Master Protocol for Early Treatment and Post-Exposure Prophylaxis of COVID-19 Adaptive Platform Trial PROTECT-APT 1
Phase: PHASE2
Conditions: SARS-CoV-2
Sponsor: Henry M. Jackson Foundation for the Advancement of Military Medicine

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Appendix C:  
A Phase 2 Safety and Efficacy Study of Upamostat for  
Early Outpatient Treatment of COVID-19 
 
Intervention: Upamostat or Placebo 
 
Industry Supporter – RedHill Biopharma Ltd. 
 
 
Information/activities described in the Master Protocol (MP) apply to this PSA. 
Any information/activities in the Master Protocol that do not apply to this Product 
Specific Appendix (PSA) are indicated by strikethrough, while evaluations that 
have been added to this PSA are indicated by bold text. Section numbering aligns 
with the master protocol. Sections that have no additional information changes 
from the master protocol are not included. 
 
 
Version 5.0 
07 Feb 2024 
 
 
 

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SUMMARY OF CHANGES FROM PREVIOUS VERSION: 
 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
C 1.2 Schedule of 
Activities,  
C 9.4.1, C 9.4.2 
Screening and 
Enrollment Visit 
Updated order of activities  
Updated to clarify that screening 
activities under the PSA (ECG) cannot 
be performed until product specific 
informed consent and Step 1 
randomization completed
C 6.3 Lifestyle 
Considerations 
Added caution for alcohol 
consumption while taking study 
drug
FDA request 
Added Table of Contents
Added table 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council on Harmonization Good 
Clinical Practice (ICH GCP) and the following: 
 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812). 
USG funded investigators and clinical trial site staff who are responsible for the conduct, 
management, or oversight of USG-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form(s) must be obtained before any participant is consented. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. All changes to the consent form(s) will be IRB approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 

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SIGNATURE PAGE 
The signature below constitutes the approval of this product appendix and the attachments and 
provides the necessary assurances that this trial will be conducted according to all stipulations of 
the master protocol and product appendix, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH guidelines. 
 
Site Investigator: ___________________________________________   
 
   Name/Title (Print/Type) 
 
Signed: 
Date: 
 
 
 

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TABLE OF CONTENTS 
SUMMARY OF CHANGES FROM PREVIOUS VERSION: ........................................................ 2 
STATEMENT OF COMPLIANCE ................................................................................................ 3 
SIGNATURE PAGE .................................................................................................................... 4 
C 1 PROTOCOL SUMMARY .................................................................................................... 7 
C 1.1 Study Synopsis ............................................................................................................. 7 
C 1.2 Schedule of Activities (SoA) ........................................................................................ 10 
C 3 INTRODUCTION .............................................................................................................. 15 
C 3.1 Study Rationale .......................................................................................................... 15 
C 3.3 Study Hypotheses ...................................................................................................... 15 
C 3.4 Risk/Benefit Assessment ............................................................................................ 16 
C 3.4.1 Known Potential Risks .......................................................................................... 16 
C 3.4.3 Assessment of Potential Risks and Benefits ......................................................... 16 
C 4 OBJECTIVES AND ENDPOINTS .................................................................................... 17 
C 4.1 Early Treatment .......................................................................................................... 17 
C 5 STUDY DESIGN .............................................................................................................. 19 
C 5.1 Overall Design ............................................................................................................ 19 
C 5.3 Scientific Rationale for Study Design .......................................................................... 19 
C 5.4 Justification for Dose .................................................................................................. 19 
C 6  STUDY POPULATION AND STUDY ENROLLMENT ...................................................... 21 
C 6.1 Inclusion Criteria ......................................................................................................... 21 
C 6.2 Exclusion Criteria ........................................................................................................ 21 
C 6.3 Lifestyle Considerations .............................................................................................. 22 
C 7 STUDY INTERVENTION .................................................................................................. 23 
C 7.1.1 Study Intervention Description .............................................................................. 23 
C 7.1.2 Dosing and Administration .................................................................................... 23 
C 7.2 Preparation/Handling/Storage/Accountability .............................................................. 23 
C 7.2.2 Acquisition ............................................................................................................ 23 
C 7.2.4 Formulation, Appearance, Packaging, and Labeling ............................................. 23 
C 7.2.5 Product Storage and Stability ................................................................................ 23 
C 7.2.6 Preparation ........................................................................................................... 23 
C 7.4 Measures to Minimize Bias: Randomization and Blinding ........................................... 24 
C 7.4.1 Randomization ...................................................................................................... 24 
C 7.4.2 Blinding and Unblinding ........................................................................................ 24 
C 7.6 Concomitant Therapy ................................................................................................. 24 
C 9 STUDY ASSESSMENTS AND PROCEDURES ............................................................... 25 
C 9.2 Clinical and Laboratory Assessments ......................................................................... 25 
C 9.2.1 Clinical Assessments ............................................................................................ 25 
C 9.2.1 Lab Assessments .................................................................................................. 25 
C 9.2.3 Screening Assessments ........................................................................................ 26 
C 9.2.5 Blood Volumes ...................................................................................................... 26 

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C 9.2.6 Pharmacokinetics ................................................................................................. 26 
C 9.4 Study Visits ................................................................................................................. 27 
C 9.4.1 Screening Visit – In Person or Remote (Within 24 hours Prior to Enrollment) ....... 27 
C 9.4.2 Enrollment Visit – In Person (Day 0) ..................................................................... 27 
C9.4.3 
Day 3 Visit – Remote or In Person ........................................................................ 29 
C 9.4.4 Day 7 Visit- Remote or In person .......................................................................... 29 
C 9.4.5 Day 10 Visit- Remote ............................................................................................ 30 
C 9.4.6 Day 14 Visit – In Person ....................................................................................... 30 
C 9.4.7 Day 28 Visit – In Person ....................................................................................... 31 
C 9.4.8 Week 8 Visit – In Person ....................................................................................... 31 
C 9.4.9 Week 12 In Person OR Remote ............................................................................ 32 
C 9.4.10 Unscheduled Visits – In Person or Remote ........................................................... 32 
C 10 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .............................................. 34 
C 10.1.9 Pregnancy and Breastfeeding ............................................................................... 34 
C 12 PAUSE AND STOPPING CRITERIA ................................................................................ 35 
C 12.1 
Individual Participant Pause and Stopping Criteria ................................................ 35 
C 12.2 
Study and/or PSA Pause and Stopping Criteria .................................................... 36 
C 13 STATISTICAL CONSIDERATIONS .................................................................................. 37 
C13.1 Statistical Hypotheses ................................................................................................ 37 
C 13.4 Primary Endpoint/Estimand Analysis .......................................................................... 37 
C 13.5 Outcome Measures and Statistical Analyses .............................................................. 38 
C 13.5.1 Early Treatment .................................................................................................... 38 
C 13.6 
Interim Analysis Plan ............................................................................................ 41 
C 13.7 
Final Analysis Plan ................................................................................................ 42 
C 13.9 Sample Size Determination ........................................................................................ 42 
APPENDIX C ABBREVIATIONS .............................................................................................. 44 
APPENDIX C AMENDMENT HISTORY .................................................................................... 45 
APPENDIX C REFERENCES ................................................................................................... 48 
C Supplement 1. CYP3A4 Strong Inhibitors and Sensitive Substrates ................................... 49 
List of Tables 
Table 1 Product Specific Criteria for Study Pause ...................................................................36 
Table 2 Analysis Schedule and Actions Reviewed at Interim Analysis .....................................41 
Table 3 Operating Characteristics for the Adaptive Design Including Superiority and Futility for 
a Range of Assumed Event (Symptomatic COVID-19) Rates for Upamostat Active 
Treatment and Upamostat Control Arm ......................................................................43 
 

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C 1 
PROTOCOL SUMMARY 
C 1.1 
Study Synopsis 
PSA Title: 
A Phase 2 safety and efficacy study of upamostat for early outpatient 
treatment of COVID-19 
Overall Study 
Description: 
This study is a global, multicenter, adaptive, randomized, double blind, 
platform trial evaluating promising investigational products (IP) for early 
outpatient treatment of SARS-CoV-2 infection
Objectives: 
 
Primary:  
To determine if early treatment with upamostat can shorten time to sustained 
symptom alleviation or resolution in participants infected with SARS-CoV-2. 
Secondary: 
 To determine if early treatment with upamostat can reduce disease 
severity in participants infected with SARS-CoV-2 
 To determine if early treatment with upamostat can decrease the 
incidence of hospitalization due to COVID-19 
 To evaluate virologic efficacy of upamostat compared to placebo 
 To evaluate the safety and tolerability of upamostat compared to 
placebo 
Exploratory: 
 To determine the presence and titer of antibodies to SARS-CoV-2 at 
baseline, the development of antibodies during study participation, and 
their association with clinical outcome 
 To assess the impact of host transmembrane protease polymorphisms on 
drug efficacy
Endpoints: 
Primary: 
Time to sustained alleviation or resolution of COVID-19 symptoms 
[Timeframe: Day 0 to Day 28]
Secondary: 
 Change in overall COVID-19 symptom severity score  
[Timeframe: Day 0 to Day 28] 
 Proportion of participants in each treatment group developing new 
COVID-19 symptoms graded as severe on the symptom score 
[Timeframe: Day 0 to 28] 
 Proportion of participants who report: 
o Return to usual state of health 
o Return to usual activities 
[Timeframe: Days 7, 14, 28 Week 8, and Week 12]

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 Proportion of participants hospitalized for COVID-19 
[Timeframe: Day 0 to Week 12] 
 Number and proportion of participants hospitalized (all cause) 
 Number and proportion of death (all cause) 
 Comparison of active and placebo treatment groups in time to negative 
PCR 
[Timeframe: Day 0 to Week 12] 
Safety: 
 Incidence of Serious Adverse Events (SAE) 
 Comparison between active and placebo treatment groups in proportion 
of all and ≥grade 3 adverse events as assessed by the National Institutes 
of Health, Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 
2.1, July 2017. 
 Incidence of AEs causing IP discontinuation 
 Incidence of all-cause IP discontinuation or interruption 
 Incidence of Adverse Events of Special Interest (AESI) (if applicable to 
PSA) 
 Number of participants hospitalized due to adverse events regardless of 
cause
 
Exploratory: 
 Assay for anti-SARS-CoV-2 IgM and IgG baseline and Week 8 
 Targeted analysis of polymorphism of known host transmembrane 
proteases which may be involved in viral entry into host cells
Study 
Population: 
Up to 300 SARS-CoV-2 infected adults 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Ivory Coast 
Abidjan:  Institute Pasteur 
Bouake:  Institut Pierre Richet / Institut National de 
Santé Publique
Republic of South 
Africa
Bloemfontein: JOSHA Research Institute 
Thailand 
Bangkok: Royal Thai Army 
Uganda 
Fort Portal Regional Referral Hospital 
United States 
Baltimore, MD: Johns Hopkins Hospital 
Bayview Medical Center 

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Description of 
Study 
Intervention: 
Upamostat Oral capsule : 400 mg (2×200 mg) daily for 14 days 
Study 
Duration: 
18 Months 
Participant 
Duration: 
12 Weeks 

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C 1.2 
Schedule of Activities (SoA) 
The SoA provided below includes all activities described in the Master Protocol. 
Activities in the Master Protocol that do not apply to participants randomized to the upamostat Appendix C are indicated by 
strikethrough, while activities that have been added are indicated by bold text. 
 
STUDY VISIT LOCATION a 
IN PERSON OR 
REMOTE b
IN PERSON 
REMOTE b 
IN PERSON
REMOTE 
IN PERSON OR
REMOTE 
STUDY PROCEDURES 
SCREENING c
ENROLLMENT
D0
D3
D7
D10
D14
D28
WEEK 8 d
WEEK 12
UNSCHEDULED e
VISIT WINDOW 
(+/- DAYS OR WEEKS) 
UP TO 24 HOURS 
PRIOR TO 
ENROLLMENT
0
1 DAY
1 DAY
1 DAY
2 DAYS
4 DAYS
1 WEEK 
2 WEEKS
NOT 
APPLICABLE
SCREENING & PROCEDURES 
Screening Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 
Vaccination History m,  j 
X 
X 
X 
X 
 
X 
X 
 
X 
 
Vital Signs f 
X 
X 
 
 
 
 
 
 
 
 
Physical Exam g,  f 
X 
X 
 
 
 
 
 
 
 
 
Height and Weight f 
X 
X 
 
 
 
 
 
 
 
 
Pregnancy Test h,  f,  j 
X 
X 
When pregnancy is suspected 
X 
When pregnancy is 
suspected 
 
Screening Symptom 
Questionnaire  i,  j 
X 
X 
 
 
 
 
 
 
 
 

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STUDY VISIT LOCATION a 
IN PERSON OR 
REMOTE b
IN PERSON 
REMOTE b 
IN PERSON
REMOTE 
IN PERSON OR
REMOTE 
STUDY PROCEDURES 
SCREENING c
ENROLLMENT
D0
D3
D7
D10
D14
D28
WEEK 8 d
WEEK 12
UNSCHEDULED e
VISIT WINDOW 
(+/- DAYS OR WEEKS) 
UP TO 24 HOURS 
PRIOR TO 
ENROLLMENT
0
1 DAY
1 DAY
1 DAY
2 DAYS
4 DAYS
1 WEEK 
2 WEEKS
NOT 
APPLICABLE
Diagnostic Test for 
SARS-CoV-2 k,  j 
X 
X 
 
 
 
 
 
 
 
 
Concomitant Medication 
Review j 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization (Step 1) 
 
X 
 
 
 
 
 
 
 
 
Study (IP) Informed 
Consent 
 
X 
 
 
 
 
 
 
 
 
Screening Assessments i, j 
X 
X 
 
 
 
 
 
 
 
 
Randomization (Step 2) 
 
X 
 
 
 
 
 
 
 
 
Dispense Study Kit 
 
X 
 
 
 
 
 
 
 
 
Collect and Update 
Contacts 
 
X 
X 
X 
 
 
 
 
 
 
EFFICACY 
Daily Follow Up 
Symptom Questionnaire 
 
 
Daily 
X 
X 
X 
Upper Respiratory 
Specimen 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Outcome 
Assessment 
 
 
X 
X 
 
X 
X 
X 
X 
X 

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STUDY VISIT LOCATION a 
IN PERSON OR 
REMOTE b
IN PERSON 
REMOTE b 
IN PERSON
REMOTE 
IN PERSON OR
REMOTE 
STUDY PROCEDURES 
SCREENING c
ENROLLMENT
D0
D3
D7
D10
D14
D28
WEEK 8 d
WEEK 12
UNSCHEDULED e
VISIT WINDOW 
(+/- DAYS OR WEEKS) 
UP TO 24 HOURS 
PRIOR TO 
ENROLLMENT
0
1 DAY
1 DAY
1 DAY
2 DAYS
4 DAYS
1 WEEK 
2 WEEKS
NOT 
APPLICABLE
SAFETY 
Vital Signs  
 
X 
X 
 
 
X 
X 
X 
 
X 
Physical Exam 
 
X 
X 
 
 
X 
X 
X 
 
X 
Venous Blood Sampling 
Hematology
 
X 
X 
 
 
X 
X 
X 
 
X 
Blood Chemistry 
 
X 
X 
 
 
X 
X 
X 
 
X 
Coagulation Studies
 
X 
X 
 
 
X 
X 
X 
 
X 
ECG  
X m  j 
 
X 
 
 
X 
 
 
 
X 
Adverse Events 
 
Continuous 
UPAMOSTAT or PLACEBO ADMINISTRATION 
Administer Upamostat 
or Control.m 
 
Daily for 14 days (drug dispensed on Day 0) 
 
 
 
 
RESEARCH LABS 
Serum Anti-SARS-CoV-
2 antibody 
 
X 
 
 
 
 
 
X 
 
 
Whole Blood, Plasma and 
Serum Storage for 
Possible Future Research 
 
X 
X 
 
 
X 
X 
X 
 
X 
Pharmacokinetics n 
 
X 
X 
 
 
X 
 
 
 
 

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STUDY VISIT LOCATION a 
IN PERSON OR 
REMOTE b
IN PERSON 
REMOTE b 
IN PERSON
REMOTE 
IN PERSON OR
REMOTE 
STUDY PROCEDURES 
SCREENING c
ENROLLMENT
D0
D3
D7
D10
D14
D28
WEEK 8 d
WEEK 12
UNSCHEDULED e
VISIT WINDOW 
(+/- DAYS OR WEEKS) 
UP TO 24 HOURS 
PRIOR TO 
ENROLLMENT
0
1 DAY
1 DAY
1 DAY
2 DAYS
4 DAYS
1 WEEK 
2 WEEKS
NOT 
APPLICABLE
Whole Blood Sample for 
Host Polymorphism 
Assessment o 
 
X 
 
 
 
 
 
 
 
 
a. In person visits may include those that take place at the research site, home visits or visits to participants admitted to hospital for social, quarantine or 
isolation purposes. Remote visits may take place over the phone or by video conferencing.  
b. If remote visit not feasible or is not permitted under local regulation, the visit may be conducted in person. 
c. If screening visit conducted remotely, SARS-CoV-2 testing (if applicable), ECG, and pregnancy test will be completed at the enrollment visit prior to 
enrollment visit activities. Screening and enrollment activities may take place on the same day. 
d. A Week 8 visit has been added for participants randomized to the upamostat Appendix C 
e. For Unscheduled Visits - These procedures may be done according to clinical judgement. 
f. These activities may take place at screening or enrollment. Activities completed at screening do not need to be repeated at enrollment 
g. Physical exam will be performed by a healthcare professional qualified in the clinical practice of medicine. This may include physicians, nurses, or other 
allied health professionals who are registered/licensed in the local jurisdiction and the performance of a physical exam is within the current scope of practice.  
Physical exam may be conducted in person or via a research staff-assisted telehealth physical exam 
h. Pregnancy testing will be completed in all females of childbearing potential defined as premenopausal females capable of becoming pregnant. This includes 
women on oral, injectable, or mechanical contraception and women whose male sexual partners have been vasectomized or are using contraceptive devices. If 
screening and enrollment are not conducted on the same day, then pregnancy testing will not be repeated for enrollment. Pregnancy testing may be performed 
with serum or urine and must be authorized for use by the relevant national authority for the detection of pregnancy in the country where the test is 
administered. 
i. The Screening Symptom Questionnaire may be completed at Screening if performed on same day as Enrollment. If Enrollment does not take place on the 
same day as Screening, then Screening Symptom Questionnaire will be repeated at Enrollment. Results of the questionnaire will be used to determine final 
eligibility for enrollment 
j. Final eligibility will be determined upon completion of these activities. For activities completed at Screening, results will be reviewed and verified at 
enrollment to determine eligibility. 
k. Diagnostic testing must be an approved molecular or antigen diagnostic test for SARS-CoV-2 from any upper respiratory specimen performed at screening or 
enrollment or within 5 days of enrollment. The test used must be authorized for use by the relevant national authority for the detection of SARS-CoV-2 in the 
country where the test is administered. Test kits can be obtained from a locally acquired source. Historical testing results will be acceptable if testing 
performed within the required window. The local testing result, specimen type, assay type, and date of test will be recorded in the CRF. The test result must 
be available and reviewed by site PI or study staff to confirm eligibility. At baseline, the specimen will also be tested to determine SARS-CoV-2 variant. 

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l. Screening assessments will include Screening symptom questionnaire, concomitant medications, pregnancy testing, SARS-CoV-2 diagnostic testing results, 
SARS-CoV-2 vaccination history, and baseline ECG. Screening assessments may be performed at screening or enrollment but must be reviewed by research 
staff before determination of final eligibility 
m. 1 bottle to be dispensed at D0, with empty bottles and/or remaining capsules to be collected at D14 visit 
n. PK sampling will be performed. All participants will have Day 0 sampling prior to administration of study drug and Day 14 sampling approximately 
22-26 hours after the last dose of study medication. Participants will then follow one of two schedules for Day 3 sampling (see Section 9.2.6  
Pharmacokinetic Testing). Study staff may call participant the day prior to the Day 3 sampling to remind them of timing of upamostat dose and 
venous blood sampling.  
o. A sample of whole blood will be stored for planned future host protease polymorphism assessment 
 

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C 3 
INTRODUCTION 
C 3.1 
Study Rationale 
There are four main sub-groupings of coronaviruses (classes alpha, beta, gamma, and delta). 
SARS-CoV-2 is a member of the beta class coronaviruses that also include the close relatives 
SARS-CoV (the first identified severe acute respiratory syndrome-related coronavirus) and 
MERS-CoV (Middle East respiratory syndrome-related coronavirus). All three viruses 
predominantly attack the respiratory system, but can also impact the gastro-intestinal system, 
heart, kidney, liver, and central nervous system, potentially leading to the failure of multiple 
organs.  
Transmembrane serine proteases are essential for viral fusion with the host cell membrane [Yao 
2022]. Upamostat is a first-in-class orally administered potent inhibitor of serine proteases 
targeting multiple indications. Upamostat was initially studied as an inhibitor of urokinase 
plasminogen activator targeting oncology indications. Subsequent studies revealed that the 
compound is a potent inhibitor of other serine proteases, especially trypsins. The presumed 
mechanism is inhibition of spike protein cleavage necessary for viral entry into host cells. It 
targets human cell rather than viral factors and as such, is expected to be effective against 
emerging variants. In vitro, upamostat inhibited the original SARS-CoV-2 virus at a 
concentration well below that achievable in patients. Preliminary results of testing against SAR-
CoV-2 BA.5 variant showed a 3-log decrease in viral titer at the highest dose tested. A pilot 
outpatient study in symptomatic, SARS-CoV-2 positive patients revealed that the drug was well 
tolerated at both dose levels tested, 200 and 400 mg daily for 14 days [Plasse 2022].  While the 
study was not powered for efficacy determination, only one of 41 patients (2.4%) receiving 
upamostat at either of the two doses used developed new severe symptoms on study, versus 4 of 
20 (20%) of placebo recipients. Importantly, no upamostat-treated patient was hospitalized for 
COVID-19 during the study versus 3 of 20 (15%) of placebo recipients. Pharmacologic 
parameters (reduction in mean D-dimer levels and increased incidence of minor increases in INR 
and PTT) demonstrated dose-dependent effects. 
C 3.3 
Study Hypotheses 
That early treatment with upamostat among outpatients infected with SARS-CoV-2 can shorten 
time to sustained symptom alleviation or resolution as compared to standard treatment. 

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C 3.4 
Risk/Benefit Assessment 
C 3.4.1 
Known Potential Risks 
C.3.4.1.1 
Risks Associated with Upamostat 
To date, 230 subjects have been treated with upamostat in clinical trials, including 41 in a 
recently concluded pilot study of upamostat for outpatient treatment of COVID-19. 
In randomized clinical trials the only events attributable to upamostat were transient increases in 
transaminases, rash and, in patients receiving capecitabine, palmar-plantar erythrodysaesthesia 
syndrome. 
In the COVID-19 study, no increase in transaminases was seen at either upamostat dose level as 
compared to placebo. International Normalized Ratio (INR) or activated partial thromboplastin 
time (aPTT) were often mildly abnormal at baseline in patients in the COVID-19 study. On-
study, 25% of placebo patients, 50% of upamostat 200 mg recipients and 62% of upamostat 
400 mg recipients developed increases in either INR or aPTT of at least one grade per National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 5.0. 
Almost all increases were Grade 1; no clinical bleeding was noted. 
C.3.4.1.2 
Steps Taken to Minimize Risks  
1. Risk to participants in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, close clinical monitoring, as well as periodic review of all safety data 
by an independent data monitoring committee 
2. Because upamostat may inhibit CYP3A4, patients receiving anticoagulants metabolized by 
CYP3A4 (warfarin, apixaban [Eliquis], or rivaroxaban [Xarelto]) may not be entered into the 
study, nor may these medications be started while a patient is receiving upamostat. 
C 3.4.3 
Assessment of Potential Risks and Benefits 
This study involves potential risks to and potential health benefits for the participant. Potential 
benefits, along with anticipated vital knowledge the trial is likely to generate, suggest that 
benefits of the study outweigh the risks.  

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C 4 
OBJECTIVES AND ENDPOINTS  
C 4.1 
Early Treatment 
In addition to those listed in the MP, the following objectives and endpoints will be included: 
 
Objectives 
Endpoints 
Secondary 
 To determine if early 
treatment with upamostat can 
reduce disease severity in 
participants infected with 
SARS-CoV-2 
 
 Change in overall COVID-19 symptom 
severity score  
[Timeframe: Day 0 to Day 28] 
 Proportion of participants in each 
treatment group developing new 
COVID-19 symptoms rated as severe  
[Timeframe: Day 0 to 28] 
 Proportion of participants who report: 
o Return to usual state of health 
o Return to usual activities 
[Timeframe: Days 7, 14, 28 Week 8, 
and Week 12]
 
 To determine if early 
treatment with upamostat can 
decrease the incidence of 
hospitalization due to 
COVID-19
 Proportion of participants hospitalized 
for COVID-19 
[Timeframe: Day 0 through Week 12] 
 
 
 To evaluate the clinical 
efficacy of upamostat 
compared to placebo 
 Number and proportion of participants 
hospitalized (all cause) 
[Timeframe: Day 0 to Day 28] 
 Number and proportion of participant 
deaths (all cause) 
[Timeframe: Day 0 to Day 28]
 
 To evaluate virologic efficacy 
of upamostat compared to 
placebo 
 Comparison of active and placebo 
treatment groups in time to negative 
PCR 
[Baseline through Week 12]

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Objectives 
Endpoints 
Safety 
 To evaluate the safety and 
tolerability of upamostat 
compared to placebo 
 
 Incidence of Serious Adverse Events 
(SAE) 
 Comparison between active and placebo 
treatment groups in proportion of all and 
≥grade 3 adverse events as assessed by 
the National Institutes of Health, 
Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse 
Events (DAIDS AE Grading Table), 
corrected Version 2.1, July 2017. 
 Incidence of AEs causing IP 
discontinuation 
 Incidence of all-cause IP discontinuation 
or interruption 
 Number of participants hospitalized due 
to adverse events regardless of cause
Exploratory 
 Characterize the impact of 
SARS-CoV-2 genetic 
variability on primary and 
secondary outcomes 
 Difference in efficacy outcomes among 
circulating variants of interest (VOI) and 
variants of concern (VOC) via 
o Geographic and temporal 
prevalence 
o SARS-CoV-2 genome sequencing
 
 To determine the presence 
and titer of antibodies  
to SARS-CoV-2 at baseline 
and the development of 
antibodies  
during study participation
 Assay for anti-SARS-CoV-2 IgM and 
IgG at baseline and Week 8 
 
 To assess the impact of host 
transmembrane protease 
polymorphisms on drug 
efficacy
 Targeted analysis of polymorphism of 
known host transmembrane proteases 
which may be involved in viral entry 
into host cells
 
 
 
 

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C 5 
STUDY DESIGN 
C 5.1 
Overall Design 
A Phase 2 adaptive, randomized, double-blind, placebo-controlled platform trial to evaluate the 
safety and efficacy of upamostat for early outpatient COVID-19 treatment. From the master 
protocol, following completion of the screening and enrollment requirement, participants who 
meet the entry criteria for upamostat are eligible for randomization to the upamostat Early 
Treatment arm of the trial. Probability of randomization to the upamostat arm will be dependent 
on the number of PSAs enrolling in the Early Treatment  indication. For example, if three 
products are enrolling in the treatment indication at the same time, probability of randomization 
to the upamostat arm is 1:3. 
Once randomized to upamostat, participants will undergo an upamostat specific informed 
consent. A second, blinded randomization will be to the active agent orplacebo. The probability 
of the second randomization will also be dependent on the number of products enrolling in the 
indication at that time. The ratio of assignment to active agent or placebo will be r:1 where r is 
the number of IPs in the Early Treatment indication that a given participant is eligible to receive.  
The total sample size is projected to be 300 (150 upamostat, 150 control). If additional IPs are 
enrolling in the treatment indication, the sample size will be adjusted based on the ability to 
share control groups of concurrently enrolled participants.  
Interim analyses and saftey monitoring will be conducted and will allow early stoppage for 
futility, efficacy, or safety described in Section C 10. Adverse Events and Serious Adverse 
Events and Section C 13. Statistical Considerations.  
C 5.3 
Scientific Rationale for Study Design  
The purpose of this PSA is to evaluate the safety and efficacy of upamostat for early outpatient 
COVID-19 treatment. The platform trial design will maximize efficiency within the trial to allow 
for sharing of controls. Interim analysis plans will allow for early stopping for success, futility or 
if there is a safety signal. 
C 5.4 
Justification for Dose 
Doses of 200 and 400 mg upamostat daily were well tolerated in previous studies. In a healthy 
volunteer study in which patients were given 100, 200 or 400 mg upamostat or placebo daily for 
14 days, no difference in tolerability was noted among the upamostat doses. Similarly, in a 
pancreatic cancer study in which all patients received standard therapy, gemcitabine, and were 
randomized to either no additional treatment, 200 or 400 mg upamostat daily, both dose levels of 
upamostat were well tolerated. 
In a pilot study of upamostat for treatment of COVID-19, patients received placebo, 200 or 
400 mg upamostat daily for 14 days. Both dose levels were well tolerated, with no increase in 
clinical adverse events over placebo. Clinical adverse event rates (Grade 1, Grade 2) were 10%, 
20% in the placebo group, 25%, 0% in the upamostat 200 mg group and 19%, 10% in the 

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upamostat 400 mg group. The only laboratory effect noted was an increase in the incidence of 
Grade 1 increases in INR or aPTT in the upamostat-treated patients as compared to those 
receiving placebo, noted in 25% of placebo patients, 50% of upamostat 200 mg patients and 65% 
of upamostat 400 mg patients. Most of these were one grade increases and none was 
accompanied by any bleeding.  
Both dose levels in this small (20-21 patients/group) study appeared to protect patients from new 
severe symptoms from and hospitalization for COVID-19. Several factors suggest that the 400 
mg dose may be more effective than the 200 mg dose. Mean D-dimer levels were stable over the 
course of the study in the placebo group but decreased by 38% and 48% in the upamostat 200 mg 
and 400 mg groups, respectively. The only new severe on-study COVID symptom in an 
upamostat patient occurred in a patient in the 200 mg group. Median time to resolution of all 
severe symptoms was 8 days in the placebo group, 4 days in the upamostat 200 mg group, and 3 
days in the upamostat 400 mg group. In summary, there was no increase in clinically significant 
adverse events in the 400 mg group as compared to the 200 mg group, and two parameters 
suggest that there may be some improvement in outcome in the high dose group as compared to 
the low dose group.  

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C 6  
STUDY POPULATION AND STUDY ENROLLMENT 
Population A: Adults seeking care or testing for COVID-19 
C 6.1 
Inclusion Criteria 
Inclusion criteria are specified in the Master Protocol and: 
1. Women of childbearing potential must agree to use an effective contraceptive method 
upon enrollment in the study through 8 weeks after the last dose of the investigational 
product. This would include oral contraceptives, implanted contraceptives, intrauterine 
devices, and barrier methods. 
o A woman is considered of childbearing potential unless post-menopausal 
(subject is at least 50 years old and has history of ≥2 years without menses 
without other known or suspected cause), or permanently surgically sterilized.  
o Participants not of reproductive potential are eligible without requiring the use 
of a contraceptive method. Participant-reported history is acceptable 
documentation of surgical sterilization and menopause. 
C 6.2 
Exclusion Criteria 
Exclusion criteria as specified in the Master Protocol and: 
1. Patient is currently taking or is expected to start taking warfarin, apixaban (Eliquis), or 
rivaroxaban (Xarelto). Patients may be taking or start on study dabigatran (Pradaxa), 
standard or low molecular weight heparin. 
2. Patients with prolonged QT/QTc interval and/or increased susceptibility to arrythmia 
defined as the presence of any of the following: 
o QTc interval > 450 msec 
o Pathological Q-waves (defined as Q-wave > 40 msec or depth > 0.4-0.5 mV) 
o Evidence of ventricular pre-excitation 
o Electrocardiographic evidence of complete LBBB, RBBB, incomplete LBBB, in 
complete RBBB 
o Evidence of second- or third-degree heart block 
o Intraventricular conduction delay with QRS duration > 120 msec 
o Bradycardia as defined by sinus rate< 50 bpm 
o Personal or family history of long QT syndrome 
o Personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, 
except for sinus arrhythmia 
o Syncopal episodes or additional risk factors for torsades de points (e.g., heart 
failure, hypokalemia) 

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C 6.3 
Lifestyle Considerations 
Lifestyle Considerations as specified in the Master Protocol and: 
1. Participants that engage in sexual activity that may lead to pregnancy in their partner 
must agree to either remain abstinent or use male contraceptives. They are also 
strongly advised to inform their non-pregnant sexual partners of reproductive potential 
to use effective contraceptives for 8 weeks after investigational agent is administered. 
2. Participants should refrain from sperm donation for 8 weeks after investigational agent 
administration. 
3. Upamostat may increase the sedative effects of alcohol so participants are encouraged 
to avoid alcohol while taking the study medication. 
 

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C 7 
STUDY INTERVENTION 
C 7.1.1 
Study Intervention Description 
Upamostat is designated chemically as ethyl 4-{3-[(E)-amino(hydroxyimino)methyl]-N-[(2,4,6-
triisopropylphenyl) sulfonyl]-L-phenylalanyl}-piperazine-1-carboxylate hydrogen sulphate.  
C 7.1.2 
Dosing and Administration 
Upamostat 400 mg will be dosed orally once daily for 14 days. 
C 7.2 
Preparation/Handling/Storage/Accountability 
C 7.2.2 
Acquisition 
Upamostat and placebo will be provided by RedHill either directly or through a third-party 
clinical supply distributer. 
C 7.2.4 
Formulation, Appearance, Packaging, and Labeling 
Size 1 oral capsules contain a white to yellowish powder of 200 mg upamostat or placebo and 
are packaged in round white, 40 cc 33-400 wide-mouth marlex bottles with a white 33mm child 
resistant polypropylene cap with an induction seal at 30 capsules per bottle. 
A standard label will be adhered to each bottle. Participants will be assigned to receive their 
treatment according to the randomization. For each cohort, randomized subjects will be assigned 
a unique number. 
The unique number will be the only participant identifier used on all sample collections and 
return of results. The site’s blinded pharmacist or qualified designee will provide each participant 
with study drug and instructions for use; the initial doses for Day 0 will be given at the site. 
C 7.2.5 
Product Storage and Stability 
Investigational drug must be kept in an appropriate, limited-access, secure place at controlled 
room temperature 15° to 25°C (60° to 77°F) and protected from light until it is used or returned 
to the industry supporter or designee for destruction. Investigational drug must be stored under 
the conditions specified on the label and remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained every working day while the drug is 
still in the research unit. 
C 7.2.6 
Preparation 
All bottles provided contain 30 capsules of 200 mg upamostat or placebo and are prelabelled 
according to country specific requirements. 1 bottle will be dispensed to each participant at 
Day 0. 

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C 7.4 
Measures to Minimize Bias: Randomization and Blinding 
C 7.4.1 
Randomization 
Once randomized to the upamostat early treatment indication, participants will undergo a second, 
blinded randomization to either upamostat or placebo through the Interactive Voice/Web 
Response System (IxRS). Probability of randomization will be dependent on the number of 
products enrolling in the early treatment indication at that time.  
The ratio of assignment to upamostat or placebo will be r:1 where r is the number of IPs 
concurrently enrolling in the early treatment indication that a given participant is eligible to 
receive. For example, if two products are enrolling in the treatment indication simultaneously, 
the probability of randomization of an eligible participant to upamostat or placebo will be 2:1. 
See also Section C 13 Statistical Considerations. 
The site research pharmacist(s) will be responsible for maintaining secure access to 
randomization assignments through the IxRS. 
C 7.4.2 
Blinding and Unblinding 
Both participants and study investigators will be blinded to this second randomization.  
Refer to the Master Protocol regarding unblinding. 
C 7.6 
Concomitant Therapy 
In vitro studies with upamostat and WX-UK1 have suggested a potential for drug interactions 
with concomitantly administered drugs that are either substrates or inhibitors of CYP3A4. 
Clinical data concerning potential CYP3A4-mediated drug interactions are not available. 
Therefore, as a safety precaution, patients that receive strong CYP3A4 inhibitors, sensitive 
CYP3A4 substrates, or CYP3A4 substrates with a narrow therapeutic range together with 
upamostat should be carefully monitored concerning potential side effects arising from increased 
exposure to upamostat or to concomitant medication. Lists of strong CYP3A4 inhibitors and 
sensitive CYP3A4 substrates can be found in Supplement 1. These lists are based on the US 
Food and Drug Administration guidance [US Food and Drug Administration, 2022]. 
Patients may not take warfarin, apixaban (Eliquis), or rivaroxaban (Xarelto).  Patients may use 
dabigatran (Pradaxa), standard or low molecular weight heparin, as these drugs are not 
metabolized through CYP mechanisms. 

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C 9 
STUDY ASSESSMENTS AND PROCEDURES 
C 9.2 
Clinical and Laboratory Assessments 
C 9.2.1 
Clinical Assessments 
Clinical assessments will be conducted according to the Master Protocol with the following 
additions and exceptions as presented in Section 1.2 Schedule of Activities. 
Clinical assessments include: 
Vaccination status 
 Vaccination status collected at baseline and Day 7 only 
Electrocardiogram (ECG)  
 A 12 lead ECG will be performed. ECG will be interpreted by clinicians qualified in 
ECG interpretation. This may include physicians, nurses, or other allied health 
professionals who are registered/licensed in the local jurisdiction and the performance 
and interpretation of ECGs is within the current scope of practice. Remote 
interpretation will also be permitted.  
C 9.2.1 Lab Assessments 
Lab assessments will be conducted according to the Master Protocol with the following additions 
and exceptions as presented in the Section 1.2 Schedule of Activities. 
Additional testing requirments: 
 Coagulation Studies 
o International Normalized Ratio (INR) 
o Partial Thromboplastin Time (PTT)  
 Anti-SARS-CoV-2 IgM and IgG 
 Polymorphisms of relevant host cellular proteases 

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C 9.2.3 
Screening Assessments 
Screening assessments will include the following: 
 Screening symptom questionnaire 
 SARS-CoV-2 vaccination history 
 Concomitant medications 
 ECG 
 Pregnancy test 
 SARS-CoV-2 diagnostic test result 
o Diagnostic testing must be an approved molecular or antigen diagnostic test for 
SARS-CoV-2 from any upper respiratory specimen performed at screening or 
enrollment or within 5 days of enrollment. The test used must be authorized for use 
by the relevant national authority for the detection of SARS-CoV-2 in the country 
where the test is administered. Historical testing results will be acceptable if testing 
performed within the required window. The test result must be available and 
reviewed by site PI or study staff to confirm eligibility. 
C 9.2.5 
Blood Volumes 
The maximum volume of blood drawn at any one visit will not exceed 30 mL. 
C 9.2.6 
Pharmacokinetics 
Plasma samples for PK evaluation will be collected at Day 0, Day 3, and Day 14. The analysis 
will include levels of upamostat and its active metabolite, WXUK1, for each of these time points.  
Day 0:  all patients will have a specimen drawn prior to first treatment with study medication. 
Patients will be randomized to one of two sampling regimens for Day 3: 
A) Day 3 specimen within 2 hours prior to dosing; 
OR 
B) Day 3 specimen 2-4 hours after dosing.  
Day 14: all patients will have a specimen drawn 22-26 hours after previous dose. 
An attempt will be made to get a specimen 22-26 hours after the last dose from patients who stop 
treatment early. 

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C 9.4 
Study Visits 
Study Visits will be conducted according to the Master Protocol with the following additions and 
exceptions as presented in Section 1.2 Schedule of Activities. 
Activities in the Master Protocol that do not apply to participants randomized to the upamostat 
Appendix C are indicated by strikethrough, while activities that have been added are indicated by 
bold text. 
C 9.4.1 
Screening Visit – In Person or Remote (Within 24 hours Prior to 
Enrollment) 
Potential participants will be screened for presumptive eligibility for the study according to the 
procedures described below. All procedures may be completed in a stepwise manner, as 
suggested below, for potential participants who meet the study eligibility criteria. For 
participants who do not meet the eligibility criteria, screening will be discontinued when 
ineligibility is determined. For potential participants who participate in the screening visit 
remotely and are found to be presumptively eligible, final eligibility will be confirmed upon 
completion of screening procedures at the Enrollment Visit scheduled to take place within 24 
hours of screening. Screening and enrollment may take place on the same day (Day 0). 
 Screening Informed Consent (in person or verbal)  
 Demographics 
 Medical history 
 SARS-CoV-2 vaccination history 
 Screening Symptom Questionnaire 
 Physical exam 
 Height and weight 
 Vital signs 
 Pregnancy test for women of childbearing potential 
 Diagnostic test for SARS-CoV-2 (for eligibility assessment) 
 Concomitant medication review 
C 9.4.2 
Enrollment Visit – In Person (Day 0) 
Participants who are found to be presumptively eligible at their Screening Visit will complete the 
Enrollment visit within 24 hours of the Screening Visit. Participants who completed the 
screening visit remotely will complete all remaining screening procedures as well as enrollment 
procedures during the in-person Enrollment Visit. Participants who do not complete an 
Enrollment Visit within 24 hours of screening must repeat the entire Screening Visit. All 
participants must complete the screening evaluation prior to study enrollment. For those who 
meet the study eligibility criteria from the screening procedures, the enrollment procedures 
below may be undertaken in a stepwise manner, as suggested below, to confirm eligibility. As 
done with the Screening Visit, procedures will be discontinued if ineligibility is determined at 

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this visit. The site investigator will determine final eligibility after review of all screening 
assessments prior to product administration. 
NOTE: If the enrollment visit is after the screening visit, the patient must still start therapy 
within 5 days of initial positive test for SARS-CoV-2 AND within 5 days of onset of initial 
symptom(s). Presumptively eligible participants who cannot start therapy within that time 
frame are not permitted to participate in the study, even if they meet all other enrollment 
qualifications. 
 Screening Symptom Questionnaire (repeat if visit not performed on same day as Screening) 
 Randomization (Step 1) 
 Study (IP) Informed Consent (in person) 
 Screening assessments (see Section C 9.2.3 Screening Assessments) 
 ECG 
 Eligibility evaluation (review of all screening and eligibility assessments) 
 Randomization (Step 2) 
 Upper respiratory specimen collection (prior to administration of upamostat or control) (for 
efficacy assessment)  
 Venous blood sampling (prior to administration of upamostat or control) 
o Hematology (prior to administration of upamostat or control) 
o Chemistry (prior to administration of upamostat or control) 
o Coagulation Studies 
o Anti-SARS-CoV-2 IgM and IgG 
o Polymorphisms of relevant host cellular proteases 
o Whole Blood, Plasma and Serum Storage for Possible Future Research (prior to 
administration of upamostat or control) 
o Pharmacokinetics 
 Administration of upamostat or control  
 Collect and update contacts 
 Dispense study kit 
 Adverse event recording and reporting 

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C9.4.3 
Day 3 Visit – Remote or In Person 
This visit is scheduled to take place In Person on Day 3. Every effort should be made to 
complete the Day 3 visit requirements on Day 3; however, the visit may take place — if 
necessary +/- 1 days.  
 SARS-CoV-2 Vaccination Status 
 Concomitant medication review 
 Collect and update contacts 
 Daily Symptom Follow Up Questionnaire (daily until day 28 then at Weeks 8 and 12)  
 Upper respiratory specimen collection 
 Clinical outcome assessment 
 Vital signs 
 Physical exam 
 Venous blood sampling (for Pharmacokinetics Group A: venous blood sampling should be 
collected within 2 hours prior to administration of upamostat or control, for 
Pharmacokinetics Group B: venous blood sampling should be collected 2-4 hours after 
administration of upamostat or control) 
o Hematology  
o Chemistry  
o Coagulation studies 
o Whole blood, plasma, and serum storage for possible future research  
o Pharmacokinetics 
 ECG 
 Adverse event recording and reporting 
C 9.4.4 
Day 7 Visit- Remote or In person 
This visit is scheduled to take place Remotely on Day 7. Every effort should be made to 
complete the Day 7 visit requirements on Day 7; however, the visit may take place — if 
necessary +/- 1 days. Remote visits may include visits by the study staff to the participant or via 
phone/video conference. If remote visit not feasible or is not permissible under local rules or 
standards, the visit may be conducted in person. 
 SARS-CoV-2 Vaccination Status 
 Concomitant medication review 
 Collect and update contacts 
 Daily Symptom Follow Up Questionnaire (daily until Day 28 then at Weeks 8 and 12) 
 Upper respiratory specimen collection (self-collection) 
 Clinical Outcome Assessment 
 Adverse event recording and reporting 

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C 9.4.5 
Day 10 Visit- Remote 
This visit is scheduled to take place Remotely on Day 10. Every effort should be made to 
complete the Day 10 visit requirements on Day 10; however, the visit may take place — if 
necessary +/- 1 days. Remote visits may include visits by the study staff to the participant or via 
phone/video conference. If remote visit not feasible or is not permissible under local rules or 
standards, the visit may be conducted in person. 
 Daily Symptom Follow Up Questionnaire (daily until Day 28 then at Weeks 8 and 12) 
 Concomitant medication review 
 Upper respiratory specimen collection (self-collection) 
 Adverse event recording and reporting 
C 9.4.6 
Day 14 Visit – In Person 
This visit is scheduled to take place In Person on Day 14. Every effort should be made to 
complete the Day 14 visit requirements on Day 14; however, the visit may take place — if 
necessary +/- 2 days 
 SARS-CoV-2 Vaccination Status 
 Concomitant medication Review 
 Daily Symptom Follow Up Questionnaire (daily until Day 28 then at Weeks 8 and 12) 
 Upper respiratory specimen collection 
 Clinical outcome assessment 
 Vital signs 
 Physical exam 
 Venous blood sampling (should be collected from all participants 22-26 hours after previous 
dose of upamostat or control) 
o Hematology  
o Chemistry  
o Coagulation studies 
o Whole blood, plasma, and serum storage for possible future research  
o Pharmacokinetics 
 ECG 
 Adverse Event Recording and Reporting 

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C 9.4.7 
Day 28 Visit – In Person 
This visit is scheduled to take place In Person on Day 28. Every effort should be made to 
complete the Day 28 visit requirements on Day 28; however, the visit may take place — if 
necessary +/- 4 days.  
 SARS-CoV-2 Vaccination Status 
 Concomitant medication Review 
 Daily Symptom Follow Up Questionnaire (daily until Day 28 then at Weeks 8 and 12) 
 Upper respiratory specimen collection 
 Clinical outcome assessment 
 Vital signs 
 Physical exam 
 Pregnancy test 
 Venous blood sampling  
o Hematology  
o Chemistry  
o Coagulation studies 
o Whole blood, plasma, and serum storage for possible future research  
 Adverse Event Recording and Reporting 
C 9.4.8 
Week 8 Visit – In Person 
This visit is scheduled to take place In Person at Week 8. Every effort should be made to 
complete the Week 8 visit requirements at Week 8; however, the visit may take place — if 
necessary +/- 1 week.  
 Concomitant medication review 
 Daily Symptom Follow Up Questionnaire (daily until Day 28 then at Weeks 8 and 12)  
 Upper respiratory specimen collection 
 Clinical outcome assessment 
 Vital signs 
 Physical exam 
 Venous blood sampling  
o Hematology  
o Chemistry  
o Coagulation Studies 
o Anti-SARS-CoV-2 IgM and IgG 
o Whole blood, plasma, and serum storage for possible future research  
 Adverse event recording and reporting 

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C 9.4.9 
Week 12 In Person OR Remote 
This visit is scheduled to take place Remotely at Week 12. Every effort should be made to 
complete the Week 12 visit requirements at Week 12; however, the visit may take place — if 
necessary +/- 2 weeks.  
 SARS-CoV-2 vaccination status 
 Concomitant medication review 
 Daily Symptom Follow Up Questionnaire (daily until Day 28 then at Weeks 8 and 12) 
 Upper respiratory specimen collection (self-collection) 
 Clinical outcome assessment 
 Adverse Event Recording and Reporting 
C 9.4.10 Unscheduled Visits – In Person or Remote 
An unscheduled visit is defined as any visit to the clinical trial site outside of the protocol 
evaluation time points, where the participant is seen by a member of the clinical research staff. 
Participants will be encouraged to report any medical problems or discomfort to the study staff 
and may be instructed to return to the clinical trial site if they experience new or worsening 
COVID-19 symptoms or become infected with SARS-CoV-2 any time after enrollment. Remote 
visits may include visits by the study staff to the participant or via phone/video conference. If 
remote visit not feasible or is not permissible under local rules or standards, the visit may be 
conducted in person. 
In the event of an unscheduled visit these procedures may be done according to clinical 
judgement: 
If conducted remotely the following procedures may be performed: 
 SARS-CoV-2 vaccination status 
 Concomitant medication review 
 Daily Symptom Follow Up Questionnaire 
 Upper respiratory specimen collection (self-collection) 
 Clinical outcome assessment 
 Adverse event recording and reporting 
If conducted in person following procedures may be performed: 
 SARS-CoV-2 vaccination status 
 Concomitant medication review 
 Daily Symptom Follow Up Questionnaire 
 Upper respiratory specimen collection 
 Clinical outcome assessment 
 Vital signs 
 Physical exam 

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 Venous blood sampling  
o Hematology  
o Chemistry  
o Coagulation studies 
o Whole blood, plasma, and serum storage for possible future research  
 ECG 
Depending on the reason for the visit, the participant may have additional assessments or 
laboratory tests, as clinically indicated, or may be referred to the appropriate service for follow 
up.  

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C 10 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
C 10.1.9 Pregnancy and Breastfeeding 
Since there are no data regarding the use of upamostat in participants who are pregnant or 
breastfeeding, participants who are pregnant or breastfeeding are not eligible for the study. 
Participants of childbearing potential and participants who may impregnate their partners are 
required to follow the instructions for prevention of pregnancy provided in Section C 6.3 
Lifestyle Considerations. 
If a participant becomes pregnant during the study (post-entry), administration of upamostat will 
be discontinued (if still taking) and study follow up will continue for the duration of the study. At 
the end of the pregnancy, outcome and adverse events for participant and infant will be recorded 
on the outcome eCRF. 

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C 12 PAUSE AND STOPPING CRITERIA 
C 12.1 
Individual Participant Pause and Stopping Criteria 
The administration of IP to any participant may be stopped or paused for any SAE, clinically 
significant AE, severe lab abnormality or any medical condition that may indicate to the 
Investigators that IP continuation is not in the best interest of the participant. In addition, a 
subject in the clinical trial may discontinue study drug at their request for any reason. Every 
effort should be made to encourage subjects to remain in the study for the duration of their 
planned outcome assessments. Unless the subject withdraws the consent, those who discontinue 
study drug early will remain in the study. The reason for subject discontinuation will be 
documented in the case report form. 
For an individual participant, the 14-day course of IP can be interrupted or stopped if there is a 
suspected drug-related event suggestive of QTc interval prolongation, anticoagulant effect, 
elevated liver enzymes or other, as per investigator or medical monitor discretion if it is deemed 
to be in the participant’s best interest. All participants will receive baseline chemistry, liver 
enzyme, and coagulation studies as well as a baseline ECG. 
The individual pause and stopping criteria will include (but not be limited to) the following: 
 The subject worsens and requires treatment for worsening COVID-19 as recommended 
by the NIH COVID-19 Treatment Guidelines. Upamostat administration will be 
discontinued. All other study activities will continue, participant will not be withdrawn 
from the study.  
 The subject worsens and requires hospitalization for worsening COVID-19. Upamostat 
administration will be discontinued. All other study activities will continue, participant 
will not be withdrawn from the study.  
 QTc Interval: QTc increase >60 msec over baseline:  repeat ECG within 48 hours and if 
>60 msec increase over baseline persists, IP will be discontinued. Participant will 
continue to be participate in follow up visits and, if necessary, until resolution or 
stabilization of the event.  
 INR, PTT:  increase over baseline > 2 Grades (per NIH DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table) corrected 
Version 2.1, July 2017):  pause therapy. Repeat INR and PTT within 48 hours of initial 
awareness of the abnormal laboratory value. If repeat testing ≤ 2 Grades above baseline, 
may resume therapy until total of 14 days from start; missed days will not be made up. If 
repeat testing > 2 Grades above baseline, IP will be discontinued. Participant will 
continue to be participate in follow up visits and, if necessary, until resolution or 
stabilization of the event.  
o If increase over baseline 1 Grade: no additional follow up 
o If increase over baseline 2 Grades: In addition to scheduled PTT/INR testing on Day 
3 and Day 14, participant will have coagulation testing on Day 28. If either PTT or 
INR is increased by ≥ 1 Grade at Day 28, repeat testing will be performed at Week 8. 
Additionally, participant will be questioned at Day 7, Day 10, Day 14 visits, and 

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twice weekly from Day 14 until resolution of the coagulation abnormality to ≤ 1 
Grade above baseline or Week 8 (whichever comes first), regarding bleeding, 
bruising or petechiae.  
 Transaminases, bilirubin:  increase over baseline >1 Grade above baseline: pause therapy. 
Repeat transaminase and bilirubin levels within 48 hours of initial awareness of the 
abnormal laboratory value. If repeat testing ≤1 Grade above baseline, may resume 
therapy until total of 14 days from start; missed days will not be made up. If repeat 
testing >1 Grade above baseline, IP will be discontinued. Participant will continue to be 
participate in follow up visits and, if necessary, until resolution or stabilization of the 
event.  
C 12.2 
Study and/or PSA Pause and Stopping Criteria 
In addition to those listed in the Master Protocol, the study pause criteria listed in Table 1 will 
apply. 
Table 1 
Product Specific Criteria for Study Pause   
Parameter 
Investigational Products Related 
Adverse Events (AEs) 
Action 
Prolonged QTc Interval 
QTc a >500 msec 
OR 
QTc a >60 msec above baseline on 
repeat ECG within 48 hours
Prompt reporting (within 24 
hours of observation or report) 
Consider pause of the PSA 
PSRT to monitor for trend
ALT (SGPT), ALP 
(SGOT), or Total 
Bilirubin, High 
 
> 1 Grade c increase in verified d 
abnormal AST, ALT, and total 
bilirubin in >2 patients 
Prompt reporting (within 24 
hours of observation or report) 
Consider pause of the PSA 
PSRT to Monitor for trend
PT, PTT, or INR, High 
(Not on anticoagulation 
therapy) 
> 2 Grade increase in verified PT, 
PTT or INR >2 patients 
Prompt reporting (within 24 
hours of observation or report) 
Consider pause of the PSA 
PSRT to Monitor for trend 
a 
Corrected QT may be calculated using any standardized formula or automated interpretation. The same 
methodology for calculating the QT interval should be applied throughout the participants enrollment in the 
study 
c 
Per NIH DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading 
Table) corrected Version 2.1, July 2017 
d 
Verified definition: If no evidence of disease is present other than the abnormal laboratory value, the test must 
be repeated at least one time in order to be considered “verified”. The verification period will be a maximum of 
48 hours after initial awareness of the abnormal laboratory value. When signs and symptoms are present, repeat 
test WILL NOT be needed 
 

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C 13 STATISTICAL CONSIDERATIONS  
C13.1 
Statistical Hypotheses   
The primary hypothesis is that early treatment with upamostat among outpatients infected with 
SARS-CoV-2 can shorten time to sustained alleviation or resolution of Targeted COVID-19 
symptoms (time to resolution) as compared to standard treatment. 
The general statistical approach will compare outcomes among participants randomized to 
receive the active agent, upamostat, to outcomes among participants who were eligible to have 
been randomized to upamostat but who were randomized instead to any of the placebo arms 
enrolling at that time. This ensures that the comparison is limited to concurrently randomized 
participants eligible to receive upamostat. 
C 13.4 Primary Endpoint/Estimand Analysis 
The primary objective is to estimate the relative time to sustained alleviation or resolution of 
symptomatic COVID-19 infection for a participant that receives upamostat compared to a 
participant that does not receive upamostat.  
The estimand of interest is the hazard ratio of a participant that has symptomatic COVID-19 with 
standard of care background therapy when starting treatment with upamostat compared to no 
upamostat. A hazard ratio greater than 1 indicates a shorter time to resolution of symptomatic 
COVID-19 infection. 
The primary analysis population for upamostat is the modified intent-to-treat population, with a 
treatment arm consisting of all participants that were randomized to upamostat active treatment 
arm and received at least one dose of the active treatment. The control arm consists of all 
participants eligible to be randomized to upamostat that were randomized to placebo and 
received at least one dose of the placebo.  
The primary analysis model is a Cox proportional hazards model for the time to alleviation or 
resolution of COVID-19 symptoms, with treatment arm (active upamostat vs placebo) as a 
covariate. The model estimated hazard ratio will be used as the estimator for the estimand of 
interest. The estimate and 95% confidence interval for the hazard ratio will be presented.  
The primary hypothesis test is that upamostat increases the hazard (decreases time to resolution) 
of COVID-19 symptoms. A hypothesis test will be conducted for testing whether the upamostat 
hazard ratio is greater than 1 at a one-sided 2.5% level.  One interim analysis will be conducted 
and a final analysis with type I error control over the two possible interims of 2.5%. 

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C 13.5 Outcome Measures and Statistical Analyses 
C 13.5.1 Early Treatment 
C 13.5.1.1 
Primary Outcome 
 Time to sustained alleviation or resolution of COVID-19 symptoms evaluated from Day 0 
through Day 28 assessed via completion of a Daily Follow Up Symptom Questionnaire. 
Sustained alleviation or resolution will be defined as the number of days from randomization to 
the first day the participant reports all symptoms as mild or none (≤ 1 or returning to pre- 
COVID-19 illness levels) for at least 3 consecutive days (the first day being considered the Event 
Day). Targeted symptoms will be used for analysis (Supplement 3 of the MP). Any patient that 
does not have alleviation or resolution of symptoms by Day 28 will be considered censored for 
alleviation or resolution at Day 28.  
The primary efficacy analyses will be conducted using the modified intention to treat (mITT) 
population. The primary analysis is a Cox proportional hazards model with treatment assignment 
as a fixed covariate with a proportional effect. A one-sided p-value for the test of a hazards ratio 
of 1 compared to the alternative of a hazard ratio greater than 1 (upamostat reduces time to 
resolution of symptoms) will be presented and used for testing superiority.  An interim analysis 
will be conducted when 50% of maximum enrollment has reached 28 days of exposure. A Kim-
Demets (with parameter 2) spending function will be utilized for testing for superiority of 
upamostat at the interim and final analysis. At the interim analysis, futility analyses will be 
conducted, where enrollment to the upamostat cohort will be stopped if the predictive probability 
of superiority by the final sample size is less than 5%. 
The hazard ratio for the time to resolution of COVID-19 will be presented with 95% confidence 
intervals. Additional sensitivity analyses for the primary analysis will utilize additional covariate 
adjustments in the Cox proportional hazards model.  
C 13.5.1.2 
Secondary Outcome: Clinical 
For each analysis, a 5% two-sided significance will be used. 95% confidence intervals will be 
presented to summarize each effect estimate. Dichotomous outcomes will be summarized with 
relative proportions. Ordinal outcomes will be summarized with stacked bar plots, cumulative 
proportion graphs, and percentiles. Kaplan-Meier plots will be used for summarizing time to 
event outcomes. Continuous measures will be summarized box plots (means, medians, and inter-
quartile ranges).  
Each of the secondary analyses will be conducted using the modified intention to treat (mITT) 
population. Each analysis will be repeated using the per protocol population. 
 Change in overall COVID-19 symptom severity score from Day 0 through Day 28 
The overall symptom severity question on the Daily Symptom Follow Up Questionnaire will be 
used for this secondary endpoint. A mixed model repeated measure (MMRM) model will be 

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used to model the symptom severity score at each day using the baseline symptom score, 
participant, day, and treatment by day as covariates. The treatment effect by day will be 
summarized.  
 Proportion of participants in each treatment group developing new COVID-19 symptoms 
rated as severe from Day 0 to Day 28 
A Cox proportional hazards model will be used to analyze development of new severe 
symptoms. A new severe symptom is defined as scoring a 0 to 1 on any symptom in the 
questionnaire and subsequently scoring a 3 for that symptom (or a 2 for change in taste or smell). 
Treatment arm will be modeled with a proportional hazard effect. The hazard ratio will be 
summarized.  
 Proportion of participants who report a return to usual state of health at Days 7, 14, 28, 
Week 8, and Week 12. 
A Cox proportional hazards model will be used to analyze the time to return to usual state of 
health. Participants without symptomatic COVID-19 will be considered a 0 for return to usual 
state of health. Treatment arm will be modeled with a proportional hazard effect. The hazard 
ratio will be summarized.  
 Proportion of participants who report a return to usual activities at Days 7, 14, 28, Week 8, 
and Week 12. 
A Cox proportional hazards model will be used to analyze the time to return to usual activities. 
Participants without symptomatic COVID-19 will be considered a 0 for return to usual activities. 
Treatment arm will be modeled with a proportional hazard effect. The hazard ratio will be 
summarized.  
 Proportion of participants in each treatment group hospitalized for COVID-19, as adjudicated 
prior to study unblinding. 
 Number and proportion of participants hospitalized (all cause) from Day 0 to Day 28 
 Number and proportion of participant deaths (all cause) from Day 0 to Day 28 
Outcomes will be summarized with relative proportions 
C 13.5.1.2 
Secondary Outcome: Virological 
 Comparison of active and placebo treatment groups in time to negative RT-PCR from 
Day 0 to Week 12 
Time to negative RT-PCR will be defined as the time of the first of two consecutive readings 
below the lower limit of detection. A Cox proportional hazards model will be used to analyze the 
time to negative PCR. 

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C 13.5.1.3 
Safety and Tolerability 
An external DSMB will conduct interim reviews for safety. Monitoring of unblinded safety data 
(including AEs, SAEs, and selected laboratory measurements) will occur monthly throughout the 
study and will be conducted by the DSMB. Only the DSMB is authorized to evaluate unblinded 
interim efficacy and safety analyses.  
Safety analyses will include: 
 Incidence of Serious Adverse Events (SAE) 
 Comparison between active and placebo treatment groups in proportion of all and ≥grade 3 
adverse events as assessed by the National Institutes of Health, Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), 
corrected Version 2.1, July 2017. 
 Incidence of AEs causing IP discontinuation 
 Incidence of all-cause IP discontinuation or interruption 
 Number of participants hospitalized due to adverse events regardless of cause 
All adverse events will be listed by participant and will include:  
 Event description 
 Treatment group (active agent vs placebo) 
 Clinician's assessment of severity and relationship to upamostat 
 Outcome 
The number and percentage of participants with AEs will be summarized for each treatment 
group. Overall treatment group differences may be compared using Chi-square tests or Fisher’s 
exact tests. 
Serious AEs, TEAEs, and hypersensitivity reactions will also be summarized. The counts and 
proportion of participants experiencing these events will be reported for each treatment arm. 
Treatment groups may be compared by Chi-square tests or Fisher’s exact tests. 
Permanent discontinuations or interruptions of upamostat due to AEs will be listed. The count 
and proportion of discontinuations of the study drug due to AEs will be reported.  
Categorical safety measures including hospitalization will be summarized with counts and 
proportions of participants and may be compared by treatment using either a Chi-square test or a 
Fisher’s exact test. 

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C 13.5.1.4 
Exploratory 
Prevalence and titer of anti-SARS-CoV-2 IgM and IgG antibodies at baseline and at Week 8 will 
be determined, and the effect of presence and titer of anti-SARS-CoV-2 IgG at baseline on 
treatment outcome will be assessed.  
For participants receiving upamostat, targeted analysis of known host transmembrane protease 
polymorphisms will be described and compared to time to resolution of symptoms among key 
subgroups including by sex, race, and ethnicity. 
C 13.5.1.5 Sub-Group Analyses 
The primary analysis and each of the secondary analyses will be conducted in different patient 
subgroups of the mITT population for exploration of heterogeneity of treatment effect. The 
following patient subgroups will be analyzed: 
 Age (< 30, 30-50, >50 years old) 
 Sex  
 Race 
 Baseline symptom severity 
 SARS-CoV-2 vaccination status 
 Location (by continent) 
C 13.6 Interim Analysis Plan   
An interim analysis will be conducted when 50% (n=150) of participants have reached Day 28 of 
study. There are prospectively defined criteria for determining superiority of upamostat to its 
control arm or determining futility on upamostat to its control arm. The DSMB will evaluate 
safety and need to stop for safety concerns. The detailed rules for declaring superiority/futility 
are described in C 13.9 Sample Size Determination. Table 2 highlights the interim analysis plans 
for upamostat. 
Table 2 
Analysis Schedule and Actions Reviewed at Interim Analysis 
Analysis Point 
Test for Superiority 
Futility Analysis 
Safety Analysis 
75 randomized to 
upamostat 
completing Day 28 
post enrollment 
Cox Proportional hazards 
analysis for superiority on the 
primary outcome; Kim-Demets 
alpha-spending adjustment 
Futility triggered if 
predictive probability of 
superiority is less than 
5% 
DSMB review 
of safety for 
continued 
randomization 
150 randomized to 
upamostat 
completing Day 28 
post enrollment
Final analysis of superiority; 
Adjusted final nominal alpha 
 
 

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The interim analyses will be conducted by an unblinded and firewalled external DSMB. The 
DSMB will provide any recommendations based on the interim efficacy analysis triggers and 
additionally will review and make recommendations on safety at each interim analysis.  
The nominal alpha at the interim analysis will be calculated based on the exact sample size for 
the interim analysis using the Kim-Demets spending function. As an example, if there are exactly 
75 patients on the upamostat arm at the interim analysis then the nominal one-sided alpha at the 
interim would be 0.00625 with a final analysis nominal alpha of 0.02178.   
C 13.7 Final Analysis Plan 
Statistical analysis of this PSA will be the responsibility of the IND Sponsor. A statistical 
analysis plan (SAP) will be finalized prior to the interim analysis and will provide a detailed 
description of the statistical analyses described in this section. 
C 13.9 Sample Size Determination 
The maximum sample size for the upamostat arm primary analysis is 300 participants with 1:1 
allocation to the upamostat arm and its control arm. The maximum sample size of 300 
participants (150 active and 150 controls) and the adaptive design provides 90% power to detect 
a hazard ratio of 1.50 (a 33% reduction in median time to resolution) and approximately 80% 
power for a hazard ratio of 1.42 (a 30% reduction in the median time to resolution). 
Table 3 presents the likelihood of the trial determining superiority at the interim analysis (50%) 
and the final analysis for a range of assumed effect sizes for upamostat and a range of placebo 
median times to resolution. The expected median time to symptom resolution of 9 days for the 
control arm is based on review of relevant literature [Akaishi 2022, Akavian 2022, Zhang 2022]. 
The probabilities of determining futility at 50% is reported (5000 simulations pre scenario based 
operating characteristics in FACTS, 6.4).  Simulations use a log-rank test for calculations of 
power as an approximation to the Cox proportional hazards model.  

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Table 3 
Operating Characteristics for the Adaptive Design Including 
Superiority and Futility for a Range of Assumed Event (Symptomatic 
COVID-19) Rates for Upamostat Active Treatment and Upamostat 
Control Arm 
Control 
Median Time 
to Resolution
Upamostat 
Hazard Ratio
Cumulative Proportion Superiority for 
Upamostat 
Proportion Futility 
150 total 
300 total 
150 total 
12 days 
1
0.008
0.025
0.610
1.25
0.109
0.405
0.165
1.42
0.315
0.786
0.045
1.50
0.436
0.883
0.021
1.67
0.678
0.981
0.004
2
0.939
1.000
0.000
9 days 
1
0.008
0.026
0.612
1.25
0.122
0.434
0.153
1.42
0.340
0.812
0.035
1.50
0.464
0.906
0.018
1.67
0.709
0.986
0.003
2
0.953
1.000
0.000
6 days 
1
0.007
0.024
0.612
1.25
0.131
0.458
0.138
1.42
0.363
0.830
0.033
1.50
0.488
0.916
0.015
1.67
0.728
0.990
0.002
2
0.956
1.000
0.000

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APPENDIX C ABBREVIATIONS 
In addition to those listed in the Master Protocol 
 
aPTT 
Activated Partial Thromboplastin Time 
CDER 
Center for Drug Evaluation and Research 
ECG 
Electrocardiogram 
INR 
International Normalized Ratio 
ITT 
Intention to Treat 
IxRS 
Interactive Voice/Web Response System 
MERS-CoV 
Middle East respiratory syndrome-related coronavirus 
mITT 
Modified ITT 
NGS 
Next Generation Sequencing 
PTT 
Partial Thromboplastin Time 
TMPRSS2 
Transmembrane protease serine 2 
 
 
 

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APPENDIX C AMENDMENT HISTORY  
 
Version
Date
Description of Change
Brief Rationale
V 1.0
25 Mar 2022
N/A
Initial Protocol
V 2.0 
26 Apr 2023 1. Specified that this is a Phase 2 
study. 
2. Updated formatting and section  
numbering. 
3. Updated study objectives and 
endpoints. 
4. Updated study visits to clarify 
activities and procedures. 
5. Added new information about the 
effectiveness of upamostat against 
current SARS-CoV-2 variants and 
pharmacologic parameters. 
6. Updated hypotheses to look at 
sustained symptom alleviation or 
resolution. 
7. Added clinical adverse event rates 
and percentages and new 
information for the 200 mg and 
400 mg doses. 
8. Removed the exclusion criteria for 
requires supplemental oxygen. 
Added exclusion criteria for 
patients with prolonged QT/QTc 
interval and/or increased 
susceptibility to arrythmia with a 
list of defining criteria. 
9. Added a new section with 
information regarding potential 
drug interactions and prohibited 
medications. 
10. Specified that vaccination status 
will only be collected at baseline 
and Day 7 and that a 12 lead ECG 
will be performed. 
11. Added Polymorphisms of relevant 
host cellular proteases to 
additional testing requirements. 
12. Added specific screening 
assessments. 
13. Added sample collection and 
testing information for PK 
evaluation. 
14. Added and updated sections to 
outline pause and stopping criteria 
at the individual participant or 
1. Clarify study phase. 
2. Consistency with Master 
Protocol. 
3. Clarified for clear 
expectations. 
4. Clarified for clear 
expectations. 
5. Updated with current known 
information. 
6. Consistency with Master 
Protocol. 
7. Updated with new 
information. 
8. Updated based off current 
information. 
9. Updated with new 
information. 
10. Clarified for clear 
expectations.  
11. Clarified for clear 
expectations.  
12. Clarified for clear 
expectations.  
13. Clarified for clear 
expectations.  
14. Added per FDA 
recommendation. 
15. Updated with current 
information. 
16. Clarified for clear 
expectations.  
17. Consistency with Master 
Protocol. 
18. Clarify concomitant 
medications with potential 
drug interactions. 

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Version
Date
Description of Change
Brief Rationale
Study/PSA level. 
15. Updated the primary, secondary: 
virological, safety and tolerability, 
exploratory, and sub-group 
analysis outcome analysis 
information. 
16. Updated interim analysis criteria 
and added information for the 
DSMB. 
17. Added new section with sample 
size information. 
18. Added a list of CYP3A4 Strong 
inhibitors and sensitive substrates 
for reference.
V 3.0 
01 Jun 2023 
1. Pregnancy test added at D28 
visit. 
2. Race added as a sub-group for 
analysis.
1. Added per FDA 
recommendation. 
2. Added per FDA 
recommendation.
V 4.0 
01 Nov 2023 
1. Updated storage temperature 
range to be consistent with 
pharmacy manual. 
2. Changed bullets to numbering. 
3. Added clarification that overall 
symptom severity assessme879nt 
question on the Dailly Symptom 
Follow Up Questionnaire will be 
used for this endpoint. 
4. Added upamostat dose to 
Description of Study Intervention
5. Added study staff may remind 
participant of Day 3 dose and 
venous blood draw according to 
PK regimen assignment. 
6. Added reference to recently 
published upamostat pilot study. 
7. Clarified corrected QT 
requirement and calculation. 
Moved from Master Protocol to 
PSA 
8. Clarified "women of childbearing 
potential" definition. 
9. Removed FSH requirement. 
10. Removed one South Africa site. 
Added Uganda site
1. Updated for consistency. 
2. Data monitoring request 
3. DSMB recommendation 
4. DSMB recommendation 
5. Site feedback and 
recommendation 
6. Updated information 
7. Sites may apply different 
formulas or automated 
algorithms for recording 
the corrected QT interval. 
Clarified that same 
methodology for the 
calculation should be 
applied throughout the 
participant’s study 
participation. 
8. Clarification 
9. Removed as most 
international sites not able 
to meet this testing 
requirement. 
10. Updated site list 

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Version
Date
Description of Change
Brief Rationale
V 5.0 
26 Jan 2024 
1. Updated order of activities 
2. Added caution for alcohol 
consumption while taking study 
drug 
3. Added Table of Contents 
1. Updated to clarify that 
screening activities under 
the PSA (ECG) cannot be 
performed until product 
specific informed consent 
and Step 1 randomization 
completed 
2. FDA request 
3. Added table
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX C REFERENCES 
Akaishi T, Kushimoto S, Katori Y, et al. COVID-19-Related Symptoms during the SARS-CoV-2 
Omicron (B.1.1.529) Variant Surge in Japan. Tohoku J Exp Med. 2022. 
Akavian I, Nitzan I, Talmy T, Nitecki M, Gendler S, Besor O. SARS-CoV-2 Omicron Variant: 
Clinical Presentation and Occupational Implications in Young and Healthy IDF Soldiers. Mil 
Med. 2022. 
Plasse T et al. A randomized, placebo-controlled pilot study of upamostat, a host-
directed serine protease inhibitor, for outpatient treatment of COVID-19. Int J Infect 
Dis. 2023 Mar;128:148-156.  
US Food and Drug Administration. Drug Development and Drug Interactions. Table of 
Substrates, Inhibitors and Inducers. 2022  [cited 2023 Jan 5]; Available from: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers#table2-1. 
Yao Y, et al., Surface translocation of ACE2 and TMPRSS2 upon TLR4/7/8 activation 
is required for SARS-CoV-2 infection in circulating monocytes. Cell Discov, 2022. 
8(1): p. 89 
Zhang J, et al., Clinical Characteristics of COVID-19 Patients Infected by the Omicron 
Variant of SARS-CoV-2. Front Med (Lausanne), 2022. 9: p. 912367. 

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C Supplement 1. CYP3A4 Strong Inhibitors and Sensitive Substrates 
Strong Inhibitors 
Source: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers  
boceprevir 
nefazodone 
clarithromycin
nelfinavir 
cobicistat
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir)
danoprevir and ritonavir 
posaconazole 
elvitegravir and ritonavir 
ritonavir 
grapefruit juice 
saquinavir and ritonavir 
idelalisib 
telaprevir 
indinavir and ritonavir
telithromycin
itraconazole 
tipranavir and ritonavir 
ketoconazole 
troleandomycin 
lopinavir and ritonavir 
voriconazole
Sensitive Substrates 
Source: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers  
alfentanil 
everolimus 
midazolam 
avanafil   
felodipine 
naloxegol 
budesonide 
ibrutinib 
nisoldipine 
buspirone 
indinavir 
saquinavir 
conivaptan 
quetiapine 
simvastatin 
darifenacin 
sildenafil 
sirolimus 
darunavir 
ticagrelor 
tacrolimus 
dasatinib 
tolvaptan
tipranavir 
dronedarone 
lomitapide 
triazolam 
ebastine 
lovastatin 
vardenafil 
eletriptan
lurasidone
eplerenone
maraviroc