A Phase 2 Double-blind, Randomized Study to Evaluate the Antiviral Activity, Safety, and Efficacy of Orally Administered PBI-0451(Pomotrelvir) Compared With Placebo in Nonhospitalized Symptomatic Adults With COVID-19
Phase: PHASE2
Conditions: COVID-19
Sponsor: Pardes Biosciences, Inc.

Pomotrelvir (PBI-0451) 
Study PBI-0451-0002 Abbreviated Clinical Study Report 
Final 
CONFIDENTIAL 
Page 1 
9.1.1 
Protocol and Protocol Amendments 
This section includes the following: 
Original 
07 July 2022 
Amendment 1 Summary of Changes 
26 August 2022 
Amendment 1 
26 August 2022 
Clarification Letter 1 
30 September 2022 
Administrative Letter 1 
31 October 2022 
Administrative Letter 2 
17 November 2022 
Clarification Letter 2 
10 February 2023 
Protocol Termination Letter 
10 April 2023 
 

 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
A Phase 2 Double-blind, Randomized Study to Evaluate the 
Antiviral Activity, Safety, and Efficacy of Orally Administered 
PBI-0451 Compared with Placebo in Nonhospitalized Symptomatic 
Adults with COVID-19  
Sponsor: 
Pardes Biosciences, Inc.  
2173 Salk Avenue 
PMB #052 
Carlsbad, CA 92008 
IND Number: 
158228 
EudraCT Number: 
2022-001195-33 
ClinicalTrials.gov 
Identifier: 
Not available 
Indication: 
Treatment and prevention of SARS-CoV-2 infection and associated 
diseases (ie, COVID-19) 
Protocol ID: 
PBI-0451-0002 
Contact Information: 
The medical monitor’s name and contact information will be 
provided on the Key Study Team Contact List. 
Protocol 
Version/Date: 
Original 
07 July 2022  
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or under 
control of Pardes Biosciences, Inc., and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable institutional review board or 
independent ethics committee. The information is to be used only by you in connection with authorized 
clinical studies of the investigational drug described in the protocol. You will not disclose any of the 
information to others without written authorization from Pardes Biosciences, Inc., except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered. 
 
 
Pomotrelvir (PBI-0451) 
Study PBI-0451-0002 Abbreviated Clinical Study Report 
Final 
 
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PBI-0451 
 
Protocol PBI-0451-0002 
 
Pardes Biosciences, Inc.  
Original 
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07 July 2022 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 4 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................................. 5 
PROTOCOL SYNOPSIS .............................................................................................................................................. 7 
STUDY SCHEMA ...................................................................................................................................................... 16 
STUDY PROCEDURES TABLE ............................................................................................................................... 17 
1. 
INTRODUCTION .............................................................................................................................................. 20 
1.1. 
Background ............................................................................................................................................ 20 
1.2. 
PBI-0451 ................................................................................................................................................ 21 
1.2.1. 
General Information ............................................................................................................. 21 
1.2.2. 
Preclinical Pharmacology and Toxicology ........................................................................... 22 
1.2.3. 
Clinical Studies of PBI-0451 ................................................................................................ 22 
1.2.4. 
Rationale for This Study....................................................................................................... 23 
1.3. 
Rationale for Dose Selection of PBI-0451 ............................................................................................. 23 
1.4. 
Risk/Benefit Assessment for the Study .................................................................................................. 24 
1.5. 
Compliance ............................................................................................................................................ 24 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................................................... 25 
3. 
STUDY DESIGN ................................................................................................................................................ 27 
3.1. 
Study Treatments ................................................................................................................................... 27 
3.2. 
Duration of Treatment ............................................................................................................................ 27 
3.3. 
Discontinuation Criteria ......................................................................................................................... 27 
3.4. 
End of Study ........................................................................................................................................... 28 
3.5. 
Source Data ............................................................................................................................................ 28 
3.6. 
Biomarker Testing Samples for Optional Future Research .................................................................... 28 
3.7. 
Biomarker Sample for Optional Genomic Testing ................................................................................. 28 
4. 
SUBJECT POPULATION .................................................................................................................................. 30 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 30 
4.1.1. 
Subject Replacement ............................................................................................................ 30 
4.2. 
Inclusion Criteria .................................................................................................................................... 30 
4.3. 
Exclusion Criteria................................................................................................................................... 31 
5. 
STUDY INTERVENTION AND CONCOMMITANT MEDICATIONS ......................................................... 32 
5.1. 
Randomization, Blinding, and Procedures for Breaking Treatment Codes ............................................ 32 
5.1.1. 
Randomization ..................................................................................................................... 32 
5.1.2. 
Blinding ................................................................................................................................ 32 
5.1.3. 
Procedures for Breaking Treatment Codes ........................................................................... 33 
5.2. 
Description and Handling of PBI-0451 .................................................................................................. 33 
5.2.1. 
Formulation .......................................................................................................................... 33 
5.2.2. 
Packaging and Labeling ....................................................................................................... 33 
5.2.3. 
Storage and Handling ........................................................................................................... 33 
5.3. 
Dosage and Administration .................................................................................................................... 34 
5.4. 
Prior and Concomitant Medications ....................................................................................................... 34 
5.5. 
Accountability for Study Drugs ............................................................................................................. 34 
5.5.1. 
Investigational Medicinal Product Return or Disposal ......................................................... 35 
Pomotrelvir (PBI-0451) 
Study PBI-0451-0002 Abbreviated Clinical Study Report 
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Protocol PBI-0451-0002 
 
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6. 
STUDY PROCEDURES .................................................................................................................................... 36 
6.1. 
Informed Consent ................................................................................................................................... 36 
6.1.1. 
Consent for Optional Research ............................................................................................. 36 
6.2. 
Subject Enrollment and Treatment Assignment ..................................................................................... 36 
6.3. 
Pretreatment Assessments ...................................................................................................................... 36 
6.3.1. 
Screening Visit ..................................................................................................................... 36 
6.3.2. 
Baseline/Day 1 Assessments ................................................................................................ 37 
6.4. 
Treatment Assessments .......................................................................................................................... 38 
6.5. 
Posttreatment Assessments .................................................................................................................... 39 
6.6. 
Assessments for Early Discontinuation from Study ............................................................................... 39 
6.7. 
Pharmacokinetics Assessments .............................................................................................................. 39 
6.8. 
Safety Assessments ................................................................................................................................ 40 
6.8.1. 
Adverse Events/Concomitant Medications/Protocol Restrictions ........................................ 40 
6.8.2. 
Patient-Reported Outcomes .................................................................................................. 40 
6.8.3. 
Household Transmission Survey .......................................................................................... 40 
6.8.4. 
ECG assessment ................................................................................................................... 40 
6.8.5. 
Physical Examination ........................................................................................................... 41 
6.8.6. 
Vital Signs ............................................................................................................................ 41 
6.8.7. 
Body Mass Index .................................................................................................................. 41 
6.8.8. 
Clinical Laboratory Tests/Assessments ................................................................................ 41 
6.8.9. 
Creatinine Clearance and Estimated Glomerular Filtration Rate ......................................... 42 
6.9. 
Virology Assessments ............................................................................................................................ 43 
6.10. 
Sample Storage....................................................................................................................................... 43 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 44 
7.1. 
Definitions of Adverse Events and Serious Adverse Events .................................................................. 44 
7.1.1. 
Adverse Events ..................................................................................................................... 44 
7.1.2. 
Serious Adverse Events ........................................................................................................ 45 
7.1.3. 
Study Drugs and Concomitant Therapy Special Situations Reports .................................... 45 
7.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 46 
7.2.1. 
Assessment of Causality for Study Drugs and Procedures ................................................... 46 
7.2.2. 
Assessment of Severity ........................................................................................................ 47 
7.3. 
Investigator Reporting Requirements and Instructions .......................................................................... 47 
7.3.1. 
Requirements for Collection Prior to Study Drug Initiation................................................. 47 
7.3.2. 
Adverse Events ..................................................................................................................... 47 
7.3.3. 
Serious Adverse Events ........................................................................................................ 47 
7.3.4. 
Study Drug Special Situations Reports ................................................................................ 47 
7.3.5. 
Concomitant Therapy Reports .............................................................................................. 48 
7.4. 
Reporting Process for Serious Adverse Events and Special Situation Reports ...................................... 48 
7.4.1. 
Serious Adverse Event Reporting Process ........................................................................... 48 
7.4.2. 
Special Situations Reporting Process ................................................................................... 49 
7.5. 
Sponsor Reporting Requirements ........................................................................................................... 51 
7.6. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events .......................................................................................................................... 51 
7.7. 
Toxicity Management ............................................................................................................................ 52 
8. 
STATISTICAL CONSIDERATIONS ................................................................................................................ 53 
8.1. 
Analysis Objectives and Endpoints ........................................................................................................ 53 
8.2. 
Planned Analysis .................................................................................................................................... 53 
8.2.1. 
Interim Analysis ................................................................................................................... 53 
8.2.2. 
Final Analysis ....................................................................................................................... 53 
8.3. 
Analysis Conventions ............................................................................................................................. 53 
8.3.1. 
Analysis Sets ........................................................................................................................ 53 
Pomotrelvir (PBI-0451) 
Study PBI-0451-0002 Abbreviated Clinical Study Report 
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8.3.2. 
Data Handling Conventions ................................................................................................. 54 
8.4. 
Demographic and Baseline/Day 1 Characteristics Analysis .................................................................. 54 
8.5. 
Efficacy Analysis ................................................................................................................................... 54 
8.5.1. 
Primary Analysis .................................................................................................................. 54 
8.5.2. 
Secondary Analyses ............................................................................................................. 55 
8.6. 
Safety Analysis....................................................................................................................................... 55 
8.6.1. 
Extent of Exposure ............................................................................................................... 55 
8.6.2. 
Adverse Events ..................................................................................................................... 55 
8.6.3. 
Laboratory Evaluations ........................................................................................................ 56 
8.6.4. 
Other Safety Evaluations ...................................................................................................... 56 
8.7. 
Pharmacokinetics Analysis .................................................................................................................... 56 
8.8. 
Sample Size ............................................................................................................................................ 56 
9. 
RESPONSIBILITIES.......................................................................................................................................... 57 
9.1. 
Investigator Responsibilities .................................................................................................................. 57 
9.1.1. 
Good Clinical Practice.......................................................................................................... 57 
9.1.2. 
Financial Disclosure ............................................................................................................. 57 
9.1.3. 
Institutional Review Board/Independent Ethics Committee Review and 
Approval............................................................................................................................... 57 
9.1.4. 
Informed Consent ................................................................................................................. 57 
9.1.5. 
Confidentiality ...................................................................................................................... 58 
9.1.6. 
Study Files and Retention of Records .................................................................................. 58 
9.1.7. 
Case Report Forms ............................................................................................................... 60 
9.1.8. 
Investigator Inspections ........................................................................................................ 60 
9.1.9. 
Protocol Compliance ............................................................................................................ 60 
9.2. 
Sponsor Responsibilities ........................................................................................................................ 60 
9.2.1. 
Protocol Modifications ......................................................................................................... 60 
9.2.2. 
Study Report and Publications ............................................................................................. 61 
9.3. 
Joint Investigator/Sponsor Responsibilities ........................................................................................... 61 
9.3.1. 
Payment Reporting ............................................................................................................... 61 
9.3.2. 
Access to Information for Monitoring .................................................................................. 61 
9.3.3. 
Access to Information for Auditing or Inspections .............................................................. 62 
9.3.4. 
Study Discontinuation .......................................................................................................... 62 
10. REFERENCES ................................................................................................................................................... 63 
11. APPENDICES .................................................................................................................................................... 65 
 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Study PBI-0451-0002: Study Procedures Table ..................................................................... 17 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Study PBI-0451-0002: Study Schema .................................................................................... 16 
Pomotrelvir (PBI-0451) 
Study PBI-0451-0002 Abbreviated Clinical Study Report 
Final 
 
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Protocol PBI-0451-0002 
 
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Original 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
adverse event 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BMI 
body mass index 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration (2021) 
CLCR 
creatinine clearance 
CoV 
coronavirus 
COVID-19 
Coronavirus Disease 2019 
CRO 
contract research organization 
CVAP 
Clinical Virology Analysis Plan 
CYP 
cytochrome P450 
DAA 
direct-acting antiviral 
DDI 
drug-drug interaction 
EC50 
concentration (or dose) effective in producing 50% of the maximal 
response 
EC90 
concentration (or dose) effective in producing 90% of the maximal 
response 
ECG 
electrocardiogram 
(e)CRF 
(electronic) case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ET 
early termination (visit) 
GCP 
Good Clinical Practice 
GPCR 
G protein-coupled receptor 
HBV 
hepatitis B virus 
HbcAb 
hepatitis B core antibody 
HbsAg 
hepatitis B surface antigen 
HCoV 
human coronavirus 
HCV 
hepatitis C virus 
HIV(-1) 
human immunodeficiency virus (Type 1) 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
Pomotrelvir (PBI-0451) 
Study PBI-0451-0002 Abbreviated Clinical Study Report 
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Protocol PBI-0451-0002 
 
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ICH 
International Conference for Harmonisation (of Technical Requirements 
for Pharmaceuticals for Human Use) 
IEC 
independent ethics committee 
IND 
investigational new drug 
IRB 
institutional review board 
IUD 
intrauterine device 
IVA 
infectious virus assay 
IXRS 
interactive voice and web response system 
LOD 
limit of detection 
mAb 
monoclonal antibody 
MERS 
Middle Eastern respiratory syndrome 
(m)ITT 
(modified) intention-to-treat 
Mpro 
main protease  
MT 
mid-turbinate 
NAAT 
nucleic acid amplification test 
PK 
pharmacokinetic(s) 
P-gp 
P-glycoprotein 
PTM 
placebo-to-match 
PVE 
pharmacovigilance 
(q)RT-PCR 
(quantitative) reverse transcriptase polymerase chain reaction 
RAT 
rapid antigen test 
RNA 
ribonucleic acid 
RTV 
ritonavir 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SOP 
standard operating procedure 
SSR 
special situation report 
SUSAR 
suspected unexpected serious adverse reaction 
TCID50 
median tissue culture infectious dose 
 
 
 
Pomotrelvir (PBI-0451) 
Study PBI-0451-0002 Abbreviated Clinical Study Report 
Final 
 
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Protocol PBI-0451-0002 
 
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Original 
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PROTOCOL SYNOPSIS 
Pardes Biosciences, Inc. 
2173 Salk Ave. Suite 250 
PMB #052 
Carlsbad, CA 92008 
 
Study Title: A Phase 2 Double-blind, Randomized Study to Evaluate the Antiviral Activity, 
Safety, and Efficacy of Orally Administered PBI-0451 Compared with Placebo in 
Nonhospitalized Symptomatic Adults with COVID-19 
IND Number: IND 158228 
EudraCT Number: 2022-001195-33 
Study Centers Planned: Up to 100 study centers are planned. 
Objectives and Endpoints: 
Primary Objective 
Primary Endpoint 
 To evaluate the antiviral activity of 
PBI-0451  
 Proportion of subjects below the limit of 
detection (LOD) for infectious 
SARS-CoV-2 on Day 3 of treatment by 
infectious virus assay (IVA) 
Secondary Objectives 
Secondary Endpoint 
 To evaluate safety and tolerability of 
PBI-0451 
 Number of treatment-emergent adverse 
events (AEs), serious adverse events 
(SAEs), discontinuation due to AEs, and 
Grade 3 or 4 laboratory abnormalities  
 To evaluate clinical efficacy of PBI-0451 
versus placebo through study Day 28 
 Proportion of subjects with sustained 
symptom resolution through Day 28 
 Time to sustained symptom resolution 
through Day 28  
 Proportion of subjects with COVID-19 
related hospitalization or death from any 
cause through Day 28 
 Severity of targeted COVID-19 
symptoms  
 
Pomotrelvir (PBI-0451) 
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 Number of COVID-19 related medical 
visits other than hospitalization, 
including acute/critical care visits 
through Day 28 
 Number of days in any hospital unit for 
treatment of COVID-19 
 To evaluate the effect of PBI-0451 on 
SARS-CoV-2  
 Presence of SARS-CoV-2 infection 
based on IVA, quantitative reverse 
transcriptase polymerase chain reaction 
(qRT-PCR), and rapid antigen test 
(RAT), as specified in the Clinical 
Virology Analysis Plan (CVAP) 
Exploratory Objectives 
Exploratory Endpoints 
 To evaluate SARS-CoV-2 resistance to 
PBI-0451 
 Sequence analysis of the SARS-CoV-2 
main protease (Mpro) gene (nsp5) and 
Mpro cleavage sites  
 To evaluate SARS-CoV-2 resistant 
variant susceptibility to PBI-0451 
 Susceptibility analysis of SARS-CoV-2 
variants with Mpro amino acid 
substitutions and variants with 
substitutions in Mpro cleavage sites in the 
SARS-CoV-2 polyprotein 
 To evaluate the relationship between 
SARS-CoV-2 detection methods 
 Correlation of SARS-CoV-2 detection by 
IVA, RAT, and qRT-PCR, as specified 
in the CVAP  
 To evaluate the incidence of rebound 
SARS-CoV-2 infection 
 Proportion of subjects with clinical 
and/or virologic rebound 
 To evaluate PBI-0451 pharmacokinetics 
(PK) 
 PBI-0451 PK analysis from an intensive 
PK substudy of up to 50 subjects  
 PK parameters from sparse sampling of 
all subjects for population PK analysis 
 
Study Design: Phase 2, double-blind, randomized, placebo-controlled study 
Number of Subjects Planned: Approximately 210 subjects will be randomized.  
 
Pomotrelvir (PBI-0451) 
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Target Population: Nonhospitalized, symptomatic male and nonpregnant, nonlactating female 
subjects 18 to < 65 years of age with a positive direct test of SARS-CoV-2 infection (antigen 
based or nucleic acid amplification test [NAAT]) who are not at high-risk of progressing to 
severe disease 
Duration of Treatment: 5 days 
Study Duration: Up to 28 days of assessments (ie, the study period) and a Week 24 follow-up 
to assess symptoms and survival status 
Diagnosis and Main Eligibility Criteria: 
Inclusion Criteria 
1. Can understand and sign a written informed consent form (ICF), which must be 
obtained prior to initiation of any study procedures.  
2. Onset of COVID-19 symptoms ≤ 5 days prior to randomization with a positive 
SARS-CoV-2 test ≤ 24 hours prior to randomization. Authorized NAAT or antigen 
tests that detect viral RNA or protein, respectively, are allowed.  
3. ≥ 2 symptoms of acute COVID-19 infection as determined by the investigator from the 
symptoms listed on the COVID-19 symptoms questionnaire present at randomization 
4. Male and nonpregnant, nonlactating female subjects 18 to < 65 years of age. Females 
must have a negative serum or urine pregnancy test at screening and prior to the first 
dose of study drug unless permanently sterile or > 2 years post menopause.  
5. Male and female subjects and/or their heterosexual partners must either be of 
nonchildbearing potential or must use effective contraception from screening through 
90 days after the last dose of study drug 
6. Female subjects must refrain from egg donation and in vitro fertilization during 
treatment and for ≥ 28 days after the last dose of study drug 
7. Male subjects must refrain from sperm donation from screening through 90 days after 
the last dose of study drug 
8. Normal 12-lead electrocardiogram (ECG) evaluation without clinically significant 
abnormalities 
9. Able and willing to comply with all study requirements 
Exclusion Criteria 
10. If unvaccinated, ≥ 1 Centers for Disease Control and Prevention defined underlying 
medical condition associated with an increased risk of developing severe illness from 
COVID-19  
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11. ≥ 1 SARS-CoV-2 vaccination (including a booster) within 3 months prior to 
randomization or anticipated to receive a SARS-CoV-2 vaccination (including a 
booster) during the 28-day study period 
12. Currently hospitalized or expected to require hospitalization for COVID-19 within 
48 hours of randomization 
13. Currently being treated or expected to be treated for COVID-19 with monoclonal 
antibodies, convalescent serum, or direct-acting antiviral agents  
14. Any clinical condition or laboratory result considered by the investigator to indicate 
any unstable or poorly controlled underlying clinically significant medical condition(s), 
active disseminated infection (other than SARS-CoV-2), or other medical condition 
that could represent a risk to the subject, including increasing the likelihood of a safety 
event, affect subject compliance, or affect efficacy and/or safety data collected during 
the 28-day study period  
15. Known active liver disease, including nonalcoholic steatohepatitis/nonalcoholic fatty 
liver disease, chronic or active hepatitis B virus (HBV) or hepatitis C virus (HCV) 
infection, primary biliary cirrhosis, Child-Pugh Class B or C, chronic alcoholic liver 
disease, or acute liver failure 
16. Receiving dialysis or having known severe renal impairment (chronic kidney disease, 
Stage 4 or above) 
17. Unable or unwilling to comply with the protocol procedures 
18. Participating in another interventional study with an investigational compound or 
device, including those for COVID-19 
19. Known prior participation in this study or another study involving PBI-0451 
20. Females who are pregnant or breastfeeding 
21. Oxygen saturation of < 94% on room air 
Study Procedures/Frequency: Following completion of screening and eligibility assessments, 
eligible subjects will be randomized 2:1 to one of 2 treatment groups on Day 1 as follows: 
 PBI-0451: 2 × 350 mg tablets administered orally twice daily (BID) (1400 mg/day) 
with food for 5 days (10 total doses) 
 Placebo: 2 × placebo to match PBI-0451 tablets administered orally BID with food for 
5 days (10 total doses) 
Randomization will be stratified as follows: 
 SARS-CoV-2 positive direct test diagnosis ≤ 3 days (target 30%) versus > 3 days from 
first onset of COVID-19 symptom(s) ≤ 5 days prior to randomization 
 Vaccinated (ie, ≥ 1 dose of an approved vaccine) versus unvaccinated  
 PK substudy participation versus nonparticipation  
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Note: Screening assessments may be considered as baseline/Day 1 assessments if the subject 
meets eligibility requirements, is randomized, and receives the first dose of study drug on same 
day.  
Study Visits: Following randomization on Day 1, subjects will complete baseline assessments 
prior to receiving their first dose of study drug (PBI-0451 or placebo). All subjects will have 
additional safety and efficacy assessments during the 28-day study period.  
A follow-up visit (eg, telephone, televisit, clinic visit, etc. as convenient) will be conducted at 
Week 24 (± 20 days) after the last dose of study drug for all subjects. Information regarding 
ongoing or recurrent COVID-19 symptoms, survival status, pregnancy status (for female 
subjects of childbearing potential and female partners of male subjects), and any 
hospitalizations or acute/critical care visits (eg, non-admitted hospital or other care facility) 
that have occurred since the last study visit will be collected. 
Study Drug Administration: Subjects will take their first dose of study drug (PBI-0451 or 
placebo) with food as soon as possible after randomization, with the first dose designated as 
Day 1, and the second dose taken with the evening meal on Day 1 to ensure that a full total 
daily dose (1400 mg PBI-0451) is taken on the first day of treatment. Study drug will be taken 
with food, approximately 12 hours between doses, at approximately the same time for each 
BID dose for the remainder of 5 days of treatment. 
Patient-Reported Outcomes: Subject self-reports will be assessed daily at screening, Days 1 
through 28 or early termination (ET), and the Week 24 follow-up as follows: 
 COVID-19 symptom questionnaire  
 COVD-19 related hospitalizations or acute/critical care visits (eg, non-admitted 
hospital or other care facility) since the last study visit  
Hospitalization is defined as > 24 hours of acute care in a hospital or similar acute care 
facility, including emergency rooms or temporary facilities instituted to address medical 
needs of those with severe COVID-19. This includes any special medical care unit within 
an assisted living facility or nursing home.  
 Optional household transmission survey of confirmed SARS-CoV-2 infections in 
subject’s household members (baseline/Day 1 and Days 5, 10, 15, and 28 or ET only) 
Serology Testing: Serology samples at screening and/or baseline/Day 1: 
 SARS-CoV-2 (using the Roche Elecsys® Anti-SARS-CoV-2 assay) 
 Human immunodeficiency virus Type 1 
 HBV (hepatitis B serum antigen; hepatitis B core antibody) 
 HCV (hepatitis C antibody, reflex to HCV RNA) 
Virologic Assessments: The following tests will be performed from mid-turbinate (MT) nasal 
swab and saliva samples at screening, baseline/Day 1, and Days 2, 3, 5, 10, 15, and 28 or early 
termination (ET) 
 SARS-CoV-2 qRT-PCR (MT swab and saliva) 
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 SARS-CoV-2 RAT (MT swab)  
 SARS-CoV-2 IVA (MT swab and saliva) at baseline/Day 1 and Days 2, 3, 5, and 
10 only 
 SARS-CoV-2 sequence analysis (MT swab) at baseline/Day 1 and Day 5 for all 
subjects to evaluate the potential for the development of resistance in response to 
treatment with PBI-0451. Additional time points may be evaluated in the case of 
virologic rebound or if the subject remains viremic through Day 28 (ie, if SARS-CoV-2 
RNA by qRT-PCR is ≥ 3.85 log10 copies/mL, which is the threshold for the minimum 
amount of viral RNA required for whole genome sequencing).  
RAT will be conducted for subjects at the study clinic with results recorded in real time. 
All other MT and saliva samples will be shipped to the central laboratory on the day of 
collection for subsequent qRT-PCR and IVA testing. 
Note: SARS-CoV-2 RAT or qRT-PCR tests for household members will not be performed 
at the study clinic; that data will be captured as part of an optional self-reported assessment 
of confirmed SARS-CoV-2 infections in household members.  
Safety Assessments: 
 Complete physical examination: Screening and baseline/Day 1 and Day 28 or ET  
 Symptom-driven physical examination: Days 2, 3, 5, 10, and 15  
 Vital signs: All visits 
 12-lead ECG: Screening; baseline/Day 1 (predose;) and Days 5, 10, and 28 or ET 
 Clinical laboratory blood draws (hematology and chemistry) and urinalysis: 
baseline/Day 1 (predose) and Days 5, 10, and 28 or ET 
 Serum/urine pregnancy test (females of childbearing potential only): Screening, 
baseline/Day 1, and Day 28 or ET 
AEs and concomitant medications will be monitored throughout the study, including 
worsening of COVID-19 symptoms per the COVID-19 symptoms questionnaire and any 
hospitalizations or acute/critical care visits (eg, non-admitted hospital or other care 
facility). 
Pharmacokinetic Assessments: 
 All subjects will have single PK blood draws at baseline/Day 1 (after first dose of study 
drug) and Day 5, with the time of the blood draw relative to the last dose of study drug 
recorded.  
 An intensive PK substudy will be conducted in a subset of up to 50 subjects at select 
sites who provide separate specific consent. Intensive PK blood draws will be collected 
at the following time points: predose (ie, ≤ 5 minutes of dosing) and 0.5, 1, 1.5, 2, 3, 4, 
6, 8, and (optional) 10 to 12 hours postdose. Intensive PK sampling may occur on any 
treatment day (ie, baseline/Day 1 [after first dose of study drug] through Day 5). 
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Any remaining PK samples will be stored and may be used for exploratory assessments, 
such as metabolites, protein binding, endogenous markers of drug-drug interactions, 
biomarkers of host responsiveness, and other investigational experiments. 
Test Product, Dose, and Mode of Administration: 2 × 350 mg tablets administered orally 
BID (1400 mg/day) with food for 5 days (10 total doses)  
Subjects will take their first dose with food as soon as possible after randomization, with the 
first dose designated as Day 1, and the second dose taken with the evening meal on Day 1 to 
ensure that a full total daily dose (1400 mg PBI-0451) is taken on the first day of treatment. 
Study drug will be taken with food, approximately 12 hours between doses, at approximately 
the same time for each BID dose for the remainder of 5 days of treatment 
Reference Therapy, Dose, and Mode of Administration: 2 × placebo to match PBI-0451 
tablets administered orally BID for 5 days (10 total doses). 
Subjects will take their first dose with food as soon as possible after randomization, with the 
first dose designated as Day 1, and the second dose taken with the evening meal on Day 1. 
Study drug will be taken with food, approximately 12 hours between doses, at approximately 
the same time for each BID dose for the remainder of 5 days of treatment 
Statistical Methods: Detailed methodology for summary and statistical analyses of the data 
collected in this study will be documented in a statistical analysis plan. Summary statistics will 
be used to analyze the study data. Any statistical testing will be conducted to ensure that the 
overall alpha = 0.05 level (2 sided). Unless otherwise specified, the data summaries and 
analyses described below will be reported by treatment group. 
The modified intention-to-treat (mITT) analysis set includes all randomized subjects with 
≥ 2 symptoms consistent with COVID-19 ≤ 5 days prior to randomization and a positive 
SARS-CoV-2 test (RT-PCR or RAT) ≤ 24 hours prior to randomization who received ≥ 1 dose 
of study drug. This is the primary analysis set for all clinical endpoints.  
The mITT virologic analysis set is a subset of the mITT analysis set that includes subjects who 
had detectable infectious SARS-CoV-2 by IVA at baseline/Day 1. This is the primary analysis 
set for the primary efficacy endpoint. 
Efficacy: The primary efficacy endpoint is the proportion of subjects below the LOD for 
infectious SARS-CoV-2 on Day 3 by IVA. For the primary endpoint, differences between PBI-
0451 and placebo will be evaluated using stratum-adjusted Mantel-Haenszel proportions 
(adjusted for randomization strata). The proportion of subjects below the LOD for infectious 
SARS-CoV-2 at other time points will be summarized in a similar manner. 
The time to resolution of targeted COVID-19 symptoms will be estimated with the 
Kaplan-Meier method and summarized by treatment group. Differences between treatment 
groups will be determined using a Wilcoxon-Gehan test. The analysis of time to resolution of 
each targeted COVID-19 symptom will be conducted in a similar manner. 
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The proportion of subjects with COVID-19 related hospitalization or death from any cause will 
be summarized by treatment group. Differences between treatment groups will be assessed 
using Mantel-Haenszel proportions.  
The number of COVID-19 related hospitalizations or acute/critical care visits and the number 
of days in any hospital unit for the treatment of COVID-19 will be summarized. Differences 
between treatment groups will be assessed using a van Elteren test stratified by the 
randomization factors. 
SARS-CoV-2 viral load kinetics will be summarized by study visit. Differences between the 
treatment groups will be assessed with a van Elteren test stratified by the randomization 
factors.  
SARS-CoV-2 clinical and virologic rebound will be summarized by the amount of viral RNA 
detected at baseline/Day 1, time to loss of clinical symptoms, time to negative RAT or IVA, 
and time to the first confirmed reappearance of symptoms and/or a positive RAT or qRT-PCR 
sample. 
A correlation of the results of IVA, RAT, and qRT-PCR assessments will be evaluated. 
Virologic outcomes will be summarized by subject serology status determined using the Roche 
Elecsys Anti-SARS-CoV-2 assay, which uses a recombinant protein representing the 
nucleocapsid (N) antigen to detect antibodies against SARS-CoV-2. 
Safety: The safety analysis set includes all randomized subjects who received ≥ 1 dose of 
study drug. This is the primary analysis set for safety analyses. 
AEs will be coded using the current version of the Medical Dictionary for Regulatory 
Activities. Treatment-emergent AEs, SAEs, and AEs leading to premature discontinuation of 
study drug/study will be summarized by treatment, system organ class, and preferred term. 
Laboratory results and change from predose values for selected laboratory tests will be 
summarized by treatment at scheduled visits. The incidence of treatment-emergent laboratory 
abnormalities (Division of AIDS Toxicity Grading Scale) will be summarized by treatment. 
Pharmacokinetics: The PK analysis set includes all subjects who participated in the intensive 
PK substudy and have ≥ 1 nonmissing PK concentration reported by the PK laboratory. This is 
the primary analysis set for PK analyses.  
PBI-0451 plasma concentrations and PK parameters will be derived using noncompartmental 
methods (including metabolite[s] as applicable) and listed and summarized using descriptive 
statistics.  
PBI-0451 plasma concentrations from the PK substudy and sparse sampling from the overall 
study population will be used in a population PK analysis and reported separately.  
Sample Size: The sample size will be approximately 210 subjects to account for 
approximately 60% of randomized subjects who are anticipated to be SARS-CoV-2 negative 
by IVA at baseline/Day 1 and would be excluded from the mITT virologic analysis set. It 
should be noted that this sample size is sufficient with ≥ 80 power to detect a > 19% absolute 
difference in the proportion of subjects below the LOD for infectious SARS-CoV-2 virus (99% 
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vs 81%) at Day 3 by IVA among subjects who had detectable infectious SARS-CoV-2 at 
baseline/Day 1. This assumes alpha = 0.05 and that 40% of subjects have detectable infectious 
virus at baseline/Day 1. 
 
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STUDY SCHEMA 
Figure 1. 
Study PBI-0451-0002: Study Schema 
 
BID = twice daily; PTM = placebo to match 
 
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STUDY PROCEDURES TABLE 
Table 1. 
Study PBI-0451-0002: Study Procedures Table 
Screeninga 
(Day -5 to Day 1) Baseline/Day 1b 
Day 2 
(±1 day)c 
Day 3 
(±1 day)c 
Day 5 
(±1 day)c 
Day 10 
(±2 days) 
Day 15 
(±2 days) 
Rebound
Ad Hoc 
Visitd 
Day 28 
(±3 days) 
Week 24 
Follow Up  
(±20 days)e 
ET 
Written Informed 
Consent 
X 
  
 
  
  
  
 
 
  
 
  
Medical History 
X 
  
 
  
  
  
 
 
  
 
  
Complete Physical 
Examination 
X 
 (X) 
 
  
 
 
 
 
X 
 
X 
Symptom-Driven  
Physical 
Examination 
 
 
X 
X 
 X 
X 
X 
X 
 
 
  
Height 
X 
(X) 
  
  
  
  
 
 
  
 
  
Weight 
X 
(X) 
  
  
  
  
 
 
X 
 
X 
Vital Signsf 
X 
(X) 
X 
X 
X 
X 
X 
 
X 
 
X 
SARS-CoV-2 
N-antibodies 
X 
(X) 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 RATg  
X 
(X) 
X  
X  
X  
X 
X 
X 
X 
 
X 
SARS-CoV-2 
qRT-PCR Testg  
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
 
X 
SARS-CoV-2 
Sequence Analysisg,h 
X 
(X) 
(X) 
(X) 
X 
(X) 
(X) 
X 
(X) 
 
(X) 
SARS-CoV-2 IVAg 
X 
(X) 
X 
X 
X 
 X 
 
 
 
 
(X)  
HIV-1, HBV (HbsAg 
and HbcAb), and 
HCV (HCV antibody 
reflex to HCV RNA) 
Testing 
X 
(X) 
  
  
  
  
 
 
  
 
  
12-Lead ECG 
X 
(X) 
 
 
X 
X 
 
 
X 
 
X 
Optional Genomic 
Sample 
 
X 
 
 
 
 
 
 
 
 
 
Hematologyi 
  
X 
 
 
X 
X  
 
 
X 
 
X 
 
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Screeninga 
(Day -5 to Day 1) Baseline/Day 1b 
Day 2 
(±1 day)c 
Day 3 
(±1 day)c 
Day 5 
(±1 day)c 
Day 10 
(±2 days) 
Day 15 
(±2 days) 
Rebound
Ad Hoc 
Visitd 
Day 28 
(±3 days) 
Week 24 
Follow Up  
(±20 days)e 
ET 
Coagulation Panel 
 
X 
 
 
X 
X 
 
 
X 
 
X 
Chemistryj 
  
X 
 
 
X 
 X 
 
 
X 
 
X 
Urinalysisk 
  
X 
 
 
X 
 X 
 
 
X 
 
X 
Creatinine Clearance 
and eGFR 
  
X 
 
 
X 
 X 
 
 
X 
 
X 
Serum/Urine 
Pregnancy Testl 
X 
(X) 
 
 
 
 
 
 
X 
 
X 
Study Drug 
Dispensing 
 
X 
 
 
 
 
 
 
 
 
 
Study Drug 
Administration 
 
2 × 350 mg PBI-0451 or Placebo BID orally for 
5 days (10 total doses) 
 
 
 
 
 
 
Patient Reported 
Outcomesm 
X 
(X) 
X 
X 
X 
Intensive PK 
Samplingn 
 
X 
 
 
 
 
 
 
Single PK Sampleo 
  
X 
 
 
X 
 
 
 
 
 
 
Household 
Transmission 
Surveyp 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
Survival Statusq 
 
 
 
 
X 
X 
X 
 
X 
X 
 
Review and Assess 
AEs and 
Concomitant 
Medicationr 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
 
X 
AE = adverse event; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; ET = early termination; HbcAb = hepatitis B core antibody; 
HbsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV-1 = human immunodeficiency virus Type 1; IVA = infectious virus 
assay; PK = pharmacokinetics; qRT-PCR = quantitative reverse-transcriptase polymerase chain reaction; RAT = rapid antigen test; SARS-CoV-2 = severe acute 
respiratory syndrome coronavirus 2 
a. 
Prospective subjects should be screened ≤ 5 days prior to administration of first dose of study drug (ie, randomization/Day 1) 
b. Screening assessments may be considered as baseline/Day 1 if the subject is eligible for the study and is randomized and receives the first dose of study 
drug on that day. Parentheses indicate that assessment is not required if performed at screening, and screening and baseline/Day 1 are the same. 
c. 
Individual study visits must occur on separate calendar days within the visit window, with the time(s) of sample collection recorded.  
 
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d. Subjects who experience a relapse in symptom(s) after having no COVID-19 symptom(s) for ≥3 days or have a positive RAT (or clinic qRT-PCR test) 
after testing negative by RAT or qRT-PCR will be requested to return to clinic within 2 days for mid-turbinate nasal swab and saliva samples for RAT, 
qRT-PCR, and sequencing. 
e. 
Week 24 visit performed via telephone, televisit, or clinic visit, as convenient. 
f. 
Vital signs include blood pressure, heart rate, respiratory rate, and temperature (predose and postdose on Day 1). 
g. Mid-turbinate nasal swabs will be collected to measure SARS-CoV-2 using qRT-PCR, IVA, RAT, and viral sequencing. Saliva samples will be collected 
to measure SARS-CoV-2 using qRT-PCR and IVA. Parentheses indicate sample at ET visit if the subject discontinues treatment prior to Day 10. 
h. SARS-CoV-2 sequence analysis (nasal mid-turbinate sample) will be conducted only if the subject is viremic and above the limit of detection (LOD) of 
the sequencing assay. Sequence analysis may be conducted on samples obtained at other study visits for subjects who experience virologic rebound or if 
the subject remains viremic through Day 28. Parentheses indicate sequencing samples where sequencing is dependent on the subject being viremic and 
experiencing virologic rebound and viral RNA is above the LOD of the sequencing assay by qRT-PCR. 
i. 
Hematology includes complete blood count with differential and platelets.  
j. 
Serum chemistry includes comprehensive metabolic panel. 
k. Urinalysis includes microscopic reflex. 
l. 
Pregnancy tests for females of childbearing potential only; screening urine test required for eligibility. 
m. Self-reported daily assessment of targeted COVID-19 symptoms (per the COVID-19 symptoms questionnaire) and any hospitalizations or acute/critical 
care visits (eg, non-admitted hospital or other care facility) will be assessed daily at screening and from baseline/Day 1 through Day 28. 
n. Intensive PK sampling for substudy subjects only. Sampling will occur relative to study drug administration at the following times: predose (ie, 
≤ 5 minutes prior to dosing) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and (optional) 10-12 hours postdose; intensive PK sampling will occur on any day of treatment 
from Day 1 (subject’s first dose of study drug) to Day 5. 
o. Sparse PK samples will be obtained at baseline/Day 1 (subsequent to subject’s first dose of study drug) and Day 5. 
p. Optional subject self-reported assessment of number of confirmed SARS-CoV-2 infections (RAT or qRT-PCR) in household members. No specific 
identifying information will be collected. 
q. Survival status also includes current supplemental oxygen use, pregnancy status (for female subjects of childbearing potential and female partners of 
male subjects), and any hospitalizations or acute/critical care visits that occurred since the last study visit during the 28-day study period. 
r. 
All AEs recorded from the time of obtaining informed consent through Day 28; all ongoing AE’s will be followed to resolution or condition is 
considered permanent.  
 
 
 
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1. 
INTRODUCTION 
1.1. 
Background 
Pardes Biosciences, Inc. (hereafter referred to as Pardes) is developing PBI-0451, a new 
chemical entity and orally bioavailable direct-acting antiviral (DAA) inhibitor of the main 
protease (Mpro) of coronaviruses (CoVs), including the novel severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) that causes Coronavirus Disease 2019 (COVID-19) (Jin et al. 
2020). PBI-0451 is an investigational agent that, by inhibiting the ability of the virus to replicate, 
has the potential for use as treatment and prevention of SARS-CoV-2 infection and associated 
diseases (ie, COVID-19). Additionally, it is anticipated that an effective DAA may reduce the 
magnitude and duration of viral shedding of replicating virus and therefore reduce the likelihood 
of transmission of SARS-CoV-2. 
CoVs are positive, single-stranded RNA viruses, of which 7 infect humans and are believed to 
result in 5% to 30% of “common colds” for which therapeutic intervention is generally limited to 
over-the-counter symptomatic relief (Paules et al. 2020). CoV infection in humans is transmitted 
from person to person via shedding of replicating virus within the respiratory tract through 
aerosolization (Tang et al. 2020). SARS-CoV-2 is a novel strain of CoV discovered in late 2019 
and responsible for COVID-19 that can range from mild to severe disease with symptoms, 
including extreme fatigue and dyspnea, that can be short-lived or prolonged (eg, “long COVID”) 
with some cases developing pneumonia that can progress into acute respiratory distress 
syndrome and sometimes death, despite aggressive supportive care (Tang et al. 2020) (Sharma et 
al. 2020) (Marshall 2020). All persons are at risk for infection with SARS-CoV-2 and developing 
COVID-19. SARS-CoV-2 represents the third novel CoV (in addition to SARS-Co-V and 
Middle Eastern respiratory syndrome [MERS] CoV) to make a zoonotic transfer in the last 
2 decades and result in significant human disease (Dhama et al. 2020). The potential for new 
CoV outbreaks is likely to continue. 
Natural history data for nonpandemic CoV infection has established that reinfection with the 
same or different strains of CoV (including SARS-CoV-2) can occur (Tillett et al. 2021) (Harvey 
et al. 2021). Moreover, throughout the pandemic, surveillance has identified multiple spike 
protein mutations resulting in the global emergence of several SARS-CoV-2 variants of concern 
(ie, Delta, Omicron) due to potentially higher levels of transmissibility or immune escape 
(Korber et al. 2020) (Campbell et al. 2021) (Zella et al. 2021). This is particularly important as 
CoVs are known to mutate and undergo genetic recombination, which may facilitate 
transmission, replicative fitness, and pathogenicity across species (Lau and Chan 2015). A 
consequence of this has already been seen with some monoclonal antibodies (mAbs), where 
reduced efficacy against emerging SARS-CoV-2 variants (ie, Delta, Omicron) has led to 
recommendation against their use. 
Near-universal vaccination is desired to reduce transmission and severity of COVID-19 disease; 
however, access to and acceptance of vaccines are suboptimal, and it is unknown if vaccines will 
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provide adequate duration of protection against current and future SARS-CoV-2 variants 
(Edridge et al. 2020). 
While the details of the pathobiology and risk factors for developing severe COVID-19 disease 
remain unclear, it is established that early intervention to inhibit viral replication provides 
clinical benefit. Experience with influenza and emerging evidence with COVID-19 indicates that 
early treatment via a short course (eg, 5 days) of oral DAA therapy results in less severe disease 
and that preventing transmission is also possible (Muthuri et al. 2014) (Uyeki et al. 2019) (Chow 
et al. 2019) (Ikematsu et al. 2020). 
Orally administered small molecule protease inhibitors are a clinically validated treatment and a 
standard of care for multiple viral diseases, including hepatitis C virus (HCV) and human 
immunodeficiency virus (HIV) infections (Ghany and Morgan 2020) (Department of Health and 
Human Services 2022). These agents can exhibit favorable drug-like properties and a favorable 
benefit:risk profile, including when used at high doses and exposures in both the short-term 
(weeks to months in HCV) and chronic (life-long therapy for HIV) settings (Patick and Potts 
1998). 
Small molecule DAAs that are orally administered and suitable for outpatient use are needed to 
treat people who become infected and are at high risk for severe COVID-19. In addition, 
treatment with oral DAAs is warranted to reduce the time to symptom resolution and decrease 
the duration of shedding infectious virus. Moreover, such agents can also be deployed in “ring 
prophylaxis” to contacts of infected individuals or in the setting of mitigating the spread of new, 
localized outbreaks. Small molecule oral DAAs are attractive therapeutics as they target viral and 
not host processes that may reduce the risk for off-target effects, and thus increase the likelihood 
of a favorable therapeutic index. Consequently, there remains a high unmet medical need for an 
easy to use, oral antiviral drug for the treatment and prevention of SARS-CoV-2 infection and 
associated diseases (ie, COVID-19). 
1.2. 
PBI-0451 
1.2.1. 
General Information 
PBI-0451 is an investigational agent that has the potential for use as treatment and prevention 
SARS-CoV-2 infection and associated diseases (ie, COVID-19) by inhibiting the ability of the 
virus to replicate and thereby reduce the incidence and magnitude of the pathologic immune 
response responsible for the morbidity and mortality associated with severe disease. PBI-0451 is 
a potent inhibitor of SARS-CoV-2 Mpro, an essential enzyme for viral replication with 
EC50 = 23 nM and EC90 = 113.5 nM in SARS-CoV-2 antiviral assays. In nonclinical studies, 
PBI-0451 has broad-spectrum activity against SARS-CoV-2 clinical variants Alpha, Beta, Delta, 
Epsilon, Gamma, Mu, and Omicron and human coronaviruses (HCoVs) 229E and OC43 in cell-
based antiviral assays. It has broad-spectrum activity in in vitro enzyme assays against the Mpro 
from HCoVs SARS, 229E, HKUI, OC43, NL63, and MERS, suggesting that it interacts with the 
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most essential elements of the Mpro binding pocket. This hypothesis is supported by in vitro 
resistance studies which suggest that PBI-0451 has a high barrier to resistance. In in vivo 
pharmacodynamic animal model of infection studies in mice, PBI-0451 showed a trend towards 
improved lung function at the higher PBI-0451 doses that correlated with a 10-fold decrease in 
viral load in the lung. Screens for off-target activity on host cysteine proteases and other targets 
revealed no significant concerns. A ritonavir (RTV)-boosted SARS-CoV-2 protease inhibitor 
targeting the same active enzyme pocket has shown significant benefit for high risk COVID-19 
patients in the clinic (nirmatrelvir [Pfizer]). PBI-0451, at an appropriate dose and dosing 
regimen, thus has potential to provide similar clinical benefit for SARS-CoV-2-infected patients 
with PBI-0451. 
PBI-0451 has completed toxicology studies conducted under Good Laboratory Practice 
guidelines, including 14-day studies in mice and dogs without evidence of adverse findings. For 
further information on PBI-0451, refer to the current Investigator’s Brochure (IB). 
1.2.2. 
Preclinical Pharmacology and Toxicology 
PBI-0451 has shown a favorable selectivity profile at anticipated clinical exposures relative to 
activity against a panel of human (and rat) GPCRs, ion channels, transporters, nuclear receptors, 
and select enzymes (WuXi Mini Safety Panel).  
For further information on PBI-0451, refer to the current IB. 
1.2.3. 
Clinical Studies of PBI-0451 
As of 1 July 2022, two clinical studies of PBI-0451 have been initiated and have completed 
clinical assessment: Study PBI-0451-0001 is a first-in-human, single ascending dose/multiple 
ascending dose study of PBI-0451 with nested food effect and drug-drug interaction (DDI) 
screening cohorts, and Study PBI-0451-0004 is a relative bioavailability (food effect) study.  
Safety 
Preliminary clinical data indicate that PBI-0451 has been well tolerated at single and multiple 
oral doses (ie, 10 days) up to 2100 mg/day. All reported treatment-emergent adverse events 
(AEs) have been mild or moderate in severity and none have been considered definitely related 
to study drug. No serious adverse events (SAEs) or deaths have been reported. No clinically 
significant treatment-emergent laboratory abnormalities, no treatment-emergent AEs due to 
laboratory abnormalities, and no clinically significant abnormal findings with respect to vital 
signs or safety electrocardiogram (ECG) assessments have been reported.  
Pharmacokinetics  
Preliminary clinical data demonstrate that PBI-0451 has a favorable human pharmacokinetics 
(PK) profile following single and multiple ascending oral doses up to 2100 mg/day. PBI-0451 
demonstrates dose-linear exposures when administered with food, achieves rapid systemic 
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exposures that exceed the target protein-binding adjusted EC90 against SARS-CoV-2, and 
exhibits a 2-compartment PK profile that supports administration as a stand-alone agent when 
administered with food. PBI-0451 has been shown to be a weak CYP34A inhibitor and a 
nonsensitive substrate of CYP3A4, P-gp, and BCRP. DDI evaluation in vitro; in vivo; and in 
silico, using physiological-based PK modeling and simulation, indicated that the DDI potential 
of PBI-0451 as a victim or perpetrator for other major CYP enzymes and transporters is 
negligible. Overall, the DDI assessments suggest that PBI-0451 presents no to minimal DDI 
potential at the proposed clinical dose. 
1.2.4. 
Rationale for This Study 
PBI-0451 is a new chemical entity intended as an orally available DAA whose mechanism of 
action is inhibition of the Mpro of CoV, including the SARS-CoV-2 that causes COVID-19. 
Short-term administration (eg, 5 days) of antivirals with similar (nirmatrelvir [Pfizer]) and 
different (molnupiravir [Merck]) mechanisms of action have been reported to improve the 
outcomes (hospitalization or death) in nonhospitalized patients with SARS-CoV-2 infection at 
high risk for severe COVID-19. The incidence of COVID-19 remains high, mainly in 
unvaccinated persons, but breakthrough infections have also occurred in persons who have been 
fully vaccinated. PBI-0451 is an oral DAA with broad activity against CoVs, including 
SARS-CoV-2, and has the potential to address this unmet medical need.  
1.3. 
Rationale for Dose Selection of PBI-0451 
Dose selection for PBI-0451 included consideration of all relevant nonclinical and clinical data 
and knowledge from the development of DAAs used for the treatment of both acute 
(eg, influenza and COVID-19) and chronic (ie, HIV, hepatitis B virus (HBV), and HCV viral 
infections (Department of Health and Human Services 2022) (Ghany and Morgan 2020) with the 
goal of providing systemic drug exposures that will maximally reduce viral burden. Specifically, 
the goal is to achieve and maintain (accounting for protein binding) concentration multiples 
above the EC50 (US Food and Drug Administration 2006) and whenever possible also above the 
EC90 over the duration of the dosing interval.  
Nonclinical and clinical data support the Phase 2 evaluation of a total daily dose of PBI-0451 
1400 mg as 700 mg (2 × 350 mg tablets) BID administered with food for 5 days. This dose has 
been shown to achieve desired PK exposures. For additional information on PBI-0451 dose 
selection refer to the current IB. 
Due to the desire to rapidly initiate treatment with maximally suppressive drug concentrations 
against SARS-CoV-2, a loading dose approach has been selected to provide the highest peak and 
trough PBI-0451 concentrations at the initiation of treatment (ie, Day 1), followed by the 
establishment of steady-state conditions for the remainder of the treatment period as described in 
Section 5.3). The dosing regimen is designed to assure initiation of therapy as soon as possible 
after randomization and administration of the full 1400 mg total daily dose on Day 1 of treatment 
to provide maximal antiviral activity at the point of highest viral burden and when the potential 
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DAA benefit is greatest. The safety of this dosing regimen is supported by single and multiple 
doses equal to or greater in magnitude (up to 2100 mg) and for longer duration (up to 10 days) 
than proposed in this Phase 2 study.  
The duration of treatment in this study is 5 days, consistent with other acute antiviral treatments, 
such as oseltamivir for influenza. The 5-day treatment duration is identical to that shown to result 
in reduced rates of clinically meaningful endpoints in DAA treatment studies of COVID-19 
(Jayk Bernal et al. 2022) that include SARS-CoV-2 viral load (Sasaki et al. 2022) and 
hospitalization due to COVID-19 or death from any cause, including nirmatrelvir (an Mpro 
inhibitor with the same mechanism of action of PBI-0451) coadministered with RTV (Hammond 
et al. 2022). 
1.4. 
Risk/Benefit Assessment for the Study 
No clinical safety issues specifically related to PBI-0451 have been identified to date.  
The expected benefit to subjects being treated with PBI-0451 is a rapid decrease of SARS-CoV-2 
viral load within a short treatment period, without the need for coadministration of a second 
agent for pharmacoenhancement and its potential for DDIs and potentially reduce the duration of 
symptomatic illness and the risk of progression to more severe disease. 
Potential risks include unforeseen safety issues. For the population of subjects with 
SARS-CoV-2 infection, the expected benefit of eliminating SARS-CoV-2 virus within 5 days of 
treatment outweighs the risks associated with the possible development of previously 
unidentified safety issues. Subjects randomized to the placebo group may benefit from frequent 
medical monitoring during the study. 
The overall benefit/risk balance for this study is considered favorable.  
During a pandemic, additional potential risks to subjects may include interruptions to the study 
visit schedule and adherence to protocol-specified safety monitoring or laboratory assessments. 
Refer to Appendix 2 for details on the risks and risk mitigation strategy. 
1.5. 
Compliance 
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements. 
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2. 
OBJECTIVES AND ENDPOINTS 
Primary Objective 
Primary Endpoint 
 To evaluate the antiviral activity of 
PBI-0451  
 Proportion of subjects below the limit of 
detection (LOD) for infectious 
SARS-CoV-2 on Day 3 of treatment by 
infectious virus assay (IVA) 
Secondary Objectives 
Secondary Endpoint 
 To evaluate safety and tolerability of 
PBI-0451 
 Number of treatment-emergent AEs, 
SAEs, discontinuation due to AEs, and 
Grade 3 or 4 laboratory abnormalities  
 To evaluate clinical efficacy of PBI-0451 
versus placebo through study Day 28 
 Proportion of subjects with sustained 
symptom resolution through Day 28 
 Time to sustained symptom resolution 
through Day 28  
 Proportion of subjects with COVID-19 
related hospitalization or death from any 
cause through Day 28 
 Severity of targeted COVID-19 symptoms  
 Number of COVID-19 related medical 
visits other than hospitalization, including 
acute/critical care visits through Day 28 
 Number of days in any hospital unit for 
treatment of COVID-19 
 To evaluate the effect of PBI-0451 on 
SARS-CoV-2  
 Presence of SARS-CoV-2 infection based 
on IVA, quantitative reverse transcriptase 
polymerase chain reaction (qRT-PCR), 
and rapid antigen test (RAT), as specified 
in the Clinical Virology Analysis Plan 
(CVAP) 
Exploratory Objectives 
Exploratory Endpoints 
 To evaluate SARS-CoV-2 resistance to 
PBI-0451 
 Sequence analysis of the SARS-CoV-2 
Mpro gene (nsp5) and Mpro cleavage sites  
 To evaluate SARs-CoV-2 resistant variant 
susceptibility to PBI-0451 
 Susceptibility analysis of SARS-CoV-2 
variants with Mpro amino acid 
substitutions and variants with 
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substitutions in Mpro cleavage sites in the 
SARS-CoV-2 polyprotein 
 To evaluate the relationship between 
SARS-CoV-2 detection methods 
 Correlation of SARS-CoV-2 detection by 
IVA, RAT, and qRT-PCR, as specified in 
the CVAP  
 To evaluate the incidence of rebound 
SARS-CoV-2 infection 
 Proportion of subjects with clinical and/or 
virologic rebound 
 To evaluate PBI-0451 PK 
 PBI-0451 PK analysis from an intensive 
PK substudy of up to 50 subjects  
 PK parameters from sparse sampling of 
all subjects for population PK analysis 
 
 
 
 
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3. 
STUDY DESIGN 
This protocol describes a Phase 2, randomized, double-blind, placebo-controlled study to 
evaluate efficacy and safety of PBI-0451 in nonhospitalized symptomatic adults with COVID-19 
who are at standard risk of progressing to severe illness. Approximately 210 subjects will be 
randomized in the study.  
An overview of the study design is provided in Figure 1. 
3.1. 
Study Treatments 
Following completion of screening and eligibility assessments, eligible subjects will be 
randomized 2:1 to 1 of 2 treatment groups on Day 1 as follows: 
 PBI-0451: 2 × 350 mg tablets administered orally twice daily (BID) (1400 mg/day) with 
food for 5 days (10 total doses) 
 Placebo: 2 × placebo to match PBI-0451 tablets administered orally BID with food for 
5 days (10 total doses) 
Randomization will be stratified as follows: 
 SARS-CoV-2 positive direct test diagnosis ≤ 3 days (target 30%) versus > 3 days from 
first onset of COVID-19 symptom(s) ≤ 5 days prior to randomization 
 Vaccinated (ie, ≥ 1 dose of an approved vaccine) versus unvaccinated  
 PK substudy participation versus nonparticipation 
3.2. 
Duration of Treatment 
Eligible subjects will begin treatment immediately following randomization and completion of 
Day 1 assessments (first daily dose) and with the evening meal on Day 1 (second daily dose); 
subjects will continue BID dosing for a total of 5 days (10 total doses). 
3.3. 
Discontinuation Criteria 
Study drug will be discontinued in the following instances: 
 Unacceptable toxicity, or toxicity that, in the judgement of the investigator, compromises the 
ability to continue study-specific procedures or is considered not to be in the subject’s best 
interest 
 Subject request to discontinue for any reason 
 Pregnancy during the study (see Appendix 3) 
 Concurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree 
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 Subject noncompliance 
 Discontinuation of the study at the request of Pardes, a regulatory agency, or an institutional 
review board (IRB) or independent ethics committee (IEC) 
Subjects who discontinue study drug are encouraged to continue participation in the study for 
safety follow up.  Subjects can discontinue participation at any time.  
3.4. 
End of Study 
The end of this study will be the last subject’s last observation (or visit) up to Week 24. 
3.5. 
Source Data 
The source data for this study will be obtained from electronic data capture (EDC), central 
laboratory, local laboratory, specialty laboratory (for PK and/or ECG data). 
3.6. 
Biomarker Testing Samples for Optional Future Research  
The following biological specimens will be collected from all subjects who have provided 
consent to participate in this study, and may be used to evaluate the association of systemic 
and/or tissue-based biomarkers with study drug response (including AEs) and/or dosage 
selection, and to better understand the biological pathways, biology of SARS-CoV-2 or related 
diseases caused by other CoVs, and/or the validation of a companion diagnostic for COVID-19 
or PBI-0451. Because biomarker science is a rapidly evolving area of investigation, and AEs in 
particular are difficult to predict, it may not be possible to specify prospectively all tests that may 
be done on the specimens provided. The specific analyses will include, but may not be limited to, 
the biomarkers and assays listed below. The testing outlined below is based upon the current 
state of scientific knowledge. It may be modified during or after the end of the study to remove 
tests that are no longer indicated and/or to add new tests based upon new state-of-the-art 
knowledge.  
 Biological samples (blood and urine) will be collected relative to dosing (if applicable) to 
measure biomarkers with corresponding PK time points. 
 Mid-turbinate (MT) nasal swabs will be collected to measure SARS-CoV-2 using qRT-PCR, 
IVA, RAT, and viral sequencing. Saliva samples will be collected to measure SARS-CoV-2 
using qRT-PCR and IVA. 
Samples collected for biomarker assessments will be destroyed no later than 15 years after the 
end of study or per country requirements.  
3.7. 
Biomarker Sample for Optional Genomic Testing 
In addition to the study-specific informed consent to be signed by each subject participating in 
the study, subjects will be offered to document agreement to provide additional blood sample for 
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optional genomic research. The sample will be obtained from subjects who agree to participate 
and provide their additional specific consent.  
A blood specimen will be collected for the evaluation of immune biomarkers that could regulate 
or be involved in the disposition of SARS-CoV-2 or PBI-0451. This sample will be collected at 
baseline/Day 1 prior to administration of the first dose of study drug but may be collected at any 
time during the study, if necessary. 
The specimen collected for optional future genomic research may be used to advance the 
development of the drug and/or increase our knowledge and understanding of the biology of the 
disease under investigation or related diseases. This specimen may also be used to study the 
association of biomarkers with biological pathways, disease pathogenesis, progression, and/or 
treatment outcomes, including efficacy, AEs, and the processes of drug absorption and 
disposition. In addition, the specimen may be used to develop biomarker and/or diagnostic 
assays and establish the performance characteristics of these assays. The collection and analysis 
of optional genomic research specimens may facilitate the design of new pharmaceutical agents 
and the development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future. 
The samples collected for optional genomic research will be destroyed no later than 15 years 
after the end of study or per country requirements. 
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4. 
SUBJECT POPULATION 
4.1. 
Number of Subjects and Subject Selection 
A total of 210 subjects will be randomized in the study. Subjects are nonhospitalized, 
symptomatic male and nonpregnant, nonlactating female subjects 18 to < 65 years of age with a 
positive direct test of SARS-CoV-2 infection (antigen based or nucleic acid amplification test 
[NAAT]) who are not at high-risk of progressing to severe disease.  
4.1.1. 
Subject Replacement 
Subjects who prematurely discontinue the study due to adverse events will not be replaced. 
4.2. 
Inclusion Criteria 
Subjects must meet all the following inclusion criteria to be eligible for participation in this 
study: 
1. Can understand and sign a written informed consent form (ICF), which must be obtained 
prior to initiation of any study procedures 
2. Onset of COVID-19 symptoms ≤ 5 days prior to randomization with a positive 
SARS-CoV-2 test ≤ 24 hours prior to randomization. Authorized NAAT or antigen tests 
that detect viral RNA or protein, respectively, are allowed  
3. ≥ 2 symptoms of acute COVID-19 infection as determined by the investigator from the 
symptoms listed on the COVID-19 symptoms questionnaire present at randomization 
4. Male and nonpregnant, nonlactating female subjects 18 to < 65 years of age. Females 
must have a negative serum or urine pregnancy test at screening and prior to the first dose 
of study drug unless permanently sterile or > 2 years post menopause  
5. Male and female subjects and/or their heterosexual partners must either be of 
nonchildbearing potential or must use effective contraception from screening through 
90 days after the last dose of study drug 
6. Female subjects must refrain from egg donation and in vitro fertilization during treatment 
and for ≥ 28 days after the last dose of study drug 
7. Male subjects must refrain from sperm donation from screening through 90 days after the 
last dose of study drug 
8. Normal 12-lead ECG evaluation without clinically significant abnormalities 
9. Able and willing to comply with all study requirements 
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4.3. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not eligible to participate in this 
study: 
1.  If unvaccinated, ≥ 1 Centers for Disease Control and Prevention defined underlying 
medical condition associated with an increased risk of developing severe illness from 
COVID-19 (see Appendix 5)  
2. ≥ 1 SARS-CoV-2 vaccination (including a booster) within 3 months prior to 
randomization or anticipated to receive a SARS-CoV-2 vaccination (including a 
booster) during the 28-day study period 
3. Currently hospitalized or expected to require hospitalization for COVID-19 within 
48 hours of randomization 
4. Currently being treated or expected to be treated for COVID-19 with mAbs, 
convalescent serum, or DAA agents during the study period  
5. Any clinical condition or laboratory result considered by the investigator to indicate 
any unstable or poorly controlled underlying clinically significant medical condition(s), 
active disseminated infection (other than SARS-CoV-2), or other medical condition that 
could represent a risk to the subject, including increasing the likelihood of a safety 
event, affect subject compliance, or affect efficacy and/or safety data collected during 
the 28-day study period  
6. Known active liver disease, including nonalcoholic steatohepatitis/nonalcoholic fatty 
liver disease, chronic or active HBV or HCV infection, primary biliary cirrhosis, 
Child-Pugh Class B or C, chronic alcoholic liver disease, or acute liver failure 
7. Receiving dialysis or having known severe renal impairment (chronic kidney disease, 
Stage 4 or above) 
8. Unable or unwilling to comply with the protocol procedures 
9. Participating in another interventional study with an investigational compound or 
device, including those for COVID-19 
10. Known prior participation in this study or another study involving PBI-0451 
11. Females who are pregnant or breastfeeding 
12. Oxygen saturation of < 94% on room air 
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5. 
STUDY INTERVENTION AND CONCOMMITANT 
MEDICATIONS 
5.1. 
Randomization, Blinding, and Procedures for Breaking Treatment Codes 
5.1.1. 
Randomization 
Subjects who meet eligibility criteria will be randomized in a 2:1 ratio to PBI-0451 or placebo 
and assigned a unique subject number via an interactive voice and web response system (IXRS) 
prior to initiation of dosing on Day 1. Randomization will be stratified as follows: 
 SARS-CoV-2 positive direct test diagnosis ≤ 3 days (target 30%) versus > 3 days from first 
onset of COVID-19 symptom(s) ≤ 5 days prior to randomization 
 Vaccinated (ie, ≥ 1 dose of an approved vaccine) versus unvaccinated  
 PK substudy participation versus nonparticipation 
5.1.2. 
Blinding 
The study is double-blinded. Subjects, investigators and all internal and external personnel 
directly involved in the conduct of the study will be blinded to treatment assignment. Study drug 
will be dispensed to subjects by the study pharmacist or designee in a blinded fashion.  
Specified personnel may be unblinded based on their study role as follows: 
 The statistician or designee in Biostatistics and/or Clinical Data Management who 
facilitates transfer of PK and/or virology sample logistics and data files between Pardes 
and vendors will be unblinded.  
 Individuals in Clinical Packaging and Labeling or Clinical Supply Management who 
have an Inventory Manager role in the IXRS for purpose of study drug inventory 
management will remain unblinded.  
 Individuals in Pharmacovigilance (PVE) responsible for safety signal detection, 
investigational new drug (IND) safety reporting, and/or expedited reporting of suspected 
unexpected serious adverse reactions (SUSARs) may be unblinded to individual case data 
and/or group-level summaries.  
 Individuals in Clinical Virology responsible for monitoring for virologic rebound 
detection will be unblinded to individual case data. In particular, RAT and qRT-PCR data 
will be monitored on a per subject basis to trigger the request for confirmatory sample 
collection in the case of a potential virologic rebound. 
 External (ie, contract research organizations [CROs]) biostatisticians and programmers 
will be unblinded for IND safety reporting.  
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 A select internal team that will not participate in any other study-related activities will be 
responsible for preparing unblinded analyses and documents to support regulatory 
activities that may be required while the study is ongoing. This team will be unblinded 
only at the study group level and will not have access to individual subject treatment 
assignment.  
5.1.3. 
Procedures for Breaking Treatment Codes 
In the event of a medical emergency for which breaking the blind is required to provide medical 
care to a subject, the investigator may obtain treatment assignment directly from the IXRS for 
that subject. Pardes recommends, but does not require, that the investigator contact the CRO 
medical monitor prior to breaking the blind. Treatment assignment should remain blinded unless 
that knowledge is necessary to determine a subject’s emergency medical care. The rationale for 
unblinding must be clearly explained in source documentation, along with the date on which the 
treatment assignment was unblinded. The investigator is requested to contact the CRO medical 
monitor promptly in case of any treatment unblinding. 
Blinding of study treatment is critical to the integrity of this clinical study. Therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will discontinue study 
treatment. All subjects will be followed until study completion unless consent to do so is 
specifically withdrawn by the subject. 
5.2. 
Description and Handling of PBI-0451  
5.2.1. 
Formulation 
PBI-0451 350 mg tablets are modified oval tablets.  
Refer to latest version of the IB for additional information. 
5.2.2. 
Packaging and Labeling 
PBI-0451 tablets are packaged in 20-count high-density polyethylene bottles with silica gel 
desiccant(s) and labeled “For Investigational Purposes Only”.  
Refer to the latest version of the IB for additional information. 
5.2.3. 
Storage and Handling 
PBI-0451 should be stored at controlled room temperature (15 °C to 30 °C [59°F to 86°F]) or as 
otherwise labeled. 
Drug product should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
drug product should not be stored in a container other than the container in which it is supplied. 
Consideration should be given to handling, preparation, and disposal through measures that 
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minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure. 
A sufficient quantity of PBI-0451 (and matching placebo tables) to complete the study will be 
shipped to the investigator or qualified designee from Pardes or its designee. 
Refer to the latest version of the IB for additional information. 
5.3. 
Dosage and Administration  
 PBI-0451: 2 × 350 mg tablets administered orally twice daily (BID) (1400 mg/day) with 
food for 5 days (10 total doses) 
 Placebo: 2 × placebo to match PBI-0451 tablets administered orally BID with food for 
5 days (10 total doses) 
Subjects will take their first dose of study drug (PBI-0451 or placebo) with food as soon as 
possible after randomization, with the first dose designated as Day 1, and the second dose taken 
with the evening meal on Day 1 to ensure that a full total daily dose (1400 mg PBI-0451) is 
taken on the first day of treatment. Study drug will be taken with food, approximately 12 hours 
between doses, at approximately the same time for each BID dose for the remainder of 5 days of 
treatment. 
5.4. 
Prior and Concomitant Medications 
Concomitant use of certain medications or herbal/natural supplements and study drug may result 
in PK interactions resulting in increases or decreases in exposure of study drug or the 
medications. 
The following medications are disallowed from screening through completion of study treatment. 
If a subject requires use of a disallowed medication, a request for such use must be reviewed by 
Pardes and, if approved, the subject may continue to participate in the study. 
 Any and all illegal or illicit drug use (eg, amphetamines, cocaine, opiates), including use 
of prescription drugs outside the care of the prescribing physician 
 Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance  
5.5. 
Accountability for Study Drugs  
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. This includes acknowledgment of receipt of each shipment of study drug (quantity and 
condition). All used and unused study drug dispensed to subjects must be returned to the site. 
Each study site must keep accountability records that capture: 
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 The date received and quantity of study drug  
 The date, subject number, and the study drug kit number dispensed 
The date and quantity of used and unused study drug returned, along with the initials of the 
person recording the information. 
5.5.1. 
Investigational Medicinal Product Return or Disposal 
Pardes recommends that used and unused study drug supplies be destroyed at the site. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
CRO, the site may destroy used (empty or partially empty) and unused study drug supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for the electronic trial master file. If study drug is destroyed at the site, the investigator must 
maintain accurate records for all study drugs destroyed. Records must show the identification 
and quantity of each unit destroyed, the method of destruction, and the person who disposed of 
the study drug. Upon study completion, copies of the study drug accountability records must be 
filed at the site. Another copy will be returned to CRO.  
If the site does not have an appropriate SOP for drug destruction, used and unused study drug 
supplies are to be sent to the designated disposal facility for destruction. The study monitor will 
provide instructions for disposal return. 
The study monitor will review study drug supplies and associated records at periodic intervals. 
For both disposal options listed above, the study monitor must first perform drug accountability. 
 
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6. 
STUDY PROCEDURES 
The study assessments to be conducted for each randomized subject are presented in Table 1 and 
described in the following sections. The investigator must document any deviation from the 
protocol procedures and notify Pardes and CRO.  
6.1. 
Informed Consent 
Written informed consent must be obtained from each prospective subject before initiation of 
any screening procedure.  
6.1.1. 
Consent for Optional Research 
Subjects who provide additional, specific consent may provide additional samples for optional 
biomarker research as described in Section 3.7. 
6.2. 
Subject Enrollment and Treatment Assignment 
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to randomization and that subjects remain eligible for the duration of the study. 
Once informed consent has been obtained, all screening tests and assessments have been 
conducted, and study eligibility has been confirmed, a subject will be randomized to receive 
PBI-0451 or placebo on Day 1. Up to 50 subjects at select sites who provide separate specific 
consent will participate in an intensive PK substudy. 
Entry into screening does not guarantee enrollment into the study. To manage the total study 
enrollment, Pardes, at its sole discretion, may suspend screening and/or enrollment at any site or 
study-wide at any time. 
6.3. 
Pretreatment Assessments 
Screening assessments may be considered as baseline/Day 1 if the subject is eligible for the 
study and is randomized and receives the first dose of study drug on same day.  
6.3.1. 
Screening Visit 
Prospective subjects will be screened ≤ 5 days prior to randomization to determine eligibility for 
participation in the study. The following will be performed and documented at screening: 
 Obtain written informed consent 
 Obtain medical history 
 Complete physical examination, including vital signs, body weight, and height 
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 Testing for SARS-CoV-2 N-antibodies using the Roche Elecsys® Anti-SARS-CoV-2 
assay 
 MT nasal swabs for SARS-CoV-2 RAT  
 MT nasal swabs and saliva samples, as appropriate, for SARS-CoV-2 IVA, qRT-PCR, 
and sequence analysis  
 Blood sample collection for the following analyses: hematology, chemistry, serology 
(HIV-1, HBV, HCV, SARS-CoV-2), serum pregnancy test (women of childbearing 
potential only, see Appendix 3) 
 Serum/urine pregnancy test (females of childbearing potential only) 
 12-lead ECG 
 Patient-reported outcomes (COVID-19 symptom questionnaire) and any hospitalizations 
or acute/critical care visits (eg, non-admitted hospital or other care facility)  
 Review of AEs and concomitant medication 
From the time of obtaining informed consent through administration of the first dose of study 
drug, record all SAEs, as well as any AEs related to protocol-specified procedures on the 
Adverse Events electronic case report form (eCRF). All other untoward medical occurrences 
observed during the screening period, including exacerbation or changes in medical history, are 
considered medical history (see Section 7.2). 
6.3.2. 
Baseline/Day 1 Assessments 
Note: Screening assessments may be considered as baseline/Day 1 assessments if the subject 
meets eligibility requirements, is randomized, and receives the first dose of study drug on same 
day.  
The following assessments will be completed on Day 1. The investigator must have received the 
results from either a direct SARS-CoV-2 antigen or qRT-PCR test and results from the 
serum/urine pregnancy test (females of childbearing potential only) and confirmed eligibility 
prior to randomization. Serology tests results for HIV, HBV, HCV and SARS-CoV-2 are not 
required for eligibility. 
At the time of randomization, subjects will be assigned a unique subject number via the IXRS. 
The following study assessments must be completed prior to the administration of the first dose 
of study drug: 
 Complete physical examination, including vital signs, body weight, and height 
 MT nasal swabs for SARS-CoV-2 RAT  
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 MT nasal swabs and saliva samples, as appropriate, for SARS-CoV-2 IVA, qRT-PCR, 
and sequence analysis  
 Blood sample collection for the following analyses: hematology, chemistry, serology 
(HIV-1, HBV, HCV, SARS-CoV-2), serum pregnancy test (women of childbearing 
potential only, see Appendix 3) 
 Creatinine clearance (CLCR) (Cockcroft-Gault) 
 Estimated glomerular filtration rate (eGFR, using Chronic Kidney Disease Epidemiology 
Collaboration [CKD-EPI] 2021) 
 12-lead ECG 
 Biomarker sample for optional genomic testing 
 Patient-reported outcomes (COVID-19 symptom questionnaire) and any hospitalizations 
or acute/critical care visits (eg, non-admitted hospital or other care facility) since last 
study visit, optional household transmission survey 
 Review of AEs and concomitant medications 
 Dispense study drug for all 10 doses  
Subjects will take their first dose of study drug with food immediately after randomization 
and completion of Day 1 assessments with the second dose taken with the evening meal on 
Day 1. The investigator will counsel subjects as to the importance of adherence to dosing and 
taking study drug at approximately the same times each day (see Section 5.3). 
The following Day 1 assessments will occur after the subject has taken their first dose of 
study drug: 
 Single PK sample 
 Intensive PK sampling (substudy subjects only) (Note that the intensive PK sample may 
be collected at any study visit from Day 1 to 5.) 
6.4. 
Treatment Assessments 
During treatment, individual study visits must occur on separate calendar days within the visit 
window, with the time(s) of sample collection recorded. 
Study procedures and assessments during treatment Days 2 to 5 are outlined in Table 1. 
Symptom-driven physical examination, including vital signs; sample collection for SARS-CoV-2 
RAT, qRT-PCR, and IVA; and review of AEs and concomitant medications will occur at study 
visits on Days 2, 3, and 5.  
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Assessments on Day 5 will also include a single PK sample, an evaluation of “survival status” 
(see Table 1), completion of the optional household transmission survey, and sample collection 
for SARS-CoV-2 sequence analysis (if appropriate).  
6.5. 
Posttreatment Assessments 
Posttreatment study procedures and assessments at Days 10, 15, and 28 are outlined in Table 1.  
Subjects who experience a relapse in symptom(s) after having no COVID-19 symptom(s) for 
≥3 days or have a positive RAT (or clinic qRT-PCR test) after testing negative by RAT or 
qRT-PCR will be requested to return to clinic within 2 days for MT swab and saliva samples for 
RAT, qRT-PCR, and sequencing. 
A Week 24 follow-up assessment will be performed for all subjects (via telephone, televisit, or 
clinic visit, as convenient). Information regarding ongoing or recurrent COVID-19 symptoms, 
survival status, pregnancy status (for female subjects of childbearing potential and female 
partners of male subjects), and any hospitalizations or acute/critical care visits (eg, non-admitted 
hospital or other care facility) that have occurred since the last study visit will be collected.  
6.6. 
Assessments for Early Discontinuation from Study 
If a subject prematurely discontinues study drug, for example as a result of an AE, every attempt 
should be made to keep the subject in the study and continue to perform the required 
study-related procedures until stabilization per the investigator. If this is not possible or 
acceptable to the subject or investigator, the subject may be withdrawn from the study and 
undergo an ET visit within 72 hours of permanently discontinuing the study drug as outlined in 
Table 1. Evaluations indicating abnormal results believed to be possibly or probably related to 
study drug at the ET visit should be repeated weekly or as often as deemed appropriate by the 
investigator until the abnormality resolves, returns to baseline level, or is otherwise explained.  
6.7. 
Pharmacokinetics Assessments 
Plasma samples will be collected for measurement of PBI-0451 concentrations and estimation of 
PK parameters (and metabolite[s], as applicable). Plasma collection for subjects participating in 
the intensive PK substudy may occur at any study visit from Day 1 (the first dose of study drug) 
to Day 5. Samples will be drawn at the following time points relative to PBI-0451 dosing:  
Predose (≤ 5 minutes before dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and (optional) 10-12-hours 
postdose.  
A single PK sample will be collected from all subjects at study visits at baseline/Day 1 (after the 
first dose of study drug) and Day 5  
Any remaining PK samples will be stored in a plasma bank and may be used for exploratory 
assessments, such as metabolites, protein binding, endogenous markers of drug-drug interactions, 
biomarkers of host responsiveness, and other investigational experiments. 
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6.8. 
Safety Assessments 
Safety will be evaluated throughout the study. Refer to Table 1 for the schedule of assessments. 
Collection of any additional assessments for routine safety monitoring at additional time points is 
at the discretion of the investigator based on GCP. 
6.8.1. 
Adverse Events/Concomitant Medications/Protocol Restrictions 
Evaluation for AEs, review of concomitant medications, and review of protocol restrictions will 
occur as outlined in Table 1. Refer to Section 7 for information regarding AEs. 
Concomitant use of certain medications or herbal/natural supplements and study drug may result 
in PK interactions resulting in increases or decreases in exposure of study drug or the 
medications. 
Medications that are disallowed from screening through completion of study treatment are listed 
below. If a subject requires use of a disallowed medication, a request for such use must be 
reviewed by Pardes and, if approved, the subject may continue to participate in the study. 
 Any and all illegal or illicit drug use (eg, amphetamines, cocaine, opiates), including use 
of prescription drugs outside the care of the prescribing physician 
 Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance  
6.8.2. 
Patient-Reported Outcomes 
Subjects will complete the following daily self-reported outcomes as outlined in Table 1. 
 COVID-19 symptoms questionnaire  
 Hospitalizations or acute/critical care visits (eg, nonadmitted hospital or other care 
facility) that have occurred since the last study visit  
6.8.3. 
Household Transmission Survey 
Subjects may complete the optional household transmission survey of confirmed SARS-CoV-2 
infections in subject’s household members as outlined in Table 1. 
6.8.4. 
ECG assessment 
ECG assessments will be conducted throughout the study as outlined in Table 1. Subjects should 
rest quietly in the supine position for a minimum of 5 minutes prior to each scheduled ECG 
acquisition and should remain in that position until the recording is complete. 
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6.8.5. 
Physical Examination 
Complete and symptom-driven physical examinations will be conducted throughout the study as 
outlined in Table 1. The complete physical examination conducted at screening will include the 
following assessments:  
 A complete physical examination must include source documentation of general 
appearance, and the following body systems: head, neck, thyroid; eyes, ears nose, throat, 
mouth, and tongue; chest (excluding breasts); respiratory; cardiovascular; lymph nodes, 
abdomen; skin, hair, nails; musculoskeletal; neurological.  
 Review medical history, including history of allergies, prior and current use of nicotine or 
nicotine-containing products, alcohol and illegal drug use, and prior (≤ 30 days) and 
current medication use. 
6.8.6. 
Vital Signs 
The schedule of vital signs assessments is provided in Table 1. Vital sign measurements include 
blood pressure, heart rate, respiration rate, and temperature and should be taken once subjects 
have been seated or in the supine position for a minimum of 5 minutes. A subject’s position for 
measurement should remain consistent throughout the study.  
6.8.7. 
Body Mass Index  
Height and weight will be collected at screening for calculation of body mass index for inclusion 
criteria. 
6.8.8. 
Clinical Laboratory Tests/Assessments 
Blood and urine samples for safety evaluations will be collected throughout the study as outlined 
in Table 1. 
6.8.8.1. 
Blood Samples 
Blood samples will be collected for the following laboratory analyses: 
 Hematology: Hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell 
count with differential (absolute and percentage), including lymphocytes, monocytes, 
neutrophils, eosinophils, basophils, and mean corpuscular volume  
 Coagulation panel: D-dimer, prothrombin time, activated partial thromboplastin time and 
international normalized ratio  
 Chemistry: alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total 
bilirubin, direct and indirect bilirubin, total cholesterol, high-density lipoprotein, low-density 
lipoprotein, triglycerides, total protein, albumin, lactic acid dehydrogenase, creatine 
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phosphokinase, bicarbonate, blood urea nitrogen, calcium, chloride, creatinine (see below), 
glucose, phosphorus, magnesium, potassium, sodium, uric acid, and amylase (reflex lipase 
testing is performed in subjects with total amylase > 1.5 × upper limit of normal) 
 Serum pregnancy test (females of childbearing potential only) 
 Serology (SARS-CoV-2 [using the Roche Elecsys® Anti-SARS-CoV-2 assay], HIV-1, 
HBV [hepatitis B serum antigen; hepatitis B core antibody], HCV [hepatitis C antibody, 
reflex to HCV RNA]) 
6.8.8.2. 
Urine Samples 
Urine samples will be collected for urinalysis.  
6.8.9. 
Creatinine Clearance and Estimated Glomerular Filtration Rate  
Weight will be collected at screening to calculate CLCR and eGFR.  
 CLCR (using the Cockcroft-Gault method based on serum creatinine and actual body 
weight as measured at screening): 
 
 eGFR (using CKD-EPI 2021) expressed as a single equation:  
eGFRcr = 142 × min(Scr/κ, 1) × max(Scr/κ, 1)-1.200 × 0.9938Age × 1.012 [if female] 
where: 
Scr = serum creatinine in mg/dL 
κ = 0.7 (females) or 0.9 (males) 
α = -0.241 (female) or -0.302 (male) 
min(Scr/κ, 1) is the minimum of Scr/κ or 1.0 
max(Scr/κ, 1) is the maximum of Scr/κ or 1.0 
Age (years) 
(140 – Age [years]) × (Weight [kg]) 
(× 0.85 for females) = CLCR (mL/min) 
72 × (Serum Creatinine [mg/dL]) 
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6.9. 
Virology Assessments 
MT nasal swab and saliva samples for virology assessment will be collected throughout the study 
as outlined in Table 1. The following virologic analyses are planned: 
 SARS-CoV-2 IVA: TCID50 (infected Vero E6 cell immunoassay) 
 SARS-CoV-2 sequence analysis (MT nasal swab only) 
 SARS-CoV-2 RAT (lateral flow immunoassay; MT nasal swab only) 
 SARS-CoV-2 qRT-PCR  
6.10. 
Sample Storage 
Stored biological samples may be used by Pardes or its research partner(s) for future testing to 
provide additional data to answer questions that relate to the main study (refer to Section 3.6). At 
the end of this study, these samples may be retained in storage by Pardes for a period up to 
15 years. If subjects provide additional specific consent, residual PK samples will be destroyed 
no later than 15 years after the end of study.  
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7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT 
7.1. 
Definitions of Adverse Events and Serious Adverse Events 
7.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a clinical study subject administered a study drug 
that does not necessarily have a causal relationship with the study drug. An AE can therefore be 
any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use 
of a study drug, whether or not the AE is considered related to the study drug. Adverse events 
may also include pretreatment or posttreatment complications that occur as a result of 
protocol-specified procedures or special situations (Section 7.1.3). Preexisting events that 
increase in severity or change in nature during or as a consequence of participation in the clinical 
study will also be considered AEs. 
An AE does not include the following: 
 Medical or surgical procedures, such as surgery, endoscopy, tooth extraction, and 
transfusion. The condition that led to the procedure may be an AE and must be reported. 
 Preexisting diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen 
 Situations in which an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions) 
 Overdose without clinical sequelae (Section 7.1.3) 
 Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed and not related to a protocol-specified procedure is not an AE but 
rather considered to be preexisting and should be documented as medical history. 
Preexisting events that increase in severity or change in nature after study drug initiation or 
during study treatment or as a consequence of participation in the clinical study are considered 
AEs. 
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7.1.2. 
Serious Adverse Events 
A SAE is defined as an event occurring at any time during the study that results in the following: 
 Death 
 A life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at 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.) 
 Inpatient hospitalization or prolongation of existing hospitalization 
 Persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 A medically important event or reaction. Such events may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes constituting SAEs. Medical and scientific 
judgment must be exercised to determine whether such an event is reportable under 
expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, and development of drug dependency or 
drug abuse.  
7.1.3. 
Study Drugs and Concomitant Therapy Special Situations Reports 
Special situation reports (SSRs) include all reports of medication error, abuse, misuse, overdose, 
occupational exposure, drug interactions, exposure via breastfeeding, unexpected benefit, 
transmission of infectious agents via the drug product, counterfeit or falsified medicine, and 
pregnancy, regardless of an associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, preparation for 
administration, or administration of a study drug while the study drug is in the control of a health 
care professional, patient, or consumer. Medication errors may be classified as a medication error 
without an AE, which includes situations of missed dose; medication error with an AE; 
intercepted medication error; or potential medication error. 
Abuse is defined as persistent or sporadic intentional excessive use of a study drug by a subject. 
Misuse is defined as any intentional and inappropriate use of a study drug that is not in 
accordance with the protocol instructions or the local prescribing information. 
An overdose is defined as an accidental or intentional administration of a quantity of a study 
drug given per administration or cumulatively that is above the maximum recommended dose as 
per protocol or in the product label (as it applies to the daily dose of the subject in question). In 
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cases of a discrepancy in drug accountability, overdose will be established only when it is clear 
that the subject has taken excess dose(s). Overdose cannot be established when the subject 
cannot account for the discrepancy, except in cases in which the investigator has reason to 
suspect that the subject has taken the additional dose(s). 
Occupational exposure is defined as exposure to a study drug as a result of one’s professional or 
nonprofessional occupation. 
Drug interaction is defined as any drug/drug, drug/food, or drug/device interaction. 
Unexpected benefit is defined as an unintended therapeutic effect where the results are judged to 
be desirable and beneficial.  
Transmission of infectious agents is defined as any suspected transmission of an infected agent 
through a study drug. 
Counterfeit or falsified medicine is defined as any study drug with a false representation of (a) its 
identity, (b) its source, or (c) its history. 
7.2. 
Assessment of Adverse Events and Serious Adverse Events 
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity and for final review and confirmation of accuracy of event information and 
assessments. 
7.2.1. 
Assessment of Causality for Study Drugs and Procedures 
The investigator or qualified subinvestigator is responsible for assessing AE relationship to study 
drug using clinical judgment and the following considerations: 
 No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (eg, preexisting condition, underlying disease, 
intercurrent illness, concomitant medication). 
 Yes: There is reasonable possibility that the AE may have been caused by the study drug. 
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting.  
The relationship of an AE to a study procedure (eg, invasive procedures such as venipuncture or 
biopsy) should be assessed using the following considerations: 
 No: Evidence exists that the AE has an etiology other than the study procedure. 
 Yes: The AE occurred as a result of the study procedure (eg, venipuncture). 
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7.2.2. 
Assessment of Severity  
The severity of AEs will be graded using the Division of AIDS Toxicity Grading Scale, Version 
2.1. For each episode, the highest grade attained should be reported as defined in the grading 
scale (Appendix 4). 
7.3. 
Investigator Reporting Requirements and Instructions  
7.3.1. 
Requirements for Collection Prior to Study Drug Initiation 
After informed consent, but prior to initiation of study drug, the following types of events must 
be reported on the applicable eCRFs: all SAEs and AEs related to protocol-specified procedures. 
7.3.2. 
Adverse Events 
Following initiation of study drug, collect all AEs, regardless of cause or relationship to study 
drug, until Day 28, and report them on the eCRFs as instructed. 
All AEs should be followed until resolution or until the AE is stable, if possible. Pardes may 
request that certain AEs be followed beyond the protocol-specified follow-up period. 
7.3.3. 
Serious Adverse Events 
All SAEs, regardless of cause or relationship to study drug or a protocol-specified procedure, 
that occur after a subject consents to participate in the study (ie, after signing the ICF) through 
study Day 28, must be reported on the applicable eCRFs and to the CRO PVE as instructed 
below in this section.  
Any SAEs and deaths that occur after Day 28, regardless of causality, should also be reported. 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
Investigators are not obligated to actively seek SAEs after study Day 28; however, if the 
investigator learns of any SAEs that occur after Day 28, and the event is deemed relevant to the 
use of study drug, the investigator should promptly document and report the event to CRO PVE. 
Instructions for reporting SAEs are described in Section 7.4.1. 
7.3.4. 
Study Drug Special Situations Reports 
All study drug special situations that occur from study drug initiation through study Day 28 must 
be reported to CRO PVE (Section 7.4.2). AEs and SAEs resulting in SSRs must be reported in 
accordance with the AE and SAE reporting guidance. 
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7.3.5. 
Concomitant Therapy Reports 
7.3.5.1. 
Concomitant Therapy Special Situations Report 
SSRs involving a concomitant therapy (not considered study drug) that occur after the subject 
first consents to participate in the study (ie, after signing the ICF) through study Day 28, must be 
reported to CRO PVE utilizing the paper SSR (Section 7.4.2.3). 
7.3.5.2. 
Concomitant Therapy Report 
Special situations involving concomitant medications do not need to be reported on the SSR 
form; however, for special situations that result in AEs due to a concomitant medication, the AE 
should be reported on the AE form.  
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation. 
All clinical sequelae in relation to these SSRs will be reported as AEs or SAEs at the same time 
using the AE eCRF and/or the SAE report form. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available. 
7.4. 
Reporting Process for Serious Adverse Events and Special Situation Reports 
7.4.1. 
Serious Adverse Event Reporting Process 
 For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be transmitted by email or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers. 
 Additional information may be requested to ensure the timely completion of accurate safety 
reports. 
 Any medications necessary for treatment of the SAE must be recorded in the concomitant 
medication section of the subject’s eCRF and the SAE narrative section of the Safety Report 
Form eCRF. 
7.4.1.1. 
Electronic Serious Adverse Event Reporting Process  
 Site personnel will record all SAE data on the applicable eCRFs and transmit the SAE 
information to CRO PVE within 24 hours of the investigator’s knowledge of the event from 
ICF signature through study Day 28.  
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 If it is not possible to record and transmit the SAE information electronically, record the SAE 
on the paper SAE reporting form and transmit to CRO PVE within 24 hours: 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
 If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. If the database is not locked, any SAE reported via paper must be 
transcribed as soon as possible on the applicable eCRFs and transmitted to CRO PVE. 
7.4.1.2. 
Paper Serious Adverse Event Reporting Process 
 All SAEs will be recorded on the SAE report form and transmitted by email or fax within 
24 hours of the investigator’s knowledge of the event to the attention of CRO PVE from ICF 
signature through study Day 28. 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
7.4.2. 
Special Situations Reporting Process  
7.4.2.1. 
Electronic Special Situations Reporting Process for Study Drug 
 Site personnel will record all special situation data on the applicable eCRFs and transmit the 
information to CRO PVE from study drug initiation through study Day 28.  
 If for any reason it is not possible to record the special situation information electronically, 
record the special situation on the paper SSR form and transmit to CRO PVE: 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
 If a special situation has been reported via a paper form because the eCRF database has been 
locked, no further action is necessary. If the database is not locked, any special situation 
reported via paper must be transcribed as soon as possible on the applicable eCRFs and 
transmitted to CRO PVE. 
 See Section 7.4.2.3 for instructions on reporting special situations with concomitant 
medications.  
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7.4.2.2. 
Paper Special Situations Reporting Process for Study Drug 
 All special situations will be recorded on the SSR form and transmitted by email or fax 
within 24 hours of the investigator’s knowledge of the event to the CRO PVE from study 
drug initiation through Day 28. 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
7.4.2.3. 
Reporting Process for Concomitant Medications 
 Special situations that involve concomitant medications that are not considered study drug 
must be reported within 24 hours of the investigator’s knowledge of the event to CRO PVE 
utilizing the paper SSR form to: 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
 Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation. 
 Special situations involving concomitant medications do not need to be reported on the SSR 
form; however, special situations that result in AEs due to a concomitant medication, must be 
reported as AEs. 
7.4.2.4. 
Pregnancy Reporting Process 
 The investigator should report pregnancies in female study subjects and/or female partners of 
male subjects that are identified after initiation of study drug and throughout the study, 
including the posttreatment follow-up period, to CRO PVE using the pregnancy report form 
within 24 hours of becoming aware of the pregnancy. Contact details for transmitting the 
pregnancy report form are as follows: 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
 The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate 
a pregnancy without medical reasons. 
 Any other premature termination of pregnancy (eg, a spontaneous abortion, an induced 
therapeutic abortion due to complications or other medical reasons) must be reported within 
24 hours as an SAE, as described in Section 7.4.1. The underlying medical reason for this 
procedure should be recorded as the AE term. 
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 A spontaneous abortion is always considered to be an SAE and will be reported as described 
in Section 7.4.1. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to the CRO PVE. 
 The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome of the pregnancy/partner pregnancy should be reported to CRO 
PVE using the pregnancy outcome report form. If the end of the pregnancy/partner 
pregnancy occurs after the study has been completed, the outcome should be reported 
directly to CRO PVE.  
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
 Refer to Appendix 3 for pregnancy precautions, definition of female of childbearing 
potential, and contraceptive requirements. 
7.5. 
Sponsor Reporting Requirements 
Depending on relevant local legislation and regulations, including the applicable FDA Code of 
Federal Regulations, the European Union Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation and regulations, Pardes may be required to 
expedite to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions, or 
SUSARs. In accordance with the European Union Clinical Trials Directive (2001/20/EC), Pardes 
or a specified designee will notify worldwide regulatory agencies and the relevant IEC(s) in 
concerned Member States of applicable SUSARs as outlined in current regulations. 
Assessment of expectedness for SAEs will be determined by CRO PVE using reference safety 
information specified in the IB or relevant local label, as applicable.  
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.  
7.6. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Laboratory abnormalities without clinical significance are not to be recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, urinalysis) that require 
medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as AEs or SAEs as applicable. In addition, laboratory or other 
abnormal assessments (eg, ECGs, x-rays, vital signs) that are associated with signs and/or 
symptoms must be recorded as AEs or SAEs if they meet the definition of an AE or SAE as 
described in Sections 7.1.1 and 7.1.2, respectively. If the laboratory abnormality is part of a 
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syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result (ie, decreased 
hemoglobin). 
Severity should be recorded and graded according to the Division of AIDS Toxicity Grading 
Scale, Version 2.1 (Appendix 4). AEs associated with laboratory abnormalities should be graded 
on the basis of the clinical severity in the context of the underlying conditions; this may or 
may not be in agreement with the grading of the laboratory abnormality. 
7.7. 
Toxicity Management  
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the CRO medical monitor, who will have a discussion with the investigator and decide the 
appropriate course of action. Whether or not considered treatment related, all subjects 
experiencing AEs must be monitored periodically until symptoms subside, any abnormal 
laboratory values have resolved or returned to baseline levels or are considered irreversible, or 
until there is a satisfactory explanation for the changes observed.  
Severity of AEs should be recorded and graded according to the following: 
 Grade 1 (Mild) clinical AE defined as mild symptoms causing no or minimal interference 
with usual social and functional activities with intervention not indicated will continue with 
study participation. 
 Grade 2 (Moderate) clinical AE defined as moderate symptoms causing greater than minimal 
interference with usual social and functional activities with intervention indicated will 
continue with study participation if interventions are not contraindicated and the investigator 
and medical monitor agree to continue. 
 Grade 3 (Severe) clinical AEs defined as severe symptoms causing inability to perform usual 
social and functional activities with intervention or hospitalization indicated will discontinue 
study drug administration and continue with study follow-up assessments. 
 Grade 4 (Potentially Life-Threatening) clinical AEs are defined as potentially life-threatening 
symptoms causing inability to perform basic self-care functions with intervention indicated 
to prevent permanent impairment, persistent disability; and will discontinue study 
participation. 
 Grade 5 indicates death. 
Any questions regarding toxicity management should be directed to the CRO medical monitor. 
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8. 
STATISTICAL CONSIDERATIONS 
Summary statistics will be used to analyze the study data. Any statistical testing will be 
conducted to ensure that the overall alpha = 0.05 level (2 sided). Unless otherwise specified, data 
summaries and analyses will be reported by treatment group. Details of the statistical methods 
will be provided in the statistical analysis plan (SAP), including any deviations from the original 
planned analyses. 
8.1. 
Analysis Objectives and Endpoints 
The primary, secondary, and exploratory study objectives and endpoints are listed in Section 2.  
8.2. 
Planned Analysis 
8.2.1. 
Interim Analysis 
An analysis of the primary and secondary endpoints will be conducted after 210 subjects 
complete the Day 28 study visit.  
8.2.2. 
Final Analysis 
The final analysis will be conducted after the last randomized subject has completed their 
Week 24 follow-up visit or discontinued the study, all outstanding data queries have been 
resolved, and the database has been cleaned and locked. 
8.3. 
Analysis Conventions 
8.3.1. 
Analysis Sets 
8.3.1.1. 
All Enrolled Analysis Set 
The all enrolled analysis set includes all subjects who sign the ICF. This is the primary analysis 
set for disposition. 
8.3.1.2. 
Intention-to-Treat Analysis Set 
The intention-to-treat (ITT) analysis set includes all randomized subjects. This is the primary 
analysis set for demographics and data listings. 
8.3.1.3. 
Modified Intention to Treat Analysis Set 
The modified intention-to-treat (mITT) analysis set includes all randomized subjects with 
≥ 2 symptoms consistent with COVID-19 ≤ 5 days prior to randomization and a positive 
SARS-CoV-2 test (RT-PCR or RAT) ≤ 24 hours prior to randomization who received ≥ 1 dose 
of study drug. This is the primary analysis set for all clinical endpoints. 
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8.3.1.4. 
Modified Intent to Treat Virologic Analysis Set 
The mITT virologic analysis set is a subset of the mITT analysis set that includes subjects who 
had detectable infectious SARS-CoV-2 at baseline/Day 1. This is the primary analysis set for the 
primary efficacy endpoint. 
8.3.1.5. 
Safety Analysis Set 
The safety analysis set includes all randomized subjects who received ≥ 1 dose of study drug. 
This is the primary analysis set for safety analyses. 
8.3.1.6. 
Pharmacokinetics Analysis Set 
The PK analysis set includes all subjects who participated in the intensive PK substudy and have 
≥ 1 nonmissing PK concentration reported by the PK laboratory. This is the primary analysis set 
for PK analyses 
8.3.2. 
Data Handling Conventions 
8.3.2.1. 
Missing Data 
Missing data can have an impact upon the interpretation of the study data. As this study is of 
short duration, it is anticipated that missing data will be minimal. Every effort will be made to 
obtain required data at each scheduled evaluation from all subjects who have been enrolled. Any 
imputations of missing data will be described in the SAP.  
8.3.2.2. 
Adjustments for Multiplicity 
No adjustments for multiplicity are planned. 
8.4. 
Demographic and Baseline/Day 1 Characteristics Analysis 
Demographics (age, gender, race/ethnicity), and subject characteristics (SARS-CoV-2 Pango 
lineage, SARS-CoV-2 seropositivity, qRT-PCR, time since onset of symptoms) will be 
summarized by treatment group using descriptive statistics for the ITT analysis set.  
8.5. 
Efficacy Analysis 
8.5.1. 
Primary Analysis 
The primary efficacy endpoint is the proportion of subjects below the LOD for infectious 
SARS-CoV-2 on Day 3 by IVA. For the primary endpoint, differences between PBI-0451 and 
placebo will be evaluated using stratum-adjusted Mantel-Haenszel proportions (adjusted for 
randomization strata). The proportion of subjects below the LOD for infectious SARS-CoV-2 at 
other time points will be summarized in a similar manner. 
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8.5.2. 
Secondary Analyses 
The time to resolution of targeted COVID-19 symptoms will be estimated with the Kaplan-Meier 
method and summarized by treatment group. Differences between treatment groups will be 
determined using a Wilcoxon-Gehan test. The analysis of time to resolution of each targeted 
COVID-19 symptom will be conducted in a similar manner. 
The proportion of subjects with COVID-19 related hospitalization or death from any cause will 
be summarized by treatment group. Differences between treatment groups will be assessed using 
Mantel-Haenszel proportions.  
The number of COVID-19 related hospitalizations or acute/critical care visits and the number of 
days in any hospital unit for the treatment of COVID-19 will be summarized. Differences 
between treatment groups will be assessed using a van Elteren test stratified by the 
randomization factors. 
SARS-CoV-2 viral load kinetics will be summarized by study visit. Differences between the 
treatment groups will be assessed with a van Elteren test stratified by the randomization factors.  
SARS-CoV-2 clinical and virologic rebound will be summarized by the amount of viral RNA 
detected at baseline/Day 1, time to loss of clinical symptoms, time to negative RAT or IVA, and 
time to the first confirmed reappearance of symptoms and/or a positive RAT or qRT-PCR 
sample. 
A correlation of the results of IVA, RAT, and qRT-PCR assessments will be evaluated. 
8.6. 
Safety Analysis 
8.6.1. 
Extent of Exposure 
A subject’s extent of exposure to study drug will be determined from the study drug 
administration data. Exposure data will be summarized using descriptive statistics and listed.  
8.6.2. 
Adverse Events 
Clinical and laboratory AEs will be coded using the current version of the Medical Dictionary 
for Regulatory Activities. A treatment-emergent AE is defined as any AE that begins on or after 
the date of first dose of study drug up to the date of last dose of study drug plus 14 days. 
Treatment-emergent AEs, SAEs, and AEs leading to premature discontinuation of study 
drug/study will be summarized by treatment, system organ class, and preferred term.  
Laboratory results and change from predose values for selected laboratory tests will be 
summarized by treatment at scheduled visits. The incidence of treatment-emergent laboratory 
abnormalities (Division of AIDS Toxicity Grading Scale) will be summarized by treatment. 
By-subject listings of safety data will be provided. 
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8.6.3. 
Laboratory Evaluations 
Listings of individual subject laboratory results will be provided. Selected laboratory data will be 
summarized using only observed data. Data and change from baseline/Day 1 at all scheduled 
time points will be summarized.  
Graded laboratory abnormalities will be defined in the SAP. Incidence of treatment-emergent 
laboratory abnormalities, defined as values that increase ≥ 1 toxicity grade from baseline/Day 1 
at any postbaseline time point up to and including the date of last dose of study drug plus 14 days 
will be summarized by treatment group. If baseline/Day 1 data are missing, any graded 
abnormality (ie, ≥ Grade 1) will be considered treatment emergent. 
Laboratory abnormalities that occur before the first dose of study drug or after the subject has 
discontinued study drug for ≥ 14 days will be listed. 
8.6.4. 
Other Safety Evaluations 
Vital signs and (safety) ECG data will be listed. 
8.7. 
Pharmacokinetics Analysis  
PBI-0451 plasma concentrations and PK parameters will be derived using noncompartmental 
methods (including metabolite[s] as applicable) and listed and summarized using descriptive 
statistics.  
PBI-0451 plasma concentrations from the PK substudy and sparse sampling from the overall 
study population will be used in a population PK analysis and reported separately.  
8.8. 
Sample Size 
The sample size will be approximately 210 subjects to account for approximately 60% of 
randomized subjects who are anticipated to be SARS-CoV-2 negative by IVA at baseline/Day 1 
and would be excluded from the mITT virologic analysis set. It should be noted that this sample 
size is sufficient with ≥ 80 power to detect a > 19% absolute difference in the proportion of 
subjects below the LOD for infectious SARS-CoV-2 virus (99% vs 81%) at Day 3 by IVA 
among subjects who had detectable infectious SARS-CoV-2 at baseline/Day 1. This assumes 
alpha = 0.05 and that 40% of subjects have detectable infectious virus at baseline/Day 1. 
 
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9. 
RESPONSIBILITIES 
9.1. 
Investigator Responsibilities 
9.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with International Council 
for Harmonisation (of Technical Requirements for Pharmaceuticals for Human Use) (ICH) 
E6(R2) addendum to its guideline for GCP and applicable laws and regulations. 
9.1.2. 
Financial Disclosure 
The investigator and subinvestigators will provide prompt and accurate documentation of their 
financial interest or arrangements with Pardes or proprietary interests in the study drug during 
the course of a clinical study. This documentation must be provided prior to the investigator’s 
(and any subinvestigator’s) participation in the study. The investigator and subinvestigator agree 
to notify Pardes or CRO of any change in reportable interests during the study and for 1 year 
following completion of the study. Study completion is defined as the date when the last subject 
completes the protocol-defined activities. 
9.1.3. 
Institutional Review Board/Independent Ethics Committee Review 
and Approval 
The investigator (or designated personnel as appropriate according to local regulations) will 
submit this protocol, the ICF, and any accompanying material to be provided to the subject (such 
as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator. 
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects. 
9.1.4. 
Informed Consent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study before undertaking any study-related procedures. The investigator 
must use the most current IRB/IEC-approved ICF for documenting written informed consent. 
Each ICF (or assent as applicable) will be appropriately signed and dated by the subject or the 
subject’s legally authorized representative, the person conducting the consent discussion, and an 
impartial witness (if required by IRB/IEC or local requirements).  
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The ICF will inform subjects about genomic testing and/or planned sample retention. In addition 
to the study-specific ICF to be signed by each subject participating in the study, subjects will be 
required to document agreement to provide additional samples or to allow the use of the 
remainder of their already-collected specimens for optional future research, in accordance with 
applicable regulations. In addition to the study specific ICF to be signed by each subject 
participating in the study, subjects will be required to document agreement to provide additional 
samples for optional genomic research. The results of the tests done on the samples will not be 
given to the subject or the investigator. 
9.1.5. 
Confidentiality 
The investigator must ensure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of birth) will be recorded on any form 
or biological sample submitted to Pardes, IRB/IEC, or the laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions in accordance with local 
regulations. NOTE: The investigator must keep a screening log with details for all subjects 
screened and enrolled in the study, in accordance with the site procedures and regulations. 
Subject data will be processed in accordance with all applicable regulations.  
The investigator agrees that all information received from Pardes or its partner(s), including but 
not limited to the IB, this protocol, CRFs/eCRFs, study drug information, and any other study 
information, remain the sole and exclusive property of Pardes during the conduct of the study 
and thereafter. This information is not to be disclosed to any third party (except employees or 
agents directly involved in the conduct of the study or as required by law) without prior written 
consent from Pardes. The investigator further agrees to take all reasonable precautions to prevent 
the disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain. 
9.1.6. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file and (2) subject 
clinical source documents. 
The investigator’s study file will contain the protocol/amendments, CRFs/eCRFs, IEC and 
government approval with correspondence, the ICF(s), drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence. 
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The required source data should include sequential notes containing at least the following 
information for each subject: 
 Subject identification 
 Documentation that subject meets eligibility criteria (ie, medical history, physical 
examination, and confirmation of diagnosis) to support inclusion and exclusion criteria 
 Documentation of the reason(s) a consented subject is not enrolled 
 Participation in study (including study number) 
 Study discussed and date of informed consent 
 Dates of all visits 
 Documentation that protocol-specific procedures were performed 
 Results of efficacy parameters, as required by the protocol 
 Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return 
 Record of all AEs and other safety parameters (start and end date; causality and severity) and 
documentation that adequate medical care has been provided for any AE 
 Concomitant medication (start and end date; dose if relevant; dose changes) 
 Date of study completion and reason for early discontinuation if it occurs 
All clinical study documents must be retained by the investigator for ≥ 2 years or according to 
local laws, whichever is longer, after the last approval of a marketing application in an ICH 
region (ie, US, Europe, or Japan) and until there are no pending or planned marketing 
applications in an ICH region; or, if no application is filed or if the application is not approved 
for such indication, for 2 years after the investigation is discontinued and regulatory authorities 
have been notified. Investigators may be required to retain documents longer if specified by 
regulatory requirements, by local regulations, or by an agreement with Pardes. The investigator 
must notify Pardes before destroying any clinical study records. 
Should the investigator wish to assign the study records to another party or move them to another 
location, Pardes must be notified in advance. 
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Pardes to store 
these records securely away from the site so that they can be returned sealed to the investigator 
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in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site. 
9.1.7. 
Case Report Forms 
For each subject consented, an eCRF casebook will be completed by an authorized study staff 
member whose training for this function is completed in the EDC system. The eCRF casebook 
will capture only the data required per the protocol schedule of events and procedures. The 
Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only after all data 
related to eligibility have been received. Data entry should be performed in accordance with the 
CRF Completion Guidelines (CCGs). Subsequent to data entry, a study monitor will perform 
source data verification within the EDC system. System-generated or manual queries will be 
issued in the EDC system as data discrepancies are identified by the monitor or CRO staff who 
routinely review the data for completeness, correctness, and consistency. The site investigator, 
site coordinator, or other designee is responsible for responding to the queries in a timely 
manner, within the system, either by confirming the data as correct or updating the original entry, 
and providing the reason for the update (eg, data entry error). Original entries, as well as any 
changes to data fields, will be stored in the audit trail of the system. At a minimum, prior to any 
interim time points or database lock (as instructed by CRO), the investigator will use his/her 
login credentials to confirm that the forms have been reviewed and that the entries accurately 
reflect the information in the source documents. At the conclusion of the study, CRO will 
provide the site investigator with a read-only archive copy of the data entered by that site. This 
archive must be stored in accordance with the records retention requirements outlined in 
Section 9.1.6. 
9.1.8. 
Investigator Inspections 
The investigator will make available all source documents and other records for this study to 
CRO’s appointed study monitors, IRBs/IECs, and regulatory or health authority inspectors. 
9.1.9. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
9.2. 
Sponsor Responsibilities 
9.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Pardes. The investigator must submit all protocol modifications to the IRB/IEC in 
accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented. 
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9.2.2. 
Study Report and Publications 
A clinical study report will be prepared and provided to the regulatory agency. Pardes will ensure 
that the report meets the standards set out in the ICH Guideline for Structure and Content of 
Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.  
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met: 
 The results of the study in their entirety have been publicly disclosed by or with the 
consent of Pardes in an abstract, manuscript, or presentation form or the study has been 
completed at all study sites for ≥ 2 years. 
 The investigator will submit to Pardes any proposed publication or presentation along 
with the respective scientific journal or presentation forum ≤ 30 days before submission 
of the publication or presentation.  
 No such communication, presentation, or publication will include Pardes’s confidential 
information (see Section 9.1.5). 
 The investigator will comply with Pardes’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to 
withhold publication or presentation for an additional 60 days to obtain patent protection 
if deemed necessary. 
9.3. 
Joint Investigator/Sponsor Responsibilities 
9.3.1. 
Payment Reporting 
Investigators and their study staff may be asked to provide services performed under this 
protocol (eg, attendance at investigator meetings). If required under the applicable statutory and 
regulatory requirements, Pardes will capture and disclose to federal and state agencies any 
expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value. 
9.3.2. 
Access to Information for Monitoring 
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries in the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on-site) are resolved. 
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9.3.3. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or Pardes/CRO may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority, the 
investigator agrees to notify the CRO medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Pardes/CRO access to records, facilities, and 
personnel for the effective conduct of any inspection or audit. 
9.3.4. 
Study Discontinuation 
Both Pardes and the investigator reserve the right to terminate the study at any time. Should this 
be necessary, both parties will arrange discontinuation procedures and notify the subjects, 
appropriate regulatory authority, and IRB/IEC. In terminating the study, Pardes/CRO and the 
investigator will ensure that adequate consideration is given to the protection of the subjects’ 
interests. 
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10. 
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main protease inhibitor, decreases viral load and accelerates recovery from clinical 
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16(5):E1008536. doi:10.1371/journal.ppat.1008536. 
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al. 2021. Genomic evidence for reinfection with SARS-CoV-2: a case study. Lancet 
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FG, Harper SA, Hirshon JM, et al. 2019. Clinical practice guidelines by the Infectious 
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and institutional outbreak management of seasonal influenzaa. Clin Infect Dis. 
68(6):895–902. doi:10.1093/cid/ciy874. 
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2021. The variants question: What is the problem? Journal of Medical Virology. 
93(12):6479–6485. doi:10.1002/jmv.27196. 
 
 
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11. 
APPENDICES 
Appendix 1. 
Investigator Signature Page 
Appendix 2 
Pandemic Risk Assessment and Mitigation Plan 
Appendix 3 
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements 
Appendix 4  
Toxicity Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities 
Appendix 5 
Modified Centers for Disease Control and Prevention: Underlying Medical 
Conditions Associated with Higher Risk for Severe COVID-19 
 
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Appendix 1. 
Investigator Signature Page 
 
PARDES BIOSCIENCES, INC. 
2173 SALK AVE SUITE 250 
PMB #052 
CARLSBAD, CA 92008 
 
STUDY ACKNOWLEDGMENT 
 
A Phase 2 Double-blind, Randomized Study to Evaluate the Antiviral Activity, Safety, and 
Efficacy of Orally Administered PBI-0451 Compared with Placebo in Nonhospitalized 
Symptomatic Adults with COVID-19 
Original  
07 July 2022 
This protocol has been approved by Pardes Biosciences, Inc. The following signature documents 
this approval. 
Brian Kearney, PharmD 
 
 
Name (Printed) 
Chief Development Officer  
 
Signature 
 
 
 
 
Date 
 
 
INVESTIGATOR STATEMENT 
 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein, and I will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Pardes or its partner(s). I will discuss this material with them to ensure 
that they are fully informed about the drugs, the study, and the undertaking of confidentiality. 
I agree that all information received from Pardes or its partner(s), including but not limited to the 
Investigator’s Brochure, this protocol, CRFs/eCRFs, study drug information, and any other study 
information, remain the sole and exclusive property of Pardes during the conduct of the study 
and thereafter. This information is not to be disclosed to any third party (except employees or 
agents directly involved in the conduct of the study or as required by law) without prior written 
7/8/2022
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consent from Pardes. I further agree to take all reasonable precautions to prevent the disclosure 
by any employee or agent of the study site to any third party or otherwise into the public domain. 
 
 
 
Principal Investigator Name (Printed) 
 
Signature 
 
 
 
 
Date 
 
Site Number 
 
 
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Appendix 2 
Pandemic Risk Assessment and Mitigation Plan 
During an ongoing pandemic, potential risks associated with subjects being unable to attend 
study visits have been identified for this study.  
These risks can be summarized as follows: 
1) Study drug supplies to subjects and sites: 
a) Subjects may be unable to return to the site to get the study drug, or the site may be 
unable to accept any subject visits. Without study drug, a subject would not be able to 
stay on the study drug as planned per protocol. 
Mitigation plan: Study drug supplies may be provided to the subject from the site without 
a clinic visit, once it is confirmed that the subject may safely continue on study drug as 
determined by the investigator. A virtual study visit, via telephone or video conferencing, 
must be performed prior to remote study drug resupply. At the earliest opportunity, the 
site will schedule in-person subject visits and return to the protocol’s regular schedule of 
assessments. A qualified courier may be utilized to ship the study drug from sites to study 
subjects if permitted by local institutional review board (IRB)/ independent ethics 
committee (IEC) as applicable and with Pardes's approval. 
b) Shipments of study drug could be delayed because of transportation issues. Without study 
drug, a subject would not be able to stay on the study drug as planned per protocol. 
Mitigation plan: The sites' study drug inventory should be closely monitored. Site staff 
should notify Pardes or delegate if they foresee shortage in study drug inventory or if 
there is any interruption in local shipping service. Pardes will continue to monitor 
inventory at the study drug depot and study sites. Manual shipments will be triggered as 
necessary. 
2) Subject safety monitoring and follow-up: 
a) Subjects may be unable or unwilling to come to the study site for their scheduled study 
visits as required per protocol. 
Mitigation plan: For subjects who may be unable or unwilling to come to the study site 
for their scheduled study visits as required per protocol, the Investigator or qualified 
delegate will conduct a virtual study visit, via telephone or video conferencing, to assess 
the subject within the target visit window date whenever possible. During the virtual 
study visit, the following information at minimum will be reviewed:  
i) Confirm if subject has experienced any adverse events (AEs)/serious adverse events 
(SAEs)/special situations (including pregnancy) and follow-up on any unresolved 
AE/SAEs. 
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ii) Review current list of concomitant medications and document any new concomitant 
medications. 
iii) If applicable, confirm electronic diary questionnaires and patient-reported outcomes 
have been completed and transmitted. 
iv) If applicable, confirm subjects study drug supply is sufficient to last until the next 
planned visit date. If study drug resupply is needed, it will be provided as described 
above in Item 1 above. 
v) If applicable, remind subject to maintain current dosing and to keep all dispensed 
study drug kits for return at the next onsite visit. 
b) Subjects may be unable or unwilling to travel to the site for planned assessments 
(eg, safety blood draws); hence samples may not be sent for central laboratory analyses. 
Mitigation plan: Local laboratories may be used as appropriate to monitor subject safety 
until the subject can return to the site for their scheduled visit per protocol. Any 
laboratory assessments conducted at a local lab due to the pandemic will be documented 
accordingly. Pregnancy testing may be performed using a home urine pregnancy test if 
local laboratory pregnancy testing is not feasible. 
c) Subjects may be unable or unwilling to attend the study visit to sign an updated informed 
consent form (ICF) version. 
Mitigation plan: The site staff will follow their approved consent process and remain in 
compliance with local IRB/IEC and national laws and regulations. Remote consent will 
be allowed if has been approved by the local IRB/IEC. The consent process will be 
documented and confirmed by the normal consent procedure at the earliest opportunity. 
3) Protocol and monitoring compliance: 
a) Protocol deviations may occur if scheduled visits cannot occur as planned per protocol. 
Mitigation plan: If it is not possible to complete a required scheduled procedure, an 
unscheduled visit should be conducted as soon as possible when conditions allow. The 
situation should be recorded and explained as a protocol deviation. Any missed subject 
visits or deviation to the protocol due to the pandemic must be reported in the eCRF and 
described in the clinical study report. Any virtual study visits that are conducted in lieu of 
clinic visits due to the pandemic will be documented as a protocol deviation related to the 
pandemic. 
b) Monitors may be unable to carry out source data review or source data verification (SDV) 
or study drug accountability or assess protocol and Good Clinical Practice compliance. 
This may lead to delays in SDV, an increase in protocol deviations, or under-reporting of 
AEs. 
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Mitigation plan: The study monitor is to remain in close communication with the site to 
ensure data entry and query resolution. In compliance with CRO policy, a remote SDV 
should not be arranged). The study monitor is to reference the Study Monitoring Plan for 
guidance on how to conduct a remote monitoring visit. The study staff is to save and 
document all relevant communication in the study files. The status of sites that cannot 
accept monitoring visits and/or subjects on site, must be tracked centrally and updated on 
a regular basis. 
4) Missing data and data integrity: 
a) There may be an increased amount of missing data due to subjects missing 
visits/assessments. This could have an impact on the analysis and the interpretation of 
clinical study data.  
Mitigation plan: Implications of a pandemic on methodological aspects for the study will 
be thoroughly assessed and documented, and relevant actions will be taken as appropriate 
(ie, modification of the statistical analysis plan) and in compliance with Regulatory 
Authorities’ guidance. Overall, the clinical study report will describe the impact of the 
pandemic on the interpretability of study data. 
Risks will be assessed continuously, and temporary measures will be implemented to mitigate 
these risks as part of a mitigation plan, as described above. These measures will be 
communicated to the relevant stakeholders as appropriate and are intended to provide alternate 
methods that will ensure the evaluation and assessment of the safety of subjects who are enrolled 
in this study.  
Since these potential risks are considered mitigated with the implementation of these measures, 
the expected benefit-risk assessment of PBI-0451 in study subjects remains unchanged. 
 
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Appendix 3 
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements 
1) Definitions 
a. Definition of Childbearing Potential 
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming postmenopausal unless the 
subject is permanently sterile or has medically documented ovarian failure. 
Females are considered to be in a postmenopausal state when they are ≥ 54 years of age with 
cessation of previously occurring menses for ≥ 12 months without an alternative cause. In 
addition, women < 54 years of age with amenorrhea ≥ 12 months may also be considered 
postmenopausal if their follicle-stimulating hormone level is in the postmenopausal range and 
they are not using hormonal contraception or hormonal replacement therapy. Permanent 
sterilization includes hysterectomy, bilateral oophorectomy, or bilateral salpingectomy in a 
female subject of any age. 
b. Definition of Male Fertility 
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless the subject is permanently sterile by bilateral orchidectomy or medical 
documentation. 
2) 
Contraception Requirements for Female Subjects 
a. 
Study Drug Effects on Pregnancy and Hormonal Contraception 
PBI-0451 is contraindicated in pregnancy because a malformation effect is unknown, taking into 
consideration class effects and genotoxic potential. PBI-0451 has insufficient data to exclude the 
possibility of a clinically relevant interaction with hormonal contraception that results in reduced 
contraception efficacy. Therefore, as there is limited safety information available to exclude the 
possibility of DDIs between PBI-0451 and hormonal contraception, hormonal contraception 
methods are not an acceptable form of contraception for female subject participating in this 
study. Female subjects must use one of the highly effective contraceptive methods outlined 
below in Section 2.b.  
Refer to the latest version of the IB for additional information. 
b. Contraception Requirements for Female Subjects of Childbearing Potential 
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures with a failure rate of < 1% per year. They must also not rely on hormonal 
contraceptives as a form of birth control during the study. They must have a negative serum 
pregnancy test at screening and a negative pregnancy test on Day 1 prior to randomization. 
Pregnancy tests will be performed at monthly intervals thereafter until the end of the 
contraception requirement. 
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Duration of required contraception for female subjects in this study is from screening and until 
90 days after the last dose of study drug. Female subjects must agree to one of the following 
contraceptive methods: 
 Complete abstinence from intercourse of reproductive potential. Abstinence is an 
acceptable method of contraception only when it is in line with the subject’s preferred 
and usual lifestyle. 
Or 
 Consistent and correct use of ≥ 1 of the following methods of birth control:  
 Nonhormonal intrauterine device (IUD)  
 Bilateral tubal occlusion (upon medical assessment of surgical success) 
 Vasectomy in the male partner (upon medical assessment of surgical success) 
 Consistent and correct use of a double barrier method of contraception using two of 
the following barriers concurrently: 
- Male condoms 
- Female condoms 
- Female diaphragm (‘cap’) 
Inclusion of methods of contraception in this list of permitted methods does not imply that the 
method is approved in any country or region. Methods should only be used if locally approved. 
Local requirements of combining a single barrier method with either IUD or surgical sterilization 
are endorsed.  
Female subjects must refrain from egg donation and in vitro fertilization during treatment and for 
≥ 28 days after the last dose of study drug. 
3) 
Contraception Requirements for Male Subjects 
Male subjects must agree to use a male condom and an additional effective contraceptive method 
with their female partners, if their female partners are of childbearing potential (see Section 1.a), 
from treatment Day 1 until 90 days following the last dose of study drug. Effective methods of 
contraception for female partners of male subjects may include hormonal contraception or one of 
the methods outlined in Section 2.b. 
Male subjects must refrain from sperm donation from screening throughout the study period and 
for at least 90 days following the last dose of study drug. 
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4) 
Unacceptable Birth Control Methods 
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method. A female condom and a male condom should not be used 
together. 
5) 
Procedures to be Followed in the Event of Pregnancy 
Female subjects will be instructed to notify the investigator if they become pregnant or suspect 
they are pregnant at any time from screening to 90 days after the last dose of study drug. Study 
drug must be discontinued immediately if pregnancy is confirmed during treatment. 
Male subjects whose partner has become pregnant or suspects she is pregnant from screening to 
90 days after the last dose of study drug must report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.4.2.4. 
 
 
 
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Appendix 4  
Toxicity Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities 
Please refer to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (Version 2.1 – July 2017) 
 
 
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Appendix 5 
Modified Centers for Disease Control and Prevention: Underlying 
Medical Conditions Associated with Higher Risk for Severe 
COVID-19 
At least 1 underlying medical condition associated with increased risk for severe COVID-19 
illness (“high-risk” and consequently increased risk of hospitalization and death). Applicable 
comorbidities are to be derived from the Centers for Disease Control and Prevention list of 
high-risk underlying conditions as outlined below and detailed at 
https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html 
a. ≥65 years of age 
b. Asthma 
c. Active cancer 
d. Cerebrovascular disease 
e. Chronic kidney disease (if no history of CKD Stage 3 or above) 
f. Chronic lung diseases limited to: 
i. Interstitial lung disease 
ii. Pulmonary embolism 
iii. Pulmonary hypertension 
iv. Bronchiectasis 
v. COPD (chronic obstructive pulmonary disorder) 
g. Chronic liver diseases limited to: 
i. Cirrhosis (Child-Pugh A) 
ii. Non-alcoholic fatty liver disease 
iii. Alcoholic liver disease 
iv. Autoimmune hepatitis 
h. Cystic fibrosis 
i. Diabetes mellitus, Type 1 and Type 2 
j. Disabilities 
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i. Attention-Deficit/Hyperactivity Disorder (ADHD) 
ii. Cerebral Palsy 
iii. Congenital Malformations (Birth Defects) 
iv. Limitations with self-care or activities of daily living 
v. Intellectual and Developmental Disabilities 
vi. Learning Disabilities 
vii. Spinal Cord Injuries 
k. Heart conditions such as: 
i. heart failure 
ii. Coronary artery disease 
iii. Cardiomyopathies 
l. HIV (human immunodeficiency virus) 
m. Mental health disorders limited to: 
i. Mood disorders, including depression 
ii. Schizophrenia spectrum disorder 
n. Neurological conditions limited to dementia 
o. Obesity (BMI ≥30 kg/m2) 
p. Primary Immunodeficiencies 
q. Solid organ or blood stem cell transplantation 
r. Tuberculosis 
s. Use of corticosteroids or other immunosuppressive medications 
t. Immune deficiencies (except people with moderate to severe immune 
compromise due to a medical condition or receipt of immunosuppressive 
medications or treatments) 
 
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PBI-0451 
PBI-0451-0001 
 
Summary of Changes 
Pardes Biosciences, Inc. 
 
Amendment 1 
1 
Confidential 
 
26 August 2022 
 
 
SUMMARY OF CHANGES 
 
PBI-0451-0002 
 
A Phase 2 Double-blind, Randomized Study to Evaluate the Antiviral Activity, Safety, and Efficacy of 
Orally Administered PBI-0451 Compared with Placebo in Nonhospitalized Symptomatic Adults with 
COVID-19 
The following summary of changes outline the 
rationale for the changes made from the prior 
version of the study protocol to the current 
version of the study protocol 
Original, 07 July 2022 
Amendment 1, 26 August 2022 
 
General: 
Administrative corrections to spelling, grammar, formatting, version updates, 
pagination, and cross-references are not itemized.
 
Section and 
page 
Synopsis, Primary Endpoint, page 7 
Original Text 
 
Proportion of subjects below the limit of detection (LOD) for infectious SARS-
CoV-2 on Day 3 of treatment by infectious virus assay (IVA) 
New Text 
 
Proportion of subjects below the limit of detection (LOD) for infectious SARS-
CoV-2 on Day 3 of treatment by infectious virus assay (IVA) from mid-turbinate 
(MT) swabs 
Rationale for 
Change
Detail of swab method requested by FDA. 
 
Section and 
page 
Synopsis, Secondary Endpoint, page 8 
Original Text 
 
Presence of SARS-CoV-2 infection based on IVA, quantitative reverse 
transcriptase polymerase chain reaction (qRT-PCR), and rapid antigen test 
(RAT), as specified in the Clinical Virology Analysis Plan (CVAP)
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New Text 
 
Presence of SARS-CoV-2 virus, viral RNA or viral antigen based on IVA, 
quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and 
rapid antigen test (RAT), as specified in the Clinical Virology Analysis Plan 
(CVAP)
Rationale for 
Change
Detail of IVA methodology requested by FDA. 
 
Section and 
page 
Synopsis, Inclusion Criteria, Page 9 
Original Text 
New Text Inserted 
AND 
4. Male and nonpregnant, nonlactating female subjects 18 to < 65 years of age. 
Females must have a negative serum or urine pregnancy test at screening and 
prior to the first dose of study drug unless permanently sterile or >2 years 
postmenopause. 
New Text 
3. Received primary vaccination series as defined by Centers for Disease Control and 
Prevention (CDC). (Subjects should be advised during informed consent that alternate 
therapies may be available outside of study participation.) 
AND 
5. Male and nonpregnant, nonlactating female subjects 18 to < 65 years of age. 
Females must have a negative serum or urine pregnancy test at screening and 
prior to the first dose of study drug unless permanently sterile or in a 
postmenopausal state. 
Rationale for 
Change 
Clarified subjects must meet minimum vaccination standards to participate and must 
be informed of alternate therapies at request of Advarra IRB. Numbered items 
formatted. Criteria 5 aligned with Appendix 3 of protocol and referenced, for clarity 
and consistency.
 
Section and 
page 
Synopsis, Exclusion Criteria, Page 10-11 
Original Text 
10. If unvaccinated, ≥1 Centers for Disease Control and Prevention defined 
underlying medical condition associated with an increased risk of developing severe 
illness from COVID-19. 
AND 
New Text Inserted 
AND 
11. ≥1 SARS-CoV-2 vaccination (including a booster) within 3 months prior to 
randomization or anticipated to receive a SARS-CoV-2 vaccination (including a 
booster) during the 28-day study period 
AND 
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13. Currently begin treated or expected to be treated for COVID-19 with monoclonal 
antibodies, convalescent serum, or direct-acting antiviral agents 
New Text 
1. Considered at high-risk of developing severe illness from COVID-19 defined as ≥1 
CDC underlying medical condition associated with an increased risk of developing 
severe illness from COVID-19 (see Appendix 5) 
AND 
2. Unvaccinated against SARS-CoV-2 (defined as having not completed a primary 
vaccination series) 
AND 
3. Any SARS-CoV-2 vaccination within 3 months prior to randomization or 
anticipated to receive a SARS-CoV-2 vaccination (including a booster) during the 28-
day study period 
AND 
5. Currently begin treated or expected to be treated for COVID-19 with monoclonal 
antibodies, convalescent serum, or direct-acting antiviral agents (all potential subjects 
should be informed of evolving treatment options during informed consent that 
alternate therapies may or may not be available to them outside of study participation) 
Rationale for 
Change 
Formatted numbering.  Excluded unvaccinated subjects from study participation at 
request of Advarra IRB. Clarified exclusion of subjects who have at least one CDC 
defined risk factor for developing severe COVID-19 illness (listed in Appendix 5) and 
by denoting that if subjects have begun treatment or expect to begin treatment of 
listed products, then they meet definition of high-risk and must be excluded.  All 
subjects (qualified or not) should be informed of available COVID-19 treatment 
options to reduce risk of severe COVID-19 disease progression.
 
Section and 
page 
Synopsis, Study Procedures/Frequency, Page 11 
Original Text 
Randomization will be stratified as follows: 
 
SARS-CoV-2 positive direct test diagnosis ≤ 3 days (target 30%) versus 
> 3 days from first onset of COVID-19 symptom(s) ≤ 5 days prior to 
randomization 
 
Vaccinated (ie, ≥1 dose of an approved vaccine) versus unvaccinated 
 
PK substudy participation versus nonparticipation 
 
New Text 
Randomization will be stratified as follows: 
 
SARS-CoV-2 positive direct test diagnosis ≤ 3 days (target 30%) versus 
> 3 days from first onset of COVID-19 symptom(s) ≤ 5 days prior to 
randomization 
 
Received primary vaccination series, alone versus any booster shots 
 
PK substudy participation versus nonparticipation 
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Rationale for 
Change 
Unvaccinated subjects excluded from participation at request of Advarra IRB. 
Stratification will now include subjects who have received primary vaccination only 
versus subjects who have a least one COVID-19 booster.
 
 
Section and 
page 
Synopsis, Patient Reported Outcomes, Page 11 
Original Text 
 
COVID-19 symptom questionnaire  
 
COVD-19 related hospitalizations or acute/critical care visits (eg, 
non-admitted hospital or other care facility) since the last study visit  
Hospitalization is defined as > 24 hours of acute care in a hospital or similar acute 
care facility, including emergency rooms or temporary facilities instituted to 
address medical needs of those with severe COVID-19. This includes any special 
medical care unit within an assisted living facility or nursing home.  
 
Optional household transmission survey of confirmed SARS-CoV-2 
infections in subject’s household members (baseline/Day 1 and Days 5, 10, 
15, and 28 or ET only) 
 
New Text 
 
COVID-19 symptom questionnaire  
 
COVID-19 weekly questionnaire 
 
COVD-19 related hospitalizations or acute/critical care visits (eg, 
non-admitted hospital or other care facility) since the last study visit  
Hospitalization is defined as > 24 hours of acute care in a hospital or similar acute 
care facility, including emergency rooms or temporary facilities instituted to 
address medical needs of those with severe COVID-19. This includes any special 
medical care unit within an assisted living facility or nursing home.  
 
Optional household transmission survey of confirmed SARS-CoV-2 
infections in subject’s household members (baseline/Day 1 and Days 5, 10, 
15, 28 or ET only, and rebound ad hoc visit (if applicable)) 
Rationale for 
Change 
Weekly COVID-19 questionnaire added at request of FDA.  Optional household 
transmission survey added to rebound ad hoc visit added to enhance rebound or re-
infection ad hoc analysis.
 
Section and 
page 
Synopsis, Serology Testing AND Virologic Assessments, Page 12 
Original Text 
Serology Testing: Serology samples at screening and/or baseline/Day 1 
AND 
 
SARS-CoV-2 (using the Roche Elecsys® Anti-SARS-CoV-2 assay) 
AND 
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Virologic Assessments: The following tests will be performed from mid-turbinate 
(MT) nasal swab and saliva samples at screening, baseline/Day 1, and Days 2, 3, 5, 
10, 15, 28 or early termination (ET) 
AND 
 
SARS-CoV-2 IVA (MT swab and saliva) at baseline/Day 1 and Days 2, 3, 5, 
and 10, only 
 
SARS-CoV-2 sequence analysis (MT swab) at baseline/Day 1 and Day 5 for 
all subjects to evaluate the potential for the development of resistance in 
response to treatment with PBI-0451. Additional time points may be 
evaluated in the case of virologic rebound or if the subject remains viremic at 
other study visits through Day 28 (ie, if SARS-CoV-2 RNA by qRT-PCR is 
≥ 3.85 log10 copies/mL, which is the threshold for the minimum amount of 
viral RNA required for whole genome sequencing).  
New Text 
Serology Testing: Serology samples at screening and/or baseline/Day 1 
AND 
 
SARS-CoV-2 N-antibodies (using the Roche Elecsys® Anti-SARS-CoV-2 
assay) 
AND 
Virologic Assessments: The following tests will be performed from mid-turbinate 
(MT) nasal swab and saliva samples at screening, baseline/Day 1, and Days 2, 3, 5, 
10, 15, 28 or early termination (ET), and rebound ad hoc visit (if applicable) 
AND 
 
SARS-CoV-2 IVA (MT swab and saliva) at baseline/Day 1 and Days 2, 3, 5, 
10, Day 15, rebound and early termination 
SARS-CoV-2 sequence analysis (MT swab) at baseline/Day 1 and Day 5 for all 
subjects to evaluate the potential for the development of resistance in response to 
treatment with PBI-0451. Additional time points may be evaluated in the case of 
virologic rebound or if the subject remains viremic at other study visits (ie, if SARS-
CoV-2 RNA by qRT-PCR is ≥ 3.85 log10 copies/mL, which is the threshold for the 
minimum amount of viral RNA required for whole genome sequencing). 
Rationale for 
Change
Additional detail of SARS-CoV-2 antibody test and additional timepoints added at 
rebound and/or beyond Day 10 at request of FDA.
 
Section and 
page 
Synopsis, Safety Assessments AND Medical Monitoring AND Rescue Therapy, Page 
12-13
Original Text 
Safety Assessments: 
AND 
 
Vital signs: All visits 
AND 
New Text Inserted 
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New Text 
Safety Assessments: 
AND 
 
Vital signs: All visits through Day 28 
AND 
Medical Monitoring 
A team of medically qualified individuals, including but not limited to, the Sponsor 
and the CRO Medical Monitors, and the Drug Safety Consultant are responsible for 
ongoing review of all AEs, concomitant medications, laboratory values (including 
virology), and vital signs (including pulse oximetry), worsening of symptoms 
(COVID-19 symptom questionnaire, including dyspnea), acute/critical care visits (eg, 
nonadmitted hospital or other care facility), and study drug discontinuations, at a 
minimum monthly basis throughout the study, per the Safety Monitoring Plan.  
Serious adverse events (eg, hospitalizations, life threatening events, medically 
important events, deaths) will be evaluated by the Sponsor and the CRO Medical 
Monitor within 24 hours after being reported by the Investigator.  Blinded study data 
will be evaluated for trends and any event which occurs in greater frequency will be 
evaluated for updating risk language and notifying the IRB and regulatory authorities, 
as required.   
Rescue Therapy 
Subjects who experience severe COVID-19 illness (defined in this study as sustained 
pulse oximetry <94%, a respiratory rate of >30 breaths/min, or dyspnea that requires 
medical attention) should discontinue study drug and be immediately referred by the 
Investigator to emergency care or treated by the Investigator for standard of care 
treatment of symptoms including, but not limited to, other antivirals, supplemental 
oxygen, corticosteroids, Janus kinase inhibitors, or interleukin-6 blockers, in 
accordance with the NIH Treatment Guidelines (NIH 2022). The subject should 
continue participation in the study, with study drug discontinued, for safety follow-up 
and clinical outcome of the medically attended visit. 
Rationale for 
Change 
Clarified vital signs assessed at all visits through Day 28. Medical Monitoring and 
Rescue Therapy details provided at request of Advarra IRB to ensure subject safety 
through study conduct.
 
Section and 
page 
Table 1. Study Procedures Table, Page 17-19 
Original Text
Table updated to reflect changes in body of text. 
New Text
Rationale for 
Change
Updates to table made based on requests from FDA, Advarra IRB, and administrative 
clarifications.
 
Section and 
page 
Section 1.4. Risk/Benefit Assessment for the Study, Page 24 
Original Text 
No clinical safety issues specifically related to PBI-0451 have been identified to date. 
Pomotrelvir (PBI-0451) 
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The expected benefit to subjects being treated with PBI-0451 is a rapid decrease of 
SARS-CoV-2 viral load within a short treatment period, without the need for 
coadministration of a second agent for pharmacoenhancement and its potential for 
DDIs and potentially reduce the duration of symptomatic illness and the risk of 
progression to more severe disease. 
Potential risks include unforeseen safety issues. For the population of subjects with 
SARS-CoV-2 infection, the expected benefit of eliminating SARS-CoV-2 virus 
within 5 days of treatment outweighs the risks associated with the possible 
development of previously unidentified safety issues. Subjects randomized to the 
placebo group may benefit from frequent medical monitoring during the study.  
The overall benefit/risk balance for this study is considered favorable.  
During a pandemic, additional potential risks to subjects may include interruptions to 
the study visit schedule and adherence to protocol-specified safety monitoring or 
laboratory assessments. Refer to Appendix 2 for details on the risks and risk 
mitigation strategy. 
New Text 
The overall benefit/risk balance for this study is considered favorable. 
The target patient population under study for this protocol is designed to exclude 
patients who are at high risk of progression to severe COVID-19 and thus for which 
there may be no approved or authorized treatments. 
During a pandemic, additional potential risks to subjects may include interruptions to 
the study visit schedule and adherence to protocol-specified safety monitoring or 
laboratory assessments. Refer to Appendix 2 for details on the risks and risk 
mitigation strategy 
Rationale for 
Change 
Section 1.4.1, Risk/Benefit for PBI-0451; Section 1.4.2, Risk/Benefit for Placebo; and 
Section 1.4.3, Potential Alternatives to Placebo added to provide more guidance and 
detail to Investigators at the request of Advarra IRB. 
 
Section and 
page 
Section 1.4.1. Risk/Benefit for PBI-0451, Page 24 
Original Text 
New Text Inserted 
New Text 
No clinical safety issues specifically related to PBI-0451 have been identified to date.  
The expected benefit to subjects being treated with PBI-0451 is a rapid decrease of 
SARS-CoV-2 viral load within a short treatment period, without the need for 
coadministration of a second agent for pharmacoenhancement and its potential for 
DDIs and potentially reduce the duration of symptomatic illness and the risk of 
progression to more severe disease. 
Potential risks include unforeseen safety issues, the lack of efficacy and the risk of 
progression to more severe COVID-19 disease progression.  For the population of 
subjects with SARS-CoV-2 infection, the expected benefit of eliminating SARS-
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CoV-2 virus within 5 days of treatment outweighs the risks associated with the 
possible development of previously unidentified safety issues. 
Rationale for 
Change 
Section 1.4.1, Risk/Benefit for PBI-0451; Section 1.4.2, Risk/Benefit for Placebo; and 
Section 1.4.3, Potential Alternatives to Placebo added to provide more guidance and 
detail to Investigators at the request of Advarra IRB.
 
Section and 
page 
Section 1.4.2. Risk/Benefit for Placebo, Page 24 
Original Text 
New Text Inserted 
New Text 
Subjects randomized to the placebo group may benefit from frequent medical 
monitoring during the study as there is a potential risk of severe COVID-19 disease 
progression 
Rationale for 
Change 
Section 1.4.1, Risk/Benefit for PBI-0451; Section 1.4.2, Risk/Benefit for Placebo; and 
Section 1.4.3, Potential Alternatives to Placebo added to provide more guidance and 
detail to Investigators at the request of Advarra IRB.
 
Section and 
page 
Section 1.4.3. Potential Alternatives to Placebo, Page 25 
Original Text 
New Text Inserted 
New Text 
Investigators should review all available treatment options for each individual subject, 
including those outside of this study, and risks associated with placebo with the 
potential subject.  The Investigator should refer to the “NIH Treatment Guidelines” 
(NIH 2022), and the CDC “Interim Clinical Considerations for COVID-19 Treatment 
in Outpatients” and “Underlying Medical Conditions Associated with Higher Risk for 
Severe COVID-19: Information for Healthcare Professionals” to appropriately discuss 
the alternative options and risks for being in this study (CDC 2022).  The potential 
participant should also be referred to or receive a printout of the CDC “People with 
Certain Medical Conditions” and “COVID-19 Treatments and Medications” which 
includes language appropriate for the lay person regarding medical conditions 
attributed to a higher risk of severe COVID-19 and potential treatment (CDC 2022). 
1. The following products are either FDA approved or authorized for emergency 
use for the treatment of mild-to-moderate COVID-19 in adults with positive 
results of direct SARS-CoV-2 viral testing, and who are at high risk for 
progression to severe COVID-19, including hospitalization or death, and are 
recommended as first line agents by the NIH Treatment Guidelines:  
 
Veklury (remdesivir) – FDA approved (Gilead Sciences 2022)   
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 
Paxlovid (nirmatrelvir) boosted with ritonavir – Emergency Use 
Authorization (US Food and Drug Administration 2022c) 
2. The following products have emergency use authorization by the FDA for the 
treatment of mild-to-moderate COVID-19 in adults with positive results of 
direct SARS-CoV-2 viral testing, and who are high risk for progression to 
severe COVID-19, including hospitalization or death, and for whom 
alternative COVID-19 treatment options approved or authorized by 
FDA are not accessible or clinically appropriate per the NIH Treatment 
Guidelines. 
 
Lagevrio (molnupiravir) – Emergency Use Authorization (US Food and Drug 
Administration 2022a) 
 
Bebtelovimab – Emergency Use Authorization (US Food and Drug 
Administration 2022b) 
3. The list of approved or authorized products is subject to change during the 
course of the study, the complete list of FDA products can be found here: 
https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-
regulatory-and-policy-framework/emergency-use-authorization#coviddrugs 
and the NIH Treatment Guidelines can be found here; 
https://www.covid19treatmentguidelines.nih.gov/ 
Rationale for 
Change 
Section 1.4.1, Risk/Benefit for PBI-0451; Section 1.4.2, Risk/Benefit for Placebo; and 
Section 1.4.3, Potential Alternatives to Placebo added to provide more guidance and 
detail to Investigators at the request of Advarra IRB.
 
Section and 
page 
Section 2. OBJECTIVES AND ENDPOINTS, Page 27 
Original Text 
 
Proportion of subjects below the limit of detection (LOD) for infectious SARS-
CoV-2 on Day 3 of treatment by infectious virus assay (IVA) 
AND 
 
Presence of SARS-CoV-2 infection based on IVA, quantitative reverse 
transcriptase polymerase chain reaction (qRT-PCR), and rapid antigen test 
(RAT), as specified in the Clinical Virology Analysis Plan (CVAP) 
New Text 
 
Proportion of subjects below the limit of detection (LOD) for infectious SARS-
CoV-2 on Day 3 of treatment by infectious virus assay (IVA) from mid-turbinate 
(MT) swabs 
AND 
 
Presence of SARS-CoV-2 virus, viral RNA, or viral antigen based on IVA, 
quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), 
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and rapid antigen test (RAT), as specified in the Clinical Virology 
Analysis Plan (CVAP) 
Rationale for 
Change
Detail of swab method and detail of IVA methodology requested by FDA. 
 
Section and 
page 
Section 3.1. Study Treatments, Page 29 
Original Text 
Randomization will be stratified as follows: 
 
SARS-CoV-2 positive direct test diagnosis ≤ 3 days (target 30%) versus 
> 3 days from first onset of COVID-19 symptom(s) ≤ 5 days prior to 
randomization 
 
Vaccinated (ie, ≥1 dose of an approved vaccine) versus unvaccinated 
 
PK substudy participation versus nonparticipation 
New Text 
Randomization will be stratified as follows: 
 
SARS-CoV-2 positive direct test diagnosis ≤ 3 days (target 30%) versus 
> 3 days from first onset of COVID-19 symptom(s) ≤ 5 days prior to 
randomization 
 
Received primary vaccination series, alone versus any booster shots 
 
PK substudy participation versus nonparticipation 
Rationale for 
Change 
Unvaccinated subjects excluded from participation at request of Advarra IRB. 
Stratification will now include subjects who have received primary vaccination only 
versus subjects who have a least one COVID-19 booster.
 
Section and 
page 
Section 3.3. Discontinuation Criteria, Page 30 
Original Text 
New Text Inserted 
New Text 
 
Subjects develop severe or critical COVID-19 illness defined as sustained pulse 
oximetry <94%, a respiratory rate of >30 breaths/min or dyspnea that requires 
medical attention 
Rationale for 
Change
Specific stopping rules for subjects who develop severe COVID-19 illness added at 
the request of Advarra IRB.
 
Section and 
page 
Section 3.3.1. Rescue Therapy for Discontinuation, Page 30 
Original Text 
New Text Inserted 
New Text 
Subjects who experience severe COVID-19 illness (defined in this study as sustained 
pulse oximetry <94%, a respiratory rate of >30 breaths/min, or dyspnea that requires 
medical attention) should discontinue study drug and be immediately referred by the 
Investigator to emergency care or treated by the Investigator for standard of care 
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treatment of symptoms including, but not limited to, other antivirals, supplemental 
oxygen, corticosteroids, Janus kinase inhibitors, or interleukin-6 blockers, in 
accordance with the NIH Treatment Guidelines (NIH 2022). The subject should 
continue participation in the study, with study drug discontinued, for safety follow-up 
and clinical outcome of the medically attended visit 
Rationale for 
Change
Specific guidance for rescue therapy during study conduct for subjects who 
experience severe COVID-19 illness added at the request of Advarra IRB.  
 
Section and 
page 
Section 4.2. Inclusion Criteria, Page 32 
Original Text 
New Text Inserted 
AND 
4. Male and nonpregnant, nonlactating female subjects 18 to < 65 years of age. 
Females must have a negative serum or urine pregnancy test at screening and 
prior to the first dose of study drug unless permanently sterile or >2 years 
postmenopause. 
New Text 
3. Received primary vaccination series as defined by Centers for Disease Control and 
Prevention (CDC). (Subjects should be advised during informed consent that alternate 
therapies may be available outside of study participation.) 
AND 
5. Male and nonpregnant, nonlactating female subjects 18 to < 65 years of age. 
Females must have a negative serum or urine pregnancy test at screening and 
prior to the first dose of study drug unless permanently sterile or in a 
postmenopausal state. 
Rationale for 
Change 
Clarified subjects must meet minimum vaccination standards to participate and must 
be informed of alternate therapies at request of Advarra IRB. Numbered items 
formatted. Criteria 5 aligned with Appendix 3 of protocol and referenced, for clarity 
and consistency.
 
Section and 
page 
Section 4.3. Inclusion Criteria, Page 33 
Original Text 
10. If unvaccinated, ≥1 Centers for Disease Control and Prevention defined 
underlying medical condition associated with an increased risk of developing severe 
illness from COVID-19. 
AND 
New Text Inserted 
AND 
11. ≥1 SARS-CoV-2 vaccination (including a booster) within 3 months prior to 
randomization or anticipated to receive a SARS-CoV-2 vaccination (including a 
booster) during the 28-day study period 
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AND 
13. Currently begin treated or expected to be treated for COVID-19 with monoclonal 
antibodies, convalescent serum, or direct-acting antiviral agents 
New Text 
1. Considered at high-risk of developing severe illness from COVID-19 defined as ≥1 
CDC underlying medical condition associated with an increased risk of developing 
severe illness from COVID-19 (see Appendix 5) 
AND 
2. Unvaccinated against SARS-CoV-2 (defined as having not completed a primary 
vaccination series) 
AND 
3. Any SARS-CoV-2 vaccination within 3 months prior to randomization or 
anticipated to receive a SARS-CoV-2 vaccination (including a booster) during the 28-
day study period 
AND 
5. Currently begin treated or expected to be treated for COVID-19 with monoclonal 
antibodies, convalescent serum, or direct-acting antiviral agents (all potential subjects 
should be informed of evolving treatment options during informed consent that 
alternate therapies may or may not be available to them outside of study participation) 
Rationale for 
Change 
Formatted numbering.  Excluded unvaccinated subjects from study participation at 
request of Advarra IRB. Clarified exclusion of subjects who have at least one CDC 
defined risk factor for developing severe COVID-19 illness (listed in Appendix 5) and 
by denoting that if subjects have begun treatment or expect to begin treatment of 
listed products, then they meet definition of high-risk and must be excluded.  All 
subjects (qualified or not) should be informed of available COVID-19 treatment 
options to reduce risk of severe COVID-19 disease progression.
 
Section and 
page 
5.1.1. Randomization, Page 35 
Original Text 
Randomization will be stratified as follows: 
 
SARS-CoV-2 positive direct test diagnosis ≤ 3 days (target 30%) versus 
> 3 days from first onset of COVID-19 symptom(s) ≤ 5 days prior to 
randomization 
 
Vaccinated (ie, ≥1 dose of an approved vaccine) versus unvaccinated 
 
PK substudy participation versus nonparticipation 
 
New Text 
Randomization will be stratified as follows: 
 
SARS-CoV-2 positive direct test diagnosis ≤ 3 days (target 30%) versus 
> 3 days from first onset of COVID-19 symptom(s) ≤ 5 days prior to 
randomization 
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 
Received primary vaccination series, alone versus any booster shots 
 
PK substudy participation versus nonparticipation 
Rationale for 
Change 
Unvaccinated subjects excluded from participation at request of Advarra IRB. 
Stratification will now include subjects who have received primary vaccination only 
versus subjects who have a least one COVID-19 booster.
 
Section and 
page 
6.3.1. Screening Visit, Page 39-40 
Original Text 
 
Testing for SARS-CoV-2 N-antibodies using the Roche Elecsys ® Anti-SARS-
CoV-2 assay 
 
AND 
 
Blood sample collection for the following analyses: hematology, chemistry, 
serology (HIV-1, HBV, HCV, SARS-CoV-2), serum pregnancy test (women of 
childbearing potential only, see Appendix 3) 
New Text 
Text Deleted 
AND 
 
Blood sample collection for the following analyses: serum pregnancy test (women 
of childbearing potential only, see Appendix 3) 
Rationale for 
Change 
Blood draws for serology tests: SARS-CoV-2 N-antibodies using the Roche Elecsys 
® Anti-SARS-CoV-2 assay, HIV-1, HBV, and HCV will only be done as part of 
baseline assessments to limit blood draw from patient.
 
Section and 
page 
6.3.2. Baseline/Day 1 Assessments, Page 40-41 
Original Text 
New Text Inserted 
 
 
Blood sample collection for the following analyses: hematology, chemistry, 
serology (HIV-1, HBV, HCV, SARS-CoV-2), serum pregnancy test (women of 
childbearing potential only, see Appendix 3) 
 
New Text Inserted
New Text 
 Testing for SARS-CoV-2 N-antibodies using the Roche Elecsys® 
Anti-SARS-CoV-2 assay 
 Blood sample collection for the following analyses: hematology, 
chemistry, serology (HIV-1, HBV, HCV), coagulation panel, serum 
pregnancy test (women of childbearing potential only, see Appendix 
3Error! Reference source not found.) 
 Urine sample collection for urinalysis 
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Rationale for 
Change
Correcting that all serology tests are completed as part of Baseline/Day 1 assessments, 
only. Corrected body text to match Table 1, Study Procedures Table. 
 
Section and 
page 
6.5. Posttreatment Assessments, Page 42 
Original Text 
Subjects who experience a relapse in symptom(s) after having no COVID-19 
symptom(s) for ≥3 days or have a positive RAT (or clinic qRT-PCR test) after testing 
negative by RAT or qRT-PCR will be requested to return to clinic within 2 days for 
MT swab and saliva samples for RAT, IVA, qRT-PCR, and sequencing.
New Text 
Subjects who experience a relapse in symptom(s) after having no COVID-19 
symptom(s) for ≥3 days or have a positive RAT (or clinic qRT-PCR test) after testing 
negative by RAT or qRT-PCR will be requested to return to clinic within 2 days for 
symptom-drive physical examination, vital signs, MT swab and saliva samples for 
RAT, IVA, qRT-PCR, and sequencing, household transmission survey, and review of 
AEs and concomitant medications 
Rationale for 
Change 
Added vital signs, AE and concomitant medicatin review to ad hoc rebound visits to 
ensure pulse oximetry is collected as part of safety monitoring for potential severe 
COVID-19 disease progression and optional household transmission survey for future 
analysis of rebound or reinfection. 
 
Section and 
page 
Section 6.7. Pharmacokinetic Assessments, Page 42-43 
Original Text 
Plasma samples will be collected for measurement of PBI-0451 concentrations and 
estimation of PK parameters (and metabolite[s], as applicable). Plasma collection for 
subjects participating in the intensive PK substudy may occur at any study visit from 
Day 1 (the first dose of study drug) to Day 5. Samples will be drawn at the following 
time points relative to PBI-0451 dosing:
New Text 
Plasma samples will be collected for measurement of PBI-0451 concentrations and 
estimation of PK parameters (and metabolite[s], as applicable). Some subjects will 
have PK assessed by sparse sampling and other subjects by intensive PK substudy. 
Plasma collection for subjects participating in the intensive PK substudy may occur at 
any study visit from Day 1 (the first dose of study drug) to Day 5. Samples for the 
intensive PK substudy will be drawn at the following time points relative to PBI-0451 
dosing: 
Rationale for 
Change
Clarification of text for comprehension of sparse PK sampling and intensive PK 
substudy sampling.
 
 
Section and 
page 
Section 6.8. Safety Assessments, Page 43 
Original Text 
Safety will be evaluated throughout the study. Refer to Table 1 for the schedule of 
assessments. Collection of any additional assessments for routine safety monitoring at 
additional time points is at the discretion of the investigator based on GCP 
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New Text 
Safety will be evaluated throughout the study, including physical examinations, vital 
signs, 12-lead ECG, laboratory studies (hematology, coagulation panel, chemistry, 
urinalysis), and review of AEs. Refer to Table 1 for the schedule of assessments. 
Collection of any additional assessments for routine safety monitoring at additional 
time points is at the discretion of the investigator based on GCP 
Rationale for 
Change
Body text expanded to reflect specific Safety Assessment in Table 1 for clarity. 
 
Section and 
page 
6.8.2. Patient Reported Outcomes, Page 43 
Original Text 
 
COVID-19 symptoms questionnaire  
 
Hospitalizations or acute/critical care visits (eg, nonadmitted hospital or other 
care facility) that have occurred since the last study visit 
New Text 
 
COVID-19 symptoms questionnaire  
 
COVID-19 weekly questionnaire 
 
Hospitalizations or acute/critical care visits (eg, nonadmitted hospital or other 
care facility) that have occurred since the last study visit 
Rationale for 
Change
Weekly COVID-19 questionnaire added at request of FDA.   
 
Section and 
page 
6.8.3. Household Transmission Survey, Page 44 
Original Text 
Subjects may complete the optional household transmission survey of confirmed 
SARS-CoV-2 infections in subject’s household members as outlined in Table 1. 
New Text 
Subjects may complete the optional household transmission survey of confirmed 
SARS-CoV-2 infections in subject’s household members as outlined in Table 1.  No 
specific identifying information will be collected. 
Rationale for 
Change
Clarifying no specific identifying information will be collected as part of household 
transmission survey to protect individual identities.
 
Section and 
page 
6.8.6 Vital Signs, Page 44 
Original Text 
The schedule of vital signs assessments is provided in Table 1. Vital sign 
measurements include blood pressure, heart rate, respiration rate, and temperature and 
should be taken once subjects have been seated or in the supine position for a 
minimum of 5 minutes. A subject’s position for measurement should remain 
consistent throughout the study 
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New Text 
The schedule of vital signs assessments is provided in Table 1.  Vital sign 
measurements include blood pressure, heart rate, respiration rate, pulse oximetry, and 
temperature and should be taken once subjects have been seated or in the supine 
position for a minimum of 5 minutes. A subject’s position for measurement should 
remain consistent throughout the study. 
Rationale for 
Change
Updated text to include pulse oximetry as part of vital signs assessments. 
 
Section and 
page 
6.8.8.1 Blood Samples, Page 45 
Original Text 
 
Serology (SARS-CoV-2 [using the Roche Elecsys® Anti-SARS-CoV-2 assay], 
HIV-1, HBV [hepatitis B serum antigen; hepatitis B core antibody], HCV 
[hepatitis C antibody, reflex to HCV RNA]) 
New Text 
 
Serology (SARS-CoV-2 N-antibodies [using the Roche Elecsys® Anti-SARS-
CoV-2 assay], HIV-1, HBV [hepatitis B serum antigen; hepatitis B core 
antibody], HCV [hepatitis C antibody, reflex to HCV RNA]) 
Rationale for 
Change
Additional detail of SARS-CoV-2 antibody test at request of FDA 
 
Section and 
page 
6.8.9. Creatinine Clearance and Estimated Glomerular Filtration Rate, Page 45 
Original Text
Weight will be collected at screening to calculate CLCR and eGFR.
New Text
Weight will be collected at Baseline/Day 1 to calculate CLCR and eGFR.
Rationale for 
Change
Body weight collected at Baseline/Day 1 for consistency with safety laboratory 
draws.
 
Section and 
page 
Section 7.8. Medical Monitoring, page 55-56 
Original Text
New Text Inserted
New Text 
A team of medically qualified individuals, including but not limited to, the Sponsor 
and the CRO Medical Monitors, and the Drug Safety Consultant are responsible for 
ongoing review of all AEs, concomitant medications, laboratory values (including 
virology), and vital signs (including pulse oximetry), worsening of symptoms 
(COVID-19 symptom questionnaire, including dyspnea), acute/critical care visits (eg, 
nonadmitted hospital or other care facility), and study drug discontinuations, at a 
minimum monthly basis throughout the study, per the Safety Monitoring Plan.  
Serious adverse events (eg, hospitalizations, life threatening events, medically 
important events, deaths) will be evaluated by the Sponsor and the CRO Medical 
Monitor within 24 hours after being reported by the Investigator.  Blinded study data 
will be evaluated for trends and any event which occurs in greater frequency will be 
evaluated for updating risk language and notifying the IRB and regulatory authorities, 
as required.   
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An independent select team that will not participate in any other study-related 
activities will be responsible for preparing unblinded analyses and documents to 
support regulatory activities that may be required while the study is ongoing (See 
Section 5.1.2), which may include, but not limited to, study termination or 
modification of the study to protect subject safety. 
Rationale for 
Change
Medical Monitoring responsibilities and details added to protocol at request of 
Advarra IRB to ensure subject safety through study conduct.
 
Section and 
page 
Section 9.1.1. Good Clinical Practice, page 57 
Original Text
New Text Inserted
New Text 
Investigators should review all available treatment options for each individual 
potential subject, including those outside of this study, and risks associated with 
possibly receiving placebo with the potential subject.  The Investigator should refer to 
the “NIH Treatment Guidelines” (NIH 2022), and the CDC “Interim Clinical 
Considerations for COVID-19 Treatment in Outpatients” and “Underlying Medical 
Conditions Associated with Higher Risk for Severe COVID-19: Information for 
Healthcare Professionals” to appropriately discuss the alternative options and risks for 
being in this study (CDC 2022).  The potential subject should also be referred or 
receive a printout of the CDC “People with Certain Medical Conditions” and 
“COVID-19 Treatments and Medications” which includes language appropriate for 
the lay person regarding medical conditions attributed to a higher risk of severe 
COVID-19 and potential treatment (CDC 2022). 
Rationale for 
Change 
Add text to emphasize importance of Investigators utilizing consistent CDC and NIH 
guidance to inform patients on evolving guidelines and access to treatment 
availability outside of this clinical trial or as part of rescue therapy.
 
 
Investigator 
Acknowledgement:
 
 
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CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
A Phase 2 Double-blind, Randomized Study to Evaluate the 
Antiviral Activity, Safety, and Efficacy of Orally Administered 
PBI-0451 Compared with Placebo in Nonhospitalized Symptomatic 
Adults with COVID-19  
Sponsor: 
Pardes Biosciences, Inc.  
2173 Salk Avenue 
PMB #052 
Carlsbad, CA 92008 
IND Number: 
158228 
EudraCT Number: 
2022-001195-33 
ClinicalTrials.gov 
Identifier: 
Not available 
Indication: 
Treatment and prevention of SARS-CoV-2 infection and associated 
diseases (ie, COVID-19) 
Protocol ID: 
PBI-0451-0002 
Contact Information: 
The medical monitor’s name and contact information will be 
provided on the Key Study Team Contact List. 
Protocol 
Version/Date: 
Original 
07 July 2022  
Amendment 1             26 August 2022 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or under 
control of Pardes Biosciences, Inc., and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable institutional review board or 
independent ethics committee. The information is to be used only by you in connection with authorized 
clinical studies of the investigational drug described in the protocol. You will not disclose any of the 
information to others without written authorization from Pardes Biosciences, Inc., except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered. 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 4 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................................. 5 
PROTOCOL SYNOPSIS .............................................................................................................................................. 7 
STUDY SCHEMA ...................................................................................................................................................... 16 
STUDY PROCEDURES TABLE ............................................................................................................................... 17 
1. 
INTRODUCTION .............................................................................................................................................. 20 
1.1. 
Background ............................................................................................................................................ 20 
1.2. 
PBI-0451 ................................................................................................................................................ 21 
1.2.1. 
General Information ............................................................................................................. 21 
1.2.2. 
Preclinical Pharmacology and Toxicology ........................................................................... 22 
1.2.3. 
Clinical Studies of PBI-0451 ................................................................................................ 22 
1.2.4. 
Rationale for PBI-0451-0002 ............................................................................................... 23 
1.3. 
Rationale for Dose Selection of PBI-0451 ............................................................................................. 23 
1.4. 
Risk/Benefit Assessment for the Study .................................................................................................. 24 
1.4.1. 
Risk/Benefit for PBI-0451 .................................................................................................... 24 
1.4.2. 
Risk/Benefit for Placebo ...................................................................................................... 24 
1.4.3. 
Potential Alternatives to Placebo .......................................................................................... 25 
1.5. 
Compliance ............................................................................................................................................ 26 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................................................... 27 
3. 
STUDY DESIGN ................................................................................................................................................ 29 
3.1. 
Study Treatments ................................................................................................................................... 29 
3.2. 
Duration of Treatment ............................................................................................................................ 29 
3.3. 
Discontinuation Criteria ......................................................................................................................... 29 
3.3.1. 
Rescue Therapy for Discontinuation .................................................................................... 30 
3.4. 
End of Study ........................................................................................................................................... 30 
3.5. 
Source Data ............................................................................................................................................ 30 
3.6. 
Biomarker Samples for Optional Future Research ................................................................................. 30 
3.7. 
Biomarker Sample for Optional Genomic Testing ................................................................................. 31 
4. 
SUBJECT POPULATION .................................................................................................................................. 32 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 32 
4.1.1. 
Subject Replacement ............................................................................................................ 32 
4.2. 
Inclusion Criteria .................................................................................................................................... 32 
4.3. 
Exclusion Criteria................................................................................................................................... 33 
5. 
STUDY INTERVENTION AND CONCOMMITANT MEDICATIONS ......................................................... 35 
5.1. 
Randomization, Blinding, and Procedures for Breaking Treatment Codes ............................................ 35 
5.1.1. 
Randomization ..................................................................................................................... 35 
5.1.2. 
Blinding ................................................................................................................................ 35 
5.1.3. 
Procedures for Breaking Treatment Codes ........................................................................... 36 
5.2. 
Description and Handling of PBI-0451 .................................................................................................. 36 
5.2.1. 
Formulation .......................................................................................................................... 36 
5.2.2. 
Packaging and Labeling ....................................................................................................... 36 
5.2.3. 
Storage and Handling ........................................................................................................... 36 
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5.3. 
Dosage and Administration .................................................................................................................... 37 
5.4. 
Prior and Concomitant Medications ....................................................................................................... 37 
5.5. 
Accountability for Study Drugs ............................................................................................................. 37 
5.5.1. 
Investigational Medicinal Product Return or Disposal ......................................................... 38 
6. 
STUDY PROCEDURES .................................................................................................................................... 39 
6.1. 
Informed Consent ................................................................................................................................... 39 
6.1.1. 
Consent for Optional Research ............................................................................................. 39 
6.2. 
Subject Enrollment and Treatment Assignment ..................................................................................... 39 
6.3. 
Pretreatment Assessments ...................................................................................................................... 39 
6.3.1. 
Screening Visit ..................................................................................................................... 39 
6.3.2. 
Baseline/Day 1 Assessments ................................................................................................ 40 
6.4. 
Treatment Assessments .......................................................................................................................... 41 
6.5. 
Posttreatment Assessments .................................................................................................................... 42 
6.6. 
Assessments for Early Discontinuation from Study ............................................................................... 42 
6.7. 
Pharmacokinetics Assessments .............................................................................................................. 42 
6.8. 
Safety Assessments ................................................................................................................................ 43 
6.8.1. 
Adverse Events/Concomitant Medications/Protocol Restrictions ........................................ 43 
6.8.2. 
Patient-Reported Outcomes .................................................................................................. 43 
6.8.3. 
Household Transmission Survey .......................................................................................... 44 
6.8.4. 
12-Lead Electrocardiogram Assessment .............................................................................. 44 
6.8.5. 
Physical Examination ........................................................................................................... 44 
6.8.6. 
Vital Signs ............................................................................................................................ 44 
6.8.7. 
Body Mass Index .................................................................................................................. 44 
6.8.8. 
Clinical Laboratory Tests/Assessments ................................................................................ 44 
6.8.9. 
Creatinine Clearance and Estimated Glomerular Filtration Rate ......................................... 45 
6.9. 
Virology Assessments ............................................................................................................................ 46 
6.10. 
Sample Storage....................................................................................................................................... 46 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 47 
7.1. 
Definitions of Adverse Events and Serious Adverse Events .................................................................. 47 
7.1.1. 
Adverse Events ..................................................................................................................... 47 
7.1.2. 
Serious Adverse Events ........................................................................................................ 48 
7.1.3. 
Study Drugs and Concomitant Therapy Special Situations Reports .................................... 48 
7.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 49 
7.2.1. 
Assessment of Causality for Study Drugs and Procedures ................................................... 49 
7.2.2. 
Assessment of Severity ........................................................................................................ 50 
7.3. 
Investigator Reporting Requirements and Instructions .......................................................................... 50 
7.3.1. 
Requirements for Collection Prior to Study Drug Initiation................................................. 50 
7.3.2. 
Adverse Events ..................................................................................................................... 50 
7.3.3. 
Serious Adverse Events ........................................................................................................ 50 
7.3.4. 
Study Drug Special Situations Reports ................................................................................ 50 
7.3.5. 
Concomitant Therapy Reports .............................................................................................. 51 
7.4. 
Reporting Process for Serious Adverse Events and Special Situation Reports ...................................... 51 
7.4.1. 
Serious Adverse Event Reporting Process ........................................................................... 51 
7.4.2. 
Special Situations Reporting Process ................................................................................... 52 
7.5. 
Sponsor Reporting Requirements ........................................................................................................... 54 
7.6. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events .......................................................................................................................... 54 
7.7. 
Toxicity Management ............................................................................................................................ 55 
7.8. 
Medical Monitoring ............................................................................................................................... 55 
8. 
STATISTICAL CONSIDERATIONS ................................................................................................................ 57 
8.1. 
Analysis Objectives and Endpoints ........................................................................................................ 57 
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8.2. 
Planned Analysis .................................................................................................................................... 57 
8.2.1. 
Interim Analysis ................................................................................................................... 57 
8.2.2. 
Final Analysis ....................................................................................................................... 57 
8.3. 
Analysis Conventions ............................................................................................................................. 57 
8.3.1. 
Analysis Sets ........................................................................................................................ 57 
8.3.2. 
Data Handling Conventions ................................................................................................. 58 
8.4. 
Demographic and Baseline/Day 1 Characteristics Analysis .................................................................. 58 
8.5. 
Efficacy Analysis ................................................................................................................................... 58 
8.5.1. 
Primary Analysis .................................................................................................................. 58 
8.5.2. 
Secondary Analyses ............................................................................................................. 59 
8.6. 
Safety Analysis....................................................................................................................................... 59 
8.6.1. 
Extent of Exposure ............................................................................................................... 59 
8.6.2. 
Adverse Events ..................................................................................................................... 59 
8.6.3. 
Laboratory Evaluations ........................................................................................................ 60 
8.6.4. 
Other Safety Evaluations ...................................................................................................... 60 
8.7. 
Pharmacokinetics Analysis .................................................................................................................... 60 
8.8. 
Sample Size ............................................................................................................................................ 60 
9. 
RESPONSIBILITIES.......................................................................................................................................... 61 
9.1. 
Investigator Responsibilities .................................................................................................................. 61 
9.1.1. 
Good Clinical Practice.......................................................................................................... 61 
9.1.2. 
Financial Disclosure ............................................................................................................. 61 
9.1.3. 
Institutional Review Board/Independent Ethics Committee Review and 
Approval............................................................................................................................... 61 
9.1.4. 
Informed Consent ................................................................................................................. 62 
9.1.5. 
Confidentiality ...................................................................................................................... 62 
9.1.6. 
Study Files and Retention of Records .................................................................................. 63 
9.1.7. 
Case Report Forms ............................................................................................................... 64 
9.1.8. 
Investigator Inspections ........................................................................................................ 64 
9.1.9. 
Protocol Compliance ............................................................................................................ 64 
9.2. 
Sponsor Responsibilities ........................................................................................................................ 65 
9.2.1. 
Protocol Modifications ......................................................................................................... 65 
9.2.2. 
Study Report and Publications ............................................................................................. 65 
9.3. 
Joint Investigator/Sponsor Responsibilities ........................................................................................... 65 
9.3.1. 
Payment Reporting ............................................................................................................... 65 
9.3.2. 
Access to Information for Monitoring .................................................................................. 66 
9.3.3. 
Access to Information for Auditing or Inspections .............................................................. 66 
9.3.4. 
Study Discontinuation .......................................................................................................... 66 
10. REFERENCES ................................................................................................................................................... 67 
11. APPENDICES .................................................................................................................................................... 70 
 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Study PBI-0451-0002: Study Procedures Table ..................................................................... 17 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Study PBI-0451-0002: Study Schema .................................................................................... 16 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
adverse event 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BMI 
body mass index 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration (2021) 
CLCR 
creatinine clearance 
CoV 
coronavirus 
COVID-19 
Coronavirus Disease 2019 
CRO 
contract research organization 
CVAP 
Clinical Virology Analysis Plan 
CYP 
cytochrome P450 
DAA 
direct-acting antiviral 
DDI 
drug-drug interaction 
EC50 
concentration (or dose) effective in producing 50% of the maximal 
response 
EC90 
concentration (or dose) effective in producing 90% of the maximal 
response 
ECG 
electrocardiogram 
(e)CRF 
(electronic) case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ET 
early termination (visit) 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GPCR 
G protein-coupled receptor 
HBV 
hepatitis B virus 
HbcAb 
hepatitis B core antibody 
HbsAg 
hepatitis B surface antigen 
HCoV 
human coronavirus 
HCV 
hepatitis C virus 
HIV(-1) 
human immunodeficiency virus (Type 1) 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
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ICH 
International Conference for Harmonisation (of Technical Requirements 
for Pharmaceuticals for Human Use) 
IEC 
independent ethics committee 
IND 
investigational new drug 
IRB 
institutional review board 
IUD 
intrauterine device 
IVA 
infectious virus assay 
IXRS 
interactive voice and web response system 
LOD 
limit of detection 
mAb 
monoclonal antibody 
MERS 
Middle East respiratory syndrome 
(m)ITT 
(modified) intention-to-treat 
Mpro 
main protease  
MT 
mid-turbinate 
NAAT 
nucleic acid amplification test 
PK 
pharmacokinetic(s) 
P-gp 
P-glycoprotein 
PTM 
placebo-to-match 
PVE 
pharmacovigilance 
(q)RT-PCR 
(quantitative) reverse transcriptase polymerase chain reaction 
RAT 
rapid antigen test 
RNA 
ribonucleic acid 
RTV 
ritonavir 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SOP 
standard operating procedure 
SSR 
special situation report 
SUSAR 
suspected unexpected serious adverse reaction 
TCID50 
median tissue culture infectious dose 
 
 
 
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PROTOCOL SYNOPSIS 
Pardes Biosciences, Inc. 
2173 Salk Ave. Suite 250 
PMB #052 
Carlsbad, CA 92008 
 
Study Title: A Phase 2 Double-blind, Randomized Study to Evaluate the Antiviral Activity, 
Safety, and Efficacy of Orally Administered PBI-0451 Compared with Placebo in 
Nonhospitalized Symptomatic Adults with COVID-19 
IND Number: IND 158228 
EudraCT Number: 2022-001195-33 
Study Centers Planned: Up to 100 study centers are planned. 
Objectives and Endpoints: 
Primary Objective 
Primary Endpoint 
 To evaluate the antiviral activity of 
PBI-0451  
 Proportion of subjects below the limit of 
detection (LOD) for infectious 
SARS-CoV-2 on Day 3 of treatment by 
infectious virus assay (IVA) from mid-
turbinate (MT) swabs 
Secondary Objectives 
Secondary Endpoint 
 To evaluate safety and tolerability of 
PBI-0451 
 Number of treatment-emergent adverse 
events (AEs), serious adverse events 
(SAEs), discontinuations due to AEs, 
and Grade 3 or 4 laboratory 
abnormalities  
 To evaluate clinical efficacy of PBI-0451 
versus placebo through study Day 28 
 Proportion of subjects with sustained 
symptom resolution through Day 28 
 Time to sustained symptom resolution 
through Day 28  
 Proportion of subjects with COVID-19 
related hospitalization or death from any 
cause through Day 28 
 Severity of targeted COVID-19 
symptoms  
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 Number of COVID-19 related medical 
visits other than hospitalization, 
including acute/critical care visits 
through Day 28 
 Number of days in any hospital unit for 
treatment of COVID-19 
 To evaluate the effect of PBI-0451 on 
SARS-CoV-2  
 Presence of SARS-CoV-2 virus, viral 
RNA or viral antigen based on IVA, 
quantitative reverse transcriptase 
polymerase chain reaction (qRT-PCR), 
and rapid antigen test (RAT), as 
specified in the Clinical Virology 
Analysis Plan (CVAP) 
Exploratory Objectives 
Exploratory Endpoints 
 To evaluate SARS-CoV-2 resistance to 
PBI-0451 
 Sequence analysis of the SARS-CoV-2 
main protease (Mpro) gene (nsp5) and 
Mpro cleavage sites  
 To evaluate SARS-CoV-2 resistant 
variant susceptibility to PBI-0451 
 Susceptibility analysis of SARS-CoV-2 
variants with Mpro amino acid 
substitutions and variants with 
substitutions in Mpro cleavage sites in the 
SARS-CoV-2 polyprotein 
 To evaluate the relationship between 
SARS-CoV-2 detection methods 
 Correlation of SARS-CoV-2 detection by 
IVA, RAT, and qRT-PCR, as specified 
in the CVAP  
 To evaluate the incidence of rebound 
SARS-CoV-2 infection 
 Proportion of subjects with clinical 
and/or virologic rebound 
 To evaluate PBI-0451 pharmacokinetics 
(PK) 
 PBI-0451 PK analysis from an intensive 
PK substudy of up to 50 subjects  
 PK parameters from sparse sampling of 
all subjects for population PK analysis 
Study Design: Phase 2, double-blind, randomized, placebo-controlled study 
Number of Subjects Planned: Approximately 210 subjects will be randomized.  
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Target Population: Nonhospitalized, symptomatic male and nonpregnant, nonlactating female 
subjects 18 to < 65 years of age with a positive direct test of SARS-CoV-2 infection (antigen 
based or nucleic acid amplification test [NAAT]) who are not at high-risk of progressing to 
severe disease 
Duration of Treatment: 5 days 
Study Duration: Up to 28 days of assessments (ie, the study period) and a Week 24 follow-up 
to assess symptoms and survival status 
Diagnosis and Main Eligibility Criteria: 
Inclusion Criteria 
1. Can understand and sign a written informed consent form (ICF), which must be 
obtained prior to initiation of any study procedures.  
2. Onset of COVID-19 symptoms ≤ 5 days prior to randomization with a positive 
SARS-CoV-2 test ≤ 24 hours prior to randomization. Authorized NAAT or antigen 
tests that detect viral RNA or protein, respectively, are allowed. 
3. Received primary vaccination series as defined by Centers for Disease Control and 
Prevention (CDC). Subjects should be advised during informed consent that alternate 
therapies may be available outside of study participation. 
4. ≥ 2 symptoms of acute COVID-19 infection as determined by the investigator from the 
symptoms listed on the COVID-19 symptoms questionnaire present at randomization 
5. Male and nonpregnant, nonlactating female subjects 18 to < 65 years of age. Females 
must have a negative serum or urine pregnancy test at screening and prior to the first 
dose of study drug unless permanently sterile or in a postmenopausal state (see 
Appendix 3).  
6. Male and female subjects and/or their heterosexual partners must either be of 
nonchildbearing potential or must use effective contraception from screening through 
90 days after the last dose of study drug (see Appendix 3) 
7. Female subjects must refrain from egg donation and in vitro fertilization during 
treatment and for ≥ 28 days after the last dose of study drug 
8. Male subjects must refrain from sperm donation from screening through 90 days after 
the last dose of study drug 
9. Normal 12-lead electrocardiogram (ECG) evaluation without clinically significant 
abnormalities 
10. Able and willing to comply with all study requirements 
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Exclusion Criteria 
1. Considered at high-risk of developing severe illness from COVID-19 defined as ≥ 1 
CDC underlying medical condition associated with an increased risk of developing 
severe illness from COVID-19 (see Appendix 5) 
2. Unvaccinated against SARS-CoV-2 (defined as having not completed a primary 
vaccination series) 
3. Any SARS-CoV-2 vaccination within 3 month prior to randomization or anticipated to 
receive a SARS-CoV-2 vaccination (including a booster) during the 28-day study 
period 
4. Currently hospitalized or expected to require hospitalization for COVID-19 within 
48 hours of randomization 
5. Currently being treated or expected to be treated for COVID-19 with monoclonal 
antibodies, convalescent serum, or direct-acting antiviral agents (all potential subjects 
should be informed of evolving treatment options during informed consent that 
alternate therapies may or may not be available to them outside of study participation)  
6. Any clinical condition or laboratory result considered by the investigator to indicate 
any unstable or poorly controlled underlying clinically significant medical condition(s), 
active disseminated infection (other than SARS-CoV-2), or other medical condition 
that could represent a risk to the subject, including increasing the likelihood of a safety 
event, affect subject compliance, or affect efficacy and/or safety data collected during 
the 28-day study period  
7. Known active liver disease, including nonalcoholic steatohepatitis/nonalcoholic fatty 
liver disease, chronic or active hepatitis B virus (HBV) or hepatitis C virus (HCV) 
infection, primary biliary cirrhosis, Child-Pugh Class B or C, chronic alcoholic liver 
disease, or acute liver failure 
8. Receiving dialysis or having known severe renal impairment (chronic kidney disease, 
Stage 4 or above) 
9. Unable or unwilling to comply with the protocol procedures 
10. Participating in another interventional study with an investigational compound or 
device, including those for COVID-19 
11. Known prior participation in this study or another study involving PBI-0451 
12. Females who are pregnant or breastfeeding 
13. Oxygen saturation of < 94% on room air 
Study Procedures/Frequency: Following completion of screening and eligibility 
assessments, eligible subjects will be randomized 2:1 to one of 2 treatment groups on Day 1 as 
follows: 
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 PBI-0451: 2 × 350 mg tablets administered orally twice daily (BID) (1400 mg/day) 
with food for 5 days (10 total doses) 
 Placebo: 2 × placebo to match PBI-0451 tablets administered orally BID with food for 
5 days (10 total doses) 
Randomization will be stratified as follows: 
 SARS-CoV-2 positive direct test diagnosis ≤ 3 days (target 30%) versus > 3 days from 
first onset of COVID-19 symptom(s) ≤ 5 days prior to randomization 
 Received primary vaccination series, alone versus any booster shots 
 PK substudy participation versus nonparticipation  
Note: Screening assessments may be considered as baseline/Day 1 assessments if the subject 
meets eligibility requirements, is randomized, and receives the first dose of study drug on same 
day.  
Study Visits: Following randomization on Day 1, subjects will complete baseline assessments 
prior to receiving their first dose of study drug (PBI-0451 or placebo). All subjects will have 
additional safety and efficacy assessments during the 28-day study period.  
A follow-up visit (eg, telephone visit, virtual visit, clinic visit, etc. as convenient) will be 
conducted at Week 24 (± 20 days) after the last dose of study drug for all subjects. Information 
regarding ongoing or recurrent COVID-19 symptoms, survival status, pregnancy status (for 
female subjects of childbearing potential and female partners of male subjects), and any 
hospitalizations or acute/critical care visits (eg, non-admitted hospital or other care facility) 
that have occurred since the last study visit will be collected. 
Study Drug Administration: Subjects will take their first dose of study drug (PBI-0451 or 
placebo) with food as soon as possible after randomization, with the first dose designated as 
Day 1, and the second dose taken with the evening meal on Day 1 to ensure that a full total 
daily dose (1400 mg PBI-0451) is taken on the first day of treatment. Study drug will be taken 
with food, approximately 12 hours between doses, at approximately the same time for each 
BID dose for the remainder of the 5 days of treatment. 
Patient-Reported Outcomes: Subject self-reports will be assessed daily at screening, Days 1 
through 28 or early termination (ET), and the Week 24 follow-up as follows: 
 COVID-19 symptom questionnaire 
 COVID-19 weekly questionnaire  
 COVD-19 related hospitalizations or acute/critical care visits (eg, non-admitted 
hospital or other care facility) since the last study visit  
Hospitalization is defined as > 24 hours of acute care in a hospital or similar acute care 
facility, including emergency rooms or temporary facilities instituted to address medical 
needs of those with severe COVID-19. This includes any special medical care unit within 
an assisted living facility or nursing home.  
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 Optional household transmission survey of confirmed SARS-CoV-2 infections in 
subject’s household members (baseline/Day 1 and Days 5, 10, 15, 28 or ET only, and 
rebound ad hoc visit (if applicable)) 
Serology Testing: Serology samples at screening and/or baseline/Day 1: 
 SARS-CoV-2 N-antibodies (using the Roche Elecsys® Anti-SARS-CoV-2 assay) 
 Human immunodeficiency virus Type 1 
 HBV (hepatitis B serum antigen; hepatitis B core antibody) 
 HCV (hepatitis C antibody, reflex to HCV RNA) 
Virologic Assessments: The following tests will be performed from mid-turbinate (MT) nasal 
swab and saliva samples at screening, baseline/Day 1, and Days 2, 3, 5, 10, 15, 28 or early 
termination (ET), and rebound ad hoc visit (if applicable) 
 SARS-CoV-2 qRT-PCR (MT swab and saliva) 
 SARS-CoV-2 RAT (MT swab)  
 SARS-CoV-2 IVA (MT swab and saliva) at baseline/Day 1 and Days 2, 3, 5, 10, Day 
15, rebound and early termination 
 SARS-CoV-2 sequence analysis (MT swab) at baseline/Day 1 and Day 5 for all 
subjects to evaluate the potential for the development of resistance in response to 
treatment with PBI-0451. Additional time points may be evaluated in the case of 
virologic rebound or if the subject remains viremic at other study visits (ie, if SARS-
CoV-2 RNA by qRT-PCR is ≥ 3.85 log10 copies/mL, which is the threshold for the 
minimum amount of viral RNA required for whole genome sequencing).  
RAT will be conducted for subjects at the study clinic with results recorded in real time. 
All other MT and saliva samples will be shipped to the central laboratory on the day of 
collection for subsequent qRT-PCR and IVA testing. 
Note: SARS-CoV-2 RAT or qRT-PCR tests for household members will not be performed 
at the study clinic; that data will be captured as part of an optional self-reported assessment 
of confirmed SARS-CoV-2 infections in household members.  
Safety Assessments: 
 Complete physical examination: Screening and baseline/Day 1 and Day 28 or ET  
 Symptom-driven physical examination: Days 2, 3, 5, 10, and 15  
 Vital signs: All visits through Day 28 
 12-lead ECG: Screening; baseline/Day 1 (predose;) and Days 5, 10, and 28 or ET 
 Clinical laboratory blood draws (hematology and chemistry) and urinalysis: 
baseline/Day 1 (predose) and Days 5, 10, and 28 or ET 
 Serum/urine pregnancy test (females of childbearing potential only): Screening, 
baseline/Day 1, and Day 28 or ET 
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Medical Monitoring 
A team of medically qualified individuals, including but not limited to, the Sponsor and the 
CRO Medical Monitors, and the Drug Safety Consultant are responsible for ongoing 
review of all AEs, concomitant medications, laboratory values (including virology), and 
vital signs (including pulse oximetry), worsening of symptoms (COVID-19 symptom 
questionnaire, including dyspnea), acute/critical care visits (eg, nonadmitted hospital or 
other care facility), and study drug discontinuations, at a minimum monthly basis 
throughout the study, per the Safety Monitoring Plan.  Serious adverse events (eg, 
hospitalizations, life threatening events, medically important events, deaths) will be 
evaluated by the Sponsor and the CRO Medical Monitor within 24 hours after being 
reported by the Investigator.  Blinded study data will be evaluated for trends and any event 
which occurs in greater frequency will be evaluated for updating risk language and 
notifying the IRB and regulatory authorities, as required.   
Rescue Therapy 
Subjects who experience severe COVID-19 illness (defined in this study as sustained pulse 
oximetry <94%, a respiratory rate of >30 breaths/min, or dyspnea that requires medical 
attention) should discontinue study drug and be immediately referred by the Investigator to 
emergency care or treated by the Investigator for standard of care treatment of symptoms 
including, but not limited to, other antivirals, supplemental oxygen, corticosteroids, Janus 
kinase inhibitors, or interleukin-6 blockers, in accordance with the NIH Treatment 
Guidelines (NIH 2022). The subject should continue participation in the study, with study 
drug discontinued, for safety follow-up and clinical outcome of the medically attended 
visit. 
Pharmacokinetic Assessments: 
 All subjects will have single PK blood draws at baseline/Day 1 (after first dose of study 
drug) and Day 5, with the time of the blood draw relative to the last dose of study drug 
recorded.  
 An intensive PK substudy will be conducted in a subset of up to 50 subjects at select 
sites who provide separate specific consent. Intensive PK blood draws will be collected 
at the following time points: predose (ie, ≤ 5 minutes of dosing) and 0.5, 1, 1.5, 2, 3, 4, 
6, 8, and (optional) 10 to 12 hours postdose. Intensive PK sampling may occur on any 
treatment day (ie, baseline/Day 1 [after first dose of study drug] through Day 5). 
Any remaining PK samples will be stored and may be used for exploratory assessments, 
such as metabolites, protein binding, endogenous markers of drug-drug interactions, 
biomarkers of host responsiveness, and other investigational experiments. 
Test Product, Dose, and Mode of Administration: 2 × 350 mg tablets administered orally 
BID (1400 mg/day) with food for 5 days (10 total doses)  
Subjects will take their first dose with food as soon as possible after randomization, with the 
first dose designated as Day 1, and the second dose taken with the evening meal on Day 1 to 
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ensure that a full total daily dose (1400 mg PBI-0451) is taken on the first day of treatment. 
Study drug will be taken with food, approximately 12 hours between doses, at approximately 
the same time for each BID dose for the remainder of 5 days of treatment 
Reference Therapy, Dose, and Mode of Administration: 2 × placebo to match PBI-0451 
tablets administered orally BID for 5 days (10 total doses). 
Subjects will take their first dose with food as soon as possible after randomization, with the 
first dose designated as Day 1, and the second dose taken with the evening meal on Day 1. 
Study drug will be taken with food, approximately 12 hours between doses, at approximately 
the same time for each BID dose for the remainder of 5 days of treatment 
Statistical Methods: Detailed methodology for summary and statistical analyses of the data 
collected in this study will be documented in a statistical analysis plan. Summary statistics will 
be used to analyze the study data. Any statistical testing will be conducted to ensure that the 
overall alpha = 0.05 level (2 sided). Unless otherwise specified, the data summaries and 
analyses described below will be reported by treatment group. 
The modified intention-to-treat (mITT) analysis set includes all randomized subjects with 
≥ 2 symptoms consistent with COVID-19 ≤ 5 days prior to randomization and a positive 
SARS-CoV-2 test (RT-PCR or RAT) ≤ 24 hours prior to randomization who received ≥ 1 dose 
of study drug. This is the primary analysis set for all clinical endpoints.  
The mITT virologic analysis set is a subset of the mITT analysis set that includes subjects who 
had detectable infectious SARS-CoV-2 by IVA at baseline/Day 1. This is the primary analysis 
set for the primary efficacy endpoint. 
Efficacy: The primary efficacy endpoint is the proportion of subjects below the LOD for 
infectious SARS-CoV-2 on Day 3 by IVA. For the primary endpoint, differences between PBI-
0451 and placebo will be evaluated using stratum-adjusted Mantel-Haenszel proportions 
(adjusted for randomization strata). The proportion of subjects below the LOD for infectious 
SARS-CoV-2 at other time points will be summarized in a similar manner. 
The time to resolution of targeted COVID-19 symptoms will be estimated with the 
Kaplan-Meier method and summarized by treatment group. Differences between treatment 
groups will be determined using a Wilcoxon-Gehan test. The analysis of time to resolution of 
each targeted COVID-19 symptom will be conducted in a similar manner. 
The proportion of subjects with COVID-19 related hospitalization or death from any cause will 
be summarized by treatment group. Differences between treatment groups will be assessed 
using Mantel-Haenszel proportions.  
The number of COVID-19 related hospitalizations or acute/critical care visits and the number 
of days in any hospital unit for the treatment of COVID-19 will be summarized. Differences 
between treatment groups will be assessed using a van Elteren test stratified by the 
randomization factors. 
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SARS-CoV-2 viral load kinetics will be summarized by study visit. Differences between the 
treatment groups will be assessed with a van Elteren test stratified by the randomization 
factors.  
SARS-CoV-2 clinical and virologic rebound will be summarized by the amount of viral RNA 
detected at baseline/Day 1, time to loss of clinical symptoms, time to negative RAT or IVA, 
and time to the first confirmed reappearance of symptoms and/or a positive RAT or qRT-PCR 
sample. 
A correlation of the results of IVA, RAT, and qRT-PCR assessments will be evaluated. 
Virologic outcomes will be summarized by subject serology status determined using the Roche 
Elecsys Anti-SARS-CoV-2 assay, which uses a recombinant protein representing the 
nucleocapsid (N) antigen to detect antibodies against SARS-CoV-2. 
Safety: The safety analysis set includes all randomized subjects who received ≥ 1 dose of 
study drug. This is the primary analysis set for safety analyses. 
AEs will be coded using the current version of the Medical Dictionary for Regulatory 
Activities. Treatment-emergent AEs, SAEs, and AEs leading to premature discontinuation of 
study drug/study will be summarized by treatment, system organ class, and preferred term. 
Laboratory results and change from predose values for selected laboratory tests will be 
summarized by treatment at scheduled visits. The incidence of treatment-emergent laboratory 
abnormalities (Division of AIDS Toxicity Grading Scale) will be summarized by treatment. 
Pharmacokinetics: The PK analysis set includes all subjects who participated in the intensive 
PK substudy and have ≥ 1 nonmissing PK concentration reported by the PK laboratory. This is 
the primary analysis set for PK analyses.  
PBI-0451 plasma concentrations and PK parameters will be derived using noncompartmental 
methods (including metabolite[s] as applicable) and listed and summarized using descriptive 
statistics.  
PBI-0451 plasma concentrations from the PK substudy and sparse sampling from the overall 
study population will be used in a population PK analysis and reported separately.  
Sample Size: The sample size will be approximately 210 subjects to account for 
approximately 60% of randomized subjects who are anticipated to be SARS-CoV-2 negative 
by IVA at baseline/Day 1 and would be excluded from the mITT virologic analysis set. It 
should be noted that this sample size is sufficient with ≥ 80 power to detect a > 19% absolute 
difference in the proportion of subjects below the LOD for infectious SARS-CoV-2 virus (99% 
vs 81%) at Day 3 by IVA among subjects who had detectable infectious SARS-CoV-2 at 
baseline/Day 1. This assumes alpha = 0.05 and that 40% of subjects have detectable infectious 
virus at baseline/Day 1. 
 
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STUDY SCHEMA 
Figure 1. 
Study PBI-0451-0002: Study Schema 
 
BID = twice daily; PTM = placebo to match 
 
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STUDY PROCEDURES TABLE 
Table 1. 
Study PBI-0451-0002: Study Procedures Table 
Screeninga 
(Day -5 to Day 1) Baseline/Day 1b 
Day 2 
 
Day 3 
 
Day 5 
(±1 day) 
Day 10 
(±2 days) 
Day 15 
(±2 days) 
Rebound
Ad Hoc 
Visitd 
Day 28 
(±3 days) 
Week 24 
Follow Up  
(±20 days)e 
ET 
Written Informed 
Consent 
X 
  
 
  
  
  
 
 
  
 
  
Medical History 
X 
  
 
  
  
  
 
 
  
 
  
Complete Physical 
Examination 
X 
 (X) 
 
  
 
 
 
 
X 
 
X 
Symptom-Driven  
Physical 
Examination 
 
 
X 
X 
 X 
X 
X 
X 
 
 
  
Height 
X 
 
  
  
  
  
 
 
  
 
  
Weight 
X 
(X) 
  
  
  
  
 
 
X 
 
X 
Vital Signsf 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
 
X 
SARS-CoV-2 
N-antibodies 
 
X 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 RATg  
X 
(X) 
X  
X  
X  
X 
X 
X 
X 
 
X 
SARS-CoV-2 
qRT-PCR Testg  
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
 
X 
SARS-CoV-2 
Sequence Analysisg,h 
X 
(X) 
(X) 
(X) 
X 
(X) 
(X) 
X 
(X) 
 
(X) 
SARS-CoV-2 IVAg 
X 
(X) 
X 
X 
X 
 X 
X 
X 
 
 
(X)  
HIV-1, HBV (HbsAg 
and HbcAb), and 
HCV (HCV antibody 
reflex to HCV RNA) 
Testing 
 
X 
  
  
  
  
 
 
  
 
  
12-Lead ECG 
X 
(X) 
 
 
X 
X 
 
 
X 
 
X 
Optional Genomic 
Sample 
 
X 
 
 
 
 
 
 
 
 
 
Hematologyi 
  
X 
 
 
X 
X  
 
 
X 
 
X 
 
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Screeninga 
(Day -5 to Day 1) Baseline/Day 1b 
Day 2 
 
Day 3 
 
Day 5 
(±1 day) 
Day 10 
(±2 days) 
Day 15 
(±2 days) 
Rebound
Ad Hoc 
Visitd 
Day 28 
(±3 days) 
Week 24 
Follow Up  
(±20 days)e 
ET 
Coagulation Panel 
 
X 
 
 
X 
X 
 
 
X 
 
X 
Chemistryj 
  
X 
 
 
X 
 X 
 
 
X 
 
X 
Urinalysisk 
  
X 
 
 
X 
 X 
 
 
X 
 
X 
Creatinine Clearance 
and eGFR 
  
X 
 
 
X 
 X 
 
 
X 
 
X 
Serum/Urine 
Pregnancy Testl 
X 
(X) 
 
 
 
 
 
 
X 
 
X 
Study Drug 
Dispensing 
 
X 
 
 
 
 
 
 
 
 
 
Study Drug 
Administration 
 
2 × 350 mg PBI-0451 or Placebo BID orally for 
5 days (10 total doses) 
 
 
 
 
 
 
Patient Reported 
Outcomesm 
X 
(X) 
X 
X 
X 
Intensive PK 
Samplingn 
 
X 
 
 
 
 
 
 
Single PK Sampleo 
  
X 
 
 
X 
 
 
 
 
 
 
Household 
Transmission 
Surveyp 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Survival Statusq 
 
 
 
 
X 
X 
X 
 
X 
X 
 
Review and Assess 
AEs and 
Concomitant 
Medicationr 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
 
X 
AE = adverse event; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; ET = early termination; HbcAb = hepatitis B core antibody; 
HbsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV-1 = human immunodeficiency virus Type 1; IVA = infectious virus 
assay; PK = pharmacokinetics; qRT-PCR = quantitative reverse-transcriptase polymerase chain reaction; RAT = rapid antigen test; SARS-CoV-2 = severe acute 
respiratory syndrome coronavirus 2 
a. 
Prospective subjects should be screened ≤ 5 days prior to administration of first dose of study drug (ie, randomization/Day 1) 
b. Screening assessments may be considered as baseline/Day 1 if the subject is eligible for the study and is randomized and receives the first dose of study 
drug on that day. Parentheses indicate that assessment is not required if performed at screening, and screening and baseline/Day 1 are the same. 
c. 
Individual study visits must occur on separate calendar days within the visit window, with the time(s) of sample collection recorded.  
 
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d. Subjects who experience a relapse in symptom(s) after having no COVID-19 symptom(s) for ≥3 days or have a positive RAT (or clinic qRT-PCR test) 
after testing negative by RAT or qRT-PCR will be requested to return to clinic within 2 days for mid-turbinate nasal swab and saliva samples for RAT, 
qRT-PCR, and sequencing. 
e. 
Week 24 visit performed via telephone visit, virtual visit, or clinic visit, as convenient. 
f. 
Vital signs include blood pressure, heart rate, respiratory rate, pulse oximetry and temperature (predose and postdose on Day 1). 
g. Mid-turbinate nasal swabs will be collected to measure SARS-CoV-2 using qRT-PCR, IVA, RAT, and viral sequencing. Saliva samples will be collected 
to measure SARS-CoV-2 using qRT-PCR and IVA. Parentheses indicate sample at ET visit if the subject discontinues treatment prior to Day 10. 
h. SARS-CoV-2 sequence analysis (nasal mid-turbinate sample) will be conducted only if the subject is viremic and above the limit of detection (LOD) of 
the sequencing assay. Sequence analysis may be conducted on samples obtained at other study visits for subjects who experience virologic rebound or if 
the subject remains viremic through Day 28. Parentheses indicate sequencing samples where sequencing is dependent on the subject being viremic and 
experiencing virologic rebound and viral RNA is above the LOD of the sequencing assay by qRT-PCR. 
i. 
Hematology includes complete blood count with differential and platelets.  
j. 
Serum chemistry includes comprehensive metabolic panel. 
k. Urinalysis includes microscopic reflex. 
l. 
Pregnancy tests for females of childbearing potential only; screening urine test required for eligibility. 
m. Self-reported daily assessment of targeted COVID-19 symptoms (per the COVID-19 symptoms questionnaire) and any hospitalizations or acute/critical 
care visits (eg, non-admitted hospital or other care facility) will be assessed daily and weekly at screening and from baseline/Day 1 through Day 28. 
n. Intensive PK sampling for substudy subjects only. Sampling will occur relative to study drug administration at the following times: predose (ie, 
≤ 5 minutes prior to dosing) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and (optional) 10-12 hours postdose; intensive PK sampling will occur on any day of treatment 
from Day 1 (subject’s first dose of study drug) to Day 5. 
o. Sparse PK samples will be obtained at baseline/Day 1 (subsequent to subject’s first dose of study drug) and Day 5. 
p. Optional subject self-reported assessment of number of confirmed SARS-Co V-2 infections (RAT or qRT-PCR) in household members. No specific 
identifying information will be collected. 
q. Survival status also includes current supplemental oxygen use, pregnancy status (for female subjects of childbearing potential and female partners of 
male subjects), and any hospitalizations or acute/critical care visits that occurred since the last study visit during the 28-day study period. 
r. 
All AEs recorded from the time of obtaining informed consent through Day 28; all ongoing AE’s will be followed to resolution or condition is 
considered permanent.  
 
 
 
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1. 
INTRODUCTION 
1.1. 
Background 
Pardes Biosciences, Inc. (hereafter referred to as Pardes) is developing PBI-0451, a new 
chemical entity and orally bioavailable direct-acting antiviral (DAA) inhibitor of the main 
protease (Mpro) of coronaviruses (CoVs), including the novel severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) that causes Coronavirus Disease 2019 (COVID-19) (Jin et al. 
2020). PBI-0451 is an investigational agent that, by inhibiting the ability of the virus to replicate, 
has the potential for use as treatment and prevention of SARS-CoV-2 infection and associated 
diseases (ie, COVID-19). Additionally, it is anticipated that an effective DAA may reduce the 
magnitude and duration of viral shedding of replicating virus and therefore reduce the likelihood 
of transmission of SARS-CoV-2. 
CoVs are positive, single-stranded RNA viruses, of which 7 infect humans and are believed to 
result in 5% to 30% of “common colds” for which therapeutic intervention is generally limited to 
over-the-counter symptomatic relief (Paules et al. 2020). CoV infection in humans is transmitted 
from person to person via shedding of replicating virus within the respiratory tract through 
aerosolization (Tang et al. 2020) (Tang et al. 2020). SARS-CoV-2 is a novel strain of CoV 
discovered in late 2019 and responsible for COVID-19 that can range from mild to severe 
disease with symptoms, including extreme fatigue and dyspnea, that can be short-lived or 
prolonged (eg, “long COVID”) with some cases developing pneumonia that can progress into 
acute respiratory distress syndrome and sometimes death, despite aggressive supportive 
care(Tang, Comish, and Kang 2020) (Tang et al. 2020) (Sharma et al. 2020) (Marshall 2020) 
(Marshall 2020). All persons are at risk for infection with SARS-CoV-2 and developing COVID-
19. SARS-CoV-2 represents the third novel CoV (in addition to SARS-Co-V and Middle East 
respiratory syndrome [MERS] CoV) to make a zoonotic transfer in the last 2 decades and result 
in significant human disease (Dhama et al. 2020). The potential for new CoV outbreaks is likely 
to continue. 
Natural history data for nonpandemic CoV infection has established that reinfection with the 
same or different strains of CoV (including SARS-CoV-2) can occur (Tillett et al. 2021) (Harvey 
et al. 2021). Moreover, throughout the pandemic, surveillance has identified multiple spike 
protein mutations resulting in the global emergence of several SARS-CoV-2 variants of concern 
(ie, Delta, Omicron) due to potentially higher levels of transmissibility or immune escape 
(Korber et al. 2020) (Campbell et al. 2021) (Zella et al. 2021). This is particularly important as 
CoVs are known to mutate and undergo genetic recombination, which may facilitate 
transmission, replicative fitness, and pathogenicity across species (Lau and Chan 2015). A 
consequence of this has already been seen with some monoclonal antibodies (mAbs), where 
reduced efficacy against emerging SARS-CoV-2 variants (ie, Delta, Omicron) has led to 
recommendation against their use. 
Near-universal vaccination is desired to reduce transmission and severity of COVID-19 disease; 
however, access to and acceptance of vaccines are suboptimal, and it is unknown if vaccines will 
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provide adequate duration of protection against current and future SARS-CoV-2 variants 
(Edridge et al. 2020). 
While the details of the pathobiology and risk factors for developing severe COVID-19 disease 
remain unclear, it is established that early intervention to inhibit viral replication provides 
clinical benefit. Experience with influenza and emerging evidence with COVID-19 indicates that 
early treatment via a short course (eg, 5 days) of oral DAA therapy results in less severe disease 
and that preventing transmission is also possible (Muthuri et al. 2014) (Uyeki et al. 2019) (Chow 
et al. 2019) (Ikematsu et al. 2020). 
Orally administered small molecule protease inhibitors are a clinically validated treatment and a 
standard of care for multiple viral diseases, including hepatitis C virus (HCV) and human 
immunodeficiency virus (HIV) infections (Ghany and Morgan 2020) (Department of Health and 
Human Services 2022). These agents can exhibit favorable drug-like properties and a favorable 
benefit:risk profile, including when used at high doses and exposures in both the short-term 
(weeks to months in HCV) and chronic (life-long therapy for HIV) settings (Patick and Potts 
1998). 
Small molecule DAAs that are orally administered and suitable for outpatient use are needed to 
treat people who become infected and are at high risk for severe COVID-19. In addition, 
treatment with oral DAAs is warranted to reduce the time to symptom resolution and decrease 
the duration of shedding infectious virus. Moreover, such agents can also be deployed in “ring 
prophylaxis” to contacts of infected individuals or in the setting of mitigating the spread of new, 
localized outbreaks. Small molecule oral DAAs are attractive therapeutics as they target viral and 
not host processes that may reduce the risk for off-target effects, and thus increase the likelihood 
of a favorable therapeutic index. Consequently, there remains a high unmet medical need for an 
easy to use, oral antiviral drug for the treatment and prevention of SARS-CoV-2 infection and 
associated diseases (ie, COVID-19). 
1.2. 
PBI-0451 
1.2.1. 
General Information 
PBI-0451 is an investigational agent that has the potential for use as treatment and prevention of 
SARS-CoV-2 infection and associated diseases (ie, COVID-19) by inhibiting the ability of the 
virus to replicate and thereby reduce the incidence and magnitude of the pathologic immune 
response responsible for the morbidity and mortality associated with severe disease. PBI-0451 is 
a potent inhibitor of SARS-CoV-2 Mpro, an essential enzyme for viral replication with 
EC50 = 23 nM and EC90 = 113.5 nM in SARS-CoV-2 antiviral assays. In nonclinical studies, 
PBI-0451 has broad-spectrum activity against SARS-CoV-2 clinical variants Alpha, Beta, Delta, 
Epsilon, Gamma, Mu, and Omicron and human coronaviruses (HcoVs) 229E and OC43 in cell-
based antiviral assays. It has broad-spectrum activity in in vitro enzyme assays against the Mpro 
from HcoVs SARS, 229E, HKUI, OC43, NL63, and MERS, suggesting that it interacts with the 
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most essential elements of the Mpro binding pocket. This hypothesis is supported by in vitro 
resistance studies which suggest that PBI-0451 has a high barrier to resistance. In in vivo 
pharmacodynamic animal model of infection studies in mice, PBI-0451 showed a trend towards 
improved lung function at the higher PBI-0451 doses that correlated with a 10-fold decrease in 
viral load in the lung. Screens for off-target activity on host cysteine proteases and other targets 
revealed no significant concerns. A ritonavir (RTV)-boosted SARS-CoV-2 protease inhibitor, 
nirmatrelvir [Pfizer]), targeting the same active enzyme pocket has shown significant benefit for 
high risk COVID-19 patients in the clinic. PBI-0451, at an appropriate dose and dosing regimen, 
thus has potential to provide similar clinical benefit for SARS-CoV-2-infected patients with 
PBI-0451. 
PBI-0451 has completed toxicology studies conducted under Good Laboratory Practice 
guidelines, including 14-day studies in mice and dogs without evidence of adverse findings. For 
further information on PBI-0451, refer to the current Investigator’s Brochure (IB). 
1.2.2. 
Preclinical Pharmacology and Toxicology 
PBI-0451 has shown a favorable selectivity profile at anticipated clinical exposures relative to 
activity against a panel of human (and rat) GPCRs, ion channels, transporters, nuclear receptors, 
and select enzymes (WuXi Mini Safety Panel).  
For further information on PBI-0451, refer to the current IB. 
1.2.3. 
Clinical Studies of PBI-0451 
As of 1 July 2022, two clinical studies of PBI-0451 have been initiated and have completed 
clinical assessment: Study PBI-0451-0001 is a first-in-human, single ascending dose/multiple 
ascending dose study of PBI-0451 with nested food effect and drug-drug interaction (DDI) 
screening cohorts, and Study PBI-0451-0004 is a relative bioavailability (food effect) study.  
Safety 
Preliminary clinical data indicate that PBI-0451 has been well tolerated at single and multiple 
oral doses (ie, 10 days) up to 2100 mg/day. All reported treatment-emergent adverse events 
(AEs) have been mild or moderate in severity and none have been considered definitely related 
to study drug. No serious adverse events (SAEs) or deaths have been reported. No clinically 
significant treatment-emergent laboratory abnormalities, no treatment-emergent AEs due to 
laboratory abnormalities, and no clinically significant abnormal findings with respect to vital 
signs or safety electrocardiogram (ECG) assessments have been reported.  
Pharmacokinetics  
Preliminary clinical data demonstrate that PBI-0451 has a favorable human pharmacokinetics 
(PK) profile following single and multiple ascending oral doses up to 2100 mg/day. PBI-0451 
demonstrates dose-linear exposures when administered with food, achieves rapid systemic 
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exposures that exceed the target protein-binding adjusted EC90 against SARS-CoV-2, and 
exhibits a 2-compartment PK profile that supports administration as a stand-alone agent when 
administered with food. PBI-0451 has been shown to be a weak CYP3A4 inhibitor and a 
nonsensitive substrate of CYP3A4, P-gp, and BCRP. DDI evaluation in vitro; in vivo; and in 
silico, using physiological-based PK modeling and simulation, indicated that the DDI potential 
of PBI-0451 as a victim or perpetrator for other major CYP enzymes and transporters is 
negligible. Overall, the DDI assessments suggest that PBI-0451 presents no to minimal DDI 
potential at the proposed clinical dose. 
1.2.4. 
Rationale for PBI-0451-0002 
PBI-0451 is a new chemical entity intended as an orally available DAA whose mechanism of 
action is inhibition of the Mpro of CoV, including the SARS-CoV-2 that causes COVID-19. 
Short-term administration (eg, 5 days) of antivirals with similar (nirmatrelvir [Pfizer]) and 
different (molnupiravir [Merck]) mechanisms of action have been reported to improve the 
outcomes (hospitalization or death) in nonhospitalized patients with SARS-CoV-2 infection at 
high risk for severe COVID-19. The incidence of COVID-19 remains high, mainly in 
unvaccinated persons, but breakthrough infections have also occurred in persons who have been 
fully vaccinated. PBI-0451 is an oral DAA with broad activity against CoVs, including 
SARS-CoV-2, and has the potential to address this unmet medical need.  
1.3. 
Rationale for Dose Selection of PBI-0451 
Dose selection for PBI-0451 included consideration of all relevant nonclinical and clinical data 
and knowledge from the development of DAAs used for the treatment of both acute 
(eg, influenza and COVID-19) and chronic (ie, HIV, hepatitis B virus (HBV), and HCV viral 
infections) (Department of Health and Human Services 2022) (Ghany and Morgan 2020) with 
the goal of providing systemic drug exposures that will maximally reduce viral burden. 
Specifically, the goal is to achieve and maintain (accounting for protein binding) concentration 
multiples above the EC50 (US Food and Drug Administration 2006) and whenever possible also 
above the EC90 over the duration of the dosing interval.  
Nonclinical and clinical data support the Phase 2 evaluation of a total daily dose of PBI-0451 
1400 mg as 700 mg (2 × 350 mg tablets) BID administered with food for 5 days. This dose has 
been shown to achieve desired PK exposures. For additional information on PBI-0451 dose 
selection refer to the current IB. 
Due to the desire to rapidly initiate treatment with maximally suppressive drug concentrations 
against SARS-CoV-2, a loading dose approach has been selected to provide the highest peak and 
trough PBI-0451 concentrations at the initiation of treatment (ie, Day 1), followed by the 
establishment of steady-state conditions for the remainder of the treatment period as described in 
Section 5.3). The dosing regimen is designed to assure initiation of therapy as soon as possible 
after randomization and administration of the full 1400 mg total daily dose on Day 1 of treatment 
to provide maximal antiviral activity at the point of highest viral burden and when the potential 
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DAA benefit is greatest. The safety of this dosing regimen is supported by single and multiple 
doses equal to or greater in magnitude (up to 2100 mg) and for longer duration (up to 10 days) 
than proposed in this Phase 2 study.  
The duration of treatment in this study is 5 days, consistent with other acute antiviral treatments, 
such as oseltamivir for influenza. The 5-day treatment duration is identical to that shown to result 
in reduced rates of clinically meaningful endpoints in DAA treatment studies of COVID-19 
(Jayk Bernal et al. 2022) that include SARS-CoV-2 viral load (Sasaki et al. 2022) and 
hospitalization due to COVID-19 or death from any cause, including nirmatrelvir (an Mpro 
inhibitor with the same mechanism of action of PBI-0451) coadministered with RTV (Hammond 
et al. 2022). 
1.4. 
Risk/Benefit Assessment for the Study 
The overall benefit/risk balance for this study is considered favorable. 
The target patient population under study for this protocol is designed to exclude patients who 
are at high risk of progression to severe COVID-19 and thus for which there may be no approved 
or authorized treatments. 
During a pandemic, additional potential risks to subjects may include interruptions to the study 
visit schedule and adherence to protocol-specified safety monitoring or laboratory assessments. 
Refer to Appendix 2 for details on the risks and risk mitigation strategy. 
1.4.1. 
Risk/Benefit for PBI-0451 
No clinical safety issues specifically related to PBI-0451 have been identified to date.  
The expected benefit to subjects being treated with PBI-0451 is a rapid decrease of SARS-CoV-2 
viral load within a short treatment period, without the need for coadministration of a second 
agent for pharmacoenhancement and its potential for DDIs and potentially reduce the duration of 
symptomatic illness and the risk of progression to more severe disease. 
Potential risks include unforeseen safety issues, the lack of efficacy and the risk of progression to 
more severe COVID-19 disease progression.  For the population of subjects with SARS-CoV-2 
infection, the expected benefit of eliminating SARS-CoV-2 virus within 5 days of treatment 
outweighs the risks associated with the possible development of previously unidentified safety 
issues.  
1.4.2. 
Risk/Benefit for Placebo 
Subjects randomized to the placebo group may benefit from frequent medical monitoring during 
the study as there is a potential risk of severe COVID-19 disease progression. 
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1.4.3. 
Potential Alternatives to Placebo 
Investigators should review all available treatment options for each individual subject, including 
those outside of this study, and risks associated with placebo with the potential subject.  The 
Investigator should refer to the “NIH Treatment Guidelines” (NIH 2022), and the CDC “Interim 
Clinical Considerations for COVID-19 Treatment in Outpatients” and “Underlying Medical 
Conditions Associated with Higher Risk for Severe COVID-19: Information for Healthcare 
Professionals” to appropriately discuss the alternative options and risks for being in this study 
(CDC 2022).  The potential participant should also be referred to or receive a printout of the 
CDC “People with Certain Medical Conditions” and “COVID-19 Treatments and Medications” 
which includes language appropriate for the lay person regarding medical conditions attributed to 
a higher risk of severe COVID-19 and potential treatment (CDC 2022). 
1. The following products are either FDA approved or authorized for emergency use for the 
treatment of mild-to-moderate COVID-19 in adults with positive results of direct SARS-
CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, 
including hospitalization or death, and are recommended as first line agents by the NIH 
Treatment Guidelines:  
 Veklury (remdesivir) – FDA approved (Gilead Sciences 2022)   
 Paxlovid (nirmatrelvir) boosted with ritonavir – Emergency Use Authorization (US Food 
and Drug Administration 2022c) 
2. The following products have emergency use authorization by the FDA for the treatment 
of mild-to-moderate COVID-19 in adults with positive results of direct SARS-CoV-2 
viral testing, and who are high risk for progression to severe COVID-19, including 
hospitalization or death, and for whom alternative COVID-19 treatment options 
approved or authorized by FDA are not accessible or clinically appropriate per the 
NIH Treatment Guidelines. 
 Lagevrio (molnupiravir) – Emergency Use Authorization (US Food and Drug 
Administration 2022a) 
 Bebtelovimab – Emergency Use Authorization (US Food and Drug Administration 
2022b) 
3. The list of approved or authorized products is subject to change during the course of the 
study, the complete list of FDA products can be found here: 
https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-
policy-framework/emergency-use-authorization#coviddrugs and the NIH Treatment 
Guidelines can be found here; https://www.covid19treatmentguidelines.nih.gov/ 
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1.5. 
Compliance 
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements. 
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2. 
OBJECTIVES AND ENDPOINTS 
Primary Objective 
Primary Endpoint 
 To evaluate the antiviral activity of 
PBI-0451  
 Proportion of subjects below the limit of 
detection (LOD) for infectious 
SARS-CoV-2 on Day 3 of treatment by 
infectious virus assay (IVA) from mid-
turbinate (MT) swab 
Secondary Objectives 
Secondary Endpoint 
 To evaluate safety and tolerability of 
PBI-0451 
 Number of treatment-emergent AEs, 
SAEs, discontinuations due to AEs, and 
Grade 3 or 4 laboratory abnormalities  
 To evaluate clinical efficacy of PBI-0451 
versus placebo through study Day 28 
 Proportion of subjects with sustained 
symptom resolution through Day 28 
 Time to sustained symptom resolution 
through Day 28  
 Proportion of subjects with COVID-19 
related hospitalization or death from any 
cause through Day 28 
 Severity of targeted COVID-19 symptoms  
 Number of COVID-19 related medical 
visits other than hospitalization, including 
acute/critical care visits through Day 28 
 Number of days in any hospital unit for 
treatment of COVID-19 
 To evaluate the effect of PBI-0451 on 
SARS-CoV-2  
 Presence of SARS-CoV-2 virus, viral 
RNA or viral antigen based on IVA, 
quantitative reverse transcriptase 
polymerase chain reaction (qRT-PCR), 
and rapid antigen test (RAT), as specified 
in the Clinical Virology Analysis Plan 
(CVAP) 
Exploratory Objectives 
Exploratory Endpoints 
 To evaluate SARS-CoV-2 resistance to 
PBI-0451 
 Sequence analysis of the SARS-CoV-2 
Mpro gene (nsp5) and Mpro cleavage sites  
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 To evaluate SARs-CoV-2 resistant variant 
susceptibility to PBI-0451 
 Susceptibility analysis of SARS-CoV-2 
variants with Mpro amino acid 
substitutions and variants with 
substitutions in Mpro cleavage sites in the 
SARS-CoV-2 polyprotein 
 To evaluate the relationship between 
SARS-CoV-2 detection methods 
 Correlation of SARS-CoV-2 detection by 
IVA, RAT, and qRT-PCR, as specified in 
the CVAP  
 To evaluate the incidence of rebound 
SARS-CoV-2 infection 
 Proportion of subjects with clinical and/or 
virologic rebound 
 To evaluate PBI-0451 PK 
 PBI-0451 PK analysis from an intensive 
PK substudy of up to 50 subjects  
 PK parameters from sparse sampling of 
all subjects for population PK analysis 
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3. 
STUDY DESIGN 
This protocol describes a Phase 2, randomized, double-blind, placebo-controlled study to 
evaluate efficacy and safety of PBI-0451 in nonhospitalized symptomatic adults with COVID-19 
who are at standard risk of progressing to severe illness. Approximately 210 subjects will be 
randomized in the study.  
An overview of the study design is provided in Figure 1. 
3.1. 
Study Treatments 
Following completion of screening and eligibility assessments, eligible subjects will be 
randomized 2:1 to 1 of 2 treatment groups on Day 1 as follows: 
 PBI-0451: 2 × 350 mg tablets administered orally twice daily (BID) (1400 mg/day) with 
food for 5 days (10 total doses) 
 Placebo: 2 × placebo to match PBI-0451 tablets administered orally BID with food for 
5 days (10 total doses) 
Randomization will be stratified as follows: 
 SARS-CoV-2 positive direct test diagnosis ≤ 3 days (target 30%) versus > 3 days from 
first onset of COVID-19 symptom(s) ≤ 5 days prior to randomization 
 Received primary vaccination series, alone versus any booster shots  
 PK substudy participation versus nonparticipation 
3.2. 
Duration of Treatment 
Eligible subjects will begin treatment immediately following randomization and completion of 
Day 1 assessments (first daily dose) and with the evening meal on Day 1 (second daily dose); 
subjects will continue BID dosing for a total of 5 days (10 total doses). 
3.3. 
Discontinuation Criteria 
Study drug will be discontinued in the following instances: 
 Unacceptable toxicity, or toxicity that, in the judgement of the investigator, compromises the 
ability to continue study-specific procedures or is considered not to be in the subject’s best 
interest 
 Subject request to discontinue for any reason 
 Pregnancy during the study (see Appendix 3) 
 Concurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree 
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 Subject noncompliance 
 Discontinuation of the study at the request of Pardes, a regulatory agency, or an institutional 
review board (IRB) or independent ethics committee (IEC) 
 Subjects develop severe or critical COVID-19 illness defined as sustained pulse oximetry 
<94%, a respiratory rate of >30 breaths/min or dyspnea that requires medical attention 
Subjects who discontinue study drug are encouraged to continue participation in the study for 
safety follow up.  Subjects can discontinue participation at any time.  
3.3.1. 
Rescue Therapy for Discontinuation 
Subjects who experience severe COVID-19 illness (defined in this study as sustained pulse 
oximetry <94%, a respiratory rate of >30 breaths/min, or dyspnea that requires medical attention) 
should discontinue study drug and be immediately referred by the Investigator to emergency care 
or treated by the Investigator for standard of care treatment of symptoms including, but not 
limited to, other antivirals, supplemental oxygen, corticosteroids, Janus kinase inhibitors, or 
interleukin-6 blockers, in accordance with the NIH Treatment Guidelines (NIH 2022). The 
subject should continue participation in the study, with study drug discontinued, for safety 
follow-up and clinical outcome of the medically attended visit. 
3.4. 
End of Study 
The end of this study will be the last subject’s last observation (or visit) up to Week 24. 
3.5. 
Source Data 
The source data for this study will be obtained from electronic data capture (EDC), central 
laboratory, local laboratory, specialty laboratory (for PK and/or ECG data). 
3.6. 
Biomarker Samples for Optional Future Research  
The following biological specimens will be collected from all subjects who have provided 
consent to participate in this study, and may be used to evaluate the association of systemic 
and/or tissue-based biomarkers with study drug response (including AEs) and/or dosage 
selection, and to better understand the biological pathways, biology of SARS-CoV-2 or related 
diseases caused by other CoVs, and/or the validation of a companion diagnostic for COVID-19 
or PBI-0451. Because biomarker science is a rapidly evolving area of investigation, and AEs in 
particular are difficult to predict, it may not be possible to prospectively specify all tests that may 
be done on the specimens provided. The specific analyses will include, but may not be limited to, 
the biomarkers and assays listed below. The testing outlined below is based upon the current 
state of scientific knowledge. It may be modified during or after the end of the study to remove 
tests that are no longer indicated and/or to add new tests based upon new state-of-the-art 
knowledge.  
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 Biological samples (blood and urine) will be collected relative to dosing (if applicable) to 
measure biomarkers with corresponding PK time points. 
 Mid-turbinate (MT) nasal swabs will be collected to measure SARS-CoV-2 using qRT-PCR, 
IVA, RAT, and viral sequencing. Saliva samples will be collected to measure SARS-CoV-2 
using qRT-PCR and IVA. 
Samples collected for biomarker assessments will be destroyed no later than 15 years after the 
end of study or per country requirements.  
3.7. 
Biomarker Sample for Optional Genomic Testing 
In addition to the study-specific informed consent to be signed by each subject participating in 
the study, subjects will be offered to document agreement to provide additional blood sample for 
optional genomic research. The sample will be obtained from subjects who agree to participate 
and provide their additional specific consent.  
A blood specimen will be collected for the evaluation of immune biomarkers that could regulate 
or be involved in the disposition of SARS-CoV-2 or PBI-0451. This sample will be collected at 
baseline/Day 1 prior to administration of the first dose of study drug but may be collected at any 
time during the study, if necessary. 
The specimen collected for optional future genomic research may be used to advance the 
development of the drug and/or increase our knowledge and understanding of the biology of the 
disease under investigation or related diseases. This specimen may also be used to study the 
association of biomarkers with biological pathways, disease pathogenesis, progression, and/or 
treatment outcomes, including efficacy, AEs, and the processes of drug absorption and 
disposition. In addition, the specimen may be used to develop biomarker and/or diagnostic 
assays and establish the performance characteristics of these assays. The collection and analysis 
of optional genomic research specimens may facilitate the design of new pharmaceutical agents 
and the development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future. 
The samples collected for optional genomic research will be destroyed no later than 15 years 
after the end of study or per country requirements. 
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4. 
SUBJECT POPULATION 
4.1. 
Number of Subjects and Subject Selection 
A total of 210 subjects will be randomized in the study. Subjects are nonhospitalized, 
symptomatic males and nonpregnant, nonlactating females 18 to < 65 years of age with a 
positive direct test of SARS-CoV-2 infection (antigen based or nucleic acid amplification test 
[NAAT]) who are not at high-risk of progressing to severe disease.  
4.1.1. 
Subject Replacement 
Subjects who prematurely discontinue the study due to adverse events will not be replaced. 
4.2. 
Inclusion Criteria 
Subjects must meet all the following inclusion criteria to be eligible for participation in this 
study: 
1. Can understand and sign a written informed consent form (ICF), which must be obtained 
prior to initiation of any study procedures 
2. Onset of COVID-19 symptoms ≤ 5 days prior to randomization with a positive 
SARS-CoV-2 test ≤ 24 hours prior to randomization. Authorized NAAT or antigen tests 
that detect viral RNA or protein, respectively, are allowed  
3. Received primary vaccination series as defined by Centers for Disease Control and 
Prevention (CDC). Subjects should be advised during informed consent that alternate 
therapies may be available outside of study participation. 
4. ≥ 2 symptoms of acute COVID-19 infection as determined by the investigator from the 
symptoms listed on the COVID-19 symptoms questionnaire present at randomization 
5. Male and nonpregnant, nonlactating female subjects 18 to < 65 years of age. Females 
must have a negative serum or urine pregnancy test at screening and prior to the first dose 
of study drug unless permanently sterile or in a postmenopausal state (see Appendix 3)  
6. Male and female subjects and/or their heterosexual partners must either be of 
nonchildbearing potential or must use effective contraception from screening through 
90 days after the last dose of study drug (see Appendix 3) 
7. Female subjects must refrain from egg donation and in vitro fertilization during treatment 
and for ≥ 28 days after the last dose of study drug 
8. Male subjects must refrain from sperm donation from screening through 90 days after the 
last dose of study drug 
9. Normal 12-lead ECG evaluation without clinically significant abnormalities 
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10. Able and willing to comply with all study requirements 
4.3. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not eligible to participate in this 
study: 
1. Considered at high-risk of developing severe illness from COVID-19 defined as ≥ 1 
CDC underlying medical condition associated with an increased risk of developing 
severe illness from COVID-19 (see Appendix 5) 
2. Unvaccinated against SARS-CoV-2 (defined as having not completed a primary 
vaccination series) 
3. Any SARS-CoV-2 vaccination within 3 month prior to randomization or anticipated to 
receive a SARS-CoV-2 vaccination (including a booster) during the 28-day study 
period 
4. Currently hospitalized or expected to require hospitalization for COVID-19 within 
48 hours of randomization 
5. Currently being treated or expected to be treated for COVID-19 with monoclonal 
antibodies, convalescent serum, or direct-acting antiviral agents (all potential subjects 
should be informed of evolving treatment options during informed consent that 
alternate therapies may or may not be available to them outside of study participation)  
6. Any clinical condition or laboratory result considered by the investigator to indicate 
any unstable or poorly controlled underlying clinically significant medical condition(s), 
active disseminated infection (other than SARS-CoV-2), or other medical condition that 
could represent a risk to the subject, including increasing the likelihood of a safety 
event, affect subject compliance, or affect efficacy and/or safety data collected during 
the 28-day study period  
7. Known active liver disease, including nonalcoholic steatohepatitis/nonalcoholic fatty 
liver disease, chronic or active HBV or HCV infection, primary biliary cirrhosis, 
Child-Pugh Class B or C, chronic alcoholic liver disease, or acute liver failure 
8. Receiving dialysis or having known severe renal impairment (chronic kidney disease, 
Stage 4 or above) 
9. Unable or unwilling to comply with the protocol procedures 
10. Participating in another interventional study with an investigational compound or 
device, including those for COVID-19 
11. Known prior participation in this study or another study involving PBI-0451 
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12. Females who are pregnant or breastfeeding 
13. Oxygen saturation of < 94% on room air 
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5. 
STUDY INTERVENTION AND CONCOMMITANT 
MEDICATIONS 
5.1. 
Randomization, Blinding, and Procedures for Breaking Treatment Codes 
5.1.1. 
Randomization 
Subjects who meet eligibility criteria will be randomized in a 2:1 ratio to PBI-0451 or placebo 
and assigned a unique subject number via an interactive voice and web response system (IXRS) 
prior to initiation of dosing on Day 1. Randomization will be stratified as follows: 
 SARS-CoV-2 positive direct test diagnosis ≤ 3 days (target 30%) versus > 3 days from first 
onset of COVID-19 symptom(s) ≤ 5 days prior to randomization 
 Received primary vaccination series, alone versus any booster shots  
 PK substudy participation versus nonparticipation 
5.1.2. 
Blinding 
The study is double-blinded. Subjects, investigators and all internal and external personnel 
directly involved in the conduct of the study will be blinded to treatment assignment. Study drug 
will be dispensed to subjects by the study pharmacist or designee in a blinded fashion.  
Specified personnel may be unblinded based on their study role as follows: 
 The statistician or designee in Biostatistics and/or Clinical Data Management who 
facilitates transfer of PK and/or virology sample logistics and data files between Pardes 
and vendors will be unblinded.  
 Individuals in Clinical Packaging and Labeling or Clinical Supply Management who 
have an Inventory Manager role in the IXRS for purpose of study drug inventory 
management will remain unblinded.  
 Individuals in Pharmacovigilance (PVE) responsible for safety signal detection, 
investigational new drug (IND) safety reporting, and/or expedited reporting of suspected 
unexpected serious adverse reactions (SUSARs) may be unblinded to individual case data 
and/or group-level summaries.  
 Individuals in Clinical Virology responsible for monitoring for virologic rebound 
detection will be unblinded to individual case data. In particular, RAT and qRT-PCR data 
will be monitored on a per subject basis to trigger the request for confirmatory sample 
collection in the case of a potential virologic rebound. 
 External (ie, contract research organizations [CROs]) biostatisticians and programmers 
will be unblinded for IND safety reporting.  
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 A select independent team that will not participate in any other study-related activities 
will be responsible for preparing unblinded analyses and documents to support regulatory 
activities that may be required while the study is ongoing. This team will be unblinded 
only at the study group level and will not have access to individual subject treatment 
assignment.  
5.1.3. 
Procedures for Breaking Treatment Codes 
In the event of a medical emergency for which breaking the blind is required to provide medical 
care to a subject, the investigator may obtain treatment assignment directly from the IXRS for 
that subject. Pardes recommends, but does not require, that the investigator contact the CRO 
medical monitor prior to breaking the blind. Treatment assignment should remain blinded unless 
that knowledge is necessary to determine a subject’s emergency medical care. The rationale for 
unblinding must be clearly explained in source documentation, along with the date on which the 
treatment assignment was unblinded. The investigator is requested to contact the CRO medical 
monitor promptly in case of any treatment unblinding. 
Blinding of study treatment is critical to the integrity of this clinical study. Therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will discontinue study 
treatment. All subjects will be followed until study completion unless consent to do so is 
specifically withdrawn by the subject. 
5.2. 
Description and Handling of PBI-0451  
5.2.1. 
Formulation 
PBI-0451 350 mg tablets are modified oval tablets.  
Refer to latest version of the IB for additional information. 
5.2.2. 
Packaging and Labeling 
PBI-0451 tablets are packaged in 20-count high-density polyethylene bottles with silica gel 
desiccant(s) and labeled “For Investigational Purposes Only”.  
Refer to the latest version of the IB for additional information. 
5.2.3. 
Storage and Handling 
PBI-0451 should be stored at controlled room temperature (15°C to 30°C [59°F to 86°F]) or as 
otherwise labeled. 
Drug product should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
drug product should not be stored in a container other than the container in which it is supplied. 
Consideration should be given to handling, preparation, and disposal through measures that 
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minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure. 
A sufficient quantity of PBI-0451 (and matching placebo tablets) to complete the study will be 
shipped to the investigator or qualified designee from Pardes or its designee. 
Refer to the latest version of the IB for additional information. 
5.3. 
Dosage and Administration  
 PBI-0451: 2 × 350 mg tablets administered orally twice daily (BID) (1400 mg/day) with 
food for 5 days (10 total doses) 
 Placebo: 2 × placebo to match PBI-0451 tablets administered orally BID with food for 
5 days (10 total doses) 
Subjects will take their first dose of study drug (PBI-0451 or placebo) with food as soon as 
possible after randomization, with the first dose designated as Day 1, and the second dose taken 
with the evening meal on Day 1 to ensure that a full total daily dose (1400 mg PBI-0451) is 
taken on the first day of treatment. Study drug will be taken with food, approximately 12 hours 
between doses, at approximately the same time for each BID dose for the remainder of 5 days of 
treatment. 
5.4. 
Prior and Concomitant Medications 
Concomitant use of certain medications or herbal/natural supplements and study drug may result 
in PK interactions resulting in increases or decreases in exposure of study drug or the 
medications. 
The following medications are disallowed from screening through completion of study treatment. 
If a subject requires use of a disallowed medication, a request for such use must be reviewed by 
Pardes and, if approved, the subject may continue to participate in the study. 
 Any and all illegal or illicit drug use (eg, amphetamines, cocaine, opiates), including use 
of prescription drugs outside the care of the prescribing physician 
 Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance  
5.5. 
Accountability for Study Drugs  
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. This includes acknowledgment of receipt of each shipment of study drug (quantity and 
condition). All used and unused study drug dispensed to subjects must be returned to the site. 
Each study site must keep accountability records that capture: 
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 The date received and quantity of study drug  
 The date, subject number, and the study drug kit number dispensed 
The date and quantity of used and unused study drug returned, along with the initials of the 
person recording the information. 
5.5.1. 
Investigational Medicinal Product Return or Disposal 
Pardes recommends that used and unused study drug supplies be destroyed at the site. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
CRO, the site may destroy used (empty or partially empty) and unused study drug supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for the electronic trial master file. If study drug is destroyed at the site, the investigator must 
maintain accurate records for all study drugs destroyed. Records must show the identification 
and quantity of each unit destroyed, the method of destruction, and the person who disposed of 
the study drug. Upon study completion, copies of the study drug accountability records must be 
filed at the site. Another copy will be returned to CRO.  
If the site does not have an appropriate SOP for drug destruction, used and unused study drug 
supplies are to be sent to the designated disposal facility for destruction. The study monitor will 
provide instructions for disposal return. 
The study monitor will review study drug supplies and associated records at periodic intervals. 
For both disposal options listed above, the study monitor must first perform drug accountability. 
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6. 
STUDY PROCEDURES 
The study assessments to be conducted for each randomized subject are presented in Table 1 and 
described in the following sections. The investigator must document any deviation from the 
protocol procedures and notify Pardes and CRO.  
6.1. 
Informed Consent 
Written informed consent must be obtained from each prospective subject before initiation of 
any screening procedure.  
6.1.1. 
Consent for Optional Research 
Subjects who provide additional, specific consent may provide additional samples for optional 
biomarker research as described in Section 3.7. 
6.2. 
Subject Enrollment and Treatment Assignment 
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to randomization and that subjects remain eligible for the duration of the study. 
Once informed consent has been obtained, all screening tests and assessments have been 
conducted, and study eligibility has been confirmed, a subject will be randomized to receive 
PBI-0451 or placebo on Day 1. Up to 50 subjects at select sites who provide separate specific 
consent will participate in an intensive PK substudy. 
Entry into screening does not guarantee enrollment into the study. To manage the total study 
enrollment, Pardes, at its sole discretion, may suspend screening and/or enrollment at any site or 
study-wide at any time. 
6.3. 
Pretreatment Assessments 
Screening assessments may be considered as baseline/Day 1 if the subject is eligible for the 
study and is randomized and receives the first dose of study drug on same day.  
6.3.1. 
Screening Visit 
Prospective subjects will be screened ≤ 5 days prior to randomization to determine eligibility for 
participation in the study. The following will be performed and documented at screening: 
 Obtain written informed consent 
 Obtain medical history 
 Complete physical examination, including vital signs, body weight, and height 
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 MT nasal swabs for SARS-CoV-2 RAT  
 MT nasal swabs and saliva samples, as appropriate, for SARS-CoV-2 IVA, qRT-PCR, 
and sequence analysis  
 Blood sample collection for the following analyses: serum pregnancy test (women of 
childbearing potential only, see Appendix 3) 
 Serum/urine pregnancy test (females of childbearing potential only) 
 12-lead ECG 
 Patient-reported outcomes (COVID-19 symptom questionnaire) and any hospitalizations 
or acute/critical care visits (eg, non-admitted hospital or other care facility)  
 Review of AEs and concomitant medications 
From the time of obtaining informed consent through administration of the first dose of study 
drug, record all SAEs, as well as any AEs related to protocol-specified procedures on the 
Adverse Events electronic case report form (eCRF). All other untoward medical occurrences 
observed during the screening period, including exacerbation or changes in medical history, are 
considered medical history (see Section 7.2). 
6.3.2. 
Baseline/Day 1 Assessments 
Note: Screening assessments may be considered as baseline/Day 1 assessments if the subject 
meets eligibility requirements, is randomized, and receives the first dose of study drug on same 
day.  
The following assessments will be completed on Day 1. The investigator must have received the 
results from either a direct SARS-CoV-2 antigen or qRT-PCR test and results from the 
serum/urine pregnancy test (females of childbearing potential only) and confirmed eligibility 
prior to randomization. Serology tests results for HIV, HBV, HCV and SARS-CoV-2 are not 
required for eligibility. 
At the time of randomization, subjects will be assigned a unique subject number via the IXRS. 
The following study assessments must be completed prior to the administration of the first dose 
of study drug: 
 Complete physical examination, including vital signs, and body weight 
 MT nasal swabs for SARS-CoV-2 RAT  
 MT nasal swabs and saliva samples, for SARS-CoV-2 IVA, qRT-PCR, and sequence 
analysis  
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 Testing for SARS-CoV-2 N-antibodies using the Roche Elecsys® Anti-SARS-CoV-2 
assay 
 Blood sample collection for the following analyses: hematology, chemistry, serology 
(HIV-1, HBV, HCV), coagulation panel, serum pregnancy test (women of childbearing 
potential only, see Appendix 3) 
 Urine sample collection for urinalysis 
 Creatinine clearance (CLCR) (Cockcroft-Gault) 
 Estimated glomerular filtration rate (eGFR, using Chronic Kidney Disease Epidemiology 
Collaboration [CKD-EPI] 2021) 
 12-lead ECG 
 Biomarker sample for optional genomic testing 
 Patient-reported outcomes (COVID-19 symptom questionnaire) 
 Any hospitalizations or acute/critical care visits (eg, non-admitted hospital or other care 
facility) since last study visit 
 Optional household transmission survey 
 Review of AEs and concomitant medications 
 Dispense study drug for all 10 doses  
Subjects will take their first dose of study drug with food immediately after randomization 
and completion of Day 1 assessments with the second dose taken with the evening meal on 
Day 1. The investigator will counsel subjects as to the importance of adherence to dosing and 
taking study drug at approximately the same times each day (see Section 5.3). 
The following Day 1 assessments will occur after the subject has taken their first dose of 
study drug: 
 Single PK sample 
 Intensive PK sampling (substudy subjects only) (Note that the intensive PK sample may 
be collected at any study visit from Day 1 to 5.) 
6.4. 
Treatment Assessments 
During treatment, individual study visits must occur on separate calendar days within the visit 
window, with the time(s) of sample collection recorded. 
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Study procedures and assessments during treatment Days 2 to 5 are outlined in Table 1. 
Symptom-driven physical examination, including vital signs; sample collection for SARS-CoV-2 
RAT, qRT-PCR, and IVA; and review of AEs and concomitant medications will occur at study 
visits on Days 2, 3, and 5.  
Assessments on Day 5 will also include a single PK sample, an evaluation of “survival status” 
(see Table 1), completion of the optional household transmission survey, and sample collection 
for SARS-CoV-2 sequence analysis (if appropriate).  
6.5. 
Posttreatment Assessments 
Posttreatment study procedures and assessments at Days 10, 15, and 28 are outlined in Table 1.  
Subjects who experience a relapse in symptom(s) after having no COVID-19 symptom(s) for 
≥3 days or have a positive RAT (or clinic qRT-PCR test) after testing negative by RAT or 
qRT-PCR will be requested to return to clinic within 2 days for symptom-drive physical 
examination, vital signs, MT swab and saliva samples for RAT, IVA, qRT-PCR, and sequencing, 
household transmission survey, and review of AEs and concomitant medications. 
A Week 24 follow-up assessment will be performed for all subjects (via telephone visit, virtual 
visit, or clinic visit, as convenient). Information regarding ongoing or recurrent COVID-19 
symptoms, survival status, pregnancy status (for female subjects of childbearing potential and 
female partners of male subjects), and any hospitalizations or acute/critical care visits (eg, 
non-admitted hospital or other care facility) that have occurred since the last study visit will be 
collected.  
6.6. 
Assessments for Early Discontinuation from Study 
If a subject prematurely discontinues study drug, for example as a result of an AE, every attempt 
should be made to keep the subject in the study and continue to perform the required 
study-related procedures until stabilization per the investigator. If this is not possible or 
acceptable to the subject or investigator, the subject may be withdrawn from the study and 
undergo an ET visit within 72 hours of permanently discontinuing the study drug as outlined in 
Table 1. Evaluations indicating abnormal results believed to be possibly or probably related to 
study drug at the ET visit should be repeated weekly or as often as deemed appropriate by the 
investigator until the abnormality resolves, returns to baseline level, or is otherwise explained.  
6.7. 
Pharmacokinetics Assessments 
Plasma samples will be collected for measurement of PBI-0451 concentrations and estimation of 
PK parameters (and metabolite[s], as applicable). Some subjects will have PK assessed by sparse 
sampling and other subjects by intensive PK substudy. 
Plasma collection for subjects participating in the intensive PK substudy may occur at any study 
visit from Day 1 (the first dose of study drug) to Day 5. Samples for the intensive PK substudy 
will be drawn at the following time points relative to PBI-0451 dosing:  
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Predose (≤ 5 minutes before dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and (optional) 10-12-hours 
postdose.  
A single PK sample will be collected from all subjects at study visits at baseline/Day 1 (after the 
first dose of study drug) and Day 5  
Any remaining PK samples will be stored in a plasma bank and may be used for exploratory 
assessments, such as metabolites, protein binding, endogenous markers of drug-drug interactions, 
biomarkers of host responsiveness, and other investigational experiments. 
6.8. 
Safety Assessments 
Safety will be evaluated throughout the study, including physical examinations, vital signs, 12-
lead ECG, laboratory studies (hematology, coagulation panel, chemistry, urinalysis), and review 
of AEs. Refer to Table 1 for the schedule of assessments. Collection of any additional 
assessments for routine safety monitoring at additional time points is at the discretion of the 
investigator based on GCP. 
6.8.1. 
Adverse Events/Concomitant Medications/Protocol Restrictions 
Evaluation for AEs, review of concomitant medications, and review of protocol restrictions will 
occur as outlined in Table 1. Refer to Section 7 for information regarding AEs. 
Concomitant use of certain medications or herbal/natural supplements and study drug may result 
in PK interactions resulting in increases or decreases in exposure of study drug or the 
medications. 
Medications that are disallowed from screening through completion of study treatment are listed 
below. If a subject requires use of a disallowed medication, a request for such use must be 
reviewed by Pardes and, if approved, the subject may continue to participate in the study. 
 Any and all illegal or illicit drug use (eg, amphetamines, cocaine, opiates), including use 
of prescription drugs outside the care of the prescribing physician 
 Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance  
6.8.2. 
Patient-Reported Outcomes 
Subjects will complete the following daily self-reported outcomes as outlined in Table 1. 
 COVID-19 symptoms questionnaire  
 COVID-19 weekly questionnaire 
 Hospitalizations or acute/critical care visits (eg, nonadmitted hospital or other care 
facility) that have occurred since the last study visit  
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6.8.3. 
Household Transmission Survey 
Subjects may complete the optional household transmission survey of confirmed SARS-CoV-2 
infections in subject’s household members as outlined in Table 1.  No specific identifying 
information will be collected. 
6.8.4. 
12-Lead Electrocardiogram Assessment 
ECG assessments will be conducted throughout the study as outlined in Table 1. Subjects should 
rest quietly in the supine position for a minimum of 5 minutes prior to each scheduled ECG 
acquisition and should remain in that position until the recording is complete. 
6.8.5. 
Physical Examination 
Complete and symptom-driven physical examinations will be conducted throughout the study as 
outlined in Table 1. The complete physical examination conducted at screening will include the 
following assessments:  
 A complete physical examination must include source documentation of general 
appearance, and the following body systems: head, neck, thyroid; eyes, ears, nose, throat, 
mouth, and tongue; chest (excluding breasts); respiratory; cardiovascular; lymph nodes; 
abdomen; skin, hair, nails; musculoskeletal; neurological.  
Medical History and Concomitant Medications 
 Review medical history, including history of allergies, prior and current use of nicotine or 
nicotine-containing products, alcohol and illegal drug use, and prior (≤ 30 days) and 
current medication use. 
6.8.6. 
Vital Signs 
The schedule of vital signs assessments is provided in Table 1. Vital sign measurements include 
blood pressure, heart rate, respiration rate, pulse oximetry, and temperature and should be taken 
once subjects have been seated or in the supine position for a minimum of 5 minutes. A subject’s 
position for measurement should remain consistent throughout the study.  
6.8.7. 
Body Mass Index  
Height and weight will be collected at screening for calculation of body mass index for inclusion 
criteria. 
6.8.8. 
Clinical Laboratory Tests/Assessments 
Blood and urine samples for safety evaluations will be collected throughout the study as outlined 
in Table 1. 
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6.8.8.1. 
Blood Samples 
Blood samples will be collected for the following laboratory analyses: 
 Hematology: Hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell 
count with differential (absolute and percentage), including lymphocytes, monocytes, 
neutrophils, eosinophils, basophils, and mean corpuscular volume  
 Coagulation panel: D-dimer, prothrombin time, activated partial thromboplastin time and 
international normalized ratio  
 Chemistry: alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total 
bilirubin, direct and indirect bilirubin, total cholesterol, high-density lipoprotein, low-density 
lipoprotein, triglycerides, total protein, albumin, lactic acid dehydrogenase, creatine 
phosphokinase, bicarbonate, blood urea nitrogen, calcium, chloride, creatinine (see below), 
glucose, phosphorus, magnesium, potassium, sodium, uric acid, and amylase (reflex lipase 
testing is performed in subjects with total amylase > 1.5 × upper limit of normal) 
 Serum pregnancy test (females of childbearing potential only) 
 Serology (SARS-CoV-2 N-antibodies [using the Roche Elecsys® Anti-SARS-CoV-2 assay], 
HIV-1, HBV [hepatitis B serum antigen; hepatitis B core antibody], HCV [hepatitis C 
antibody, reflex to HCV RNA]) 
6.8.8.2. 
Urine Samples 
Urine samples will be collected for urinalysis.  
6.8.9. 
Creatinine Clearance and Estimated Glomerular Filtration Rate  
Weight will be collected at Baseline/Day 1 to calculate CLCR and eGFR.  
 CLCR (using the Cockcroft-Gault method based on serum creatinine and actual body 
weight as measured at screening): 
 
 eGFR (using CKD-EPI 2021) expressed as a single equation:  
eGFRcr = 142 × min(Scr/κ, 1) × max(Scr/κ, 1)-1.200 × 0.9938Age × 1.012 [if female] 
where: 
Scr = serum creatinine in mg/dL 
κ = 0.7 (females) or 0.9 (males) 
α = -0.241 (female) or -0.302 (male) 
min(Scr/κ, 1) is the minimum of Scr/κ or 1.0 
max(Scr/κ, 1) is the maximum of Scr/κ or 1.0 
Age (years) 
(140 – Age [years]) × (Weight [kg]) 
(× 0.85 for females) = CLCR (mL/min) 
72 × (Serum Creatinine [mg/dL]) 
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6.9. 
Virology Assessments 
MT nasal swab and saliva samples for virology assessment will be collected throughout the study 
as outlined in Table 1. The following virologic analyses are planned: 
 SARS-CoV-2 IVA: TCID50 (infected Vero E6 cell immunoassay) 
 SARS-CoV-2 sequence analysis (MT nasal swab only) 
 SARS-CoV-2 RAT (lateral flow immunoassay; MT nasal swab only) 
 SARS-CoV-2 qRT-PCR  
6.10. 
Sample Storage 
Stored biological samples may be used by Pardes or its research partner(s) for future testing to 
provide additional data to answer questions that relate to the main study (refer to Section 3.6). At 
the end of this study, these samples may be retained in storage by Pardes for a period up to 
15 years. If subjects provide additional specific consent, residual PK samples will be destroyed 
no later than 15 years after the end of study.  
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7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT 
7.1. 
Definitions of Adverse Events and Serious Adverse Events 
7.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a clinical study subject administered a study drug 
that does not necessarily have a causal relationship with the study drug. An AE can therefore be 
any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use 
of a study drug, whether or not the AE is considered related to the study drug. Adverse events 
may also include pretreatment or posttreatment complications that occur as a result of 
protocol-specified procedures or special situations (Section 7.1.3). Preexisting events that 
increase in severity or change in nature during or as a consequence of participation in the clinical 
study will also be considered AEs. 
An AE does not include the following: 
 Medical or surgical procedures, such as surgery, endoscopy, tooth extraction, and 
transfusion. The condition that led to the procedure may be an AE and must be reported. 
 Preexisting diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen 
 Situations in which an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions) 
 Overdose without clinical sequelae (Section 7.1.3) 
 Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed and not related to a protocol-specified procedure is not an AE but 
rather considered to be preexisting and should be documented as medical history. 
Preexisting events that increase in severity or change in nature after study drug initiation or 
during study treatment or as a consequence of participation in the clinical study are considered 
AEs. 
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7.1.2. 
Serious Adverse Events 
A SAE is defined as an event occurring at any time during the study that results in the following: 
 Death 
 A life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at 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.) 
 Inpatient hospitalization or prolongation of existing hospitalization 
 Persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 A medically important event or reaction. Such events may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes constituting SAEs. Medical and scientific 
judgment must be exercised to determine whether such an event is reportable under 
expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, and development of drug dependency or 
drug abuse.  
7.1.3. 
Study Drugs and Concomitant Therapy Special Situations Reports 
Special situation reports (SSRs) include all reports of medication error, abuse, misuse, overdose, 
occupational exposure, drug interactions, exposure via breastfeeding, unexpected benefit, 
transmission of infectious agents via the drug product, counterfeit or falsified medicine, and 
pregnancy, regardless of an associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, preparation for 
administration, or administration of a study drug while the study drug is in the control of a health 
care professional, patient, or consumer. Medication errors may be classified as a medication error 
without an AE, which includes situations of missed dose; medication error with an AE; 
intercepted medication error; or potential medication error. 
Abuse is defined as persistent or sporadic intentional excessive use of a study drug by a subject. 
Misuse is defined as any intentional and inappropriate use of a study drug that is not in 
accordance with the protocol instructions or the local prescribing information. 
An overdose is defined as an accidental or intentional administration of a quantity of a study 
drug given per administration or cumulatively that is above the maximum recommended dose as 
per protocol or in the product label (as it applies to the daily dose of the subject in question). In 
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cases of a discrepancy in drug accountability, overdose will be established only when it is clear 
that the subject has taken excess dose(s). Overdose cannot be established when the subject 
cannot account for the discrepancy, except in cases in which the investigator has reason to 
suspect that the subject has taken the additional dose(s). 
Occupational exposure is defined as exposure to a study drug as a result of one’s professional or 
nonprofessional occupation. 
Drug interaction is defined as any drug/drug, drug/food, or drug/device interaction. 
Unexpected benefit is defined as an unintended therapeutic effect where the results are judged to 
be desirable and beneficial.  
Transmission of infectious agents is defined as any suspected transmission of an infected agent 
through a study drug. 
Counterfeit or falsified medicine is defined as any study drug with a false representation of (a) its 
identity, (b) its source, or (c) its history. 
7.2. 
Assessment of Adverse Events and Serious Adverse Events 
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity and for final review and confirmation of accuracy of event information and 
assessments. 
7.2.1. 
Assessment of Causality for Study Drugs and Procedures 
The investigator or qualified subinvestigator is responsible for assessing AE relationship to study 
drug using clinical judgment and the following considerations: 
 No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (eg, preexisting condition, underlying disease, 
intercurrent illness, concomitant medication). 
 Yes: There is reasonable possibility that the AE may have been caused by the study drug. 
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting.  
The relationship of an AE to a study procedure (eg, invasive procedures such as venipuncture or 
biopsy) should be assessed using the following considerations: 
 No: Evidence exists that the AE has an etiology other than the study procedure. 
 Yes: The AE occurred as a result of the study procedure (eg, venipuncture). 
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7.2.2. 
Assessment of Severity  
The severity of AEs will be graded using the Division of AIDS Toxicity Grading Scale, Version 
2.1. For each episode, the highest grade attained should be reported as defined in the grading 
scale (Appendix 4). 
7.3. 
Investigator Reporting Requirements and Instructions  
7.3.1. 
Requirements for Collection Prior to Study Drug Initiation 
After informed consent, but prior to initiation of study drug, the following types of events must 
be reported on the applicable eCRFs: all SAEs and AEs related to protocol-specified procedures. 
7.3.2. 
Adverse Events 
Following initiation of study drug, collect all AEs, regardless of cause or relationship to study 
drug, until Day 28, and report them on the eCRFs as instructed. 
All AEs should be followed until resolution or until the AE is stable, if possible. Pardes may 
request that certain AEs be followed beyond the protocol-specified follow-up period. 
7.3.3. 
Serious Adverse Events 
All SAEs, regardless of cause or relationship to study drug or a protocol-specified procedure, 
that occur after a subject consents to participate in the study (ie, after signing the ICF) through 
study Day 28, must be reported on the applicable eCRFs and to the CRO PVE as instructed 
below in this section.  
Any SAEs and deaths that occur after Day 28, and is deemed relevant to the use of study drug, 
should also be reported. 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
Investigators are not obligated to actively seek SAEs after study Day 28; however, if the 
investigator learns of any SAEs that occur after Day 28, and the event is deemed relevant to the 
use of study drug, the investigator should promptly document and report the event to CRO PVE. 
Instructions for reporting SAEs are described in Section 7.4.1. 
7.3.4. 
Study Drug Special Situations Reports 
All study drug special situations that occur from study drug initiation through study Day 28 must 
be reported to CRO PVE (Section 7.4.2). AEs and SAEs resulting in SSRs must be reported in 
accordance with the AE and SAE reporting guidance. 
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7.3.5. 
Concomitant Therapy Reports 
7.3.5.1. 
Concomitant Therapy Special Situations Report 
Special Situations Reports (SSR) involving a concomitant therapy (not considered study drug) 
that occur after the subject first consents to participate in the study (ie, after signing the ICF) 
through study Day 28, must be reported to CRO PVE utilizing the paper SSR (Section 7.4.2.3). 
7.3.5.2. 
Concomitant Therapy Report 
Special situations involving concomitant medications do not need to be reported on the SSR 
form; however, for special situations that result in AEs due to a concomitant medication, the AE 
should be reported on the AE form.  
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation. 
All clinical sequelae in relation to these SSRs will be reported as AEs or SAEs at the same time 
using the AE eCRF and/or the SAE report form. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available. 
7.4. 
Reporting Process for Serious Adverse Events and Special Situation Reports 
7.4.1. 
Serious Adverse Event Reporting Process 
 For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be transmitted by email or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers. 
 Additional information may be requested to ensure the timely completion of accurate safety 
reports. 
 Any medications necessary for treatment of the SAE must be recorded in the concomitant 
medication section of the subject’s eCRF and the SAE narrative section of the Safety Report 
Form eCRF. 
7.4.1.1. 
Electronic Serious Adverse Event Reporting Process  
 Site personnel will record all SAE data on the applicable eCRFs and transmit the SAE 
information to CRO PVE within 24 hours of the investigator’s knowledge of the event from 
ICF signature through study Day 28.  
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 If it is not possible to record and transmit the SAE information electronically, record the SAE 
on the paper SAE reporting form and transmit to CRO PVE within 24 hours: 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
 If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. If the database is not locked, any SAE reported via paper must be 
transcribed as soon as possible on the applicable eCRFs and transmitted to CRO PVE. 
7.4.1.2. 
Paper Serious Adverse Event Reporting Process 
 All SAEs will be recorded on the SAE report form and transmitted by email or fax within 
24 hours of the investigator’s knowledge of the event to the attention of CRO PVE from ICF 
signature through study Day 28. 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
7.4.2. 
Special Situations Reporting Process  
7.4.2.1. 
Electronic Special Situations Reporting Process for Study Drug 
 Site personnel will record all special situation data on the applicable eCRFs and transmit the 
information to CRO PVE from study drug initiation through study Day 28.  
 If for any reason it is not possible to record the special situation information electronically, 
record the special situation on the paper SSR form and transmit to CRO PVE: 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
 If a special situation has been reported via a paper form because the eCRF database has been 
locked, no further action is necessary. If the database is not locked, any special situation 
reported via paper must be transcribed as soon as possible on the applicable eCRFs and 
transmitted to CRO PVE. 
 See Section 7.4.2.3 for instructions on reporting special situations with concomitant 
medications.  
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7.4.2.2. 
Paper Special Situations Reporting Process for Study Drug 
 All special situations will be recorded on the SSR form and transmitted by email or fax 
within 24 hours of the investigator’s knowledge of the event to the CRO PVE from study 
drug initiation through Day 28. 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
7.4.2.3. 
Reporting Process for Concomitant Medications 
 Special situations that involve concomitant medications that are not considered study drug 
must be reported within 24 hours of the investigator’s knowledge of the event to CRO PVE 
utilizing the paper SSR form to: 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
 Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation. 
 Special situations involving concomitant medications do not need to be reported on the SSR 
form; however, special situations that result in AEs due to a concomitant medication, must be 
reported as AEs. 
7.4.2.4. 
Pregnancy Reporting Process 
 The investigator should report pregnancies in female study subjects and/or female partners of 
male subjects that are identified after initiation of study drug and throughout the study, 
including the posttreatment follow-up period, to CRO PVE using the pregnancy report form 
within 24 hours of becoming aware of the pregnancy. Contact details for transmitting the 
pregnancy report form are as follows: 
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
 The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate 
a pregnancy without medical reasons. 
 Any other premature termination of pregnancy (eg, a spontaneous abortion, an induced 
therapeutic abortion due to complications or other medical reasons) must be reported within 
24 hours as an SAE, as described in Section 7.4.1. The underlying medical reason for this 
procedure should be recorded as the AE term. 
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 A spontaneous abortion is always considered to be an SAE and will be reported as described 
in Section 7.4.1. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to the CRO PVE. 
 The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome of the pregnancy/partner pregnancy should be reported to CRO 
PVE using the pregnancy outcome report form. If the end of the pregnancy/partner 
pregnancy occurs after the study has been completed, the outcome should be reported 
directly to CRO PVE.  
PPD NA PVE 
Phone: +1 888 483 7729 
Fax: +1 888 529 3580 
 Refer to Appendix 3 for pregnancy precautions, definition of female of childbearing 
potential, and contraceptive requirements. 
7.5. 
Sponsor Reporting Requirements 
Depending on relevant local legislation and regulations, including the applicable FDA Code of 
Federal Regulations, the European Union Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation and regulations, Pardes may be required to 
expedite to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions, or 
SUSARs. In accordance with the European Union Clinical Trials Directive (2001/20/EC), Pardes 
or a specified designee will notify worldwide regulatory agencies and the relevant IEC(s) in 
concerned Member States of applicable SUSARs as outlined in current regulations. 
Assessment of expectedness for SAEs will be determined by CRO PVE using reference safety 
information specified in the IB or relevant local label, as applicable.  
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.  
7.6. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Laboratory abnormalities without clinical significance are not to be recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, urinalysis) that require 
medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as AEs or SAEs as applicable. In addition, laboratory or other 
abnormal assessments (eg, ECGs, radiologic studies, vital signs) that are associated with signs 
and/or symptoms must be recorded as AEs or SAEs if they meet the definition of an AE or SAE 
as described in Sections 7.1.1 and 7.1.2, respectively. If the laboratory abnormality is part of a 
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syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result (ie, decreased 
hemoglobin). 
Severity should be recorded and graded according to the Division of AIDS Toxicity Grading 
Scale, Version 2.1 (Appendix 4). AEs associated with laboratory abnormalities should be graded 
on the basis of the clinical severity in the context of the underlying conditions; this may or 
may not be in agreement with the grading of the laboratory abnormality. 
7.7. 
Toxicity Management  
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the CRO medical monitor, who will have a discussion with the investigator and decide the 
appropriate course of action. Whether or not considered treatment related, all subjects 
experiencing AEs must be monitored periodically until symptoms subside, any abnormal 
laboratory values have resolved or returned to baseline levels or are considered irreversible, or 
until there is a satisfactory explanation for the changes observed.  
Severity of AEs should be recorded and graded according to the following: 
 Grade 1 (Mild) clinical AE defined as mild symptoms causing no or minimal interference 
with usual social and functional activities with intervention not indicated will continue with 
study participation. 
 Grade 2 (Moderate) clinical AE defined as moderate symptoms causing greater than minimal 
interference with usual social and functional activities with intervention indicated will 
continue with study participation if interventions are not contraindicated and the investigator 
and medical monitor agree to continue. 
 Grade 3 (Severe) clinical AEs defined as severe symptoms causing inability to perform usual 
social and functional activities with intervention or hospitalization indicated will discontinue 
study drug administration and continue with study follow-up assessments. 
 Grade 4 (Potentially Life-Threatening) clinical AEs are defined as potentially life-threatening 
symptoms causing inability to perform basic self-care functions with intervention indicated 
to prevent permanent impairment, persistent disability; and will discontinue study 
participation. 
 Grade 5 indicates death. 
Any questions regarding toxicity management should be directed to the CRO medical monitor. 
7.8. 
Medical Monitoring 
A team of medically qualified individuals, including but not limited to, the Sponsor and the CRO 
Medical Monitors, and the Drug Safety Consultant are responsible for ongoing review of all 
AEs, concomitant medications, laboratory values (including virology), and vital signs (including 
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pulse oximetry), worsening of symptoms (COVID-19 symptom questionnaire, including 
dyspnea), acute/critical care visits (eg, nonadmitted hospital or other care facility), and study 
drug discontinuations, at a minimum monthly basis throughout the study, per the Safety 
Monitoring Plan.  Serious adverse events (eg, hospitalizations, life threatening events, medically 
important events, deaths) will be evaluated by the Sponsor and the CRO Medical Monitor within 
24 hours after being reported by the Investigator.  Blinded study data will be evaluated for trends 
and any event which occurs in greater frequency will be evaluated for updating risk language and 
notifying the IRB and regulatory authorities, as required.   
An independent select team that will not participate in any other study-related activities will be 
responsible for preparing unblinded analyses and documents to support regulatory activities that 
may be required while the study is ongoing (See Section 5.1.2), which may include, but not 
limited to, study termination or modification of the study to protect subject safety. 
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8. 
STATISTICAL CONSIDERATIONS 
Summary statistics will be used to analyze the study data. Any statistical testing will be 
conducted to ensure that the overall alpha = 0.05 level (2 sided). Unless otherwise specified, data 
summaries and analyses will be reported by treatment group. Details of the statistical methods 
will be provided in the statistical analysis plan (SAP), including any deviations from the original 
planned analyses. 
8.1. 
Analysis Objectives and Endpoints 
The primary, secondary, and exploratory study objectives and endpoints are listed in Section 2.  
8.2. 
Planned Analysis 
8.2.1. 
Interim Analysis 
An analysis of the primary and secondary endpoints will be conducted after 210 subjects 
complete the Day 28 study visit.  
8.2.2. 
Final Analysis 
The final analysis will be conducted after the last randomized subject has completed their 
Week 24 follow-up visit or discontinued the study, all outstanding data queries have been 
resolved, and the database has been cleaned and locked. 
8.3. 
Analysis Conventions 
8.3.1. 
Analysis Sets 
8.3.1.1. 
All Enrolled Analysis Set 
The all enrolled analysis set includes all subjects who sign the ICF. This is the primary analysis 
set for disposition. 
8.3.1.2. 
Intention-to-Treat Analysis Set 
The intention-to-treat (ITT) analysis set includes all randomized subjects. This is the primary 
analysis set for demographics and data listings. 
8.3.1.3. 
Modified Intention to Treat Analysis Set 
The modified intention-to-treat (mITT) analysis set includes all randomized subjects with 
≥ 2 symptoms consistent with COVID-19 ≤ 5 days prior to randomization and a positive 
SARS-CoV-2 test (RT-PCR or RAT) ≤ 24 hours prior to randomization who received ≥ 1 dose 
of study drug. This is the primary analysis set for all clinical endpoints. 
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8.3.1.4. 
Modified Intent to Treat Virologic Analysis Set 
The mITT virologic analysis set is a subset of the mITT analysis set that includes subjects who 
had detectable infectious SARS-CoV-2 by IVA at baseline/Day 1. This is the primary analysis 
set for the primary efficacy endpoint. 
8.3.1.5. 
Safety Analysis Set 
The safety analysis set includes all randomized subjects who received ≥ 1 dose of study drug. 
This is the primary analysis set for safety analyses. 
8.3.1.6. 
Pharmacokinetics Analysis Set 
The PK analysis set includes all subjects who participated in the intensive PK substudy and have 
≥ 1 nonmissing PK concentration reported by the PK laboratory. This is the primary analysis set 
for PK analyses. 
8.3.2. 
Data Handling Conventions 
8.3.2.1. 
Missing Data 
Missing data can have an impact upon the interpretation of the study data. As this study is of 
short duration, it is anticipated that missing data will be minimal. Every effort will be made to 
obtain required data at each scheduled evaluation from all subjects who have been enrolled. Any 
imputations of missing data will be described in the SAP.  
8.3.2.2. 
Adjustments for Multiplicity 
No adjustments for multiplicity are planned. 
8.4. 
Demographic and Baseline/Day 1 Characteristics Analysis 
Demographics (age, gender, race/ethnicity), and subject characteristics (SARS-CoV-2 Pango 
lineage, SARS-CoV-2 seropositivity, qRT-PCR, time since onset of symptoms) will be 
summarized by treatment group using descriptive statistics for the ITT analysis set.  
8.5. 
Efficacy Analysis 
8.5.1. 
Primary Analysis 
The primary efficacy endpoint is the proportion of subjects below the LOD for infectious 
SARS-CoV-2 on Day 3 by IVA. For the primary endpoint, differences between PBI-0451 and 
placebo will be evaluated using stratum-adjusted Mantel-Haenszel proportions (adjusted for 
randomization strata). The proportion of subjects below the LOD for infectious SARS-CoV-2 at 
other time points will be summarized in a similar manner. 
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8.5.2. 
Secondary Analyses 
The time to resolution of targeted COVID-19 symptoms will be estimated with the Kaplan-Meier 
method and summarized by treatment group. Differences between treatment groups will be 
determined using a Wilcoxon-Gehan test. The analysis of time to resolution of each targeted 
COVID-19 symptom will be conducted in a similar manner. 
The proportion of subjects with COVID-19 related hospitalization or death from any cause will 
be summarized by treatment group. Differences between treatment groups will be assessed using 
Mantel-Haenszel proportions.  
The number of COVID-19 related hospitalizations or acute/critical care visits and the number of 
days in any hospital unit for the treatment of COVID-19 will be summarized. Differences 
between treatment groups will be assessed using a van Elteren test stratified by the 
randomization factors. 
SARS-CoV-2 viral load kinetics will be summarized by study visit. Differences between the 
treatment groups will be assessed with a van Elteren test stratified by the randomization factors.  
SARS-CoV-2 clinical and virologic rebound will be summarized by the amount of viral RNA 
detected at baseline/Day 1, time to loss of clinical symptoms, time to negative RAT or IVA, and 
time to the first confirmed reappearance of symptoms and/or a positive RAT or qRT-PCR 
sample. 
A correlation of the results of IVA, RAT, and qRT-PCR assessments will be evaluated. 
8.6. 
Safety Analysis 
8.6.1. 
Extent of Exposure 
A subject’s extent of exposure to study drug will be determined from the study drug 
administration data. Exposure data will be summarized using descriptive statistics and listed.  
8.6.2. 
Adverse Events 
Clinical and laboratory AEs will be coded using the current version of the Medical Dictionary 
for Regulatory Activities. A treatment-emergent AE is defined as any AE that begins on or after 
the date and time of first dose of study drug up to the date of last dose of study drug plus 14 
days. Treatment-emergent AEs, SAEs, and AEs leading to premature discontinuation of study 
drug/study will be summarized by treatment, system organ class, and preferred term.  
Laboratory results and change from predose values for selected laboratory tests will be 
summarized by treatment at scheduled visits. The incidence of treatment-emergent laboratory 
abnormalities (Division of AIDS Toxicity Grading Scale) will be summarized by treatment. 
By-subject listings of safety data will be provided. 
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8.6.3. 
Laboratory Evaluations 
Listings of individual subject laboratory results will be provided. Selected laboratory data will be 
summarized using only observed data. Data and change from baseline/Day 1 at all scheduled 
time points will be summarized.  
Graded laboratory abnormalities will be defined in the SAP. Incidence of treatment-emergent 
laboratory abnormalities, defined as values that increase ≥ 1 toxicity grade from baseline/Day 1 
at any postbaseline time point up to and including the date of last dose of study drug plus 14 days 
will be summarized by treatment group. If baseline/Day 1 data are missing, any graded 
abnormality (ie, ≥ Grade 1) will be considered treatment emergent. 
Laboratory abnormalities that occur before the first dose of study drug or after the subject has 
discontinued study drug for ≥ 14 days will be listed. 
8.6.4. 
Other Safety Evaluations 
Vital signs and (safety) ECG data will be listed. 
8.7. 
Pharmacokinetics Analysis  
PBI-0451 plasma concentrations and PK parameters will be derived using noncompartmental 
methods (including metabolite[s] as applicable) and listed and summarized using descriptive 
statistics.  
PBI-0451 plasma concentrations from the PK substudy and sparse sampling from the overall 
study population will be used in a population PK analysis and reported separately.  
8.8. 
Sample Size 
The sample size will be approximately 210 subjects to account for approximately 60% of 
randomized subjects who are anticipated to be SARS-CoV-2 negative by IVA at baseline/Day 1 
and would be excluded from the mITT virologic analysis set. It should be noted that this sample 
size is sufficient with ≥ 80 power to detect a > 19% absolute difference in the proportion of 
subjects below the LOD for infectious SARS-CoV-2 virus (99% vs 81%) at Day 3 by IVA 
among subjects who had detectable infectious SARS-CoV-2 at baseline/Day 1. This assumes 
alpha = 0.05 and that 40% of subjects have detectable infectious virus at baseline/Day 1. 
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9. 
RESPONSIBILITIES 
9.1. 
Investigator Responsibilities 
9.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with International Council 
for Harmonisation (of Technical Requirements for Pharmaceuticals for Human Use) (ICH) 
E6(R2) addendum to its guideline for GCP and applicable laws and regulations. 
Investigators should review all available treatment options for each individual potential subject, 
including those outside of this study, and risks associated with possibly receiving placebo with 
the potential subject.  The Investigator should refer to the “NIH Treatment Guidelines” (NIH 
2022), and the CDC “Interim Clinical Considerations for COVID-19 Treatment in Outpatients” 
and “Underlying Medical Conditions Associated with Higher Risk for Severe COVID-19: 
Information for Healthcare Professionals” to appropriately discuss the alternative options and 
risks for being in this study (CDC 2022).  The potential subject should also be referred or receive 
a printout of the CDC “People with Certain Medical Conditions” and “COVID-19 Treatments 
and Medications” which includes language appropriate for the lay person regarding medical 
conditions attributed to a higher risk of severe COVID-19 and potential treatment (CDC 2022). 
9.1.2. 
Financial Disclosure 
The investigator and subinvestigators will provide prompt and accurate documentation of their 
financial interest or arrangements with Pardes or proprietary interests in the study drug during 
the course of a clinical study. This documentation must be provided prior to the investigator’s 
(and any subinvestigator’s) participation in the study. The investigator and subinvestigator agree 
to notify Pardes or CRO of any change in reportable interests during the study and for 1 year 
following completion of the study. Study completion is defined as the date when the last subject 
completes the protocol-defined activities. 
9.1.3. 
Institutional Review Board/Independent Ethics Committee Review and 
Approval 
The investigator (or designated personnel as appropriate according to local regulations) will 
submit this protocol, the ICF, and any accompanying material to be provided to the subject (such 
as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator. 
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
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provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects. 
9.1.4. 
Informed Consent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study before undertaking any study-related procedures. The investigator 
must use the most current IRB/IEC-approved ICF for documenting written informed consent. 
Each ICF (or assent as applicable) will be appropriately signed and dated by the subject or the 
subject’s legally authorized representative, the person conducting the consent discussion, and an 
impartial witness (if required by IRB/IEC or local requirements).  
The ICF will inform subjects about genomic testing and/or planned sample retention. In addition 
to the study-specific ICF to be signed by each subject participating in the study, subjects will be 
required to document agreement to provide additional samples or to allow the use of the 
remainder of their already-collected specimens for optional future research, in accordance with 
applicable regulations. In addition to the study specific ICF to be signed by each subject 
participating in the study, subjects will be required to document agreement to provide additional 
samples for optional genomic research. The results of the tests done on the samples will not be 
given to the subject or the investigator. 
9.1.5. 
Confidentiality 
The investigator must ensure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of birth) will be recorded on any form 
or biological sample submitted to Pardes, IRB/IEC, or the laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions in accordance with local 
regulations. NOTE: The investigator must keep a screening log with details for all subjects 
screened and enrolled in the study, in accordance with the site procedures and regulations. 
Subject data will be processed in accordance with all applicable regulations.  
The investigator agrees that all information received from Pardes or its partner(s), including but 
not limited to the IB, this protocol, CRFs/eCRFs, study drug information, and any other study 
information, remain the sole and exclusive property of Pardes during the conduct of the study 
and thereafter. This information is not to be disclosed to any third party (except employees or 
agents directly involved in the conduct of the study or as required by law) without prior written 
consent from Pardes. The investigator further agrees to take all reasonable precautions to prevent 
the disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain. 
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9.1.6. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file and (2) subject 
clinical source documents. 
The investigator’s study file will contain the protocol/amendments, CRFs/eCRFs, IEC and 
government approval with correspondence, the ICF(s), drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence. 
The required source data should include sequential notes containing at least the following 
information for each subject: 
 Subject identification 
 Documentation that subject meets eligibility criteria (ie, medical history, physical 
examination, and confirmation of diagnosis) to support inclusion and exclusion criteria 
 Documentation of the reason(s) a consented subject is not enrolled 
 Participation in study (including study number) 
 Study discussed and date of informed consent 
 Dates of all visits 
 Documentation that protocol-specific procedures were performed 
 Results of efficacy parameters, as required by the protocol 
 Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return 
 Record of all AEs and other safety parameters (start and end date; causality and severity) and 
documentation that adequate medical care has been provided for any AE 
 Concomitant medication (start and end date; dose if relevant; dose changes) 
 Date of study completion and reason for early discontinuation if it occurs 
All clinical study documents must be retained by the investigator for ≥ 2 years or according to 
local laws, whichever is longer, after the last approval of a marketing application in an ICH 
region (ie, US, Europe, or Japan) and until there are no pending or planned marketing 
applications in an ICH region; or, if no application is filed or if the application is not approved 
for such indication, for 2 years after the investigation is discontinued and regulatory authorities 
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have been notified. Investigators may be required to retain documents longer if specified by 
regulatory requirements, by local regulations, or by an agreement with Pardes. The investigator 
must notify Pardes before destroying any clinical study records. 
Should the investigator wish to assign the study records to another party or move them to another 
location, Pardes must be notified in advance. 
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Pardes to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site. 
9.1.7. 
Case Report Forms 
For each subject consented, an eCRF casebook will be completed by an authorized study staff 
member whose training for this function is completed in the EDC system. The eCRF casebook 
will capture only the data required per the protocol schedule of events and procedures. The 
Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only after all data 
related to eligibility have been received. Data entry should be performed in accordance with the 
CRF Completion Guidelines (CCGs). Subsequent to data entry, a study monitor will perform 
source data verification within the EDC system. System-generated or manual queries will be 
issued in the EDC system as data discrepancies are identified by the monitor or CRO staff who 
routinely review the data for completeness, correctness, and consistency. The site investigator, 
site coordinator, or other designee is responsible for responding to the queries in a timely 
manner, within the system, either by confirming the data as correct or updating the original entry, 
and providing the reason for the update (eg, data entry error). Original entries, as well as any 
changes to data fields, will be stored in the audit trail of the system. At a minimum, prior to any 
interim time points or database lock (as instructed by CRO), the investigator will use his/her 
login credentials to confirm that the forms have been reviewed and that the entries accurately 
reflect the information in the source documents. At the conclusion of the study, CRO will 
provide the site investigator with a read-only archive copy of the data entered by that site. This 
archive must be stored in accordance with the records retention requirements outlined in 
Section 9.1.6. 
9.1.8. 
Investigator Inspections 
The investigator will make available all source documents and other records for this study to 
CRO’s appointed study monitors, IRBs/IECs, and regulatory or health authority inspectors. 
9.1.9. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
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9.2. 
Sponsor Responsibilities 
9.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Pardes. The investigator must submit all protocol modifications to the IRB/IEC in 
accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented. 
9.2.2. 
Study Report and Publications 
A clinical study report will be prepared and provided to the regulatory agency. Pardes will ensure 
that the report meets the standards set out in the ICH Guideline for Structure and Content of 
Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.  
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met: 
 The results of the study in their entirety have been publicly disclosed by or with the 
consent of Pardes in an abstract, manuscript, or presentation form or the study has been 
completed at all study sites for ≥ 2 years. 
 The investigator will submit to Pardes any proposed publication or presentation along 
with the respective scientific journal or presentation forum ≤ 30 days before submission 
of the publication or presentation.  
 No such communication, presentation, or publication will include Pardes’s confidential 
information (see Section 9.1.5). 
 The investigator will comply with Pardes’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to 
withhold publication or presentation for an additional 60 days to obtain patent protection 
if deemed necessary. 
9.3. 
Joint Investigator/Sponsor Responsibilities 
9.3.1. 
Payment Reporting 
Investigators and their study staff may be asked to provide services performed under this 
protocol (eg, attendance at investigator meetings). If required under the applicable statutory and 
regulatory requirements, Pardes will capture and disclose to federal and state agencies any 
expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value. 
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9.3.2. 
Access to Information for Monitoring 
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries in the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on-site) are resolved. 
9.3.3. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or Pardes/CRO may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority, the 
investigator agrees to notify the CRO medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Pardes/CRO access to records, facilities, and 
personnel for the effective conduct of any inspection or audit. 
9.3.4. 
Study Discontinuation 
Both Pardes and the investigator reserve the right to terminate the study at any time. Should this 
be necessary, both parties will arrange discontinuation procedures and notify the subjects, 
appropriate regulatory authority, and IRB/IEC. In terminating the study, Pardes/CRO and the 
investigator will ensure that adequate consideration is given to the protection of the subjects’ 
interests. 
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10. 
REFERENCES 
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Vandemaele K, Van Kerkhove MD, Jombart T, et al. 2021. Increased transmissibility and 
global spread of SARS-CoV-2 variants of concern as at June 2021. Euro surveillance : 
bulletin Europeen sur les maladies transmissibles = European communicable disease 
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CDC - Interim Clinical Considertions for COVID-19 Treatment in Outpatient. 
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CDC - People with Certain Medical Condition. https://www.cdc.gov/coronavirus/2019-
ncov/need-extra-precautions/people-with-medical-conditions.html. August 24, 2022. 
CDC - Stay Up to Date with COVID-19 Vaccines Including Boosters, 
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2022. 
CDC - Underlying Medical Conditions Associated with Higher Risk for Severe COVID-19: 
Information for Healthcare Professionals. https://www.cdc.gov/coronavirus/2019-
ncov/hcp/clinical-care/underlyingconditions.html. August 24, 2022. 
Chow EJ, Doyle JD, Uyeki TM. 2019. Influenza virus-related critical illness: prevention, 
diagnosis, treatment. Crit Care. 23(1). doi:10.1186/s13054-019-2491-9. 
COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment 
Guidelines. National Institutes of Health. Available at 
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Department of Health and Human Services. 2022. Guidelines for the use of antiretroviral agents 
in adults and adolescents with HIV. [accessed 2022 Jun 30]. 
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Dhama, Patel, Sharun, Pathak, Tiwari, Yatoo, Malik, Sah, Rabaan, Panwar, et al. 2020. SARS-
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advances to combat this pandemic virus. Travel Med Infect Dis. 37. 
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Edridge AWD, Kaczorowska J, Hoste ACR, Bakker M, Klein M, Loens K, Jebbink MF, Matser 
A, Kinsella CM, Rueda P, et al. 2020. Seasonal coronavirus protective immunity is short-
lasting. Nature Medicine. 26(11):1691–1693. doi:10.1038/s41591-020-1083-1. 
Ghany MG, Morgan TR. 2020. Hepatitis C guidance 2019 update: American Association for the 
Study of Liver Diseases–Infectious Diseases Society of America recommendations for 
testing, managing, and treating Hepatitis C virus infection. Hepatology. 71(2):686–721. 
doi:10.1002/hep.31060. 
Gilead Sciences. 2022. 'VEKLURY Patient Information', Accessed August 25, 2022. 
https://www.gilead.com/-/media/files/pdfs/medicines/covid-19/veklury/veklury_pi.pdf. 
Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, Baniecki M, 
Hendrick VM, Damle B, Simón-Campos A, et al. 2022. Oral nirmatrelvir for high-risk, 
nonhospitalized adults with Covid-19. N Engl J Med. 386(15):1397–1408. 
doi:10.1056/NEJMoa2118542. 
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Harvey WT, Carabelli AM, Jackson B, Gupta RK, Thomson EC, Harrison EM, Ludden C, Reeve 
R, Rambaut A, Peacock SJ, et al. 2021. SARS-CoV-2 variants, spike mutations and 
immune escape. Nat Rev Microbiol. 19(7):409–424. doi:10.1038/s41579-021-00573-0. 
Ikematsu H, Hayden FG, Kawaguchi K, Kinoshita M, de Jong MD, Lee N, Takashima S, Noshi 
T, Tsuchiya K, Uehara T. 2020. Baloxavir marboxil for Prophylaxis against influenza in 
household contacts. N Engl J Med. 383(4):309–320. doi:10.1056/NEJMoa1915341. 
Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, 
Martín-Quirós A, Caraco Y, Williams-Diaz A, Brown ML, et al. 2022. Molnupiravir for 
oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 386(6):509–520. 
doi:10.1056/NEJMoa2116044. 
Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, Zhang B, Li X, Zhang L, Peng C, et al. 2020. 
Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature. 
582(7811):289–293. doi:10.1038/s41586-020-2223-y. 
Korber, Fischer, Gnanakaran, Yoon, Theiler, Abfalterer, Hengartner, Giorgi, Bhattacharya, 
Foley, et al. 2020. Tracking changes in SARS-CoV-2 spike: evidence that D614G 
increases infectivity of the COVID-19 virus. Cell. 182(4):812–827. 
doi:10.1016/j.cell.2020.06.043. 
Lau SKP, Chan JFW. 2015. Coronaviruses: emerging and re-emerging pathogens in humans and 
animals. Virol J. 12:209. doi:10.1186/s12985-015-0432-z. 
Marshall M. 2020. The lasting misery of coronavirus long-haulers. Nature. 585(7825):339–341. 
doi:10.1038/d41586-020-02598-6. 
Muthuri SG, Venkatesan S, Myles PR, Leonardi-Bee J, Al Khuwaitir TSA, Al Mamun A, 
Anovadiya AP, Azziz-Baumgartner E, Báez C, Bassetti M, et al. 2014. Effectiveness of 
neuraminidase inhibitors in reducing mortality in patients admitted to hospital with 
influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. 
Lancet Respir Med. 2(5):395–404. doi:10.1016/S2213-2600(14)70041-4. 
Patick AK, Potts KE. 1998. Protease inhibitors as antiviral agents. Clin Microbiol Rev. 
11(4):614–627. doi:10.1128/CMR.11.4.614. 
Paules CI, Marston HD, Fauci AS. 2020. Coronavirus infections-more than just the common 
cold. JAMA. 323(8):707–708. doi:10.1001/jama.2020.0757. 
Sasaki M, Tabata K, Kishimoto M, et al. 2022. Oral administration of S-217622, a SARS-CoV-2 
main protease inhibitor, decreases viral load and accelerates recovery from clinical 
aspects of COVID-19. bioRxiv. doi:https://doi.org/10.1101/2022.02.14.480338. 
[accessed 2022 Jul 1]. https://www.biorxiv.org/content/10.1101/2022.02.14.480338v1. 
Sharma, Tiwari, Deb, Marty. 2020. Severe acute respiratory syndrome coronavirus-2 (SARS-
CoV-2): a global pandemic and treatment strategies. Int J Antimicrob Agents. 56(2). 
doi:10.1016/j.ijantimicag.2020.106054. 
Tang D, Comish P, Kang R. 2020. The hallmarks of COVID-19 disease. PLoS Pathog. 
16(5):E1008536. doi:10.1371/journal.ppat.1008536. 
Tang, S., Y. Mao, R. M. Jones, Q. Tan, J. S. Ji, N. Li, J. Shen, Y. Lv, L. Pan, P. Ding, X. Wang, 
Y. Wang, C. R. MacIntyre, and X. Shi. 2020. 'Aerosol transmission of SARS-CoV-2? 
Evidence, prevention and control', Environ Int, 144: 106039. 
Tillett, Sevinsky, Hartley, Kerwin, Crawford, Gorzalski, Laverdure, Verma, Rossetto, Jackson, et 
al. 2021. Genomic evidence for reinfection with SARS-CoV-2: a case study. Lancet 
Infect Dis. 21(1):52–58. doi:10.1016/S1473-3099(20)30764-7. 
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US Food and Drug Administration. 2006. Guidance for industry antiviral product development: 
Conducting and submitting virology studies to the Agency. 
Uyeki TM, Bernstein HH, Bradley JS, Englund JA, File TM, Fry AM, Gravenstein S, Hayden 
FG, Harper SA, Hirshon JM, et al. 2019. Clinical practice guidelines by the Infectious 
Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, 
and institutional outbreak management of seasonal influenzaa. Clin Infect Dis. 
68(6):895–902. doi:10.1093/cid/ciy874. 
Zella D, Giovanetti M, Benedetti F, Unali F, Spoto S, Guarino M, Angeletti S, Ciccozzi M. 
2021. The variants question: What is the problem? Journal of Medical Virology. 
93(12):6479–6485. doi:10.1002/jmv.27196. 
———. 2022b. 'Fact Sheet for Healthcare Providers: Emergency Use Authorization for 
BEBTELOVIMAB', Accessed August 25, 2022. 
https://www.fda.gov/media/156152/download. 
———. 2022c. 'Fact Sheet for Healthcare Providers: Emergency Use Authorization for 
PAXLOVID'. https://www.fda.gov/media/155050/download. 
 
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11. 
APPENDICES 
Appendix 1. 
Investigator Signature Page 
Appendix 2. 
Pandemic Risk Assessment and Mitigation Plan 
Appendix 3. 
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements 
Appendix 4. 
Toxicity Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities 
Appendix 5. 
Modified Centers for Disease Control and Prevention: Underlying Medical 
Conditions Associated with Higher Risk for Severe COVID-19 
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Appendix 1. 
Investigator Signature Page 
 
PARDES BIOSCIENCES, INC. 
2173 SALK AVE SUITE 250 
PMB #052 
CARLSBAD, CA 92008 
 
STUDY ACKNOWLEDGMENT 
 
A Phase 2 Double-blind, Randomized Study to Evaluate the Antiviral Activity, Safety, and 
Efficacy of Orally Administered PBI-0451 Compared with Placebo in Nonhospitalized 
Symptomatic Adults with COVID-19 
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This protocol has been approved by Pardes Biosciences, Inc. The following signature documents 
this approval. 
David Wilfret, MD 
 
 
Name (Printed) 
Vice President, Clinical Research  
 
Signature 
 
 
 
 
Date 
 
 
INVESTIGATOR STATEMENT 
 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein, and I will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Pardes or its partner(s). I will discuss this material with them to ensure 
that they are fully informed about the drugs, the study, and the undertaking of confidentiality. 
I agree that all information received from Pardes or its partner(s), including but not limited to the 
Investigator’s Brochure, this protocol, CRFs/eCRFs, study drug information, and any other study 
information, remain the sole and exclusive property of Pardes during the conduct of the study 
and thereafter. This information is not to be disclosed to any third party (except employees or 
agents directly involved in the conduct of the study or as required by law) without prior written 
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consent from Pardes. I further agree to take all reasonable precautions to prevent the disclosure 
by any employee or agent of the study site to any third party or otherwise into the public domain. 
 
 
 
Principal Investigator Name (Printed) 
 
Signature 
 
 
 
 
Date 
 
Site Number 
 
 
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Appendix 2. 
Pandemic Risk Assessment and Mitigation Plan 
During an ongoing pandemic, potential risks associated with subjects being unable to attend 
study visits have been identified for this study.  
These risks can be summarized as follows: 
1) Study drug supplies to subjects and sites: 
a) Subjects may be unable to return to the site to get the study drug, or the site may be 
unable to accept any subject visits. Without study drug, a subject would not be able to 
stay on the study drug as planned per protocol. 
Mitigation plan: Study drug supplies may be provided to the subject from the site without 
a clinic visit, once it is confirmed that the subject may safely continue on study drug as 
determined by the investigator. A virtual study visit, via telephone or video conferencing, 
must be performed prior to remote study drug resupply. At the earliest opportunity, the 
site will schedule in-person subject visits and return to the protocol’s regular schedule of 
assessments. A qualified courier may be utilized to ship the study drug from sites to study 
subjects if permitted by local institutional review board (IRB)/ independent ethics 
committee (IEC) as applicable and with Pardes's approval. 
b) Shipments of study drug could be delayed because of transportation issues. Without study 
drug, a subject would not be able to stay on the study drug as planned per protocol. 
Mitigation plan: The sites' study drug inventory should be closely monitored. Site staff 
should notify Pardes or delegate if they foresee shortage in study drug inventory or if 
there is any interruption in local shipping service. Pardes will continue to monitor 
inventory at the study drug depot and study sites. Manual shipments will be triggered as 
necessary. 
2) Subject safety monitoring and follow-up: 
a) Subjects may be unable or unwilling to come to the study site for their scheduled study 
visits as required per protocol. 
Mitigation plan: For subjects who may be unable or unwilling to come to the study site 
for their scheduled study visits as required per protocol, the Investigator or qualified 
delegate will conduct a virtual study visit, via telephone or video conferencing, to assess 
the subject within the target visit window date whenever possible. During the virtual 
study visit, the following information at minimum will be reviewed:  
i) Confirm if subject has experienced any adverse events (AEs)/serious adverse events 
(SAEs)/special situations (including pregnancy) and follow-up on any unresolved 
AE/SAEs. 
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ii) Review current list of concomitant medications and document any new concomitant 
medications. 
iii) If applicable, confirm electronic diary questionnaires and patient-reported outcomes 
have been completed and transmitted. 
iv) If applicable, confirm subjects study drug supply is sufficient to last until the next 
planned visit date. If study drug resupply is needed, it will be provided as described 
above in Item 1 above. 
v) If applicable, remind subject to maintain current dosing and to keep all dispensed 
study drug kits for return at the next onsite visit. 
b) Subjects may be unable or unwilling to travel to the site for planned assessments 
(eg, safety blood draws); hence samples may not be sent for central laboratory analyses. 
Mitigation plan: Local laboratories may be used as appropriate to monitor subject safety 
until the subject can return to the site for their scheduled visit per protocol. Any 
laboratory assessments conducted at a local lab due to the pandemic will be documented 
accordingly. Pregnancy testing may be performed using a home urine pregnancy test if 
local laboratory pregnancy testing is not feasible. 
c) Subjects may be unable or unwilling to attend the study visit to sign an updated informed 
consent form (ICF) version. 
Mitigation plan: The site staff will follow their approved consent process and remain in 
compliance with local IRB/IEC and national laws and regulations. Remote consent will 
be allowed if has been approved by the local IRB/IEC. The consent process will be 
documented and confirmed by the normal consent procedure at the earliest opportunity. 
3) Protocol and monitoring compliance: 
a) Protocol deviations may occur if scheduled visits cannot occur as planned per protocol. 
Mitigation plan: If it is not possible to complete a required scheduled procedure, an 
unscheduled visit should be conducted as soon as possible when conditions allow. The 
situation should be recorded and explained as a protocol deviation. Any missed subject 
visits or deviation to the protocol due to the pandemic must be reported in the eCRF and 
described in the clinical study report. Any virtual study visits that are conducted in lieu of 
clinic visits due to the pandemic will be documented as a protocol deviation related to the 
pandemic. 
b) Monitors may be unable to carry out source data review or source data verification (SDV) 
or study drug accountability or assess protocol and Good Clinical Practice compliance. 
This may lead to delays in SDV, an increase in protocol deviations, or under-reporting of 
AEs. 
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Mitigation plan: The study monitor is to remain in close communication with the site to 
ensure data entry and query resolution. In compliance with CRO policy, a remote SDV 
should be arranged. The study monitor is to reference the Study Monitoring Plan for 
guidance on how to conduct a remote monitoring visit. The study staff is to save and 
document all relevant communication in the study files. The status of sites that cannot 
accept monitoring visits and/or subjects on site, must be tracked centrally and updated on 
a regular basis. 
4) Missing data and data integrity: 
a) There may be an increased amount of missing data due to subjects missing 
visits/assessments. This could have an impact on the analysis and the interpretation of 
clinical study data.  
Mitigation plan: Implications of a pandemic on methodological aspects for the study will 
be thoroughly assessed and documented, and relevant actions will be taken as appropriate 
(ie, modification of the statistical analysis plan) and in compliance with Regulatory 
Authorities’ guidance. Overall, the clinical study report will describe the impact of the 
pandemic on the interpretability of study data. 
Risks will be assessed continuously, and temporary measures will be implemented to mitigate 
these risks as part of a mitigation plan, as described above. These measures will be 
communicated to the relevant stakeholders as appropriate and are intended to provide alternate 
methods that will ensure the evaluation and assessment of the safety of subjects who are enrolled 
in this study.  
Since these potential risks are considered mitigated with the implementation of these measures, 
the expected benefit-risk assessment of PBI-0451 in study subjects remains unchanged. 
 
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Appendix 3. 
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements 
1) Definitions 
a. Definition of Childbearing Potential 
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming postmenopausal unless the 
subject is permanently sterile or has medically documented ovarian failure. 
Females are considered to be in a postmenopausal state when they are ≥ 54 years of age with 
cessation of previously occurring menses for ≥ 12 months without an alternative cause. In 
addition, women < 54 years of age with amenorrhea ≥ 12 months may also be considered 
postmenopausal if their follicle-stimulating hormone level (FSH) is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy. Permanent 
sterilization includes hysterectomy, bilateral oophorectomy, or bilateral salpingectomy in a 
female subject of any age. 
b. Definition of Male Fertility 
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless the subject is permanently sterile by bilateral orchidectomy or medical 
documentation. 
2) 
Contraception Requirements for Female Subjects 
a. 
Study Drug Effects on Pregnancy and Hormonal Contraception 
PBI-0451 is contraindicated in pregnancy because a malformation effect is unknown, taking into 
consideration class effects and genotoxic potential. PBI-0451 has insufficient data to exclude the 
possibility of a clinically relevant interaction with hormonal contraception that results in reduced 
contraception efficacy. Therefore, as there is limited safety information available to exclude the 
possibility of DDIs between PBI-0451 and hormonal contraception, hormonal contraception 
methods are not an acceptable form of contraception for female subjects participating in this 
study. Female subjects must use one of the highly effective contraceptive methods outlined 
below in Section 2.b.  
Refer to the latest version of the IB for additional information. 
b. Contraception Requirements for Female Subjects of Childbearing Potential 
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures with a failure rate of < 1% per year. They must also not rely on hormonal 
contraceptives as a form of birth control during the study. They must have a negative serum 
pregnancy test at screening and a negative pregnancy test on Day 1 prior to randomization. 
Pregnancy tests will be performed at monthly intervals thereafter until the end of the 
contraception requirement. 
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Duration of required contraception for female subjects in this study is from screening and until 
90 days after the last dose of study drug. Female subjects must agree to one of the following 
contraceptive methods: 
 Complete abstinence from intercourse of reproductive potential. Abstinence is an 
acceptable method of contraception only when it is in line with the subject’s preferred 
and usual lifestyle. 
Or 
 Consistent and correct use of one or more of the following methods of birth control:  
 Nonhormonal intrauterine device (IUD)  
 Bilateral tubal occlusion (upon medical assessment of surgical success) 
 Vasectomy in the male partner (upon medical assessment of surgical success) 
 Consistent and correct use of a double barrier method of contraception using two of 
the following barriers concurrently: 
- Male or female condoms (not to be used together) 
and 
- Female diaphragm (‘cap’) 
Inclusion of methods of contraception in this list of permitted methods does not imply that the 
method is approved in any country or region. Methods should only be used if locally approved. 
Local requirements of combining a single barrier method with either IUD or surgical sterilization 
are endorsed.  
Female subjects must refrain from egg donation and in vitro fertilization during treatment and for 
≥ 28 days after the last dose of study drug. 
3) 
Contraception Requirements for Male Subjects 
Male subjects must agree to use a male condom and an additional effective contraceptive method 
with their female partners, if their female partners are of childbearing potential (see Section 1.a), 
from treatment Day 1 until 90 days following the last dose of study drug. Effective methods of 
contraception for female partners of male subjects may include hormonal contraception or one of 
the methods outlined in Section 2.b. 
Male subjects must refrain from sperm donation from screening throughout the study period and 
for at least 90 days following the last dose of study drug. 
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4) 
Unacceptable Birth Control Methods 
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method. A female condom and a male condom should not be used 
together. 
5) 
Procedures to be Followed in the Event of Pregnancy 
Female subjects will be instructed to notify the investigator if they become pregnant or suspect 
they are pregnant at any time from screening to 90 days after the last dose of study drug. Study 
drug must be discontinued immediately if pregnancy is confirmed during treatment. 
Male subjects whose partner has become pregnant or suspects she is pregnant from screening to 
90 days after the last dose of study drug must report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.4.2.4. 
 
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Appendix 4. 
Toxicity Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities 
Please refer to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (Version 2.1 – July 2017) 
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Appendix 5. 
Modified Centers for Disease Control and Prevention: Underlying 
Medical Conditions Associated with Higher Risk for Severe 
COVID-19 
The potential subject should be excluded from the study (exclusion criteria 1) if they have at 
least 1 underlying medical condition associated with increased risk for severe COVID-19 illness 
(“high-risk” and consequently increased risk of hospitalization and death) derived from the 
Centers for Disease Control and Prevention list of high-risk underlying conditions as outlined 
below and detailed at https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-
care/underlyingconditions.html 
a. ≥65 years of age 
b. Asthma 
c. Active cancer 
d. Cerebrovascular disease 
e. Chronic kidney disease (if no history of CKD Stage 3 or above) 
f. Chronic lung diseases limited to: 
i. Interstitial lung disease 
ii. Pulmonary embolism 
iii. Pulmonary hypertension 
iv. Bronchiectasis 
v. COPD (chronic obstructive pulmonary disorder) 
g. Chronic liver diseases limited to: 
i. Cirrhosis (Child-Pugh A) 
ii. Non-alcoholic fatty liver disease 
iii. Alcoholic liver disease 
iv. Autoimmune hepatitis 
h. Cystic fibrosis 
i. Diabetes mellitus, Type 1 and Type 2 
j. Disabilities 
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i. Attention-Deficit/Hyperactivity Disorder (ADHD) 
ii. Cerebral Palsy 
iii. Congenital Malformations (Birth Defects) 
iv. Limitations with self-care or activities of daily living 
v. Intellectual and Developmental Disabilities 
vi. Learning Disabilities 
vii. Spinal Cord Injuries 
k. Heart conditions such as: 
i. Heart failure 
ii. Coronary artery disease 
iii. Cardiomyopathies 
l. HIV (human immunodeficiency virus) 
m. Mental health disorders limited to: 
i. Mood disorders, including depression 
ii. Schizophrenia spectrum disorder 
n. Neurological conditions limited to dementia 
o. Obesity (BMI ≥30 kg/m2) 
p. Primary Immunodeficiencies 
q. Solid organ or blood stem cell transplantation 
r. Tuberculosis 
s. Use of corticosteroids or other immunosuppressive medications 
t. Immune deficiencies (except people with moderate to severe immune 
compromise due to a medical condition or receipt of immunosuppressive 
medications or treatments) 
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2173 Salk Avenue | Suite 250, PMB #052 | Carlsbad | CA 92008 
 
September 30, 2022 
Re: A Phase 2 Double-blind, Randomized Study to Evaluate the Antiviral Activity, Safety, and 
Efficacy of Orally Administered PBI-0451 Compared with Placebo in Nonhospitalized 
Symptomatic Adults with COVID-19 (PBI-0451-0002) 
Dear Investigator, 
I am writing to make clarifications to the following sections of the PBI-0451-0002 protocol. 
 
Exclusion Criterion #8 in Section 4.3: Exclusion Criteria: 
 
Receiving dialysis or having known severe renal impairment (chronic kidney disease, Stage 4 or 
above) 
 
Contrary to Exclusion Criterion #8, Exclusion Criterion #1 excludes potential subjects who are: 
 
Considered at high-risk of developing severe illness from COVID-19 defined as ≥ 1 CDC 
underlying medical condition associated with an increased risk of developing severe illness from 
COVID-19 (see Appendix 5) 
 
Appendix 5 is a list of CDC underlying medical conditions associated with higher risk for severe 
COVID-19 and includes the following: 
 
o Chronic kidney disease (if no history of CKD Stage 3 or above) 
 
Subjects who have chronic kidney disease Stage 3 or above are considered at higher risk of 
developing severe illness from COVID-19 and are therefore excluded from the study. 
 
 
Footnote g in Table 1: Study PBI-0451-0002 Study Procedures Table states: 
 
Mid-turbinate nasal swabs will be collected to measure SARS-CoV-2 using qRT-PCR, IVA, RAT, 
and viral sequencing. Saliva samples will be collected to measure SARS-CoV-2 using qRT-PCR 
and IVA. Parentheses indicate sample at ET visit if the subject discontinues treatment prior to 
Day 10. 
 
Footnote g in Table 1 stating “Day 10” is a typographical error. The parentheses indicate 
sample at the Early Termination (ET) visit for SARS-CoV-2 IVA only if the subject 
discontinues prior to Day 15. 
 
 
 
 
 
 
 
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If you have any questions regarding the items discussed above or any other study-related issue, please 
reach out to your CRA. 
 
Sincerely, 
 
 
 
 
David Wilfret, MD 
Vice President, Clinical Research Development 
Pardes Biosciences, Inc. 
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Administrative Letter #1 
2173 Salk Avenue | Suite 250, PMB #052 | Carlsbad | CA 92008 
 
October 31, 2022 
Re: Collection of saliva samples for Study PBI-0451-0002: A Phase 2 Double-blind, Randomized 
Study to Evaluate the Antiviral Activity, Safety, and Efficacy of Orally Administered PBI-0451 
Compared with Placebo in Nonhospitalized Symptomatic Adults with COVID-19  
Dear Investigator, 
This Administrative Letter is about the collection of saliva samples for testing in the infectious virus 
assay (IVA) in Study PBI-0451-0002. 
On 07 Oct 2022, Pardes Biosciences requested that all clinical sites quarantine the pre-filled cryovials 
(Lot No2203674-1) created for the collection of saliva samples for analysis of IVA due to a possible vial 
contamination indicated by discoloration and/or growth.  These cryovials were prepared by 
DDL/Viroclinics Biosciences.  The investigation at DDL in conjunction with Pardes into this issue is 
ongoing and provisions are being made for the return of the contaminated cryovials. The contamination 
issue is completely independent of Pardes operations and the investigational product, PBI-0451. 
The initial observation of contaminated cryovials as well as an evaluation of study-related risks and 
mitigations addressing the issue were addressed by Pardes internally and is documented in a memo-to-file 
dated 14 Oct 2022, which is archived by the Pardes Quality department. Pardes Clinical Operation and 
PPD have informed all sites to quarantine the contaminated cryovials until provisions are made for their 
return to DDL. 
The PBI-0451-0002 Study Team has been working diligently to re-supply all the study sites with a new 
lot of Saliva IVA sample collection cryovials. However, due to supply chain issues, it has been a 
challenge to ensure that all sites have the proper amount of Saliva IVA sample collection cryovials. 
The purpose of this Administrative Letter for study PBI-0451-0002 is to inform all investigators and site 
personnel about a change in protocol for the continued collection of the SARS-CoV-2 Saliva IVA 
samples at Screening/Baseline, Day 2, Day 3, Day 5, Day 10, Day 15, Rebound Ad Hoc Visit, and Early 
Termination Visit (if prior to Day 15).  
 
Sites that have been re-supplied with the replacement batch of cryovials should continue to 
collect Saliva IVA samples as described in the protocol for Study PBI-0451-0002.  
 
Sites who have not yet received a replacement batch of cryovials should stop collecting Saliva 
IVA samples until they receive the replacement cryovials.  These sites should continue to collect 
all other samples for virology testing (Rapid antigen test, mid-turbinate [MT] nasal swabs for 
IVA and qRT-PCR using the BD 3mL collection kits, and Saliva collection for qRT-PCR using 
the Omnigene kit) as described in the study protocol.  
 
Sites should resume collection of Saliva for IVA once they have been re-supplied with the new 
cryovials.  
The primary endpoint in study PBI-0451-0002 will be assessed based on the detection of infectious virus 
from the MT nasal collections, not the saliva collections. Therefore, the MT swab for IVA must still be 
collected per protocol. Saliva IVA is an exploratory endpoint for this clinical trial and every effort should 
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be made to collect these samples, where possible.  If it is not possible, then the missed samples will not be 
documented as a protocol violation.   
Thank you for your partnership in this important clinical program for COVID-19.  The modifications 
described in this Administrative Letter are considered non-substantial to the primary and secondary 
endpoints and non-critical (no impact to patient safety, patient care, nor data integrity). The full protocol 
will be amended to reflect this change at the next available opportunity. 
As a reminder, all virologic samples must be shipped to arrive refrigerated at DDL’s processing lab by 
World Courier within 36 hours of collection.  Please do not ship any virologic samples to the PPD Central 
Lab. Please refer to the Collection Flow Chart (CFC) found in your lab manual for the full virology 
collection details. 
If you have any questions regarding this or any other study-related concerns, please reach out to your PPD 
CRA directly. 
 
Sincerely, 
 
 
 
 
David Wilfret, MD 
Vice President, Clinical Research  
Pardes Biosciences, Inc. 
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             Administrative Letter #2 
2173 Salk Avenue | Suite 250, PMB #052 | Carlsbad | CA 92008 
 
November 17, 2022 
Re: Collection of Saliva Samples for Infectious Virus Assay in Study PBI-0451-0002: A Phase 
2 Double-blind, Randomized Study to Evaluate the Antiviral Activity, Safety, and Efficacy 
of Orally Administered PBI-0451 Compared with Placebo in Nonhospitalized Symptomatic 
Adults with COVID-19  
Dear Investigator,  
The purpose of this Administrative Letter #2 for Study PBI-0451-0002 is to inform all 
investigators and site personnel about a change in study procedures for stopping collection of the 
SARS-CoV-2 saliva samples for infectious virus assay (IVA) at all study visits (Screening, 
Baseline/Day 1, Day 2, Day 3, Day 5, Day 10, Day 15, Rebound Ad Hoc Visit, and Early 
Termination Visit [if prior to Day 15]).  All sites should stop collecting saliva samples for IVA 
immediately (saliva samples for qRT-PCR should continue to be collected).  The exploratory 
endpoint of correlation of SARS-CoV-2 detection by IVA from saliva samples will no longer be 
evaluated.   
As communicated in Administrative Letter #1, the availability of pre-filled 5 mL UTM cryovials 
created for the collection of saliva samples for the IVA continues to be impacted by contamination 
and supply chain issues. Due to ongoing challenges in supply logistics, we are unable to source 
viable cryovials for this assay. 
The following collection materials for the saliva IVA should be destroyed immediately: 
1. SalivaBio kits (saliva collection aid) 
2. Pre-filled 5 mL cryovials with 1.5 mL UTM 
a. Lot No. 2203674-2 
b. Lot No. G9999-647/648 
3. “SARS-CoV-2 IVA Saliva” label 
Pre-filled cryovials should be treated as a biohazard for the purposes of destruction. Prior to 
destruction, please record the quantities and lot numbers of the items destroyed. 
The following IVA Saliva collection materials should be placed in quarantine immediately and 
returned to DDL (instructions for return will be forthcoming): 
1. Pre-filled 5 mL cryovials with 1.5 mL UTM 
a. Lot No. 2203674-1 
 
 
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Sites should continue to collect all other samples for virology testing as described in the study 
protocol: 
 MT nasal swabs for rapid antigen test 
 MT nasal swabs for IVA and qRT-PCR using the BD 3 mL collection kits  
 Saliva for qRT-PCR using the Omnigene kit  
As a reminder, all virologic samples must be shipped refrigerated to DDL’s processing lab by 
World Courier on the day the samples are collected (do not ship any virologic samples to the 
PPD Central Lab).  Please refer to the Collection Flow Chart found in your laboratory manual 
for the full virology collection details. 
Thank you for your partnership in this important clinical program for COVID-19. The 
modifications described in this Administrative Letter are considered non-substantial to the primary 
and secondary endpoints and non-critical (no impact to patient safety, patient care, nor data 
integrity). The full protocol will be amended to reflect this change at the next available opportunity.  
If you have any questions regarding this or any other study-related concerns, please reach out to 
your PPD CRA directly. 
Sincerely, 
 
 
David Wilfret, MD 
Vice President, Clinical Research 
Pardes Biosciences, Inc. 
 
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2173 Salk Avenue | Suite 250, PMB #052 | Carlsbad | CA 92008 
 
February 10, 2023 
Re: A Phase 2 Double-blind, Randomized Study to Evaluate the Antiviral Activity, Safety, 
and Efficacy of Orally Administered PBI-0451 Compared with Placebo in Nonhospitalized 
Symptomatic Adults with COVID-19 (PBI-0451-0002) 
Dear Investigator, 
The purpose of this letter is to clarify the following sections of the PBI-0451-0002 protocol 
regarding the unblinding of the study for the planned interim analysis after all subjects have 
completed the Day 28 study visit and the reporting of safety events. 
 Section 5.1.2, Blinding, defines the study blinding for the clinical trial and specifies those 
instances and/or personnel who may require unblinding during study conduct prior to the 
interim analysis. 
 Section 8.2.1, Interim Analysis, defines that a planned interim analysis of the primary and 
secondary endpoints will be conducted after 210 subjects complete the Day 28 study 
visit.   
 Section 7.3, Investigator Reporting Requirements and Instructions, states that safety 
information, including Adverse Events (Section 7.3.2) and Serious Adverse Events 
(Section 7.3.3), is collected through Day 28, unless an SAE or death after Day 28 is 
deemed relevant to the use of study drug.  
Therefore, the Study PBI-0451-0002 unblinding to occur as part of the planned interim analysis 
as defined in Section 8.2.1 is separate and unique from the reference to potential and unplanned 
unblinding prior to Day 28 referenced in Section 5.1.2, which has not occurred.   
Treatment codes will be shared with Investigators following the Final Analysis, defined in 
Section 8.2.2, once the last randomized patient has completed the Week 24 follow-up visit or 
discontinued the study, and as a point of procedure, after the final database has been cleaned and 
locked. 
If you have any questions regarding the items discussed above or any other study-related issue, 
please reach out to your CRA. 
Sincerely, 
 
 
 
David Wilfret, MD 
Vice President, Clinical Research 
Pardes Biosciences, Inc. 
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2173 Salk Avenue | Suite 250, PMB #052 | Carlsbad | CA 92008 
 
April 10, 2023 
Re: A Phase 2 Double-blind, Randomized Study to Evaluate the Antiviral Activity, Safety, 
and Efficacy of Orally Administered PBI-0451 Compared with Placebo in Nonhospitalized 
Symptomatic Adults with COVID-19 (PBI-0451-0002) 
Dear Investigator, 
Attached, please find the Pardes Biosciences press release dated Monday, 03 April 2023, which 
announces the top-line results from the Phase 2 clinical trial PBI-0451-0002 evaluating 
pomotrelvir (PBI-0451) for the treatment of COVID-19.  In summary, pomotrelvir did not meet 
the primary endpoint measured by the proportion of participants below the limit of detection for 
infectious SARS-CoV-2 on day 3 of treatment with pomotrelvir versus placebo.   
Based on these results, Pardes is suspending further clinical development of pomotrelvir and is 
notifying you, effective 14 April 2023, that clinical trial PBI-0451-0002 is terminated per 
protocol Section 9.3.4, where Pardes has the right to terminate the study at any time.  Participants 
who have not completed the Week 24 questionnaires by 14 April 2023 will not have this data 
collected as development of pomotrelvir is currently suspended.  Terminating the clinical trial 
and not collecting all Week 24 questionnaires poses no risk to participant safety as all adverse 
event collection completed on Day 28 of the clinical trial assessments and all participants have 
completed the contraception requirement window. 
Your CRA will contact you regarding study closeout procedures and treatment codes will be 
shared with all of the Investigators following final database lock. 
If you have any questions regarding the items discussed above or any other study-related issues, 
please reach out to your CRA. 
Sincerely, 
 
 
 
David Wilfret, MD 
Vice President, Clinical Research 
Pardes Biosciences, Inc. 
 
 
Link to Press Release: https://ir.pardesbio.com/news-releases/news-release-details/pardes-
biosciences-announces-top-line-results-phase-2-trial 
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