Clinical trial NCT05616728
Conditions: COVID-19
Keywords: SARS-CoV-2, Standard Risk
Sponsor: Enanta Pharmaceuticals, Inc
Start date: 2022-11-10; Completion date: 2023-06-29
Enrollment: 231 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study of EDP-235 in Non-hospitalized Adults with Mild or Moderate COVID-19.

Detailed description:

Arms: arm 1: Once a day orally for 5 days arm 2: Once a day orally for 5 days arm 3: Once a day orally for 5 days
Interventions: intervention 1: EDP-235 intervention 2: Placebo
Intervention descriptions: intervention 1: capsule intervention 2: capsule

Protocol documents:
Prot_002.pdf: 
Clinical Study Protocol  
EDP 235-101 
.13 February 2023 
Enanta Pharmaceuticals, Inc. 
CONFIDENTIAL
 
Page 1 of 65 
 
Protocol Title:  
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel 
Group Study to Evaluate the Effects of EDP-235 in Non-hospitalized 
Adults with Mild or Moderate COVID-19 
Protocol Number:  
EDP 235-101 
Protocol Version 
and Date: 
Version 
, 13 February 2023 
Compound:  
EDP-235 
Study Phase: 
2 
Sponsor: 
Enanta Pharmaceuticals, Inc. 
500 Arsenal St. 
Watertown, MA 02472 
 
CONFIDENTIAL 
Information and data in this protocol contain trade secrets and privileged or confidential 
information, which is the property of Enanta Pharmaceuticals, Inc. No person is authorized to 
make it public without the written permission of Enanta Pharmaceuticals, Inc.  


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SPONSOR SIGNATORY 
 
Study Title 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel 
Group Study to Evaluate the Effects of EDP-235 in Non-hospitalized 
Adults with Mild or Moderate COVID-19 
 
 
Protocol Number 
EDP 235-101 
Protocol Version, 
Date 
13 February 2023 
 
 
Enanta Pharmaceuticals, Inc. 
500 Arsenal St. 
Watertown, MA 02472 


Clinical Study Protocol  
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Enanta Pharmaceuticals, Inc. 
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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATORY ...............................................................................................................2 
SIGNATURE PAGE .......................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
1.1. 
Synopsis ......................................................................................................................11 
1.2. 
Study Schema .............................................................................................................14 
1.3. 
Schedule of Assessments ............................................................................................15 
1.4. 
Laboratory Assessments .............................................................................................21 
2. 
INTRODUCTION ......................................................................................................22 
2.1. 
Overview .....................................................................................................................22 
2.2. 
Background .................................................................................................................22 
2.3. 
Benefit/Risk Assessment ............................................................................................22 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................23 
4. 
STUDY POPULATION .............................................................................................26 
4.1. 
Inclusion Criteria ........................................................................................................26 
4.2. 
Exclusion Criteria .......................................................................................................27 
4.3. 
Lifestyle Considerations .............................................................................................28 
4.4. 
Screen Failures ............................................................................................................28 
4.5. 
Contraception Requirements ......................................................................................28 
5. 
STUDY DESIGN .......................................................................................................30 
5.1. 
Overall Design ............................................................................................................30 
5.2. 
Scientific Rationale for Study Design ........................................................................30 
5.2.1. 
Justification of Study Design ......................................................................................31 
5.2.2. 
Rationale for Endpoints ..............................................................................................31 
5.2.2.1. 
Rationale for Primary Endpoint ..................................................................................31 
5.2.2.2. 
Rationale for Secondary Endpoints ............................................................................32 
5.2.3. 
Rationale for Use of Placebo ......................................................................................32 
5.2.4. 
Rationale for the Participant Population .....................................................................32 
5.2.4.1. 
Participants with Mild and Moderate COVID-19 ......................................................32 


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5.2.4.2. 
Standard Risk Participants ..........................................................................................33 
5.2.4.3. 
Participants With COVID-19 Signs/Symptoms for ≤5 days ......................................33 
5.3. 
Justification of EDP-235 Dose ...................................................................................33 
5.4. 
End of Study Definition ..............................................................................................34 
6. 
STUDY DRUG AND PROHIBITED MEDICATIONS ............................................35 
6.1. 
Study Drug(s) Administered .......................................................................................35 
6.2. 
Administration of Study Drug ....................................................................................35 
6.3. 
Preparation, Handling, Storage, and Accountability ..................................................36 
6.4. 
Assignment to Study Drug..........................................................................................37 
6.5. 
Blinding ......................................................................................................................37 
6.5.1. 
Maintaining the Blind .................................................................................................37 
6.5.2. 
Unblinding ..................................................................................................................37 
6.6. 
Study Drug Compliance .............................................................................................38 
6.7. 
Dose Modification ......................................................................................................38 
6.8. 
Continued Access to Study Drug after the End of the Study .....................................38 
6.9. 
Treatment of Overdose ...............................................................................................38 
6.10. 
Prohibited Medications ...............................................................................................39 
7. 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................39 
7.1. 
Discontinuation of Study Intervention........................................................................39 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................40 
7.3. 
Lost to Follow-up .......................................................................................................40 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................40 
8.1. 
Administrative and Baseline Procedures ....................................................................40 
8.1.1. 
Screening Procedures ..................................................................................................40 
8.1.2. 
Demographics and Medical, Smoking, COVID-19 Disease History .........................41 
8.1.3. 
Prior and Concomitant Medications and Therapies ....................................................41 
8.1.4. 
Physical Examination .................................................................................................41 
8.1.5. 
Height, Weight, and Body Mass Index .......................................................................42 
8.1.6. 
Pregnancy and Menopausal Laboratory Testing ........................................................42 
8.1.7. 
Electronic Device ........................................................................................................42 
8.1.8. 
Other Baseline Procedures ..........................................................................................42 
8.2. 
Efficacy Assessments .................................................................................................43 


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8.2.1. 
SARS-CoV-2 Viral Load and Cell Culture Infectivity Assessments .........................43 
8.2.2. 
COVID-19 Symptom Diary (Patient Reported Outcome [PRO]) ..............................43 
8.2.3. 
COVID-19 Related Medically Attended Visits and Therapies ..................................44 
8.3. 
Safety Assessments .....................................................................................................44 
8.3.1. 
Vital Sign Measurements ............................................................................................44 
8.3.2. 
Electrocardiograms .....................................................................................................45 
8.3.3. 
Clinical Safety Laboratory Assessments ....................................................................45 
8.4. 
Adverse Events ...........................................................................................................45 
8.5. 
Pharmacokinetics ........................................................................................................46 
8.6. 
Genetics ......................................................................................................................46 
9. 
SAFETY MONITORING AND REPORTING .........................................................48 
9.1. 
Definitions ..................................................................................................................48 
9.1.1. 
Pretreatment Events ....................................................................................................48 
9.1.2. 
Adverse Events ...........................................................................................................48 
9.1.3. 
Serious Adverse Events ..............................................................................................49 
9.2. 
Documenting and Reporting of Adverse Events (Including Serious Adverse 
Events) ........................................................................................................................49 
9.2.1. 
Documenting and Reporting Adverse Events .............................................................49 
9.2.2. 
Assigning Attribution of Adverse Events ...................................................................50 
9.2.3. 
Classifying Action Taken with Study Drug................................................................51 
9.2.4. 
Classifying Adverse Event Outcome ..........................................................................51 
9.2.5. 
Documenting and Reporting Serious Pretreatment Events and Serious 
Adverse Events ...........................................................................................................52 
9.2.6. 
Documenting and Reporting of Pregnancy .................................................................53 
9.3. 
Follow-up of Adverse Events and Serious Adverse Events .......................................53 
9.4. 
Data Monitoring Committee .......................................................................................54 


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10. 
STUDY DISCONTINUATION RULES ...................................................................54 
10.1. 
Study Stopping Rules .................................................................................................54 
10.2. 
Study Discontinuation ................................................................................................54 
10.3. 
Site Termination .........................................................................................................55 
10.4. 
Study Termination Procedures ...................................................................................55 
11. 
STATISTICAL CONSIDERATIONS .......................................................................55 
11.1. 
General Considerations ...............................................................................................55 
11.2. 
Sample Size Considerations .......................................................................................56 
11.3. 
Analysis Populations ..................................................................................................56 
11.4. 
Participant Disposition and Demographic Data .........................................................56 
11.5. 
Safety Analyses ..........................................................................................................57 
11.5.1. 
Adverse Events ...........................................................................................................57 
11.5.2. 
Clinical Laboratory Data ............................................................................................58 
11.5.3. 
Vital Sign Measurements ............................................................................................58 
11.5.4. 
Electrocardiograms .....................................................................................................58 
11.5.5. 
Concomitant Medications and Therapies ...................................................................58 
11.6. 
Efficacy and Antiviral Activity Analyses ...................................................................58 
11.6.1. 
Multiplicity Testing Procedure ...................................................................................59 
11.6.2. 
Handling of Missing Data ...........................................................................................59 
11.7. 
Pharmacokinetic Analyses ..........................................................................................59 
11.8. 
Subgroup and Covariate Analyses ..............................................................................59 
12. 
STUDY ADMINISTRATION ...................................................................................60 
12.1. 
Ethical Considerations ................................................................................................60 
12.1.1. 
Ethical Conduct of the Study ......................................................................................60 
12.1.2. 
Ethical Review ............................................................................................................60 
12.1.3. 
Written Informed Consent ..........................................................................................60 
12.1.4. 
Investigator Compliance .............................................................................................61 
12.2. 
Data Collection ...........................................................................................................61 
12.3. 
Study Monitoring ........................................................................................................62 
12.4. 
Quality Assurance .......................................................................................................62 


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12.5. 
Retention of Records ..................................................................................................62 
12.6. 
Information Disclosure ...............................................................................................62 
12.6.1. 
Confidentiality ............................................................................................................62 
12.6.2. 
Publication Policy .......................................................................................................63 
13. 
REFERENCES ...........................................................................................................64 
APPENDIX ....................................................................................................................................65 
APPENDIX 1. CONDITIONS ASSOCIATED WITH HIGH RISK FOR SEVERE 
COVID-19 ..................................................................................................................65 
 
LIST OF TABLES 
Table 1: 
Clinical and SARS-CoV-2 Laboratory Assessments .................................................21 
Table 2: 
Study Drug(s) and Study Arms ...................................................................................35 
Table 3: 
COVID-19 Symptom Diary ........................................................................................43 
Table 4: 
Time Windows for Intensive PK Sampling* ..............................................................46 
Table 5: 
Global Impression Questions ......................................................................................47 
Table 6: 
Options for Action Taken with Study Drug ...............................................................51 
Table 7:  
Classification and Definition of Adverse Event Outcomes ........................................52 
 


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LIST OF ABBREVIATIONS 
3CLpro 
SARS-CoV-2 3-chymotrypsin–like cysteine protease 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the curve 
AUCtau 
area under the curve during the dosing interval 
BMI 
body mass index 
C24 
concentration at 24 hours postdose 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
Ctrough 
trough plasma concentration (measured concentration at the end of a dosing 
interval) 
CRO 
contract research organization 
CYP 
cytochrome P450 
DAIDS 
Division of AIDS 
DMC 
Data Monitoring Committee 
EC 
ethics committee 
EC90 
90% maximal effective concentration 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EOFU 
end of follow-up 
EOS 
end-of-study 
EOT 
end-of-treatment 
 
FDA 
United States Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HCP 
healthcare provider 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
intensive care unit 
IRB 
institutional review board 


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IRT 
interactive response technology 
ITT-c 
intent-to-treat 
IWRS 
Interactive Web Response System 
LLON 
lower limit of normal 
LLOQ 
lower limit of quantitation 
LTFU 
long-term follow-up 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Authorities 
mITT 
modified intent-to-treat 
NP 
nasopharyngeal 
PCR 
polymerase chain reaction 
PE 
physical examination 
 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PRO 
patient-reported outcome 
QD 
once daily 
QRS 
electrocardiographic deflection between the beginning of the Q wave and 
termination of the S wave, representing the time for ventricular depolarization 
QTcF 
QT interval corrected for heart rate according to Fridericia 
RNA 
ribonucleic acid 
RR 
interval between successive heartbeats using the R-wave peaks 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAF 
safety (for the analysis population) 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SCR 
Screening 
SoA 
Schedule of Assessments 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TND 
target not detected 
ULN 
upper limit of normal 
VOC 
variant of concern 
WHO 
World Health Organization 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Name of Sponsor/Company: Enanta Pharmaceuticals, Inc. 
Name of Investigational Product: EDP-235 
Study Title: Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to 
Evaluate the Effects of EDP-235 in Non-hospitalized Adults with Mild or Moderate COVID-19 
Protocol Number: EDP 235-101 
Phase of Development: 2 
Number of Participants Planned: Approximately 200 participants will be randomized. 
Planned Study Population: Male and female non-hospitalized participants aged from 18 to 64 years, 
inclusive, who have mild or moderate COVID-19. 
Investigational Product, Dosage, and Mode of Administration: EDP-235 will be supplied as
 
capsules for oral administration. Participants will receive EDP-235 
, EDP-235 
, or 
placebo administered once daily [QD] for 5 days. 
Duration of Treatment: 5 days 
Objectives 
Endpoints 
Primary Objective 
• To evaluate the safety 
and tolerability of 
EDP-235 
Primary Endpoint 
• Safety and tolerability of EDP-235 compared to placebo as assessed 
by, but not limited to, adverse events (AEs), clinical laboratory results, 
and vital signs through Day 33 
Secondary Objectives 
Secondary Endpoints 
• To evaluate the effect 
of EDP-235 on 
COVID-19 clinical 
symptoms and 
outcomes 
• Time to improvement of targeted COVID-19 signs/symptoms using 
the COVID-19 Symptom Diary through Day 33  
• Proportion of participants with targeted COVID-19 signs/symptom 
improvement using the COVID-19 Symptom Diary through Day 33 
• Change from baseline in targeted COVID-19 signs/symptom score 
using the COVID-19 Symptom Diary through Day 33 
• Proportion of participants with medically attended visits for 
COVID-19 through Day 33 
• Proportion of participants requiring hospitalization (defined as 
≥24 hours of acute care) for COVID-19 through Day 33 
• Proportion of participants who require hospitalization and mechanical 
ventilation (invasive and non-invasive) through Day 33 
• All-cause mortality through Day 33 
• Proportion of participants with any of the following COVID-19 related 
events or all-cause mortality through Day 33 
o complications based on the investigator’s assessment 
o medically attended visits  
o hospitalizations 
o intensive care unit (ICU) admissions 


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o requirement for supplemental oxygen or increased in supplemental 
oxygen requirement 
o requirement for mechanical ventilation (invasive and non-invasive) 
• To evaluate the effect 
of EDP-235 on 
SARS-CoV-2 viral 
load  
• Change from baseline in SARS-CoV-2 RNA levels relative to placebo 
through Day 5 
• Change from baseline in SARS-CoV-2 RNA viral load through 
Day 14 
• Change from baseline in infectious SARS-CoV-2 viral load through 
Day 14 
• AUC of SARS-CoV-2 RNA viral load through Day 14 
• Proportion of participants with SARS-CoV-2 RNA viral load <lower 
limit of quantitation (LLOQ), target not detected (TND) over time 
through Day 14 
• Time to SARS-CoV-2 RNA <LLOQ, TND through Day 33 
• To evaluate the 
pharmacokinetics of 
EDP-235 
• Plasma concentrations of EDP-235 
 


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Study Design: 
This is a randomized, double-blind, placebo-controlled, parallel group, multi-site study in 
non-hospitalized adult patients who test positive for SARS-CoV-2 and have COVID-19 symptom onset 
within 5 days of randomization and who are not at high risk for progression to severe COVID-19.  
Participants can be vaccinated or unvaccinated for COVID-19. Participants with prior COVID-19 
infection <90 days before enrollment and/or who received any COVID-19 vaccine dose <90 days before 
enrollment are excluded from trial participation. 
The study is composed of 4 periods:  
• 
Screening period (D-1 to D1): Screening will occur within a 24-hour period between time of 
signing the informed consent and time of randomization (for those participants meeting study 
criteria). 
• 
Treatment period: The treatment period will begin with the first dose of study drug on Day 1 and 
will conclude with the end-of-treatment (EOT) visit on Day 5.  
• 
Follow-up period: The follow-up period will begin following the last dose of study drug and will 
conclude at the end of follow-up (EOFU) visit on Day 33. 
• 
Long-term follow-up period (LTFU): The LTFU will begin at Day 34 and will concludes at the 
end-of-study (EOS) visit at Week 24. 
The study duration for each participant is up to 24 weeks. 
The design of the study is shown in Section 1.2. Study procedures are detailed in the Schedule of 
Assessments (SoA; Section 1.3). 
Statistical Methods: The primary endpoint of the study is safety and tolerability of EDP-235 compared 
to placebo as assessed by, but not limited to, AEs, clinical laboratory results, and vital signs. All safety 
parameters will be analyzed descriptively. Safety analyses will be based on the Safety Population, 
defined as all randomized participants who receive at least one dose of double-blind investigational 
product. Analysis for the primary objective will be conducted after all randomized subjects complete the 
EOFU visit. 
Analyses of clinical efficacy and antiviral activity will be based on the Intent-to-Treat (ITT-c) 
Population, defined as all participants in the Safety Population with their positive SARS-CoV-2 status 
confirmed by a central RT-PCR viral load at baseline >LLOQ and with at least one post-baseline 
primary efficacy measurement. An analysis of covariance (ANCOVA) model, with treatment group, 
serostatus (i.e., seropositive or seronegative), stratification factors, ie, age (≤50 years or 51 to 64 years) 
and duration of COVID-19 symptoms (≤ 3 days or >3 days and ≤5 days), as factors, and baseline score 
as the covariate, will be used for treatment comparisons. Time to improvement of targeted COVID-19 
signs/symptoms through Day 33 will be summarized graphically using Kaplan-Meier plots and analyzed 


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by the Cox proportional hazard model. The proportion of participants demonstrating targeted 
COVID-19 signs/symptoms improvement through Day 33 will be summarized.  
Plasma pharmacokinetic (PK) data concentration will be analyzed descriptively. PK analyses will be 
based on the PK population, which is defined as all participants in the Safety Population who receive 
active study drug and have measurable plasma concentration of study drug at any timepoint. 
 
Sample size: Approximately 200 participants are planned. This sample size was selected to provide 
adequate safety data and evaluation of antiviral activity, PK, and clinical efficacy endpoints. 
Data Monitoring Committee: Safety data will be reviewed by an independent Data Monitoring 
Committee (DMC) throughout the study. The DMC will be headed by a DMC Chair and will include 
members who are independent from the Sponsor. Procedures for data review, including timing and 
potential outcomes, roles and responsibilities, and interactions with the Sponsor and contract research 
organization (CRO), will be governed by a separate DMC charter. 
 
1.2. 
Study Schema 
 
 
 


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1.3. 
Schedule of Assessments 
Period 
SCR 
Treatment 
Follow-upa 
LT Follow-up Notes 
Day 
-1 to 
1b 
1c 
Rand. 2 
3 
4 
5e 
6 to 
8 
9 
(±1d) 
10 to 
13 
14 
(±1d) 
15 to 
32 
33 
(±1d)e 
Wk 12 
(±7d) 
Wk 24 
(±7d) 
(C=clinic, T=telephone call or telehealth, H=home 
visit by trained health care provider) 
Visit Name 
SCR V1 
T1 
V2 
T2 
V3 
EOT 
 
V4 
 
V5 
 
V6 
EOFU 
V7 
V8 
EOS 
Type of Visit  
C 
C 
T C/Hf T 
C/Hf 
 
C/ Hf 
 
C/ Hf 
 
C/Hf 
C/Hf 
C/Hf 
Eligibility 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent form 
X 
 
 
 
 
 
 
 
 
 
 
 
X* 
 
Informed consent must be obtained before conducting 
any study specific assessments.  
*Participants who completed the study at the EOFU 
(Day 33) visit will be asked to participate in the 
long-term follow-up. If the participant agrees to 
participate, informed consent must be obtained for the 
long-term follow-up. Section 12.1.3 AEs, concomitant 
medications and therapies, and medically attended visits 
should be captured in the eCRF retrospectively for 
subjects who re-enter the study; data will be collected 
starting the next day after the participant completes the 
EOFU visit.  
Inclusion/exclusion review 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Section 4.1 and Section 4.2  
SARS-CoV-2 diagnostic 
test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
The SARS-CoV-2 diagnostic test should be a PCR or 
rapid antigen test approved for use in the country; PCR 
test is preferred. A test is required at Screening if a 
positive result from a SARS-CoV-2 diagnostic test 
performed as part of clinical care within 24 hours prior 
to randomization is not available. If an NP swab is 
collected for the SARS-CoV-2 diagnostic test, one swab 
from the left nostril will be collected. Section 8.1.1  
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.2  
Medical, smoking and 
COVID-19 disease history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.2  
Prior medications and 
therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.3  
Physical examination (PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full PE at Screening. Subsequent PEs performed at the 
discretion of investigator will be targeted to new signs 
and symptoms, including specific assessments for any 
changes from previous status. Section 8.1.4  


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Period 
SCR 
Treatment 
Follow-upa 
LT Follow-up Notes 
Day 
-1 to 
1b 
1c 
Rand. 2 
3 
4 
5e 
6 to 
8 
9 
(±1d) 
10 to 
13 
14 
(±1d) 
15 to 
32 
33 
(±1d)e 
Wk 12 
(±7d) 
Wk 24 
(±7d) 
(C=clinic, T=telephone call or telehealth, H=home 
visit by trained health care provider) 
Visit Name 
SCR V1 
T1 
V2 
T2 
V3 
EOT 
 
V4 
 
V5 
 
V6 
EOFU 
V7 
V8 
EOS 
Type of Visit  
C 
C 
T C/Hf T 
C/Hf 
 
C/ Hf 
 
C/ Hf 
 
C/Hf 
C/Hf 
C/Hf 
Weight, height, BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI=weight (kg)/height (m)2. Section 8.1.5  
Vital signs 
X 
Xd 
 
X 
 
X 
 
X 
 
X 
 
Xg 
 
 
Vital signs include heart rate, respiratory rate, systolic 
and diastolic blood pressure, body temperature, and 
pulse oximetry. Vital signs will be measured after the 
participant has been supine for at least 5 minutes. If 
screening and randomization occur on different calendar 
days, vital signs should be repeated on D1 for baseline 
values. Section 8.3.1  
Pregnancy test 
X 
Xd 
 
 
 
 
 
 
 
 
 
X 
 
 
For female participants of childbearing potential. Urine 
test will be performed at Screening. On D1 and Day 33 
(EOFU), blood will be collected for serum pregnancy 
test to be performed by central laboratory. The 
screening urine pregnancy test results will be used to 
qualify participants at study entry. Section 8.1.6  
Randomization and Study Drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.4  
Dispense study drug and 
study supplies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study supplies may include an electronic device to 
record COVID-19 Symptom Diary and other PRO 
assessments. Section 8.1.7  
Study drug dosing 
 
X* 
X 
X* 
X 
X* 
 
 
 
 
 
 
 
 
*Study drug (EDP-235 or placebo) administered at 
approximately the same time every day (+ 1 hour) at the 
clinic on clinic visit days (D1, D3, and D5). If this is not 
possible, the participant should take the medication at 
home before the visit. Self-administered dosing date and 
time of study drug will be recorded in source based on 
participant recall. Section 6.1  
Study drug accountability 
 
 
 
X 
 
X* 
 
 
 
 
 
X* 
 
 
Study drug accountability by capsule count will be 
completed by study staff. Section 6.2 and Section 6.3 * 
If a participant discontinues treatment before 
completing 5 days of dosing but remains in the study, 
the participant should return study drug for 
accountability at the EOT visit. If a participant 
withdraws from the study before day 5, the participant 


Clinical Study Protocol  
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Period 
SCR 
Treatment 
Follow-upa 
LT Follow-up Notes 
Day 
-1 to 
1b 
1c 
Rand. 2 
3 
4 
5e 
6 to 
8 
9 
(±1d) 
10 to 
13 
14 
(±1d) 
15 to 
32 
33 
(±1d)e 
Wk 12 
(±7d) 
Wk 24 
(±7d) 
(C=clinic, T=telephone call or telehealth, H=home 
visit by trained health care provider) 
Visit Name 
SCR V1 
T1 
V2 
T2 
V3 
EOT 
 
V4 
 
V5 
 
V6 
EOFU 
V7 
V8 
EOS 
Type of Visit  
C 
C 
T C/Hf T 
C/Hf 
 
C/ Hf 
 
C/ Hf 
 
C/Hf 
C/Hf 
C/Hf 
should return study drug for accountability at the EOFU 
visit. 
Study Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
assessments (chemistry, 
hematology, coagulation) 
 
Xd* 
 
X 
 
X 
 
X 
 
X 
 
Xg 
 
 
*Blood samples for select laboratory assessments 
should be taken from all randomized subjects and sent 
to the local laboratory for these identified tests (noted 
with superscript “a” in Table 1), which should be 
assayed and reported in an expedited manner. Review of 
laboratory results is not required prior to randomization 
or dosing. In parallel, hematology, chemistry, and 
coagulation panels should be sent to the central 
laboratory with the other Day 1 samples. 
From D1 through D5, samples should be collected 
predose. See Section 1.4 for the list of laboratory 
assessments. 
Follicle stimulating 
hormone  
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
Follicle-stimulating hormone should be tested in 
selected postmenopausal females. Section 8.1.6  
12-lead ECG (resting) 
 
Xd 
 
 
 
X 
 
 
 
X 
 
Xg 
 
 
Section 8.3.2  
COVID-19 Symptom 
Diary 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
The COVID-19 Symptom Diary will be completed by 
participants during Screening to determine eligibility 
and after randomization, predose on Day 1 as a baseline 
measurement. If Screening and Day 1 occur on the same 
calendar day, the Screening Diary entry will be used as 
the baseline measurement and a separate Day 1 Diary 
will not be collected. In addition, the diary will be 
completed once daily at the same time each day 
±2 hours. Section 8.2.2  
Global Impression 
Questions 
 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
Global impression questions include Return to Usual 
Health, Return to Usual Activities, 
, which will be answered every day from D 1 
to D33 after the COVID-19 symptom diary is 
completed. Section 8.7.2.1  


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Period 
SCR 
Treatment 
Follow-upa 
LT Follow-up Notes 
Day 
-1 to 
1b 
1c 
Rand. 2 
3 
4 
5e 
6 to 
8 
9 
(±1d) 
10 to 
13 
14 
(±1d) 
15 to 
32 
33 
(±1d)e 
Wk 12 
(±7d) 
Wk 24 
(±7d) 
(C=clinic, T=telephone call or telehealth, H=home 
visit by trained health care provider) 
Visit Name 
SCR V1 
T1 
V2 
T2 
V3 
EOT 
 
V4 
 
V5 
 
V6 
EOFU 
V7 
V8 
EOS 
Type of Visit  
C 
C 
T C/Hf T 
C/Hf 
 
C/ Hf 
 
C/ Hf 
 
C/Hf 
C/Hf 
C/Hf 
NP swabs collection 
 
Xd 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
NP swab samples will be collected predose by a study 
nurse or other trained healthcare professional (HCP) at 
the clinic or the participant’s home. Two NP swabs, one 
from the right nostril (primary and first to be collected) 
and one from the left nostril (back-up) will be collected 
at each visit. Section 8.2.1  
SARS-CoV-2 serology 
sample collection 
 
Xd 
 
 
 
 
 
 
 
 
 
X 
 
 
Serology tests are SARS-CoV-2 anti-spike and 
anti-nucleocapsid IgG and IgM antibodies. Section 8.7.1 
Serum/plasma sample 
collection for exploratory 
research 
 
Xd 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
Exploratory biomarkers that will be evaluated include, 
but are not limited to, serum/plasma levels of 
SARS-CoV-2, C-reactive protein, D-dimer, troponin, 
high-sensitivity cardiac troponin, and absolute 
lymphocyte and neutrophil counts.. Section 8.7.1   
Assess ICU admissions, 
hospitalizations, and 
medically attended visits 
 
Continuous from randomization through end of study participation 
Medically attended visits include any unscheduled 
interactions with healthcare professionals other than 
study staff or designees that are not for routine health 
maintenance. Section 8.2.3  
Adverse events 
Continuous from signing of ICF through end of study participationi 
Section 8.4  
Concomitant medications 
and therapies 
Continuous from signing of ICF through end of study participation 
Concomitant medications and therapies will include the 
use of supplemental oxygen, increased use per PI 
judgment and mechanical ventilation. Section 8.1.3  


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Period 
SCR 
Treatment 
Follow-upa 
LT Follow-up Notes 
Day 
-1 to 
1b 
1c 
Rand. 2 
3 
4 
5e 
6 to 
8 
9 
(±1d) 
10 to 
13 
14 
(±1d) 
15 to 
32 
33 
(±1d)e 
Wk 12 
(±7d) 
Wk 24 
(±7d) 
(C=clinic, T=telephone call or telehealth, H=home 
visit by trained health care provider) 
Visit Name 
SCR V1 
T1 
V2 
T2 
V3 
EOT 
 
V4 
 
V5 
 
V6 
EOFU 
V7 
V8 
EOS 
Type of Visit  
C 
C 
T C/Hf T 
C/Hf 
 
C/ Hf 
 
C/ Hf 
 
C/Hf 
C/Hf 
C/Hf 
PK sample collection 
 
X+ 
 
X 
 
X+* 
 
 
 
 
 
X* 
 
 
On D1, collect one postdose plasma PK sample at least 
1 hr after dosing or right before the participant leaves 
the site, whichever is later. On D3 and D5, collect one 
plasma PK sample predose at the same approximate 
time as the NP swab collection. If the participant takes 
the study drug before the study site visit, a PK sample 
should be taken at the same approximate time as the NP 
swab collection. 
+ On D1 and D5, intensive PK sampling will be 
conducted in a subset of participants. Additional PK 
samples will be drawn at 1, 2, 4, and 8 hours postdose. 
See Table 4 for time windows for intensive PK 
sampling. 
* If a participant discontinues treatment before D5 and 
remains in the study, a PK sample should be taken at the 
approximate time as the NP swab at the EOT Visit. If 
the subject discontinues treatment before D5 and does 
NOT remain in the study, a PK sample should be taken 
at the approximate time as the NP swab at the EOFU 
visit (Section 8.5). 
Abbreviations: BMI=body mass index; D=day; ECG=electrocardiogram; EOFU=end of follow-up; EOS=end-of-study; EOT=end-of-treatment; ICF=informed consent form; 
LT=long-term; NP=nasopharyngeal; PGI-C: Patient Global Impression of Change; PGI-S: Patient Global Impression of Severity; PK=pharmacokinetic; SARS-CoV-2=severe 
acute respiratory syndrome coronavirus 2; SCR=screening 
a 
During the Follow-up period (Day 6 through Day 33), if the participant has symptom recurrence or symptom worsening, an unscheduled visit should be done within 2 days of 
patient reported symptom recurrence or worsening. At the unscheduled visit, NP swabs will be collected in addition to clinical assessments deemed necessary by the 
Investigator. 
b 
Screening assessments should occur within 24 hours of randomization. 
c 
D1 assessments are to be done only in randomized participants. Randomization, predose baseline measurements, and dosing must occur on the same calendar date. 
d 
These assessments should be done predose as baseline measurements.  
e 
Participants who discontinue treatment before completing 5 days of dosing should return to the study site within 24 hours of their last dose to complete EOT procedures and 
proceed to complete all follow up assessments 4, 9 and 28 days (EOFU visit) after their last dose of study drug. Participants who discontinue the study before Day 33 (EOFU) 
should return to the study site within 24 hours and no more than 48 hours later to complete the EOFU procedures. 
f 
Visits may be completed at the study site or by study site personnel via a home visit, if feasible.  


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Period 
SCR 
Treatment 
Follow-upa 
LT Follow-up Notes 
Day 
-1 to 
1b 
1c 
Rand. 2 
3 
4 
5e 
6 to 
8 
9 
(±1d) 
10 to 
13 
14 
(±1d) 
15 to 
32 
33 
(±1d)e 
Wk 12 
(±7d) 
Wk 24 
(±7d) 
(C=clinic, T=telephone call or telehealth, H=home 
visit by trained health care provider) 
Visit Name 
SCR V1 
T1 
V2 
T2 
V3 
EOT 
 
V4 
 
V5 
 
V6 
EOFU 
V7 
V8 
EOS 
Type of Visit  
C 
C 
T C/Hf T 
C/Hf 
 
C/ Hf 
 
C/ Hf 
 
C/Hf 
C/Hf 
C/Hf 
g 
These assessments are only required for participants who discontinued the study before Day 5 (ie, do not have an EOT visit before discontinuing the study) or participants who 
discontinued the study after Day 5 and before Day 14. These participants should have an EOFU visit with additional assessments as indicated. 
h 
For the Week 12 and Week 24 assessments, paper questionnaires may be used for the Global Impression Questions 
 and transcribed into the eCRF. 
i 
At Week 12 and Week 24, study staff will ask each participant if they have COVID-19 signs and symptoms and record that information into the AE eCRF. 
 


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1.4. 
Laboratory Assessments 
Table 1: 
Clinical and SARS-CoV-2 Laboratory Assessments 
CHEMISTRY PANEL 
Alanine aminotransferasea 
Albumin, seruma 
Alkaline phosphatase, serum a 
Amylasea 
Aspartate aminotransferasea 
Bilirubin, total and directa 
Blood urea nitrogen  
Blood urea nitrogen /creatinine ratio (calculation) 
Calcium, serum 
Creatine kinase 
Creatinine, seruma 
Glomerular filtration rate, estimatedb 
Uric acid 
Electrolyte panel (sodium, potassium, chloride, 
bicarbonate)a 
Phosphorus 
Gamma glutamyl transferase 
Globulin, total 
Glucose, seruma 
Cholesterol 
Triglycerides 
Lactate dehydrogenase 
Lipase 
Protein, total serum 
COAGULATION PANEL 
International normalized ratioa 
Prothrombin timea 
Activated thromboplastin timea 
PREGNANCY AND OTHER 
ASSESSMENTS  
Urine pregnancy test  
Serum pregnancy test (Day 1 only for central 
laboratory) 
Follicle-stimulating hormone 
SARS-CoV-2 ASSESSMENTS  
SARS-CoV-2 diagnostic test (nasal or 
nasopharyngeal secretions) 
SARS-CoV-2 RNA quantitation of viral load 
(nasopharyngeal secretions) 
SARS- CoV-2 infectious viral load 
(nasopharyngeal secretions) 
Respiratory pathogen panel (nasopharyngeal 
secretions)  
SARS-CoV-2 RNAemia (plasma or serum) 
SARS-CoV-2 nucleocapsid antigenemia 
(plasma or serum) 
SARS-CoV-2 serology (anti-spike and 
anti-nucleocapsid antibodies; serum) 
 
HEMATOLOGY PANEL 
Hemoglobina 
Hematocrita 
Differential white blood cell count, percentage 
and absolute (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils)a 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
Platelet counta 
Red blood cell count 
White blood cell counta 
a 
On Day 1, blood samples for these assessments should be collected and sent to the local laboratory for testing 
and reporting in an expedited manner. In parallel, all required samples as specified in the laboratory manual 
should be sent to the central laboratory. 
b 
Estimated glomerular filtration rate will be calculated using the CKD-EPI equation. 


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2. 
INTRODUCTION 
2.1. 
Overview 
EDP-235 is a novel inhibitor of the SARS-CoV-2 3CL protease. This study will evaluate the 
safety, pharmacokinetics, antiviral activity, and clinical efficacy of EDP-235 in non-hospitalized, 
symptomatic adult participants with mild or moderate COVID-19. 
2.2. 
Background 
In December, 2019, reports of a series of pneumonia cases of unknown etiology emerged from 
Wuhan in the Hubei province of central China.1 On January 7, 2020, Chinese health authorities 
reported that this cluster of cases was associated with a novel coronavirus, 2019-nCoV.2  Based 
on the phylogenetic- and taxonomic-relatedness of 2019-nCoV to the human and bat severe 
acute respiratory syndrome coronaviruses (SARS-CoVs), the virus was designated 
SARS-CoV-2, and the resultant disease termed COVID-19. 
With millions of confirmed cases and deaths worldwide, COVID-19 continues to represent a 
significant medical and social burden to the world community. Despite the availability of 
COVID-19 vaccines, direct acting antiviral agents and monoclonal antibodies for the treatment 
of COVID-19, there is still a need for highly effective antiviral therapies. 
EDP-235 is a highly potent inhibitor of SARS-CoV-2 3CL protease (3CLpro), one of two 
cysteine proteases that are indispensable for SARS-CoV-2 replication. EDP-235 is a 
slow -onset, -slow reversible inhibitor of 3CLpro, with an IC50 (half-maximal inhibitory 
concentration) of 5.8 
 nM. 
 Additional information 
about EDP-235 is available in the Investigator’s Brochure. 
2.3. 
Benefit/Risk Assessment 
EDP-235 exhibits slow-onset, slow-reversible binding to the target protein, is competitive with 
the peptide substrate, and is highly selective for the viral protease over host proteases. EDP-235 
does not induce measurable cytotoxicity in any of the cell culture models used in these studies. 
EDP-235 is an orally administered antiviral agent targeting the SARS-CoV-2 3-chymotrypsin–
like cysteine protease (3CLpro) enzyme. The 3CLpro enzyme represents an attractive antiviral 
target because it is essential in the viral replication cycle (ie, in processing viral polyproteins into 
functional units) and has a low likelihood of off-target activity, owing to the absence of 
recognized human analogues. 
Study EDP 235-101 is the first trial to evaluate the safety, PK, antiviral activity and clinical 
efficacy, of EDP-235 in non-hospitalized adults with mild or moderate COVID-19; 
consequently, the efficacy and safety of EDP-235 in this population are not known. Because 
EDP-235 shares the same mechanism of action as nirmatrelvir, it is possible that participants in 
the present study may have a more rapid clearance of SARS-CoV-2 infection and a reduction in 
the symptoms associated with SARS-CoV-2 infection compared with those who do not receive 


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EDP-235. When nirmatrelvir was evaluated in standard-risk patients with COVID-19, although 
the primary efficacy endpoint of self-reported, sustained alleviation of all symptoms for 
4 consecutive days, as compared to placebo, was not met, a 70% reduction in hospitalization and 
no deaths was observed in the treated population compared to placebo.5 However, it is possible 
that no such effect will be observed. Additionally, participants randomized to the placebo 
treatment group will not be expected to derive any such benefit. 
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary Objective 
• To evaluate the 
safety and 
tolerability of 
EDP-235 
Primary Endpoint 
• Safety and tolerability of EDP-235 compared to placebo as 
assessed by, but not limited to, adverse events (AEs), clinical 
laboratory results, and vital signs through Day 33 
Secondary Objectives Secondary Endpoints 
• To evaluate the 
effect of EDP-235 
on COVID-19 
clinical symptoms 
and outcomes 
• Time to improvement of targeted COVID-19 signs/symptoms 
using the COVID-19 Symptom Diary through Day 33 
• Proportion of participants with targeted COVID19 
signs/symptom improvement using the COVID-19 Symptom 
Diary through Day 33 
• Change from baseline in targeted COVID-19 signs/symptom 
score using the COVID-19 Symptom Diary through Day 33 
• Proportion of participants with medically attended visits for 
COVID-19 through Day 33 
• Proportion of participants requiring hospitalization (defined as 
≥24 hours of acute care) for COVID-19 through Day 33 
• Proportion of participants who require hospitalization and 
mechanical ventilation (invasive and non-invasive) through 
Day 33 
• All-cause mortality through Day 33 
• Proportion of participants with any of the following COVID-19 
related events or all-cause mortality through Day 33 
o complications based on the investigator’s assessment 
o medically attended visits  
o hospitalizations 
o intensive care unit (ICU) admissions 
o requirement for supplemental oxygen or increased in 
supplemental oxygen requirement 
o requirement for mechanical ventilation (invasive and non-
invasive) 
• To evaluate the 
effect of EDP-235 
on SARS-CoV-2 
viral load  
• Change from baseline in SARS-CoV-2 RNA levels relative to 
placebo through Day 5 
• Change from baseline in SARS-CoV-2 RNA viral load through 
Day 14 


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• Change from baseline in infectious SARS- CoV-2 viral load 
through Day 14 
• AUC of SARS-CoV-2 RNA viral load through Day 14 
• Proportion of participants with SARS-CoV-2 RNA viral load 
<LLOQ, target not detected (TND), over time through Day 14 
• Time to SARS-CoV-2 RNA <LLOQ, TND through Day 33 
• To evaluate the 
pharmacokinetics 
of EDP-235 
• Plasma concentrations of EDP-235 


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4. 
STUDY POPULATION 
Approximately 200 participants are planned to be randomized into this study. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
4.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age and Sex 
1. Male or female individuals who are 18 to 64 years of age, inclusive, at the Screening visit. 
Type of Participant and Disease Characteristics 
2. Tested positive for SARS-CoV-2 ≤24 hours before randomization by a diagnostic test 
approved for use in the country (PCR or rapid antigen test). 
3. Initial onset of COVID-19 symptoms ≤5 days before randomization and at least 2 of the 
following signs/symptoms attributable to COVID-19 present and one of at least moderate 
severity at Screening as reported by the participant in the COVID-19 Symptom Diary: 
Stuffy or runny nose, sore throat, shortness of breath (difficulty breathing), cough, low 
energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or 
feverish, nausea. 
Contraceptive Requirements 
4. Female participants: Heterosexually active female participants of childbearing potential 
must agree to use 2 effective birth control methods for the duration of the study and for 
30 days after the last dose of study drug (Section 4.5). 
5. Male participants: Heterosexually active male participants and their female partners of 
childbearing potential must agree to use 2 effective birth control methods for the duration 
of the study and for 90 days after the last dose of study drug (Section 4.5). 
Informed Consent 
6. Capable of giving signed informed consent as described in Section 12.1.3, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
Other Inclusion Criteria 
7. Willing and able to adhere to the study assessments, visit schedules, prohibitions, and 
restrictions, as described in the protocol. 


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4.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Prior SARS-CoV-2 infection <90 days before enrollment and/or received any COVID-19 
vaccine dose <90 days before enrollment. 
2. Has one or more conditions associated with high risk for severe COVID-19 (see list of 
conditions in Appendix 1). 
3. History of hospitalization for the medical treatment of COVID-19. 
4. Currently hospitalized or anticipated need for hospitalization in the clinical opinion of the 
investigator. 
5. Known medical history of active liver disease (other than nonalcoholic hepatic steatosis), 
including chronic or active hepatitis B (defined as HBsAg-positive) or C (defined as 
detectable HCV RNA) infection, primary biliary cirrhosis, Child-Pugh Class A (mild 
hepatic impairment), B (moderate hepatic impairment) or C (severe hepatic impairment), 
or acute liver failure. 
6. Receiving dialysis or have known moderate to severe renal impairment (ie., eGFR 
<60 mL/min/1.73 m2 within 6 months of the screening visit, using the serum creatinine-
based CKD-EPI formula). 
7. Suspected or confirmed concurrent active systemic infection other than COVID-19 that 
may interfere with the evaluation of response to the study drug, as determined by the 
investigator. 
8. Any comorbidity requiring hospitalization and/or surgery within 7 days before study entry, 
or that is considered life threatening within 30 days before study entry, as determined by 
the investigator. 
9. Known HIV infection with a HIV viral load greater than 400 copies/mL or medication for 
HIV treatment that is prohibited in this study (Section 6.10) based on medical history 
within 6 months before the screening visit. 
10. History of hypersensitivity or other contraindication to any of the components of the study 
drug, as determined by the investigator. 
11. Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior, laboratory abnormality or other finding that, in the opinion of 
the investigator, might confound the results of the study, pose an additional risk in 
administering study drug to the participant, could prevent, limit, or confound the protocol 
specified assessments, or deems the participant unsuitable for the study. 
Prior/Concomitant Medications 
12. Has received or is expected to receive pre-exposure prophylactic SARS-CoV-2 mAb. 
13. Has received or is expected to receive convalescent COVID-19 plasma. 


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Diagnostic Assessments 
16. Oxygen saturation of ≤93% on room air obtained at rest within 24 hours before 
randomization. 
Note: For a potential participant who regularly receives chronic supplementary oxygen 
for an underlying lung condition, oxygen saturation should be measured while on their 
standard home oxygen supplementation. 
Prior/Concurrent Clinical Study Experience 
17. Participating in another interventional clinical study with an investigational agent or 
device, including those for COVID-19, within 30 days or five half-lives of the agent, 
whichever is longer, before signing the ICF. 
Other Exclusion Criteria 
18. Females who are pregnant or breastfeeding. 
4.3. 
Lifestyle Considerations 
There are no lifestyle restrictions for this study. 
4.4. 
Screen Failures 
A screen failure occurs when a participant who has consented to participate in the clinical study 
is not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the CONSORT publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE.  
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 
4.5. 
Contraception Requirements 
A woman of childbearing potential who is sexually active with a male must agree to use two 
effective methods of contraception from the date of Screening until 30 days after her last dose of 
study drug. Effective methods of contraception are defined as follows: 


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A condom for the male partner and at least one of the following for the female participant: 
• Intrauterine device 
• Oral, injectable, implantable, transdermal, or intravaginal hormonal contraceptive 
(Note: hormonal contraception must be associated with the inhibition of ovulation) 
The above does not apply to 1) a female participant who has a vasectomized male partner 
provided that partner is the sole sexual partner of the participant, and the vasectomized partner 
has received medical assessment of surgical success, or 2) a female participant who is of 
nonchildbearing potential (ie, physiologically incapable of becoming pregnant) as defined below: 
• Has had a partial or complete hysterectomy,  
• Has had a bilateral oophorectomy (ovariectomy),  
• Has had a bilateral tubal ligation or fallopian tube inserts, or 
• Is postmenopausal (a total cessation of menses for at least 2 years; participants with a 
cessation of menses up to 2 years and a follicle stimulating hormone [FSH] level of 
>35 mIU/mL will also be considered to be postmenopausal.) 
A male participant who has not had a vasectomy and is sexually active with a woman of 
childbearing potential must agree to use effective contraception from the date of Screening to 
90 days after his last dose of study drug. Effective contraception is defined as a condom and at 
least one of the following for a female partner: 
• Intrauterine device 
• Oral, injectable, implantable, transdermal, or intravaginal contraceptive 
(Note: hormonal contraception must be associated with the inhibition of ovulation). 
Male participants must agree to refrain from sperm donation from the date of Screening until 
90 days after his last dose of study drug. 


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5. 
STUDY DESIGN 
5.1. 
Overall Design 
This is a randomized, double-blind, placebo-controlled, parallel group, multi-site study in 
non-hospitalized adult patients who have mild or moderate COVID-19 and COVID-19 symptom 
onset within 5 days of randomization.  
Participants will be randomized in a 1:1:1 ratio to receive either EDP -235 
, EDP-235 
, or placebo orally once daily for 5 days. Randomization will be stratified by age 
(≤50 years or 51 to 64 years) and the duration of COVID-19 symptoms (≤3 days or >3 days and 
≤5 days). 
The study includes 4 periods:  
• Screening period (D-1 to D1): Screening should occur within a 24-hour period 
between time of signing the informed consent and time of randomization (for 
participants meeting study entry criteria).   
• Treatment period: The treatment period will begin with the first dose of study drug on 
Day 1 and will conclude with the end-of-treatment (EOT) visit on Day 5.  
• Follow-up period: The follow-up period will begin following the last dose of study 
drug and will conclude at the EOFU visit on Day 33 (28 days after the last dose of 
study drug). 
• Long-term follow-up period (LTFU): The LTFU period will begin on Day 34 and end 
at the end of study (EOS) visit at Week 24.  
Participants meeting all study criteria and randomized into the study are considered enrolled.  
Screening and Day 1 should occur at the study site as a clinic visit. All other visits may be 
completed at the study site or via a home visit, if feasible. The total duration of the study is 
24 weeks. 
Participants who completed the study at the EOFU (Day 33) visit will be asked to participate in 
the LTFU. If the participant agrees to participate, informed consent must be obtained for the 
LTFU. AEs, concomitant medications and therapies, and medically attended visits should be 
captured in the eCRF retrospectively for participants who re-enter the study; data will be 
collected starting the day after the participant completes the EOFU visit. 
Safety data will be reviewed by an independent Data Monitoring Committee (DMC) throughout 
the study (see Section 9.4). 
5.2. 
Scientific Rationale for Study Design 
The novel SARS-CoV-2 coronavirus, which is responsible for COVID-19 disease, was first 
reported in Wuhan, China, in December 2019. The virus rapidly spread, and the World Health 
Organization declared a pandemic by March 2020. With millions of confirmed cases worldwide 


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and deaths, COVID-19 continues to represent a significant medical and social burden to the 
world community. Despite the availability of effective COVID-19 vaccines, the duration of 
immunity conferred by vaccine has varied considerably. Moreover, lifelong immunity is 
provided by neither natural infection nor vaccination. Furthermore, the emergence of variants 
and sub-variants with increased transmissibility and immune evasion capacity has been 
associated with new waves of infection worldwide. 
Despite the availability of effective direct acting antiviral agents and monoclonal antibodies for 
the treatment of COVID-19, there is still a need for highly effective therapies. In one study, 
nirmatrelvir/ritonavir failed to demonstrate a clinical benefit with regards to self-reported, 
sustained alleviation of all symptoms in a pivotal phase 2/3 trial in standard risk patients.5 
Currently, no antivirals have received emergency use authorization (EUA) or approval for the 
treatment of COVID-19 in non-hospitalized patients at standard risk for severe disease. 
Therefore, this represents an unmet medical need. Antivirals that have received EUA for the 
treatment of mild to moderate COVID-19 in non-hospitalized subjects include 
nirmatrelvir/ritonavir, remdesivir and molnupiravir.  
5.2.1. 
Justification of Study Design 
Study EDP 235-101 aims to evaluate the safety, pharmacokinetics and antiviral activity and 
clinical efficacy of EDP-235 in outpatient participants with mild to moderate COVID-19 who are 
not at high risk of progression to severe COVID-19. To fully investigate the effects of EDP- 235, 
a double-blind, placebo-controlled study design was selected, where participants will be 
randomized 1:1:1 to receive either EDP-235 
, EDP-235 
, or placebo. Because the 
study will enroll only participants that are not at high risk for severe or critical COVID-19, and 
there is no EUA or approved treatments for this population, use of a placebo-controlled design is 
justified.  
Early in the clinical course, COVID-19 is primarily driven by the replication of SARS-CoV-2. 
Later in the clinical course, the disease appears to be driven by a dysregulated 
immune/inflammatory response to SARS-CoV-2 that leads to tissue damage. Based on this, it is 
anticipated that therapies that directly target SARS-CoV-2 would have the greatest effect early in 
the course of the disease, while immunosuppressive/anti-inflammatory therapies are likely to be 
more beneficial in the later stages of COVID-19. Because the window for optimal intervention 
for SARS-CoV-2 infection may be limited, individuals are eligible for participation in the 
present study if their initial onset of COVID-19 symptoms is ≤5 days before randomization. 
Symptom improvement over time will be assessed using a self-reported questionnaire, in line 
with regulatory guidance.6 Given the risk for disease progression associated with SARS-CoV-2 
infection, several secondary clinical endpoints will be evaluated, including but not limited to 
requirement for hospitalization, requirement for ICU care, and requirement for oxygen 
supplementation. 
5.2.2. 
Rationale for Endpoints 
5.2.2.1. 
Rationale for Primary Endpoint 
The primary endpoint is the safety and tolerability of EDP-235 compared to placebo as assessed 
by, but not limited to, adverse events (AEs), clinical laboratory results, and vital signs. The 


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selection of the safety endpoints is appropriate to generate additional safety information in the 
patients with mild to moderate COVID-19 who are not high risk for progression to severe 
COVID-19. Treatment with antiviral agents targeting the chymotrypsin–like cysteine protease 
enzyme in patients with mild to moderate COVID-19 have yielded a similar safety and 
tolerability profile compared to placebo with regards to incidence of adverse events, grade 3 or 4 
AEs, SAEs (1.6% vs. 6.6%), and adverse events leading to discontinuation of study drug. 
5.2.2.2. 
Rationale for Secondary Endpoints 
Secondary endpoints include those related to antiviral activity and clinical outcomes of 
COVID--19 and safety of EDP -235 treatment. The antiviral activity of EDP-235 on viral 
kinetics over 14 days including SARS-CoV-2 RNA levels and infectious viral load will be 
evaluated. The proportion of participants with viral load below the level of detection will also be 
assessed as a measure of antiviral activity. Antiviral activity endpoints are based on EDP-235 
acting as an inhibitor of the SARS-CoV-2 3CL protease. Exhibiting slow-onset, slow-reversible 
binding to the target protein, it is competitive with the peptide substrate and is highly selective 
for the viral protease over host proteases. In tissue culture models of infection, EDP-235 
consistently demonstrated potent antiviral activity against multiple SARS-CoV-2 clinical isolates 
(EDP-235 Investigator’s Brochure). The antiviral activity of EDP-235 supports the development 
of EDP-235 for treatment of COVID-19. Clinical outcomes, such as time to improvement in 
targeted signs and symptoms, will be evaluated along with the proportion of participants showing 
improvement and those participants requiring additional and/or prolonged medical treatment. 
These endpoints are clinically meaningful measures of the effect of EDP-235 on COVID-19 
disease progression.  
 
5.2.3. 
Rationale for Use of Placebo 
This study will use a matched placebo for EDP-235 to allow for unbiased assessment of the 
clinical safety and efficacy profile of EDP-235. Use of placebo is justified because the approved 
treatments for COVID-19 (full approval, emergency use authorization, or country-specific 
equivalent) are for individuals at high risk of disease progression to severe or critical COVID-19. 
5.2.4. 
Rationale for the Participant Population 
5.2.4.1. 
Participants with Mild and Moderate COVID-19  
Participants who have mild to moderate symptoms of COVID-19 are treated on an out-patient 
basis.  Therefore, evaluation of this population is reasonable regarding disease progression or 
improvement.   


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5.2.4.2. 
Standard Risk Participants 
Participants who are not at high risk for disease progression are included in this study. High risk 
for disease progression (Appendix 1) is defined based on criteria from the Centers for Disease 
Control and Prevention 2020.9 Multiple comorbidities and underlying conditions have been 
associated with a higher risk for severe COVID-19 (ie, infection resulting in hospitalization, 
admission to the ICU, intubation or mechanical ventilation, or death).10 Although high risk 
participants have an increased risk of developing severe COVID-19 disease, standard risk 
participants can also develop severe disease and long-term COVID-19 related complications. Of 
note, in one study, the use of an antiviral agent in standard risk patients with mild or moderate 
COVID-19 was associated with a non-significant 51% relative risk reduction in hospitalization 
or death (treatment arm: 5/576; placebo: 10/569), as well as a 62% reduction in COVID-19-
related medical visits (eg, emergency room, urgent care, hospital admissions, telehealth calls) per 
day relative to placebo (p=0.0228).11 
5.2.4.3. 
Participants With COVID-19 Signs/Symptoms for ≤5 days 
Study participants must have onset of COVID-19 related signs and symptoms within 5 days of 
randomization. The study aims to evaluate participants early in the clinical course of the disease 
when COVID-19 is primarily driven by the replication of SARS-CoV-2 and for which the early 
administration of the study drug is expected to have the greatest impact in lowering viral load 
and preventing further post-infectious inflammatory response to SARS-CoV-2 infection. 
5.3. 
Justification of EDP-235 Dose 
The EDP-235 doses selected for this study are 200 and 400 mg once daily (QD), administered 
with food, orally for 5 days.  These doses were selected based on all relevant available 
nonclinical and clinical data, including repeat-dose toxicology studies, in vitro pharmacology 
studies with EDP-235, and clinical safety and PK data from the first-in-human phase 1 study 
(EDP 235-001). The selected doses are expected to provide exposures in the anticipated 
therapeutic range.  
In Study EDP 235-001, EDP-235 was well tolerated at doses evaluated, including single doses 
up to
 and multiple doses up to 
 once daily for 7 days. 
  
Consistent with the literature for other viral 3CL protease inhibitors, a robust antiviral effect is 
predicted when unbound plasma concentrations are sustained above multiples of the EC90 (ie, 
concentration at which 90% inhibition of viral replication occurs) for the entire dosing interval. 
The unbound target minimum plasma concentration (C24 or Ctrough) to be maintained 
corresponded to the in vitro drug concentration at which 90% inhibition of SARS-CoV-2 viral 
replication is observed. Available data from nirmatrelvir, a drug with a similar mechanism to 
EDP-235 (a SARS-CoV-2 3CLpro protease inhibitor, currently under Emergency Use 
Authorization for subjects infected with SARS-CoV-2 and are at high risk to progression to 


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severe COVID-19), doses leading to significant reduction in death and hospitalization (~90% 
reduction compared to placebo), were associated with PK exposures above the in vitro antiviral 
EC90. 
  
The exposures associated with the selected doses are expected to be safe and efficacious.   
5.4. 
End of Study Definition 
The end of the study is defined as the date when the last participant completes the last visit, 
withdraws consent or is lost to follow-up. 
The participant is considered completing treatment if the participant completed the treatment 
period. The participant is considered completing the study if the participant did not permanently 
discontinue from the study during the duration of the treatment and follow-up periods.  


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6. 
STUDY DRUG AND PROHIBITED MEDICATIONS 
6.1. 
Study Drug(s) Administered 
Table 2: 
Study Drug(s) and Study Arms 
Study Drugs 
 
 
Intervention Label 
EDP-235 
Placebo to Match EDP-235  
Type  
Drug 
Drug 
Dose Formulation 
Capsule 
Capsule 
Unit Dose Strength(s) 
 
0 mg 
Route of Administration 
Oral 
Oral 
Use 
Experimental 
Placebo 
IMP/NIMP 
IMP 
IMP 
Sourcing 
Provided centrally by the 
sponsor 
Provided centrally by the 
sponsor 
Packaging and Labeling 
Study Arms 
Arm Title 
EDP-235 
EDP-235 
 
Placebo 
Arm Type 
Experimental 
Experimental 
Placebo comparator 
Dosage 
Participants will receive EDP-
235 
 QD on Days 1 to 5 
Participants will receive 
EDP-235 
 QD on Days 1 
to 5 
Participants will receive
 placebo QD 
on Days 1 to 5 
6.2. 
Administration of Study Drug 
Complete instructions for dispensing and administering study drugs are presented in the study 
specific Pharmacy Manual. Study drug will be dispensed on Day 1. Participants will receive 
instructions on study drug storage and dosing. 
Following randomization on Day 1, participants will receive the first dose of EDP-235 or 
placebo orally while at the study site. After the first dose, participants will be instructed to take 
or be administered the study drug orally on each of the 4 subsequent days, at approximately the 
same time every day (±1 hour). 
   


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On Day 3 and/or Day 5, if the participant will have the visit at the study site, the visit should be 
scheduled close to the time the participant normally takes the study drug (± 1 hour) so that it can 
be taken at the site during the visit. On days participants took their study drug at home, 
participants should be asked for the time that dose was self-administered and record it in source 
and the electronic case report form (eCRF). 
If a participant forgets to take their study drug at the scheduled time, the dose should be taken as 
soon as the participant remembers; however, the following rules apply: 
• No more than one dose should be taken on any calendar day and 
• There must be a minimum of 16 hours between doses. 
Site staff will record the time and date of all study drug doses taken at the site. 
The investigator or designee will administer the study drug provided for this study exclusively to 
participants randomized in this protocol. The investigator will not supply study drug to any 
person not authorized to receive it. 
6.3. 
Preparation, Handling, Storage, and Accountability 
Study drug (EDP-235 or placebo) must be dispensed by a licensed pharmacist or other 
authorized personnel with appropriate training.  
Documentation will be maintained at the clinical study site as outlined in the Pharmacy Manual. 
Site staff will maintain adequate records of the receipt and disposition of all study drug shipped 
to and/or procured by the site for this study. 
Unused study drug must not be discarded until the end of the study after full drug accountability 
is performed. Study drug that is dispensed to a participant, but not administered or completely 
ingested by the participant, must be returned to the pharmacy and the amount remaining recorded 
in the source documents. 
In addition, for drug accountability, participants should bring study drug (including empty 
bottles) with them to the study site at each visit. 
Enanta Pharmaceuticals, Inc. will provide instructions for the return or destruction of any unused 
study drug in the study specific Pharmacy Manual. If Enanta Pharmaceuticals, Inc. authorizes 
destruction at the study site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any special 
instructions provided by Enanta Pharmaceuticals, Inc., and, that the destruction was adequately 
documented. 


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6.4. 
Assignment to Study Drug 
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an IWRS. The IWRS will be used to assign investigational product to each participant.  
Eligible participants will be randomized in a 1:1:1 ratio to 5 days of treatment as follows: 
• EDP-235 
, orally QD 
• EDP-235 
, orally QD 
• Placebo, orally QD 
Randomization will be stratified by age (≤50 years or 51 to 64 years) and duration of COVID-19 
symptoms (≤3 days or >3 days and ≤5 days). 
6.5. 
Blinding 
6.5.1. 
Maintaining the Blind 
The study will be double-blinded, meaning that the participants, investigators, and site staff will 
be blinded to treatment assignment until the completion of the study. All study personnel will be 
blinded to treatment assignment except for the following individuals:  
• Unblinded Enanta representatives/unblinded 
 statistician not associated with the day-
to-day conduct of the study as outlined in a separate DMC charter 
• Unblinded members of the DMC for purposes of unblinded data review 
• Unblinded Drug Supply Chain personnel for the purpose of monitoring drug supplies 
• Unblinded Enanta representatives, 
 Medical Safety Services, 
, and Regulatory Affairs representatives when required to 
satisfy regulatory reporting requirements 
 
• Bioanalytical laboratory for the purpose of measuring drug concentrations 
During the study, investigators, site personnel, and blinded contract research 
organization/Sponsor staff will not have access to results for individual participants that could 
impact clinician assessments, including results for SARS-CoV-2 viral load, respiratory pathogen 
panel testing, certain biomarkers, and PK. 
6.5.2. 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will use the IWRS process which will allow the investigator to 
have immediate access to the unblinding system. 
Unblinding of individual participant treatment by the investigator should be limited to medical 
emergencies or urgent clinical situations in which knowledge of the participant’s study treatment 
is necessary for clinical management. In situations where the urgency of the case requires 
immediate action, investigators should use their best judgment, based on the nature and urgency 


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of the clinical situation, and proceed with unblinding. In emergency situations, the decision to 
unblind resides solely with the investigator. 
Once a participant’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the 
 Medical Monitor should be notified within 24 hours of unblinding of 
the treatment and should inform the Sponsor's Medical Monitor. Information relating to 
unblinding (eg, the reason, date) should be clearly recorded in the participant’s study file. 
 Medical Monitor 24-Hour Safety Hotline for Protocol Inquiries 
Europe, Middle East and Africa (EMEA) and Asia-Pacific (APAC) 
 
United States 
Latin America 
 
 Medical Safety Services will unblind any SAE reports in 
compliance with regulatory reporting requirements. In addition, Enanta Pharmaceuticals, Inc. 
may unblind individual participants at any time for matters relating to safety concerns. 
6.6. 
Study Drug Compliance 
Both accountability and study drug compliance will be reviewed at each study site visit as 
indicated in the SoA (Section 1.3). The number of capsules will be counted, and the site staff will 
ask the participants why any doses were missed and document in source, if applicable. Any 
potential reasons for lack of compliance with dosing will be monitored and followed up by the 
site staff. Compliance assessment may be completed at the study site or by a study site personnel 
via a home visit. 
For any participant considered to demonstrate continued noncompliance of study drug dosing 
despite continued educational efforts, the investigator should contact 
 the Sponsor’s 
Medical Monitor to discuss possible discontinuation of the participant from the study. 
6.7. 
Dose Modification 
Dose modifications are not permitted for participants in this study. 
6.8. 
Continued Access to Study Drug after the End of the Study 
There is no continued access to study drug after the end of the study. 
6.9. 
Treatment of Overdose 
In this study, an overdose is the receipt of any number of capsules greater than the number of 
capsules to be taken as outlined in the pharmacy manual. 
No specific information is available on the treatment of overdose. 
Decisions regarding dose interruptions will be made by the investigator in consultation with the 
 Medical Monitor and Sponsor Medical Monitor based on the clinical evaluation of the 
participant. 


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6.10. 
Prohibited Medications 
The following treatments will be prohibited from the first dose of study drug on Day 1 through 
Day 33 or early termination: 
• SARS-CoV-2 vaccines 
• COVID-19 therapeutics, including all therapies intended for treatment of COVID-19; 
therapies to manage the symptoms of COVID-19 will be allowed 
• Convalescent COVID-19 plasma 
• All non-study investigational agents including devices. 
7. 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
In cases of early discontinuation of study drug or early discontinuation/withdrawal from the 
study, the reason for early discontinuation/withdrawal/lost to follow-up of any participant from 
the study must be documented in source and on the appropriate eCRF.  
7.1. 
Discontinuation of Study Intervention 
It may be necessary for a participant to discontinue study intervention. Reasons for 
discontinuation include but are not limited to the following: 
• AE 
• Withdrawal by participant 
• Protocol deviation (including noncompliance with study drug or study procedures) 
• Pregnancy 
• Study terminated by the Sponsor 
• Other 
If study intervention is discontinued, the participant should, if at all possible, remain in the study 
and enter the follow-up period. See the Schedule of Assessments (Section 1.3) for data to be 
collected at the time of discontinuation of study drug and follow-up for any further evaluations 
that need to be completed. 


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7.2. 
Participant Discontinuation/Withdrawal from the Study 
Participants who discontinue treatment before completing 5 days of dosing will return for an 
end-of-treatment (EOT) visit immediately (ideally within 24 hours of discontinuing treatment) 
and will continue with the post-treatment follow-up assessments in the 28-day follow up period. 
Participants who discontinue the study before Day 33 should return to the study site within 
24 hours and no more than 48 hours later to complete the EOFU procedures. 
If a participant withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected. Enanta Pharmaceuticals, Inc. will retain and continue to use any data collected before 
such withdrawal of consent. 
Randomized participants who withdraw or are withdrawn from the study will not be replaced. 
7.3. 
Lost to Follow-up 
Site staff will attempt to contact any participant who does not return to the site for the EOS visit 
at least three times using the participant’s preferred method of communication, followed by a 
letter requiring delivery notification if the three attempts were unsuccessful. Any participant who 
still cannot be reached following those attempts will be considered lost to follow-up. These 
participants will be included in the PK and safety analysis as indicated in Section 11.3. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study assessments and their timing are summarized in the SoA (Section 1.3). Adherence to the 
study design requirements, including those specified in the SoA, is essential and required for 
study conduct. 
Except for Screening and Day 1, assessments may be completed at the study site or via a home 
visit, if feasible. 
8.1. 
Administrative and Baseline Procedures 
8.1.1. 
Screening Procedures 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm and record eligibility or record reasons for screening failure, 
as applicable. 
Screening procedures will occur after the participant signs and dates an institutional review 
board (IRB)- or ethics committee (EC)-approved ICF and provides authorization to use protected 
health information (see Section 12.1.3). After signing the ICF, screening assessments should be 
performed within 24 hours before randomization. Some procedures performed as part of 
standard-of-care before Screening may be used in determining study eligibility, such as the 
SARS-CoV-2 diagnostic test, provided the procedures met the protocol-specified criteria and 
were performed within the timeframe defined in the SoA (Section 1.3). Review of laboratory 
results is not required prior to randomization or dosing. 


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During the Screening Period, participants will be identified by a unique screening number 
assigned by the clinical site. Participants who have completed screening assessments and are 
eligible for participation in the study will be randomized before the first dose of study drug 
(Day 1) and assigned a unique participant number that will be used to identify the participant 
throughout the study. The first dose of study drug should be administered on the same calendar 
day as randomization.  
8.1.2. 
Demographics and Medical, Smoking, COVID-19 Disease History 
Demographics and baseline characteristics including age, sex, race (if available), ethnicity (if 
available), medical history, COVID-19 disease history, and smoking history will be obtained and 
entered in the respective eCRF as reported at Screening. Significant medical history will be 
obtained by consulting with the participant. As a general rule, all medical events occurring 
within the last 6 months should be recorded. For events that occurred more than 6 months ago 
(and that are not ongoing), only significant or relevant events should be recorded on source and 
entered in the eCRF. All surgeries occurring in adulthood should be recorded in the eCRF, 
whereas surgical methods of contraception, if applicable, should only be documented in the 
source documents. 
If there is a question concerning a participant’s medical history, medical records may be 
requested from the participant’s primary care physician, as appropriate. 
8.1.3. 
Prior and Concomitant Medications and Therapies 
Prior medications and therapies (including diagnostics, surgeries and other interventions) are 
those that end before the first dose of study drug. Concomitant therapies will include medications 
and other therapies (including diagnostics, surgeries and other interventions) ongoing at the first 
dose of study drug or that started any time after the first dose of study drug.  
Any medication or therapy taken within 1 month of signing the ICF and during the study will be 
recorded in source documents and reported on the eCRF with indication, dosage, route of 
administration, and start and stop dates of administration as applicable. Only relevant 
medications and therapies should be recorded if they were discontinued more than 1 month 
before signing the ICF. All prior or concomitant therapeutics/vaccines for COVID-19 including 
supportive therapies to manage COVID-19 signs/symptoms, must be reported. 
All participants will be questioned about concomitant therapies at each study site visit.  
8.1.4. 
Physical Examination 
The investigator or designee will perform the physical examination. A full physical examination 
will be conducted at Screening and will include examination of all pertinent body systems. Any 
subsequent physical examinations performed at the discretion of the investigator will be targeted 
to new signs and symptoms including specific assessments of any changes from previous status. 
Clinically significant abnormalities should be recorded as AEs. 
The physical examination performed at Screening will be used as the baseline assessment. If the 
physical examination was performed on the calendar day before randomization (though within 
the 24-hour period per protocol), a targeted physical examination may be performed on Day 1 if 


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deemed necessary by the investigator due to new signs and symptoms or for specific assessments 
of changes from the previous status. 
8.1.5. 
Height, Weight, and Body Mass Index 
Height and body weight should be obtained with the participant in light clothes and no shoes. 
Height and weight will be documented at Screening only.  
Body mass index will be calculated at Screening (to assess eligibility) according to the following 
equation: BMI = weight (kg)/height (m)2. 
8.1.6. 
Pregnancy and Menopausal Laboratory Testing 
All female participants of childbearing potential will undergo a urine pregnancy test at 
Screening. In addition, on Day 1 and Day 33 (EOT + 4 weeks), a blood sample will be collected 
for a serum pregnancy test to be performed by the central laboratory. The screening urine 
pregnancy test results will be used to qualify participants at study entry. 
To confirm nonsurgical postmenopausal status for women stating that they are amenorrhoeic for 
up to 2 years, documentation of follicle-stimulating hormone (FSH) levels >35 mIU/mL will be 
required. Where such documentation is not available, FSH levels will be measured on Day 1. In 
such participants, urine and serum pregnancy testing should also be performed at 
Screening/Day 1, and these participants will be required to follow appropriate contraceptive 
practices for women of childbearing potential until a confirmatory FSH level is available. 
8.1.7. 
Electronic Device 
During Screening, participants will complete the PRO assessment COVID-19 Symptom Diary on 
an electronic device to assess eligibility. 
Randomized participants will complete the PRO assessments COVID-19 Symptom Diary, 
general impression questions
 on an electronic 
device. PRO assessments completed after randomization, predose on Day 1 will be the baseline 
measurement. For the COVID-19 Symptom Diary, if Screening and Day 1 occur on the same 
calendar day, the Screening Diary entry will be used as the baseline measurement and a separate 
Day 1 Diary will not be collected. 
Participants will receive reminders to complete entries on their own as specified in the SoA. The 
first entry should be completed after randomization but predose on Day 1. Entries should be 
completed at approximately the same time every day. Study staff will review the participant’s 
entries online as specified in the SoA. Study staff should contact participants who are not 
successfully completing Diary and questionnaire entries to retrain or assist participants with any 
technical issues in completing entries to minimize the amount of missing data. 
8.1.8. 
Other Baseline Procedures 
Following randomization on Day 1, participants must complete all baseline assessments before 
receiving the first dose of EDP-235 or placebo. See the SoA (Section 1.3) for a complete list of 
baseline assessments. 


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If Screening and randomization/first dose occur on the same day (Day 1), screening assessments 
for vital signs and pulse oximetry will be used as baseline values. If Screening (Day -1) and 
randomization/first dose (Day 1) occur on different calendar days within a 24-hour period, then 
vital signs and pulse oximetry will be performed again on Day 1 (predose). 
8.2. 
Efficacy Assessments  
8.2.1. 
SARS-CoV-2 Viral Load and Cell Culture Infectivity Assessments 
NP swabs for virology assessments, including for SARS-CoV-2 diagnostic test and viral load 
measurements, will be collected predose at visits specified in the SoA (Section 1.3). Collection, 
storage, and shipping instructions will be provided in the Laboratory Manual. Multiple NP swab 
samples may be collected at each timepoint. With the exception of the SARS-CoV-2 diagnostic 
test that will be performed at the local site laboratory, virology assessments will be analyzed at 
the central laboratory(ies). 
 
8.2.2. 
COVID-19 Symptom Diary (Patient Reported Outcome [PRO]) 
Symptoms of COVID-19 will be reported daily from Days 1 through 33 using the COVID-19 
Symptom Diary.  on an electronic medium. Participants will self-complete the first COVID-19 
Symptom Diary on Day1 before receiving study drug as a baseline measurement. The COVID-
19 symptoms and the response options and scoring are shown in Table 3. 
Table 3: 
COVID-19 Symptom Diary 
Symptoms 
Response Options and Scoring 
What was the severity of your [insert 
symptoms] at its worst over the past 24 hours? 
None = 0 
Mild = 1 
Moderate = 2 
Severe = 3 
1. Stuffy or runny nose 
2. Sore throat 
3. Shortness of breath (difficulty breathing) 
4. Cough 
5. Low energy or tiredness 
6. Muscle or body aches 
7. Headache 
8. Chills or shivering 
9. Feeling hot or feverish 
10. Nausea (feeling like you wanted to throw up) 


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Symptoms 
Response Options and Scoring 
11. How many times did you vomit (throw up) in 
the last 24 hours? 
I did not vomit at all =0 
1 to 2 times = 1 
3 to 4 times = 2 
5 or more times = 3 
12. How many times did you have diarrhea (loose 
or watery stools) in the last 24 hours? 
I did not have diarrhea at all = 0 
1 to 2 times =1 
3 to 4 times = 2 
5 or more times = 3 
13. Rate your sense of smell in the last 24 hours 
My sense of smell is THE SAME AS 
usual = 0 
My sense of smell is LESS THAN  
usual = 1 
I have NO sense of smell = 2 
14. Rate your sense of taste in the last 24 hours 
My sense of taste is THE SAME AS  
usual = 0 
My sense of taste is LESS THAN  
usual = 1 
I have NO sense of taste = 2 
8.2.3. 
COVID-19 Related Medically Attended Visits and Therapies 
COVID-19 related medical attended visits include any unscheduled interactions with healthcare 
professionals other than study staff or designees that are not for routine health maintenance, 
including virtual visits (telemedicine), telephone calls, hospitalization, in-person emergency 
room visits, urgent care, or primary care visits, home healthcare visits, or any other in-person 
visit attended by the participant and a healthcare professional. 
Information on admissions to the Intensive Care Unit (ICU) and hospitalizations will be 
collected, including dates of utilization. Hospitalization is defined as ≥24 hours of acute care in a 
hospital or similar acute care facility, including emergency rooms or facilities specifically 
created to meet hospitalization needs during the COVID-19 pandemic. 
COVID-19 related concomitant therapies, including the requirement for supplemental oxygen or 
invasive or non-invasive mechanical ventilation will be assessed. Increased oxygen 
supplementation should be assessed by the site and documented in source. 
8.3. 
Safety Assessments 
8.3.1. 
Vital Sign Measurements  
Vital signs include heart rate, respiratory rate, systolic and diastolic blood pressure, and body 
temperature. Vital signs will be measured at times shown in the SoA (Section 1.3) after the 
participant has been supine for a minimum of 5 minutes. Pulse oximetry will be performed to 
measure oxygen saturation when vital signs are measured. 


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8.3.2. 
Electrocardiograms  
A resting 12 lead ECG will be performed locally and recorded as specified in the SoA 
(Section 1.3) after the participant has been supine for 5 minutes and before dosing. A standard 
bedside 12 lead ECG machine that calculates heart rate and measures PR, QRS, QT, RR, and 
QTcF intervals will be used.  
On Day 1, before dosing, the ECG must be reviewed by the investigator or designee to confirm 
that no clinically significant cardiac abnormalities are present. The investigator or designee 
should review the ECG for gross abnormalities and interval measurements of concern (absolute 
readings). The clinical interpretation by the investigator or designee of the ECGs should be 
recorded on a hard copy of the ECG (ie, clinically significant or not clinically significant).  
An ECG may be repeated at the discretion of the investigator to address suspected errors in 
performance.  
8.3.3. 
Clinical Safety Laboratory Assessments 
Safety laboratory assessments include chemistry, hematology, and coagulation. Blood and urine 
samples will be collected for analysis of the analytes as shown in Table 1; the SoA (Section 1.3) 
shows the timing of sample collection. Samples will be processed as indicated in the Laboratory 
Manual.  
The investigator must review the laboratory results, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory results must 
be retained with source documents. All laboratory assessments with values considered clinically 
significantly abnormal during participation should be repeated until the values return to normal 
or baseline, are no longer considered clinically significant by the investigator or Medical 
Monitor, or until a pre-defined outcome is reached. 
On Day 1, predose blood samples for select clinical laboratory assessments (Table 1) will be 
performed at the local site laboratory for expedited testing and reporting, and in addition, blood 
samples will be collected and sent to the central laboratory(ies) for baseline measurements. 
Subsequent clinical laboratory evaluations will all be performed by the central laboratory(ies). 
Only central laboratory values will be used for analysis. 
8.4. 
Adverse Events 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE as provided in Section 9.1 of this protocol. All AEs and SAEs 
must be recorded in the source documents and eCRF as described in Section 9.2. At all study site 
visits, the investigator or designee should inquire about the occurrence of AEs. The following are 
examples of open-ended questions that may be used to obtain this information: “How are you 
feeling?”; “Have you had any medical problems recently?”; and “Have you taken any new 
medicines since your last visit/assessment?” All events of SARS-CoV-2 re-infection should be 
recorded. 
It is the investigator’s responsibility to ensure any necessary additional therapeutic measures and 
follow-up procedures are performed and documented in the participant source notes and eCRF.  


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8.5. 
Pharmacokinetics 
Blood (plasma) samples for PK analysis will be collected as outlined in the SoA (Section 1.3). 
Instructions for the collection and handling of PK samples will be provided in the laboratory 
manual. 
The time and date of PK sample collection should be recorded in source and in the eCRF. In 
addition, the site should record the date and time of last dose taken before the PK sample 
collection. 
Time windows for intensive PK sampling are shown in Table 4. 
Table 4: 
Time Windows for Intensive PK Sampling* 
Intensive Plasma PK Sampling Timepoints 
Time Windows 
Predose 
Within 2 hours before dosing 
≤2 hours 
± 5 minutes 
>2 hours to 8 hours 
± 15 minutes 
*Only applies to intensive PK subset on Day 1 and 5 
8.6. 
Genetics 
Genetics are not evaluated in this study. 


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9. 
SAFETY MONITORING AND REPORTING 
9.1. 
Definitions 
9.1.1. 
Pretreatment Events 
A pretreatment event is any event that meets the criteria for an AE/SAE and occurs after the 
participant signs the ICF but before receiving the first administration of study drug. 
9.1.2. 
Adverse Events 
An AE is any event, side effect, or untoward medical occurrence in a participant enrolled in a 
clinical study whether or not it is considered to have a causal relationship to the study drug. An 
AE can therefore be any unfavorable and unintended sign, symptom, laboratory finding outside 
of normal range with associated clinical symptoms or suspected latent clinical symptoms in the 
opinion of the investigator, including those requiring therapeutic intervention, physical 
examination finding, or disease temporally associated with the use of the study drug, whether or 
not the event is considered related to the study drug.  
The occurrence of AEs should be sought by nondirective questioning of the participant at each 
study site visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between study site visits or through physical examination, laboratory 
tests, or other assessments. 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the participant was enrolled in the study are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the study (eg, surgery was performed earlier than 
planned). 


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9.1.3. 
Serious Adverse Events 
An SAE is any untoward medical occurrence at any dose that:  
• Results in death: This includes deaths that appear to be completely unrelated to study 
drug (eg, a car accident)  
• Is a life-threatening event: An event that places the participant at immediate risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe  
• Requires inpatient hospitalization or prolonged hospitalization of an existing 
hospitalization, unless hospitalization is for: 
o Routine treatment or monitoring of the studied indication 
o SARS-CoV-2 disease progression 
o Elective or preplanned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the ICF 
o Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
o Social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• Results in permanent or prolonged (at least 28 days in duration) disability or incapacity  
• Is a congenital anomaly or birth defect in the offspring of a study participant  
• Medically important event: An event that may not be immediately life-threatening, or 
result in death or hospitalization, or require intervention to prevent one of the outcomes 
listed above but is considered medically significant for other reasons. An opportunistic or 
otherwise unusual infection for the investigator’s practice, such as tuberculosis, will be 
considered medically significant.  
The term severe is used to describe the intensity of a specific event (as in mild, moderate, or 
severe); the event itself, however, may be of minor medical significance (such as severe 
headache). This is not the same as serious, which is based on outcome of the event, as described 
above. Seriousness, not intensity, serves as a guide for defining regulatory reporting obligations. 
9.2. 
Documenting and Reporting of Adverse Events (Including Serious 
Adverse Events) 
Adverse events will be evaluated and documented using the National Institute of Allergy and 
Infectious Diseases Division of Aids (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events Corrected Version 2.1 dated July 2017. 
9.2.1. 
Documenting and Reporting Adverse Events 
All AEs reported from the time of informed consent to the EOS visit for each participant will be 
recorded in the participant’s source documents. For participants who did not randomize 
(ie, screen failures), AEs will only be recorded in the source documents. For participants 


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randomized into the study, all AEs will be recorded in the participant’s AE eCRF and the SAE 
form (if applicable). The site should record all AEs regardless of the intensity, seriousness, or 
relationship to study drug. 
If a participant discontinues the study prematurely because of an AE, the specific AE should be 
recorded on the AE eCRF and the participant should be monitored until the event is resolved or 
deemed stable by the investigator. 
Adverse events (serious and nonserious) will be graded in accordance with the DAIDS scale as 
follows:  
• Grade 1 indicates a mild event 
• Grade 2 indicates a moderate event 
• Grade 3 indicates a severe event 
• Grade 4 indicates a potentially life-threatening event 
• Grade 5 indicates death 
Any recurrence of an AE with similar causality to study drug will be reported as recurrence or 
exacerbation of the initial event, and not as a new event. Whenever possible, AEs will be 
reported as a specific diagnosis or syndrome (eg, flu syndrome) rather than as individual signs or 
symptoms. If no specific diagnosis or syndrome is identified, AEs should be reported as separate 
and individual events.  
An AE includes the following:  
• Pre-existing event that increases in frequency or intensity  
• Condition detected or diagnosed during the study period, even though it may have been 
present, in retrospect, before the first dose of study drug 
• Laboratory abnormalities outside of normal limits with associated clinical symptoms or 
suspected latent clinical symptoms in the opinion of the investigator, including those 
requiring therapeutic intervention 
The following events will not be identified as AEs in this study:  
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition 
• Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, etc.); however, 
the condition (the “triggering event”) that leads to the procedure may be an AE  
• Pre-existing conditions present or detected before the first dose of study drug that do not 
worsen 
9.2.2. 
Assigning Attribution of Adverse Events 
The investigator must attempt to determine the cause of each event. Every effort will be made by 
the investigator to assess the relationship of each AE to study drug. To ensure consistency of 
AE/SAE causality assessments, the investigator should apply the following guidelines:  


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• Related: There is an association between the event and the administration of study drug, 
a plausible mechanism for the event to be related to the study drug and causes other than 
the study drug have been ruled out, and/or the event reappeared on re-exposure to the 
study drug.  
• Possibly related: There is an association between the event and the administration of the 
study drug and there is a plausible mechanism for the event to be related to study drug, 
but there may also be alternative etiology, such as characteristics of the participant’s 
clinical status or underlying disease.  
• Unlikely related: The event is unlikely to be related to the study drug and likely to be 
related to factors other than study drug.  
• Not related: The event is related to an etiology other than the study drug (the alternative 
etiology must be documented in the study participant’s medical record). 
9.2.3. 
Classifying Action Taken with Study Drug 
In the case of an AE, the actions that can be taken with study drug by the investigator or designee 
are defined in Table 6. 
Table 6: 
Options for Action Taken with Study Drug 
Classification  
Definition  
Dose not changed 
Study drug dose not changed in response to the adverse event. 
Drug interrupted 
Study drug administration interrupted in response to an adverse event. 
Drug withdrawn 
Study drug administration permanently discontinued in response to an adverse 
event. 
Not applicable 
Action taken regarding study drug administration does not apply. “Not applicable” 
should be used in circumstances when no opportunity to decide whether to 
continue, interrupt, or withdraw treatment was possible such as when the 
investigational treatment had been completed before the adverse event began. 
9.2.4. 
Classifying Adverse Event Outcome 
For every AE/SAE, the possible outcomes of the event and the definition of the outcome are 
shown in Table 7. One outcome must be entered into the appropriate field on the AE and (if 
appropriate) SAE form for each event. 


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Table 7:  
Classification and Definition of Adverse Event Outcomes  
Classification  
Definition  
Recovered/resolved  
Resolution of an adverse event with no residual signs or symptoms  
Recovered/resolved with sequelae  
Resolution of an adverse event with residual signs or symptoms  
Is Recovering/is resolving 
Incomplete improvement to date but adverse event continues to 
improve/resolve and complete resolution is expected over time 
Not Recovered/not resolved 
Either incomplete improvement or no improvement of an adverse 
event, such that it remains ongoing  
Fatal  
Outcome of an adverse event is death. “Fatal” should be used 
when death is at least possibly related to the adverse event 
Unknown  
Outcome of an adverse event is not known (eg, a participant lost to 
follow-up)  
9.2.5. 
Documenting and Reporting Serious Pretreatment Events and Serious Adverse 
Events 
All SAEs that occur after obtaining informed consent through the EOS visit, regardless of 
causality, must be reported by the investigator or designee to 
 Medical 
Safety Services and Enanta Pharmaceuticals, Inc. In addition, all SAEs, including those that 
result in death, that occur after the EOS visit and that are considered related to study drug must 
be reported to 
 Medical Safety Services and Enanta Pharmaceuticals, 
Inc. within 24 hours of learning of its occurrence. Additional details are provided in the Safety 
Management Plan. The SAE form should be sent to 
 Medical Safety 
Services. 
Serious Adverse Event and Pregnancy Reporting 
 
Medical Safety Services 
ICON Safety Fax Lines:  
• North/South America:
  
• Europe/Asia-Pacific: 
  
 Drug Safety Centers: 
• North/South America:
 
• Europe/Asia-Pacific: 
Phone: 
 
All SAEs will be recorded on the SAE form using a recognized medical term or diagnosis that 
accurately reflects the event. All SAEs will be assessed by the investigator for severity, 
relationship to the investigational study drug, and possible etiologies. For the purposes of study 
analysis, if the event has not resolved at the end of the study reporting period, it will be 
documented as ongoing.  
For purposes of regulatory safety monitoring, the investigator is required to follow up the event 
to resolution and report the outcome of the event to 
 Medical Safety 
Services, the 
 Project Manager, and Enanta Pharmaceuticals, Inc. using the SAE form.  


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The investigator or designee is responsible for notifying the Sponsor within 24 hours of 
identifying an SAE, regardless of the presumed relationship to the investigational study drug. 
The SAE form should be completed for new/initial events as well as to report follow-up 
information on previously reported events. The investigator or designee is asked to report 
follow-up information as it becomes available.  
Enanta Pharmaceuticals, Inc. or its designee, as study Sponsor, is responsible for reporting 
suspected, unexpected, serious adverse reactions (ie, SUSARs) involving the study drug to all 
regulatory authorities, and participating investigators, in accordance with United States Food and 
Drug Administration (FDA), International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) guidelines, and/or local regulatory requirements, as 
applicable. 
9.2.6. 
Documenting and Reporting of Pregnancy 
Participants will be counseled to inform the investigator of any pregnancy that occurs during 
study drug and for 90 days after the last dose of study drug. 
If a female participant or the female partner of a male participant becomes pregnant while 
participating in the study, study drug must be permanently discontinued immediately. The 
investigator or designee must notify 
Medical Safety Services 
(Section 9.2.5), the Sponsor’s Medical Monitor, and the 
 Project Manager within 1 business 
day of the sites’ knowledge of the participant’s (or partner’s) pregnancy, by utilizing the 
study-specified pregnancy report form.  
If confirmed to be on active drug, the participant or partner will be followed up until the end of 
the pregnancy and the infant will be followed up for 3 months after the birth, provided informed 
consent is obtained. A separate ICF will be provided to explain these follow-up activities. 
Pregnancy itself does not constitute an AE. 
9.3. 
Follow-up of Adverse Events and Serious Adverse Events 
All AEs (serious and nonserious) will be followed by the investigator until resolution or 
otherwise explained (see Table 7), the participant dies, the event stabilizes and is not expected to 
further resolve with the maximum time limit for stabilization defined as 30 days after the 
occurrence of the event, or when alternative therapy is instituted, whichever occurs first. If 
alternative therapy is instituted, it should be documented. Enanta Pharmaceuticals, Inc. may 
request that the investigator perform or arrange for supplemental measurements or evaluations to 
further clarify the nature of the event. AEs outcomes are determined based on the status at the 
end of the participant’s participation in the study and at the time of database lock.  


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9.4. 
Data Monitoring Committee 
Safety data from this study will be reviewed by a DMC throughout the study. The DMC will be 
headed by a DMC Chair and will include one or more physicians with expertise in SARS-CoV-2, 
consisting of expert(s) independent from the Sponsor. Procedures for data review, including 
timing and potential outcomes, roles and responsibilities, and interactions with the Sponsor 
 will be governed by a separate DMC charter. 
10. 
STUDY DISCONTINUATION RULES 
10.1. 
Study Stopping Rules 
If any of the following events occur, enrollment will be paused pending a full review of all 
available clinical safety data and discussion with the DMC: 
• >1 subject experiences a similar Grade 4 study drug-related or possibly related AE 
• >1 subject experiences a similar study drug-related or possibly related SAE 
Unless the participant's randomization code is unblinded by the Sponsor for clinical reasons, 
only the DMC will have access to unblinded data. 
If >2 subjects experience a similar Grade 3 (severe) clinical or laboratory AE related or possibly 
related to the study drug, a full review of all available AE and relevant laboratory data will take 
place with the DMC within 15 days. 
The study will be terminated or amended to terminate the treatment arm associated with the AE 
of concern if it is deemed, following discussion with the DMC, that the study drug and not 
COVID-19 or another factor was most likely to be accountable. 
10.2. 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the following: 
• Incidence or severity of AEs in this study indicates a potential health hazard to 
participants 
• Participant enrollment is unsatisfactory 
• Data recording is inaccurate or incomplete 
• Investigator does not adhere to the protocol or applicable regulatory guidelines in 
conducting the study 
• Decision from the IRB/EC or regulatory authority to terminate the study 
If the study is suspended or terminated for safety reasons, Enanta Pharmaceuticals, Inc. will 
promptly notify the investigators and will also inform the regulatory authorities of the suspension 
or termination of the study and the reasons for the action. The investigator is responsible for 
promptly informing the IRB/EC and providing the reasons for the suspension or termination of 
the study. 


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10.3. 
Site Termination 
A single site may warrant termination under the following conditions: 
• Failure of the site to enroll participants into the study at an acceptable rate 
• Failure of the site to comply with pertinent governmental regulations as appropriate 
• Submission of knowingly false information from the research facility to the Sponsor, 
Clinical Monitor, or governmental authority 
• Failure to adhere to the protocol requirements 
• Data recording is inaccurate or incomplete 
• Investigator does not adhere to the protocol or applicable regulatory guidelines in 
conducting the study 
10.4. 
Study Termination Procedures 
If the study is terminated by Enanta Pharmaceuticals, Inc. for one of the reasons listed 
previously, or upon completion of the study, the following activities must be conducted by the 
Study Monitor and/or site staff: 
• Return of all study data to Enanta Pharmaceuticals, Inc. or designee 
• Respond to and complete all requests for data clarifications 
• Accountability and final disposition of used and unused study drug 
• Review of site records for completeness 
• Shipment of all applicable biological samples (including PK samples) to the 
designated laboratory 
11. 
STATISTICAL CONSIDERATIONS 
11.1. 
General Considerations 
Detailed methodology for summary and statistical analyses of the data collected in this trial will 
be documented in an Analysis Plan. The Statistical Analysis Plan (SAP) of this study will be 
dated and maintained by the Sponsor Enanta Pharmaceuticals, Inc. or its designee. This 
documentation may modify the plans outlined in the protocol; however, any major modifications 
of the primary endpoint definition and/or its analysis will also be reflected in a protocol 
amendment. 
Continuous endpoints will be summarized using n, mean, standard deviation, median, 
25th quartile, 75th quartile, minimum, and maximum values. Categorical endpoints will be 
summarized by the number of participants meeting the endpoint and the percentage of 
participants out of the appropriate population. The denominator will be displayed when needed. 
Statistical inference will be performed as appropriate. Inferential testing will be conducted using 
a two-sided alpha of 0.05, unless stated otherwise. Stratification factors will include age (≤50 
years or 51 to 64 years) and duration of COVID-19 symptoms (≤3 days or >3 days and ≤5 days) 


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at Screening. Time to event variables will be analyzed using the Kaplan-Meier method. This 
method will be applied to derive the median event time and a confidence interval (CI) for the 
median for each treatment arm. 
Imputation of missing data within efficacy variables and endpoints will be computed according 
to the rules specified in the SAP. 
Any change to the data analysis methods described in the protocol will require an amendment if 
it changes a principal feature of the protocol. Any other change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
clinical study report or SAP. The SAP will be developed and finalized before database lock. 
Changes to the SAP may not be made after unblinding of treatment assignments (after database 
lock). 
11.2. 
Sample Size Considerations 
Approximately 200 participants are planned. This sample size was selected to provide adequate 
safety data and evaluation of antiviral activity, PK, and clinical efficacy endpoints. 
11.3. 
Analysis Populations 
The following analysis populations are planned:  
• Randomized Population: All participants who are randomized. 
• Safety (SAF) Population: All participants in the Randomized Population who receive at 
least one dose of study drug. Participants will be analyzed in the treatment group that 
corresponds to the study drug received during the study. 
• Intent-to-Treat (ITT-c) Population: All participants in the Safety Population with their 
positive SARS-CoV-2 status confirmed by central RT-PCR viral load at baseline >LLOQ 
and with at least one post-baseline primary efficacy measurement. Participants will be 
analyzed as randomized. The ITT-c Population is designated as the primary efficacy 
population. 
• Per Protocol (PP) Population: All participants in the ITT-c Population who receive all 
planned doses of study drug and do not have major protocol deviations that may unduly 
influence efficacy outcome. Participants will be analyzed in the treatment group that 
corresponds to the study drug received during the study. 
• PK Population: All participants in the Safety Population receiving active study drug and 
having measurable plasma concentration of study drug at any timepoint. 
11.4. 
Participant Disposition and Demographic Data 
The number of participants screened, randomized, and in the SAF, ITT-c, PP, and PK 
populations will be summarized using frequencies and percentages. The denominator for the 
calculation of percentages will be from the number of participants randomized.  
The following categories will also be summarized for participant disposition:  
• Completed study drug per the protocol 


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• Discontinued study drug early and the reason for discontinuation  
• Completed the study 
• Discontinued from the study early and the reason for discontinuation  
Participant demographics will be summarized by treatment group for all participants in the SAF, 
modified ITT and PP Population. Appropriate baseline characteristics will be included in 
addition to demographic characteristics. No statistical testing will be performed. 
11.5. 
Safety Analyses 
Safety analyses will be based on the Safety Population, Statistical methods for the safety 
analyses will be descriptive in nature. Safety data, including AEs, SAEs, vital sign 
measurements, concomitant medications, and laboratory values, will be summarized separately 
by treatment group. Change from Baseline will be included in summary tables for vital sign 
measurements and laboratory parameters. Shift tables will also be generated by laboratory 
analyte. All laboratory data will be included in the data listings, and all test values outside the 
normal range will be flagged. 
Analysis for the primary objective will be conducted after all randomized subjects complete the 
EOFU visit. 
11.5.1. 
Adverse Events 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities system 
organ class and preferred term by treatment group. All participants in the SAF Population will be 
included in the summaries. Treatment emergent AEs (TEAEs) are defined as reported AEs that 
first occurred or worsened during the post-Baseline phase compared with Baseline. The 
maximum severity at Baseline will be used as baseline severity. If the maximum severity during 
post Baseline is greater than the maximum baseline severity, then the event is considered 
treatment emergent. No statistical testing will be performed.  
Summaries of AEs will include the following at a minimum:  
• An overall summary of AEs with a line for each of the categories provided below:  
o TEAEs  
o Related TEAEs  
o Maximum severity TEAE  
o TEAEs by severity  
o TEAEs leading to study drug discontinuation  
o AEs leading to death  
o SAEs  
o Related treatment emergent SAEs  


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11.5.2. 
Clinical Laboratory Data 
Laboratory assessments will be reported as mean change from Baseline across scheduled visits, 
and as the incidence rate of shift change from Baseline. Shift from Baseline tables will be 
generated for each treatment group for selected analytes. Laboratory shifts will be displayed as 
treatment-emergent abnormal, high, or low results. The following details the summary types 
where LLN = lower limit of normal and ULN = upper limit of normal.  
For categorical tests: Treatment emergent abnormal is defined as a change from normal at 
Baseline to abnormal at any post-Baseline visit.  
For continuous tests: 
• Treatment-emergent high is defined as a change from a result less than or equal to the 
high limit at Baseline to a value greater than the high limit at any time post-Baseline. 
Results will be reported according to any value greater than the high limit, any value 
greater than 2× ULN and 3× ULN.  
• Treatment-emergent low is defined as a change from a result greater than or equal to the 
low limit at Baseline to a value less than the low limit at any time post-Baseline.  
Results will be reported to any value less than the lower limit, any value less than 
2× LLN and 3× LLN. 
11.5.3. 
Vital Sign Measurements 
The incidence rate of participants with treatment-emergent vital sign changes at any post-
Baseline visit will be summarized. Specific criteria for the classification of treatment emergent 
will be documented in the SAP. Vital sign observed, change, and percentage change will be 
summarized by treatment over visits. Pulse oximetry measurements will be summarized by visit 
and treatment. 
11.5.4. 
Electrocardiograms 
ECG data will be provided in data listings. 
11.5.5. 
Concomitant Medications and Therapies 
The number and percentage of participants taking concomitant medications will be coded 
according to the latest World Health Organization Anatomical Therapeutic Chemical (ATC) 
Classification and World Health Organization preferred term. Concomitant therapies will be 
coded according to Medical Dictionary for Regulatory Authorities (MedDRA). Participants in 
the SAF Population will be summarized by treatment group. 
11.6. 
Efficacy and Antiviral Activity Analyses 
An analysis of covariance (ANCOVA) model, with treatment group, serostatus (i.e., seropositive 
or seronegative) stratification factors, ie, age (≤50 years or 51 to 64 years) and duration of 
COVID-19 symptoms (≤3 days or >3 days and ≤5 days as factors, and baseline score as the 
covariate, will be used for treatment comparisons. 


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The least-squares means and two-sided 95% confidence intervals will be presented for individual 
groups and the difference between groups. 
Categorical variables will be summarized and the between group comparison will be analyzed 
using a Cochran-Mantel-Haenszel test controlling for the stratification factors and serostatus. 
The Kaplan-Meier method will be applied to time to event variables to derive the median event 
time and a CI for the median for each treatment arm. Descriptive statistics on the Kaplan-Meier 
curve will at least include the median and 95% CI. In addition, the between group comparison 
will be conducted using the Cox proportional hazard model adjusted for stratification factors, 
serostatus, and the associated baseline values. The proportion of participants with the events will 
also be summarized.  
11.6.1. 
Multiplicity Testing Procedure 
There is no planned multiplicity control for the analysis of efficacy endpoints. 
11.6.2. 
Handling of Missing Data 
For missing efficacy data other than time to event endpoints, the last observation carried forward 
approach will be used where appropriate. For the time to event endpoints, the censoring will 
occur at the end of the study.  
11.7. 
Pharmacokinetic Analyses 
Summary of plasma PK concentration data will be descriptive in nature. Mean plasma 
concentration time figures may be created for EDP-235, as allowed by the data. Additional 
details will be provided in the SAP. 
11.8. 
Subgroup and Covariate Analyses 
Subgroup analyses will be performed on the primary endpoint using ITT-c Population.   
Subgroup analyses for the primary efficacy endpoint may be considered for the following 
baseline variables, if there are enough participants in the subgroups to support the planned 
analyses: 
• Sex (female vs male); 
• Age (<50 years of age vs 51 to 64 years of age); 
• Region; 
• Duration of COVID-19 symptoms (≤3 days or >3 days and ≤5 days),  
• Serostatus (ie, seropositive or seronegative) 
The subgroup analysis will be based on an ANCOVA model with treatment group, serostatus, 
stratification factor, subgroup, and subgroup by treatment interaction as factors, and baseline 
value as a covariate. 


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12. 
STUDY ADMINISTRATION 
12.1. 
Ethical Considerations 
12.1.1. 
Ethical Conduct of the Study 
The study will be conducted in compliance with this protocol, principles of E6 Good Clinical 
Practice: Consolidated Guidance (ICH-GCP), Declaration of Helsinki, and all applicable local 
laws and regulations governing clinical studies. 
12.1.2. 
Ethical Review 
It is the investigator’s responsibility to ensure that this protocol is reviewed and approved by an 
appropriate IRB/EC that conforms to the regulations set forth in FDA 21 Code of Federal 
Regulations (CFR) Part 56 and other national, country, and regional regulations as applicable. 
The investigator must also submit the ICF, any other written documentation provided to the 
participant, and all advertisements that may be used for study-specific recruitment to the IRB/EC 
for review and approval before commencing study specific assessments. If it is necessary to 
amend the protocol during the study, then it is the responsibility of the investigator to ensure that 
IRB/EC approval is obtained before implementation of the amended procedures. It is also the 
responsibility of the investigator to provide the IRB/EC with any SAE or Investigational New 
Drug safety reports. A copy of the ICF approved by the IRB/EC must be forwarded to Enanta 
Pharmaceuticals, Inc. for regulatory purposes. 
12.1.3. 
Written Informed Consent 
The investigator or designee must explain to each participant the purpose and nature of the study, 
the study procedures, the possible adverse effects, and all other elements of consent as defined in 
21 CFR Part 50, and other applicable national and local regulations governing informed consent.  
Each participant must provide a signed and dated ICF before enrollment into this study. Signed 
consent forms must remain in each participant’s study file and be available for verification by 
study monitors at any time. In accordance with individual local and national participant privacy 
regulations, the investigator or designee must explain to each participant before Screening that 
for the evaluation of study results, the participant’s protected health information obtained during 
the study may be shared with Enanta Pharmaceuticals, Inc. and its designee, regulatory agencies, 
and IRBs/ECs. As the study Sponsor, Enanta Pharmaceuticals, Inc. will not use the participant’s 


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protected health information or disclose it to a third party without applicable participant 
authorization. It is the investigator’s or designee’s responsibility to obtain written permission to 
use protected health information from each participant, or if appropriate, the participant’s legal 
guardian. If a participant or participant’s legal guardian withdraws permission to use protected 
health information, it is the investigator’s responsibility to obtain the withdrawal request in 
writing from the participant or participant’s legal guardian and to ensure that no further data will 
be collected from the participant. Any data collected on the participant before withdrawal will be 
used in the analysis of study results.  
12.1.4. 
Investigator Compliance 
The investigator/institution should conduct the study in compliance with the protocol agreed to 
by the Sponsor and regulatory authorities and which was given approval/favorable opinion by 
the IRB/IEC. The investigator/institution and the Sponsor should sign the protocol, or an 
alternative contract, to confirm agreement. 
The investigator should not implement any deviation from, or changes to, the protocol without 
agreement by the Sponsor and prior review and documented approval/favorable opinion from the 
IRB/IEC of an amendment, except where necessary to eliminate immediate hazard(s) to study 
participants, or when the change involves only logistical or administrative aspects of the study 
(eg, change in monitor, change of telephone number). The investigator should document and 
explain any deviation from the approved protocol.  
12.2. 
Data Collection 
Study data will be entered into an eCRF by site staff. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the participant’s 
eCRF. Participants who did not randomize will not be entered into the clinical database. See 
Section 4.3 for additional details regarding screen failure data collection.  Reasons for screen 
failure will be collected in the interactive response technology (IRT) system. In addition, criteria 
for confirming eligibility will be collected in IRT. Source documentation supporting the clinical 
data should indicate the participant’s participation in the study and should document the dates 
and details of study procedures, AEs, other observations, and participant status. The investigator 
or designated representative should complete the eCRF as soon as possible after information is 
collected. An explanation should be provided for all missing data as required per CRF. 
Assessments that occur due to standard of care are not required to be collected as unscheduled 
data in the eCRF. In addition, it is recommended unscheduled assessments be entered if 
associated with an AE during study conduct before the participant completes the EOS Visit. The 
participant completion date of the study is associated with the last required assessment conducted 
for the EOS Visit. 
After the participant has completed the study, the investigator must review and sign the signature 
page of the eCRF indicating that he or she has reviewed the completed eCRF and pertinent 
clinical data for that participant and that, to the best of his or her knowledge, all data recorded in 
the eCRF accurately reflects the participant’s clinical performance in the study. 


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12.3. 
Study Monitoring 
Representatives of Enanta Pharmaceuticals, Inc., 
, or other designees will monitor this study 
until completion. Monitoring will be conducted through both on-site and remote visits with the 
investigator and site staff as well as any appropriate communications by mail, fax, email, or 
telephone. The purpose of monitoring is to ensure compliance with the protocol and the quality 
and integrity of the data. The Study Monitor will ensure that the investigation is conducted 
according to protocol and regulatory requirements, and as described in the Study Monitoring 
Plan. 
Every effort will be made to maintain the anonymity and confidentiality of all participants during 
this clinical study. However, because of the experimental nature of this treatment, the 
investigator agrees to allow the IRB/EC, representatives of Enanta Pharmaceuticals, Inc., its 
designated agent, and authorized employees of the appropriate regulatory agencies to inspect the 
facilities used in this study and, for purposes of verification, allow direct access to the hospital or 
study site records of all participants enrolled in this study. A statement to this effect will be 
included in the ICF authorizing the use of protected health information. 
12.4. 
Quality Assurance 
At its discretion, Enanta Pharmaceuticals, Inc. or its designees may conduct a quality assurance 
audit of this study. If such an audit occurs, the investigator will give the auditor direct access to 
all relevant documents and will allocate his or her time and the time of his or her site staff to the 
auditor as required. In addition, regulatory agencies may conduct an inspection of this study. If 
such an inspection occurs, the investigator will notify the Sponsor and 
 will allow the 
inspector direct access to all source documents, eCRFs, and other study documentation for 
source data check and/or on-site audit inspection.  
12.5. 
Retention of Records 
The site will retain a copy of all study records in a safe, secure, and accessible location for a 
minimum of 2 years after notification by Enanta Pharmaceuticals, Inc. that the investigations of 
EDP-235 have been discontinued or for 2 years following marketing approval of the drug, after 
which time, Enanta Pharmaceuticals, Inc. will be contacted for instructions on the disposition of 
study materials. Study records will contain all of the appropriate documents as detailed in 
Section 8.0 of the ICH-GCP E6.  
12.6. 
Information Disclosure 
12.6.1. 
Confidentiality 
Participant names or any other identifiers will remain confidential and will not be supplied to 
Enanta Pharmaceuticals, Inc. or its designees. Only participant number and year of birth with age 
will be recorded on the eCRF. If the participant name appears on any other document collected 
(eg, unit discharge summary), it must be redacted before the document is transmitted to Enanta 
Pharmaceuticals, Inc. or its designees. All study findings will be stored in electronic databases. 
As indicated in the ICF, participants will give permission for representatives of the Sponsor, 
regulatory authorities, and the IRB/EC to inspect their medical records to verify the information 
collected. Participants will be informed that all personal information made available for 


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inspection will be handled in the strictest confidence and in accordance with local data 
protection/privacy laws. 
Individual participant medical information obtained during this study is confidential and its 
disclosure to third parties other than those mentioned in the preceding paragraph is prohibited. 
Medical information obtained during this study may be provided to the participant’s personal 
physician or other appropriate medical personnel when required in connection with the 
participant’s continued health and welfare and with the participant’s prior knowledge and 
permission. 
12.6.2. 
Publication Policy 
It is the intention of Enanta Pharmaceuticals, Inc. to publish the results of this study in their 
entirety within a reasonable period of time following conclusion of the study. The Sponsor will 
determine when and where data will be first disclosed.  
All information generated from this study is the proprietary property of Enanta Pharmaceuticals, 
Inc. The Sponsor, Enanta Pharmaceuticals, Inc. reserves the right, among other things, to the 
following: 
• Modify or amend study material to ensure that no confidential or proprietary information 
is disclosed 
• Ensure that the reported data are factually correct 
• Utilize the information generated from or as a result of this study in any manner it deems 
appropriate, including but not limited to regulatory submissions, annual reports, and other 
scientific or business affairs of the company 
• Modify the publication or disclosure or delay it a sufficient time to allow Enanta 
Pharmaceuticals, Inc.to seek patent protection of any invention contained therein. 
 


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13. 
REFERENCES 
1. 
COVID-19 - China. 2020. (Accessed June 23, 2021, at  
2. 
Situation report - 1. Novel Coronavirus (2019-nCoV). 2020. (Accessed 2021, June 23, at  
3. 
Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The 
species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and 
naming it SARS-CoV-2. Nat Microbiol 2020;5:536-44. 
4. 
Naming the coronavirus disease (COVID-19) and the virus that causes it. 2020. 
(Accessed June 23, 2021, at  
5. 
Pfizer_Inc. Pfizer Announces Additional Phase 2/3 Study Results Confirming Robust 
Efficacy of Novel COVID-19 Oral Antiviral Treatment Candidate in Reducing Risk of 
Hospitalization or Death. 2021. 
6. 
FDA. Guidance for Industry: Assessing COVID-19-Related Symptoms in Outpatient 
Adult and Adolescent Subjects in Clinical Trials of Drugs and Biological Products for COVID-
19 Prevention or Treatment. September 2020. 
7. 
Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, 
Nonhospitalized Adults with Covid-19. N Engl J Med 2022;386:1397-408. 
8. 
Ohmagari N, Yotsuyanagi H, Doi Y, et al. Phase 2b part of S-217622, a novel 3C-like 
protease inhibitor as once daily oral treatment for SARS-CoV-2 infection in Japan and South 
Korea.  European Congress of Clinical Microbiology and Infectious Diseases. Lisbon, 
Portugal2022. 
9. 
CDC. COVID-19: People with Certain Medical Conditions. (Accessed May 27, 2022, at  
10. 
Science Brief: Evidence Used to Update the List of Underlying Medical Conditions 
Associated with Higher Risk for Severe COVID-19.  
11. 
Pfizer_Inc. Pfizer Reports Additional Data on PAXLOVID™ Supporting Upcoming New 
Drug Application Submission to U.S. FDA. 2022. 
12. 
Reddy MB, Morcos PN, Le Pogam S, et al. Pharmacokinetic/Pharmacodynamic 
predictors of clinical potency for hepatitis C virus nonnucleoside polymerase and protease 
inhibitors. Antimicrob Agents Chemother 2012;56:3144-56. 
13. 
Bertz RJ, Persson A, Chung E, et al. Pharmacokinetics and pharmacodynamics of 
atazanavir-containing antiretroviral regimens, with or without ritonavir, in patients who are HIV-
positive and treatment-naive. Pharmacotherapy 2013;33:284-94. 
14. 
Singh RSP, Toussi SS, Hackman F, et al. Innovative Randomized Phase I Study and 
Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir. 
Clin Pharmacol Ther 2022. 
 


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APPENDIX 
APPENDIX 1. CONDITIONS ASSOCIATED WITH HIGH RISK FOR 
SEVERE COVID-19 
Asthma 
Bronchiectasis  
Cancer 
Cerebrovascular disease 
Chronic kidney disease 
Chronic liver disease (cirrhosis, non-alcoholic fatty liver disease, alcoholic liver disease, 
autoimmune hepatitis) 
COPD 
Cystic fibrosis 
Diabetes mellitus, type 1 
Diabetes mellitus, type 2 
Gestational diabetes 
Disabilities, including Down Syndrome 
HIV 
Heart conditions (such as heart failure, coronary artery disease, or cardiomyopathies) 
Interstitial lung disease 
Mental health conditions (such as mood disorders, including depression, and schizophrenia 
spectrum disorders) 
Neurologic conditions (Dementia) 
Obesity (BMI ≥30 kg/m2) 
Physical inactivity 
Pregnancy and recent pregnancy 
Primary immunodeficiencies 
Pulmonary hypertension and pulmonary embolism 
Smoking, current and former 
Solid organ or blood stem cell transplantation 
Tuberculosis 
Use of corticosteroids or other immunosuppressive medications 
Source: https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/underlying-evidence-table.html 
Accessed 25 September 2022 

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