological action of the drug, known or 
previously reported adverse reactions to the drug or class of drugs, or judgment 
based on the investigator’s clinical experience, the association of the event with 
the IMP seems likely. The event disappears or decreases on cessation or 
reduction of the dose of IMP. 
 
Definite: 
A definite causal relationship exists between drug administration and the AE, 
and other conditions (concurrent illness, progression/expression of disease 
state, or concurrent medication reaction) do not appear to explain the event. The 
event reappears or worsens if the IMP is re-administered. 
 
9.4.4. 
Description of Adverse Events 
When recording an AE, the Investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF and 
source documents should be consistent. Any discrepancies between the participant’s own words 
on his/her own records (e.g., diary card) and the corresponding medical terminology should be 
clarified in the source documentation. 
 
Details for completion of the Adverse Event eCRF are described in the eCRF Completion 
Guidelines. 
 
9.4.4.1. Rule for Repetition of an AE 
An increase in the intensity of an AE should lead to the repetition of the AE being reported with: 
 
• The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening”. 
 
• The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one. 
 




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9.7. 
Overdose  
Excessive dosing (greater than 4 capsules within 24 hours) should be recorded in the CRF. 
Participants will be instructed to contact the Investigator or study coordinator immediately in the 
event of a suspected overdose. 
 
Any overdose must be promptly reported to 
 via the Special Situations 
Form. Overdose itself is not to be reported as an AE. However, any AEs or SAEs associated with 
the overdose are to be reported on relevant AE/SAE sections in the eCRF and on the Paper SAE 
Form provided to 
 (Section 9.5 Reporting Serious Adverse Events).  
 
In the event of a symptomatic overdose, the Investigator should: 
 
1. Manage the patient symptomatically with supportive care. 
2. Contact the Medical Monitor urgently. 
3. Document the quantity of the excess dose in the eCRF. 
4. Document the overdose symptoms and their duration in the eCRF. 
 
Doses of EDP1815 capsules that have previously been administered include a dose of 8.0 x 1011 
cells taken once daily for 16 weeks, and 1.28 x 1012 cells taken once daily for 8 weeks. There are 
no specific expected adverse events expected in an overdose, but the participant should be closely 
and carefully monitored. There is no specific treatment or antidote, but supportive clinical care 
should be provided as dictated by the participant’s clinical status. 
 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
 
9.8. 
Safety Signal Detection 
Selected data from this study will be reviewed periodically in a blinded fashion to detect as early 
as possible any safety concern(s) related to the IMP so that Investigators, clinical study 
participants, regulatory authorities, and IRBs/IECs will be informed appropriately and as early as 
possible. 
 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs.  
DM will perform ongoing SAE reconciliations in collaboration with the PV 
representative. 
 
As appropriate for the stage of development and accumulated experience with the IMP, medically 
qualified personnel at the Sponsor may identify additional safety measures (e.g., AEs, vital signs, 
laboratory or ECG results) for which data will be periodically reviewed during the course of the 
study. 
 
9.9. 
Study Halting Criteria 
The study will be halted if any of the following occur: 
• One fatal SAE considered definitely, probably, or possibly related to the investigational 
product. 
 


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• Two or more participants with a non-fatal SAE considered definitely, probably, or possibly 
related to the investigational product. 
 
• Three or more participants with grade 3 AEs of the same type considered definitely, 
probably, or possibly related to the investigational product.  
 
• Any participant develops a documented Prevotella histicola infection in a sterile space 
confirmed by clinical culture and/or qPCR. 
 
9.10. Laboratory Measurements 
Standard laboratory analyses to understand safety and tolerability include the following 
measurements: 
 
Hematology 
Biochemistry 
Urinalysis 
Complete Blood Count 
with differentials: 
Alanine Aminotransferase 
(ALT) 
Bilirubin 
Hemoglobin 
Aspartate Aminotransferase 
(AST) 
Blood 
Hematocrit 
Creatinine 
Glucose 
Platelet count 
C-Reactive Protein (CRP) 
Ketones 
Red blood count (with 
percent reticulocytes) 
Gamma-glutamyl 
transpeptidase (GGT) 
Nitrites 
Mean Corpuscular 
Hemoglobin (MCH) 
Potassium 
pH 
Mean Corpuscular 
Hemoglobin 
Concentration (MCHC) 
Sodium 
Protein 
Mean Corpuscular 
Volume (MCV) 
Total Bilirubin 
Specific 
Gravity 
White blood cell count: 
Urea 
 
Basophils 
 
 
Eosinophils  
 
 
Lymphocytes 
 
 
Monocytes  
 
 
Neutrophils 
 
 
 
A serum pregnancy test will be performed on women of childbearing potential (WOCBP) at the 
Screening Visit.  Urine pregnancy testing will be conducted on Day 1 and then monthly thereafter.   
 
Additional testing may be ordered if needed, to further assess an adverse event (AE), or if there is 
any suspicion that a subject may be pregnant, throughout the course of the study. 
 
Only abnormal laboratory test results (hematology, clinical biochemistry, or urinalysis) or other 
safety assessments (e.g., ECGs, vital sign measurements), which are clinically significant in the 
medical and scientific judgment of the investigator, are to be recorded as AEs or SAEs.  


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A central laboratory (or specialized central laboratories) will be used for all laboratory analyses. 
Details of sample collection and handling procedures will be provided in the specific laboratory 
manual.  
 
9.10.1. Review of Laboratory Measurements 
The Investigator must review the laboratory reports, document this review, and record any 
clinically relevant changes occurring during the study. If the laboratory reports are not transferred 
electronically, the values must be filed with the source information (including reference ranges). 
In most cases, clinically significant abnormal laboratory findings are those that are not associated 
with the underlying disease, unless judged by the Investigator to be more severe than expected for 
the participant's condition. 
 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 30 days after the last dose of IMP should be repeated until the values return 
to normal or baseline value or are no longer considered clinically significant by the Investigator or 
Medical Monitor. If such values do not return to normal/baseline within a time judged reasonable 
by the Investigator, the etiology should be identified, and the Sponsor notified. 
 
All protocol-required laboratory assessments, as defined in this section, must be conducted in 
accordance with the laboratory manual and the SOA. Screening laboratory results will be used to 
confirm eligibility at Day 1.  If laboratory values from non-protocol specified laboratory 
assessments performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the Investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded on the Adverse Events eCRF.  
 
9.10.2. Blood Volumes 
The planned maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 145 mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. The 
planned maximum amount of blood collected from each participant at a single visit will not exceed 
25 mL, and the planned maximum amount of blood collected from each participant over 30 days 
will not exceed 48 mL. 
 
9.11. Biomarkers 
 
9.11.1. Genetic Testing 
Optional blood samples may be collected at Day 1 for genetic testing, such as human leukocyte 
antigen (HLA) typing and whole genome sequencing (WGS). The data will be used to correlate 
with the clinical outcomes in order to identify patient group(s) who may benefit the most from 
EDP1815 treatment.  Only genetic variants that cause different responses to EDP1815 will be 
assessed.  This sample will be stored for a maximum of 10 years and will be destroyed if not used 
within this time. This is an optional collection sample where local regulations and IRBs/IECs 
allow.  This sample will only be collected on those participants who consent to participate in this 
optional blood collection for genetic testing. 
 


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9.11.2. Immune Protein Markers 
Immunoglobulin E (IgE) are antibodies produced by the immune system and are often raised in 
patients with AD, particularly with the phenotype known as ‘extrinsic’ AD (Renert-Yuval, 2021). 
IgE is a recognized biomarker of disease severity in AD and is regularly measured in clinical 
practice. It is being measured in participants to see if treatment response can be predicted by Day 
1 IgE level, and also whether IgE levels improve on treatment as a biomarker of treatment success.  
In addition to the IgE levels, other immune protein markers such as cytokines may be measured 
from this sample in order to assess the anti-flammatory and disease-modifying effects of EDP1815. 
These samples will be collected at Day 1 and Week 16.  
 
9.11.3. Transcription Analysis 
RNA will be collected from whole blood samples at Day 1, Week 2, Week 16 and Week 20 to 
quantify inflammation markers in immune cells to assess the effect of EDP1815.  These samples 
may be analyzed subject to the clinical data in the trial.  The genes to be analyzed may include 
those related to host immune response as well as those related to the disease pathology.   
 
9.11.4. Microbiome Sample 
A fecal sample will be collected within 7 days of Day 1 to enable microbiome sampling. The 
purpose of this sample will be to perform analysis of stool bacterial DNA, to see if there is a 
correlation between background microbial content in the large intestine, and response to treatment 
with EDP1815. Participants will be provided with a fecal collection kit and instructions at the 
Screening Visit with instructions to bring the sample in at their Day 1 visit.  Any participant that 
enrolls in the study under Protocol Version 5.0 is not required to provide a fecal sample. 
  
9.12. Other Safety Measurements 
 
9.12.1. Vital Signs, Height and Weight 
Vital signs will be obtained after the participant has been in a seated position for approximately 5 
minutes. Vital signs, including systolic and diastolic blood pressure, pulse rate (radial 
artery)/minute, respiratory rate/minute, and temperature.  Height will be measured and recorded at 
the Screening Visit only. Weight will be assessed at specified visits (without shoes and street 
clothing).  Body mass index will be calculated from the height and weight.  Investigators should 
pay special attention to clinical signs related to previous serious illness.  
  
9.12.2. Physical Examination 
A physical examination (PE) will be performed and recorded in source at specified visits.  Only 
abnormal, clinically significant findings will be recorded as AEs on the eCRF. 
 
The following systems will be examined when a full PE is indicated: general appearance, 
cardiovascular, respiratory, gastrointestinal, musculoskeletal, central nervous system, lymph 
nodes and skin.  
 
The following systems will be examined when a brief PE is indicated: general appearance, 
cardiovascular, respiratory, gastrointestinal and skin. 
 


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9.12.3. 12-Lead Electrocardiogram 
A single 12-lead electrocardiogram (ECG) will be obtained at specified visits using an ECG 
machine that automatically calculates heart rate and measures PR, RR, QRS, and QT interval.  
QTcF (Fridericia) intervals will be auto derived and populated in the case report form (CRF).   
 
A single ECG tracing is to be obtained on the day of the visit after the participant has been in a 
lying position for approximately 5 minutes.  If in the opinion of the Investigator, there appear to 
be clinically significant findings, it should be repeated.  If the repeated tracing also appears 
clinically significant, the Investigator should report the abnormality as an AE and consult with the 
Medical Monitor to decide whether the participant should continue treatment in the study. 
 
9.13. Non-Safety Measurements 
 
9.13.1. Digital Photography 
Digital photographs should be taken of the upper and lower body (upper & lower anterior and 
upper & lower posterior) as half body shots at Day 1.  Additional photographs of up to six specific 
body areas, i.e., limbs, trunks, and back, will also be taken.  The same locations photographed at 
Day 1 should be followed through the study for each participant.    
 
Procedural details for digital photography will be provided to the sites. 
 
 


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10. STUDY MANAGEMENT AND ADMINISTRATION 
 
10.1. Adherence to protocol 
A deviation from the protocol is an unintended or unanticipated departure from the procedures or 
processes approved by the Sponsor and the IRB/IEC and agreed to by the Investigator. A 
significant deviation occurs when there is non-adherence to the protocol or to local regulations or 
ICH GCP guidelines that may or may not result in a significant, additional risk to the participant 
or impacts the integrity of study data. 
 
The Investigator should not deviate from the protocol. However, the Investigator may implement 
a deviation from, or a change of, the protocol to eliminate an immediate hazard/safety risk to study 
participants without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review and approval, to the Sponsor for agreement, and to 
the regulatory authorities, where required.  The deviation should be well documented in the 
participant’s source documentation. 
 
In order to keep deviations from the protocol to a minimum, the Investigator and relevant site 
personnel will be trained in all aspects of study conduct by the Sponsor or Sponsor representative. 
This training will occur either as part of the Investigator’s Meeting or Site Initiation Visit (SIV). 
Ongoing training may also be performed throughout the study during routine site monitoring 
activities. 
 
10.2. Monitoring 
Monitoring of the study will be delegated by the Sponsor to 
 the Clinical Research 
Organization (CRO) handling project, data and site management. 
 will monitor the study to 
meet their monitoring Standard Operating Procedures (SOPs), the monitoring plan, ICH-GCP 
guideline, and applicable regulatory requirements, and to ensure that study initiation, conduct, and 
closure are adequate.  
 
The Investigator and site staff are expected to cooperate with the Sponsor and 
and to be 
available during the monitoring visits (whether onsite or remote, if needed) to answer questions 
sufficiently and to provide any missing information. The Investigator(s)/institution(s) will permit 
direct, secure access to source data/documents for study -related monitoring, audits, IRB/IEC 
review, and regulatory inspection(s). 
 
The Investigator will allow the Sponsor or 
 to periodically review all eCRFs and 
corresponding source documents (e.g., hospital and laboratory records for each study participant). 
Monitoring visits (whether onsite or remote, if needed) will provide the Sponsor and 
with the 
opportunity to evaluate the progress of the study, verify the accuracy and completeness of CRFs, 
ensure that all protocol requirements, applicable authorities regulations, and investigator’s 
obligations are being fulfilled, and resolve any inconsistencies in the study records. 
 
10.2.1. Definition of Source Data  
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 


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pharmacy records, care records, ECG or other printouts, completed scales, quality of life 
questionnaires, certified copies or video, for example. Source documents should be kept in a 
secure, limited access area. 
 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments (such 
as removable self-stick notes). Photocopies and/or printouts of CRFs are not considered acceptable 
source documents. 
 
The following data will be considered as electronic source and therefore, will not be recorded 
directly into the EDC and will not appear in a separate source document as defined above. 
However, paper source documents may be utilized for collection of PROs and COAs listed below 
should there be an unforeseeable circumstance (such as a power outage) and the electronic source 
is unavailable.  Any information about a participant that is collected during this study will remain 
secured and confidential and will be handled per applicable regulations (i.e., data collected via 
mobile applications). 
 
• Participant Electronic Diary (eDiary) including IMP, emollient and rescue therapy 
usage and PP-NRS and SD-NRS daily questionnaire. A paper diary will be utilized 
between the Screening and Day 1 Visits to collect participant information on emollient 
usage, participant’s worst itch and participant’s sleep. 
 
• Patient Reported Outcome Measurements (PROs), including POEM, DLQI, ADCT, 
SF-12, and HADS. 
 
• Clinician Outcome Assessments (COAs) including EASI, BSA, vIGA, and SCORAD. 
 
Source documents that are computer generated and stored electronically must be printed for review 
by the monitor (e.g., ECG reports, laboratory reports). Once printed, these copies should be signed 
and dated by the Investigator and become a permanent part of the participant’s source documents. 
The Investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
 
10.2.2. Source Data Verification 
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (e.g., participant files, recordings from automated instruments, tracings [ECG], 
x-ray films, laboratory notes). All data reported on the eCRF should be supported by source 
documents, unless otherwise specified in Section 10.2.1 Definition of Source Documents. 
 
10.3. Data Management 
 
10.3.1. Data Quality Assurance 
This study will be conducted according to ICH E6(R2) risk and quality processes described in the 
applicable procedural documents.  The quality management approach to be implemented in this 


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study will be documented and will comply with the current ICH guidance on quality and risk 
management.  The Sponsor assumes accountability for actions delegated to 
 
 
10.3.2. Case Report Form Completion 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
electronic CRFs and in all required reports.  Any change or correction to the CRF after saving must 
be accompanied by a reason for the change. Corrections made after the Investigator’s review and 
approval (by means of a password/electronic signature) will be reapproved by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the electronic 
CRF. 
 
Detailed instructions will be provided in the CRF Completion Guidelines. 
 
10.3.3. Data Entry and Reconciliation 
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database that is validated and compliant with US Title 21 CFR Part 11.  Each person involved with 
the study will have an individual username and password that allows for record traceability. 
 
Computerized data cleaning checks will be used in addition to manual review to check for 
discrepancies and to ensure consistency of the data. A quality review of the data will be performed 
by the site with additional reviews by the clinical monitor through source data verification.  
 
An electronic audit trail system will be maintained within the CDMS to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed. 
 
Paper copies of the eCRFs and other database reports may be printed by the investigator. 
This system provides site staff, monitors, and reviewers with access to hard copy audits, 
discrepancy reviews, and investigator comment information.  
 
After all data reviews and query resolutions are complete, the SAP is approved and signed, and 
any summary/analysis populations are approved, the database will be locked. 
 
10.3.4. Participant Screening & Enrollment Log/Participant Identification Code List 
The participant’s Screening and Enrollment will be recorded in the Participant Screening and 
Enrollment Log. 
 
The Investigator will keep a Participant Identification Code list. This list remains with the 
Investigator and is used for unambiguous identification of each participant. 
 
The participant’s consent and enrollment in the study must be recorded in the participant’s medical 
record. These data should identify the study and document the dates of the participant’s 
participation. 
 


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10.4. Termination of the Study 
The Sponsor reserves the right to temporarily suspend or prematurely discontinue this study either 
at a single site, multiple sites, or at all sites at any time for any reason including, but not limited 
to, safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
 
If the study is prematurely terminated or suspended, the Sponsor (or its representative) will inform 
the Investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the Sponsor or by the Investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of all 
unused IMP/investigational device and other material in accordance with the Sponsor’s procedures 
for the study. 
 
10.5. Archiving and Data Retention 
The Investigator will maintain adequate records for the study, including CRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data. 
 
All essential documents are to be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP/investigational device. These 
documents should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or by an agreement with the Sponsor (EMEA, 2002 Jul). 
 
The Investigator will contact the Sponsor for authorization prior to the destruction of any study 
records or in the event of accidental loss or destruction of any study records. The Investigator will 
also notify the Sponsor in writing should he/she relocate or move the study--related files to a 
location other than that specified in the Sponsor’s Trial Master File (TMF). 
 
10.6. Audit and Inspection 
The Investigator will permit study--related audits mandated by the Sponsor, after reasonable 
notice, and inspections by domestic or foreign regulatory authorities. 
 
The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
participants enrolled have been protected, that enrolled participants (i.e., signing consent and 
undergoing study procedures) are appropriate for the study, and that all data relevant for the 
evaluation of the IMP/investigational device have been processed and reported in compliance with 
the planned arrangements, the protocol, investigational site, and IRB/IEC SOPs, ICH GCP, and 
applicable regulatory requirements. 
 
The Investigator will provide direct access to all study documents, source records, and source data. 
If an inspection by a regulatory authority is announced, the investigator will immediately inform 
the Sponsor (or designee). 


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10.7. Good Clinical Practice 
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the Investigator, 
institution, institution staff, or designees of the Sponsor will lead to prompt action by the Sponsor 
to secure compliance. Continued noncompliance may result in the termination of the site’s 
involvement in the study. 
 
 


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11. STATISTICS 
 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan.   
 
11.1. Definition of Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
 
11.1.1. Participant Analysis Sets 
Enrolled set: The enrolled set will consist of all participants who sign the ICF. 
 
Full analysis set: The FAS set will consist of all participants who were randomized to treatment. 
All analyses using the FAS will group participants according to randomized treatment. 
 
Safety analysis set: The SAS will consist of all participants who received any IMP. All analyses 
using the safety set will group participants according to treatment received.  
 
11.1.2. Defined Data Point Sets 
The following efficacy data point sets (EDPS) and safety data point sets (SDPS) are defined: 
 
EDPS1:  Consists of all data collected at a scheduled timepoint that is at least 28 days after use of 
topical corticosteroid rescue therapy. Data collected less than 28 days after such use or data missing 
due to withdrawal from the study for reasons considered related to study medication will be 
replaced as follows: 
• Continuous endpoints: value will be imputed with the last off-rescue observation carried 
forward (off-rescue is defined as data collected at least 28 days after use of rescue medication) 
• Responder endpoints: value will be imputed as non-response. 
• Count endpoints: N/A (No count endpoint will use this DPS). 
Data missing for other reasons, including early withdrawal from the study due to reasons not 
considered related to study medication will not be replaced and will be considered as missing. 
 
EDPS2: Consists of all data collected at a scheduled timepoint that is at least 28 days after use of 
topical corticosteroid rescue therapy. Data collected less than 28 days after such use will be 
considered as missing and excluded from the analysis. Data missing due to withdrawal from the 
study for reasons considered related to study medication will be imputed as per DPS1. Data 
missing for other reasons will not be replaced. 
 
EDPS3: Consists of EASI-50 responses collected at Week 16 that were evaluated at least 14 days 
after use of topical corticosteroid rescue therapy. Data collected less than 14 days after such use 
or missing due to withdrawal from the study for reasons considered related to study medication 
will be imputed as non-response. 
 
EASI-50 response missing for other reasons, including early withdrawal from the study due to 
reasons not considered related to study medication will not be replaced and will be considered as 
missing. 
 


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EDPS4: Consists of EASI-50 responses collected at Week 16 that were evaluated at least 28 days 
after use of topical corticosteroid rescue therapy. Data collected less than 28 days after such use 
will be replaced as per DPS1.  Data missing due to other reasons including early withdrawal from 
the study for any reason will not be replaced and be considered as missing.  
 
EDPS5: Is a subset of DPS1 for the EASI-50 response data only, excluding any data collected or 
imputed after the use of a prohibited medication or the unblinding of a participant (whichever 
occurs first) and excluding all data from subjects who take <75% of expected doses or whose 
compliance with emollient use was <75% or did not complete the 12-week treatment period. 
 
EDPS6: Consists of data collected in the absence of topical corticosteroid rescue therapy at any 
time since Day 1 for the responder endpoints relating to EASI, vIGA and PP-NRS. Data collected 
after such use or missing due to withdrawal from the study for reasons considered related to study 
medication will be imputed as non-response. 
 
Responses missing for other reasons, including early withdrawal from the study due to reasons not 
considered related to study medication will not be replaced and will be considered as missing. 
 
EDPS7: Contains all data collected as part of a count endpoint. A treatment policy strategy will be 
used for all intercurrent events other than discontinuation from the study which will use a while 
on treatment strategy (i.e., the collection period will be ended at the time of study discontinuation). 
 
SDPS1: Consists of all observed data collected at a scheduled visit.  
 
SDPS2: Consists of all observed data collected, including data from scheduled and unscheduled 
visits. 
 
The FAS with EDPS1 are used to estimate the primary estimand and all secondary and exploratory 
estimands (excluding those relating to count endpoints). 
 
The FAS with EDPS2-EDPS6 will be used to estimate supplementary estimands for the primary 
endpoint.  The FAS with EDPS2 and EDPS6 will be used to estimate supplementary estimands for 
selected secondary estimands. 
 
The FAS with EDPS7 are used to estimate the secondary estimands relating to count endpoints. 
 
The SAS and SDPS1 are used to present safety data assigned to specific scheduled visits. 
 
The SAS and SDPS2 are used to present all other safety data, including adverse events. 
 
Note that all subjects who withdraw from the study prematurely will be evaluated prior to database 
lock and unblinding will have their reason for withdrawal evaluated as being related or non-related 
to study medication.   
 
11.2. General Statistical Considerations 
Statistical analysis will be performed using SAS software Version 9.3 or later.  


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Continuous variables will be summarized using the mean, standard deviation, median, minimum 
value, and maximum value. Categorical variables will be summarized using frequency counts and 
percentages. Daily time to event response endpoints will be summarized using the Kaplan-Meier 
estimates of the proportion of responders in each study week together with the estimated median 
and quartiles for time to response. 
 
Descriptive statistics will also be used extensively in figures to visualize the data.  These include 
but are not limited to mean (SE) or LS Mean (95% CI) plots against time, waterfall plots for 
individual changes at a specific time point, vertical bar plots showing percentages of responders 
and Kaplan-Meier plots. 
Data will be listed in data listings. 
 
Baseline will be defined as the last non-missing data available prior to the first dose of IMP. Data 
on Day 1 will be assumed to have been collected before first dose of IMP. 
 
The subgroup of participants with IGA=3 at Day 1 will be used to perform subgroup analyses on 
the primary estimand. Data for the subgroups defined by IGA=2 and IGA=4 at baseline will be 
summarized but no analysis done as the sample sizes are not expected to be large enough for 
meaningful comparisons to be made. 
 
The focus of this study is on model estimation of treatment effects and as such no adjustments will 
be made for multiple testing in this study. 
 
Two sets of tables, figures and listings will be provided, one for the combined analysis of Cohorts 
1-3 and one for the analysis of Cohort 4. 
 
Cohort 1-3 Analysis 
The placebo participants from Cohorts 1, 2 and 3 will be pooled and compared to the following 
active treatment groups: 
• EDP1815 1.6x1011 QD (Cohort 1) 
• EDP1815 6.4x1011 QD (Cohort 2) 
• EDP1815 3.2x1011 BID (Cohort 3) 
• EDP1815 6.4x1011 Daily (Cohorts 2 and 3) 
• All EDP1815 (Cohorts 1, 2 and 3) 
 
For the primary analysis, the first three comparisons using the individual cohorts only will be 
considered as primary with the pooled active comparisons considered as secondary. 
 
The following comparisons between active treatment groups will also be performed but will be 
considered as exploratory in nature: 
• EDP1815 6.4x1011 QD (Cohort 2) vs EDP1815 3.2x1011 BID (Cohort 3) 
• EDP1815 1.6x1011 QD (Cohort 1) vs EDP1815 6.4x1011 QD (Cohort 2) 
 
Cohort 4 Analysis: 


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The analyses for Cohort 4 will compare EDP1815 8.0x1010 to a combined control group including 
the Cohort 4 placebo participants (approximately 35) and set of matched placebo participants from 
Cohorts 1-3 (approximately 35). This will provide a total of approximately 70 placebo participants, 
resulting in a 1:1 comparison between EDP1815 8.0x1010 and placebo. This combined placebo 
cohort will be referred to as the Cohort 4 Matched Placebo group. 
 
While not enrolled concurrently to Cohort 4, the Cohort 1-3 placebo group provides an appropriate 
population to supplement the Cohort 4 placebo group, increasing the power of the comparison of 
EDP1815 8.0x1010 to placebo and precision of the treatment effect estimates (Viele, 2014). A 
propensity-score based matching algorithm will be used to select patients from the Cohort 1-3 
Placebo group in to order balance key baseline characteristics (Austin, 2011). Matching will be 
performed based on propensity scores derived from baseline characteristics such as IGA, EASI 
score, BSA, gender, and country. Full details of the matching algorithm are provided in the SAP.  
 
Summary tables for Cohort 4 will include a column for the Cohort 4 Only Placebo group in 
addition to columns for the Cohort 4 Matched Placebo group as well as the EDP1815 8.0x1010 
group.  
 
Analysis tables and figures will include only the Cohort 4 Matched Placebo group and the 
EDP1815 8.0x1010 group and all primary and secondary comparisons will be between these two 
groups. 
 
As an exploratory analysis, analyses may be repeated including the EDP1815 1.6x1011 QD (Cohort 
1) treatment group in the statistical models for Cohort 4. For these analyses the comparison of 
interest will be between the two active EDP1815 treatment groups (Cohort 1 vs Cohort 4). 
  
11.3. Estimands and Intercurrent Events 
 
11.3.1. Primary Estimand and Supplementary Estimands of the Primary Objective 
The primary estimand and the supplementary estimands for the primary objective will consider the 
effect of each individual EDP1815 cohort compared to the relevant placebo group (Cohort 1-3 
Pooled Placebo for comparisons to C1-3 EDP1815 groups; and Cohort 4 Matched Placebo for 
comparison to the Cohort 4 EDP1815 group) on the percentage of participants achieving EASI-50 
at Week 16.  
 
The population summary measure of interest will be the odds ratio between each active EDP1815 
treatment group and the relevant placebo group. 
 
The FAS participant analysis set will be used. 
 
Strategies for intercurrent events will be accounted for in the following manner using the relevant 
EDPS as follows: 
 












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Actual and predicted probabilities of EASI-50 at Week 16 for each treatment group will be plotted.   
 
11.4.2. Analysis of Supplementary Estimands on the Primary Objective 
The four supplementary estimands defined for the primary objective will be analyzed in the same 
manner as the primary estimand. 
 
For the potential covariates of body mass index, gender, race and region: those covariates found 
to be significant in the primary analysis will be included in all models regardless of significance 
in order to ensure comparability of the models. 
 
11.4.3. Cohort 4 Sensitivity Analysis of the Primary Estimand 
A Bayesian dynamic borrowing method using a commensurate prior will be used for the placebo 
comparator in the primary analysis model, utilizing all Cohort 4 data and Cohort 1-3 placebo data 
(Hobbs, Carlin, Mandrekar, & Sargent, 2011). In contrast to the primary analysis method, this 
sensitivity analysis will borrow information from the Cohort 1-3 placebo patients dependent on 
the similarity in outcomes between the Cohort 4 and Cohorts 1-3 placebo groups further sensitivity 
analyses for the primary and secondary endpoints may also be performed on the Cohort 4 data 
either using the same dynamic borrowing methodology or using the Cohort 4 only placebo group 
as the comparator. Full details are provided in the SAP.  
 
11.4.4. Analysis of Secondary Estimands 
Continuous secondary estimands will be analyzed using a mixed model for repeated measures 
(MMRM) with parameters for treatment group, visit, baseline IGA score and relevant baseline 
score and the interaction for treatment*visit.   
 
For the potential covariates of body mass index, gender, race and region: those covariates found 
to be significant in the primary analysis will be included in all models regardless of significance 
in order to ensure comparability of the models. 
 
Least squares mean estimates and their 95% confidence intervals (CI) will be presented for the 
endpoint value at each visit. Treatment differences between each EDP1815 group and the pooled 
placebo group will be estimated using LS mean differences, 95% CI and p-values. Pairwise 
treatment differences between EDP1815 groups will be estimated with LS mean differences and 
95% CI. 
 
Least square mean (95% CI) estimates will be plotted against visit.  Least square mean (95% CI) 
treatment differences between each EDP1815 treatment group and the pooled placebo group will 
also be plotted against visit. 
 
Response estimands will be analyzed with a generalized linear mixed effects model with a logit 
link function. Treatment, visit, baseline IGA and the appropriate baseline questionnaire score will 
be included as parameters together with the treatment*visit interaction.  Odds ratios with 95% CIs 
and p-values for each EDP1815 group compared to the relevant pooled placebo group at each visit 
will be presented.  Odds ratios and 95% CIs will be presented for any comparisons between two 
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In the event that there are no responders in one of the treatment groups at a visit, data from that 
visit will be excluded from the model and only summary statistics will be produced showing the 
number and percentage of responders at that visit. 
 
Count estimands will be analyzed with a Poisson regression model fitted with treatment and 
baseline IGA as covariates. An offset of log (days in study) will also be included in the model to 
account for any data from participants who withdrew early from the study. If the distribution of 
the count data suggests over-dispersion and/or zero inflation, then other models including the 
negative binomial or zero-inflated Poisson model may be considered. 
 
Model estimated event rates and their 95% confidence intervals will be presented for each 
treatment group. Rate ratios with 95% CIs and p-values for each EDP1815 group compared to the 
relevant pooled placebo group at each visit will be presented.  Rate ratios and 95% CIs will be 
presented for any comparisons between two EDP1815 treatment groups. 
 
11.4.5. Analysis of Exploratory Estimands 
Exploratory endpoints will be summarized only. No inferential analysis is planned. 
 
For the daily PP-NRS and SD-NRS endpoints which are evaluated daily only graphical summaries 
will be presented.  
 
For the time to first response endpoints for the PP-NRS and SD-NRS scores, participants who have 
not met the response definition before the Week 16 visit will be censored at the Week 16 visit, or 
at the time of withdrawal from the study for those who withdrew before Week 16. 
 
For the time to sustained response endpoints for the PP-NRS and SD-NRS scores, it will not be 
possible for participants to start a sustained response less than two weeks before the Week 16 visit.  
Therefore, such participants will be censored at 14 days before the date of the Week 16 visit or at 
the time of treatment withdrawal for participants who do not complete the 16-week treatment 
period. 
 
For the primary and secondary responder endpoints relating to EASI, IGA and BSA, summaries 
will be provided comparing the number and percentage of participants in each treatment group 
who respond at Week 16 between the following 4 subgroups: 
• Participants with no rescue therapy use 
• Participants with no rescue therapy use after the Week 4 visit 
• Participants with no rescue therapy use after the Week 8 visit 
• Participants with no rescue therapy use within 4 weeks of the Week 16 visit 
• Participants with no rescue therapy use within 2 weeks of the Week 16 visit  
• Participants with rescue therapy use within 4 weeks of the Week 16 visit 
• Participants with rescue therapy use within 2 weeks of the Week 16 visit  
For these endpoints, all participants who have Week 16 data available for the relevant endpoint 
will be included and there will be no imputation for any intercurrent events. 
 


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For the Cohorts 1-3 analyses, pairwise treatment differences between two EDP1815 treatment 
groups will be estimated as part of the modelling done for the primary and secondary analyses, but 
such estimates will be considered as exploratory. 
 
For the Cohort 4 analyses of the primary and selected secondary estimands, separate models will 
be used which include the EDP1815 1.6x1011 (Cohort 1) treatment group in addition to the Cohort 
4 EDP1815 8.0x1010 group and the Cohort 4 Matched Placebo group. From these tables, pairwise 
treatment differences between the two active EDP1815 groups will be estimated, with all such 
estimates being considered as exploratory. 
 
11.4.6. Analysis of Safety Estimands 
All safety data will be summarized by treatment group using the safety set and the data point set 
appropriate for the endpoint type.  
 
11.4.7. Other Analyses 
Tabulations will be provided for completion/withdrawal status, protocol deviations, study 
populations, demographic and other baseline characteristics, use of concomitant medications, and 
exposure to and compliance with IMP and emollients. 
 
11.5. Handling of Protocol Deviations 
Protocol deviations will be logged within the clinical trial management system and categorized 
dependent on the type of deviation and its significance.  
 
Protocol deviations relating to the use of prohibited medications, to non-compliance with study 
treatment (including non-compliant emollient use) and to unblinding of the study before database 
lock will be accounted for as intercurrent events in the primary analysis. 
 
11.6. Handling of Dropouts or Missing Data 
Unless otherwise specified, missing data will be considered as missing at random and will be 
accounted for using mixed models for repeated measures, with all time points collected for the 
relevant endpoint included in the model. 
 
Otherwise, missing data will not be imputed. 
 
11.7. Planned Interim Analysis and Data Monitoring 
An interim analysis may be undertaken prior to the end of recruitment for Cohorts 1,2 and 3. The 
purpose of this interim analysis is to check the sample size assumptions for placebo response rates 
and drop-out rates.  
 
The balance of participants enrolled to each treatment group will also be checked during this 
analysis. Due to the use of stratification by IGA at baseline at both the cohort and treatment-within-
cohort level, there may be up to 9 incomplete blocks of treatment assignments remaining at the 
end of randomization.  This may lead to imbalance between the cohorts and/or treatment groups.  
An unblinded team within the Biostatistical Vendor will review the overall numbers of participants 
randomized to each treatment group and as a result may specify to the IRS Vendor that the 
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individual treatment within a cohort are restricted and no longer available for use for the remaining 
participants to be randomized.  The aim of this will be to ensure that each of the four treatment 
groups has a minimum of 73 randomized participants. 
 
Blinded analyses of eCOA data will be performed during the recruitment period. As a result of 
these, possible changes in the conduct of the study may be to stop recruitment from one or more 
of the baseline IGA severity strata.  No other changes to study conduct are expected. 
 
The data for Cohorts 1, 2 and 3 will be locked, unblinded and analyzed before the end of Cohort 
4.  
 
11.8. Determination of Sample Size 
 
Cohorts 1-3 
The sample size was calculated using the assumption that data from the placebo participants in the 
three cohorts can be pooled prior to comparison with the EDP1815 treatment groups. No 
adjustments for multiple testing have been made. 
 
The primary efficacy endpoint is the achievement of EASI-50 at Week 16.  The pooled placebo 
response rate is estimated to be approximately 25% and a doubling of this to 50% for EDP1815 
would be considered as clinically meaningful. 
 
Using a two-sided test at the 5% level of significance, 58 participants in each treatment group 
would give 80% power to detect a difference in one of the EDP1815 cohorts compared to the 
pooled placebo group. There would also be more than 90% power to compare the pooled EDP1815 
6.4 x1011 daily dose or all the EDP1815 group to the pooled placebo group. 
 
Under the assumption of a 20% drop-out of participants prior to Week 16 this will require a total 
of at least 73 participants to be enrolled in each treatment group.  In order to allow for the 3:1 
randomization in each cohort this has been adjusted to 75 participants per treatment group to give 
a total of 300 participants recruited.  With 75 EDP1815 participants and 25 placebo participants in 
each of the three cohorts. 
 
Cohort 4 
Using the same assumptions relating to the placebo rate, clinically meaningful difference, 
significance level, and drop-out rate as above for Cohorts 1-3, approximately 70 participants are 
required in each of the EDP1815 8.0x1010 and Cohort 4 Matched Placebo groups to provide 
approximately 80% power in detecting a difference between EDP1815 and placebo in Cohort 4. 
 
In order to allow 50% of the placebo control group to be concurrent controls and 50% to be historic 
matched controls from Cohorts 1-3, a 2:1 randomization will be used to enroll 70 EDP1815 
8.0x1010 subjects and 35 placebo participants to Cohort 4. 
 
If sensitivity analyses indicate that pooling of the Cohort 4 placebo group with the Cohort 1-3 
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EDP1815 and placebo groups is approximately 65% if only Cohort 4 placebo participants could 
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12. ETHICS AND REGULATORY REQUIREMENTS 
 
12.1. Informed Consent 
Participant’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the participant in both oral and written form by the Investigator (or 
designee).  Each participant will have the opportunity to discuss the study and its alternatives with 
the Investigator. 
 
Prior to participation in the study, the Informed Consent Form (ICF) should be signed and 
personally dated by the participant, or his/her legal representative, and by the person who 
conducted the informed consent discussion (Investigator or medically licensed Sub-Investigator). 
The participant or his/her legal representative must receive a copy of the signed and dated ICF. As 
part of the consent process, each participant must consent to direct access to his/her medical 
records for study-related monitoring, auditing, IRB/IEC review, and regulatory inspection. 
 
If the ICF is amended during the study, the Investigator (or the Sponsor, if applicable) must follow 
all applicable regulatory requirements pertaining to the approval of the amended Informed Consent 
form by the IRB/IEC and use of the amended form. 
 
All studies conducted at centers in the United States must include the use of a Health Insurance 
Portability and Accountability Act Authorization form. 
 
The participant may withdraw his/her consent to participate in the study at any time. A participant 
is considered as enrolled in the study when he/she has signed the ICF. Study specific procedures 
may not be performed for a given participant, without having obtained his/her written consent to 
participate in the study. 
 
12.2. Participant Identification Cards 
Upon signing the Informed Consent and Assent Form(s) (as applicable), the participant or legal 
representative will be provided with a participant identification card in the language of the 
participant. The Investigator will fill in the participant identifying information and medical 
emergency contact information. The Investigator will instruct the participant to keep the card with 
him/her at all times. 
 
12.3. Institutional Review Boards and Independent Ethics Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
 
The Investigator and Sponsor or their designee will ensure that an appropriately constituted 
IRB/IEC that complies with the requirements of the current ICH-GCP version or applicable 


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country--specific regulations will be responsible for the initial and continuing review and approval 
of the clinical study. Prior to initiation of the study, the Investigator or the Sponsor or their designee 
will forward copies of the protocol, Informed Consent form, Investigator’s Brochure, 
Investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all other 
participant--related documents to be used for the study to the IRB/IEC for its review and approval. 
 
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
 
The Investigator will also promptly report to the IRB/IEC all changes in the study, all unanticipated 
problems involving risks to human participants or others, and any protocol deviations, to eliminate 
immediate hazards to participants. 
 
The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the participants. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the Investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
 
As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of participant risk involved, but no less than 
once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion. 
 
The Sponsor (or its representative) will communicate safety information to the appropriate 
regulatory authorities and all active investigators in accordance with applicable regulatory 
requirements. The appropriate IRB/IEC will also be informed by the Investigator or the Sponsor, 
as specified by the applicable regulatory requirements in each concerned country. Where 
applicable, investigators are to provide the sponsor (or its representative) with evidence of such 
IRB/IEC notification. 
 
12.4. Participant Privacy 
The Sponsor or their designee will protect the participant’s confidentiality. Throughout this study, 
all data forwarded to the Sponsor or their designee, will be identified only by the participant 
number assigned at the Screening Visit and/or Day 1 Visit.  All personal data collected related to 
participants, Investigators, or any person involved in the study, which may be included in the 
Sponsor’s databases, shall be treated in accordance with applicable data protection law. 
 
The Investigator agrees that representatives of the Sponsor, its designee, representatives of the 
relevant IRB/IEC, or representatives of regulatory authorities will be allowed to review that 
portion of the participant’s primary medical records that directly concerns this study (including, 
but not limited to, laboratory test result reports, ECG reports, admission/discharge summaries for 
hospital admissions occurring during a participant’s study participation, and autopsy reports for 
deaths occurring during the study). 
 


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12.5. Protocol Amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary objective. 
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by the Sponsor, the IRB/IEC, and the regulatory authorities (if required), prior to 
being implemented. 
 
12.6. Insurance 
Insurance coverage will be handled according to local requirements. 
 
12.7. Financial Disclosures 
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the study and for 1 year after 
completion of the study. 
 
12.8. Publications 
After completion of the study, the data may be considered for reporting at a scientific meeting or 
for publication in a scientific journal. In these cases, the sponsor will be responsible for these 
activities and will work with the investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and other 
related issues. The sponsor has final approval authority over all such issues. 
 
Data are the property of the sponsor and cannot be published without prior written authorization 
from the Sponsor, but data and publication thereof will not be unduly withheld. 
 
12.8.1. Dissemination of Clinical Study Data 
The Sponsor and the Investigator are committed to publish data in accordance with applicable 
regulations and transparency guidance. Results will be published within 2 years of finalization of 
the CSR and will only be delayed to the second year if earlier publication may be detrimental to 
the financial position or intellectual property rights of the Sponsor. 
 
 


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13. REFERENCES 
de Groot PF, Belzer C, Aydin Ö, et al. Distinct fecal and oral microbiota composition in human 
type 1 diabetes, an observational study. PLoS One. 2017;12(12):e0188475.  
 
Atkinson. (2004). Retrieved from https://www.iqvia.com/-/media/iqvia/pdfs/landing-
pages/treatment-satisfaction/atkinson-2004-tsqm-14-
development.pdf?la=en&hash=D4451E03980A36AEEF0895D6B6985DA3&_=1615920
176681  
 
Austin, P. (2011). An introductions to propensity score methods for reducing the effects of 
confounding in observational studies. Multivariate Behavioral Research, 46(3), 399-424. 
 
Basra. (2015). Retrieved from https://pubmed.ncbi.nlm.nih.gov/25613671/  
 
Bieber. (2010). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2883413/ 
 
Bieber. (2010). Atopic Dermatitis. Ann Dermatol., 22(2):125-137. 
 
Dermatitis, S. s. (1993). Severity Scoring of Atopic Dermatitis: The SCORAD Index. 
Dermatology, 186, 23-31. 
 
Dias-Barbosa, C., Matos, R., & Vernon, M. (2020). Content validity of a sleep numerical rating 
scale and a sleep diary in adults and adolescents with moderate-to-severe atopic 
dermatitis. J Patient Rep Outcomes, 4, 100. 
 
EASI. (2017 Jan). Eczema Area and Severity Index (EASI) Guidance. Version 3.0. 
 
Eczema, H. f. (n.d.). Retrieved from http://www.homeforeczema.org/research/easi-for-clinical-
signs.aspx  
 
EMEA. (2002 Jul). CPMP/ICH/135/95 Note for guidance on Good Clinical Practice [Section 
4.9.5]. 
 
Finlay AY, K. G. (1994). Dermatology Life Quality Index (DLQI): a simple practical measure 
for routine clinical use. . Clin Exp Dermatol. , 19, 210-216. 
 
Hobbs, B., Carlin, B., Mandrekar, S., & Sargent, D. (2011). Hierarchical commensurate and 
power prior models for adaptive incorporation of historical information in clinical trials. 
Biometrics, 67(3), 1047-1056. 
 
Indra. (2013). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038411/ 
 
Katoh. (2019). Retrieved from https://onlinelibrary.wiley.com/doi/full/10.1111/1346-8138.15090 
 


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Kiebert. (2002). Retrieved from https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-
4362.2002.01436.x?sid=nlm%3Apubmed  
 
Lee. (2016). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773205/ 
 
Leshem, Y. A., Bissonnette, R., Paul, C., Silverberg, J. I., Irvine, A. D., Paller, A. S., . . . 
Guttman-Yassky, E. (2019). Optimization of placebo use in clinical trials with systemic 
treatments for atopic dermatitis: an International Eczema Council survey-based position 
statement. Journal of the European Academy of Dermatology and Venereology, 33(5), 
807-815. Retrieved from Reference: Optimization of placebo use in clinical trials with 
systemic 
 
Mangalam, A., Shahi, S., & Luckey, D. (017). Human gut-derived commensal bacteria suppress 
CNS inflammatory and demyelinating disease. Cell Rep, 20(6):1269-77. 
 
Marietta, E., Murray, J., & Luckey, D. (2016). Marietta EV, Murray JA, Luckey DH, et al. 
Human gut-derived Prevotella histicola suppresses inflammatory arthritis in humanized 
mice. Arthritis Rheumatol. 68(12):2878-88. 
 
National Eczema Association. (2016). https://nationaleczema.org/in-your-words-survey-series. 
 
Pariser. (2020, January 13). Evaluating patient-perceived control of atopic dermatits; design, 
validation, and scoring of the Atopic Dermatitis Control Tool (ADCT). Curr Med Res 
Opin., 367-376. 
 
Phan. (2011). Ref: Assessment of Pruritus Intensity: Prospective Study on Validity and 
Reliability of the Visual Analogue Scale, Numerical Rating Scale and Verbal Rating 
Scale in 471 Patients with Chronic Pruritus.  
 
Renert-Yuval. (2021). Retrieved from 
https://www.sciencedirect.com/science/article/pii/S0091674921000968  
 
Schatz. (2006). Retrieved from https://www.jacionline.org/article/S0091-6749(06)00174-
6/fulltext  
 
Schram, M., Spuls, P., Leeflang, M., Lindeboom, R., Bos, J., & Schmitt, J. (2011). EASI, 
(objective) SCORAD and POEM for atopic eczema: Responsiveness and minimal 
clinically important difference. Allergy, 67(1);99-106. 
 
Simpson. (2012). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671606/ 
 
Simpson E, B. R. (2020 Sep). The Validated Investigator Global Assessment for Atopic 
Dermatitis (vIGA-AD): The development and reliability testing of a novel clinical 
outcome measurement instrument for the severity of atopic dermatitis. J Am Acad 
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Snaith. (2003). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC183845/  
 
Suh. (2020). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457338/ 
 
Vandeputte, D., Kathagen, G., & D'hoe, K. (2017). Quantitative microbiome profiling links gut 
community variation to microbial load. Nature, 551:507-11. 
 
Viele, e. a. (2014). Use of historical control data for assessing treatment effects in clinical trials. 
Pharmaceutical Statistics, 41-54. 
 
Ware J, K. M. (1996). A 12-Item Short-Form Health Survey: construction of scales and 
preliminary tests of reliability and validity. Med Care. 1996. 34; 3:220-33. Med. Care, 
220-233. 
 
Yosipovitch, G., Reaney, M., Mastey, V., Eckert, L., Abbe, A., Nelson, L., . . . Gadkari, A. 
(2019). Peak Pruritus Numerical Rating Scale: psychometric validation and responder 
definition for assessing itch in moderate-to-severe atopic dermatitis. The British Journal 
of Dermatology, 181(4), 761-769. 
 
 
 


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14. APPENDICES 
14.1. Hanifin and Rajka (1980) Criteria for Diagnosis of Atopic Dermatitis 
 
From Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol. 1980;92 
(Suppl):44-47. 
 
Major Features: must have 3 or more of the following: 
1. Pruritus 
2. Typical morphology and distribution: 
a. Flexural lichenification or linearity in adults 
b. Facial and extensor involvement in infants and children 
3. Chronic or chronically-relapsing dermatitis 
4. Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis) 
 
Minor Features: plus 3 or more of the following: 
1. Xerosis 
2. Ichthyosis / palmar hyperlinearity /keratosis pilaris 
3. Immediate (type 1) skin-test reactivity 
4. Raised serum IgE 
5. Early age of onset 
6. Tendency toward cutaneous infections (especially Staph. aureus and Herpes simplex) or 
impaired cell-mediated immunity 
7. Tendency toward non-specific hand or foot dermatitis 
8. Nipple eczema 
9. Cheilitis 
10. Recurrent conjunctivitis 
11. Dennie-Morgan infraorbital fold 
12. Keratoconus 
13. Anterior subcapsular cataracts 
14. Orbital darkening 
15. Facial pallor / facial erythema 
16. Pityriasis alba 
17. Anterior neck folds 
18. Itch when sweating 
19. Intolerance to wool and lipid solvents 
20. Perifollicular accentuation 
21. Food intolerance 
22. Course influenced by environmental / emotional factors 
23. White dermographism / delayed blanch 
 
 
 


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14.2. Classification of Potency of Topical Corticosteroids 
 
 


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14.3. Contraceptive Guidance and Collection of Pregnancy Information 
Definitions 
Woman of Child-Bearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
• Documented bilateral tubal ligation 
 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months prior to the 
Screening Visit without an alternative medical cause.  In the absence of 12 months 
of amenorrhea, postmenopausal women will be assumed to be WOCBP and will 
need to follow contraceptive guidance and have pregnancy tests performed 
throughout the course of the study per the Schedule of Activities (SOA). 
 
• Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-oestrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study.  
 
Contraception Guidance 
 
Male participants with a female partner of child-bearing potential must either 
• Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
 
• Use a male condom during each episode of penile penetration during their 
participation in the study and for 90 days after the last dose of IMP.  
 
• Have a confirmed vasectomy. 
 
In addition, all male participants must refrain from donating sperm for the duration of the study 
and for at least 90 days following their last dose. 


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Female participants 
Female participants of child-bearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 14-1 below. 
 
Table 14-1: 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of < 1% per year when used consistently and correctly.  
Combined (oestrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb. 
• Oral  
• Intravaginal  
• Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral  
• Injectable  
Highly Effective Methods That Are User Independent a  
• Implantable progestogen only hormonal contraception associated with inhibition of 
ovulationb. 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
Vasectomised partner  
A vasectomised partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention, 
including at least 1 complete menstrual cycle (cycle (≥ 30 days) for women and 90 days for 
men post last dose. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.  
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study intervention, 
which may reduce the efficacy of the contraceptive method. In this case, a highly effective 
method of contraception plus condoms should be utilised during their participation in the 
study up to and including at least 1 complete menstrual cycle (≥ 30 days) for women and 
90 days for men post last dose.  


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Pregnancy Testing 
• WOCBP should only be included after a confirmed menstrual period and a negative 
pregnancy test. 
• Pregnancy testing is required at screening.  
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
 
Collection of Pregnancy Information 
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies to all male participants who receive EDP1815. 
 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor. Generally, the follow-
up will be no longer than 8 weeks following the estimated delivery date. Any termination 
of the pregnancy will be reported regardless of foetal status (presence or absence of 
anomalies) or indication for the procedure.  
Female participants who become pregnant  
• The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a participant's 
pregnancy. The participant will be followed to determine the outcome of the pregnancy. 
The investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of foetal status (presence or absence of anomalies) 
or indication for the procedure. 
 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy related- SAE considered reasonably related to the study intervention by the 
Investigator will be reported to the Sponsor as described in Section 9.5 Reporting Serious 
Adverse Events. While the Investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous reporting.  
 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 


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14.4. EDP1815 COVID-19 Risk Assessment 
Antiviral responses are activated rapidly after viral infection in order to control and prevent 
dissemination of the virus. Virus infection results in two general types of immune response. The 
first is a rapid-onset innate immune response against the virus, which involves the synthesis of 
Type 1 interferons and the stimulation of Natural Killer (NK) cells. If the infection proceeds 
beyond the first few rounds of viral replication, the innate immune response will trigger the 
adaptive immune response. The adaptive immune response itself has two components, the humoral 
response (the synthesis of virus-specific antibodies by B lymphocytes) and the cell-mediated 
response (the synthesis of specific CD8+ cytotoxic T lymphocytes that kill infected cells). Both of 
these components of the adaptive immune response result also in the production of long-lived 
memory cells that allow for a much more rapid response to a subsequent infection with the same 
virus.  Thus, an immune competent host should be able to mount both an innate and adaptive 
immune response.   
EDP1815 is a single strain of human commensal Prevotella histicola that is being clinically tested 
to treat inflammatory skin diseases such as psoriasis and atopic dermatitis (studies 1815-101, 1815-
201, and 1815-207); in a pharmacodynamic immune challenge study to Keyhole Limpet 
Haemocyanin (KLH) (study 1815-102); and also to treat the complications of infection with 
COVID-19 (study 1815-204 and 1815-205).  EDP1815 is administered orally and is gut-restricted.  
Therefore, EDP1815 exerts its anti-inflammatory effects on peripheral tissue through engagement 
of cells of the intestine, including small intestinal epithelial cells and immune cells in the lamina 
propria.   
EDP1815 has been shown in preclinical mouse inflammation models to reduce antigen-specific T 
cell responses, without impacting: 
• The anti-viral TLR3-mediated Type 1 interferon (alpha and beta) response  
• Interferon-gamma production by T cells and NK cells 
• Immune cell subsets (absolute number and percentage), including CD8 T lymphocytes, B 
lymphocytes, and myeloid lineage cells 
• The antigen-specific antibody responses (IgM and IgG) 
In human immune cell in vitro assays, EDP1815 did not alter the ability of human dendritic cells 
to induce the production of interferon-gamma from memory CD8 T cells in response to a viral 
peptide pool (Cytomegalovirus, Epstein-Bar virus, and Influenza virus), an important component 
of an anti-viral response. 
And clinically, treatment with EDP1815 was shown to reduce specific inflammatory myeloid cell 
cytokines such as IL-6 and IL-8, while not affecting levels of T cell cytokines such as interferon-
gamma, produced by circulating peripheral blood mononuclear cells.   
Taken together, the data demonstrate that treatment with EDP1815 does not result in general 
immuno-suppression of multiple immune pathways but is effective through a selective restoration 
of immune homeostasis. 
 






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KLH-specific antibody response 
 
Antibodies are one of the essential features of antigen-triggered adaptive immunity against viruses 
and requires a coordinated response between antigen-presenting cells such as dendritic cells, 
antigen-specific helper T cells, and antigen-specific B cells.  Although treatment with EDP1815 
causes a marked reduction in peripheral inflammation in the KLH delayed-type hypersensitivity 
model, no effect on KLH-specific IgM or IgG has been observed in either preclinical models or in 
a clinical study (data not shown). 
 
In vitro assay co-culture with human dendritic cells and CD8 T cells  
 
An in vitro assay with primary human DCs and autologous CD8+ T cells was carried out to 
measure the capacity of EDP1815 to modulate antigen-specific CD8+ T cell responses. Briefly, 
primary human DCs from 3 healthy donors were differentiated in vitro for 7 days. To assess the 
immuno-modulatory properties of EDP1815, DCs were incubated with EDP1815 or ES880, a 
different Prevotella strain that does not exhibit anti-inflammatory activity, for 24 hours in vitro. 
After 24 hours of microbe conditioning, microbes were removed from the DC culture and 
autologous human CD8+ T cells and CEF Class I peptide pool was added. The CEF peptide pool 
is composed of peptides from Cytomegalovirus, Epstein Bar virus, and Influenza virus, pathogens 
to which the majority of the human population has been exposed. After 24 hours of stimulation 
with CEF peptide, DC-CD8+ T cell supernatants were collected and IFNγ was measured. When 
human DCs were incubated with EDP1815, the IFNγ response to CEF was not affected (neither 
enhanced nor decreased) compared to the DC-CD8 T cell co-culture control.  In contrast, 
incubation with ES880 led to increased production of IFNγ. 
Vehicle
EDP1815
0
5×105
1×106
Cell number (absolute)
B cells
Vehicle
EDP1815
0
1×104
2×104
3×104
Cell number (absolute)
Neutrophils
Vehicle
EDP1815
0.0
5.0×104
1.0×105
1.5×105
2.0×105
2.5×105
Cell number (absolute)
Macrophages
Vehicle
EDP1815
0 0
5.0×103
1.0×104
1.5×104
Cell number (absolute)
Monocytes


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Conclusion 
 
The combination of in vitro, in vivo, and ex vivo data demonstrate that EDP1815 does not broadly 
impair either innate or adaptive immune responses.  EDP1815 is orally delivered and gut restricted, 
and therefore its effect is exerted through local interactions with cells of the small intestine, which 
are then translated from the gut to the periphery to resolve inflammation.  Anti-viral responses 
such as cytotoxic T cell production of interferon-gamma, innate anti-viral production of interferon-
alpha and interferon-beta, and the generation of high affinity antibodies are all preserved after 
treatment with EDP1815. 
 
The data demonstrate that treatment with EDP1815 results in resolution of multiple pathways of 
inflammation without leading to immunosuppression of the host response. 
 
 
 
 


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14.5. Toxicity Grading Scale 
The following scales come from the FDA Guidance for Industry Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 2007. 
 
Temperature Adverse Event Grading Scale 
 
Vitals Signs* 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially 
Life 
Threatening (Grade 
4) 
Fever (ºC)** 
          (ºF)** 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 - 104 
> 40  
>104 
 
Laboratory Results Adverse Event Grading Scale 


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15. DECLARATION AND SIGNATURE OF INVESTIGATOR 
 
I confirm that I have carefully read and understood this protocol and agree to conduct this clinical 
study as outlined in this protocol, according to current Good Clinical Practice (GCP) and local 
laws and requirements. 
 
I will ensure that all Sub-Investigators and other staff members read and understand all aspects of 
this protocol. 
 
I have received and read all study-related information provided to me. 
 
The objectives and content of this protocol as well as the results deriving from it will be treated 
confidentially, and will not be made available to third parties without prior authorization by the 
Sponsor, Evelo Biosciences, Inc. 
 
All rights of publication of the results reside with the Sponsor, Evelo Biosciences, Inc, unless other 
agreements were made in a separate contract. 
 
 
Signature of Investigator 
Date 
Investigator Name 
Investigator Title 
Name of Facility 
Location of Facility (City) 
 
 
 






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as non-responders at the Week 
16 visit. 
 
2.3 Exploratory Objectives 
 
4.3 Exploratory Variables 
Following exploratory objective was 
added to the protocol: 
 
• 
To evaluate the effect of early 
use of rescue therapy on Week 
16 responder status. 
 
Additionally, exploratory variables 
were 
updated 
to 
include 
the 
following: 
 
• 
To evaluate the effect of early 
use of topical corticosteroid 
rescue therapy on Week 16 
responder 
status, 
the 
subgroup of participants with 
no rescue use at any time 
before Week 16 will be 
compared to subgroups of 
participants 
with 
rescue 
therapy use within only the 
first 4, 8, 12 and 14 weeks 
prior to the Week 16 visit.  For 
these subgroups, the following 
endpoints will be summarized:  
Percentage of Participants 
Achieving EASI-50, EASI-75 
and EASI-90. 
• 
Percentage of Participants 
Achieving IGA 0 or 1, with and 
without a 2-point improvement 
from Baseline 
• 
Percentage of Participants 
Achieving BSA-50 and BSA-75 
 
This was added to help Evelo 
evaluate our estimand approach for 
Phase 3. 
Protocol Summary 
 
2.1 Primary Objectives 
 
4.1 Study Description 
 
4.3 Planned Number of Participants 
 
4.6 Schematic Study Design 
 
4.7. Rationale for study design and 
selection of dose 
 
6.1 
Investigational 
Medicinal 
Product(s) 
 
Table 6-1: IMP to be Administered 
Added 
Cohort 
4 
and 
made 
corresponding changes to number of 
participants, ratio and regimen, and 
cohort description throughout, and 
statistics section, as required. 
 
See rationale above. 


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11. Statistics 
 
4.5 Schedule of Study Assessments 
 
7.1 Screening Visit 
 
7.2 Day 1 Visit 
 
9.11.4 Microbiome Sample 
 
Removal 
of 
fecal 
sample 
requirement for those participants 
that enroll under Protocol Version 
5.0. 
Enough samples have been collected 
thus far for required microbiome 
analyses. 
5.1 Inclusion Criteria 
 
Inclusion criterion #4 update to 
clarify IGA caps.  The bolded, 
underlined text was added to this 
criterion: 
 
7. Have 
severity 
of 
atopic 
dermatitis meeting the below 
criteria at both Screening and 
Day 1: 
i. An IGA of 2, 3 or 4 on 
the vIGA scale, and; 
ii. A BSA of ≥5%, and; 
iii. An EASI score of ≥6. 
 
A cap will be set for each of the 
three IGA severity grades. When 
this cap is reached, Sponsor will 
notify sites and participants with 
severity score at Screening and/or 
Day 1 matching the closed stratum 
should be considered ineligible 
according to Inclusion Criterion 4i. 
See Section 11.7 Planned Interim 
Analysis and Data Monitoring. 
 
Changes were made to inclusion 
criterion #4 in order to allow for a 
cap  
 
5.2 Exclusion Criteria 
Exclusion criterion #20 changed 
from the strikethrough text to the 
bolded, underlined text below: 
 
20. Active untreated mental or 
psychiatric disorder. 
Participants who are on 
stable dosing of medication 
for a mental or psychiatric 
disorder for at least 6 months 
before signing of ICF and 
whose treating physicians 
consider them to be mentally 
stable may be enrolled. 
 
Change to: 
 
20. Active mental or psychiatric 
disorder, 
which, 
in 
the 
opinion of the Investigator or 
Changes were made to exclusion 
criterion #20 in order to allow 
physician judgement of inclusion of 
participants 
with 
an 
untreated 
mental or psychiatric disorder in the 
study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Sponsor, would make the 
participant 
unsuitable 
for 
inclusion or could interfere 
with 
the 
participant 
participating in or completing 
the study. 
 
Exclusion criterion #23 updated to 
remove the strikethrough text and 
include the bolded, underlined text: 
 
23. 
Treatment 
with 
another 
investigational 
drug 
or 
device within 3 months of 
signing the ICF or 5 half-
lives of investigational agent, 
prior 
to 
randomization 
whichever is longer. 
 
 
 
 
 
 
 
 
Changes were made to exclusion 
criterion #23 in order for the 
language regarding timing to be 
consistent with other exclusion 
criteria. 
 
 
 
6.1 
Investigational 
Medicinal 
Product(s) 
 
Description of EDP1815 enteric-
coated capsules updated to include 
Cohort 4 drug substance description 
and manufacturing details. 
 
Cohort 4 added to study protocol. 
9.12.3 12-Lead Electrocardiogram 
The following, strikethrough text 
was removed from this section: 
 
A single 12-lead electrocardiogram 
(ECG) will be obtained at specified 
visits using an ECG machine that 
automatically calculates heart rate 
and measures PR, RR, QRS, QT and 
QTcF (Fridericia) intervals.  If the 
ECG machine does not calculate 
QTcF, this will be calculated by the 
site and entered into the CRF. 
 
Electronic Data Capture (EDC) 
calculates QTcF intervals as a 
derived field. 
10.2.1 Definition of Source Data 
The following bolded, underlined 
text added to this guidance: 
 
The 
following 
data 
will 
be 
considered as electronic source and 
therefore, will not be recorded 
directly into the EDC and will not 
appear 
in 
a 
separate 
source 
document as defined above, unless 
there is a circumstance, such as a 
global power outage, making it 
difficult for site staff to collect this 
data electronically. Any information 
about a participant that is collected 
during this study will remain 
secured and confidential and will be 
handled per applicable regulations 
(i.e., data collected via mobile 
applications). 
Text added to ensure that data is not 
missed and is collected at a 
minimum via paper when electronic 
means are not possible due to 
unforeseen circumstances. 


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14.3 Contraceptive Guidance and 
Collection 
of 
Pregnancy 
Information 
The following bolded, underlined 
text added to this guidance: 
 
Women in the following categories 
are not considered WOCBP: 
4. Premenarchal 
 
5. Premenopausal 
female 
with 1 of the following: 
• 
Documented 
hysterectomy 
• 
Documented 
bilateral 
salpingectomy 
• 
Documented 
bilateral 
oophorectomy 
• 
Documented 
bilateral 
tubal 
ligation 
 
To further clarify that women with 
documented bilateral tubal ligation 
are not considered WOCBP and 
may be considered for enrollment 
in the study without the use of 
additional contraception. 




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11.2 
General 
Statistical 
Considerations 
 
11.3.1 
Primary 
Estimand 
and 
Supplementary Estimands of the 
Primary Objective 
 
11.3.2 Secondary Estimands 
 
11.8 Determination of Sample Size 
 
Language amended to clarify how 
data will be pooled and compared 
across the 3 treatment cohorts. 
The change to cohort 1 meant that 
the ‘all EDP1815’ vs placebo 
comparison 
was 
no 
longer 
appropriate as a primary analysis. In 
addition, 
the 
exploratory 
comparisons 
between 
EDP1815 
groups required updating. 
Table 11-1: Intercurrent Event 
Strategies for the Primary and 
Supplementary Estimands 
 
Table 11-2: Secondary Estimand 
Details 
 
 
Estimands clarified and reordered 
throughout both tables. 
Minor corrections to issues found 
since finalization of V3 






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Protocol Summary  
 
4. Study Design 
 
4.6. Schematic Study Diagram 
Change in number of participants 
per cohort: 75 participants per 
cohort will receive active IMP and 
25 participants per cohort will 
receive placebo, for an overall study 
total of 225 participants receiving 
active and 75 participants receiving 
placebo. 
 
Change 
in 
primary 
endpoint 
requiring new power calculation. 
4.3 Planned Number of Participants 
Increase in overall participating 
centers from 55 to 60. 
Updated due to extension in study 
treatment duration and increase in 
overall enrollment. 
 
4.5 Schedule of Study Assessments 
 
4.6. Schematic Study Diagram 
 
6.6 eDiary 
 
7. Study Procedures by Visit 
 
11. Statistics 
 
 
An additional visit was added to the 
Schedule of Assessments for a total 
of 8 study visits over a 6-month 
period.  Study visits are now 
Screening, Day 1, Week 2, Week 4, 
Week 8, Week 12, Week 16 and 
Week 20.   
 
Updated due to extension in study 
treatment duration. 
4.5 Schedule of Study Assessments 
 
7. Study Procedures by Visit 
 
9.13.1 Digital Photography 
 
Digital photography language 
updated. 
Additional photographs added to 
allow monitoring of entire skin 
surface, rather than just lesions 
present at the start of the study. 
5.2 Exclusion Criteria 
Exclusion criteria #2 updated to 
exclude all participants with prior 
exposure to EDP1815. 
 
Alignment 
with 
other 
Evelo 
protocols 
6.9.1 Permitted Concomitant 
Medications and Treatments 
 
6.9.1.2. Rescue Therapy 
Additional language added to allow 
antimicrobial therapy for secondary 
skin 
infections 
with 
permitted 
treatments listed. 
 
Language amended to allow rescue 
therapy throughout entire treatment 
period. 
 
Addresses FDA hold item 
9.4.1 Assessments of AEs 
Language added to clarify how AEs 
will 
be 
solicited 
from 
the 
participant. 
 
Addresses FDA hold item 
9.4.2 Assessments of Severity of 
AEs 
Language added to clarify that 
abnormal laboratory results that are 
found to be clinically significant 
adverse events will be graded 
according to the FDA Guidance for 
Industry Toxicity Grading Scale. 
 
Added 
per 
the 
FDA’s 
recommendation. 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
 
NCT05121480 
 
 
A PHASE 2, MULTICENTER, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTIPLE-COHORT STUDY 
INVESTIGATING THE EFFECT OF EDP1815 IN 
PARTICIPANTS FOR THE TREATMENT OF MILD, 
MODERATE AND SEVERE ATOPIC DERMATITIS 
 
EDP1815-207 SAP 
Version 2.0 / 24 April 2022 




Statistical Analysis Plan  
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EDP1815-207 
 
 
 
 
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1 
Table of Contents 
1 
Table of Contents ...................................................................................................................... 2 
2 
Abbreviations and Definitions .................................................................................................... 6 
3 
Introduction .............................................................................................................................. 8 
4 
Study Objectives and Endpoints ................................................................................................. 8 
4.1 
Study Objectives .............................................................................................................. 8 
4.2 
Endpoints ......................................................................................................................... 8 
5 
Study Methods ........................................................................................................................ 11 
5.1 
General Study Design and Plan ....................................................................................... 11 
5.2 
Randomisation and Blinding ........................................................................................... 12 
5.3 
Derived variables ........................................................................................................... 13 
5.3.1 
General .............................................................................................................. 13 
5.3.2 
Demographic and Background Data ................................................................... 14 
5.3.3 
Efficacy .............................................................................................................. 17 
5.3.4 
Safety ................................................................................................................ 21 
6 
Sample Size.............................................................................................................................. 22 
7 
General Considerations ............................................................................................................ 23 
7.1 
Analysis Populations....................................................................................................... 23 
7.1.1 
Participant Analysis Populations......................................................................... 23 
7.1.2 
Defined Data Point Sets ..................................................................................... 23 
7.2 
Covariates and Subgroups .............................................................................................. 27 
7.3 
Missing Data .................................................................................................................. 27 
7.3.1 
Partial Dates/Times ............................................................................................ 27 
7.3.2 
Adverse Event Information ................................................................................ 29 
7.4 
Interim Analyses and Data Monitoring ........................................................................... 29 
7.4.1 
Purpose of Interim Analyses ............................................................................... 29 
7.4.2 
Planned Schedule of Interim Analyses ................................................................ 29 
7.4.3 
Endpoints to be Included in the Interim Analysis ................................................ 30 
7.4.4 
Adjustment of Confidence Intervals and p-values ............................................... 30 
7.4.5 
Practical Measures to Minimise Bias .................................................................. 30 
7.4.6 
Documentation of Interim Analyses ................................................................... 30 
7.5 
Multi-centre Studies ....................................................................................................... 31 
7.6 
Multiple Testing ............................................................................................................. 31 
7.7 
Visit Windows ................................................................................................................ 31 
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8 
Summary of Study Data ........................................................................................................... 31 
8.1 
Study Disposition ........................................................................................................... 33 
8.2 
Protocol Deviations ........................................................................................................ 34 
8.3 
Demographic and Baseline Variables .............................................................................. 34 
8.4 
Medical History .............................................................................................................. 34 
8.5 
Prior and Concomitant Medications ............................................................................... 35 
8.6 
Treatment Compliance ................................................................................................... 35 
8.7 
Emollient Compliance .................................................................................................... 36 
9 
Efficacy Analyses ...................................................................................................................... 36 
9.1 
Pooling of Placebo Cohorts............................................................................................. 36 
9.2 
Selection of Additional Covariates .................................................................................. 36 
9.3 
Primary Efficacy Analysis ................................................................................................ 37 
9.3.1 
Primary Efficacy Estimand .................................................................................. 37 
9.3.2 
Supplementary Estimands for the Primary Endpoint .......................................... 39 
9.3.3 
Main Analytical Approach .................................................................................. 42 
9.3.4 
Sensitivity Analyses ............................................................................................ 43 
9.3.5 
Subgroup Analyses ............................................................................................. 43 
9.4 
Secondary Efficacy Analyses ........................................................................................... 43 
9.4.1 
Continuous Secondary Endpoints ....................................................................... 44 
9.4.2 
Response Endpoints ........................................................................................... 45 
9.4.3 
Count Endpoints ................................................................................................ 47 
9.5 
Exploratory Efficacy Analyses ......................................................................................... 48 
9.5.1 
Exploratory Efficacy Endpoints ........................................................................... 48 
10 Safety Analyses ........................................................................................................................ 51 
10.1 Extent of Exposure ......................................................................................................... 52 
10.2 Adverse Events ............................................................................................................... 52 
10.3 Deaths, Serious Adverse Events and other Significant Adverse Events ............................ 53 
10.4 Pregnancies.................................................................................................................... 53 
10.5 Clinical Laboratory Evaluations ....................................................................................... 53 
10.6 Other Safety Measures ................................................................................................... 54 
10.6.1 ECG .................................................................................................................... 54 
10.6.2 Vital Signs .......................................................................................................... 55 
10.6.3 Physical Examination ......................................................................................... 55 
11 Reporting Conventions ............................................................................................................ 55 
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12 Technical Details ...................................................................................................................... 56 
13 Summary of Changes from the Protocol ................................................................................... 56 
14 Bibliography ............................................................................................................................ 58 
15 Appendix 1: List of Tables, Figures and Listings ........................................................................ 59 
15.1 Study Population ............................................................................................................ 59 
15.1.1 Tables ................................................................................................................ 59 
15.2 Efficacy .......................................................................................................................... 60 
15.2.1 Tables ................................................................................................................ 60 
15.2.2 Figures ............................................................................................................... 66 
15.3 Safety ............................................................................................................................. 75 
15.3.1 Tables ................................................................................................................ 75 
15.4 Data Listings ................................................................................................................... 76 
16 Appendix 2: Eczema Area and Severity Index ........................................................................... 79 
17 Appendix 3: Validated Investigator Global Assessment ............................................................ 81 
18 Appendix 4: Severity Scoring of Atopic Dermatitis .................................................................... 82 
19 Appendix 5: Patient Oriented Eczema Measure ....................................................................... 83 
20 Appendix 6: Dermatology Quality of Life Index ........................................................................ 84 
21 Appendix 7: 12-Item Short Form Health Survey ........................................................................ 85 
22 Appendix 8: Hospital Anxiety and Depression Scale ................................................................. 87 
23 Appendix 9: Atopic Dermatitis Control Tool ............................................................................. 90 
24 Appendix 10: MedDRA Internationally Agreed Order for System Organ Class ........................... 92 
25 Appendix 11: Safety Laboratory Evaluations ............................................................................ 93 
 
 
 
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Table of Tables 
Table 1 
Intercurrent Event Strategies for the Primary Estimand (EDPS1) ..................................... 38 
Table 2 
Supplementary Estimands for the Primary Endpoint....................................................... 39 
Table 3 
PCI Criteria for Vital Signs ............................................................................................... 55 
Table 4:      Summary of Changes from the Protocol ......................................................................... 57 
Table 5 
MedDRA Internationally Agreed SOC Order .................................................................... 92 
Table 6 
Safety Laboratory Parameters and Units ........................................................................ 93 
 
 
Table of Figures 
Figure 1 
Study Schema ................................................................................................................ 12 
 
 
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2 
Abbreviations and Definitions 
AD 
Atopic Dermatitis 
ADCT 
Atopic Dermatitis Control Tool 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
APP 
Application 
AST 
Aspartate Aminotransferase 
BSA 
Body Surface Area 
CDMS 
Clinical Data Management System 
CI 
Confidence Intervals 
CPM 
Clinical Project Manager 
CRF 
Case Report form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DBL 
Data Base Lock 
DLQI 
Dermatology Life Quality Index 
DNA 
Deoxyribonucleic Acid 
DPS 
Data Point Set 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA/EMEA 
European Medicines Agency 
EASI 
Eczema Area and Severity Index 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLMM 
Generalised linear mixed effects model 
HADS 
Hospital Anxiety and Depression Scale 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LS 
Least Squares Mean Estimate 
MCS 
Mental Component Score  
mL 
Millilitre 
MeDDRA 
Medical Dictionary for Regulatory Activities 
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MMRM 
Mixed Model for Repeated Measures 
OLE 
Open Label Extension 
PCS 
Physical Component Score 
PBMC 
Peripheral blood mononuclear cell 
PCI 
Potentially clinically important 
POEM 
Patient Oriented Eczema Measure 
PP-NRS 
Peak Pruritus Numerical Rating Scale 
RNA 
Ribonucleic Acid 
SD-NRS 
Sleep Disturbance Numerical Rating Scale 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SCORAD 
Severity Scoring of Atopic Dermatitis (SCORing Atopic Dermatitis) 
SF-12 
12-Item Short Form Health Survey 
SLS 
Sodium Lauryl Sulfate 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
TCI 
Topical Calcineurin Inhibitors 
TCS 
Topical Corticosteroids 
TLR 
Top level results 
TMF 
Trial Master File 
ULN 
Upper Limit of Normal 
vIGA  
Validated Investigator Global Assessment 
WGS 
Whole Genome Sequencing 
WHODD 
World Health Organization Drug Dictionary 
WOCBP 
Woman of Child-Bearing Potential 
 
 
 
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3 
Introduction 
The purpose of this SAP is to provide all information that is necessary to perform the required 
statistical analyses of study EDP1815-207. It also defines the tables, figures and listings (TFLs) to be 
included in the final clinical study report (CSR) according to the protocol. The SAP is based upon, and 
assumes familiarity, with the study protocol, version 5.0, dated 25-Apr-2022. The separate SAP 
addendum covers additional details related to the analysis of the cohort 4 efficacy data. The cohort 4 
efficacy tables and figures to be included in the CSR are included in the SAP addendum.   
 
Changes to the analyses described in the protocol are summarized in Section 13. 
 
If a future protocol amendment necessitates a substantial change to the statistical analysis of the 
study data, this SAP will be amended accordingly. The content of this SAP is compatible with the ICH 
E9 Guidance document. 
 
4 
Study Objectives and Endpoints 
4.1 
Study Objectives 
The primary objective of the study is: 
 
To show superiority of EDP1815 over placebo in the proportion of participants achieving at 
least a 50% reduction in Eczema Area and Severity Index (EASI) score (EASI-50) in the 
absence of rescue medication for 28 days and in the absence of prohibited medications at 
any time. 
 
The secondary objectives of the study are: 
 
To evaluate the clinical benefit of EDP1815 in the treatment of atopic dermatitis. 
 
To evaluate the safety and tolerability of EDP1815. 
 
The exploratory objectives of the study are: 
 
To evaluate the time to onset of clinical response to EDP1815. 
 
To evaluate the most effective dose and dosing frequency of EDP1815 in the treatment of 
atopic dermatitis. 
 
To evaluate the effect of EDP1815 on patient reported outcomes. 
 
To evaluate the effect of early use of rescue therapy on Week 16 responder status. 
 
To evaluate the relationship of EDP1815 treatment with biomarkers such as immune protein 
markers, eosinophils, and immune cell RNA profile in blood. 
 
To evaluate correlation of genetic markers and EDP1815 treatment outcomes.  
 
To evaluate correlation of gut microbiome and EDP1815 treatment outcomes. 
 
4.2 
Endpoints 
The primary efficacy endpoint for the study is: 
 
Achievement of an EASI-50 response at Week 16. 
 
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The secondary efficacy endpoints for the study will be evaluated at Weeks 4, 8, 12 and 16 (unless 
otherwise specified) and are: 
 
Percentage of participants achieving EASI-50 at Weeks 4, 8 and 12. 
 
Percentage of participants achieving EASI-75. 
 
Percentage of participants achieving EASI-90. 
 
Mean absolute change and percentage change from baseline in EASI Score. 
 
Percentage of participants achieving Validated Investigator's Global Assessment (vIGA) of 0 
or 1 with a ≥2-point improvement from baseline. 
 
Percentage of participants achieving vIGA of 0 or 1. 
 
Percentage of participants achieving vIGA of 0 at Week 16. 
 
Mean absolute change and percentage change from baseline in vIGA*BSA (BSA=body 
surface area). 
 
Mean absolute change and percentage change from baseline in BSA. 
 
Percentage of participants achieving BSA-50. 
 
Percentage of participants achieving BSA-75. 
 
Percentage of participants achieving BSA reduction to 3% BSA or less. 
 
Mean absolute change and percentage change from baseline in SCORing Atopic Dermatitis 
(SCORAD) score. 
 
Percentage of participants achieving SCORAD-35. 
 
Percentage of participants achieving SCORAD-50. 
 
Percentage of participants achieving SCORAD-75. 
 
Mean absolute change and percentage change from baseline in Dermatology Life Quality 
Index (DLQI) score. 
 
Percentage of Participants achieving a reduction of ≥4 in the DLQI score, of those with a 
score of ≥4 at baseline at Week 16. 
 
Mean absolute change from baseline in Peak Pruritus Numerical Rating Scale (PP-NRS) score. 
 
Percentage of participants achieving a reduction of ≥2 in the PP-NRS, of those with a score of 
≥2 at baseline. 
 
Percentage of participants achieving a reduction of ≥4 in the PP-NRS, of those with a score of 
≥4 at baseline at Week 16. 
 
Mean absolute change from baseline in Sleep Disturbance Rating Scale (SD-NRS) score. 
 
Percentage of participants achieving a reduction of ≥2 in SD-NRS score, of those with a score 
of ≥2 at baseline at Week 16. 
 
Mean absolute change and percentage change from baseline in Patient Oriented Eczema 
Measure (POEM) score. 
 
Percentage of participants achieving a reduction of ≥4 in the POEM score, of those with a 
score of ≥4 at baseline at Week 16. 
 
Number of courses of TCS/TCI rescue therapy per participant in Weeks 1-8, 9-16 and for 
Weeks 1-16. 
 
Number of days of treatment with TCS/TCI rescue therapy per participant in Weeks 1-4, 5-8, 
9-12 and 13-16 and for Weeks 1-16. 
 
Proportion of participants requiring TCS/TCI rescue therapy in Weeks 1-4, 5-8, 9-12 and 13-
16 and for Weeks 1-16. 
 
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The secondary safety endpoints for the study are: 
 
Adverse events and serious adverse events. 
 
Change from baseline in vital signs. 
 
Change from baseline in ECG parameters. 
 
Change from baseline in clinical laboratory parameters. 
 
Change from baseline in physical examination findings. 
 
Worst-case change from baseline with respect to potentially clinical important criteria for 
vital signs, QTcF and clinical laboratory parameters. 
 
Worst-case change from baseline with respect to values outside the normal ranges for 
clinical laboratory parameters. 
 
Exploratory endpoints to evaluate the time to onset of clinical response are: 
• 
Time to first achievement of EASI-50. 
• 
Time to first achievement of sustained EASI-50. 
• 
Time to first achievement of EASI-75, 
• 
Time to first achievement of vIGA of 0 or 1 with a 2-point improvement from baseline. 
• 
Time to first achievement of vIGA of 0 or 1. 
 
Time to first achievement of a ≥2 point in improvement in PP-NRS score, in participants with 
a score of ≥2 at baseline. 
 
Time in days to first sustained ≥2 point in improvement in PP-NRS score, in participants with 
a score of ≥2 at baseline. 
 
Time to first achievement of a ≥4 point in improvement in PP-NRS score, in participants with 
a score of ≥4 at baseline. 
 
Time in days to first sustained ≥4 point in improvement in PP-NRS score, in participants with 
a score of ≥4 at baseline. 
 
Time to first achievement of a ≥2 point in improvement in SD-NRS score, in participants with 
a score of ≥2 at baseline. 
• 
Time in days to first sustained ≥2 point in improvement in SD-NRS score, in participants with 
a score of ≥2 at baseline. 
 
Exploratory endpoints to evaluate the effect of early use of topical corticosteroid rescue therapy on 
Week 16 responder status are defined in the following subgroups: the subgroup of participants with 
no rescue use at any time before Week 16 will be compared to subgroups of participants with rescue 
therapy use within only the first 4, 8, 12 and 14 weeks of treatment and to participants with rescue 
therapy use within the 2 weeks and 4 weeks prior to the Week 16 visit.  For these subgroups, the 
following endpoints will be summarized: 
 
Percentage of participants achieving EASI-50, EASI-75 and EASI-90 
 
Percentage of participants achieving IGA 0 or 1, with and without a 2-point improvement from 
baseline 
 
Percentage of participants achieving BSA-50, and BSA-75 
 
Other exploratory endpoints will be evaluated at Weeks 2, 4, 8, 12 and 16 (unless otherwise 
specified) and are: 
 
Percentage of participants achieving vIGA of 0 or 1 with a ≥2 Point Improvement from 
screening. 
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 
Mean absolute change and percentage change from Screening in EASI Score. 
 
Percentage of participants requiring topical antimicrobial or systemic antibiotic treatment 
for skin infections by Week 16. 
 
Changes from baseline in SF-12 Mental Component Score (MCS) and Physical Component 
Score (PCS) at Weeks 4, 12 and 16. 
 
Changes from baseline in HADS anxiety and depression scores at Weeks 4, 12 and 16. 
 
Changes from baseline in ADCT scores at Weeks 4, 12 and 16. 
 
Daily changes from baseline in the PP-NRS and SD-NRS (Timescale: Days 2 to 140).  
 
Percentage of participants achieving a reduction of ≥2, ≥4 in the PP-NRS, of those with a 
score of ≥2, ≥4 at baseline daily from Day 2 to 112. 
 
Percentage of participants achieving a reduction of ≥2 in SD-NRS score, of those with a 
score of ≥2 at baseline daily from Day 2 to 112. 
 
Note that analyses of the other exploratory endpoints including the following biomarkers 
exploratory endpoints will be addressed in a separate analysis plan and will not be further discussed 
in this document: 
 
Changes from baseline in eosinophils at Weeks 2, 16 and 20. 
 
Changes from baseline in serum immune protein markers including IgE at Week 16. 
 
Changes from baseline in immune cell RNA profile at Weeks 2, 16 and 20. 
  
5 
Study Methods 
5.1 
General Study Design and Plan 
This is a randomised, double-blind, placebo-controlled study to evaluate the efficacy, safety and 
tolerability of EDP1815 as compared to placebo in participants with mild, moderate and severe 
atopic dermatitis. 
 
Cohorts 1, 2 & 3 will be run concurrently, and Cohort 4 recruitment will commence after enrollment 
for Cohorts 1, 2, & 3 are completed. During the Cohorts 1, 2, & 3 enrollement after eligibility is 
confirmed during the screening period (Protocol Sections 5.1 and 5.2), participants will be randomly 
assigned in a 1:1:1 ratio to 1 of the cohorts 1, 2 or 3. Once recruitment to first three cohorts is 
completed all participants will enrol cohort 4: 
 
Cohort 1: 1.6x1011 total cells of EDP1815 or matching placebo administered as 2 capsules 
once daily.  
 
Cohort 2: 6.4x1011 total cells of EDP1815 or matching placebo administered as 2 capsules 
once daily.  
 
Cohort 3: 6.4x1011 total cells of EDP1815 or matching placebo administered as 1 capsule of 
3.2x1011 cells twice daily. 
 
Cohort 4: 8.0x1010 total cells of EDP1815 or matching placebo administered as 1 capsule 
once daily. 
 
Participants in Cohorts 1, 2, & 3 will be randomised in a 3:1 ratio (approximately 75 to EDP1815 and 
25 to placebo within each cohort, 300 in total).  Participants in Cohort 4 will be randomised in a 2:1 
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participants recruited to each strata to match the proportions of each vIGA strata in Cohorts 1, 2 & 
3. 
 
Interactive response technology (IRT) will be used for assigning eligible participants to a treatment 
regimen (cohort and treatment within cohort) based on a predetermined production randomisation 
and/or packaging schedule.  
 
The allocation to cohort is not blinded, however, treatment allocation within cohort will be fully 
blinded to participants, study staff and the sponsor with the exception of the personnel supporting 
the IRT system, the independent randomisation team, the clinical supplies team, the clinical safety 
team at 
, and an unblinded team within 
who will produce the interim analysis but 
have no other involvement in the reporting of the study. 
 
A participant’s treatment assignment will not be unblinded for the investigator or study site staff 
until EOS unless medical treatment of the participant depends on knowing the study treatment the 
participant received. Participants who are unblinded will be allowed to continue their participation 
in the study; however, the impact of unblinding will be assessed in the supplementary analysis 
where EDPS5 is used. 
 
Cohorts 1-3 data may be unblinded before the end of the study, after the cohorts 1-3 database lock 
(DBL) which will occur once all cohorts 1-3 participants have completed 4 weeks of post-treatment 
follow-up (Week 20 or Early Termination Visit) or entered the OLE study. Cohort 4 data will be 
unblinded at the end of study.   
5.3 
Derived variables 
5.3.1 
General 
5.3.1.1 
Relative Day and Time 
The relative day of an assessment will be calculated as: 
 
For measurement performed on or after the date of first dose: 
Date of assessment – date of start of treatment +1  
 
 
For measurements performed before the date of first dose: 
Date of assessment – date of start of treatment 
 
5.3.1.2 
Baseline 
The last non-missing value collected before first study dose will be taken as the baseline 
measurement for all parameters collected at scheduled visits. If data is collected on Day 1 it will be 
assumed to be pre-dose regardless of an associated time.  
 
For the daily endpoints baseline will be taken as average of the 7 days before Day 1 (including Day 1 
assessment) and will be calculated if there will be at least 4 non-missing values. 
 
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5.3.1.3 
Change and Percentage Change from Baseline 
Change from baseline will be calculated as: 
change from baseline = value at timepoint – baseline value 
Change from baseline will be presented to the same level of precision as the original value in the 
listings. 
 
Percentage change from baseline will be calculated as: 
 
percentage change from baseline = 100*(change from baseline / baseline value) 
Percentage change from baseline will be presented to 1 decimal place (dp) in the listings. 
 
5.3.2 
Demographic and Background Data 
Height may be recorded in cm or inches. Height in inches will be converted to height in cm as 
follows: 
 
Height (cm) = Height (inches)*0.3937 
Height (cm) will be presented to 1 dp in the listings. 
 
Weight may be recorded in kg or pounds.  Weight in pounds will be converted to weight in kg as 
follows: 
 
Weight (kg) = Weight (pounds) * 0.4536 
Weight (kg) will be presented to 1 dp in the listings. 
 
Body mass index (BMI) will be calculated as: 
BMI (kg/m2) = Weight (kg) / [height (cm)/100]2 
BMI (kg/m2) will be presented to 1 dp in the listings. 
 
BMI will also be categorised as:  
• 
≥30 kg/m2  
• 
<30 kg/m2  
 
5.3.2.1 
Study Drug Compliance 
Participants in cohorts 1 and 2 will be expected to dose once daily with 2 capsules per dose (2 
capsules per day); in cohort 3 – twice daily with 1 capsule (2 capsules per day). 
 
Compliance will be calculated across the whole treatment period. 
 
Compliance calculation will be based on the daily diary and drug accountability data.  
 
Expected capsules  
Expected capsules for the treatment period will be calculated as: 
Expected capsules = 2*(End date of treatment period – Start date of treatment period + 1). 
 
End date of treatment period = Date of the last dose of study drug. 
Start date of treatment period = Day 1. 
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Actual capsules taken 
Actual capsules taken will be calculated from the dosing diary using entries between the start and 
end days inclusively and drug accountability data. 
 
Dosing diary number of capsules definitely not taken will be calculated as: 
 
Number of capsules not taken from dosing diary days where participant specifically chose 
the answer ‘did not take dose’ or ‘took some of dose’. 
 
Drug accountability number of capsules definitely not taken will be calculated as: 
 
Expected capsules – (Number of capsules dispensed* – Number of capsules returned*) 
* Through the whole treatment period. 
 
Actual capsules taken will be then calculated as: 
 
Actual capsules taken = Expected capsules – max(Dosing diary number of capsules definitely 
not taken, Drug accountability number of capsules definitely not taken) 
 
Study drug compliance  
Study drug compliance will be calculated as: 
 
Study drug compliance (%) = 100*Actual capsules taken/Expected capsules taken.  
 
Study drug compliance will also be categorised as: 
 
<75% 
 
≥75% 
 
5.3.2.2 
Emollient Compliance 
All participants must use an emollient twice daily for at least 14 consecutive days immediately prior 
to randomisation and should continue the background emollient treatment twice daily until the the 
end of the study. 
 
Compliance will be calculated across the whole treatment period. 
 
Expected number of applications for the treatment period will be calculated as: 
Expected number of applications = 2*(End date of period – Start date of period +1). 
 
End date of period = End of study treatment day.  
Start date of period = Day 1. 
 
Actual number of applications will be calculated from the emollient usage diary using entries 
between the start and end days inclusively. In case of more than two applications per day participant 
will be considered compliant for that day and only two applications will be considered for 
compliance calculation.  
 
Emollient compliance will be calculated as: 
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Emollient compliance (%) = 100*Actual number of applications/Expected number of                         
applications.  
 
Emollient compliance will also be categorised as: 
 
<75% 
 
≥75% 
 
5.3.2.3 
Prohibited Concomitant Medications 
The following medications are not allowed at any point during the study: 
 
Live (attenuated) vaccinations (a non-replicating / non-live vaccine when the first dose of 
IMP was not taken within a 7-day window of the administration of vaccine is allowed).  
 
Type 1 prohibited medications are prohibited concomitant medications which may affect efficacy 
requiring the concomitant medication to be immediately discontinued where possible once the use 
is discovered. If the prohibited medication cannot be discontinued for any reason, then the IMP 
should be discontinued: 
 
Emollients containing additives including SLS. 
 
Topical Corticosteroids (TCS) or Topical Calcineurin Inhibitors (TCI) (unless considered a 
rescue therapy). 
 
Topical PDE-4 Inhibitors. 
 
Bleach baths. 
 
Tanning beds. 
 
Leukotriene Receptor Antagonists. 
 
Allergen Immunotherapy. 
 
Type 2 prohibited medications are prohibited concomitant medications which may affect efficacy 
requiring IMP discontinuation: 
• 
Phototherapy treatment 
 
Systemic treatments that may lead to clinical improvements in atopic dermatitis, e.g., oral or 
injectable corticosteroids, methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, 
JAK-inhibitors, biologic therapy, and other systemic immunosuppressive therapy (note single 
dose intra-articular or intra-lesional corticosteroid therapy is permitted). 
 
If a prohibited medication is found to have been used, this will be captured into the protocol 
deviations log. 
 
Prohibited medications will be identified by the sponsor in a separate spreadsheet.  
Any medications taken during the study and classified as type 1 prohibited medications in the 
spreadsheet will be considered as type 1 prohibited medications with exception for  
1. Medications which stopped at least 14 days before Day 1  
2. Medications which started strictly before screening and carried on throughout study to week 
16  
3. Medications which are emollients and started on or after screening, but before Day 1  
4. Medications which are emollients and started before screening and stopped before Day 1 
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Any medications taken during the study and classified as type 2 prohibited medications in the 
spreadsheet will be considered as type 2 prohibited medications with exception for medications 
which stopped at least 14 days before Day 1. 
 
5.3.3 
Efficacy 
5.3.3.1 
General 
Participants who used permitted rescue therapy less than 28 days before Week 16 or discontinued 
study due to treatment related reason should be considered as non-responder in the primary 
estimand for the primary endpoint.  
 
5.3.3.2 
Eczema Area and Severity Index (EASI) 
The Eczema Area and Severity Index (EASI) will be calculated within the 
system and taken 
directly from the supplied data.  EASI score ranges from 0 to 72. Further information on the scoring 
of the EASI is provided in Section 16. 
 
EASI -50, EASI -75 and EASI -90 responses are defined respectively by at least a 50%, 75% and 90% 
decrease from Baseline in the EASI score.  
 
Sustained EASI-50 response is defined as one which is present on at least two consecutive visits. The 
sustained response is considered to have been first achieved at the first of the consecutive visits.  
 
5.3.3.3 
The Percent of Body Surface Area Involvement (BSA) 
The Body Surface Area (BSA) will be calculated as part of EASI score in the 
 system and 
taken directly from the supplied data.  The percent of BSA involvement will be estimated for each 
participant, where 1% is approximately the area of the participant’s handprint. 
 
BSA-50 and BSA-75 responses are defined respectively by at least a 50% and 75% reduction from 
Baseline in the BSA.  
 
5.3.3.4 
Validated Investigator’s Global Assessment (vIGA) 
The Validated Investigator Global Assessment scale for Atopic Dermatitis (vIGA) will be calculated 
within the 
 system and taken directly from the supplied data.  There is a standardised 
grading system based on an overall assessment of the degree of erythema, papulation/induration, 
lichenification, and oozing/crusting. In indeterminate cases, extent will be used to differentiate 
between scores – but otherwise extent is not used in the scoring system. The vIGA score ranges from 
0 to 4.  
 
5.3.3.5 
SCORing Atopic Dermatitis (SCORAD) 
The SCORing Atopic Dermatitis (SCORAD) will be calculated within the 
 system and taken 
directly from the supplied data.  There is an investigator-rated area score which uses the rule of 
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nines to assess disease extent, and a disease intensity score comprising erythema, swelling, 
oozing/crusting, excoriation, lichenification, and dryness. Additionally, there is a subjective 
symptoms component which considers itch and sleeplessness scored using a visual analogue scale. 
These scores combine to give a SCORAD score between 0 and 103.  
 
SCORAD-35, SCORAD-50 and SCORAD-75 responses are defined respectively by at least a 35%, 50% 
and 75% reduction from Baseline in the SCORAD score.  
 
5.3.3.6 
Patient Oriented Eczema Measure (POEM) 
The Patient Oriented Eczema Measure (POEM) will be calculated within the 
 system and 
taken directly from the supplied data.  It includes a series of 7 questions, measuring itch, sleep, 
bleeding, weeping/oozing, cracking, flaking, and dryness/roughness over the last week, and is scored 
by the participant. Each of the 7 questions is scored from 0 (no days) to 4 (every day), giving a POEM 
score range from 0 to 28, with higher scores representing higher disease severity. 
 
POEM response is defined as a reduction of ≥4 in the POEM score if a participant has a score of ≥4 at 
baseline. 
 
5.3.3.7 
Dermatology Life Quality Index (DLQI) 
The DLQI is a 10-item questionnaire with each item scored from 0 to 3.   
 
The DLQI score is the sum of the 10 individual items and ranges from 0 to 30, with higher scores 
indicating greater impairment of quality of life. Further information on the scoring of the DLQI is 
provided in Section 20. 
 
DLQI response is defined as a reduction of ≥4 in the DLQI score if a participant has a score of ≥4 at 
baseline (a 4-point change from baseline is considered the minimal clinically important difference 
threshold). 
 
5.3.3.8 
Peak Pruritus Numerical Rating Scale (PP-NRS) 
The Peak Pruritus Numerical Rating Scale (PP-NRS) is a scale from 0 to 10 for participants to rate 
their worst itch that they have experienced over the previous 24 hours. The PP-NRS will be 
completed as a part of daily symptom diary from the Screening Visit to end of study. 
 
PP-NRS score at each visit is calculated as the mean itch daily score for the 7 days prior to and 
including the visit date. At least 4 daily scores must be available for the score at the relevant visit to 
be considered evaluable.  
 
PP-NRS responses are defined as a reduction of ≥2 and ≥4 in the PP-NRS score if a participant has a 
score of ≥2 and ≥4, respectively, at baseline (a ≥2-4-point change from baseline is considered the 
minimal clinically important difference threshold). 
 
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Sustained PP-NRS response is defined as one which is present at all available assessments within at 
least 14 days period. Sustained response is considered to have been first achieved at the first of the 
consecutive days.  
 
5.3.3.9 
Sleep Disturbance Numerical Rating Scale (SD-NRS) 
The Sleep Disturbance Numerical Rating Scale (SD-NRS) is a scale from 0 to 10 for participants to rate 
their worst sleep that they have experienced over the previous 24 hours. The SD-NRS will be 
completed as a part of daily symptom diary from the Screening Visit to end of study. 
 
SD-NRS score at each visit is calculated as the mean sleep daily score for the 7 days prior to and 
including the visit date. At least 4 daily scores must be available for the score at the relevant visit to 
be considered evaluable.  
 
SD-NRS response is defined as a reduction of ≥2 in the SD-NRS score if a participant has a score of ≥2 
at baseline (a 2-point change from baseline is considered the minimal clinically important difference 
threshold). 
 
Sustained SD-NRS response is defined as one which is present at all available assessments within at 
least 14 days period. Sustained response is considered to have been first achieved at the first of the 
consecutive days.  
 
5.3.3.10 Time to First Achievement of Daily Time-to-Event Endpoints   
The daily time-to-event endpoints are based on a daily questionnaire and include: 
 
Time to first achievement of a ≥2 point in improvement in PP-NRS score, in participants with 
a score of ≥2 at baseline 
 
Time to first achievement of a sustained ≥2 point in improvement in PP-NRS score, in 
participants with a score of ≥2 at baseline 
 
Time to first achievement of a ≥4 point in improvement in PP-NRS score, in participants with 
a score of ≥4 at baseline 
 
Time to first achievement of a sustained ≥4 point in improvement in PP-NRS score, in 
participants with a score of ≥4 at baseline 
 
Time to first achievement of a ≥2 point in improvement in SD-NRS score, in participants with 
a score of ≥2 at baseline 
 
Time to first achievement of a sustained ≥2 point in improvement in SD-NRS score, in 
participants with a score of ≥2 at baseline 
 
Time to event is defined as the time in days from the first dose of study drug until the date when 
event occurred. 
 
Participants who complete the study up to Week 16 visit without experiencing the relevant event 
will be censored on the date of Week 16 visit. Participants who prematurely withdraw from the 
study before Week 16 without experiencing the relevant event will be censored on the date of 
treatment discontinuation. 
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For sustained response endpoints censoring rules are adjusted to consider that sustained response 
cannot be achieved less than 14 days before the end of the relevant period. Therefore, participants 
who complete 16 weeks of study or prematurely withdraw from the study without experiencing the 
relevant event will be censored 14 days before the date of Week 16 visit/withdrawal, if before Week 
16. 
 
Time to the relevant event will be calculated as:  
 
Time to event (days) = Date of event/censoring – date of the first study drug (Day 1) +1 
 
5.3.3.11 12-Item Short Form Health Survey (SF-12) 
The 12-Item Short Form Health Survey (SF-12) is a PRO instrument consisting of twelve questions 
used to measure non-disease related outcomes in 8 health domains, including vitality, physical 
functioning, bodily pain, general health perceptions, physical role functioning, emotional role 
functioning, social functioning, and mental health. The score (ranging from 0 to 100) is presented in 
two components: a mental composite scale (MCS) and physical composite scale (PCS). The higher 
the score, the better the physical and mental health functioning. 
 
5.3.3.12 Hospital Anxiety and Depression Scale (HADS) 
The Hospital Anxiety and Depression Scale (HADS) is a PRO instrument used to measure anxiety and 
depression over the past week. It is comprised of 7 questions for anxiety and 7 questions for 
depression and each are scored using a 4-point Likert scale (e.g., 0-3). Scores for each domain 
therefore, range from 0-21, where 8-10 is mild, 11-14 is moderate and 15-21 is severe anxiety or 
depression. 
 
5.3.3.13 Atopic Dermatitis Control Tool (ADCT) 
The Atopic Dermatitis Control Tool (ADCT) is a 6-question PRO instrument used to detect change of 
disease activity in a person over time. There are six main areas that assess the multi-dimensional 
aspects of disease control over the course of a week, scored between 0-4. ADCT scores range from a 
minimum score of 0 and a maximum score of 24. A higher score indicates lower AD control. 
 
5.3.3.14 Rescue Therapy 
Rescue therapy use is allowed throughout the entire study: selected topical corticosteroids and 
calcineurin inhibitors systemic antimicrobials and topical antibacterial may be prescribed. An 
unscheduled visit will be performed to collect skin assessments prior to administering any rescue 
therapy, if needed.  
Rescue therapy use will be documented as concomitant medication once prescribed and in a daily 
symptom diary during the whole course. Each rescue therapy course will be recorded in concomitant 
medication CRF separately, resulting in a one record in a concomitant medication dataset for each 
course.  
Any medications taken during the study and classified as TCS/TCI rescue therapy medications in the 
sponsor provided spreadsheet with total course duration no more than 8 days (adjusted for dosing 
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frequency – only days with planned medication usage are counted in course duration) will be 
considered as rescue therapy with exception for medications which stopped at least 14 days before 
Day 1 – these cannot be rescue therapy. 
 
For the number of courses of TCS/TCI rescue therapy in Weeks 1-4, 5-8, 9-12, 13-16, course will only 
be counted at the start day of course. If the rescue therapy course starts in one period and continues 
to the next period it will be counted only in the first period where the start of the course belongs. 
The number of courses of rescue therapy will be also evaluated for the whole period of Weeks 1-16.  
 
For the same periods, rescue therapy use will be evaluated. In case of rescue therapy course overlap 
with the period, the participant will be considered as those who used rescue therapy in this period.  
 
The number of days requiring TCS/TCI rescue therapy in Weeks 1-8, 9-16, 1-16 will be calculated as: 
 
Number of days requiring rescue therapy (days) = min(therapy stop date, the end of the 
period date) – max(therapy start date, the start of the period date) + 1 
In case of multiple rescue therapy medications concurrently, the day still will be counted only once.  
 
5.3.4 
Safety 
5.3.4.1 
Duration of Exposure 
The duration of exposure will be calculated as 
 
Duration of exposure (days) = Treatment stop date – Treatment start date + 1 
 
5.3.4.2 
Treatment-Emergent Adverse Events 
An adverse event (AE) will be classified as ‘treatment-emergent’ if the onset date/time was on or 
after the start date/time of study treatment. Where dates or times are missing or partially missing, 
AEs will be assumed to be treatment-emergent, unless there is clear evidence (through comparison 
of partial dates/times, see Section 7.3.1) to suggest that the AE started prior to dosing. 
 
AEs will be classified into the following study phases based on the onset date/time of the AE after 
any imputations: 
 
Pre-Treatment Phase: All AEs with onset date/time prior to the first dose of randomised 
study treatment 
 
Treatment Phase: All AEs with onset date/time at the time of or after the first dose of 
randomised study treatment (Day 1) up to and including the date of the last dose of 
treatment received.  
 
Follow-up Phase: All AEs with onset date after the date of the last dose of treatment 
received.  
 
For participants who complete 16 weeks of dosing per protocol, the Treatment Phase will be from 
Day 1 to the Week 16 visit, and the Follow-up Phase will start after the Treatment Phase and last 
until their last day in the study. In all cases the day will be assumed to start at 00:00 hours and end 
at 23:59 hours. Adverse events occurring in both the Treatment Phase and Follow-up Phase are 
classified as treatment emergent. 
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The onset phase of all AEs will be included in the relevant data listings. 
 
6 
Sample Size  
Cohorts 1-3 
The sample size was calculated using the assumption that data from the placebo participants in the 
three cohorts can be pooled prior to comparison with the EDP1815 treatment groups. No 
adjustments for multiple testing have been made. 
 
The primary efficacy endpoint is the achievement of EASI-50 at Week 16. The pooled placebo 
response rate is estimated to be approximately 25% and a doubling of this to 50% for EDP1815 
would be considered as clinically meaningful. 
 
Using a two-sided test at the 5% level of significance, 58 participants in each treatment group would 
give 80% power to detect a difference in one of the EDP1815 cohorts compared to the pooled 
placebo group. There would also be more than 90% power to compare the pooled EDP1815 group to 
the pooled placebo group. 
 
Under the assumption of a 20% drop-out of participants prior to Week 16 this will require a total of 
at least 73 participants to be enrolled in each treatment group. In order to allow for the 3:1 
randomisation in each cohort this has been adjusted to 75 participants per treatment group to give a 
total of 300 participants recruited. With 75 EDP1815 participants and 25 placebo participants in each 
of the three cohorts. 
 
Cohort 4 
Using the same assumptions relating to the placebo rate, clinically meaningful difference, significance 
level, and drop-out rate as above for Cohorts 1-3, approximately 70 participants are required in each 
of the EDP1815 8.0x1010 and Cohort 4 Matched Placebo groups to provide approximately 80% power 
in detecting a difference between EDP1815 and placebo in Cohort 4. 
 
In order to allow 50% of the placebo control group to be concurrent controls and 50% to be historic 
matched controls from Cohorts 1-3, a 2:1 randomization will be used to enroll 70 EDP1815 8.0x1010 
subjects and 35 placebo participants to Cohort 4. 
 
If sensitivity analyses indicate that pooling of the Cohort 4 placebo group with the Cohort 1-3 
matched placebo data is inappropriate, then the power of the comparison between the Cohort 4 
EDP1815 and placebo groups is approximately 65% if only Cohort 4 placebo participants could be 
used in the treatment comparisons.   
 
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7 
General Considerations 
7.1 
Analysis Populations 
7.1.1 
Participant Analysis Populations 
7.1.1.1 
Enrolled Population 
The enrolled set will consist of all participants who sign the ICF. 
 
7.1.1.2 
Full Analysis Population 
The full analysis population will consist of all participants who were randomised to treatment.  
 
All analyses using the full analysis population will group participants according to randomised 
treatment. 
 
7.1.1.3 
Safety Population 
The safety population will consist of all participants who received any study drug.  
 
All analyses using the safety population will group participants according to actual treatment 
received. If participants received multiple treatment during the study, they will be assigned to 
treatment group in the following manner: 
 
If participant received both active EDP and placebo treatments, they will be assigned to the 
active treatment group. 
 
If participant received 2 or more different active dose levels, they will be assigned to the 
highest dose they received. 
 
7.1.2 
Defined Data Point Sets 
Efficacy data point sets 1-6 were designed to replicate the corresponding primary endpoint 
estimands intercurrent event strategies: 
 
EDPS1 corresponds to primary estimand 1.    
 
EDPS2 corresponds to supplementary estimand 1. 
 
EDPS3 corresponds to supplementary estimand 2. 
 
EDPS4 corresponds to supplementary estimand 3. 
 
EDPS5 corresponds to supplementary estimand 4. 
 
EDPS6 corresponds to supplementary estimand 5. 
 
The following definitions and computational methods applied to the data point sets: 
 
* TCS/TCI rescue therapy – is the rescue therapy when topical corticosteroid or calcineurin inhibitors 
medication was prescribed. Rescue therapy is reported in both the CRF and patient diary. For the 
analysis purposes rescue therapy recorded on CRF page will be used.  
 
Multiple periods with rescue therapy are allowed during the study. All periods with rescue therapy 
are considered in EDPS definitions.  
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** Study withdrawal reasons related to study medication are lack of efficacy, treatment failure, 
adverse event (if related). Also, withdrawal of consent may be considered related to study 
medication based on the clarification text provided, that will be assessed by the Evelo team and 
provided in a separate spreadsheet. Type 2 prohibited medication will be considered as treatment 
withdrawal due to related reason at the date of medication start. Non-related reasons are all other 
reasons. 
 
1Last off-rescue observation is defined as the last off-rescue observation in the period before the 
corresponding intercurrent event plus early termination visit in case of early study discontinuation 
(off-rescue is defined as data collected at least 28 days after use of rescue medication or type 1 
prohibited medication). 
 
Categorization of all concomitant medications prescribed during the study will be done by Evelo 
clinician in order to identify TCS/TCI rescue therapy, antimicrobial rescue therapy and prohibited 
medications of type 1 and 2. 
 
7.1.2.1 
Efficacy Data Point Set 1 (EDPS1) 
EDPS1 consists of all data collected at a scheduled timepoint that is at least 28 days after use of 
TCS/TCI rescue therapy* or type 1 prohibited medication and before use of type 2 prohibited 
medication. Data collected less than 28 days after such use or data missing due to withdrawal from 
the study for reasons considered related to study medication** or data collected after use of type 2 
prohibited medications will be replaced as follows: 
• 
Continuous endpoints: value will be imputed with the last off-rescue1 observation in the 
period before the event plus early termination visit in case of early study discontinuation 
(off-rescue is defined as data collected at least 28 days after use of rescue medication or 
type 1 prohibited medication) 
• 
Responder endpoints: value will be imputed as non-response. 
• 
Count endpoints: N/A (no count endpoint will use this DPS). 
Data missing for other reasons, including early withdrawal from the study due to reasons not 
considered related to study medication will not be replaced and will be considered as missing. 
 
Example 1: if patient completed 16 weeks of study with rescue therapy during week 3 and then 
during week 10 then responder endpoints will be analysed as shown in table: 
Week 0 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
As collected 
As collected 
Imputed as 
non-
responder 
  
because there 
was a rescue 
therapy 
within 28 
days before 
Week 4 visit 
As collected 
Imputed as 
non-
responder 
 
because there 
was a rescue 
therapy 
within 28 
days before 
Week 12 visit 
As collected 
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Example 2: if patient completed 16 weeks of study with rescue therapy from Day 25 to Day 31 then 
responder endpoints will be analysed as shown in table: 
Week 0 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
As collected 
As collected 
Imputed as 
non-
responder 
  
because there 
was a rescue 
therapy 
within 28 
days before 
Week 4 visit 
Imputed as 
non-
responder 
  
because there 
was a rescue 
therapy 
within 28 
days before 
Week 4 visit 
As collected 
As collected 
 
Example 3: if patient withdrew study early due to the lack of efficacy after 12 weeks of treatment 
with rescue therapy during week 3 (unscheduled rescue therapy visit was not done) and then during 
week 10 (unscheduled rescue therapy visit was done at Week 9 prior to the rescue therapy start) 
then continuous endpoints will be analysed as shown in table: 
Week 0 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
As collected 
As collected 
Imputed with 
Week 2 data  
 
because there 
was a rescue 
therapy 
within 28 
days before 
Week 4 visit 
and the last 
off-rescue 
data is at 
Week 2 visit 
As collected 
Imputed with 
Week 9 data 
 
because there 
was a rescue 
therapy 
within 28 
days before 
Week 12 visit 
and the last 
off-rescue 
data is at 
unscheduled 
Week 9 visit 
Imputed with 
Week 9 data 
 
because visit 
is missing due 
to reasons 
considered 
related to 
study 
medication 
and the last 
off-rescue 
data is at 
unscheduled 
Week 9 visit 
 
7.1.2.2 
Efficacy Data Point Set 2 (EDPS2) 
EDPS2 consists of all data collected at a scheduled timepoint that is at least 28 days after use of 
TCS/TCI rescue therapy* or type 1 prohibited medication and before use of type 2 prohibited 
medication. Data collected less than 28 days after such use will be considered as missing and 
excluded from the analysis. Data missing due to withdrawal from the study for reasons considered 
related to study medication** and data after use of type 2 prohibited medication will be imputed as 
per EDPS1. Data missing for other reasons will not be replaced. 
 
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7.1.2.3 
Efficacy Data Point Set 3 (EDPS3) 
EDPS3 consists of EASI-50 responses collected at Week 16 that were evaluated at least 14 days after 
use of TCS/TCI rescue therapy* or type 1 prohibited medication and before use of type 2 prohibited 
medication. Data collected less than 14 days after such use or missing due to withdrawal from the 
study for reasons considered related to study medication** or data after use of type 2 prohibited 
medication will be imputed as non-response. 
 
EASI-50 response missing for other reasons, including early withdrawal from the study due to 
reasons not considered related to study medication will not be replaced and will be considered as 
missing. 
 
7.1.2.4 
Efficacy Data Point Set 4 (EDPS4) 
EDPS4 consists of EASI-50 responses collected at Week 16 that were evaluated at least 28 days  
after use of TCS/TCI rescue therapy* or type 1 prohibited medication and before use of type 2 
prohibited medication. Data collected less than 28 days after such use will be replaced as per EDPS1. 
Data missing due to other reasons including early withdrawal from the study for any reason will not 
be replaced and be considered as missing. Data after use of type 2 prohibited medication will be 
considered missing.  
 
7.1.2.5 
Efficacy Data Point Set 5 (EDPS5) 
EDPS5 is a subset of EDPS1 for the EASI-50 response data only, excluding any data collected or 
imputed after the unblinding of a participant or other protocol deviations affecting efficacy 
(whichever occurs first) and excluding all data from subjects who take <75% of expected doses 
(Section 5.3.2.1) or whose compliance with emollient use was <75% (Section 5.3.2.2). 
 
7.1.2.6 
Efficacy Data Point Set 6 (EDPS6) 
EDPS6 consists of data collected in the absence of TCS/TCI rescue therapy* and type 1 prohibited 
medication at any time since Day 1 for the responder endpoints relating to EASI, vIGA and PP-NRS. 
Data collected after such use will be imputed as non-response. Data missing due to withdrawal from 
the study for reasons considered related to study medication** and data after use of type 2 
prohibited medication will be imputed as per EDPS1. 
 
Responses missing for other reasons, including early withdrawal from the study due to reasons not 
considered related to study medication will not be replaced and will be considered as missing. 
 
7.1.2.7 
Efficacy Data Point Set 7 (EDPS7) 
EDPS7 contains all data collected. A treatment policy strategy will be used for all intercurrent events 
other than discontinuation from the study which will use a while on treatment strategy (i.e., the 
collection period will be ended at the time of study discontinuation). 
 
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7.1.2.8 
Safetyagree Data Point Set 1 (SDPS1) 
SDPS1 consists of all observed data collected at a scheduled visit. 
 
7.1.2.9 
Safety Data Point Set 2 (SDPS2) 
SDPS2 consists of all observed data collected, including data from scheduled and unscheduled visits. 
 
7.2 
Covariates and Subgroups 
Subgroups based on baseline severity of disease will be defined as follows: 
 
Using baseline vIGA score of 3 for efficacy analysis 
 
Using baseline vIGA score other then 3 for summaries only (2, 4) 
 
For the inferential models defined in Section 9, in addition to the baseline vIGA score and relevant 
baseline score where applicable, the following covariates will be considered: 
 
Body mass index (<30 kg/m2, ≥30 kg/m2) 
 
Sex (male, female) 
 
Race (Non-Hispanic white and Hispanic or Non-White) 
 
Region (North America, Europe, Asia Pacific) 
Covariates selection will be done separately for cohorts 1-3 analyses and cohort 4.  
 
7.3 
Missing Data 
Missing efficacy data such as individual item scores will be dealt with as detailed in Section 5.3.3. 
Imputation of missing efficacy data due to intercurrent events will be performed in EDPS1, EDPS2, 
EDPS3, EDPS4 and EDPS5 as described in Section 7.1.2. 
 
7.3.1 
Partial Dates/Times 
Partial dates and times for AEs, medical conditions and concomitant medications will be imputed for 
the purpose of assigning study phases and calculating duration. Listings will always include the 
reported date/time information rather than any imputations. 
 
Partial AE onset and concomitant medication (from concomitant medications CRF page) start dates 
will be imputed as follows: 
 
If only the month and year are specified, and the month and year of the start of treatment 
are not the same as the month and year of the start date, then use the 1st of the month. 
 
If only the month and year are specified, and the month and year of the start of treatment 
are the same as the month and year of the start date, then use the date of start of 
treatment. If this results in a start date after a known or partial end date, then use the 1st of 
the month. 
 
If only the year is specified, and the year of the start of treatment is not the same as the year 
of the start date, then use January 1 of the year of the start date. 
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 
If only the year is specified, and the year of the start of treatment is the same as the year of 
the start date, then use the date of the start of treatment. If this results in a start date after 
a known or partial end date, then use January 1 of the year of the start date. 
 
If the start date is completely unknown, then use the date of the start of treatment. If this 
results in a start date after a known or partial end date, do not impute the start date. 
 
Concomitant medication (from atopic dermatitis past treatments CRF page) start dates will be 
imputed as follows: 
 
If only the month and year are specified, then use the 1st of the month. 
 
If only the year is specified, then use January 1 of the year of the start date. 
 
If the start date is completely unknown, then do not impute the start date. 
 
Partial AE onset start times will be imputed as follows: 
 
If the actual or imputed start date is the same as the treatment start date, and the start time 
is completely missing, then use the time of start of treatment. 
 
If the actual or imputed start date is not the same as the treatment start date, and the start 
time is completely missing, then use 00:00. 
 
If the actual or imputed start date is the same as the treatment start date, and the start time 
is partially missing (hh:XX) then use the following: 
o If the hour is the same as the hour of the start of treatment time then use the 
complete time of the start of treatment (i.e., both hours and minutes) 
o If the hour is not the same as the hour of the start time than use hh:00. 
 
If the actual or imputed start date is not the same as the treatment start date, and the start 
time is partially missing (hh:XX) then use hh:00 
 
Partial medical conditions start dates will be imputed as follows: 
 
If only the month and year are specified, then use the 1st day of the month. 
 
If only the year is specified, then use January 1st of that year. 
 
If the start date is completely unknown, do not impute the start date. 
 
Partial AE resolution, medical condition stop dates and concomitant medication (from concomitant 
medications CRF page) stop dates and date last smoked will be imputed as follows: 
 
If the event, condition or medication is flagged as ongoing, do not impute the stop date 
 
If only the month and year are specified, then use the last day of the month. 
 
If only the year is specified, then use December 31 of that year. 
 
If the stop date is completely unknown, do not impute the stop date. 
 
Concomitant medication (from atopic dermatitis past treatments CRF page) stop dates will be 
imputed as follows: 
 
If the event, condition or medication is flagged as ongoing, do not impute the stop date 
 
If only the month and year are specified, and the month and year of the screening visit are 
not the same as the month and year of the end date, then use the last day of the month. 
 
If only the month and year are specified, and the month and year of the screening visit are 
the same as the month and year of the end date, then use the date of screening visit. 
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 
If only the year is specified, and the year of the screening visit is not the same as the year of 
the end date, then use December 31 of that year. 
 
If only the year is specified, and the year of the screening visit is the same as the year of the 
end date, then use the date of screening visit. 
 
If the stop date is completely unknown, do not impute the stop date. 
 
Partial AE resolution and concomitant medication stop times will be imputed as follows: 
 
If the actual or imputed stop date is non-missing, and the stop time is completely missing, 
then use 23:59 on that date. 
 
If the actual or imputed stop date is non-missing, and the stop time is partially missing, then 
hh:59 for missing minutes. 
 
If the actual or imputed stop date is missing, do not impute the stop time. 
 
7.3.2 
Adverse Event Information 
AEs with missing relationship will be considered ‘Related’ for summary purposes but recorded as 
missing in the listings. 
 
7.4 
Interim Analyses and Data Monitoring 
7.4.1 
Purpose of Interim Analyses 
Interim analysis 
The Interim analysis will be performed to check that no imbalance of treatment groups has occurred 
due to stratified randomisation leaving multiple incomplete blocks.  
 
If an imbalance is detected, the randomisation schedule may be slightly adapted for the final 
participants to ensure that all treatment groups have enrolled at least 73 participants.  
No other decisions regarding study conduct will be made based on the interim results and the study 
will not be stopped if superior efficacy or futility is found. 
 
Cohorts 1-3 analysis 
After the last patient last visit in cohorts 1-3, DBL and cohorts 1-3 specific analysis will be performed.  
No decisions regarding the study conduct will be made based on the cohorts 1-3 analyses, but the 
results may be shared externally. Also, cohorts 1-3 efficacy tables and listings will be considered final 
and included in CSR at the end of study.  
 
7.4.2 
Planned Schedule of Interim Analyses 
The interim analysis will be performed after approximately 290 participants have been randomised.. 
 
Cohorts 1-3 specific analysis will be performed after the cohorts 1-3 DBL. 
 
 
 
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7.4.3 
Endpoints to be Included in the Interim Analysis 
Interim analysis 
No endpoints will be evaluated. Only the distribution of participants in each of the treatment groups 
(Active cohort 1-3 and pooled placebo) will be considered. 
 
Cohorts 1-3 analysis 
All analyses planned for the study will be done, but will only include cohorts 1-3 participants.  
 
7.4.4 
Adjustment of Confidence Intervals and p-values 
Interim analysis 
No comparisons of efficacy will be performed so no adjustments for alpha-spending are required. 
 
Cohorts 1-3 analysis 
Efficacy tables and figures will be considered final so no adjustments for alpha-spending are 
required.  
 
7.4.5 
Practical Measures to Minimise Bias 
Interim analysis 
Outputs featuring unblinded treatment assignments will be created by the unblinded analysis team 
within 
 and shared with the unblinded personel at 
 (Interactive Response 
Technology Vendor) who will implement the required changes to the randomisation schedule in 
their system.. Unblinded results will not be shared with any study site staff, participants, or any 
members of the study team who will be involved in the collection, review or analysis of individual 
study data.   
 
The members of the unblinded team will not be involved in any aspects of study conduct, including 
in the development of the final summaries and analyses for the study.  No data which may have the 
potential to unblind will be released beyond the unblinded personnel.   
 
Cohorts 1-3 analysis 
Cohorts 1-3 data will be unblinded to the 
study team and the sponsor after the cohorts 1-3 
DBL. Cohort 4 data will remain blinded till the end of study.  
 
7.4.6 
Documentation of Interim Analyses 
Interim analysis 
All unblinded data and summaries, together with any meeting minutes in which unblinded data is 
discussed will be held in a restricted file structure by the unblinded statistician until after the study 
has finished and the data has been unblinded after DBL. 
 
Cohorts 1-3 analysis 
Unblinded summaries will be shared with the sponsor as cohorts 1-3 data will be unblinded after the 
cohorts 1-3 DBL. 
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7.5 
Multi-centre Studies 
Results will be presented for all centres combined.  For the inferential analyses the effect of region 
will be assessed for significance in the models. 
 
7.6 
Multiple Testing 
The focus of this study is on model estimation of treatment effects and as such no adjustments will 
be made for multiple testing in this study. 
 
7.7 
Visit Windows 
All data will be reported according to nominal visits. For example, if a Week 2 visit occurred on Day 
16 instead of the nominally expected Day 14 it will be reported and included in the summary 
statistics/statistical analyses for Week 2.  
 
Scheduled visits which occur outside the protocol-specified visit window (e.g., if the Week 2 visit 
occurred on Day 19 outside of the Day 12-18 window), this will be noted as a protocol deviation but 
data collected will still be included in all summary and analysis tables. 
 
Unscheduled visits and Early Termination visit will not be included in summary or analysis tables, 
unless they are baseline measurements, provide data towards a safety endpoint which looks at 
worst-case post-baseline, or if a visit is a rescue therapy unscheduled visit.  
 
Week 20 visit will be included in the summaries, but no analysis will be done at this visit.  
 
For the rescue therapy, subjects who started rescue therapy outside of a scheduled visit should 
complete assessments required for the rescue therapy unscheduled visit.  This data will only be 
included in tables and figures in cases where the last off-rescue observation carried forward 
imputation method is used to account for the intercurrent event of rescue therapy.   
 
All listings will include all collected data even if they are from an unscheduled visit. 
 
8 
Summary of Study Data 
All continuous variables will be summarized using the following descriptive statistics: n (non-missing 
sample size), mean, SD, median, maximum and minimum. The frequency and percentages (based on 
the non-missing sample size) of observed levels will be reported for all categorical measures. 
 
In general, all data will be listed, sorted by cohort (1, 2, and 3 for the cohorts 1-3 analysis and 1-4 for 
the final analysis), randomised treatment (Placebo, EDP1815), site number and participant number.  
Relevant listings will include whether the assessment was performed and the date, study day/visit 
and time of the assessment as applicable. 
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Unless otherwise specified below, all summary tables will be structured with a column for each 
treatment. Where appropriate, columns combining all placebo participants, all EDP1815 participants 
and an overall total column may also be presented. 
 
For summaries of study disposition, demographic and baseline data and study treatment 
compliance, columns will be ordered and labelled as follows: 
 
Cohort 1 Placebo  
 
Cohort 1 EDP1815  
 
Cohort 2 Placebo  
 
Cohort 2 EDP1815  
 
Cohort 3 Placebo  
 
Cohort 3 EDP1815  
 
Cohort 4 Placebo (final analysis only) 
 
Cohort 4 EDP1815 (final analysis only) 
 
All Placebo 
 
All EDP1815 
 
Total 
 
For cohorts 1-3 efficacy outputs, columns will be ordered and labelled as follows: 
 
All Placebo 
 
Cohort 1 EDP1815  
 
Cohort 2 EDP1815  
 
Cohort 3 EDP1815  
 
Cohorts 2+3 EDP1815 
 
All EDP1815  
 
For cohort 4 efficacy outputs, columns will be ordered and labelled as follows: 
 
Cohort 4 Placebo 
 
Cohort 4 Matched Placebo  
 
Cohort 4 EDP1815  
 
Cohort 1 EDP1815  
 
For concomitant medication and safety outputs, columns will be ordered and labelled as follows: 
 
All Placebo 
 
Cohort 1 EDP1815  
 
Cohort 2 EDP1815  
 
Cohort 3 EDP1815  
 
Cohort 4 EDP1815 (final analysis only) 
 
All EDP1815 
 
 
 
 
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For the analysis: 
 
 
For study disposition summaries where it is appropriate to report information on 
participants who failed screening, the enrolled population will be used. 
 
 
For safety summaries, where data is assigned to specific scheduled visits, the safety 
population with SDPS1 will be used. 
 
 
For safety summaries, where all other safety data is presented (including adverse events and 
worst-case change from baseline endpoints), the safety population with SDPS2 will be used. 
 
 
For the primary estimand and all secondary and exploratory estimands, full analysis 
population with EDPS1 will be used. 
 
 
For the supplementary estimands for the primary endpoint, full analysis population with 
EDPS2-EDPS5 will be used. 
 
 
Selected secondary response endpoints will also have secondary supplementary estimands: 
full analysis population with EDPS2 and EDPS6 will be used for endpoints based on EASI, 
vIGA and PP-NRS. 
 
 
For the secondary count endpoints, full analysis population with EDPS7 will be used. 
 
 
For the exploratory endpoints, full analysis population with EDPS1 will be used. 
 
 
For all other summaries and analyses the full analysis population will be used. 
 
8.1 
Study Disposition 
Completion/withdrawal from the study and completion/discontinuation from treatment, together 
with reasons for withdrawal from the study or discontinuation from treatment will be listed and the 
following will also be tabulated: 
 
Number and percentage of participants who completed the study  
 
Number and percentage of participants withdrawn from the study and the reported reason 
for withdrawal  
 
For the interim analyses, the number and percentage of participants still ongoing in the 
study will also be presented 
 
Number and percentage of participants who completed the 16-week treatment period  
 
Number and percentage of participants who discontinued treatment early and reason for 
discontinuation  
 
For participants who fail screening, the reasons for screen failure including details on which 
inclusion/exclusion criteria were not met will be summarised and listed. 
 
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The number and percentage of participants enrolled within each region, country and site will be 
summarised. 
 
For the enrolled population, the number and percentage of participants in each analysis population 
will be presented.  Inclusion/exclusion in each study population will also be listed, together with 
reasons for exclusion. 
 
The number and percentage of participants with data available for each scheduled visit (including 
the early termination visit) will be summarised. 
Missed visits due to COVID-19 will also be summarised and listed. 
 
8.2 
Protocol Deviations 
The number and percentage of participants in the full analysis population with at least one 
significant protocol deviation will be summarised by deviation category.  
 
All protocol deviations will also be listed. 
 
8.3 
Demographic and Baseline Variables 
Demography data of age, sex, race, ethnicity will be summarised together with height, weight and 
BMI at screening. 
 
Baseline vIGA score (randomisation stratification factor from the IRT system and CRF data), baseline 
EASI score and baseline BSA will be summarised. 
 
Time since diagnosis (years) will be summarised. 
 
Separately atopic dermatitis medications taken pre-treatment will be summarised.  
 
8.4 
Medical History 
Medical history and concurrent illnesses will be captured and coded using the Medical Dictionary for 
Regulatory Activities (MedDRA®). The dictionary will be updated through the life of the study with 
version 24.0 used initially. 
 
Concurrent illnesses and medical conditions will be classified as ‘current’ if the end date is on or 
after the date of first dose of study drug, or the condition has been marked as ongoing.  Otherwise, 
they will be classified as ‘past’. 
 
Past and current medical history will be summarised separately by System Organ Class (SOC) and 
Preferred Term (PT).  Summary tables will contain the number and percentage of patients. A patient 
who has multiple conditions in the same SOC or with the same PT will be counted only once in the 
patient counts. Medical history summaries will be sorted by the internationally agreed SOC order 
(Table 5) and decreasing frequency of PT within SOC in the Total column. 
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All medical history data will be listed. 
 
8.5 
Prior and Concomitant Medications 
Medications will be coded according to the World Health Organization Drug Dictionary (WHODD). 
The dictionary will be updated through the life of the study with the version dated 01Mar2021 used 
initially. Medical procedures will not be coded.  
 
Concomitant medications are defined as any medications taken during the treatment period or 
follow-up period after treatment.  This includes any medications started before the first dose and 
ongoing after the first dose. Prior medications are defined as any medication taken before or during 
the screening period which were stopped before the first dose of study medication. 
 
Missing and partial start and stop dates will be imputed using the rules specified in Section 7.3.1 
before classifying therapies as prior or concomitant. If the classification is still ambiguous after 
missing and partial dates have been imputed, then the medication will be considered concomitant. 
 
Medications will be summarised by WHODD Anatomical Main Group (Level 1), Therapeutic Subgroup 
(Level 2) and preferred term.  The summaries will report incidence within each relevant level so that 
a participant taking multiple medications coded to the same relevant Level 1, Level 2 or preferred 
term would only be counted once within the incidence count for that level or term. 
 
Separate summaries will be produced for each of the following: 
 
Prior medications 
 
All concomitant medications  
 
Concomitant medications started pre-treatment  
 
Concomitant medications during the treatment period (including any which started pre-
treatment) 
 
Concomitant medications started during the follow-up period 
 
All prior and concomitant medications will be listed.  
 
8.6 
Treatment Compliance 
Treatment compliance will be summarised for the whole 16-week treatment period.   
 
Summary statistics (n, mean, SD, median and range) will be produced together with the number and 
percentage of participants within each of the categories defined in Section 5.3.2.1.  Percentages will 
use the number of participants who started the treatment period as the denominator. 
 
Data from the dosing diary, drug accountability and the calculated treatment compliance will also be 
listed. 
 
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8.7 
Emollient Compliance 
Emollient compliance will be summarised for the whole treatment period. 
 
Summary statistics (n, mean, SD, median and range) will be produced together with the number and 
percentage of participants within each of the categories defined in Section 5.3.2.2.  Percentages will 
use the number of participants who started the period as the denominator. 
 
Data from the daily diary and the calculated emollient compliance will also be listed. 
 
9 
Efficacy Analyses 
All efficacy analyses outputs will be created separately for cohorts 1-3 and cohort 4. 
 
In addition to the inferential analyses described below, descriptive statistics will be provided to 
summarize all efficacy endpoints by treatment group.  
 
For categorical variables, summary tabulations of frequency and percentage of participants within 
each category will be presented.  
 
For continuous variables and duration endpoints, the number of participants, mean, median, standard 
deviation (SD), minimum, and maximum values will be presented. 
 
For daily time to event endpoints, the number of participants with the event, the number of 
participants censored will be presented together with Kaplan-Meier estimates of the proportion of 
responders in each study week, the estimated median and quartiles for time to response. Kaplan-
Meier curves of time to event will also be presented. 
 
All efficacy data will be listed, including both individual item scores and calculated questionnaire 
summary scores. 
 
9.1 
Pooling of Placebo Cohorts 
For all cohorts 1-3 efficacy analyses, the cohorts 1-3 placebo groups will be pooled into a single ‘all 
placebo’ group and will be used as a common control group for the pooled EDP1815 treatment 
group and each individual EDP1815 treatment group.  
 
For cohort 4 the process is described in the separate SAP Addendum. 
 
9.2 
Selection of Additional Covariates 
For all cohorts 1-3 efficacy analyses, the covariates described in Section 7.2 will be considered and 
included in the primary efficacy model 1 described in Section 9.3.3 for the primary estimand if found 
to be significant (p<0.05).  A forward stepwise selection method will be used to include the 
covariates after the baseline vIGA score and baseline EASI score have already been fitted.  
 
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The covariates selected for this primary model will also be used in all other analytical models 
including covariates. 
 
For cohort 4 the process is described in the separate SAP Addendum. 
 
9.3 
Primary Efficacy Analysis 
All efficacy analysis details in this section are provided for cohorts 1-3 analysis.  
For cohort 4 analysis the same approach will be used. Any differences and additional analyses will be 
described in the SAP Addendum.  
 
9.3.1 
Primary Efficacy Estimand 
The primary efficacy estimand will be the effect of each individual EDP1815 cohort compared to the 
pooled placebo group on the percentage of participants achieving EASI-50 at Week 16. The 
population summary measure of interest will be the odds ratio between each active EDP1815 
treatment group and pooled placebo.   
 
Intercurrent events will be accounted for in the following manner: 
 
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3Type 2 prohibited medication will be considered as treatment withdrawal due to related reason at 
the date of medication start for the intercurrent event strategy. 
 
9.3.3 
Main Analytical Approach 
The primary analysis will be performed using a logistic regression model.  The model will include 
parameters for treatment group, baseline vIGA score and baseline EASI score. As described in 
Section 9.2 additional covariates for baseline factors will be assessed using this model for inclusion in 
all efficacy models. Only Week 16 data will be included in the model. 
 
Treatment will consist of 4 levels (all placebo, cohort 1 EDP1815, cohort 2 EDP1815, cohort 3 
EDP1815). Baseline vIGA will consist of 3 levels (2, 3 and 4).  
 
The following treatment differences will be of estimated: 
 
Cohort 1 EDP1815 vs Pooled placebo 
 
Cohort 2 EDP1815 vs Pooled placebo 
 
Cohort 3 EDP1815 vs Pooled placebo 
 
Cohorts 2+3 EDP1815 vs Pooled placebo* 
 
All EDP1815 vs Pooled placebo* 
 
Cohort 2 EDP1815 vs Cohort 3 EDP1815** 
 
Cohort 1 EDP1815 vs Cohort 2 EDP1815** 
 
* Comparisons between pooled EDP1815 groups and pooled placebo will be considered as 
secondary analysis. 
** Comparisons between EDP1815 treatment groups will be considered as exploratory analysis. 
 
The comparisons between pooled EDP1815 groups* and comparisons between EDP1815 treatment 
groups** will be done using contrasts (LSMESTIMATE statement) within the relevant SAS 
procedures. 
 
The actual and predicted probability of EASI-50 response at Week 16 in each treatment group 
together with the estimated odds ratios and associated confidence intervals for each treatment 
difference will be displayed. P-values will be displayed for the comparisons of active treatment 
(individual and pooled) vs pooled placebo. 
 
Vertical bar plots for the actual and predicted probabilities of EASI-50 at Week 16 for each treatment 
group will be plotted.  
 
The primary analysis approach will be repeated using the 4 supplementary estimands described in 
Section 9.3.2. 
 
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9.3.4 
Sensitivity Analyses 
Secondary estimand generalised linear mixed effects model (GLMM) analysis of EASI-50 (including all 
timepoints as described in Section 9.4.2.2) will be considered a sensitivity analysis for the primary 
endpoint.   
 
9.3.5 
Subgroup Analyses 
The analyses described in Section 9.3.3 will be repeated on the primary estimand using the subgroup 
of baseline vIGA score of 3 as defined in Section 7.2.  
 
For the subgroups of baseline vIGA score other then 3 (baseline vIGA score of 2; baseline vIGA score 
of 4), number of patients with EASI-50 response will be summarized, but no analysis will be done, as 
the sample sizes are not expected to be large enough for meaningful comparisons to be made.    
 
There will be no figures for the subgroup analyses. 
 
9.4 
Secondary Efficacy Analyses 
All efficacy analysis details in this section are provided for cohorts 1-3 analysis.  
For cohort 4 analysis the same approach will be used. Any differences and additional analyses will be 
described in the SAP Addendum.  
 
All continuous and response secondary estimands will use EDPS1 (the primary estimand approach).  
 
Secondary continuous and response endpoints based on the EASI, vIGA and PP-NRS will be analysed 
with a supportive estimands using EDPS2 (the supplementary estimand 1 approach) and EDPS6 for 
the response endpoints only (the supplementary estimand 5 approach). 
 
Count secondary endpoints will use EDPS7 (estimand includes all data as collected prior to 
completion or withdrawal from the study). 
 
The following treatment differences will be estimated: 
• 
Cohort 1 EDP1815 vs Pooled placebo 
• 
Cohort 2 EDP1815 vs Pooled placebo 
• 
Cohort 3 EDP1815 vs Pooled placebo 
• 
Cohorts 2+3 EDP1815 treatment group vs all placebo 
• 
All EDP1815 treatment group vs all placebo 
• 
Cohort 2 EDP1815 vs Cohort 3 EDP1815* 
• 
Cohort 1 EDP1815 vs Cohort 2 EDP1815* 
 
* Comparisons between EDP1815 treatment groups will be considered as exploratory analysis. 
 
The comparisons between pooled EDP1815 groups and comparisons between EDP1815 treatment 
groups* will be done using contrasts (LSMESTIMATE statement) within the relevant SAS procedures. 
 
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Summary statistics only will be presented for Week 20 for those participants who completed 
treatment but did not wish to participate in the OLE.  
 
9.4.1 
Continuous Secondary Endpoints 
The following secondary endpoints will be analysed in the same manner as described below: 
 
Mean absolute change from baseline in EASI score at Weeks 4, 8, 12, and 16  
 
Mean percentage change from baseline in EASI score at Weeks 4, 8, 12, and 16  
 
Mean absolute change from baseline in vIGA*BSA score at Weeks 4, 8, 12, and 16  
 
Mean percentage change from baseline in vIGA*BSA score at Weeks 4, 8, 12, and 16 
 
Mean absolute change from baseline in BSA score at Weeks 4, 8, 12, and 16  
 
Mean percentage change from baseline in BSA score at Weeks 4, 8, 12, and 16  
 
Mean absolute change from baseline in SCORAD score at Weeks 4, 8, 12, and 16  
 
Mean percentage change from baseline in SCORAD score at Weeks 4, 8, 12, and 16  
 
Mean absolute change from baseline in DLQI score at Weeks 4, 8, 12, and 16  
 
Mean percentage change from baseline in DLQI score at Weeks 4, 8, 12, and 16  
 
Mean absolute change from baseline in POEM score at Weeks 4, 8, 12, and 16  
 
Mean percentage change from baseline in POEM score at Weeks 4, 8, 12, and 16  
 
Mean absolute change from baseline in PP-NRS score at Weeks 4, 8, 12, and 16 
 
Mean absolute change from baseline in SD-NRS score at Weeks 4, 8, 12, and 16 
 
If a participant has a zero score for any of the secondary scores at baseline, that participant will be 
excluded from any of the percentage change from baseline summaries and analyses as the 
percentage change from baseline cannot be calculated. 
 
9.4.1.1 
Estimands 
The population summary measure of interest will be the mean difference between treatment groups 
specified in Section 9.4. 
 
Where intercurrent event strategy is composite, for continuous endpoints value will be imputed 
with the last off-rescue observation. 
Last off-rescue observation is defined as the last off-rescue observation in the period before the 
corresponding intercurrent event plus early termination visit in case of early study discontinuation 
(off-rescue is defined as data collected at least 28 days after use of rescue medication or type 1 
prohibited medication). 
 
Note, for PP-NRS and SD-NRS intercurrent event strategy should be applied for daily scores before 
the weekly scores are calculated.  
 
9.4.1.2 
Main Analytical Approach 
A mixed model for repeated measures (MMRM) with parameters for treatment group, visit 
(excluding Week 20), baseline vIGA score, baseline relevant questionnaire score and the interaction 
for treatment*visit will be used. 
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Treatment will consist of 4 levels (all placebo, cohort 1 EDP1815, cohort 2 EDP1815, cohort 3 
EDP1815). Baseline vIGA will consist of 3 levels (2, 3 and 4).  
 
As described in Section 9.2, any baseline covariates fitted into the primary analysis model will also be 
fitted in the models for these endpoints.  
 
An unstructured covariance structure will be used. If there are issues with model convergence, other 
covariance structures may be considered (e.g. compound symmetry). 
 
Distributional assumptions underlying the model used for analysis will be examined by a normal 
probability plot of the residuals and a plot of residuals versus the fitted values (i.e. checking the 
normality assumption and constant variance assumption of the model respectively) to gain 
confidence that the model assumptions are reasonable. 
 
Least squares mean estimates and their 95% confidence intervals (CI) will be presented for the 
endpoint value at each visit. Treatment differences between each EDP1815 group (including cohorts 
2+3 EDP1815 and all EDP1815 groups) and the pooled placebo group will be estimated using LS 
mean differences, 95% CI and p-values. Pairwise treatment differences between EDP1815 groups 
will be estimated with LS mean differences and 95% CI. 
 
Least square mean (95% CI) estimates will be plotted against visit. Least square mean (95% CI) 
treatment differences between each EDP1815 treatment group and the pooled placebo group will 
also be plotted against visit. Waterfall plots at Week 16 will be presented as panels for individual 
treatment groups.  
 
In addition, for the secondary endpoints based on the EASI, vIGA and PP-NRS only, a supportive 
analysis will be performed using the EDPS2.   
 
9.4.2 
Response Endpoints  
The following endpoints will be analysed in the same manner as described below: 
 
Percentage of participants achieving EASI-50, EASI-75, EASI-90 at Weeks 4, 8, 12 and 16 
 
Percentage of participants achieving vIGA of 0 or 1 with a ≥2-point improvement from 
baseline at Weeks 4, 8, 12 and 16 
 
Percentage of participants achieving vIGA of 0 or 1 at Weeks 4, 8, 12 and 16 
 
Percentage of participants achieving vIGA of 0 at Weeks 12 and 16 
 
Percentage of participants achieving BSA-50, BSA-75 at Weeks 4, 8, 12 and 16 
 
Percentage of participants achieving BSA reduction to 3% or less at Weeks 4, 8, 12 and 16 
 
Percentage of participants achieving SCORAD-35, SCORAD-50, SCORAD-75 at Weeks 4, 8, 12 
and 16 
 
Percentage of participants achieving improvement of ≥4 points in DLQI score from baseline 
at Weeks 4, 8, 12 and 16 
 
Percentage of participants achieving improvement of ≥2, ≥4 points in PP-NRS score from 
baseline at Weeks 4, 8, 12 and 16 
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 
Percentage of participants achieving improvement of ≥2 points in SD-NRS score from 
baseline at Weeks 4, 8, 12 and 16 
 
Percentage of participants achieving improvement of ≥4 points in POEM score from baseline 
at Weeks 4, 8, 12 and 16 
 
Proportion of participants requiring TCS/TCI rescue therapy in periods Weeks 1-4, 5-8, 9-12, 
13-16 and Weeks 1-16. 
 
9.4.2.1 
Estimands 
The population summary measure of interest will be the odds ratio between treatment groups 
specified in Section 9.4 for the achievement of response at the relevant time point. 
 
Note, for PP-NRS and SD-NRS intercurrent event strategy will be applied after weekly scores at 
scheduled visits are calculated from daily scores. 
 
9.4.2.2 
Main Analytical Approach 
Endpoints evaluated at selected visits 
A generalised linear mixed effects model (GLMM) with a logit link function will be fitted using data 
from all visits (excluding Week 20). Treatment, visit, baseline vIGA score and the appropriate 
baseline questionnaire score (if different from vIGA) terms will be included in the model as fixed 
effects together with treatment*visit interaction.  
 
Endpoints evaluated in periods 
A generalised linear mixed effects model (GLMM) with a logit link function will be fitted using data 
from all periods (Weeks 1-4, 5-8, 9-12 and 13-16). Treatment, period, baseline vIGA score terms will 
be included in the model as fixed effects together with treatment*period interaction. The analyses 
will be repeated for the weeks 1-16 period dropping the terms for period and treatment*period 
interaction.  
 
As described in Section 9.2, any baseline covariates fitted into the primary analysis model will also be 
fitted in the models for these endpoints. 
 
An unstructured covariance structure will be used.  If there are issues with model convergence, 
other covariance structures may be considered (e.g., compound symmetry). 
 
If responder numbers are low and there are visits/periods at which not all treatment groups have at 
least one response, the analysis may be modified to exclude one or more of the earlier visits/periods 
to ensure model convergence. For endpoints evaluated in periods, periods may be pooled in order 
to have more patients data in periods and ensure model convergence. 
 
Alternatively, the mixed effects model may be replaced with an individual logistic regression models 
at Week 16 if this approach appears to be more appropriate for the available data. Note that if there 
are insufficient responders to run the model with the Week 16 visit included then no inferential 
analysis should be performed. 
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The number and percentage of responders will be reported at each visit/period together with 95% CI 
for the percentage of responders, calculated using the exact method for binomial proportions. At 
each visit/period, the adjusted odds ratio, with 95% CI and associated p-value will also be presented 
for each EDP1815 group (including cohorts 2+3 EDP1815 and all EDP1815 groups) compared to the 
pooled placebo group. For comparison between EDP1815 groups, at each visit/period, the adjusted 
odds ratio with 95% CI will be presented. 
 
If the analysis is changed to exclude visits/periods, then only the summary statistics for the number 
of subjects with data, the number and percentage of participants with a response and the 95% CI for 
the percentage of responders will be shown for any visits/periods which were excluded from the 
model.  Table footnotes will be added as appropriate to detail any changes to the planned analysis. 
 
For Week 20 visit, only the summary statistics for the number of subjects with data, the number and 
percentage of participants with a response and the 95% CI for the percentage of responders will be 
shown. 
 
The proportions of responders and the 95% CI will be displayed graphically. The adjusted odds ratios 
(with 95% CI) will be plotted by visit.   
 
In addition, for the secondary endpoints based on the EASI, vIGA and PP-NRS only, a supportive 
analysis will be performed using the EDPS2.   
 
9.4.3 
Count Endpoints 
The following endpoints will be analysed in the same manner as described below: 
 
Number of courses of TCS/TCI rescue therapy 
 
Number of days requiring TCS/TCI rescue therapy 
 
9.4.3.1 
Estimands 
The population summary measure of interest will be the rate ratio between treatment groups 
specified in Section 9.4. 
 
Additionally, participants with rescue therapy courses recorded in CRF but with duration of more 
than 8 days (adjusted for dose frequency) will be excluded from the analysis due to the potentially 
incorrect rescue therapy data record. 
 
9.4.3.2 
Main Analytical Approach 
A Poisson regression model fitted with treatment and baseline vIGA as covariates. An offset of 
log(days in study) will also be included in the model to account for any data from participants who 
withdrew early from the study. For participants who withdrew treatment early days in study will be 
calculated up to the end of treatment date or the end of period whichever occurs first. For 
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participants who completed treatment up to Week 16 days in study will be calculated up to the end 
of period. 
 
In case of a greater variability among counts than expected for Poisson distribution, other models 
may be used (including negative binomial and zero inflated Poisson (ZIP)).  
 
Number of courses of TCS/TCI rescue therapy endpoint will be evaluated for the following periods: 
Weeks 1-4, 5-8, 9-12, 13-16 and for Weeks 1-16. 
 
Number of days requiring TCS/TCI rescue therapy endpoint will be evaluated for the following 
periods: Weeks 1-8, 9-16 and Weeks 1-16. 
 
The model will be run separately for each period. Only participants with at least one visit performed 
in a period will be included in this period model. An offset of log(days in the period) will also be 
included in the model based on the number of days from the first visit in the period to the last visit 
in the period.   
 
Model predicted event rates and their 95% CIs will be presented for each treatment group. Rate 
ratios with 95% CIs and p-values for each EDP1815 group (including cohorts 2+3 EDP1815 and all 
EDP1815 groups) compared to the relevant pooled placebo group at each visit will be presented. 
Rate ratios and 95% CIs will be presented for any comparisons between two EDP1815 treatment 
groups. If ZIP model will be used, odds ratios for no rescue medication used and the 95% CIs will also 
be presented. 
Number of courses of TCS/TCI rescue therapy in each period will be also plotted as histogram.  
 
9.5 
 Exploratory Efficacy Analyses 
All efficacy analysis details in this section are provided for cohorts 1-3 analysis.  
For cohort 4 analysis the same approach will be used. Any differences and additional analyses will be 
described in the SAP Addendum. 
 
9.5.1 
Exploratory Efficacy Endpoints 
The exploratory endpoints will be summarised using statistics appropriate to the endpoint as 
described below. 
 
Continuous, time to event and response exploratory endpoints estimands will use the same 
intercurrent event strategy as the primary estimand (EDPS1 will be used). Where intercurrent event 
strategy is composite, for continuous endpoints value will be imputed with the last off-rescue 
observation. 
Last off-rescue observation is defined as the last off-rescue observation in the period before the 
corresponding intercurrent event plus early termination visit in case of early study discontinuation 
(off-rescue is defined as data collected at least 28 days after use of rescue medication or type 1 
prohibited medication). 
 
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Count exploratory endpoints and response subgroup endpoints will use EDPS7 (estimand includes all 
data as collected prior to completion or withdrawal from the study). 
 
Exploratory estimands will be evaluated at all timepoints at which the relevant endpoints are 
collected. 
 
9.5.1.1 
Continuous Exploratory Endpoints 
Continuous exploratory endpoints: 
 
Mean absolute change and percentage change from Screening in EASI Score. 
 
Changes from baseline in SF-12 MCS and PCS scores. 
 
Changes from baseline in HADS anxiety and depression scores. 
 
Changes from baseline in ADCT scores. 
 
Daily changes from baseline in the PP-NRS and SD-NRS (Timescale: Days 2 to 112). 
 
The population summary measure of interest will be the mean value in each treatment group.  
 
Endpoints other than PP-NRS and SD-NRS will be summarized as described in Section 8. 
 
Daily PP-NRS and SD-NRS endpoints will be listed and plotted.   
 
9.5.1.2 
Time to Event Exploratory Endpoints 
Time to event exploratory endpoints: 
• 
Time to first achievement of EASI-50. 
• 
Time to first achievement of sustained EASI-50. 
• 
Time to first achievement of EASI-75. 
• 
Time to first achievement of vIGA of 0 or 1 with a 2-point improvement from baseline. 
• 
Time to first achievement of vIGA of 0 or 1. 
 
Time to first achievement of a ≥2 point in improvement in PP-NRS score, in participants with 
a score of ≥2 at baseline. 
 
Time to first sustained ≥2 point in improvement in PP-NRS score, in participants with a score 
of ≥2 at baseline. 
 
Time to first achievement of a ≥4 point in improvement in PP-NRS score, in participants with 
a score of ≥4 at baseline. 
 
Time to first sustained ≥4 point in improvement in PP-NRS score, in participants with a score 
of ≥4 at baseline. 
 
Time to first achievement of a ≥2 point in improvement in SD-NRS score, in participants with 
a score of ≥2 at baseline. 
• 
Time to first sustained ≥2 point in improvement in SD-NRS score, in participants with a score 
of ≥2 at baseline. 
 
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PP-NRS and SD-NRS time to event endpoints 
The population summary measure of interest for the PP-NRS and SD-NRS endpoints will be the 
Kaplan-Meier estimates of proportion of responders at each week from 1 to 16 in each treatment 
group.  
 
Censoring rules for these time to event endpoints are defined in Section 5.3.3.10. 
 
The total number of responders throughout the period and number of participants censored will be 
presented together with Kaplan-Meier estimates of proportion of responders at each week from 1 to 
16 and the estimated median and quartiles for time to response. 
 
A figure showing the estimated survival curves of each treatment group will also be presented. 
 
Sustained PP-NRS and SD-NRS time to event endpoints 
The population summary measure of interest for the PP-NRS and SD-NRS endpoints will be the 
Kaplan-Meier estimates of proportion of responders at each week from 1 to 14 in each treatment 
group.  
 
Censoring rules for these time to event endpoints are defined in Section 5.3.3.10. 
 
The total number of responders throughout the period and number of participants censored will be 
presented together with Kaplan-Meier estimates of proportion of responders at each week from 1 to 
14. 
 
A figure showing the estimated survival curves of each treatment group will also be presented. 
 
Other time to event endpoints 
The population summary measure of interest for other endpoints will be the cumulative proportion 
to have achieved the event at each visit in each treatment group.  
 
The number of participants meeting the criteria for the endpoint, and the number of participants ‘at 
risk’ of meeting the criteria at each visit will be presented together with the cumulative incidence 
and associated 95% CI. Cumulative incidence is calculated as the total number of events on or before 
the visit divided by the total number of participants at risk of the event.    
 
For each endpoint, the cumulative incidences for each treatment group will be plotted against time 
as bars (with an ‘error bar’ for the corresponding 95% CI).  
 
9.5.1.3 
Response Exploratory Endpoints 
Response exploratory endpoints: 
 
Percentage of participants achieving Investigator's Global Assessment (vIGA) of 0 or 1 with a 
≥2 Point Improvement from screening. 
 
Percentage of participants achieving a reduction of ≥2, ≥4 in the PP-NRS, of those with a 
score of ≥2, ≥4 at baseline daily from Day 2 to 112. 
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 
Percentage of participants achieving a reduction of ≥2 in SD-NRS score, of those with a score 
of ≥2 at baseline daily from Day 2 to 112. 
 
The population summary measure of interest will be the proportion of responders at each timepoint 
in each treatment group. 
 
The number and percentage of participants who achieve a response will be summarised by 
timepoint. Exact 95% CIs for the percentage of participants will also be displayed at each timepoint.  
 
Daily PP-NRS and SD-NRS endpoints, will be listed and plotted. 
 
9.5.1.4 
Response Subgroup Exploratory Endpoints 
For the primary and secondary responder endpoints relating to EASI, IGA and BSA, summaries will be 
provided comparing the number and percentage of participants in each treatment group who 
respond at Week 16 between the following subgroups: 
• 
Participants with no rescue therapy use 
• 
Participants with no rescue therapy use after the Week 4 visit 
• 
Participants with no rescue therapy use after the Week 8 visit 
• 
Participants with no rescue therapy use within 4 weeks of the Week 16 visit 
• 
Participants with no rescue therapy use within 2 weeks of the Week 16 visit  
• 
Participants with rescue therapy use within 4 weeks of the Week 16 visit 
• 
Participants with rescue therapy use within 2 weeks of the Week 16 visit  
 
The population summary measure of interest will be the proportion of responders in each subgroup 
in each treatment group. 
 
9.5.1.5 
Count Exploratory Endpoints 
Response exploratory endpoints: 
 
Number of uses of topical antimicrobial or systemic antibiotic treatment for skin infections 
by Week 16. 
  
The population summary measure of interest will be the proportion of participants reporting at least 
one infection on or before the Week 16 visit in each treatment group. 
 
The number and proportion of participants with skin infection requiring topical or systemic antibiotic 
treatment at least once during the study will be presented. Histogram of the number of courses will 
be plotted.  
 
10 Safety Analyses 
The Safety population will be used for all summaries of Safety.  All safety endpoints will be listed. 
 
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10.1  Extent of Exposure 
The duration of exposure (days) and number of doses taken will be summarized using summary 
statistics for continuous data.  The number and percentage of participants with at least 4, 8, 12 and 
16 weeks (28, 56, 84 and 112 days respectively) will also be presented. 
 
Treatment start and stop dates, exposure duration (days), number of doses administered, number of 
capsules taken and reasons for dose adjustments and dose interruptions will be listed by participant. 
 
10.2  Adverse Events 
Adverse events will be reported from the date of signed informed consent and through the Week 16 
visit for participants entering the OLE study/28 days after cessation of dosing for participants who 
don’t enter OLE. Adverse events occurring after the 28 days post-treatment would only be reported 
if the investigator considers it to be related to the study treatment. 
Only treatment emergent AEs (TEAEs) will be included in the summaries, pre-treatment AEs will be 
included in the listings of all AEs.   
 
All AEs will be coded using MedDRA. The dictionary will be updated through the life of the study with 
version 24.0 used initially.  Severity of event will be coded using the Common Terminology Criteria 
for Adverse Events v5.0 (CTCAE). 
 
An overview of TEAEs will be produced showing the number and percentage of participants with: 
 
Any TEAEs  
 
Any TEAE of CTCAE grade 2 or above  
 
Any TEAE of CTCAE grade 3 or above  
 
Any TEAE of CTCAE grade 4 or above  
 
Any fatal TEAE  
 
Any serious TEAE  
 
Any TEAE leading to permanent discontinuation of study drug  
 
Any TEAE leading to withdrawal from the study  
 
Any related TEAE  
 
Any related TEAE of CTCAE grade 2 or above  
 
Any related TEAE of CTCAE grade 3 or above  
 
Any related TEAE of CTCAE grade 4 or above  
 
Any related fatal TEAE  
 
Any related serious TEAE  
 
Any related TEAE leading to permanent discontinuation of study drug  
 
Any related TEAE leading to withdrawal from the study  
 
Related events are those which were considered by the investigator to be possibly, probably or 
definitely related to study drug. 
 
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TEAEs will also be summarized by system organ class (SOC) and preferred term (PT). Summary tables 
will contain the number and percentage of participants and the number of events. A participant who 
has multiple events in the same SOC or the same preferred term will be counted only once in the 
participant counts but all events will be counted in the event counts. Adverse event summaries will 
be sorted by the internationally agreed SOC order (Table 5) and decreasing incidence of preferred 
term within SOC in the EDP1815 column. 
 
Related TEAEs and TEAEs of CTCAE Grade 3 or above will also be summarized by SOC and PT in the 
same manner as described above. 
 
Non-serious TEAEs will be also summarised by SOC and PT, however, PTs will be presented only in 
case of TEAEs reported by at least 5% of participants in any treatment group. 
 
10.3 Deaths, Serious Adverse Events and other Significant Adverse Events 
Treatment emergent SAEs, TEAEs leading to discontinuation of study drug or withdrawal from the 
study will be summarized separately by treatment, SOC and preferred term. 
 
Serious AEs, fatal AEs and AEs leading to discontinuation of study drug will each be listed separately 
by participant. 
 
No specific adverse events are considered to be of special interest for EDP1815. 
 
10.4  Pregnancies 
Pregnancy test data will be listed only. 
 
10.5  Clinical Laboratory Evaluations 
Central laboratory data will be used for all safety laboratory evaluations. Table 6 (Section 25) shows 
the parameters which will be collected and the units in which they will be supplied. Lab data will be 
transformed as appropriate to the International System of Units (SI units) as part of the SDTM 
programming and SI units will be used for all summaries. 
 
Haematology and chemistry parameters will be summarised by visit, including change from baseline 
for all post-baseline visits. 
 
The number and percentage of participants showing shifts from baseline to worst-case post-baseline 
with respect to the normal ranges will also be summarised for each haematology and chemistry 
parameter.  Categories will be: 
 
Low 
 
Normal 
 
High 
 
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Haematology and chemistry values will also be flagged for potentially clinically important (PCI) 
values if they meet any of the criteria for Grade 2 or higher events according to CTCAE V5.0. The PCI 
criteria are listed in Table 6 (Section 25).  The number and percentage of participants showing shifts 
from baseline to worst-case baseline with respect to PCI criteria will be summarised for all 
parameters where PCI criteria have been defined. Categories will be: 
 
Low 
 
Within range 
 
High 
 
For both the normal range and PCI summaries, the determination of worst-case post-baseline will 
consider both scheduled and unscheduled assessments which occur after the first dose of study 
treatment.  Percentages will use the number of participants with at least one post-baseline 
assessment available as the denominator. If the baseline value is missing it will be assumed to be 
normal/within range.  Worst-case can be either High or Low and if a participant has post-baseline 
values both above and below the normal range/PCI criteria then they will be counted in both 
relevant categories. 
 
Haematology and chemistry data will be listed, including changes from baseline, normal ranges, flags 
for measurements outside the normal range, and flags for meeting PCI criteria.  In addition, for 
participants who meet at least one PCI criteria, all values within the laboratory type (haematology or 
chemistry) will be listed separately. 
 
Urinalysis data will be listed only.  
 
10.6 Other Safety Measures 
10.6.1 ECG  
Ventricular rate, PR interval, RR interval, QRS duration, QT interval and QTcF interval will be 
summarised by visit, including change from baseline. 
 
In addition, the QTcF interval will be flagged for PCI if it meets the CTCAE (v5.0) criteria for a Grade 3 
or above event (>500 ms or a >60 ms increase from baseline). 
The number and percentage of participants showing a shift from baseline to worst-case post-
baseline with respect to the QTcF PCI criteria will be summarised. Categories will be: 
 
Within range 
 
High 
 
The determination of worst-case post-baseline will consider all scheduled and unscheduled 
assessments which occur after the first dose of study treatment.  Percentages will use the number of 
participants with at least one post-baseline assessment available. If the baseline value is missing it 
will be assumed to be normal for this summary.   
 
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 
n will be an integer 
 
Mean and median will use 1 decimal place more than the original data 
 
Standard deviation will use 2 decimal places more than then original data 
 
Minimum and maximum will be reported using the same number of decimal places as the 
original value 
 
If no subjects have data at a given timepoint, for example, then only n=0 will be presented. 
However, if n<3, present the n, min and maximum only. If n=3, n, mean, median, minimum 
and maximum will be presented only. The other descriptive statistics will be left blank 
 
Where reporting estimated statistics from inferential tests and models, the following rules will apply 
in general: 
 
P-values ≥0.001 will be reported to 3 decimal places; p-values less than 0.001 will be 
reported as “<0.001”. 
 
Estimated parameters and 95% confidence intervals on the same scale as raw observations 
will be reported to 1 decimal place more than the original data, standard errors will be 
reported to 2 decimal places more 
 
Estimated parameters and 95% confidence intervals of percentage change variables will be 
reported to 2 decimal places, standard errors will be reported to 3 decimal places 
 
Estimated odds ratios, rate ratios and associated 95% confidence intervals will be reported 
to 2 decimal places. 
 
Estimated parameters and 95% confidence intervals, not on the same scale as raw 
observations or for percentage change statistics (e.g. regression coefficients) will be 
reported to 3 decimal places, standard errors will be reported to one further decimal place. 
 
12 Technical Details 
Statistical evaluation will be performed by 
 
 
The datasets for the interim analysis will not use CDISC standards but will be programmed directly 
from the raw data supplied by 
data management (eCRF data) and 
  
 
The datasets for the cohorts 1-3 and final analyses will follow analysis dataset model (ADaM) data 
specifications and will use standard data tabulation model (SDTM) data sets provided by 
data 
management as the source data. 
 
All analyses will be performed using SAS version 9.4 or higher (SAS Institute, Cary, NC, USA). 
 
13 Summary of Changes from the Protocol 
The SAP is based on the latest Protocol v5.0. 
 
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16 Appendix 2: Eczema Area and Severity Index  
Intensity 
A representative area of psoriasis is selected for each body region (head and neck, upper limbs, trunk, 
lower limbs). 
 
The average severity of each of four signs (erythema/redness, edema/papulation, excoriation, 
lichenification) in each body region is scored as: 
 
0 = None 
 
1 = Mild 
 
2 = Moderate 
 
3 = Severe 
Half points (1.5 and 2.5) may be used.  0.5 is not permitted – if a sign is present it should be at least mild. 
 
A severity score is calculated for each body region as the sum of the four scores for erythema/redness, 
edema/papulation, excoriation and lichenification. 
 
A1 = A severity score for head and neck 
 
A2 = A severity score for upper extremities 
 
A3 = A severity score for trunk 
 
A4 = A severity score for lower extremities 
 
Each subtotal is multiplied by the body surface area represented by that region as follows: 
 
B1 = 0.1 x A1 
 
B2 = 0.2 x A2 
 
B3 = 0.3 x A3 
 
B4 = 0.4 x A4 
 
Percentage area affected  
The percentage area affected by psoriasis is evaluated in each of the four body regions.  In each body 
region the area is expressed as: 
 
0 = not affected at all 
 
1 = 1 – 9% 
 
2 = 10-29% 
 
3 = 30-49% 
 
4 = 50%-69% 
 
5 = 70-89% 
 
6 = 90-100% 
 
EASI score calculation 
Each of the body area scores is multiplied by the severity score for the relevant body region (B1-B4) to 
gives four area intensity scores (C1-C4). 
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The EASI score is the sum of the four area intensity scores: 
 
EASI score = C1 + C2 + C3 + C4. 
 
EASI score ranges from 0 to 72. 
 
 
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17 Appendix 3: Validated Investigator Global Assessment 
The vIGA score is selected using the descriptors below that best describe the overall appearance of the 
lesions at a given time point. It is not necessary that all characteristics under Morphological Description 
be present. 
 
 
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. 
 
The vIGA score ranges from 0 to 4.  
 
 
 
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19 Appendix 5: Patient Oriented Eczema Measure 
The POEM consists of 7 questions: 
1. Over the last week, on how many days has your skin been itchy because of the eczema? 
2. Over the last week, on how many nights has your sleep been disturbed because of the eczema? 
3. Over the last week, on how many days has your skin been bleeding because of the eczema? 
4. Over the last week, on how many days has your skin been weeping or oozing clear fluid because 
of the eczema? 
5. Over the last week, on how many days has your skin been cracked because of the eczema? 
6. Over the last week, on how many days has your skin been flaking off because of the eczema? 
7. Over the last week, on how many days has your skin felt dry or rough because of the eczema? 
 
Each question is scored as: 
 
0 = No days 
 
1 = 1-2 days 
 
2 = 3-4 days 
 
3 = 5-6 days 
 
4 = Every day 
 
If one question is left unanswered this is scored 0 and the scores are summed and expressed as usual 
out of a maximum of 28. 
If two or more questions are left unanswered the questionnaire is not scored. 
 
The POEM score is the sum of the 7 item scores and ranges from 0 to 28. 
 
 
 
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20 Appendix 6: Dermatology Quality of Life Index 
The DLQI consists of 10 questions: 
 
1. Over the last week, how itchy, sore, painful or stinging has your skin been? 
2. Over the last week, how embarrassed or self-conscious have you been because of your skin?  
3. Over the last week, how much has your skin interfered with you going shopping or looking after 
your home or garden? 
4. Over the last week, how much has your skin influences the clothes you wear? 
5. Over the last week, how much has your skin affected any social or leisure activities? 
6. Over the last week, how much has your skin made it difficult for you to do any sport? 
7. Over the last week, has your skin prevented you from working or studying? 
If “No”, over the last week how much has your skin been a problem at work or studying? 
8. Over the last week, how much has your skin created problems for your partner or any of your 
close friends or relatives? 
9. Over the last week, how much has your skin caused any sexual difficulties? 
10. Over the last week, how much of a problem has the treatment for your skin been, for example 
by making your home messy, or taking up time? 
 
Questions 1 and 2 is scored on a four-point Likert scale: 
 
3 = Very much 
 
2 = A lot 
 
1 = A little 
 
0 = Not at all 
 
Questions 3-6 and 8-10 also have an option of not relevant and are scored as: 
 
3 = Very much 
 
2 = A lot 
 
1 = A little 
 
0 = Not at all 
 
0 = Not relevant 
 
Question 7 is a 2-part question and is scored as: 
 
3 = Yes 
 
3 = No; Very much 
 
2 = No; A lot 
 
1 = No; A little 
 
0 = No; Not at all 
 
0 = Not relevant 
 
Any unanswered question is scored as 0. 
The DLQI score is the sum of the 10 item scores. 
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21 Appendix 7: 12-Item Short Form Health Survey 
The SF-12 consists of 12 questions: 
1. In general, would you say your health is 
2. Does your health now limit you in moderate activities, such as moving a table, pushing a vacuum 
cleaner, bowling, or playing golf? If so, how much? 
3. Does your health now limit you in climbing several flights of stairs? If so, how much? 
4. During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities? Accomplished less than you would like as a 
result of your physical health 
5. During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities? Were limited in the kind of work or other 
activities as a result of your physical health 
6. During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities? Accomplished less than you would like as a 
result of any emotional problems (such as feeling depressed or anxious) 
7. During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities? Did work or other activities less carefully than 
usual as a result of any emotional problems (such as feeling depressed or anxious) 
8. During the past 4 weeks, how much did pain interfere with your normal work (including both 
work outside the home and housework)? 
9. How much of the time during the past 4 weeks have you felt calm and peaceful? 
10. How much of the time during the past 4 weeks did you have a lot of energy? 
11. How much of the time during the past 4 weeks have you felt downhearted and depressed? 
12. During the past 4 weeks, how much of the time has your physical health or emotional problems 
interfered with your social activities (like visiting with friends, relatives, etc.)? 
 
Questions 1 is scored as: 
 
Excellent 
 
Very good 
 
Good 
 
Fair 
 
Poor 
 
Questions 2 and 3 are scored as: 
 
Yes, limited a lot 
 
Yes, limited a little 
 
No, not limited at all 
 
Questions 4-7 and 9-12 are scored as: 
 
All of the time 
 
Most of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
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Question 8 is scored as: 
 
Not at all 
 
A little bit 
 
Moderately 
 
Quite a bit 
 
Extremely 
 
PCS component is based on questions 1-5 and 8. MCS component is based on questions 6-7 and 9-12. 
 
SF-12 MCS and PCS are calculated using Optum’s PRO CoRE software and ranges from 0 to 100.  
 
 
 
 
 
 
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22 Appendix 8: Hospital Anxiety and Depression Scale 
The HADS consists of 14 questions (7 anxiety and 7 depression): 
 
1. I feel tense or "wound up" (anxiety) 
2. I enjoy the things I used to enjoy (depression) 
3. I get a sort of frightened feeling as if something awful is about to happen (anxiety) 
4. I can laugh and see the funny side of things (depression) 
5. Worrying thoughts go through my mind (anxiety) 
6. I feel cheerful (depression) 
7. I can sit at ease and feel relaxed (anxiety) 
8. I feel as if I am slowed down (depression) 
9. I get a sort of anxious feeling like 'butterflies' in the stomach (anxiety) 
10. I have lost interest in my appearance (depression) 
11. I feel restless as I have to be on the move (anxiety) 
12. I look forward with enjoyment to things (depression) 
13. I get sudden feelings of panic (anxiety) 
14. I can enjoy a good book, radio or television program (depression) 
 
Each question is scored on a four-point Likert scale: 
 
Question 1: 
 
3 = Most of the time 
 
2 = A lot of the time 
 
1 = From time to time, occasionally 
 
0 = Never 
 
Question 2: 
 
0 = Definitely 
 
1 = Not quite so much 
 
2 = Only a little 
 
3 = Hardly at all 
 
Question 3: 
 
3 = Very definitely and fairly badly 
 
2 = Yes, but not too badly 
 
1 = Sometimes, but it doesn't worry me 
 
0 = Never 
 
Question 4: 
 
0 = As much as I always could 
 
1 = Not quite so much now 
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 
2 = Definitely not so much now 
 
3 = Not at all 
 
Question 5: 
 
3 = A great deal of the time 
 
2 = A lot of the time 
 
1 = From time to time, but not too often 
 
0 = Only occasionally 
 
Question 6: 
 
3 = Not at all 
 
2 = Not often 
 
1 = Sometimes 
 
0 = Most of the time 
 
Question 7: 
 
0 = Definitely 
 
1 = Usually 
 
2 = Not often 
 
3 = Not at all 
 
Question 8: 
 
3 = Nearly all the time 
 
2 = Very often 
 
1 = Sometimes 
 
0 = Not at all 
 
Question 9: 
 
0 = Not at all 
 
1 = Occasionally 
 
2 = Quite Often 
 
3 = Very Often 
 
Question 10: 
 
3 = Definitely 
 
2 = I don't take as much care as I should 
 
1 = I may not take quite as much care 
 
0 = I take just as much care as ever 
 
Question 11: 
 
3 = Very much indeed 
 
2 = Quite a lot 
 
1 = Not very much 
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 
0 = Not at all 
 
Question 12: 
 
0 = As much as I ever did 
 
1 = Rather less than I used to 
 
2 = Definitely less than I used to 
 
3 = Hardly at all 
 
Question 13: 
 
3 = Very often indeed 
 
2 = Quite often 
 
1 = Not very often 
 
0 = Not at all 
 
Question 14: 
 
0 = Often 
 
1 = Sometimes 
 
2 = Not often 
 
3 = Very seldom 
 
HADS Anxiety and Depression Total Scores 
The HADS anxiety total score is the sum of the 7 anxiety scores. The HADS depression total score is the 
sum of the 7 depression scores. 
Total scores for anxiety and depression ranges from 0 to 21 and classifies as:  
 
8-10 = Mild 
 
11-14 = Moderate 
 
15-21 = Severe 
 
 
 
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23 Appendix 9: Atopic Dermatitis Control Tool 
The ADCT consists of 6 questions: 
1. Over the last week, how would you rate your eczema-related symptoms (for example, itching, 
dry skin, skin rash)? 
2. Over the last week, how many days did you have intense episodes of itching because of your 
eczema? 
3. Over the last week, how bothered have you been by your eczema? 
4. Over the last week, how many nights did you have trouble falling or staying asleep because of 
your eczema? 
5. Over the last week, how much did your eczema affect your daily activities? 
6. Over the last week, how much did your eczema affect your mood or emotions? 
 
Questions 1 is scored as: 
 
0 = None 
 
1 = Mild 
 
2 = Moderate 
 
3 = Severe 
 
4 = Very severe 
 
Question 2 is scored as: 
 
3 = Not at all 
 
2 = 1-2 days 
 
1 = 3-4 days 
 
0 = 5-6 days 
 
0 = Every day 
 
Question 3 is scored as: 
 
0 = Not at all 
 
1 = A little 
 
2 = Moderately 
 
3 = Very 
 
4 = Extremely 
 
Question 4 are scored as: 
 
3 = No nights 
 
2 = 1-2 nights 
 
1 = 3-4 nights 
 
0 = 5-6 nights 
 
0 = Every night 
 
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Questions 5 and 6 are scored as: 
 
0 = Not at all 
 
1 = A little 
 
2 = Moderately 
 
3 = A lot 
 
4 = Extremely 
 
The ADCT total score is the sum of the 6 ADCT questions and ranges from 0 to 24.  
 
 
 
 
 
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Statistical Analysis Plan – Cohort 4 Addendum  
Version 1.0, Final 14-Mar-2023 
 
EDP1815-207 
 
 
 
 
Page 3 of 13 
1 
Table of Contents 
1 
Table of Contents ............................................................................................................................ 3 
2 
Abbreviations and Definitions .......................................................................................................... 4 
3 
Introduction .................................................................................................................................... 5 
4 
Efficacy Analyses .............................................................................................................................. 5 
4.1 
Pooling of Placebo Cohorts..................................................................................................... 5 
4.1.1 
Selection of Matched Placebo .................................................................................... 5 
4.2 
Selection of Additional Covariates .......................................................................................... 7 
4.3 
Primary Efficacy Analysis ........................................................................................................ 7 
4.3.1 
Primary Efficacy Estimand .......................................................................................... 7 
4.3.2 
Main Analytical Approach .......................................................................................... 7 
4.3.3 
Cohort 4 Specific Sensitivity Analyses ......................................................................... 8 
4.4 
Secondary Efficacy Analyses ................................................................................................... 9 
4.5 
Exploratory Efficacy Analyses ............................................................................................... 10 
5 
Technical Details ............................................................................................................................ 10 
6 
Summary of Changes from the Protocol ......................................................................................... 11 
7 
Bibliography .................................................................................................................................. 11 
8 
Appendix 1: List of Tables, Figures and Listings .............................................................................. 12 
8.1 
Efficacy ................................................................................................................................ 12 
8.1.1 
Tables ...................................................................................................................... 12 
8.1.2 
Figures ..................................................................................................................... 12 
9 
Appendix 2: List of Dr Zakrewski patients ....................................................................................... 13 
 
Table of Tables 
Table 1: Summary of Changes from the Protocol and the main SAP ................................................. 11 
 
 
 
 
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Statistical Analysis Plan – Cohort 4 Addendum  
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Page 5 of 13 
3 
Introduction 
The purpose of this SAP Cohort 4 Addendum is to provide information that, together with the main SAP, 
is necessary to perform the required cohort 4 specific statistical analyses of study EDP1815-207. It also 
defines the cohort 4 specific TFLs to be included in the final clinical study report according to the 
protocol. The SAP addendum is based upon, and assumes familiarity, with the study protocol, version 
5.0, dated 25-Apr-2022.  
Only additional information specific to cohort 4 analyses or different from what was stated in the main 
SAP is included in this SAP addendum. The main study SAP should be referred to for all derivations, 
estimand definitions and model specifications.  
 
Changes to the analyses described in the protocol or the main SAP other than those already listed in the 
main SAP are summarised in Section 0. 
 
If a future protocol amendment necessitates a substantial change to the statistical analysis of the study 
data, this SAP Addendum will be amended accordingly. The content of this SAP Addendum is compatible 
with the ICH E9 Guidance document. 
 
4 
Efficacy Analyses 
4.1 
Pooling of Placebo Cohorts 
For cohort 4 efficacy analyses, cohort 4 placebo group and set of 35 matched placebo participants from 
cohorts 1-3 will be pooled into a single ‘cohort 4 matched placebo’ group and will be used as a common 
control group for the cohort 4 EDP1815 treatment group.  
 
As a sensitivity analysis, the cohort 4 EDP1815 treatment group will also be compared to the cohort 4 
placebo group in all relevant analyses. 
 
4.1.1 
Selection of Matched Placebo  
Selection of matched placebo participants will be made separately by the unblinded team before cohort 
4 DBL but close enough to ensure that data needed for analysis is cleaned and will not change for all 
cohort 4 participants.  
Only pre-treatment data (covariates from screening or baseline) of cohorts 1-3 placebo participants and 
cohort 4 participants and treatment assignments of cohort 4 participants will be provided to the 
unblinded team for analysis.  
The process management details and team responsibilities are described in an interim analysis process 
plan. 
 
35 placebo participants will be selected from cohorts 1-3. The group will include 5 to 7 participants with 
mild vIGA score and 3 to 5 participants with severe vIGA score to match cohort 4 vIGA frequencies.  
 
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Statistical Analysis Plan – Cohort 4 Addendum  
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Page 6 of 13 
Propensity scores  
Propensity scores (PS) will be estimated by a logistic regression model. The treatment assignment 
(binary: 0 for placebo and 1 for active) is regressed through covariates.  
The following covariates will be selected for initial model:  
• 
Categorical: vIGA, sex, region (North America, rest of the world) 
• 
Continuous: BMI, BSA, EASI score  
Covariates will come from the last pre-treatment assessment which can be screening, baseline or 
unscheduled visit. To ensure the fit of the model sex or region may be excluded from covariates list.  
 
Main matching algorithm 
Each patient in active treatment group of cohort 4 will be matched with one placebo patient from 
cohort 1-3 using optimal matching to minimize overall calliper distance of matched pairs (Austin 2011). 
Initially calliper distance will be set to 0.25 (SD of logit(PS)) and may be increased to get more matches 
and ensure better balance of covariates.  
From all matched pairs, only pairs with loose* vIGA match will be selected.  
From the loose matched pairs, 5 pairs with lowest logit(PS) difference where cohort 4 matched subject 
has mild vIGA score and 3 pairs with lowest logit(PS) difference where cohort 4 matched subject has 
severe vIGA score will be selected to ensure minimum requested frequency of mild and severe vIGA.  
Another 27 pairs will be selected from the remaining loose matched pairs with the least logit(PS) 
difference to ensure that best matched candidates are chosen.  
If more than 7 pairs with mild vIGA cohort 4 matched subjects or 5 pairs with severe vIGA cohort 4 
matched subjects will be selected, excess pairs with highest logit(PS) difference will replaced by pairs 
with moderate vIGA cohort 4 matched subjects (chosen from remaining pairs with lowest logit(PS) 
difference). 
 
Placebo participants from these pairs will be considered as matched group from cohorts 1-3 and 
included in the cohort 4 matched placebo group in addition to cohort 4 placebo participants.  
 
* Loose match keeps mild – moderate and moderate – severe matches in addition to exact matches and 
only discards the matches between mild and severe in either group.  
 
Balance diagnostics 
After selection is complete, balance diagnostics will be performed. Balance of all covariates will be 
compared for before matching and after matching scenarios. 
Graphics will be presented for: 
• 
continuous covariates - side by side box plot  
• 
binary/categorical covariates - grouped bar-plot to compare frequencies 
 
Also, standardized differences will be calculated: 
• 
continuous covariates:  
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Statistical Analysis Plan – Cohort 4 Addendum  
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Page 7 of 13 
𝑑=  
𝑥̅𝑇𝑅𝑇 −𝑥̅𝐶𝑂𝑁
√𝑆𝑇𝑅𝑇
2
+𝑆𝐶𝑂𝑁
2
2
2
, 
here 𝑥̅𝑇𝑅𝑇, 𝑆𝑇𝑅𝑇
2
 is sample mean and sample variance of treatment group. 
• 
binary/categorical covariates: 
𝑑=
𝑝̂𝑇𝑅𝑇−𝑝̂𝐶𝑂𝑁
√𝑝̂𝑇𝑅𝑇 (1−𝑝̂𝑇𝑅𝑇)+𝑝̂𝐶𝑂𝑁(1−𝑝̂𝐶𝑂𝑁)
2
2
, 
here 𝑝̂ 𝑇𝑅𝑇 is response rate in treated group. For variables (e.g. region) with multiple categories, “d” will 
be measured for each category. 
 
PS matching will be assessed against pre and post matching balance diagnostics. The calliper distance 
may be modified accordingly until an acceptable balance is achieved across the covariates or some 
covariates may be excluded.  
 
In case of the main algorithm failure the alternative algorithm will be used. 
 
Alternative matching algorithm 
Perform optimal fixed ratio matching for cohort 4 placebo participants with cohort 4 EDP1815 
participants. Exact matching for vIGA covariate should be considered.  
Remaining unmatched 35 EDP1815 participants from cohort 4 will be matched (using similar fixed ratio 
optimal matching) with 35 placebos from cohorts 1-3. Placebo participants from these pairs will be 
considered as matched group and analysed in the cohort 4 matched placebo group.  
 
4.2 
Selection of Additional Covariates 
The covariates selected for cohorts 1-3 primary model will be used in all cohort 4 analytical models. 
 
4.3 
Primary Efficacy Analysis 
For all estimands intercurrent events will be accounted for as described in the main SAP. 
 
4.3.1 
Primary Efficacy Estimand 
The primary efficacy estimand will be the effect of cohort 4 EDP1815 compared to the cohort 4 matched 
placebo group on the percentage of participants achieving EASI-50 at Week 16. The population 
summary measure of interest will be the odds ratio between active EDP1815 treatment group and 
matched placebo.   
 
4.3.2 
Main Analytical Approach 
The primary analysis will be performed using a logistic regression model as described in the main SAP.   
 
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EDP1815-207 
 
 
 
 
Page 8 of 13 
Treatment will consist of 4 levels (cohort 4 placebo, matched placebo from cohorts 1-3, cohort 4 
EDP1815 and cohort 1 EDP1815). Baseline vIGA will consist of 3 levels (2, 3 and 4).  
 
The following treatment differences will be of estimated: 
• 
Cohort 4 EDP1815 vs Cohort 4 matched placebo 
• 
Cohort 4 EDP1815 vs Cohort 1 EDP1815* 
• 
Cohort 4 EDP1815 vs Cohort 4 placebo** 
 
* Comparisons between cohort 4 EDP1815 and cohort 1 EDP1815 will be considered as exploratory 
analysis. 
** Comparisons between cohort 4 EDP1815 and cohort 4 placebo will be considered as sensitivity 
analysis. 
 
P-values will be only displayed for the comparison of active treatment vs placebo groups. 
 
4.3.3 
Cohort 4 Specific Sensitivity Analyses 
4.3.3.1 
Within Cohort 4 Analysis 
Comparison between cohort 4 EDP1815 and cohort 4 placebo will be considered a sensitivity analysis for 
the primary endpoint.  Primary analysis approach will be used.  
 
4.3.3.2 
Bayesian sensitivity analysis 
A sensitivity analysis on the primary endpoint will be performed using Bayesian dynamic borrowing via 
robust mixture priors. The analysis will incorporate all Cohort 4 data and Cohort 1-3 placebo data.  
 
Robust mixture priors utilize historical data (in this case, Cohort 1-3 placebo data) to supplement 
concurrent data (Cohort 4 placebo data). In contrast to other methods, this method is more robust due 
to the inclusion of a weakly informative component in the prior distribution. The inclusion of this 
component allows for dynamic borrowing, increasing borrowing from historical data which is similar to 
the concurrent data, and decreasing borrowing in the event of prior-data conflict (Heinz Schmidli 2014).  
 
 The analysis model will be constructed as follows. Let 𝑦0, 𝑦1, and 𝑦2 be the number of EASI-50 
responses at Week 16 observed in Cohorts 1-3 placebo, Cohort 4 placebo, and Cohort 4 EDP1815 
groups.  Similarly, denote 𝑁0, 𝑁1, and 𝑁2 as the number of patients with a Week 16 observation, per the 
Primary Estimand definition. The likelihood functions for the Cohort 4 Active and Cohort 4 placebo 
groups are: 
𝑦1~𝐵𝑖𝑛(𝑁1, 𝜋1) 
𝑦2~𝐵𝑖𝑛(𝑁2, 𝜋2)  
The prior distribution for the Cohort 4 EDP1815 response rate is the weakly informative prior: 
𝜋2~Beta(1,1) 
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Statistical Analysis Plan – Cohort 4 Addendum  
Version 1.0, Final 14-Mar-2023 
 
EDP1815-207 
 
 
 
 
Page 9 of 13 
The prior distribution for the Cohort 4 placebo group response rate is based on a robust mixture of an 
informative component, based on the data observed in Cohorts 1-3 placebo group, and a weakly 
informative component:  
𝜋1~(1 −𝑤)Beta(𝑦0, 𝑁0 −𝑦0) + 𝑤𝐵𝑒𝑡𝑎(1,1) 
Here 𝑤 is the a priori weight on the weakly informative component of the prior. Based on a simulation 
study, the weight will be set to .5 to adequately control Type 1 error and provide adequate power.  
 
Posterior distributions will be calculated using the RBest package in R. The following summary statistics 
will be calculated based on the posterior distributions: 
• 
Posterior means, standard deviations and 95% credible intervals for 𝜋1, 𝜋2, and 𝜋2 −𝜋1 
• 
Posterior probability  Pr (𝜋2 −𝜋1 > 0) 
• 
Approximate number of Cohort 1-3 patients borrowed for the analysis 
The approximate number of patients borrowed will be calculated based on the difference of ESS of the 
𝜋1 posterior and number patients in the Cohort 4 placebo group: 𝐸𝑆𝑆−𝑁1. ESS will be calculated based 
on the Elir method (Beat Neuenschwander 2020).  
 
4.3.3.3 
Subgroup sensitivity analysis 
 
 
 
 
 
 
 
 
4.4 
Secondary Efficacy Analyses 
The following treatment differences will be estimated: 
• 
Cohort 4 EDP1815 vs Cohort 4 matched placebo 
• 
Cohort 4 EDP1815 vs Cohort 4 placebo 
• 
Cohort 4 EDP1815 vs Cohort 1 EDP1815 * 
 
* Comparisons between cohort 4 EDP1815 and cohort 1 EDP1815 will be considered as exploratory 
analysis. 
 
Treatment will consist of 4 levels (cohort 4 placebo, matched placebo from cohorts 1-3, cohort 4 
EDP1815 and cohort 1 EDP1815).  
 
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Statistical Analysis Plan – Cohort 4 Addendum  
Version 1.0, Final 14-Mar-2023 
 
EDP1815-207 
 
 
 
 
Page 10 of 13 
The comparison with pooled placebo groups (cohort 4 matched placebo) will be done using contrasts 
(LSMESTIMATE statement) within the relevant SAS procedures. 
 
For other information see the main study SAP.  
 
4.5 
 Exploratory Efficacy Analyses 
The exploratory efficacy analyses described in the main SAP will also be produced for cohort 4. 
 
5 
Technical Details 
In addition to the technical details of processes described in the main SAP where 
 team is 
involved, the Bayesian dynamic borrowing sensitivity analysis of the primary endpoint will be conducted 
by 
utilizing RBest package in R.  
 
 
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