Clinical trial NCT05084963
Conditions: Eosinophilic Esophagitis
Keywords: EoE
Sponsor: Revolo Biotherapeutics
Start date: 2021-10-29; Completion date: 2022-10-24
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to asses the efficacy, safety and tolerability of repeat doses of IRL201104 in Adult Participants with Active Eosinophilic Esophagitis (EoE)

Detailed description:

Arms: arm 1: IRL201104 IV on Days 0, 7, and 14 arm 2: IRL201104 IV on Days 0, 7, and 14 arm 3: Placebo IV on Days 0, 7, and 14
Interventions: intervention 1: IRL201104 intervention 2: Placebo
Intervention descriptions: intervention 1: lyophilised powder for reconstitution for IV dosing intervention 2: Matching placebo for IRL201104

Protocol documents:
Prot_000.pdf: 
Protocol 
 
Study ID: RVLO 121-04  
 
Study Title:  A Phase 2a, Double-blind, Placebo-Controlled, Multi-Center Study to Assess 
the Efficacy, Safety, and Tolerability of IRL201104 in Adult Participants with Active 
Eosinophilic Esophagitis (EoE). 
 
NCT: NCT05084963 
 
Document Date: 01 July 2021   
 


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A PHASE 2A, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTI-CENTER STUDY TO ASSESS 
THE EFFICACY, SAFETY, AND TOLERABILITY OF 
IRL201104 IN ADULT PARTICIPANTS WITH ACTIVE 
EOSINOPHILIC ESOPHAGITIS (EOE) 
Protocol Number RVLO 121-04  
Compound Number IRL201104 
PIND Number 
 
Sponsor: Revolo Biotherapeutics 
900 Camp Street 
New Orleans, LA 70130 
Sponsor¶s Responsible 
Medical Officer: 
 
Chief Medical Officer 
Revolo Biotherapeutics 
Protocol Version: 2.0 
Date of Protocol: 01 July 2021 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential and proprietary information of Revolo Biotherapeutics and 
is disclosed pursuant to confidentiality and non-disclosure obligations. This information should 
be used solely for the purposes for which it was provided and should not be copied, shared with, 
or disclosed to any third party without the express written consent of Revolo Biotherapeutics. 




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INVESTIGATOR’S AGREEMENT
I have received and read the Investigator’s Brochure for IRL201104. I have read the 
RVLO 
 protocol and agree to conduct the study as outlined.  
I agree to comply with International Council for Harmonisation (ICH) Tripartite Guideline on 
Good Clinical Practice (GCP) and applicable Food and Drug Administration (FDA) regulations/ 
guidelines set forth in Code of Federal Regulations Title 21 (21 CFR) Parts 11, 50, 54, 56 and 
312 and all locally applicable laws.  
I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol.  
 
 
 
Printed Name of Investigator 
Signature of Investigator 
Date


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2.
SYNOPSIS
Name of Sponsor/Company: Revolo Biotherapeutics
 
Name of Investigational Product: IRL201104 
 
Name of Active Ingredient: IRL201104 
 
Protocol Number:  
RVLO 121 04 
Phase: 2a 
Country: United States 
Title of Study: A Phase 2a, Double-blind, Placebo-Controlled, Multi-Center Study to Assess the 
Efficacy, Safety, and Tolerability of IRL201104 in Adult Participants with Active Eosinophilic 
Esophagitis (EoE) 
Study centers: Approximately 15 centers in the United States
Studied period (years):  
Estimated date first participant enrolled: Sep 2021 
Estimated date last participant completed: Jun 2022 
Phase of development: 2a 
 
Study Objectives 
Primary Objective: 
 
To assess the efficacy of repeat intravenous (IV) doses of 4 mg and 8 mg IRL201104 
compared to placebo in adult participants with EoE after 3 doses administered over 14 days as 
assessed by the change in peak esophageal intraepithelial eosinophilic count per high power 
field (eos/hpf) at Week 4.  
Secondary Objectives: 
 
To explore the relationship between IRL201104 treatment and change in symptoms of 
dysphagia in adult participants with EoE, using the patient-reported outcomes (PRO) 
instrument Dysphagia Symptom Questionnaire (DSQ). 
 
To assess the efficacy of repeat IV doses of IRL201104 in adult participants with EoE after 
3 doses administered over 14 days as assessed by thresholds of histologic response at Week 4. 
 
To evaluate the safety, tolerability, and immunogenicity of IRL201104 in adult participants 
with EoE. 
Exploratory Objectives: 
 
To explore the relationship between IRL201104 and change in clinical outcomes assessments, 
to include the PROs Patient Global Impression of Severity (PGI-S) and Patient Global 
Impression of Change (PGI-C), and the clinician-reported outcomes EoE-Endoscopic 
Reference Score (EREFS) and EoE Histology Scoring System (EoEHSS].  
 
To explore the relationship between IRL201104 and the relative change in RNA gene 
expression to include EoE diagnostic panel (EDP) transcriptome signature. 
 
To explore the relationship between IRL201104 treatment on immune cells and markers of 
inflammation. 




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solid food, or having solid food stick, by participant report; and completed the DSQ 
of days during the qualifying period prior to baseline (Visit 1).
4. Must remain on a stabilized diet for at least 6 weeks prior to screening and during the course of 
the study; stable diet is defined as no initiation of single or multiple elimination diets or 
reintroduction of previously eliminated food groups. 
5. Must be willing and able to continue any dietary therapy and/or medical regimens (including 
gastric acid suppression) in effect at the screening visit. There should be no change to these 
regimens during the study participation. 
6. Willing and able to comply with all clinic visits and study-related procedures. 
7. Able to understand and complete study-related questionnaires. 
8. Provide signed informed consent. 
9. Esophagogastroduodenoscopy (EGD) with photographs performed at screening (qualifying 
EGD), with a demonstration of intraepithelial eosinophilic infiltration (peak cell count 
15 eos/hpf) in at least 2 of the 3 biopsied esophageal regions (proximal, mid, or distal). 
Exclusion Criteria: 
A participant who meets any of the following criteria will be ineligible to participate in this study: 
1. Prior participation in an IRL201104 clinical study. 
2. Has any current disease of the gastrointestinal tract (aside from EoE) that may impact, in the 
investigator’s opinion, the patient’s EoE disease status. This includes, but not limited to:  
eosinophilic gastritis, eosinophilic enteritis, eosinophilic duodenitis, eosinophilic colitis, or 
proctitis; inflammatory bowel disease; or celiac disease. 
3. Has other causes of esophageal eosinophilia or the following diseases: hypereosinophilic 
syndromes, Churg-Strauss vasculitis (eosinophilic granulomatosis with polyangiitis), or 
peripheral blood absolute eosinophil count of > 
 
4. Has presence of oral or esophageal mucosal infection of any type. 
5. Has any condition affecting the esophageal mucosa or altering esophageal motility other 
than EoE. 
6. History of achalasia, active Helicobacter pylori infection, Crohn's disease, ulcerative colitis, 
celiac disease, and prior esophageal surgery (with the exception of a surgical repair of an EoE 
complication). 
7. Any esophageal stricture unable to be passed with a standard, diagnostic, adult (9 to 10 mm) 
upper endoscope or any critical esophageal stricture that requires dilation at screening; or 
dilation within 2 months prior to screening. 
8. On a pure liquid diet or any mouth or dental condition that prevents normal eating. 
9. Has initiated, discontinued, or changed dosage regimen of PPIs within the 4 weeks prior to the 
qualifying EGD, between the qualifying EGD and baseline visit (Visit 1), or anticipates 
changes in the use of PPI during the study. PPI must remain constant throughout the study. 
10. History of bleeding disorders or esophageal varices. 
11. Use of anticoagulants within 2 weeks prior to screening. Participants should not stop these 
agents solely to become eligible for entry into this study. 
12. Treatment with an investigational drug within 2 months or within 5 half-lives (if known), 
whichever is longer, prior to screening. 
13. Use of systemic corticosteroids within 3 months or swallowed topical corticosteroids within 
6 weeks prior to screening. 
14. Treatment with oral immunotherapy (OIT) within 6 months prior to screening. 


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15. Allergen immunotherapy (sublingual immunotherapy [SLIT] and/or subcutaneous 
immunotherapy [SCIT]), unless on a stable dose for at least 1 year prior to screening.
16. The following treatments within 3 months before the screening visit, or any condition that, in 
the opinion of the investigator, is likely to require such treatment(s) during the study: 
Systemic immunosuppressive/immunomodulating drugs (eg, omalizumab, cyclosporine, 
mycophenolate-
se inhibitors, azathioprine, methotrexate,
and other biologics that are ongoing [eg, dupilumab, benralizumab, mepolizumab, or
vedolizumab]). 
17. Diagnosed with active parasitic infection; or suspected parasitic infection, unless clinical and 
(if necessary) laboratory assessments have ruled out active infection before randomization. 
18. Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or 
antifungals within 1 month prior to screening. 
19. Use of oral antibiotics/anti-infectives within 2 weeks prior to screening. 
20. Known or suspected immunosuppression, including history of invasive opportunistic infections 
(eg, tuberculosis, non-tuberculous mycobacterial infections, histoplasmosis, listeriosis, 
coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or otherwise 
recurrent infections of abnormal frequency, or prolonged infections suggesting an 
immunocompromised status, as judged by the investigator. 
21. Known history of human immunodeficiency virus (HIV) infection. 
22. Positive or indeterminate hepatitis B surface antigen (HBsAg) or hepatitis C antibody at 
screening. 
23. Moderate or severe renal impairment (eGFR <60 mL/min/1.73 m2) or end stage renal disease. 
24. Elevated transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase 
[AST]) > 3 times the upper limit of normal (ULN) at screening. 
25. History of malignancy within 5 years prior to screening, except completely treated in situ 
carcinoma of the cervix and completely treated and resolved nonmetastatic squamous or basal 
cell carcinoma of the skin. 
26. Any other medical or psychological condition including relevant laboratory abnormalities at 
screening that, in the opinion of the investigator, suggest a new and/or insufficiently 
understood disease, may present an unreasonable risk to the participant as a result of his/her 
participation in this clinical study, may make the participant’s participation unreliable, or may 
interfere with study assessments. The specific justification for participants excluded under this 
criterion will be noted in study documents (eg, chart notes, electronic case report form). These 
may include participant-reported alcohol or drug abuse and severe concomitant illness(es). 
27. Planned or anticipated use of any prohibited medications and procedures (as described in the 
exclusion criteria) during study treatment. 
28. Treatment with a live (attenuated) vaccine within 3 months prior to screening and/or treatment 
of a killed vaccine within 30 days prior to screening, until the end of the study with the 
exception of a coronavirus disease of 2019 (COVID-19) vaccine, as described in Section 9.2.1. 
29. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during 
the study. 
30. Women unwilling to use adequate birth control, if of reproductive potential* and sexually 
active. Adequate birth control is defined as agreement to consistently practice an effective and 
accepted method of contraception throughout the duration of the study and for 30 days after the 
last dose of study treatment. These include: hormonal contraceptives, intrauterine device, or 
double barrier contraception (ie, condom and diaphragm), or male partner with 
documented vasectomy. 


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*For females, menopause is defined as at least 12 consecutive months without menses; to 
include laboratory confirmation of post-menopausal status (ie, a follicle stimulating hormone 
(FSH) of 2.25 U/mL must be documented). Hysterectomy, bilateral oophorectomy, or bilateral 
tubal ligation must be documented, as applicable; if documented, women with these conditions 
are not required to use additional contraception. 
Investigational product, dosage, and mode of administration: 
IRL201104 and placebo is supplied as a sterile, lyophilized cake in a standard glass vial and is 
reconstituted with sterile water for injection. 
For both the 4 and 8 mg dose levels, the amount of drug substance in each 20 mL vial is 0.8 mg/ml, 
which is reconstituted with 10-20 mL water for injection (WFI). Investigational product will be 
administered in a volume of 10 mL. 
IRL201104 4 mg and 8 mg and placebo are administered as an IV bolus injection over 30 seconds (not 
to exceed 60 seconds) on Days 0, 7, and 14 (3 total doses over 14 days). 
Pharmacy staff will be unblinded for investigational product preparation.  Investigators, study team 
members and study participants will be blinded to the dose level given (4 mg, 8 mg, or placebo) and 
will remain blinded throughout the study. 
Duration of treatment:  
Screening period: up to 6 weeks 
Double-blind treatment and follow-up period: 8 weeks  
Total study duration: up to 14 weeks 
Reference therapy, dosage, and mode of administration:  
None 
Criteria for Evaluation 
Primary Endpoints: 
 
Change from baseline in the peak esophageal intraepithelial eosinophil count at Week 4. 
Secondary Endpoints: 
 
Absolute change in DSQ score from baseline. 
The DSQ is used to measure the frequency and intensity of dysphagia. DSQ scores can range 
from 0 to 84, with a lower score indicating less frequent or less severe dysphagia. 
 
Proportion of participants achieving peak esophageal intraepithelial eosinophil count of 
< 15 eos/hpf (Week 4). 
 
Percent reduction in peak esophageal intraepithelial eosinophil count (eos/hpf) (Week 4). 
Exploratory Endpoints: 
 
Proportion of participants achieving peak esophageal intraepithelial eosinophil count of 
 6 eos/hpf (400×) at Week 4. 
 
Proportion of participants achieving peak esophageal intraepithelial eosinophil count of 
 1 eos/hpf (400x) at Week 4. 
 
Relative change in the EDP transcriptome signature  (Week 4) 




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3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1.
TITLE PAGE................................................................................................................1
SIGNATURE PAGE .......................................................................................................................2
INVESTIGATOR’S AGREEMENT...............................................................................................3
2.
SYNOPSIS ...................................................................................................................5
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............11
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................16
5.
INTRODUCTION ......................................................................................................19
5.1.
Eosinophilic Esophagitis ............................................................................................19
5.2.
Rationale for Treatment with IRL201104 ..................................................................20
5.3.
Clinical Development Program ..................................................................................21
6.
STUDY OBJECTIVES AND PURPOSE ..................................................................22
6.1.
Primary Objective .......................................................................................................22
6.2.
Secondary Objectives .................................................................................................22
6.3.
Exploratory Objectives ...............................................................................................22
6.4.
Endpoints ....................................................................................................................22
6.4.1. 
Primary Endpoint ........................................................................................................22
6.4.2. 
Secondary Endpoints ..................................................................................................22
6.4.3. 
Exploratory Endpoints ................................................................................................23
7.
INVESTIGATIONAL PLAN .....................................................................................24
7.1.
Overall Study Design and Flow Chart ........................................................................24
7.2.
Number of Participants ...............................................................................................26
7.3.
Treatment Assignment ................................................................................................26
7.4.
Definition of the End of the Study ..............................................................................26
7.5.
Dose Modification Criteria .........................................................................................26
7.6.
Planned Interim Analysis ............................................................................................26
7.7.
Independent Data Monitoring Committee ..................................................................26
7.8.
Rationale for Dose Selection ......................................................................................26
7.8.1. 
Selection of Highest Dose Level ................................................................................27
7.8.2. 
Selection of Dose Interval ..........................................................................................28


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7.9.
Schedule of Events .....................................................................................................30
8.
SELECTION AND WITHDRAWAL OF PARTICIPANTS .....................................34
8.1.
Participant Inclusion Criteria ......................................................................................34
8.2.
Participant Exclusion Criteria .....................................................................................34
8.3.
Participant Withdrawal Criteria ..................................................................................37
8.3.1. 
Withdrawal of Participants .........................................................................................37
8.3.2. 
Individual Stopping Criteria .......................................................................................37
8.3.3. 
Allowable Deviations in Timing of Study Treatment ................................................38
8.3.4. 
Replacement of Participants .......................................................................................38
9.
TREATMENT OF PARTICIPANTS .........................................................................38
9.1.
Description of Study Treatment ..................................................................................38
9.2.
Concomitant Medications ...........................................................................................39
9.2.1. 
Permitted Concomitant Medications and Procedures .................................................39
9.2.2. 
Prohibited Concomitant Medications and Procedures ................................................39
9.2.3. 
Prohibited Concomitant Medications or Procedures as Rescue .................................40
9.3.
Method of Treatment Assignment ..............................................................................40
9.3.1. 
Blinding ......................................................................................................................41
10.
STUDY TREATMENT MATERIALS AND MANAGEMENT ..............................41
10.1.
Study Treatment ..........................................................................................................41
10.2.
Study Treatment Packaging and Labeling ..................................................................41
10.3.
Study Treatment Storage ............................................................................................41
10.4.
Study Treatment Preparation ......................................................................................41
10.5.
Administration ............................................................................................................41
10.6.
Study Treatment Accountability .................................................................................41
10.7.
Study Treatment Handling and Disposal ....................................................................42
11.
ASSESSMENT OF EFFICACY ................................................................................42
11.1.
Histologic Response ...................................................................................................42
11.2.
Dysphagia Symptom Questionnaire ...........................................................................44
11.3.
Eosinophilic Esophagitis-Endoscopic Reference Score .............................................45
11.4.
Eosinophilic Esophagitis-Histology Scoring System .................................................45
11.5.
Patient Global Impression of Severity ........................................................................45
11.6.
Patient Global Impression of Change .........................................................................46
11.7.
RNA Sequencing and EDP Transcriptome .................................................................46


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11.8.
Other Biomarkers of Eosinophilic Esophagitis ..........................................................46
12.
ASSESSMENT OF SAFETY .....................................................................................46
12.1.
Screening and Baseline Assessments .........................................................................46
12.2.
Vital Signs ..................................................................................................................46
12.3.
Physical Examination .................................................................................................47
12.4.
Electrocardiogram .......................................................................................................47
12.5.
Laboratory Assessments .............................................................................................47
12.6.
Adverse and Serious Adverse Events .........................................................................48
12.6.1. 
Definition of Adverse Events .....................................................................................48
12.6.1.1. 
Adverse Event .............................................................................................................48
12.6.1.2. 
Serious Adverse Event ................................................................................................49
12.6.1.3. 
Other Adverse Events .................................................................................................49
12.6.1.4. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................50
12.6.2. 
Relationship to Study Drug ........................................................................................50
12.6.3. 
Recording Adverse Events .........................................................................................50
12.6.4. 
Reporting Adverse Events ..........................................................................................51
13.
ASSESSMENT OF PHARMACOKINETICS AND IMMUNOGENICITY ............52
14.
RESEARCH SAMPLES ............................................................................................52
15.
STATISTICS ..............................................................................................................53
15.1.
General Considerations for Data Analysis .................................................................53
15.2.
Analysis Populations ..................................................................................................53
15.2.1. 
Full Analysis Set .........................................................................................................53
15.2.2. 
Safety Analysis Set .....................................................................................................53
15.3.
Planned Analysis ........................................................................................................53
15.3.1. 
Study Population Analysis ..........................................................................................53
15.3.2. 
Efficacy Analysis ........................................................................................................53
15.3.3. 
Safety Analysis ...........................................................................................................54
15.3.4. 
Pharmacokinetic and Immunogenicity Analysis ........................................................54
15.4.
Determination of Sample Size ....................................................................................55
16.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................55
16.1.
Study Monitoring ........................................................................................................55
16.2.
Audits and Inspections ................................................................................................55
16.3.
Institutional Review Board .........................................................................................56


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17.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................56
18.
ETHICS ......................................................................................................................56
18.1.
Ethics Review .............................................................................................................56
18.2.
Ethical Conduct of the Study ......................................................................................56
18.3.
Written Informed Consent ..........................................................................................56
19.
DATA HANDLING AND RECORDKEEPING .......................................................57
19.1.
Inspection of Records .................................................................................................57
19.2.
Retention of Records ..................................................................................................57
20.
PUBLICATION POLICY ..........................................................................................57
21.
LIST OF REFERENCES ............................................................................................58
22.
APPENDIX .................................................................................................................60


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LIST OF TABLES
Table 1: 
Abbreviations and Specialist Terms ...........................................................................16
Table 2:
Safety Margins for the IRL201104 8 mg Clinical Dose .............................................27
Table 3: 
Study RVLO 121-04 Schedule of Events ...................................................................30
Table 4: 
Investigational Product ...............................................................................................39
Table 5:
Biopsy Sampling .........................................................................................................44
LIST OF FIGURES
Figure 1: 
Study RVLO 121-04 Diagram ....................................................................................25
Figure 2: 
Effect of IRL201104 (IV) on Ovalbumin-Induced Eosinophil Influx into 
Mouse Lung ................................................................................................................28
Figure 3: 
Effects of IRL201104 IN on Cellular Recruitment at the 14-Day Rechallenge 
Time Point in the Murine HDM Model ......................................................................29


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4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
The following abbreviations and specialist terms are used in this study protocol. 
0BTable 1: 
Abbreviations and Specialist Terms
Abbreviation or Specialist Term
Explanation
ADA 
antidrug antibody 
AE 
adverse event 
AESI
adverse event of special interest
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUClast 
area under the plasma concentration-time curve from time 
= 0 to the last measurable concentration 
CD 
cluster of differentiation 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease of 2019 
CPK 
creatine phosphokinase 
DSQ 
Dysphagia Symptom Questionnaire 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDN 
eosinophil derived neurotoxin 
EDP 
eosinophilic esophagitis diagnostic panel 
EGD 
esophagogastroduodenoscopy 
EoE 
eosinophilic esophagitis 
EoEHSS
Eosinophilic Esophagitis-Histology Scoring System
eos/hpf 
eosinophilic count per high-power field  
EPIT 
epicutaneous immunotherapy 
EREFS 
Eosinophilic Esophagitis-Endoscopic Reference Score 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FFAR3 
free fatty acid receptor 3 
FIH 
first-in-human 
FOXP3 
forkhead box P3 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 


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Abbreviation or Specialist Term 
Explanation 
GERD
gastroesophageal reflux disease
HBsAg
hepatitis B surface antigen
HDM 
house dust mite 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonisation 
IDMC
Independent Data Monitoring Committee
IEC 
Independent Ethics Committee 
IFN 
interferon 
Ig 
immunoglobulin 
IL 
interleukin 
IN 
intranasal(ly) 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
intravenous 
IWRS 
interactive web response system 
LDS 
Loeys-Dietz syndrome 
MAD 
multiple ascending dose 
mTB 
mycobacterium tuberculosis 
OIT 
oral immunotherapy 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
pharmacokinetic(s) 
PPI
proton pump inhibitors
PRO 
patient-reported outcomes 
QD 
once daily 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCIT 
subcutaneous immunotherapy 
SLIT 
sublingual immunotherapy 
t1/2 
terminal elimination half-life 
 
transforming growth factor–  


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Abbreviation or Specialist Term 
Explanation 
Th
T helper
Treg
regulatory T
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
WFI
water for injection
WHO 
World Health Organization 


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5.
INTRODUCTION
5.1. 
Eosinophilic Esophagitis 
Eosinophilic esophagitis (EoE) is a chronic and progressive disease of the immune system 
resulting in damage to the esophagus with subsequent loss of function resulting in difficulty 
swallowing and food impaction. If not adequately treated, symptoms and inflammation can 
progress, leading to scarring of the esophagus with irreversible damage. In the United States 
(US), there are approximately 160,000 patients with EoE who are currently treated, of which 
approximately 50,000 have failed multiple treatments. There are currently no therapies approved 
by the US Food and Drug Administration (FDA) for EoE. 
Eosinophilic esophagitis is caused by the presence of large numbers of eosinophils in the 
esophagus. The production and accumulation of eosinophils may be caused by many factors, 
such as immune hypersensitivity responses to particular foods or environmental proteins 
(allergens) in affected individuals. Eosinophilic esophagitis is characterized by esophageal 
barrier defects and eosinophilic infiltrates. Therapeutic interventions that target reduction in 
esophageal eosinophils have been shown to correlate with symptom improvement (Hirano 2020).
Regulatory T (Treg) cells are a subset of T lymphocytes that play an important role in the 
prevention and control of many autoimmune and allergic diseases. Frischmeyer-Guerrerio, et al 
noted that transforming growth factor–
that patients with Loeys-Dietz syndrome (LDS), an autosomal dominant disorder caused by 
mutations in the genes encoding receptor subun
strongly predisposed to develop allergic disease, including asthma, food allergy, eczema, allergic 
rhinitis, and eosinophilic gastrointestinal disease (Frischmeyer-Guerrerio 2013). Patients with 
LDS exhibited elevated immunoglobulin (Ig) E levels, eosinophil counts, and T helper (Th) 2 
cytokines in their plasma. They had an increased frequency of cluster of differentiation (CD)4+ 
T-cells that expressed both forkhead box P3 (FOXP3) and interleukin (IL)-13, but retained the 
ability to suppress effector T-cell proliferation. T helper 2 cytokine–producing cells accumulated 
in cultures of naïve CD4+ T-cells from LDS subjects, but not controls, after stimulation with 
h2 skewing in naïve lymphocytes in a 
cell-
signaling can predispose to allergic phenotypes in humans and underscores a prominent role for 
 the environment and foods and may 
be relevant to nonsyndromic presentations of allergic diseases such as EoE.  
Treg cells are reduced in the biopsies of adults with EoE as compared with control participants 
(Stuck 2011). In contrast, Treg cells seem to be increased in esophageal tissue of children with 
EoE compared with individuals with gastroesophageal reflux disease and healthy participants 
(Fuentebella 2010). However, Treg cell immunosuppressive function may be minimized in 
patients with EoE, similar to patients with allergic asthma. In animal models of EoE, 
epicutaneous immunotherapy (EPIT) induced Treg cells in the spleen and expression of forkhead 
box P3 (FOXP3) in the esophagus that correlated with reduced eosinophilic infiltration. 
Depletion of CD25+ cells abrogated Treg cell induction and resulted in increased esophageal 
inflammation. The transfer of Treg cells isolated from mice who had undergone EPIT prevented 
peanut-induced eosinophil infiltration and eotaxin expression in the esophagus of mice 
(Dioszeghy 2014). Interestingly, patients with the autosomal recessive form of hyper-IgE 


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syndrome caused by mutations in the dedicator of cytokinesis 8 gene have defective Treg cells 
and often develop EoE (Hsu 1993, Janssen 2014). 
Finally, Wen, et al employed single-cell ribonucleic acid (RNA) sequencing to examine the 
heterogeneity of human tissue CD3+ T-cells during allergic inflammation, focusing on EoE. 
They investigated 1088 single T-cells derived from patients with a spectrum of disease activity 
with Treg (FOXP3+) enriched in the tissue. Prodigious levels of IL-5 and IL-13 were confined to 
HPGDS+ CRTH2+IL-17RB+FFAR3+CD4+ T8 effector Th2 cells. EoE severity closely 
paralleled a lipid/fatty acid–induced activation node highlighted by the expression of the 
short-chain free fatty acid receptor 3 (FFAR3). Ligands for FFAR3 induced Th2 cytokine 
production from human and murine T-cells, including in an in vivo allergy model. In summary, 
they elucidated the defining characteristics of tissue-residing CD3+ T-cells in EoE, a specific 
enrichment of CD4+ Treg and effector Th2 cells, and confinement of type 2 cytokine production 
to the CD4+ effector population (Wen 2019). Together, these findings show that Treg cells are 
dysregulated in patients with EoE and that they can protect against an EoE-like disease in some 
cases. 
While the exact mechanism of the lack of suppressive Treg cell function in EoE isn’t known, 
Treg cells appear to be important in the pathophysiology of EoE and their modulation may 
represent an opportunity for enduring therapy for patients with EoE. 
5.2. 
Rationale for Treatment with IRL201104 
Almost one third of the worlds’ population is infected with mycobacterium tuberculosis (mTB) 
World Health Organization 
[WHO] 2012), resulting in an estimated 2 million deaths each year (Miranda 2012). In the 
2 billion people with ‘latent’ disease the bacteria survive in a dormant state entrapped in the 
lungs within a protective cellular structure known as the granuloma. The process of granuloma 
formation is initiated by the mTB bacteria being taken up by alveolar macrophages, which then 
release mediators to recruit inflammatory cells including more macrophages, dendritic cells and 
T-cells, which organize into the spherical structure of the granuloma. The bacteria can survive 
for decades inside the granuloma in a latent state. To further enhance its chances of survival the 
bacteria secrete proteins, known as chaperonins, which modulate the hosts’ inflammatory 
response (Cehovin 2010) and enable the bacteria to remain undetected in the human host. The 
sponsor has explored the therapeutic potential of these proteins to produce drug-like peptides. 
One such peptide, IRL201104, formerly known as PIN201104, has been identified via 
phenotypic drug discovery to be a potential anti-inflammatory/immunomodulatory agent and is 
being developed as a potential treatment for a range of autoimmune and allergic diseases. 
IRL201104 is a novel synthetic peptide derived from the active domain of the mTB-secreted 
protein chaperonin 60.1. It is being developed for the relief of symptoms in patients with active 
EoE. The peptide significantly decreases airway eosinophil infiltration in rodent models of 
allergic and nonallergic inflammation. IRL201104 appears to be effective in resetting the 
immune system from an inflammatory state and in inducing inflammatory disease remission in 
nonclinical models. Its short pharmacokinetic (PK) terminal elimination half-life (t1/2) decreases 
the potential for the negative off-target effects associated with current therapies. 
Importantly, in an assay using blood cells from healthy human participants, incubation with 
IRL201104 increased Treg cell concentrations in a dose-dependent manner, compared with the 


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control-treated cells. Treg cell levels were increased by more than 2-fold at the top concentration 
of IRL201104 (data on file). 
Numerous nonclinical pharmacology studies performed suggest that IRL201104 has an 
anti-inflammatory and immunomodulatory mechanism of action. IRL201104 is effective in a 
range of models of inflammation and has also demonstrated efficacy in animal models of asthma, 
with prolonged duration of action. 
5.3.
Clinical Development Program
In non-clinical safety pharmacology and toxicology studies, IRL201104 was safe and well 
tolerated at exposures up to 11 times higher than the highest dose level planned for the current 
Phase 2a clinical study. In 14-day rat and dog Good Laboratory Practice toxicology studies, the 
no-observed-effect-level was the highest dose tested (0.5 mg/kg intravenous [IV] bolus). 
IRL201104 was assessed in a first-in-human (FIH) Phase 1 study in 62 healthy participants and 
participants with mild asthma in the United Kingdom (UK) (Study C1104-001). The highest dose 
tested was a single 8 mg dose (IV bolus) in 4 healthy participants and 6 participants with mild 
asthma. Most participants in the study received a single dose by IV bolus; however, 1 group 
(4 participants) received 3 single IV bolus injections of 2 mg (2 hours apart) on a single day. In 
this study, IRL201104 was well tolerated and safe, with no significant adverse events (AEs) 
reported for single doses up to 8 mg IRL201104. After a single 2, 4, and 8 mg IV bolus, 
IRL201104 was detectable in blood up to 15, 30, and 60 minutes, respectively, with exposure 
increasing in a dose-dependent manner. The mean t1/2 of the 8 mg dose was approximately 
16 minutes. 
IRL201104 is currently being assessed for safety, tolerability, and PK in an ongoing Phase 1 
multiple ascending dose (MAD) study in 18 healthy participants in the UK (Study C1104-003). 
The IRL201104 IV dose levels were 4 mg once daily (QD) for 5 days and 8 mg QD for 7 days. 
At each dose level, up to 8 participants received IRL201104 and 2 received placebo. Following a 
blinded review of safety data, study treatment was well tolerated in the groups receiving either 
IRL201104 4 mg (6 participants), 8 mg (8 participants) or placebo (4 participants) for 5 days and 
followed through Day 21.  
In combination, these nonclinical data and a good clinical safety/tolerability profile show that 
IRL201104 is well suited for further development as a treatment for EoE.
This Phase 2a clinical study is a double-blind, placebo-controlled study designed to investigate 
the efficacy, safety, and tolerability of IRL201104 in adult participants with active EoE. 
Participants will receive a total of 3 doses of IRL201104 4 mg or 8 mg IV or placebo over a 14-
day period. Study treatment will be delivered by IV bolus injection via cannula.  
The justification for the dose levels selected in the current study is presented in Section 7.8. 
The study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
all applicable regulatory requirements. 


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6.
STUDY OBJECTIVES AND PURPOSE
6.1. 
Primary Objective 
The primary objective is to assess the efficacy of repeat IV doses of 4 mg and 8 mg IRL201104 
or placebo in adult participants with EoE after 3 doses administered over 14 days as assessed by 
the change in peak esophageal intraepithelial eosinophilic count per high-power field (eos/hpf) at 
Week 4. 
6.2.
Secondary Objectives
The secondary objectives are: 
 To explore the relationship between IRL201104 treatment and change in symptoms 
of dysphagia in adult participants with EoE, using the patient-reported outcomes 
(PRO) instrument Dysphagia Symptom Questionnaire (DSQ).
 To assess the efficacy of repeat IV doses of IRL201104 in adult participants with EoE 
after 3 doses administered over 14 days as assessed by thresholds of histologic 
response at Week 4. 
 To evaluate the safety, tolerability, and immunogenicity of IRL201104 in adult 
participants with EoE. 
6.3. 
Exploratory Objectives 
The exploratory objectives are: 
 To explore the relationship between IRL201104 and change in clinical outcomes 
assessments, to include the PROs PGI-S and PGI-C, and the clinician-reported 
outcomes EoE-Endoscopic Reference Score (EREFS) and EoE Histology Scoring 
System (EoEHSS).
 To explore the relationship between IRL201104 and the relative change in RNA gene 
expression to include EoE diagnostic panel (EDP) transcriptome signature. 
To explore the relationship between IRL201104 treatment on immune cells and 
markers of inflammation. 
6.4. 
Endpoints 
6.4.1. 
Primary Endpoint
The primary endpoint is: 
 Change from baseline in the peak esophageal intraepithelial eosinophil count at 
Week 4. 
6.4.2. 
Secondary Endpoints 
The secondary endpoints are: 
 Absolute change in DSQ score from baseline. 


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 Proportion of participants achieving peak esophageal intraepithelial eosinophil count 
of < 15 eos/hpf (Week 4). 
 Percent reduction in peak esophageal intraepithelial eosinophil count (eos/hpf) 
(Week 4). 
The safety endpoints are: 
 Monitoring of AEs, physical examinations, vital signs, electrocardiograms (ECGs), 
clinical laboratory tests, and clinical evaluations. Participants will be asked to monitor 
all AEs experienced from the time of informed consent until their last study visit. 
6.4.3. 
Exploratory Endpoints 
Exploratory endpoints include: 
 Proportion of participants achieving peak esophageal intraepithelial eosinophil count 
 6 eos/hpf (400×) at Week 4. 
 Proportion of participants achieving peak esophageal intraepithelial eosinophil count 
 1 eos/hpf (400x) at Week 4. 
 Relative change in the EDP transcriptome signature (Week 4). 
 Relative change in immune cells and markers of inflammation pre- and postdose 
administration at screening, baseline, and Weeks 1, 2, 4, 6, and 8. Immune cells and 
markers of inflammation include: immune cell phenotyping (T-subsets, B-subsets, 
and macrophage subsets); A20; serum cytokines; serum IgE/IgG4; and serum 
eosinophil derived neurotoxin (EDN) for eosinophil activation. 
 Absolute change in EoE-EREFS (Week 4). 
Absolute change in EoE grade score from the EoE Histology Scoring System 
(EoEHSS) (Week 4). 
 Absolute change in EoE stage score from the EoEHSS (Week 4). 
Absolute change in severity and/or frequency of EoE symptoms other than dysphagia 
(up to Week 8). 
 Proportion of participants with use of rescue medications or procedures (up to 
Week 8). 
Concentration of functional IRL201104 (up to Week 8). 
 Incidence of treatment-emergent antidrug antibody (ADA) responses (Week 8). 
Absolute days without dysphagia 
Change in PGI-S and PGI-C 


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7.
INVESTIGATIONAL PLAN
7.1. 
Overall Study Design and Flow Chart 
This is a Phase 2a, double-blind, placebo-controlled, multi-center study to assess the efficacy and 
safety of a repeat-dose regimen of IRL201104 in participants with active EoE. A study diagram 
is provided in Figure 1. 
Eligible participants will undergo an up-to-6-week screening period to stabilize current therapy, 
confirm diagnosis by histologic assessment, and other eligibility criteria. Participant compliance 
to DSQ reporting will be assessed for at least 2 consecutive weeks prior to randomization. 
At the end of the screening period, eligible participants will be randomized in a 1:1:1 ratio to one 
of 3 arms, as displayed in Figure 1: 
 Arm 1: IRL201104 4 mg IV with endoscopy and esophageal biopsy 2 weeks after last 
dose (Week 4). 
 Arm2: IRL201104 8 mg IV with endoscopy and esophageal biopsy 2 weeks after last 
dose (Week 4). 
 Arm 3: Placebo IV with endoscopy and esophageal biopsy 2 weeks after last dose 
(Week 4). 
Participants will receive IRL201104 (4 mg or 8 mg IV) or placebo on Days 0, 7, and 14 (3 total 
doses over 14 days). Participants will be evaluated for clinical and histologic responses at 
Week 4. All participants will be assessed for safety and continued biomarker sampling through 
Week 8. 
The Schedule of Events for the study is provided in Table 3.  
The total duration of the study for a given participant is up to 14 weeks. 
 


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1BFigure 1: 
Study RVLO 121-04 Diagram 
D = day; EGD = esophagogastroduodenoscopy; EOS = End of Study; ICF = informed consent form; IV = intravenous; R = randomization; WK = week 


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7.2.
Number of Participants 
Approximately up to 50 participants are planned to be enrolled to yield 36 participants who are 
randomized and complete the final endoscopy at Week 4. The sample size determination is 
provided in Section 15.4. 
7.3. 
Treatment Assignment 
Eligible participants will be randomized in a 1:1:1 ratio to receive IRL201104 4 mg or 8 mg or 
placebo and to complete the final endoscopy with esophageal biopsy 2 weeks after last dose 
(Week 4).  
7.4. 
Definition of the End of the Study 
The end of the study is defined as the final follow-up visit by the last participant. If the study is 
terminated prematurely, the study ends when the sponsor notifies the investigator in writing that 
the study has finished, or when the last participant attends the final follow-up visit, whichever is 
later. 
7.5. 
Dose Modification Criteria 
Dose modification for an individual participant is not allowed. 
7.6. 
Planned Interim Analysis 
No interim analysis is planned. 
7.7. 
Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC), composed of members who are 
independent from the sponsor and the study investigators, will monitor participant safety by 
conducting formal reviews of accumulated safety data. 
The IDMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the participants enrolled in the study. The 
IDMC may also institute measures required for ensuring the integrity of the study results during 
the study execution.
All activities and responsibilities of the IDMC are described in the IDMC charter. 
7.8. 
Rationale for Dose Selection 
A total of 3 doses of 4 mg or 8 mg (IV bolus) administered once on Days 0, 7, and 14 will be 
tested for efficacy in participants with active EoE in this study. 
In safety pharmacology and toxicology studies, IRL201104 was safe and well tolerated at 
exposures at least 3-fold and up to 11 times higher than the dose level planned for the current 
Phase 2a clinical study. In 14-day rat and dog Good Laboratory Practice toxicology studies, the 
no-observed-effect-level was the highest dose tested (0.5 mg/kg IV bolus). Safety margins are 
summarized in Table 2. 


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2BTable 2: 
Safety Margins for the IRL201104 8 mg Clinical Dose 
Species 
Cmax (ng/mL) 
Cmax Fold 
over Human 
Dose 
AUC 
(ng.h/mL) 
AUC Fold 
over Human 
Dose 
Human 8 mg single dose 
(N=10) (Study C1104-001) 
545.99 (Cmax) 
- 
145.1 (AUC0-t) 
- 
Dog NOEL (0.5 mg/kg 1) 14-
day GLP toxicity (Day 1) 
(Study CGH0005) 
2020 (C1min) 
3.7 
456.5 (AUC0-24) 
3.1 
Rat NOEL (0.5 mg/kg 1) 14-day 
GLP toxicity (Study CGH0004) 
(Estimated Day 1)  
5940 (Cmax) 2 
10.9 
674 (AUClast) 2 
4.6 
AUC = area under the concentration-time curve; AUC0-24 = area under the steady-state blood concentration-time 
curve over 1 dose interval (ie, from hour 0 to 24 for q24h administration); AUC0-t = area under the blood 
concentration-time curve from time = 0 to the last measurable concentration at time = t; AUClast = area under the 
plasma concentration-time curve from time = 0 to the last measurable concentration; C1min = exposure at 1 minute 
post first dose that day; Cmax = maximum observed concentration; GLP = Good Laboratory Practice; 
NOEL = no-observed-effect-level; q24h = once every 24 hours. 
1 Highest dose tested. 
2 Data extrapolated from Study PSN15-318. 
Note: The sample matrix was plasma for rat PK studies and whole blood for toxicology and clinical studies. 
 
The dose and dosing regimen have been selected from nonclinical models of allergic 
inflammation, which assess impact on eosinophils. A number of models assessing eosinophilic 
inflammation have been conducted showing significant reduction in eosinophils. 
7.8.1. 
Selection of Highest Dose Level 
In the ovalbumin challenge model, single IV doses of 2 and 20 µg/kg significantly inhibited 
eosinophil recruitment into the lung (Study D0028 GSK; refer to the Investigator’s Brochure), 
with a greater effect being seen with 20 g/kg (Figure 2). Pharmacokinetics were not measured 
in this study but were measured in a lipopolysaccharide acute inflammation mouse model, where 
an IV dose of 20 g/kg (which was maximally efficacious) resulted in a maximum observed 
concentration (Cmax) of 152 ng/mL and an area under the plasma concentration-time curve from 
time = 0 to the last measurable concentration (AUClast) of 18 ng.h/mL (Studies D0055 PNE and 
PSN18-0258; refer to the Investigator’s Brochure). This exposure is consistent with other mouse 
studies where PK has been measured. A clinical dose of 8 mg (C1104-001) gives an exposure 
approximately 4- to 8-fold higher than the maximum efficacious dose in mouse model 
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3BFigure 2: 
Effect of IRL201104 (IV) on Ovalbumin-Induced Eosinophil Influx into 
Mouse Lung 
Data represent mean ± standard error of the mean of n= 6 animals; *p<0.05 vs ovalbumin, T- test 
 
7.8.2. 
Selection of Dose Interval 
In addition, an allergic house dust mite (HDM) model has been conducted. Briefly, mice 
underwent 3 weeks of sensitization to HDM, rested for a period of 2 weeks, and then were 
challenged intranasally (IN) with HDM. Animals were treated with vehicle, IRL201104, or 
comparator drugs 15 minutes prior to HDM challenge as a single administration. Lung 
inflammatory infiltration was measured by analyzing the bronchoalveolar lavage fluid at 4 hours 
after HDM challenge (acute time point) or after 7 days (chronic time point). A third group of 
animals was rechallenged with HDM 14 days later and cellular infiltration was evaluated 4 hours 
later. 
IRL201104, given as a single IN administration, dose-dependently reduced eosinophil, 
neutrophil, and lymphocyte lung influx following both the HDM challenge and rechallenge 
(Figure 3), indicating that the effect lasted for at least 14 days. Eosinophil recruitment was 
significantly inhibited by IRL201104 and achieved the same degree of eosinophil inhibition as 
anti-interleukin (IL)-5 at the maximum dose tested (2 µg/kg).  


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4BFigure 3: 
Effects of IRL201104 IN on Cellular Recruitment at the 14-Day Rechallenge 
Time Point in the Murine HDM Model
Ab = antibody; ANOVA=analysis of variance; FF = fluticasone furoate; HDM = house dust mite; IL = interleukin; 
IN=intranasal; IV = intravenous; p.o. = oral; SEM = standard error of the mean
Data represent mean ± SEM of n=6 animals.
*p<0.05, ***p<0.001 vs HDM, ANOVA-Tukey’s post-test, +p<0.05, ++p<0.01 vs IRL201104 2 µg/kg
Therefore, 3 doses administered over a 2-week period has been selected as the dosing regimen 
based on the nonclinical evidence that, despite having a short PK t1/2, IRL201104 IV bolus is 
maximally efficacious in the ovalbumin mouse model (Studies D0028 and D0024) and that the 
effect lasts for 14 days after a single dose in the HDM mouse model (Study D0024 GSK; refer to 
the Investigator’s Brochure) but the effects appeared to subside at 20 days postdose (ovalbumin
mouse model; results published in Riffo-Vasquez 2020). This long PD effect is hypothesized to 
be because of an effect of IRL201104 on Treg cells; IRL201104 was shown to increase the 
number of Treg cells in human in vitro assays (Study D0066 KCL; data on file). 
Two dose strengths were selected to be tested in the current Phase 2a clinical study: 4 mg and 
8 mg. These dose levels have been well tolerated in healthy participant studies to date, the 
maximum doses studied to date being 8 mg on 7 consecutive days. Experience with anti-IL-5 
compounds would indicate that marked and sustained suppression of eosinophils has not been 
associated with adverse effects for example increased risk of parasitic infection.










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8.
SELECTION AND WITHDRAWAL OF PARTICIPANTS
8.1. 
Participant Inclusion Criteria 
A participant must meet the following criteria to be eligible for inclusion in the study: 
1. Age 18 to 75 years old, inclusive, at the time of signing the informed consent form. 
2. Documented diagnosis of EoE by endoscopy prior to screening. 
Note: Must include a demonstration of intraepithelial eosinophilic infiltration (peak cell 
count 
os/hpf [400×]) from esophageal biopsy specimens from endoscopy. 
3. History (by participant report) of on average at least 2 episodes of dysphagia (with intake 
of solids off anti-inflammatory therapy) per week in the 4 weeks prior to screening, and 
on average at least 2 episodes of documented dysphagia per week during any 
2 consecutive weeks (qualifying period) between screening and baseline; dysphagia is 
defined as trouble swallowing solid food, or having solid food stick, by participant report; 
and completed the DSQ
 to baseline 
(Visit 1).
4. Must remain on a stabilized diet for at least 6 weeks prior to screening and during the 
course of the study; stable diet is defined as no initiation of single or multiple elimination 
diets or reintroduction of previously eliminated food groups. 
5. Must be willing and able to continue any dietary therapy and/or medical regimens 
(including gastric acid suppression) in effect at the screening visit. There should be no 
change to these regimens during the study participation. 
6. Willing and able to comply with all clinic visits and study-related procedures. 
7. Able to understand and complete study-related questionnaires.
8. Provide signed informed consent. 
9. Esophagogastroduodenoscopy (EGD) with photographs performed at screening 
(qualifying EGD), with a demonstration of intraepithelial eosinophilic infiltration (peak 
cell count 
 eos/hpf) in at least 2 of the 3 biopsied esophageal regions (proximal, mid, 
or distal). 
8.2. 
Participant Exclusion Criteria 
A participant who meets any of the following criteria will be ineligible to participate in this 
study: 
1. Prior participation in an IRL201104 clinical study. 
2. Has any current disease of the gastrointestinal tract (aside from EoE) that may impact, in 
the investigator’s opinion, the patient’s EoE disease status. This includes, but not limited 
to: eosinophilic gastritis, eosinophilic enteritis, eosinophilic duodenitis, eosinophilic 
colitis, or proctitis; inflammatory bowel disease; or celiac disease. 


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3. Has other causes of esophageal eosinophilia or the following diseases: hypereosinophilic 
syndromes, Churg-Strauss vasculitis (eosinophilic granulomatosis with polyangiitis), or 
peripheral blood absolute eosinophil count of > 
 
4. Has presence of oral or esophageal mucosal infection of any type. 
5. Has any condition affecting the esophageal mucosa or altering esophageal motility other 
than EoE. 
6. History of achalasia, active Helicobacter pylori infection, Crohn's disease, ulcerative 
colitis, celiac disease, and prior esophageal surgery (with the exception of a surgical 
repair of an EoE complication). 
7. Any esophageal stricture unable to be passed with a standard, diagnostic, adult 
(9 to 10 mm) upper endoscope or any critical esophageal stricture that requires dilation at 
screening; or dilation within 2 months prior to screening. 
8. On a pure liquid diet or any mouth or dental condition that prevents normal eating. 
9. Has initiated, discontinued, or changed dosage regimen of PPIs within the 4 weeks prior 
to the qualifying EGD, between the qualifying EGD and baseline visit (Visit 1), or 
anticipates changes in the use of PPI during the study. PPI must remain constant 
throughout the study. 
10. History of bleeding disorders or esophageal varices. 
11. Use of anticoagulants within 2 weeks prior to screening. Participants should not stop 
these agents solely to become eligible for entry into this study. 
12. Treatment with an investigational drug within 2 months or within 5 half-lives (if known), 
whichever is longer, prior to screening. 
13. Use of systemic corticosteroids within 3 months or swallowed topical corticosteroids 
within 6 weeks prior to screening. 
14. Treatment with oral immunotherapy (OIT) within 6 months prior to screening. 
15. Allergen immunotherapy (sublingual immunotherapy [SLIT] and/or subcutaneous 
immunotherapy [SCIT]), unless on a stable dose for at least 1 year prior to screening. 
16. The following treatments within 3 months before the screening visit, or any condition 
that, in the opinion of the investigator, is likely to require such treatment(s) during the 
study: 
Systemic immunosuppressive/immunomodulating drugs (eg, omalizumab, cyclosporine, 
mycophenolate-
methotrexate, and other biologics that are ongoing [eg, dupilumab, benralizumab, 
mepolizumab, or vedolizumab]). 
17. Diagnosed with active parasitic infection; or suspected parasitic infection, unless clinical 
and (if necessary) laboratory assessments have ruled out active infection before 
randomization. 
18. Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or 
antifungals within 1 month prior to screening. 


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19. Use of oral antibiotics/anti-infectives within 2 weeks prior to screening.
20. Known or suspected immunosuppression, including history of invasive opportunistic 
infections (eg, tuberculosis, non-tuberculous mycobacterial infections, histoplasmosis, 
listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection 
resolution, or otherwise recurrent infections of abnormal frequency, or prolonged 
infections suggesting an immunocompromised status, as judged by the investigator. 
21. Known history of human immunodeficiency virus (HIV) infection. 
22. Positive or indeterminate hepatitis B surface antigen (HBsAg) or hepatitis C antibody at 
screening. 
23. Moderate or severe renal impairment (eGFR <60 mL/min/1.73 m2) or end stage renal 
disease. 
24. Elevated transaminases (alanine aminotransferase [ALT] and/or aspartate 
aminotransferase [AST]) > 3 times the upper limit of normal (ULN) at screening. 
25. History of malignancy within 5 years prior to screening, except completely treated in situ 
carcinoma of the cervix and completely treated and resolved nonmetastatic squamous or 
basal cell carcinoma of the skin. 
26. Any other medical or psychological condition including relevant laboratory abnormalities 
at screening that, in the opinion of the investigator, suggest a new and/or insufficiently 
understood disease, may present an unreasonable risk to the participant as a result of 
his/her participation in this clinical study, may make the participant’s participation 
unreliable, or may interfere with study assessments. The specific justification for 
participants excluded under this criterion will be noted in study documents (eg, chart 
notes, electronic case report form). These may include participant-reported alcohol or 
drug abuse and severe concomitant illness(es). 
27. Planned or anticipated use of any prohibited medications and procedures (as described in 
the exclusion criteria) during study treatment. 
28. Treatment with a live (attenuated) vaccine within 3 months prior to screening and/or 
treatment of a killed vaccine within 30 days prior to screening, until the end of the study 
with the exception of a coronavirus disease of 2019 (COVID-19) vaccine, as described in 
Section 9.2.1. 
29. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed 
during the study. 
30. Women unwilling to use adequate birth control, if of reproductive potential* and sexually 
active. Adequate birth control is defined as agreement to consistently practice an 
effective and accepted method of contraception throughout the duration of the study and 
for 30 days after the last dose of study treatment. These include: hormonal 
contraceptives, intrauterine device, or double barrier contraception (ie, condom and 
diaphragm), or male partner with documented vasectomy.
*For females, menopause is defined as at least 12 consecutive months without menses; to 
include laboratory confirmation of post-menopausal status (ie, a follicle stimulating 
hormone (FSH) of 2.25 U/mL must be documented). Hysterectomy, bilateral 


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oophorectomy, or bilateral tubal ligation must be documented, as applicable; if 
documented, women with these conditions are not required to use 
additional contraception. 
8.3.
Participant Withdrawal Criteria
8.3.1. 
Withdrawal of Participants 
Participants are free to withdraw from the study at any time without giving reasons. Furthermore, 
the investigator may withdraw a participant for reasons such as intolerance to study treatment, 
intercurrent illness, need for medication that is contraindicated, significant noncompliance with 
the requirements of the study, or withdrawal of consent. The investigator will assess the reasons 
for withdrawal as far as possible and will fully record the circumstances and medical details.
Participants who permanently discontinue study treatment and who do not withdraw from the 
study will be asked to return to the clinic for all remaining study treatment visits and participate 
in all follow-up assessments according to the visit schedule.  
8.3.2. 
Individual Stopping Criteria
Participants will be permanently discontinued from study treatment in the event of:
 Anaphylactic reaction to study treatment 
 Treatment with any prohibited concomitant medication or procedure (Section 9.2.2) 
 Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix or 
squamous or basal cell carcinoma of the skin 
 Evidence of pregnancy 
 Any infection that: 
Requires parenteral treatment with antibiotic, antifungal, antiviral, anti-parasitic, 
or anti-protozoal agent 
 Requires oral treatment with such agents for longer than 2 weeks 
 Is opportunistic, such as tuberculosis and other infections whose nature or course 
may suggest an immunocompromised status 
 Severe laboratory abnormalities, such as: 
 Neutrophil count <0.5 x 103/µL 
Platelet count <50 x 103/µL 
ALT and/or AST values >3 x ULN with total bilirubin >2 x ULN, excluding 
confirmed Gilbert's Syndrome
 Confirmed AST and/or ALT >5 x ULN (for more than 2 weeks) 
 Other reasons that may lead to the permanent discontinuation of study treatment 
include: 




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6BTable 4: 
Investigational Product
Investigational Product 
Product Name: 
IRL201104 
Placebo 
Dosage Form: 
Lyophilized cake 
reconstituted with 
sterile water for 
injection 
Lyophilized cake 
reconstituted with sterile 
water for injection 
Lyophilized cake 
reconstituted with 
sterile water for 
injection 
Unit Dose 
4 mg  
(0.8 mg/ml per 20 mL 
vial reconstituted with 
20 mL) 
8 mg 
(0.8 mg/ml per 20 mL 
vial reconstituted with 
10 mL) 
N/A 
Volume Required 
for 
Reconstitution 
20 mL 
10 mL 
10 mL 
Volume for 
Administration 
10 mL 
10 mL 
10 mL 
Route of 
Administration 
IV injection 
IV injection 
IV injection 
9.2. 
Concomitant Medications 
Any treatment (including nutritional supplements) or procedure administered from the time of 
informed consent to the end of the final study visit is considered concomitant 
medication/procedures. This includes medications that were started before the study and are 
ongoing during the study. All concomitant treatments will be reported in the eCRF along with 
their daily dosage, duration, and reasons for administration. Participants who have received any 
concomitant treatment may be withdrawn from the study at the discretion of an investigator. 
9.2.1. 
Permitted Concomitant Medications and Procedures
Other than the prohibited medications listed in Section 9.2.2, treatment with concomitant 
medications are permitted during the study. 
The dosage regimen of PPIs for any condition (such as gastroesophageal reflux disease, asthma, 
or allergic rhinitis) must remain constant throughout the study. 
Participants in this study may be offered COVID-19 vaccines during this study. Where possible, 
vaccinations should not occur within 7 days of a clinical visit (7 days either before or after the 
visit). The date of vaccination should be accurately recorded in the CRF. Study treatment should 
not be administered within 48 hours (48 hours before or after) of the COVID-19 vaccine.  
Other vaccines are prohibited as specified in Section 9.2.2. 
9.2.2. 
Prohibited Concomitant Medications and Procedures 
Treatment with the following concomitant medications is prohibited. Study treatment will be 
permanently discontinued if any of the following are used: 


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 Medications used for the treatment of EoE (these are considered rescue medications): 
Swallowed topical corticosteroids
Systemic corticosteroids
Dose change of systemic leukotriene inhibitors, topical, nasal, and/or inhaled 
corticosteroids 
Systemic treatment for EoE with an immunosuppressive/immunomodulating 
substance (including, but not limited to, omalizumab, cyclosporine, 
mycophenolate-
ate, 
leukotriene inhibitors and other biologics [eg, dupilumab, benralizumab, 
mepolizumab, vedolizumab]) 
 Allergen immunotherapy (SCIT and SLIT are allowed if dose is stable for 1 year or 
more; however, OIT is prohibited) 
 Participants who are not using PPI in the 8 weeks prior to screening cannot start PPI 
therapy prior to End of Study visit 
 Treatment with a live attenuated vaccine
 Treatment with a killed vaccine, with the exception of a COVID-19 vaccine 
(Section 9.2.1)  
 Treatment with an investigational drug (other than IRL201104) 
 The following concomitant procedures are prohibited during the study: 
 Major elective surgical procedures 
 Esophageal dilation (considered rescue procedure)
Diet change (participants should remain on stable diet for at least 6 weeks prior to 
screening and during the course of the study; stable diet is defined as no initiation 
of single or multiple elimination diets or reintroduction of previously eliminated 
food groups)
9.2.3.
Prohibited Concomitant Medications or Procedures as Rescue
If medically necessary (eg, for treatment of intolerable EoE symptoms), participants may be 
rescued with a prohibited medication or procedure (as defined in Section 9.2.2) at the discretion 
of the investigator. Participants who receive rescue treatment with a prohibited medication or 
procedure will be permanently discontinued from study treatment. These participants will be 
asked to return to the clinic for all remaining study treatment visits and participate in all 
follow-up assessments according to the visit schedule. Investigators should make every attempt 
to obtain efficacy measurements before initiation of rescue treatment. 
9.3. 
Method of Treatment Assignment 
Approximately 36 participants will be randomized in a 1:1:1ratio to receive IRL201104 4 mg or 
8 mg or placebo according to a central randomization scheme provided by an interactive web 
response system (IWRS).  


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9.3.1. 
Blinding
This is a double-blind study using open-label investigational product. Pharmacy staff will be 
unblinded for investigational product preparation.  Investigators, study team members and study 
participants will be blinded to the dose level given (4 mg, 8 mg, or placebo) and will remain 
blinded throughout the study.  
10. 
STUDY TREATMENT MATERIALS AND MANAGEMENT 
10.1. 
Study Treatment 
IRL201104 drug product and placebo is packaged as a sterile, lyophilized cake in a standard 
glass vial and is reconstituted with sterile water for injection (WFI) (Table 4). The WFI used to 
reconstitute the drug product will be an authorized product supplied by the clinical study center.  
For both the 4 and 8 mg doses, the amount of drug substance in each 20 mL vial is 0.8 mg/ml, 
which is reconstituted with 10 or 20 mL WFI. Investigational product will be administered in a 
volume of 10 mL.  
The process for reconstitution will be detailed in the sponsor pharmacy manual. 
10.2. 
Study Treatment Packaging and Labeling 
The study treatment will be packaged and labeled according to Good Manufacturing Practice 
(GMP) guidelines and applicable laws and regulations.  
10.3. 
Study Treatment Storage 
Investigational product will be stored at –20°C ± 5°C. 
If an out-of-range temperature is noted, the procedures will be followed as set forth in the 
sponsor pharmacy manual. 
10.4. 
Study Treatment Preparation 
Instructions for the preparation and reconstitution of study treatment will be provided in the 
sponsor pharmacy manual.
10.5. 
Administration 
IRL201104 is administered by IV injection over 30 seconds (not to exceed 60 seconds) via a 
cannula. Study dosing is considered completed when the study treatment and subsequent 
flushing of the line has been fully administered. Additional dosing details will be provided in the 
Pharmacy Manual. 
10.6. 
Study Treatment Accountability 
Accountability is ensured by administering the study treatment as an IV injection by designated 
personnel at the study center. 
All study treatment accountability records must be kept current. 


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The investigator is accountable for proper storage temperature and conditions of study treatment. 
At the end of the study, all unused study treatment supplies will be returned to the sponsor or 
destroyed in accordance with the sponsor’s instructions. 
The investigator must be able to account for all opened and unopened study treatment. These 
records should contain the dates, quantity, and study treatment dispensed to each participant and 
disposed of at the study center. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
10.7. 
Study Treatment Handling and Disposal 
Procedures for study treatment handling and disposal are provided in the study manuals.  
11. 
ASSESSMENT OF EFFICACY 
All efficacy assessments will be collected at the time points specified in Table 3. 
11.1. 
Histologic Response 
Esophageal biopsies will be obtained by endoscopy. The peak eos/hpf is the primary measure of 
efficacy. 
The screening endoscopy should be performed during the screening period to allow results to be 
available prior to Visit 1 for assessment of eligibility. A total of 9 mucosal pinch biopsies will be 
collected at each time point from across 3 esophageal regions: proximal, mid-esophagus, and 
distal. Three samples from each region will be used for the histology (needed for study inclusion 
criteria, as well as efficacy endpoints). Biopsy tissue will be placed in level-specific vials and 
sent to the central pathology laboratory for processing of tissue into slides. Esophageal biopsies 
will be used to assess histologic changes and to examine EoE gross esophageal mucosal features 
based on a validated scoring system for inflammatory and remodeling aspects of the disease. To 
be randomized in the study, participants must have a peak intraepithelial eosinophil count of at 
least 15 eos/hpf [400×]) from esophageal biopsy specimens in at least 2 of the 3 esophageal 
regions sampled. 
Eosinophil counts, histopathologic features, and gross endoscopic findings will be evaluated and 
scored for each endoscopy. Eight histopathologic epithelial features (basal layer hyperplasia, 
eosinophil density, eosinophil microabscesses, eosinophil surface layering, dilated intercellular 
spaces, surface epithelial alteration, dyskeratotic epithelial cells, lamina propria fibrosis) will be 
scored on a 4-point scale (0 = normal, 3 = worst) for both the severity of the abnormality (ie, 
grade) and the amount of tissue affected by the abnormality (ie, stage). 
Endoscopic findings with separate evaluations of the proximal and distal esophagus will be 
recorded with respect to 5 categories by the endoscopist: 1) exudates or plaques (grade 0–2); 
2) fixed esophageal rings (grade 0–3); 3) edema (grade 0–1); 4) furrows (grade 0–1); and 
5) strictures (grade 0–1). An endoscopy score for each category will be calculated and summed 
for each anatomic location (proximal and distal). The maximum endoscopy score is 10 points for 


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each location, and a Total Endoscopy Score is the sum of the scores for the proximal and distal 
locations. 
In addition, the general appearance of the stomach and duodenum will be assessed by the 
endoscopist. Biopsies will be taken from the stomach and duodenum for the screening EGD as 
follows: gastric body (greater curvature): 2 specimens, gastric antrum: 2 specimens, and 
duodenum (third part or distal): 2 specimens. Biopsies from the stomach should be submitted in 
one vial; biopsies from the duodenum should be submitted in a separate vial to the central 
pathology laboratory for processing of tissue into slides. If the pre-treatment biopsy identifies 
eosinophilia in the stomach and/or duodenum, the participant will be excluded from the study. 
As a secondary endpoint, histologic response will be defined as eosinophil count < 15 eos/hpf 
(400×) in all available esophageal levels following 14 days of treatment with IRL201104 based 
on anatomical and histological findings from endoscopy with esophageal biopsies. Change in 
peak esophageal eos/hpf from baseline will be determined by counting eosinophils in the most 
inflamed areas of each esophageal region sampled at each time point and calculating the change 
in the peak count at each location obtained at baseline compared with the count obtained at 
subsequent time points. 
Histology results will be interpreted by a pathologist at a central pathology reading center. 
Gastric and duodenal biopsies may be repeated at the discretion of the investigator, but are not 
required. Detailed instructions for biopsy sample collection and handling will be provided in the 
study manuals. 
Tissue blocks remaining after the histological assessment will be banked for exploratory 
research. Remaining samples from each region will be processed to bank tissue RNA for EDP 
transcriptome signature (Section 11.7) and other EoE related gene expression exploratory 
research (Section 11.8). Biopsy samples will be sent to a central pathology laboratory for 
processing and analysis. If required by the investigator institution, biopsy samples will be 
processed and analyzed by the local laboratory, and the processed specimen will be sent to the 
central pathology laboratory for central reading.  
In addition to the samples to assess histological response, the next set of biopsies will be taken 
from the most inflamed area of the esophagus. A total of 4 biopsies will be obtained and stored 
in RNAlater™(1 fragment), flash frozen (1 fragment), and formalin-fixed (2 fragments). The 
banked samples will be used for exploratory analysis which could include, but are not limited to, 
gene expression, epigenetics, cell culture, and microbiome, etc. Detailed instructions for biopsy 
sample collection and handling will be provided in the study manuals. 
The number of and locations of required biopsy sampling is summarized in Table 5. 


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7BTable 5: 
Biopsy Sampling
Screening: # Biopsy Samples 
Postdose: # Biopsy Samples 
Histologic 
Exploratory 
Histologic 
Exploratory 
RNAseq
Flash 
Frozen 
Formalin-
fixed 
RNAseq
Flash 
Frozen 
Formalin-
fixed 
Esophagus
 
 
 
 
 
 
 
 
Proximal
3 
 
 
 
3 
 
 
 
Mid
3 
 
 
 
3 
 
 
 
Distal
3
3
Most Inflamed 
Area
 
1 
1 
2 
 
1 
1 
2 
 
 
 
 
 
 
 
 
Stomach and 
Duodenum
 
 
 
 
 
 
 
 
Gastric body
2 
 
 
 
 
 
 
 
Gastric antrum
2 
 
 
 
 
 
 
 
Duodenum
2 
 
 
 
 
 
 
 
11.2. 
Dysphagia Symptom Questionnaire 
The DSQ is used to measure the frequency and intensity of dysphagia. The DSQ scores can 
range from 0 to 84, with a lower score indicating less frequent or less severe dysphagia 
(Dellon 2013). 
The questionnaire will be completed by participants daily. Each evening before bedtime, 
participants will be asked to indicate if they experienced dysphagia symptoms (eg, food passing 
slowly or food sticking) during that day. Participants must have experienced dysphagia (response 
of “yes” to Question 2 on DSQ) on a minimum of 2 
 
of days in at least 2 consecutive weeks (qualifying period) prior to the baseline visit (Visit 1). 
Participants must fill out the DSQ at least 5 or more days during a given week in order to be 
compliant. 
Calculations will be performed on daily ePRO entries from the qualifying period prior to 
baseline, and prior to each study visit during the treatment and follow-up periods. The DSQ 
score for the secondary endpoints will be calculated by summing the scores of responses to 
Questions 2 and 3 only. Questions 1 and 4 will be excluded from the DSQ score. 
DSQ score for 14-day period =  
(Sum of points from questions 2+3 in the daily DSQ with 
non-missing data over the interval being reported)×14 
Number of diaries reported with non-missing data over the interval 
being reported 


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For each DSQ calculation, the sum of the specified question(s) from each reported daily diary 
with non-missing data over the interval being reported will be obtained, dividing this by the 
number of reported daily diaries with non-missing data in that same interval. This result will then 
be multiplied by the interval. This normalizes each DSQ sum over the interval. For the DSQ 
score, if a response of “No” is recorded for Question 2, the DSQ score will be set to zero for that 
day. The DSQ calculations during the interval being reported prior to the baseline visit will be 
defined as the baseline DSQ evaluation. For each 14-day period, at least 8 reported diaries are 
needed to effectuate a DSQ calculation for that period. If at least 8 diaries are not available, the 
DSQ result for that 14-day period will be set to missing. 
11.3.
Eosinophilic Esophagitis-Endoscopic Reference Score
The EoE-EREFS will be used to measure the endoscopically identified EoE esophageal mucosal 
inflammatory and remodeling features. This instrument includes a total of 17 items related to the 
presence and severity of esophageal features. The specific esophageal features include: rings 
(absent, mild, moderate, severe, not applicable); stricture (yes, no, not applicable); diameter of 
the stricture (if applicable); exudates (absent, mild, severe); furrows (absent, present); edema 
(absent, present); crepe paper esophagus (absent, present); overall general appearance 
incorporating all endoscopically identified EoE findings (ie, fixed rings, strictures, whitish 
exudates, furrowing, edema, and crepe paper mucosa). In addition, mucosal changes associated 
with gastroesophageal reflux disease (GERD) will also be recorded using the Los Angeles 
classification system for erosions (No Erosions or LA Classification A, B, C, D). The EoE 
esophageal characteristics will be analyzed based on the EoE-EREFS, a validated scoring system 
for inflammatory and remodeling features of disease using both overall scores and scores for 
each individual characteristic (Hirano 2013). The EoE-EREFS should be performed by the 
physician who performs the endoscopy procedure at the time of the endoscopy. In addition to the 
local read, images will be submitted to the central imaging laboratory for central reading. 
11.4. 
Eosinophilic Esophagitis-Histology Scoring System 
The EoEHSS is a validated histology scoring system for esophageal biopsies that evaluates 8 
features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface 
layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, 
and lamina propria fibrosis (absent/present) (Collins 2017). Severity (grade) and extent (stage) of 
abnormalities will be scored using a 4-point scale (0 normal; 3 maximum change). 
11.5. 
Patient Global Impression of Severity 
The PGI-S is a PRO measure that uses a verbal rating scale of severity. The PGI-S uses a recall 
period that aligns with the assessment period used for calculating DSQ endpoint scores (ie, DSQ 
endpoints are based on 14-day scores, and the PGI-S is administered on the last day of the 14-
day assessment period. The PGI-S instructs participants to recall over the past 14 days, such that 
the anchor covers the same 14-day period as the 14-day DSQ endpoint score). 


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11.6.
Patient Global Impression of Change
The PGI-C is a PRO measure that assesses change compared with prior to starting treatment and 
reflects the participant’s belief about the efficacy of treatment. The PGI-C is a scale depicting a 
participant’s rating of overall improvement. 
11.7. 
RNA Sequencing and EDP Transcriptome 
RNA sequencing and EDP transcriptome will be evaluated.  
A molecular EDP has been identified that is composed of 94 EoE genes and distinguishes EoE 
from control individuals without esophagitis or with GERD (Wen 2013).  
The EDP signature will be evaluated in biopsy samples. Using a method reported by 
Wen (2015), the EoE transcriptome will be determined using the EDP from extracted RNA.  
Further details will be provided in the study manuals. 
11.8. 
Other Biomarkers of Eosinophilic Esophagitis  
Other biomarkers of disease will be explored and may include, but are not limited to: 
immunohistochemistry and immunofluorescence, DNA analysis, microdissection further 
immunophenotyping, gene expression, epigenetics, cell culture, and microbiome, etc.  
12. 
ASSESSMENT OF SAFETY 
All safety assessments will be collected at the time points specified in the Schedule of Events 
(Table 3). 
12.1. 
Screening and Baseline Assessments 
A screening assessment to determine study eligibility will be performed after the participant has 
provided signed informed consent. The participant will be assigned a unique participant number 
once the ICF has been signed.  
Demographic characteristics will include standard demography (eg, age, race, and weight), 
medical history, medication history, and diet history for each participant. Characteristics of 
disease, including duration, and disease symptoms, will be collected. Viral serology, 
demographic characteristics, medical and medication history, and height are collected at 
screening only. 
12.2. 
Vital Signs  
Vital sign measurements include systolic and diastolic blood pressure, heart rate, temperature, 
and respiratory rate and will be assessed within 15 minutes predose and at 15 minutes (+/-5 
minutes) postdose.  
Measurements should be made with participants in a sitting position, after resting for at least 
5 minutes. 
Height will be measured at screening only. 


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12.3.
Physical Examination
A complete physical examination comprises a routine medical examination, including gross 
neurological assessments. The following body systems will be examined: general appearance, 
neurological, eyes, ear/nose/throat, cardiovascular, respiratory, abdominal, hepatic, 
gastrointestinal, musculoskeletal, and dermatological. 
For each body system the result will be recorded as “normal”, “abnormal not clinically 
significant”, or “abnormal clinically significant”. 
12.4. 
Electrocardiogram 
A standard 12-lead ECG will be performed before blood is drawn during visits requiring blood 
draws. The ECG strips or reports will be retained with the source documentation, and the results 
will be documented in the eCRF. Electrocardiogram results will be locally interpreted.  
12.5. 
Laboratory Assessments 
Detailed instructions for blood sample collection are in the study manuals provided to study 
centers.  
Local Laboratory Assessments: 
The following clinical laboratory parameters will be assessed: 
Blood Chemistry
 
 
Sodium 
Total protein, serum 
Total and indirect bilirubin
Potassium 
Creatinine 
Total cholesterol 
Chloride 
Blood urea nitrogen 
Low-density lipoprotein  
Carbon dioxide 
AST
High-density lipoprotein  
Calcium 
ALT 
Triglycerides 
Glucose 
Alkaline phosphatase 
Uric acid 
Albumin
Lactate dehydrogenase 
CPK
Hematology
 
 
Hemoglobin 
Differential:
 
Hematocrit 
Neutrophils 
 
Red blood cells 
Lymphocytes 
 
White blood cells 
Monocytes 
 
Red cell indices 
Basophils 
 
Platelet count 
Eosinophils 
 
Urinalysis
 
 
Microscopic analysis will only be done in the event of abnormal dipstick results. 
Color
Glucose 
Red blood cells 
Clarity 
Blood
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pH
Bilirubin
Bacteria 
Specific gravity
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein
White blood cells 
Yeast
Serological markers
 
 
HIV-1/2 antibodies
HBsAg
Hepatitis C virus antibodies
Other laboratory tests: 
Serum pregnancy tests will be performed for females of reproductive potential at 
screening, after which urine pregnancy tests will be performed. 
 FSH testing will be performed at screening to confirm post-menopausal status in female 
participants who have had at least 12 months without menses. 
 Coagulation testing (prothrombin time and partial thromboplastin time) will be performed 
as indicated in the Schedule of Events (Table 3). Samples for coagulation tests should be 
obtained before the procedures of endoscopy with esophageal biopsies are performed. 
Abnormal laboratory values and laboratory AEs: 
 All laboratory values must be reviewed by the investigator or authorized designee. 
 Significantly abnormal tests must be repeated to confirm the nature and degree of the 
abnormality. When necessary, appropriate ancillary investigations should be initiated. If 
the abnormality fails to resolve or cannot be explained by events or conditions unrelated 
to the study treatment or its administration, the medical monitor must be consulted.
 The clinical significance of an abnormal test value, within the context of the disease 
under study, must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 12.6.1.4. 
Central laboratory assessments for the assessment of PK and immunogenicity are described in 
Section 13. 
12.6. 
Adverse and Serious Adverse Events 
12.6.1. 
Definition of Adverse Events
12.6.1.1. Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. In clinical studies, an AE can include 
an undesirable medical condition occurring at any time, including baseline or washout periods, 
even if no study treatment has been administered. 
All AEs that occur after any participant has been enrolled, before treatment, during treatment, or 
within 30 days following the cessation of treatment, whether or not they are related to the study, 
must be recorded on forms provided by the sponsor. 


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12.6.1.2. Serious Adverse Event 
A serious adverse event (SAE) is an AE occurring during any study phase (ie, baseline, 
treatment, washout, or follow-up), and at any dose of the study treatment, that fulfils one or more 
of the following: 
 Results in death 
 It is immediately life-threatening
 It requires in-patient hospitalization or prolongation of existing hospitalization 
 It results in persistent or significant disability or incapacity 
 Results in a congenital abnormality or birth defect 
 It is an important medical event that may jeopardize the participant or may require 
medical intervention to prevent one of the outcomes listed above. 
All SAEs that occur after any participant has been enrolled, before treatment, during treatment, 
or within 30 days following the cessation of treatment, whether or not they are related to the 
study, must be recorded on forms provided by the sponsor. 
12.6.1.3. Other Adverse Events 
The following events require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Pregnancy 
Should a pregnancy occur, it must be reported and recorded on the sponsor’s pregnancy form. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication. 
Although pregnancy is not considered an AE, it is the responsibility of the investigator to report 
to the sponsor (or designee) by telephone within 24 hours of identification, any pregnancy 
occurring in a female participant or female partner of a male participant, during the study or 
within 120 days of the last dose of study treatment. Any complication of pregnancy affecting a 
female study participant or female partner of a male study participant, and/or fetus, and/or 
newborn must be reported as an SAE. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the participant was 
discontinued from the study. 
Overdose of Study Treatment 
Any accidental or intentional overdose over the intended dose of study treatment within the 
intended therapeutic window, if associated with an AE, should be reported within 24 hours. 
Adverse Events of Special Interest
Adverse events of special interest (AESIs) must be reported within 24 hours of identification. 
Adverse events of special interest in this study include:


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 Anaphylactic reactions or acute allergic reactions that require immediate treatment 
 Severe injection site reactions that last longer than 24 hours 
Any severe infection, any bacterial infection requiring treatment with parenteral 
antibiotics or treatment with oral antibiotics for longer than 2 weeks, any clinical 
endoparasitosis, any opportunistic infection, any viral infection requiring antiviral 
treatment 
 Note: Generally, all uncommon, atypical, peculiar, or unusually persistent infections, 
especially viral infections, should be reported as AESI. 
Refer to the study manuals for the procedures to be followed. 
12.6.1.4. Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 the test result is associated with accompanying symptoms; and/or 
 the test result requires additional diagnostic testing or medical/surgical intervention; 
and/or 
 the test result leads to discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy. 
Contact the medical monitor in the event the investigator feels that an abnormal test finding 
should be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
12.6.2. 
Relationship to Study Drug 
An investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Possibly Related or Probably Related). The 
investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. If no valid reason 
exists for suggesting a relationship, then the AE should be classified as “unrelated.” If there is 
any valid reason, even if undetermined, for suspecting a possible cause-and-effect relationship 
between the investigational product and the occurrence of the AE, then the AE should be 
considered “related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” the event will be considered to be related to the investigational product 
for the purposes of expedited regulatory reporting. 
12.6.3. 
Recording Adverse Events 
Adverse events spontaneously reported by the participant and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 


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investigational study center. Clinically significant changes in laboratory values, blood pressure, 
and pulse need not be reported as AEs. However, abnormal values that constitute an SAE or lead 
to discontinuation of administration of study treatment must be reported and recorded as an AE. 
Information about AEs will be collected from the signing of the consent form until 30 days 
following the last dose of study treatment. Serious AE information will be collected from signing 
of the consent form until 30 days following the last dose of study treatment. The AE term should 
be reported in standard medical terminology when possible. For each AE, the investigator will 
evaluate and report the onset (date and time), resolution (date and time), intensity, causality, 
action taken, serious outcome (if applicable), and whether or not it caused the participant to 
discontinue the study.
Intensity will be assessed according to the following scale:
 Mild (awareness of sign or symptom, but easily tolerated) 
 Moderate (discomfort sufficient to cause interference with normal activities)
 Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.6.1.2. An AE of severe intensity 
may not be considered serious. 
12.6.4. 
Reporting Adverse Events
All SAEs (related and unrelated) will be recorded from the signing of consent form until 30 days 
following the end of treatment exposure. Any SAEs considered possibly or probably related to 
the investigational product and discovered by the investigator at any time after the study should 
be reported. All SAEs must be reported to the sponsor within 24 hours of the first awareness of 
the event. The investigator must complete, sign, and date the SAE pages, verify the accuracy of 
the information recorded on the SAE pages with the corresponding source documents, and send 
to the sponsor.  
Additional follow-up information, if required or available, should all be reported to the sponsor 
within 24 hours of receipt and this should be completed on a follow-up SAE form and placed 
with the original SAE information and kept with the appropriate section of the eCRF and/or 
study file. 
The sponsor is responsible for notifying the relevant regulatory authorities of certain events. It is 
the Principal Investigator’s responsibility to notify the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) of all SAEs that occur at his or her study center. 
Investigators will also be notified of all unexpected, serious, drug-related events (7/15 Day 
Safety Reports) that occur during the clinical study. Each study center is responsible for 
notifying its IRB or IEC of these additional SAEs. 
All AEs that lead to a participant’s withdrawal from the study must be reported to the sponsor's 
medical monitor within 30 days. 
Refer to the study manuals for procedures to be followed. 


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13.
ASSESSMENT OF PHARMACOKINETICS AND
IMMUNOGENICITY 
Samples will be collected pre- and postdose at the time points listed in the Schedule of Events 
(Table 3) for the following assessments: 
 IRL201104 PK concentrations  
 Antidrug antibodies (ADA)   
 Immune cell phenotyping (T-subsets, B-subsets, and macrophage subsets) 
 A20 
Serum cytokines
Serum IgE/IgG4
 Serum EDN 
Immunogenicity variables include ADA status. Results are reported as an optical density (OD) 
unit with a cut-off value. If the OD value is lower than the cut-off value, it is reported as 
negative, and if OD value is higher than the cut-off value it is positive. Participants who are 
assessed as ADA positive at their last study visit (early termination or end of study) will be 
considered for follow-up based on the overall clinical presentation at that time. Participants who 
are identified for follow-up may be asked to return to the clinic to have additional ADA samples 
collected for analysis. 
The PK and immunogenicity assessments will be analyzed by a central laboratory. 
14. 
RESEARCH SAMPLES 
Research samples (blood/esophageal biopsies) will be collected at time points listed in the 
Schedule of Events (Table 3). 
Use and Storage of Research Samples (Serum/Plasma/Esophageal Biopsies)
Research blood samples and esophageal biopsy samples will be banked and may be used to study 
the effects of the study treatment on target pathway modulation and EoE pathophysiology. 
Stored samples may also be used to discover markers predictive of IRL201104 response as well 
as identify markers associated with toxicity. Details for banking samples will be provided in the 
study manuals. 
Technologies that may be employed include circulating protein marker analyses (eg, 
enzyme-linked-immunosorbent serologic assay, electrochemiluminescence), 
immunohistochemistry and/or histology of biopsies, and/or transcriptome analyses of blood 
and/or biopsy samples (eg, microarray, transcriptome sequencing, and/or quantitative reverse 
transcriptase-polymerase chain reaction). 
Detailed instructions for sample collection and handling will be provided in the study manuals. 


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15.
STATISTICS
15.1. 
General Considerations for Data Analysis 
No formal statistical analysis will be conducted for this study. Summary statistics appropriate for 
categorical and continuous variables will be presented by treatment group and all inferences will 
be based on clinical evaluation of those results. A detailed statistical analysis plan (SAP) will be 
prepared that describes the method and style of the data summaries and listings for each 
endpoint. 
15.2. 
Analysis Populations 
15.2.1. 
Full Analysis Set
The full analysis set (FAS) will consist of all participants randomized at baseline who receive at 
least one dose of treatment.  
This is the principal data set for the formal evaluation of the primary and secondary efficacy 
endpoints at Week 4. Participants will be evaluated based on the treatment group to which they 
were randomized. 
15.2.2. 
Safety Analysis Set
The safety analysis set will include all participants who were documented to have taken at least 
1 dose of study treatment. Safety evaluations will consider participants according to the actual 
treatment they received.  
15.3. 
Planned Analysis 
15.3.1. 
Study Population Analysis 
Demographics and baseline disease characteristics and medical history will be summarized 
descriptively by treatment group. Participant disposition will be summarized, including the 
reasons for discontinuation. The number of participants in each analysis population will be 
displayed and an accounting of exclusions from each study population will be provided. 
15.3.2. 
Efficacy Analysis
For the primary efficacy endpoint, the change from baseline in histologic eosinophil count in 
each treatment group will be summarized as the mean, standard deviation, median, minimum, 
and maximum, appropriately presented as defined by the treatment group of interest.  
As a secondary endpoint of interest, number and the proportion of participants with a histologic 
eosinophil count of < 15 eos/hpf will also be summarized for each treatment group. The 
secondary endpoint, DSQ change from baseline, will be summarized in the same manner as the 
primary endpoint.  
For the exploratory EoE-EREFS and EoEHSS endpoints, a categorical summary of the scores 
obtained will be highlighted along with the mean, standard deviation, median, minimum, and 
maximum change from baseline. The PGI-S and PGI-C will be summarized categorically and as 
summarized continuous data. Post-baseline evaluation for each PRO measure will be undertaken 


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as described in the Schedule of Events (Table 3). The EREFS data will be summarized as the 
frequency and percentage distribution of observed scores within each EREFS domain. 
15.3.3. 
Safety Analysis 
All on-treatment safety data will be assessed descriptively for AEs, SAEs, clinical laboratory 
measurements, viral serology, vital signs, physical examinations, and ECGs. No formal statistical 
analysis will be performed on safety outcomes; inferences, if any, will be derived through 
clinical review and interpretation.
All TEAEs will be summarized overall and for each body system and preferred term by
treatment group, relationship to investigational product, and severity. For tabulations by severity, 
only a participant’s most severe event within the category (eg, overall, body system, or preferred 
term) will be counted. Adverse events will be dichotomized into “related” (definitely, probably, 
and possibly) and “unrelated” (unlikely and not related). “Treatment-emergent” will be defined 
as starting or worsening after the first dose of investigational product. If the start date is missing, 
the event is assumed to be treatment emergent. All SAEs will be tabulated. 
Vital signs, including blood pressure, heart rate, body temperature, respiration rate, and weight 
will be summarized by treatment group at baseline and at each scheduled visit. 
Clinical safety laboratory data will be summarized descriptively by treatment group at baseline 
and at subsequent scheduled visits. Summaries of safety laboratory parameters will include the 
first measurement of each scheduled assessment but repeat assessments done at the same study 
time point will not be included in summary calculations. Laboratory data will also be listed by 
treatment, participant, and visit. Listings will include scheduled, unscheduled, and repeat 
evaluations. A listing of markedly abnormal values, as defined in the SAP, will additionally be 
generated. 
Abnormal physical examination findings that suggest a clinically significant worsening from 
baseline will be reported as AEs and analyzed as such. Clinically significant findings noted prior 
to start of investigational product treatment will be recorded as medical history and analyzed as 
such. 
Concomitant medications will be tabulated by preferred term, and treatment group. For the 
purposes of data collection, a medication’s usage will be considered concomitant if it was started 
within 14 days prior to informed consent and continued after administration of the 
investigational product. If the start date is missing, it will be assumed that the medication was 
used concomitantly. 
15.3.4. 
Pharmacokinetic and Immunogenicity Analysis 
Concentrations of IRL201104 will be listed by participant and summarized by treatment group 
and time point from predose to Week 8 based on the safety set. 
Antidrug antibody status (negative or positive based on whether results are lower or higher, 
respectively, than the OD cut-off value) will be listed and summarized by treatment group and 
time point from predose to Week 8based on the safety set. 
Details will be provided in the SAP. 


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15.4.
Determination of Sample Size
The chosen sample size for this study reflects reasonable clinical expectations of the number of 
participants who could be evaluated in this observational investigation for the purpose of 
obtaining preliminary estimates of histological response to treatment. It also provides for some 
level of accounting of the variability of estimates and the repeatability of results among a small 
group of participants treated in each proposed arm. 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
Before an investigational study center can enter a participant into the study, a representative of 
the sponsor will assess the investigational study center to: 
 Determine the adequacy of the facilities
 Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of the sponsor or its representatives. This will 
be documented in a Clinical Study Agreement between the sponsor and the investigator. 
During the study, a monitor from the sponsor or representative will have regular contacts with 
the investigational study center, for the following: 
 Provide information and support to the investigator(s). 
Confirm that facilities remain acceptable. 
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that investigational product accountability checks 
are being performed. 
 Perform source data verification. This includes a comparison of the data in the eCRFs 
with the participant’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records or certified 
copies for each participant (eg, clinic charts). 
 Record and report any protocol deviations not previously sent to the sponsor. 
 Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to the sponsor and those SAEs that met criteria for reporting 
have been forwarded to the IRB. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
16.2. 
Audits and Inspections 
Authorized representatives of the sponsor, a regulatory authority, IEC, or an IRB may visit the 
study center to perform audits or inspections, including source data verification. The purpose of a 
sponsor audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were 


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recorded, analyzed, and accurately reported according to the protocol, GCP guidelines of the 
International Council for Harmonisation (ICH), and any applicable regulatory requirements. The 
investigator should contact the sponsor immediately if contacted by a regulatory agency about an 
inspection. 
16.3. 
Institutional Review Board 
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB for this study including the ICF and recruitment materials 
must be maintained by the investigator and made available for inspection. 
17.
QUALITY CONTROL AND QUALITY ASSURANCE
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Please see Section 16.2 for more details regarding the audit 
process. 
18. 
ETHICS 
18.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The investigator must submit 
written approval to the sponsor before he or she can enroll any participant into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit participants for the study. The protocol must be re-approved by the 
IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. To the sponsor will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
18.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with the ICH/GCP, applicable regulatory requirements 
and the sponsor’s policy on Bioethics. 
18.3. 
Written Informed Consent 
The Principal Investigator at each center will ensure that the participant is given full and 
adequate oral and written information about the nature, purpose, possible risk and benefit of the 
study. Participants must also be notified that they are free to discontinue from the study at any 


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time. The participant should be given the opportunity to ask questions and allowed time to 
consider the information provided. 
The participant’s signed and dated informed consent must be obtained before conducting any 
study procedures. 
The Principal Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the participant. 
19.
DATA HANDLING AND RECORDKEEPING
19.1. 
Inspection of Records 
The sponsor will be allowed to conduct study center visits to the investigational facilities for the 
purpose of monitoring any aspect of the study. The investigator agrees to allow the monitor to 
inspect the drug storage area, study treatment stocks, drug accountability records, participant 
charts and study source documents, and other records relative to study conduct. 
19.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for the sponsor or the 
Regulatory Authority to review any documentation relating to the study, the investigator must 
permit access to such records.
20. 
PUBLICATION POLICY 
If the data merit, the investigator and the sponsor will discuss the preparation of a manuscript for 
publication in a peer-reviewed professional journal or an abstract for presentation, oral or 
written, to a learned society or symposium. Either party may undertake the task, but both must 
agree to the strategy before the work is started. Each party will allow the other 30 days to 
comment before any results are submitted for publication or presentation. Authorship should 
reflect work done by the investigators and personnel of the sponsor, in accordance with generally 
recognized principles of scientific collaboration. 


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21.
LIST OF REFERENCES
Cehovin A, Coates ARM, Hu Y, et al. Comparison of the moonlighting actions of the two highly 
homologous chaperonin 60 proteins of mycobacterium tuberculosis. Infection and Immunity, 
2010 Jul: 3196–3206. 
Collins MH, Martin LJ, Alexander ES, et al. Newly developed and validated eosinophilic 
esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for 
disease diagnosis and monitoring. Dis Esophagus 2017 Mar;30(3):1-8. 
Dellon ES, Collins MH, Katzka DA, et al. Improvements in dysphagia and pain with swallowing 
in patients with eosinophilic esophagitis receiving budesonide oral suspension. Clin 
Gastroenterol Hepatol 2021 Apr;19(4):699-706.e4. doi: 10.1016/j.cgh.2020.03.060. Epub 2020 
Apr 6. PMID: 32272243.  
Dellon ES, Irani A-M, Hill MR, Hirano I. Development and field testing of a novel patient-
reported outcome measure of dysphagia in patients with eosinophilic esophagitis. Aliment 
Pharmacol Ther 2013 Sep;38(6):634-642. 
Dellon ES, Rothenberg M, Hirano I, et al. Dupilumab improves health-related quality of life 
(HRQoL) and reduces symptom burden in patients with eosinophilic esophagitis (EoE): results 
from part A of a randomized, placebo-controlled three-part phase 3 study. J Allergy Clin Immun
2021 Feb;147(2):AB91. 
Dioszeghy V, Mondoulet L, Dhelft V, et al. The regulatory T cells induction by epicutaneous 
immunotherapy is sustained and mediates long-term protection from eosinophilic disorders in 
peanut-sensitized mice. Clin Exp Allergy 2014 Jun;44(6):867-881. 
Frischmeyer-Guerrerio PA, Gue
strong predisposition for human allergic disease. Sci Transl Med. 2013;5(195):195ra94. 
doi:10.1126/scitranslmed.3006448. 
Fuentebella J, Patel A, Nguyen T, et al. Increased number of regulatory T cells in children with 
eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 2010 Sep;51(3):283-289. 
Hirano I, Dillon ES, Hamilton JD, et al. Efficacy of dupilumab in a Phase 2 randomized trial of 
adults with active eosinophilic esophagitis. Gastroenterology 2020 Jan;158(1):111-122.e10. 
Hirano I, Moy N, Heckman MG, et al. Endoscopic assessment of the oesophageal features of 
eosinophilic oesophagitis: validation of a novel classification and grading 
system. Gut 2013;62:489–495. 
Hsu AP, Davis J, Puck JM, Holland SM, Freeman AF. STAT3 hyper IgE syndrome. In: Adam 
MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® Seattle: University of Washington 
1993-2021. 
Janssen E, Morbach H, Ullas S, et al. Dedicator of cytokinesis 8-deficient patients have a 
breakdown in peripheral B-cell tolerance and defective regulatory T cells. J Allergy Clin 
Immunol 2014 Dec;134(6):1365-1374. 


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Miranda MS, Breiman A, Allain S, Deknuydt F, Altare F. The tuberculous granuloma: an 
unsuccessful host defence mechanism providing a safety shelter for the bacteria? Clin Dev 
Immunol 2012 Jul:139127. 
Riffo-Vasquez Y, Kanabar V, Keir SD, et al. Modulation of allergic inflammation in the lung by 
a peptide derived from Mycobacteria tuberculosis chaperonin 60.1. Clin Exp Allergy 
2020 Apr;50(4):508-519. 
Stuck MC, Straumann A, Simon HU. Relative lack of T regulatory cells in adult eosinophilic 
esophagitis—no normalization after corticosteroid therapy. Allergy 2011 May;66(5):705-707. 
Wen T, Dellon ES, Moawad FJ, Furuta GT, Aceves SS, Rothenberg ME. Transcriptome analysis 
of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor-
reversible allergic inflammation. J Allergy Clin Immunol 2015 Jan;135(1):187-197. 
Wen T, Aronow BJ, Rochman Y, et al. Single-cell RNA sequencing identifies inflammatory 
tissue T cells in eosinophilic esophagitis. J Clin Invest. 2019 Apr 8;129(5):2014-2018. 
Wen T, Stucke EM, Grotjan TM, et al. Molecular diagnosis of eosinophilic esophagitis by gene 
expression profiling. Gastroenterology 2013;145:1289–1299. 
WHO Library Cataloguing-in-Publication Data, Global tuberculosis report 2012. 


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22.
APPENDIX
The following scales/assessments will be utilized in this study: 
Full Title of Scale/Assessment 
Completed By 
DSQ  
Participant 
EoE-EREFS  
Endoscopist / Central reader 
EoEHSS
Central reader
PGI-S  
Participant 
PGI-C  
Participant 
DSQ = Dysphagia Symptom Questionnaire; EREFS = Eosinophilic Esophagitis-Endoscopic Reference Score; 
EoEHSS = Eosinophilic Esophagitis-Histology Scoring System; PGI-C = Patient Global Impression of Change; 
PGI-S = Patient Global Impression of Severity 
 
A separate master file containing each scale/assessment listed above will be provided to the 
study centers. Updates to scales/assessments during the study (if applicable) will be documented 
in the table above, and a new master file containing the revised scale/assessment will be provided 
to the study centers. 

SAP_001.pdf: 


STATISTICAL ANALYSIS PLAN 
 
TITLE PAGE  
 
 
 
A Phase 2a, Double-blind, Placebo-Controlled, Multi-Center Study to Assess 
the Efficacy, Safety, and Tolerability of IRL201104 in Adult Participants with 
Active Eosinophilic Esophagitis (EoE) 
 
  
 
 
 
Final 1.0: DEC 15, 2022  
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential.  Do not copy, 
circulate, or otherwise distribute without written authorization from  
Revolo Biotherapeutics  


Revolo Biotherapeutics
Statistical Analysis Plan  
Final Version 1.0
Private and Confidential
                                                       Protocol No. RVLO 121-04 
Date: DEC 15, 2022
 
TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................................... 1 
TABLE OF CONTENTS ......................................................................................................... 2 
DECLARATION ..................................................................................................................... 4 
REVISION HISTORY............................................................................................................. 5 
LIST OF ABBREVIATIONS .................................................................................................. 6 
1 
INTRODUCTION ................................................................................................... 8 
2 
STUDY DETAILS .................................................................................................. 9 
2.1 
Study Objectives...................................................................................................... 9 
2.2 
Study Design ......................................................................................................... 10 
2.3 
Determination of Sample Size ............................................................................... 14 
2.4 
Randomization....................................................................................................... 15 
2.5 
Blinding ................................................................................................................. 15 
3 
DATA ANALYSIS CONSIDERATION .............................................................. 15 
4 
DEFINITIONS AND DERIVATIONS................................................................. 17 
5 
PRIMARY, SECONDARY AND EXPLORATORY ENDPOINTS ................... 18 
5.1 
Primary Endpoint .................................................................................................. 18 
5.2 
Secondary Endpoints ............................................................................................. 18 
5.3 
Exploratory Endpoints ........................................................................................... 18 
6 
ANALYSIS POPULATION AND TREATMENT GROUPS ............................. 19 
6.1 
Analysis Population ............................................................................................... 19 
6.2 
Treatment Groups .................................................................................................. 19 
7 
ANALYSIS METHODS AND REPORTING DESCRIPTIONS......................... 20 
7.1 
Disposition............................................................................................................. 20 
7.2 
Demographic and Baseline Characteristics ........................................................... 20 
7.3 
Medical History ..................................................................................................... 21 
7.4 
Prior and Concomitant Medications ...................................................................... 21 
7.5 
Protocol Deviation ................................................................................................. 21 
7.6 
Study Drug Exposure ............................................................................................ 22 


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 Page 3 of 31 
 
 
 
7.7 
Efficacy Analysis .................................................................................................. 22 
7.7.1 
Analysis of Primary Endpoint ............................................................................... 22 
7.7.2 
Analysis of Secondary Endpoint(s) ....................................................................... 22 
7.7.3 
Analysis of Exploratory Endpoint(s) ..................................................................... 23 
7.8 
Safety Analysis ...................................................................................................... 25 
7.9 
PK/PD Analysis ..................................................................................................... 29 
8 
POOLED ANALYSES ......................................................................................... 30 
9 
SUBGROUP ANALYSES .................................................................................... 30 
10 
INTERIM ANALYSIS.......................................................................................... 30 
11 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ................................ 30 
12 
REFERENCE ........................................................................................................ 31 
 




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REVISION HISTORY 
 
Version 
Date 
Author 
Reasons 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan  
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                                                           Protocol No. RVLO 121-04 
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CONFIDENTIAL  
 
 
 
 
 
 
 
 
 
 Page 6 of 31 
 
 
 
LIST OF ABBREVIATIONS 
Abbreviation or Special Term 
Explanation 
ADA 
Antidrug Antibody 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CPK 
Creatine phosphokinase 
DSQ 
Dysphagia Symptom Questionnaire 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDN 
Eosinophil derived neurotoxin 
EDP 
Eosinophilic esophagitis diagnostic panel 
EoE 
Eosinophilic esophagitis 
EoEHSS 
Eosinophilic Esophagitis-Histology Scoring System 
eos/hpf 
Eosinophilic count per high-power field 
EREFS 
Eosinophilic Esophagitis-Endoscopic Reference Score 
FAS 
Full Analysis Set 
FSH 
Follicle Stimulating Hormone 
HBsAg 
Hepatitis B surface antigen 
HIV 
Human Immunodeficiency Virus 
ICH 
International Council for Harmonisation 
ICF  
Informed Consent Form 
IV 
Intravenous 
IWRS 
Interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
mTB 
mycobacterium tuberculosis 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 


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Abbreviation or Special Term 
Explanation 
PK 
Pharmacokinetic(s) 
PRO 
Patient-reported outcomes 
PT 
Preferred Term 
RNA 
Ribonucleic acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TLFs 
Tables, Listings, and Figures 
WHO 
World Health Organization 
WHODRUG 
World Health Organization Drug Dictionary 
 
 
 


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1 INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the statistical methods and data handling procedures to be 
followed during the final analyses and reporting of data collected for the study Protocol RVLO 121-04. 
Its purpose is to provide specific guidelines from which the analysis will proceed. It provides in detail the 
algorithms and conventions to be used in the analysis and presentation of the efficacy and safety data for 
this study. Any deviations from these guidelines will be documented in the clinical study report (CSR). In 
the event where discrepancies in statistical analysis may be encountered between the SAP and what is 
described in the study protocol, the SAP will take precedence. 
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol Version 2.0 dated JUL 01, 2021 and CRF Version 4.0 
dated SEP 27, 2022.  
This is a Phase 2a, double-blind, placebo-controlled, multi-center study to assess the efficacy and safety 
of a repeat-dose regimen of IRL201104 in participants with active eosinophilic esophagitis (EoE). 
Eosinophilic esophagitis (EoE) is a chronic and progressive disease of the immune system resulting in 
damage to the esophagus with subsequent loss of function resulting in difficulty swallowing and food 
impaction. If not adequately treated, symptoms and inflammation can progress, leading to scarring of the 
esophagus with irreversible damage. In the United States (US), there are approximately 160,000 patients 
with EoE who are currently treated, of which approximately 50,000 have failed multiple treatments. There 
are currently no therapies approved by the US Food and Drug Administration (FDA) for EoE. 
Eosinophilic esophagitis is caused by the presence of large numbers of eosinophils in the esophagus. The 
production and accumulation of eosinophils may be caused by many factors, such as immune 
hypersensitivity responses to particular foods or environmental proteins (allergens) in affected individuals. 
Eosinophilic esophagitis is characterized by esophageal barrier defects and eosinophilic infiltrates. 
Therapeutic interventions that target reduction in esophageal eosinophils have been shown to correlate 
with symptom improvement. 
IRL201104 is a novel synthetic peptide derived from the active domain of the mTB-secreted protein 
chaperonin 60.1. It is being developed for the relief of symptoms in patients with active EoE. The peptide 
significantly decreases airway eosinophil infiltration in rodent models of allergic and nonallergic 
inflammation. IRL201104 appears to be effective in resetting the immune system from an inflammatory 
state and in inducing inflammatory disease remission in nonclinical models.  


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2 STUDY DETAILS 
2.1 
Study Objectives 
 
The Primary Objective of the study is: 
 
 To assess the efficacy of repeat IV doses of 4 mg and 8 mg IRL201104 or placebo in adult 
participants with EoE after 3 doses administered over 14 days as assessed by the change in peak 
esophageal intraepithelial eosinophilic count per high-power field (eos/hpf) at Week 4. 
 
The Secondary Objectives of the study are: 
 
 To explore the relationship between IRL201104 treatment and change in symptoms of dysphagia 
in adult participants with EoE, using the patient-reported outcomes (PRO) instrument Dysphagia 
Symptom Questionnaire (DSQ). 
 
 To assess the efficacy of repeat IV doses of IRL201104 in adult participants with EoE after 3 doses 
administered over 14 days as assessed by thresholds of histologic response at Week 4. 
 
 To evaluate the safety, tolerability, and immunogenicity of IRL201104 in adult participants with 
EoE. 
 
 
The Exploratory Objectives of the study are: 
 
 To explore the relationship between IRL201104 and change in clinical outcomes assessments, to 
include the PROs PGI-S and PGI-C, and the clinician-reported outcomes EoE-Endoscopic 
Reference Score (EREFS) and EoE Histology Scoring System (EoEHSS). 
 
 To explore the relationship between IRL201104 and the relative change in RNA gene expression 
to include EoE diagnostic panel (EDP) transcriptome signature. 
 
 To explore the relationship between IRL201104 treatment on immune cells and markers of 
inflammation. 
 


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2.2 
Study Design 
This is a Phase 2a, double-blind, placebo-controlled, multi-center study to assess the efficacy and safety 
of a repeat-dose regimen of IRL201104 in participants with active EoE. Eligible participants will undergo 
an up-to-6-week screening period to stabilize current therapy, confirm diagnosis by histologic assessment, 
and other eligibility criteria. Participant compliance to DSQ reporting will be assessed for at least 2 
consecutive weeks prior to randomization. At the end of the screening period, eligible participants will be 
randomized in a 1:1:1 ratio to one of 3 arms, as displayed in Figure 1 
 
 
Arm 1: IRL201104 4 mg IV with endoscopy and esophageal biopsy 2 weeks after last dose (Week 
4). 
 
Arm 2: IRL201104 8 mg IV with endoscopy and esophageal biopsy 2 weeks after last dose (Week 
4). 
 
Arm 3: Placebo IV with endoscopy and esophageal biopsy 2 weeks after last dose (Week 4). 
 
Participants will receive IRL201104 (4 mg or 8 mg IV) or placebo on Days 0, 7, and 14 (3 total doses over 
14 days). Participants will be evaluated for clinical and histologic responses at Week 4. All participants 
will be assessed for safety and continued biomarker sampling through Week 8. 
 
Figure 1: Overview on the Study Procedures 
 
D = day; EGD = esophagogastroduodenoscopy; EOS = End of Study; ICF = informed consent form; IV = intravenous; R = 
randomization; WK = week 
 


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Table 1: Study Schema 
 
The Schedule of Events for the study is 
 
 
 


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2.3 
Determination of Sample Size  
The chosen sample size for this study reflects reasonable clinical expectations of the number of 
participants who could be evaluated in this observational investigation for the purpose of 
obtaining preliminary estimates of histological response to treatment. It also provides for some 
level of accounting of the variability of estimates and the repeatability of results among a small 
group of participants treated in each proposed arm. 
 
Approximately up to 50 participants are planned to be enrolled to yield 36 participants who are 
randomized and complete the final endoscopy at Week 4. 


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2.4 
Randomization 
Approximately 36 participants will be randomized in a 1:1:1 ratio to receive IRL201104  
4 mg or 8 mg or placebo according to a central randomization scheme provided by an interactive 
web response system (IWRS). 
 
Participants who discontinue from the study will be replaced if they did not receive 3 doses of 
study treatment and the final endoscopy as randomized. 
2.5 
Blinding 
This is a double-blind study using open-label investigational product. Pharmacy staff will be 
unblinded for investigational product preparation. Investigators, study team members and study 
participants will be blinded to the dose level given (4 mg, 8 mg, or placebo) and will remain 
blinded throughout the study. 
3 DATA ANALYSIS CONSIDERATION 
Output processing will be undertaken by 
, using SAS 
Version 9.3 (or higher). All Tables, Listings and Figures (TLFs) will be produced in landscape format. In 
general, all data will be listed by the participant and visit. The number of variables presented in each listing 
can vary. Please refer to mock tables, listings and figures.  
 
No formal statistical analysis will be conducted for this study. Summary statistics appropriate for 
categorical and continuous variables will be presented by treatment group and all inferences will be based 
on clinical evaluation of those results. 
 
Data will be summarized by treatment group where appropriate. The total number of participants (N) in 
each treatment group under the stated population will be displayed in the header of summary tables. 
 
Continuous data will be summarized using descriptive statistics for continuous variables. Unless otherwise 
stated, descriptive statistics will include the number of participants (n), mean, standard deviation (SD), 
minimum, median and maximum. When n=0, summary statistics (other than n) will be displayed as blank 
fields. When n=1, only the minimum and maximum will be reported; all other summary statistics will be 
displayed as blank entries. The number of missing values associated with an n that is less than the expected 
n for the visit or time point of interest will also be presented. 
 
For summary tables of categorical variables, counts and percentages will be presented. The count [n] 
indicates the actual number of participants with a particular value of a variable or event, which should 
always be less than or equal to the total number of participants in the respective treatment group [N].  The 
number and percentage of participants with missing values for a variable/category/event will also be 
 


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Percentage will be obtained by: % = (n/N) *100.  
 
All dates will be displayed in DDMMMYYYY format. 
 
Decimal Precision Convention: 
  
The minimum and maximum statistics will be presented to the same number of decimal places as the 
original data. The mean and median will be presented to one more decimal place than the original data, 
whereas the standard deviation will be presented to two more decimal places than the original data. Unless 
otherwise stated, all percentages will be expressed to one decimal place. 
 
Handling of Missing Data: Imputation of missing data will not be performed and will be analyzed as 
missing. To handle missing or partial AEs and concomitant medication dates, the following rules will be 
applied. 
 
For partial Start Dates: 
 
 
1. If the year is unknown, then do not impute the date but assign a missing value. 
 
2. If the month is unknown, then: 
i. 
If the year matches the year of the first dose date, then impute the month and day of the dose 
date. 
ii. 
 
 
3. If the day is unknown, then: 
i. 
If the month and year match the month and year of the first dose date, then impute the day of the 
dose date. 
ii. 
 
 
For partial end dates: 
 
1. If the year is unknown, then do not impute the date but assign a missing value. 
2.
 
3. If the day is unknown, then assign the last day of the month. 
 
After implementing the rules above, to determine whether AEs (or medications) with missing start or stop 
dates are pre-treatment or on/after treatment, the following strategy will be used: 
 
1. If the start date and stop date are both missing, then the most conservative approach is taken and the 
AE (or medication) is considered to be treatment emergent (or concomitant medication). 
 


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2. If the start date is missing but the stop date is not missing and is on or after the date of signed informed 
consent, then the most conservative approach is taken, and the AE (or medication) is considered to be 
treatment emergent (or concomitant medication). 
 
3. If the start date is missing but the stop date is not missing and is before the date of signed informed 
consent, then the AE (or medication) is considered to be before treatment (or prior medication). 
 
4. If the start date is not missing but the stop date is missing, then the most conservative approach is 
taken, and medication is considered to be concomitant while the AE is defined by start date. 
 
5. If the Adverse Event Relationship flag is missing, the relationship for adverse event will be imputed 
and will be considered as Definitely related. If the Adverse Event Severity flag is missing, the severity 
will be imputed and will be considered as severe & undesirable (Grade 3). 
 
 
4 DEFINITIONS AND DERIVATIONS 
 
Baseline: Baseline is defined as the last non-missing value (whether from scheduled or unscheduled visit) 
prior to the first study drug administration. 
Change from Baseline: The change from baseline values at all post-baseline visits will be calculated by 
subtracting the baseline value from the corresponding post-baseline value. 
Change from Baseline = Post baseline value - Baseline value. 
Percent reduction: The percent reduction is the ratio of the reduction in the post-baseline value to its 
baseline value multiplied by 100.  
Percent reduction = 
 
 
End of the Study: The end of the study is defined as the final follow-up visit by the last participant. If the 
study is terminated prematurely, the study ends when the sponsor notifies the investigator in writing that 
the study has finished, or when the last participant attends the final follow-up visit, whichever is later. 
Study Day: This is the number of days from the date of the first study drug administration to a target date: 
Study Day = (Target Date - Date of the first study drug administration) + 1 
(If target date is greater than or equal to the date of the first study drug administration) 
or 
Study Day = (Target Date  Date of the first study drug administration) 
(If target date is less than date of the first study drug administration.) 


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5 PRIMARY, SECONDARY AND EXPLORATORY ENDPOINTS 
 
5.1 
Primary Endpoint 
 
The Primary evaluation parameter is: 
 
 Change from baseline in the peak esophageal intraepithelial eosinophil count at Week 4. 
5.2 
Secondary Endpoints 
 Absolute change in DSQ score from baseline (see DSQ score definition in Section 7.7.2) 
 
 Proportion of participants achieving peak esophageal intraepithelial eosinophil count of < 
15 eos/hpf (Week 4) 
 
 Percent reduction in peak esophageal intraepithelial eosinophil count (eos/hpf) (Week 4) 
 
 The safety endpoints are Monitoring of AEs, physical examinations, vital signs, 
electrocardiograms (ECGs), clinical laboratory tests, and clinical evaluations. Participants 
will be asked to monitor all AEs experienced from the time of informed consent until their 
last study visit. 
5.3 
Exploratory Endpoints 
 
eos/hpf (400×) at Week 4 
 
 Proportion of participants achieving peak esophageal intraepithelial eosinophil 
eos/hpf (400x) at Week 4 
 
 Relative change in the EDP transcriptome signature (Week 4) 
 
 Relative change in immune cells and markers of inflammation pre- and postdose 
administration at screening, baseline, and Weeks 1, 2, 4, 6, and 8. Immune cells and markers 
of inflammation include: immune cell phenotyping (T-subsets, B-subsets, and macrophage 
subsets); A20; serum cytokines; serum IgE/IgG4; and serum eosinophil derived neurotoxin 
(EDN) for eosinophil activation. 
 
 Absolute change in EoE-EREFS (Week 4) 
 


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 Absolute change in EoE grade score from the EoE Histology Scoring System (EoEHSS) 
(Week 4) 
 
 Absolute change in EoE stage score from the EoEHSS (Week 4) 
 
 Proportion of participants with use of rescue medications or procedures (up to Week 8) 
 
 Concentration of functional IRL201104 (up to Week 8) 
 
 Incidence of treatment-emergent antidrug antibody (ADA) responses (Week 8) 
 
 Absolute days without dysphagia. 
 
 Change in PGI-S and PGI-C. 
 
Note that an additional exploratory endpoint: absolute change in severity and/or frequency of EoE 
symptoms other than dysphagia (up to Week 8) was included in the protocol but will not be evaluated 
because the relevant information is being captured only as part of the screening visit evaluation. It was 
inadvertently left in the most current version of the protocol. 
6 ANALYSIS POPULATION AND TREATMENT GROUPS 
6.1 
Analysis Population  
 
Full Analysis Set: The full analysis set (FAS) will consist of all participants randomized at baseline who 
receive at least one dose of treatment and who had a baseline and at least one post-baseline measure of 
the primary or any one of the secondary endpoints. Efficacy evaluations will consider participants 
according to the treatment group to which they were assigned. 
 
Safety Analysis Set: The safety analysis set will include all participants who were documented to have 
taken at least 1 dose of study treatment. Safety evaluations will consider participants according to the 
actual treatment they received. 
6.2 
Treatment Groups 
Participants will be randomized 1:1:1 to 4 mg or 8 mg IRL201104 or placebo respectively. Participants 
will receive a dose of IRL201104 4 mg IV with endoscopy, IRL201104 8 mg IV with endoscopy or 
Placebo IV with endoscopy.  
 
The 3 Arms will be labelled as IRL201104 4 mg IV
IRL201104 8 mg IV  and 
 in 
respective header of TLFs.  


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The below table includes the treatment labeling for all Tables, Listings and Figures (wherever as 
appropriate): 
 
Treatment 
Treatment Label for 
TLF 
IRL201104 4 mg IV with endoscopy and esophageal biopsy 2 weeks after 
last dose (Week 4). 
IRL201104 4 mg IV 
IRL201104 8 mg IV with endoscopy and esophageal biopsy 2 weeks after 
last dose (Week 4). 
IRL201104 8 mg IV 
Placebo IV with endoscopy and esophageal biopsy 2 weeks after last dose 
(Week 4) 
Placebo  
All treatments 
Overall 
 
 
7 ANALYSIS METHODS AND REPORTING DESCRIPTIONS 
7.1 Disposition 
Participant disposition will summarize the number and percentage of participants included in the FAS and 
Safety Analysis Sets, along with a summary of those who completed the study and those who discontinued 
from the study along with the reasons for discontinuation from study by treatment group using FAS. Study 
discontinuation will also be summarized by study week interval (through Week 1, >Week 1 through Week 
2, >Week 2 through Week 4, and >Week 4 through Week 8). 
 
A listing of participant disposition will be also presented describing all details of the reason for 
discontinuation, investigator comments, date and study day from randomization of the discontinuation, 
and any other relevant information, e.g., adverse events or other information that determined the grounds 
for discontinuation. 
7.2 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will include age (years), sex, ethnicity, race, data for 
childbearing potential, height (cm), weight (kg) and BMI (kg/m2) of the participants and will be 
summarized by treatment group for the FAS and repeated for the Safety Analysis Set if the two sets are 
different. 
 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) will be generated for continuous 
variables and the number and percentage of participants in each class of the categorical variables will be 
tabulated. 
 
All individual participant demographic and baseline characteristics data will be listed by treatment group. 


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7.3 Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 
24.0. 
Medical/Surgical history will be summarized by treatment group with the number and percentage of 
participants in each system organ class (SOC), preferred term (PT), and overall, on the Safety Analysis 
Set. Participants will be counted only once at the PT, only once at the SOC, and only once at participant 
level for the counting of total number of participants with a medical history term. 
Listings of medical history events for participants in the Safety Analysis Set will be provided. 
EOE-specific medical history of participants will be listed and summarized separately. 
 
7.4 Prior and Concomitant Medications 
Prior Medications 
Prior medications are those medications that are taken before the ICF signed. i.e., prior medications have 
a stop date/time before ICF signed. Medications stopped on the same day as the ICF signed will be 
considered as prior medication only. 
Concomitant Medications 
Any treatment (including nutritional supplements) or procedure administered from the time of informed 
consent to the end of the final study visit is considered concomitant medication/procedures. This includes 
medications that were started before the study and are ongoing during the study. 
 
Prior and concomitant medication will be categorized by preferred name and ATC level 4 class per 
World Health Organization Drug Dictionary (WHODRUG; Version 01MARCH GLOBAL 2021), will 
be summarized overall for the Safety Analysis Set. If ATC level 4 class is missing, we will use highest 
non missing available ATC level data. The number and percentage of participants using each medication 
will be displayed together with the number and percentage of participants using at least one medication. 
All prior and concomitant medications will be presented in separate listings for the Safety Analysis Set. 
7.5 Protocol Deviation 
A summary table of protocol deviations will be presented by treatment group using the Safety Analysis 
Set. A listing of participants with protocol deviations will be presented along with the specific deviation(s) 
and recorded time/visit of the deviation(s) for each participant. 


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7.6 Study Drug Exposure  
A listing will be provided for study drug administration information, including date and time of 
IRL201104 4 mg and 8 mg and placebo administration using the Safety Analysis Set. That listing will 
also contain, if applicable, relevant information recorded by the investigational site that describes or 
otherwise explains deviations from the protocol not already captured in the protocol deviation listing. 
Such information may be included as part of a post-hoc appendix to the clinical study report (CSR). 
7.7 Efficacy Analysis 
7.7.1 Analysis of Primary Endpoint 
The primary efficacy endpoint is change from baseline in peak esophageal intraepithelial eosinophil count 
at Week 4. 
The change from baseline will be summarized as the n, mean, standard deviation, median, minimum, and 
maximum by the treatment group of interest using the FAS. Analysis will also be done using the SAS. 
7.7.2 Analysis of Secondary Endpoint(s) 
For the secondary endpoints, continuous variables will be summarized using the descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum) for each observed measurement and change 
from baseline at each time point by treatment group while categorical variables will be summarized using 
the counts and percentages as applicable. The FAS will be used for this evaluation. Analysis will also be 
done using the SAS. 
Dysphagia Symptom Questionnaire (DSQ) 
The DSQ is used to measure the frequency and intensity of dysphagia. The DSQ scores can range from 0 
to 84, with a lower score indicating less frequent or less severe dysphagia. 
The questionnaire will be completed by participants daily. Each evening before bedtime, participants will 
be asked to indicate if they experienced dysphagia symptoms (eg, food passing slowly or food sticking) 
during that day. Participants must have experienced dysphagia (response 
on a minimum of 2 days total and completed the DSQ on 
 of days in at least 2 consecutive weeks 
(qualifying period) prior to the baseline visit (Visit 1). Participants must fill out the DSQ at least 5 or more 
days during a given week in order to be compliant. Calculations will be performed on daily ePRO entries 
from the qualifying period prior to baseline, and prior to each study visit during the treatment and follow-
up periods. The DSQ score for the secondary endpoints will be calculated by summing the scores of 
responses to Questions 2 and 3 only. Questions 1 and 4 will be excluded from the DSQ score. 
DSQ score for 14-day period 
 
 


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For each DSQ calculation, the sum of the specified question(s) from each reported daily diary with non-
missing data over the interval being reported will be obtained, dividing this by the number of reported 
daily diaries with non-missing data in that same interval. This result will then be multiplied by the interval. 
This normalizes each DSQ sum over the interval. For the DSQ 
for Question 2, the DSQ score will be set to zero for that day. The DSQ calculations during the interval 
being reported prior to the baseline visit will be defined as the baseline DSQ evaluation. For each 14-day 
period, at least 8 reported diaries are needed to effectuate a DSQ calculation for that period. If at least 8 
diaries are not available, the DSQ result for that 14-day period will be set to missing. 
The absolute change in DSQ score from baseline will be summarized as the n, mean, standard deviation, 
median, minimum, and maximum by treatment group. 
Additionally, exploratory endpoint analysis of absolute days without dysphagia will be summarized as the 
n, mean, standard deviation, median, minimum, and maximum by treatment group. Absolute days without 
dysphagia will be obtained through a counting process of the number of DSQ records between baseline 
 
Esophageal intraepithelial Eosinophil 
The proportion of participants achieving peak esophageal intraepithelial eosinophil count of < 15 eos/hpf 
(Week 4) will be summarized using frequency and percentage. 
Also, percent reduction in peak esophageal intraepithelial eosinophil count (eos/hpf) (Week 4) will be 
summarized as the n, mean, standard deviation, median, minimum, and maximum by treatment group. 
 
Also, exploratory endpoint analysis will be performed for esophageal intraepithelial eosinophil. The 
proportion of participants achieving peak esophageal intraepithelial eosinophil count of 
1 and 
eos/hpf (400×) at Week 4 will be summarized separately using frequency and percentage. 
 
7.7.3 Analysis of Exploratory Endpoint(s) 
The Exploratory endpoints will be summarized using the FAS. 
Patient Global Impression of Severity (PGI-S) 
 
The PGI-S is a PRO measure that uses a verbal rating scale of severity. The PGI-S uses a recall period 
that aligns with the assessment period used for calculating DSQ endpoint scores (ie, DSQ endpoints are 
based on 14-day scores, and the PGI-S is administered on the last day of the 14- day assessment period. 
The PGI-S instructs participants to recall over the past 14 days, such that the anchor covers the same 14-
day period as the 14-day DSQ endpoint score). 
 


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A numeric scoring for the PGI-S would be 0, 1, 2, and 3. Therefore, while the PGI-S will be summarized 
categorically, this measure will be also summarized as change from baseline to post-baseline visits.  
 
Patient Global Impression of Change (PGI-C) 
 
The PGI-C is a PRO measure that assesses change compared with prior to starting treatment and reflects 
-
of overall improvement. 
 
A numeric scoring for the PGI-C it would be -2, -1, 0, 1, 2. Therefore, the PGI-C will be summarized 
using categorical and continuous variable summary statistics.  
 
Eosinophilic Esophagitis-Endoscopic Reference Score (EoE-EREFS) 
 
The EoE-EREFS will be used to measure the endoscopically identified EoE esophageal mucosal 
inflammatory and remodeling features. This instrument includes a total of 17 items related to the presence 
and severity of esophageal features. The specific esophageal features include: rings (absent, mild, 
moderate, severe, not applicable); stricture (yes, no, not applicable); diameter of the stricture (if 
applicable); exudates (absent, mild, severe); furrows (absent, mild, severe); edema (absent, present); crepe 
paper esophagus (absent, present); overall general appearance incorporating all endoscopically identified 
EoE findings (ie, fixed rings, strictures, whitish exudates, furrowing, edema, and crepe paper mucosa).  
In addition, mucosal changes associated with gastroesophageal reflux disease (GERD) will also be 
recorded using the Los Angeles classification system for erosions (No Erosions or LA Classification A, 
B, C, D). The EoE esophageal characteristics will be analyzed based on the EoE-EREFS, a validated 
scoring system for inflammatory and remodeling features of disease using both overall scores and scores 
for each individual characteristic (Hirano 2013). The EoE-EREFS should be performed by the physician 
who performs the endoscopy procedure at the time of the endoscopy. In addition to the local read, images 
will be submitted to the central imaging laboratory for central reading. 
 
The EoE-EREFS will be summarized descriptively by absolute change from baseline to week 4 by 
treatment group. Centrally and individual site locally read data will be summarized both across sites and 
by site. Maximum features (highest score for each feature including both proximal and distal areas) EoE-
EREFS will also be summarized across sites. 
 
Eosinophilic Esophagitis-Histology Scoring System 
 
The EoEHSS is a validated histology scoring system for esophageal biopsies that evaluates 8 features: 
eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated 
intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis 
(absent/present) (Collins 2017). Severity (grade) and extent (stage) of abnormalities will be scored using 
a 4-point scale (0 normal; 3 maximum change). 


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Absolute change in EoE grade score and EoE stage score from the EoE Histology Scoring System 
(EoEHSS) (Week 4) will be summarized separately using descriptive statistics. 
For the exploratory EoE-EREFS and EoEHSS endpoints, a categorical summary of the scores will be 
obtained using frequency count and percentage along with the mean, standard deviation, median, 
minimum, and maximum change from baseline. 
Rescue Medications 
 
Use of rescue medication will be summarized separately. The proportion of participants with use of rescue 
medications or procedures (up to Week 8) will be summarized using frequency and counts. Separate listing 
will be provided. 
ADA (Antidrug antibody) 
 
Antidrug antibody status (negative or positive based on whether results are lower or higher, respectively, 
than the optical density OD cut-off value) will be listed and summarized by treatment group and time 
point at scheduled visit based on the Safety Analysis Set.  
Incidence of treatment-emergent antidrug antibody (ADA) responses (Week 8). This data will be 
summarized using frequency, count and percentage. 
 
7.8 Safety Analysis 
The analysis of safety endpoint variables will include assessments of AEs, vital signs, 12-lead ECGs, 
physical examinations, and clinical laboratory tests. All Safety assessments will be summarized and 
tabulated as appropriate and will be listed by participant as applicable. All safety analyses will be 
performed on Safety Analysis Set. No formal statistical analysis will be performed on safety outcomes. 
Example: The following variables will be evaluated to assess the safety: 
 Adverse Events 
 Clinical Laboratory Data 
 12 Lead Electrocardiogram (12-Lead ECG) 
 Vital Sign measurements 
 Physical Examination 
 
 
 
 


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Adverse Events: 
 
Adverse Events will be coded using (MedDRA version 24.0 or latest) AE coding system for purpose of 
summary tables. Adverse events will be summarized using frequency count and percentage by MedDRA 
SOC and PT. 
 
-
starting or worsening after the first dose of investigational 
product. If the start date is missing, the event is assumed to be treatment emergent. 
 
All AEs and TEAEs during the study will be summarized for the respective treatment group. A 
participant experiencing the same AEs and TEAEs multiple times will be counted only once for that PT. 
Similarly, if a participant experience multiple AEs and TEAEs (preferred terms) within the same SOC 
then that participant will be counted only once for that SOC. When summarizing by severity or 
relationship, only event with highest severity / relationship will be counted. Adverse events will be 
dichotomized into related (definitely, probably, and possibly) and unrelated (unlikely and not related) 
All AEs will be listed in chronological order of the events occurred. 
 
An overview of AE summary will be presented. It will include the following: 
 AEs 
 Serious AEs 
 TEAEs 
 Serious TEAEs 
 Treatment related TEAEs 
 Treatment related Serious TEAEs 
 TEAEs leading to study discontinuation 
 TEAEs leading to death 
 
The incidence and frequency of AEs will be summarized by treatment according to SOC and PT. 
 
Treatment-Emergent Adverse Events (TEAEs) 
A summary of the frequency (number and percentage of participants) of TEAEs will be presented by SOC, 
PT. 
TEAEs will be summarized by treatment, system organ class, preferred term, and severity (mild, moderate, 
severe and undesirable, life-threatening or disabling and death).  
TEAEs will be summarized by treatment, system organ class, preferred term and relationship to the 
study treatment is recorded as related (definitely, probably, and possibly) and unrelated (unlikely and not 
related). The number (%) of participants having relationship for each event and the number of events 
will be presented. 
All AEs (including non-TEAEs) recorded on the CRF will be listed. 


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Adverse Events of Special Interest 
A summary of the frequency (number and percentage of participants) of AESIs will be presented by SOC, 
PT and Listed separately. 
Serious Adverse Events 
SAEs and treatment related SAEs will be summarized separately by SOC and PT. All SAEs recorded on 
the CRF will be listed for all participants. 
Adverse Events Leading to Study Drug Discontinuation 
All AEs leading to discontinuation recorded on the CRF will be listed. 
Deaths 
Deaths occurring in the study will be listed for all participants. 
 
Clinical Laboratory Data 
The Clinical Laboratory test category will include the following assessments: 
 
Hematology: Hemoglobin, Hematocrit, Red blood cells count, white blood cell count, red cell indices, 
Platelet count and differential (neutrophil, lymphocyte, monocyte, eosinophil, and basophil). Visits 
include screening, Day 0, Day 7
56. 
 
Biochemistry: Sodium, Total protein, Total and indirect bilirubin, Potassium, Creatinine, Total 
cholesterol, Chloride, Blood urea nitrogen, Low-density lipoprotein, Carbon dioxide, AST, High-density 
lipoprotein, Calcium, ALT, Triglycerides, Glucose, Alkaline phosphatase, Uric acid, Albumin, Lactate 
dehydrogenase, CPK. Visits include screening, Day 0, Day 7
56. 
 
Coagulation: Prothrombin time and partial thromboplastin time. Visits include screening, Day 0, Day 7, 
56. 
 
Urinalysis: Color, Glucose, Red blood cells, Clarity, Blood, Hyaline and other casts, pH, Bilirubin, 
Bacteria, Specific gravity, Leukocyte esterase, Epithelial cells, Ketones, Nitrite, Crystals, Protein, White 
blood cells, Yeast. Visits include screening, Day 0, Day 7
56. 
 
Serology: HIV-1/2 antibodies, HBsAg Hepatitis, C virus antibodies. Collecting at screening visit only. 
 
Pregnancy: Serum pregnancy tests will be performed for females of reproductive potential at screening, 
after which urine pregnancy tests will be performed. Visits include screening, Day 0 and Day 56. 


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FSH: Follicle stimulating hormone testing will be performed at screening to confirm post-menopausal 
status in female participants who have had at least 12 months without menses. Collecting at screening visit 
only. 
 
All observed and change from baseline results of hematology, biochemistry, and coagulation parameters 
data will be summarized by treatment group, at each scheduled visit using descriptive statistics (n, mean, 
SD, median, minimum, and maximum) for each scheduled study assessment for the Safety Analysis Set. 
 
For urinalysis data, the continuous variables will be summarized by treatment group at each scheduled 
visit using descriptive statistics (n, mean, SD, median, minimum, and maximum).  
 
Individual participant data listings of laboratory results will be presented. Values outside of the 
laboratory's reference range (i.e., those with low or high values) will be flagged in the listings. 
 
The other laboratory tests: FSH, serology and serum pregnancy test will be listed. 
 
12-Lead ECG 
The 12-lead ECG will include the following measurements: Ventricular Rate, PR Interval, RR Interval, 
QRS Duration, QT Interval, QTcF Interval. And it will be summarized for the Safety Analysis Set. 
 
Overall evaluation of safety ECGs will be summarized by treatment group, using frequency counts and 
percentage of participants as normal or abnormal, and the relevance of the abnormality will be summarized 
by clinically significant (CS) or not clinically significant (NCS). 
 
Observed and change from baseline in ECG parameters will be summarized by treatment over each 
scheduled time-point/visit in terms of absolute values using descriptive statistics (n, mean, SD, median, 
minimum, and maximum). 
 
Individual data listings of ECG results along with the Investigator-identified ECG abnormalities will be 
presented for each participant by treatment group. 
 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature) will be 
summarized using the descriptive statistics for each vital sign measurement and change from baseline by 
treatment group, visit and timepoint using the Safety Analysis Set.  
Vital Sign data will be listed by individual time course for each parameter. 
 
 


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Physical Examination 
 
Physical examinations will include examination of the following body systems: head, eyes, ears, nose and 
throat (HEENT); cardiovascular, respiratory, gastrointestinal, dermatological, musculoskeletal, nervous 
systems, lymph nodes and general appearance. 
The physical examination findings (normal, abnormal NCS, abnormal CS) will be summarized using 
counts and percentages by treatment group for each body system using the Safety Analysis Set. 
All physical examination findings will also be listed individually for each participant by treatment. 
 
7.9 PK/PD Analysis 
Concentrations of IRL201104 will be listed by participant and summarized by treatment group and time 
point from predose to Week 8 based on the Safety Analysis Set. 
PK analysis will be detailed in the PK plan. 
 


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8 POOLED ANALYSES 
No pooled analyses will be conducted in this trial. 
 
9 SUBGROUP ANALYSES 
No subgroup analyses will be conducted in this trial. 
 
10 INTERIM ANALYSIS 
No interim analyses will be conducted in this trial. 
 
11 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
The below mentioned endpoints will not be analysed for this study. 
Eosinophilic Esophagitis Diagnostic Panel (EDP) Transcriptome 
 
RNA sequencing and EDP transcriptome will be evaluated. A molecular EDP has been identified that is 
composed of 94 EoE genes and distinguishes EoE from control individuals without esophagitis or with 
GERD (Wen 2013). 
 
The EDP signature will be evaluated in biopsy samples. Using a method reported by (Wen 2015), the EoE 
transcriptome will be determined using the EDP from extracted RNA. 
 
The Relative change will be provided for EDP transcriptome signature by treatment group. 
 
Relative change = {(Post baseline value  Baseline value)/ Baseline value} *100. 
 
Immune Cells and Markers of Inflammation 
 
Immune cells and markers of inflammation include: immune cell phenotyping (T-subsets, B-subsets, and 
macrophage subsets); A20; serum cytokines; serum IgE/IgG4; and serum eosinophil derived neurotoxin 
(EDN) for eosinophil activation. 
Relative change in immune cells and markers of inflammation pre- and post dose administration at 
baseline, and Weeks 1, 2, 4, 6, and 8 will be provided. Separate listing will be provided. 
 
 


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Statistical Analysis Plan  
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12 REFERENCE 
 
1. ICH E9: Statistical Principles for Clinical Trials 
 
2. ICH E3: Structure and Content of Clinical Study Reports. 
 
3. Clinical Study Protocol RVLO 121-04, Version 2.0 / Jul 01, 2021. 
 
4. eCRF Version and Date: Version 1.0 and Sep 29, 2021. 
 
5. Wen T, Dellon ES, Moawad FJ, Furuta GT, Aceves SS, Rothenberg ME. Transcriptome analysis of 
proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitorreversible 
allergic inflammation. J Allergy Clin Immunol 2015 Jan;135(1):187-197. 
 
6. Wen T, Stucke EM, Grotjan TM, et al. Molecular diagnosis of eosinophilic esophagitis by gene 
expression profiling. Gastroenterology 2013;145:1289 1299. 
 
7. Collins MH, Martin LJ, Alexander ES, et al. Newly developed and validated eosinophilic esophagitis 
histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis 
and monitoring. Dis Esophagus 2017 Mar;30(3):1-8. 
 
8. Hirano I, Moy N, Heckman MG, et al. Endoscopic assessment of the oesophageal features of 
eosinophilic oesophagitis: validation of a novel classification and grading system. Gut 2013;62:489
495.