Clinical trial NCT04723537
Conditions: Covid19
Sponsor: RedHill Biopharma Limited
Start date: 2021-02-16; Completion date: 2021-12-28
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A 2-part, multicenter, Phase 2/3, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of upamostat in adult patients with COVID-19 disease who do not require inpatient care.

Detailed description:
Patients will be seen in a medical facility (ER or COVID-19 clinic) for initial evaluation. Consenting, diagnostically-confirmed COVID-19 patients not in need of hospitalization per investigator assessment and who meet all other inclusion and exclusion criteria will be randomized to treatment and provided with medication and home monitoring devices, and instructed in drug administration and use of the devices. They will take medication daily for two weeks, complete a smartphone-based questionnaire, provide additional monitoring information via devices provided periodically over an 8-week period. Patients will be seen at home by a study nurse or return to the clinic after 2, 4 and 8 weeks on study ("follow up" visits); additional televisits will also be conducted. At the follow up visits nasal swab specimens for COVID-19 PCR and blood specimens for safety labs and disease markers will be collected.

In part A of the study, patients will be randomized 1:1:1 to one of two doses of upamostat or placebo. Based on safety results of part A, a dose for part B will be selected, and patients will be randomized 3:2 to active vs placebo.

Arms: arm 1: Each day participants will receive a single 200 mg dose of upamostat along with a single matching placebo, for a total of 14 days. arm 2: Each day participants will receive two 200 mg doses of upamostat, for a total of 14 days. arm 3: Each day participants will receive two matching placebos, for a total of 14 days. arm 4: Based on dose selected from Part A, each day participants will receive EITHER a single 200 mg dose of upamostat OR two 200 mg doses of upamostat, for a total of 14 days. arm 5: Based on dose selected from Part A, each day participants will receive EITHER a single matching placebo OR two matching placebos, for a total of 14 days.
Interventions: intervention 1: Part A: Upamostat 200 mg intervention 2: Part A: Upamostat 400 mg intervention 3: Part A and B: Placebo intervention 4: Part B: Upamostat 200 or 400 mg
Intervention descriptions: intervention 1: 1 capsule comprising 200 mg of upamostat and 1 capsule comprising matching placebo. intervention 2: 2 capsules, each capsule comprising 200 mg of upamostat intervention 3: 1 or 2 capsules, each capsule a matching placebo intervention 4: Based on dose selection from Part A, "Part B Upamostat" will be EITHER a single 200 mg dose of upamostat OR two 200 mg doses of upamostat, for a total of 14 days.

Protocol documents:
Prot_000.pdf: 
Phase 2/3 Study of Upamostat, a Serine Protease 
Inhibitor, or Placebo for Treatment of COVID-19 Disease 
 
Protocol RHB-107-01 
 
NCT number 04723537 
 
Amendment 4:  15 June 2021 
 
 
 


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Phase 2/3 Study of Upamostat, a Serine Protease 
Inhibitor, or Placebo for Treatment of COVID-19 Disease 
 
Protocol RHB-107-01 
 
Sponsor: 
 
 
RedHill Biopharma Ltd. 
21 Ha’arba’a St. 
Tel-Aviv 64739, Israel 
Tel: +972 (0)3 541 3131 
Fax: +972 (0)3 541 3144 
EudraCT number                2021-002036-22 
 
Original Protocol Date: 
13 October 2020  
Current Protocol Version: Amendment 4:  15 June 2021 
Previous Versions:   
Amendment 3:    8 March 2021 
 
 
 
 
Amendment 2:    4 February 2021 
 
 
 
 
Amendment 1:    8 December 2020 
 
 
 
 
 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
The information in this document is confidential and is the property of RedHill 
Biopharma Ltd. It is understood that this information will not be disclosed to any 
third party, in any form, without prior written authorization from RedHill 
Biopharma, Ltd. 
 
 


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Table of Contents 
Table of Contents .................................................................................................. 3 
Approvals .............................................................................................................. 6 
Approvals .............................................................................................................. 7 
Protocol Synopsis ................................................................................................. 8 
Schedule of Evaluations ..................................................................................... 17 
List of Abbreviations ............................................................................................ 20 
1. 
Background and Rationale ....................................................................... 22 
1.1COVID-19 Disease ..................................................................................... 22 
1.2Upamostat .................................................................................................. 23 
1.3Study Rationale .......................................................................................... 24 
2. 
Objectives ................................................................................................ 26 
3. 
Study Population ...................................................................................... 28 
3.1Inclusion Criteria ......................................................................................... 28 
3.2Exclusion Criteria ....................................................................................... 28 
4. 
Study Design ............................................................................................ 29 
4.1Overview .................................................................................................... 29 
4.2Study Drug Administration .......................................................................... 31 
4.2.1 
Upamostat ......................................................................................... 31 
4.2.2 
Placebo ............................................................................................. 31 
4.2.3 
Dose modifications ............................................................................ 31 
4.3Randomization and Blinding ....................................................................... 32 
4.4Concomitant Therapy ................................................................................. 32 
4.5Duration and Discontinuation of Treatment ................................................ 33 
4.6Replacement of Patients ............................................................................ 33 
4.7Discontinuation of Study ............................................................................. 33 
4.8Data and Safety Monitoring Board ............................................................. 34 
5. 
Study Evaluations .................................................................................... 36 
5.1Schedule of Evaluations ............................................................................. 36 
5.2Description of Study Procedures ................................................................ 36 
5.3Unscheduled Visit ....................................................................................... 38 
6. 
Safety Reporting ...................................................................................... 39 
6.1Terminology ................................................................................................ 39 


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6.2Assessment of Causal Relationship ........................................................... 40 
6.3Adverse Event Grading and Coding ........................................................... 40 
6.4Handling of Serious Adverse Events .......................................................... 41 
6.5Laboratory Test Abnormalities .................................................................... 42 
6.6 
Other Safety Considerations ............................................................. 42 
7. 
Data Analysis and Statistical Considerations ........................................... 44 
7.1Sample Size Considerations ...................................................................... 44 
7.2Analysis Datasets ....................................................................................... 45 
7.3Study Population and Demographics ......................................................... 46 
7.4Efficacy Analyses ....................................................................................... 46 
7.4.1 
Analysis of the primary efficacy endpoints ........................................ 46 
7.4.2 
Analysis of the secondary efficacy endpoints .................................... 47 
7.4.3 
Type 1 error control ........................................................................... 48 
7.5Safety Analyses .......................................................................................... 48 
7.5.1 
Adverse Events ................................................................................. 49 
7.5.2 
Clinical Safety Laboratory Tests ....................................................... 49 
7.5.3 
Other Parameters ............................................................................. 49 
7.6Interim Analyses ......................................................................................... 49 
8. 
Study Medications .................................................................................... 51 
9. 
Investigator Responsibilities ..................................................................... 52 
9.1Compliance with Declaration of Helsinki and Good Clinical Practices ........ 52 
9.2  Institutional Review Board (IRB)/Ethics Committee (EC) Review and 
Approval .......................................................................................................... 52 
9.3  Informed Consent ..................................................................................... 52 
9.4  Confidentiality ........................................................................................... 52 
9.5  Source Documentation ............................................................................. 52 
9.6  Drug Accountability .................................................................................. 53 
9.7  Data Monitoring and Collection ................................................................ 53 
9.8  Case Report Forms, Investigator’s Study File and Record Retention ...... 53 
9.9  Non-Protocol Research ............................................................................ 53 
10. 
Sponsor Responsibilities .......................................................................... 54 
10.1  General................................................................................................... 54 
10.2  Case Report Forms ................................................................................ 54 


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10.3Data Monitoring and Collection ................................................................ 54 
10.4  Audit ....................................................................................................... 54 
10.5  Confidentiality ......................................................................................... 54 
11. 
Protocol Modifications .............................................................................. 55 
12. 
Publication ................................................................................................ 56 
13. 
References ............................................................................................... 57 
Appendices ......................................................................................................... 59 
Appendix 1. 
Nasal Mid-Turbinate (NMT) Specimen Collection .................. 59 
Appendix 2.  Patient diary ............................................................................... 61 
Appendix 3.  CYP3A4 Strong inhibitors and sensitive substrates.................... 67 
 
Table 1.  Study Procedures and Schedule of Events .......................................... 17 
Table 2.  Dose Modification Plan for Treatment-Related Toxicities..................... 31 
Table 3.  Dose Levels ......................................................................................... 32 
Table 4.  Relationship of Study Medication to Adverse Events ........................... 40 
 
 
 
 
 
 


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Approvals 
Sponsor Representatives 
 
 
 
 
 
 
 
 
 
 
___________________________ 
 
15 June 2021 
Reza Fathi, PhD 
 
 
 
 
Date 
Senior Vice President, Research and Development 
RedHill Biopharma Ltd. 
 
___________ 
 
15 June 2021 
Terry Plasse, MD 
 
 
 
 
Date 
Medical Monitor 
 


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Approvals 
The investigator agrees to conduct the trial as described in the protocol in 
accordance with all FDA regulations, and according to current ICH GCP. 
By agreement to this protocol, the investigator agrees to allow direct access to all 
essential documents, including source documents to authorized individuals 
representing the sponsor (including monitors, auditors and other personnel), to 
institutional review boards (IRBs) and to regulatory authorities. 
Principal Investigator: 
 
___________________________ 
 
____________ 
Name  
 
 
 
 
 
Date 
 
___________________________ 
Signature 
 
 
 


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Protocol Synopsis 
Title: Phase 2/3 Study of Upamostat, a Serine Protease Inhibitor, or Placebo for 
Treatment of COVID-19 Disease  
Study drugs: upamostat (RHB-107) 
Comparator: placebo  
Brief Summary: 
This is a 2-part, multicenter, Phase 2/3, randomized, double-blind, placebo-
controlled, parallel group study to evaluate the safety and efficacy of upamostat 
in adult patients with COVID-19 disease.  The primary objective at the end of part 
A, after 60 patients have completed the study (defined in Section 4.5), is dose 
selection.  An analysis of part A will be performed by a data safety monitoring 
board (DSMB) who will determine, based primarily on safety results, if the study 
should proceed to part B and, if so, which dose to proceed with.  For part B, the 
primary endpoint is time to sustained recovery from illness in the entire study 
population and the first secondary endpoint is incidence of hospitalization or 
death during the eight-week study period among the high risk patients. The target 
sample size in part B will be determined at the end of part A but will be at least 
250 patients.  An interim analysis for adjustment of criteria for high risk, early 
termination for futility or increase in sample size (to an additional 50% of the 
initially planned total) will be performed after approximately half  of the initially 
planned patient population has reached end of study;  the timing of the interim 
analysis may also be adjusted at the end of part A.   
Rationale: 
COVID-19 is a disease caused by a recently discovered coronavirus, designated 
SARS-CoV-2. It is highly contagious and generally causes fever and respiratory 
symptoms in symptomatic individuals; additional symptoms are gastrointestinal, 
cardiac, taste and smell abnormalities, and neurological.  The disease spectrum 
varies from asymptomatic infection through fatal pneumonia and multiorgan 
failure.  Males, older adults and individuals with significant comorbidities, 
including respiratory diseases, diabetes, obesity and cancer under treatment, are 
most severely affected. 
One medication, remdesivir, has shown efficacy in treatment of COVID-19 in 
hospitalized patients with severe illness;  several monoclonal antibody 
combinations have demonstrated preliminary evidence of efficacy in the 
outpatient setting as well. Based on CDC data (CDC, 2020), fewer than 10% of 
COVID-19 patients are hospitalized.  Therefore, an oral, room temperature 
stable, easily administered medication for treatment of COVID-19 is a major 
unmet medical need and can be used for both inpatients and outpatients. 
Upamostat, a serine protease inhibitor, is a potent inhibitor of trypsin and trypsin-
related enzymes.  
Several serine proteases, including TMPRSS isoenzymes, which are related to 
trypsin, are required for attachment of coronavirus particles to host cells.  In 


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addition, trypsin plays a role in tissue damage due to various types of pneumonia 
as well as gastrointestinal tract irritation, so inhibition of trypsin may decrease 
pulmonary damage and gastrointestinal symptomatology caused by infections of 
various etiologies.   
In vitro studies in two systems have demonstrated the activity of upamostat 
against SARS-CoV-2. Entry of vesicular stomatitis virus (VSV) transfected with 
SARS-CoV-2 S-protein in Calu-3 cells, which express TMPRSS2, was inhibited 
by upamostat.  An in vitro assessment in an organotypic air-liquid-interface (ALI) 
culture of human primary bronchial epithelial cells (HBEC; EpiAirway™, MatTek) 
evaluated whether infection and spread of SARS-CoV-2 could be inhibited by 
several agents.  Upamostat at concentrations below that which is 
pharmacologically achievable inhibited virus growth by several orders of 
magnitude, somewhat more than camostat, another serine protease inhibitor 
which has previously demonstrated in vitro activity against SARS-CoV-2 (data on 
file for both studies, RedHill Biopharma).  Thus, based on two in vitro studies, 
upamostat appears to be a potent inhibitor of SARS-CoV-2 at nontoxic levels. 
Enabling toxicology studies for nononcologic indications have been performed. 
Upamostat has been administered to 189 individuals, both healthy volunteers 
and cancer patients, with a very favorable safety profile. 
Many agents are being tested in hospitalized patients with SARS-CoV-2 
infection.  However relatively few studies are currently under way to treat 
symptomatic outpatients, although these patients constitute the majority of 
COVID-19 patients, infect others and may progress to pneumonia.   
This study will assess the activity of upamostat against placebo for treatment of 
COVID-19 patients who, in the investigator’s judgment, do not require 
hospitalization. 
Objectives: 
  Primary: 
Part A of the study:  determination of the safety and tolerability of two dose 
levels and selection of an upamostat dose for part B. 
Part B of the study:   
Primary objective: 
In the entire patient population:  comparison between upamostat and placebo in 
time to sustained recovery from symptomatic illness.  A patient will be 
considered to have recovered once he or she meets the following criteria: 
1) is afebrile (<38.0° C core temperature) for at least 48 hours without use of 
antipyretics; 
2) all symptoms have resolved or returned to pre-illness levels (e.g., if 
patient had respiratory compromise prior to the onset of COVID-19), 
except for: 


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a. fatigue, anosmia, ageusia or dysgeusia, which may be persistent at 
level similar to that during the acute illness, i.e., the same level per 
symptom questionnaire; 
b. chest pain, cough or dyspnea which if persistent must be at least one 
grade lower than at the start of treatment and no worse than grade 1 
(mild). 
Sustained recovery is recovery, per above definition, maintained for at least 14 or 
28 days, or through end of study, whichever comes first.  The period required to 
confirm sustained recovery, 14 versus 28 days, will be assessed in part A of the 
study and a decision reached as to which period to use for definition of sustained 
recovery in part B. 
Symptoms to be followed and their grading are given in Appendix 2, Patient 
Diary. 
  Secondary: 
Comparison between active treatment group and placebo of:  
1) Hospitalization or death from any cause by end of study, i.e, day 57. 
2) In part A and at the interim analysis in part B, assessment of the risk of 
hospitalization or death as a function of the presence, number and 
severity of concerning conditions will be undertaken.  This information 
may be used to develop a definition of very high risk for calculation of the 
incidence of hospitalization or death in the high risk/very high risk 
population in part B. 
3) Proportion of patients who are PCR-negative at days 8, 15, 29 and 57 
from the start of treatment (landmark analyses); 
4) Time to resolution of individual disease-related symptoms present at 
baseline; 
5) Development of new disease-related symptoms and/or pneumonia on 
study; 
6) Changes in laboratory markers of disease severity, i.e., oxygen 
saturation, CRP, lymphocyte count, cardiac troponin, ferritin and D-dimer 
levels, from baseline to time points at which these are measured on 
study; 
7) Adverse events. 
In addition to analysis within the entire study population, subgroup analyses for 
secondary endpoints 1, 3-6 will be performed in the high risk population. 
Analysis for secondary endpoint 1 will focus primarily on the high risk and very 
high risk subgroups. 


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Exploratory 
1) Percent of patients who report household contacts who have developed 
symptomatic, PCR- or antigen-confirmed COVID-19 by day 57; 
2) Levels of serum IgM and IgG antibodies to SARS-CoV-2 at 57days from 
the start of treatment. 
Population: 
  Inclusion criteria: 
1. Patients with symptomatic, diagnostically confirmed COVID-19, per RT-
PCR or antigen assay of respiratory tract sample. 
2. Patient must have either become symptomatic or found positive by RT-
PCR or antigen assay within 5 days, whichever is greater, of 
randomization. 
3. Patients must have at least two symptoms of at least moderate severity on 
initial questionnaire.  Fatigue, anosmia, ageusia or dysgeusia may not be 
counted among the symptoms of at least moderate severity qualifying the 
patient for entry. 
Note:  patients should NOT be informed prior to completion of the 
questionnaire that presence of at least 2 symptoms of at least moderate 
severity is a criterion for study entry. 
4. Males and females ≥age 18 years. 
5. Oxygen saturation by pulse oximeter ≥92% on room air. 
6. Negative urine or serum pregnancy test (if woman of childbearing 
potential). 
7. Females of childbearing potential and males with female partners of 
childbearing potential must agree to use acceptable contraceptive 
methods during the study and for at least two months after the last dose of 
study medication. 
8. Ability to complete the daily diary independently 
9. The patient must give informed consent.   
  Exclusion criteria: 
1. Patient is in need of acute hospitalization per clinician assessment. 
2. Pregnant or nursing women.   
3. Unwillingness or inability to comply with procedures required in this 
protocol. 
4. Patient requires supplemental oxygen. 


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5. Patient is currently receiving, has received within the past 7 days or is 
expected to receive during the course of the study remdesivir, or other 
specific antiviral or anticytokine therapy for COVID-19, other than 
therapeutic monoclonal antibodies allowed or approved in the region in 
which the patient lives, or systemic corticosteroid equivalent to ≥20 mg 
daily prednisone/3 mg dexamethasone daily. 
6. Patient is currently receiving or has received within 30 days prior to 
screening any other investigational agent for any indication, including 
approved agents given for investigational indications (e.g., anti-cytokine 
treatments). 
7. Patient is currently taking or is expected to start taking warfarin, apixabain 
(Eliquis), or rivaroxaban (Xarelto).  Patients may be taking or start on 
study dabigatran (Pradaxa), standard or low molecular weight heparin. 


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Design: 
This is a randomized, double-blind, placebo-controlled, parallel group study of 
upamostat compared to placebo in patients with symptomatic COVID-19 who do 
not require immediate treatment with specific approved (either fully approved or 
available under emergency use authorization) antiviral or anticytokine therapy, 
other than therapeutic monoclonal antibodies.  The study uses phase 2/3 
operationally seamless design methodology for dose selection (part A) and 
inferentially independent confirmatory phase 3 study (part B). The phase 3 
portion will include an interim analysis for revision of the high risk/very high risk 
subgroup definition, early termination for futility or increase in sample size, as 
indicated by initial results. 
Methodology: 
Part A:  After qualification for study, patients will be stratified by age, <65 or ≥65, 
and randomized to treatment as described below.  They will then be randomized 
1:1:1 to one of the following treatment groups: 
1. Upamostat 200 mg two capsules qd (n=20); 
2. Upamostat 200 mg one capsule and matching placebo one capsule qd 
(n=20) 
3. Placebo two capsules qd (n=20). 
In order to maintain blinding, patients will be given two bottles of medication and 
instructed to take one pill from each bottle each day. Both pills are to be taken at 
the same time. 
Medication should be taken with water and may be taken with or without food. 
Patients are to take medication for 14 days or until one of the following occurs: 
• Adverse events, whether related or unrelated to study medication which, 
in the judgement of the investigator, necessitate discontinuation of 
treatment; 
• The patient or investigator decides that it is in the patient’s best interest to 
stop treatment. 
An analysis will be performed by a data safety monitoring board (DSMB) after a 
total of 60 patients complete part A of the study.   
• If the DSMB determines that safety of both regimens is similar, accrual in 
part B will proceed with the 400 mg qd dose. 
• If safety is more favorable with the 200 mg qd regimen, accrual in part B 
will proceed with the 200 mg qd dose. 
The DSMB process is further defined in the body of the protocol and will be 
detailed in a separate DSMB charter.  While the DSMB will perform the 
evaluation at the end of part A independent of the Sponsor, the results will be 
provided when available in open label fashion to the Sponsor. 


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Part B:  Based on safety results from part A, either a 200 mg or 400 mg (i.e., one 
or two 200 mg capsules) treatment regimen will be selected.  Patients enrolled in 
part B will be stratified by  
• Presence of one or more high risk characteristics: 
o Age ≥65 
o Hypertension 
o Chronic lung disease (for example, chronic obstructive pulmonary 
disease, moderate-severe asthma, interstitial lung disease, cystic fibrosis 
and pulmonary hypertension)  
o Diabetes 
o Obesity (BMI≥30) 
o Cardiovascular disease (including congenital heart disease, coronary 
artery disease, history of thrombotic events, including stroke and transient 
ischemic attacks [TIA])  
o Chronic renal disease 
o Immunosuppressive disease or immunosuppressive treatment  
o Sickle cell disease  
o Neurodevelopmental disorders (for example, cerebral palsy) or other 
conditions that confer medical complexity (for example, genetic or 
metabolic syndromes and severe congenital anomalies)  
o Having a medical-related technological dependence (for example, 
tracheostomy, gastrostomy, or positive pressure ventilation (not related to 
COVID-19)) 
• Planned receipt of therapeutic monoclonal antibody treatment for COVID-19 
(whether or not patient has already received the antibody infusion); 
• Region in which they are treated; and  
• Whether or not the patient is at least 14 days after his or her last dose of 
COVID-19 vaccine 
They will then be randomized 3:2 to active drug or placebo at the schedule 
selected based on part A.  A total of at least 250 patients will be enrolled in part B 
of the study, at least 150 receiving active drug and at least 100 receiving 
placebo.  Thus, combining both parts of the study, at least 170 patients will 
receive active drug at the dose selected in part A and at least 120 will receive 
placebo.  However, analyses will be performed independently for parts A and B. 
Based on analyses of outcomes at the end of part A and an interim analysis 
during part B, the risk categories may be adjusted, and the requirements for 
enrollment may be modified, e.g., a certain percentage of patients may be 
required to have at least one risk factor and/or some specific combination or 
number of risk factors. 
Patients will complete questionnaires about symptoms, including adverse events, 
vital signs, including temperature and pulse oximetry, and a log of medications 
taken, according to the schedule in Table 1.  Viral swabs and bloods for safety 
laboratory and pharmacodynamic markers (where available) will be obtained at 
home or clinic visits by medical personnel per the schedule in Table 1. 


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After completion of treatment, patients will be followed through day 57 from the 
start of treatment. 
Study evaluations are shown in Table 1, below. 
Endpoints: 
  Efficacy: 
The primary objective of part A is to determine which treatment regimen to carry 
into part B, which will be based on safety rather than efficacy.  However, all 
parameters to be followed in part B will also be followed in part A.   Time to 
sustained recovery and the proportion of patients who are hospitalized or die will 
be calculated, although given the small sample size and expected variability of 
outcome, clinically meaningful differences are unlikely. 
The primary endpoint of part B of the study is, for all patients, time to sustained 
recovery from COVID-19 illness, as defined in the primary objective, above. 
The first secondary endpoint is hospitalization or death from any cause by end of 
study. Analysis of this endpoint will focus primarily on the high risk or very high 
risk subgroups. 
Additional secondary endpoints include:  
1) Proportion of patients with PCR-negative viral swabs at the times tested, 
i.e., days 8, 15, 29 and 57 from the start of treatment; 
2) Time to resolution of individual disease-related symptoms present at 
baseline; 
3) Development of new disease-related symptoms or pneumonia on study; 
4) Changes in laboratory markers of disease severity, e.g., oxygen 
saturation, CRP, lymphocyte count and D-dimer levels, from baseline to 
time points at which these are measured on study; 
Exploratory endpoints 
1) Percent of patients who have household contacts who have developed 
symptomatic, PCR-confirmed COVID-19 by day 57; 
2) Levels of anti-SARS-CoV-2 serum IgM and IgG at day 57. 
 
Safety: 
Patients will be followed for adverse events, including both clinical and laboratory 
events, throughout the course of the study. 
In particular, toxicities resulting in dose reductions or discontinuation of therapy 
will be followed and tabulated. 
Statistics: 
In part A of this study, two dose levels of active drug and placebo will be tested.  
Based on the incidence and severity of toxicities in each active group, overall 
assessment of safety by the DSMB, a regimen for part B of the study will be 
selected.  In the absence of marked differences in toxicity between the two active 


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groups, the default choice for continuation into part B will be the 400 mg daily 
regimen.  
Efficacy data from parts A and B will be analyzed separately. 
The part B sample size may be expanded and the definition of high risk revised 
based on interim study results.  At the end of part A, along with determination of 
the dose to take into part B and assessment of risk of various factors, RedHill will 
make a determination regarding whether to pursue the hospitalization/death 
endpoint, which is needed for consideration for EUA, or continue the study as 
originally planned, for consideration for NDA, should results warrant.  This 
decision will be based both on results of part A of the study and the clinical 
situation at that time. 
The sample size currently planned, 250 patients, was determined based on the 
primary endpoint, time to sustained recovery from COVID-19 illness, as defined 
in the primary objective. It was calculated that in order to detect an hazard 
ratio=1.5 comparing an active group to placebo group with 3:2 allocation ratio a 
total of 201 recovery events are required, to provide 80% power using a log-rank 
test at a two-sided significance level of 0.05. Assuming 80% sustained recovery 
rate by end of follow-up (assumed equal follow-up for all enrolled patients), the 
minimum number of patients enrolled in part B  to achieve the primary objective 
will be 250 in total, 150 in the active arm on the regimen taken into part B of the 
study and 100 in the placebo arm.  If a decision is made to power the study for 
the hospitalization/death endpoint, the protocol will be amended to include the 
sample size and the rationale for its determination. 
Further information on statistical considerations is provided in section 7 of this 
protocol and detailed in the statistical analysis plan (SAP). 


Schedule of Evaluations  
Table 1.  Study Procedures and Schedule of Events 
Activity 
BL 
Rx Week 1 
Rx Week 
2 
EOTa 
Follow-up 
EOSb 
Day/window 
 
1 
3+1 
8±2 
15±2 
22±4 
29±4 
43±4 
57±4 
Contactc 
F 
 
T 
H/F 
H/F 
T 
H/F 
T 
F 
Initial proceduresd 
X 
 
 
 
 
 
 
 
 
Physical examination inc VSe 
X 
 
 
X 
X 
 
X 
 
X 
Temperaturef 
 
Measure and record temperature three times daily until afebrile for 14 days, then 
once daily in the evening until afebrile for 28 days 
Pulse oximetryf 
X 
Twice daily through day 15 
Thrice weekly through 
day 29 
 
 
Weight 
X 
 
 
 
 
 
 
 
X 
Questionnaire and diary 
X 
Every evening days 2-28; days 1, 3, 5 weekly thereafterg 
ECGh 
X 
 
 
X 
X 
 
X 
 
 
Nasal mid-turbinate (NMT) swab for SAR-CoV-2 PCRi 
X 
 
 
X 
X 
 
X 
 
X 
CBC, biochem profilej, D-dimer, INR, PTT 
X 
 
 
X 
X 
 
X 
 
X 
CRP, D-dimer, troponin, ferritin 
X 
 
 
X 
X 
 
X 
 
X 
Serum IgG and IgM antibodies to SARS-CoV-2 
X 
 
 
 
 
 
 
C 
X 
Alpha-1-antitrypsin and G6PD testing 
 
 
 
 
 
 
 
Ck 
Xk 
Study medication 
 
<---------------------------------------------- 
 
 
 
 
Adverse eventsl 
 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationsl 
X 
 
X 
X 
X 
X 
X 
X 
X 


Abbreviations:  BL: Baseline; EOS:  end of study;  EOT:  end of treatment 
aEnd of treatment visit, regardless of actual study day. Should generally be day 15, the day AFTER 
last dose of study medication. 
bEnd of study visit:  generally day 57±4 from start of treatment, regardless of duration of treatment.  If 
patient discontinues study participation prior to then, end of study procedures should be carried out, if 
possible, at the time of discontinuation from study, even if earlier than day 53. 
cType of contact/location:  F:  in facility:  emergency department, clinic, COVID-19 special facility;  H:  
home visit;  H/F:  option for either home or facility visit; T:  televisit, either phone or video.  Note:  
additional televisits may be arranged as needed.  If patient returns to medical facility for outpatient 
visit, if possible, relevant procedures and tests should be performed at that time. 
At all clinic and home health visits, temperature, pulse, respiratory rate, blood pressure, pulse 
oximetry and ECG measurements will be performed.  Home health staff will obtain all vital signs 
independently of patient measurements, to verify that data are being collected accurately.   
dWithin 3 days prior to planned start of treatment:  initial procedures include signing informed consent, 
review of medical history, review of documentation of COVID-19 disease and source/exposure, if 
available, height (measured or per patient), pregnancy test for women of childbearing potential, as 
detailed in section 5.2.  When feasible, BL and day 1 procedures, i.e., start of treatment, should be 
completed on the same day. 
ePhysical examination:  physical examination of pertinent systems at baseline, then interim 
examinations on day 1 of week 2, within 72 h of discontinuation of study medication, study day 29 
and within last week of follow-up period.  Baseline physical is mandatory for study participation.  At 
each physical examination, a full set of vital signs (temperature, pulse, respiratory rate, blood 
pressure, and oxygen saturation) will be obtained by the examiner. If one or more on-study visits is 
not feasible, document in CRF. 
fThe patient will be provided with an electronic thermometer and instructed to measure and record 
temperature three times daily until afebrile (<38.0°C) for 14 days.  Temperature should be measured 
within an hour of getting up in the morning, between 4-7 pm and within an hour of bedtime each day.  
Additional temperature readings may be taken at patient initiative or at the instruction of the 
investigator.  
Oxygen saturation will be measured by patients twice daily for the first 2 weeks of study and then 
three times weekly for the next two weeks.  During the first two weeks of study, oxygen saturation 
should be measured within an hour of arising and within an hour of bedtime, in coordination with the 
morning and evening temperature readings.  After that, oxygen saturation should be measured in the 
evening, at the time of the evening temperature reading if temperature is still being measured or at 
the time the patient completes the symptom questionnaire.  Additional pulse oximetry readings may 
be performed at the request of the investigator. 
gWhen baseline day = day 1, the patient should not repeat the questionnaire in the evening that day. 
After day 28 of the study, if a patient does not complete the questionnaire on an assigned day (days 
1, 3 and 5 of each week), he or she should complete it during the usual timeframe, 7:00-11:59 pm, on 
the following day. 
hElectrocardiogram:  full 12-lead ECG at baseline visit.  At baseline visit and additional days noted, 6-
lead ECG is to be performed, either by clinic or home health staff. 
iSwab at baseline (confirmatory of pre-study test, if a prior swab obtained).  At baseline, a rapid PCR 
or antigen test for diagnosis will be performed on site (if PCR or antigen has not been obtained within 
5 days of planned start of treatment), and a quantitative PCR, the same as will be used on other 
study days, also taken and sent to the central laboratory. Then days 8, 15, 29 and 57.    Procedure 
shown in Appendix 1.  The baseline specimen will also be sequenced. 
iBiochemistry profile to include, at a minimum, albumin, alkaline phosphatase, ALT, AST, bilirubin 
(total). Bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, potassium, sodium, and total 
protein.  


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kTests for serum alpha-1-antitrypsin level and whole blood glucose-6-phosphate dehydrogenase 
(G6PD) deficiency, both to be taken at the day 57 visit only, are optional and will require a separate 
consent (C), which should be obtained at the day 43 telemedicine visit. 
lAdverse events and concomitant medications will be recorded by the patient or caregiver daily (first 4 
weeks) or d1, 3 and 5 each week (weeks 5-8) in their diary.  These will be reviewed at each home or 
clinic visit or televisit and entered by study staff in the appropriate eCRF forms. 


List of Abbreviations 
AE 
 
 
Adverse Event 
ALT 
 
 
Alanine Aminotransferase 
AST  
 
Aspartate Aminotransferase 
BL 
 
 
Baseline 
BUN  
 
Blood urea nitrogen 
COVID-19 
 
Coronavirus disease 2019 
CBC  
 
Complete Blood Count 
CC50  
 
Cytotoxic Concentration of 50% 
CDC  
 
United States Centers for Disease Control 
CMH  
 
Cochran-Mantel-Haenszel 
CRF  
 
Case Report Form 
CRP  
 
C-reactive protein 
CXR  
 
Chest X-ray 
DSMB  
 
Data Safety Monitoring Board 
EC 
 
 
Ethics Committee 
EC50  
 
50% Effective (Virus-Inhibitory) 
ECG   
 
Electrocardiogram 
EOS  
 
End of Study 
EOT  
 
End of Treatment 
FDA  
 
Food and Drug Administration 
GCP   
 
Good Clinical Practice 
G6PD  
 
Glucose 6-Phosphate Dehydrogenase 
HIPAA 
 
Health Insurance Portability and Accountability Act 
HR 
 
 
Hazard Ratio 
ICH 
International Council for Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IgG 
 
 
Immunoglobulin G 
IgM 
 
 
Immunoglobulin M 
INR 
 
 
International Normalized Ratio 
IRB 
 
 
Institutional Review Board 
Ki 
 
 
Inhibitory Constant 
LDH  
 
Lactate Dehydrogenase 
MedDRA 
 
Medical Dictionary for Regulatory Authorities 
mITT  
 
modified Intent-to-Treat 


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NDA  
 
New Drug Application 
PA 
 
 
Posterior Anterior 
PCR  
 
Polymerase Chain Reaction 
PP 
 
 
Per Protocol  
PTT 
 
 
Partial Thromboplastin Time 
QD 
 
 
Quaque Die (Latin), once a day 
RT-PCR 
 
Reverse Transcription Polymerase Chain Reaction 
S-Protein 
 
Spike Protein 
SAE  
 
Serious Adverse Event 
SAP  
 
Statistical Analysis Plan 
SARA-Cov-19 
Severe Acute Respiratory Syndrome Coronavirus 2 
SGOT  
 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT  
 
Serum Glutamic-Pyruvic Transaminase 
SUSAR 
 
suspected unexpected serious adverse reaction 
TMPRSS 
 
Transmembrane protease, serine  
TMPRSS2 
 
Transmembrane protease, serine 2 
ubSSR 
 
Unblinded Comparative Size Re-Estimation 
ULN  
 
Upper Limit of Normal 
VSV  
 
vesicular stomatitis virus 
WHO  
 
World Health Organization 


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1. 
Background and Rationale 
1.1 
COVID-19 Disease 
COVID-19 is a disease caused by a coronavirus, SARS-CoV-2.  The disease was first 
noted in December 2019, in Wuhan, China, and subsequently attributed to a virus 
similar to the SARS coronavirus and now designated SARS-CoV-2.  The clinical 
spectrum of SAR-CoV-2 infection ranges from asymptomatic infection to fatal 
pneumonia and multiorgan failure (Zhou et al, 2020).  Many organ systems, including 
prominently gastrointestinal and neurological, as well as cardiorespiratory, may be 
affected.  Infected individuals may be infectious for one to three days before onset of 
symptoms;  up to half of new cases may be transmitted during that asymptomatic period 
(Gandhi et al, 2020).  Common symptoms, with their incidence on presentation in the 
191 patients in the initially reported severe Wuhan cohort were fever (94%), cough 
(79%), sputum production and fatigue (each 23%) and myalgia (15%).  Bilateral 
pulmonary infiltrates were noted in 75% of patients on chest X-ray.  In many patients, 
the illness is quite mild, with only a mild sore throat or upper respiratory tract symptoms, 
without fever.  
In a large series from China, 81% of patients diagnosed with COVID-19 disease had 
mild cases (Wu and McGoogan, 2020).  Over the past year, information on milder 
COVID-19 disease has been obtained (Ghandi et al, 2020;  Han et al, 2020).  Han and 
colleagues noted in particular that a large group of patients with mild COVID-19 disease 
has only gastrointestinal symptoms or a combination of gastrointestinal and mild 
pulmonary symptoms.  Thus, the majority of patients have mild disease, and the 
spectrum of abnormalities appears to be different from that of severe COVID-19.  Data 
from the Centers for Disease Control (CDC) show that as of mid-September, 2020, the 
overall incidence of confirmed or probable SARS-CoV-2 infection was approximately 
2,000 per 100,000 population in the US;  the overall incidence of hospitalization was 
170 per 100,000.  Thus, the hospitalization rate is under 10% of all confirmed and 
probable cases, i.e., the vast majority of COVID-19 patients are not hospitalized (CDC 
COVID Data Tracker). 
People over age 65 and those with significant comorbidities, such as diabetes, obesity, 
or pulmonary disease, are more susceptible to severe infection, require hospitalization 
and have a higher mortality rate than do younger, otherwise healthy individuals.  Men 
have an approximately 60% higher hospitalization or death rate than women 
(Williamson et al, 2020;  van Gerwen et al, 2021) 
For most people, the disease is self-limited.  Many patients with relatively mild-moderate 
symptoms have now been diagnosed based on PCR as having SARS-CoV-2 infection.  
The majority of patients with COVID-19 symptoms are told to self-isolate, rest, and take 
symptomatic medications.  But a major danger of the disease is spread through a 
generally nonimmune population, with infection of those who are at risk of severe 
infection. SARS-CoV-2 is highly contagious, with spread by aerosol and surface contact 
(van Doremalen et al, 2020) and potentially through stool (Wang et al, 2020).  As the 
disease was first noted about a year and a half ago and testing and interpretation of 
data take some time, the clinical picture is still evolving.  To date, no oral medication 
has demonstrated efficacy against SARS-CoV-2 infection of any severity.  Monoclonal 
antibody combinations directed against the virus have shown preliminary evidence of 
efficacy in outpatient studies.  However, certain SARS-CoV-2 strains have 
demonstrated resistance to some of the antibodies.  In addition, these antibodies are 


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not available in many areas and, when available, are not always well accepted by 
patients.  Thus, an effective, low toxicity oral medication will fulfill a major unmet 
medical need. 
1.2 
Upamostat 
Upamostat, WX-671, is an orally bioavailable prodrug of WX-UK1, a serine protease 
inhibitor which inhibits several proteases in families which are involved in cleavage of 
the S-protein of coronaviruses.  Cleavage of viral S-protein is important for viral binding 
and subsequent entry into host cells (Abe et al, 2013;  Bertram et al, 2011; Zmora et al, 
2018).  In particular, WX-UK1 inhibits trypsin isoenzymes with Ki’s of 19-190 nM, and 
several other related enzymes with Ki’s under 1 µM (Oldenburg et al, 2018).  In addition, 
trypsin and other enzymes are upregulated in inflammatory lung conditions (Tsujimura 
et al, 2005;  Yamada et al, 2006).  Inhibiting these serine proteases may, in addition to a 
direct antiviral effect, also decrease tissue damage from the virus. 
Two in vitro studies have demonstrated that upamostat inhibits SARS-CoV-2 infection 
(data on file, RedHill Biopharma, Ltd).   
Upamostat inhibited entry of vesicular stomatitis virus transduced with the SARS-CoV-2 
spike protein (VSVpp+SARS-2-S Δ18).  When tested against VSVpp+SARS-2-S Δ18 in 
Calu3 cells, which have surface TMPRSS2, upamostat showed moderate inhibitory 
activity, though somewhat less than camostat, another serine protease inhibitor.  
Interestingly, when tested in Vero76 cells, which do not express surface TMPRSS2, 
moderate activity was still noted;  camostat was inactive in this situation. Upamostat 
also had similar activity in native VSV infecting Calu3 cells as they did against S-protein 
transfected VSV.  Again, in this setting camostat was inactive.  All three compounds 
were inactive against native VSV infection in Vero76 cells.  These results demonstrate 
activity and suggest that the activity may not be due solely to TMPRSS2. Due to the 
nature of the model, specific extrapolation to actual in vitro or in vivo inhibitory 
concentrations is not possible. 
Upamostat was studied in a tissue culture model of primary human bronchial epithelial 
cells (HBEC; EpiAirway™ , MatTek).  Camostat was included for comparison and 
remdesivir was included as a positive control (Pruijssers et al., 2020)..  A 3-log 
reduction in TCID50 was noted at the lowest concentration of upamostat tested, 0.12 
µg/mL, rising to 4.5-log reduction at 1 µg/mL.  Cytopathic effects were noted only at 30 
µg/mL.  At equal concentrations, the virus inhibitory effect of upamostat was somewhat 
greater than that of camostat, while the cytopathic effects were similar for both 
compounds. 
Upamostat has been studied in 40 healthy volunteers and 152 cancer patients in phase 
1 and phase 2 studies.  Once daily dosing with 200 or 400 mg daily upamostat resulted 
in WX-UK1 tissue levels ≥0.6 µM (0.4 µg/gm tissue) in most patients and ≥1.0 µM (0.67 
µg/gm tissue) in 6 of 10 patients studied (Meyer et al, 2008).  Several-fold higher levels 
of WX-UK1 were found in stool after single doses of upamostat, which may be important 
given the possible fecal excretion of the virus. The drug was very well tolerated as a 
single agent and in combination with cytotoxic agents.  In a multidose phase 1 study in 
healthy volunteers, upamostat caused some increases in transaminases, but not to a 
level to be considered problematic per Hy’s law, nor were there changes in bilirubin.  In 
addition, there was no dose-response relationship.  In randomized phase 2 studies in 
cancer patients, in which all patients received a standard agent (either capecitabine or 


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gemcitabine) in combination with upamostat or control/placebo, there was no 
transaminase safety signal.  Grade 3 or 4 anemia was more common at the 400 mg 
daily dose of upamostat than in patients receiving 200 mg daily or in the control groups.  
Other than that, there was no safety signal in the adverse event profiles in the phase 2 
studies.  Interestingly, in the breast cancer study, but not in the pancreatic cancer study, 
the incidence of grade 3 or 4 vascular events was 10% lower in patients receiving 
upamostat than in those receiving placebo. 
1.3 
Study Rationale 
Upamostat will be studied for treatment of patients with symptomatic, PCR- or antigen-
confirmed COVID-19. Several findings support the use of upamostat for treatment of 
COVID-19: 
• Analysis of the structure of TMPRSS2 as compared to proteases tested for 
sensitivity to WX-UK1 suggests that the compound would have a Ki against 
TMPRSS2 in the high nanomolar to low micromolar range (J Jensen, personal 
communication);   
• In vitro data in two experimental systems demonstrate that upamostat inhibits 
SARS-CoV-2 at noncytotoxic concentrations, concentrations well below that which 
are achievable clinically; 
• The potent trypsin inhibitory effect of upamostat may decrease pulmonary tissue 
damage and gastrointestinal symptomatology due to infection; 
• Decrease in circulating D-dimer by upamostat, demonstrated in experimental 
systems, may indicate a systematic anticoagulant effect, which may decrease the 
incidence or severity of thrombotic events in COVID-19 patients. 
The primary endpoint of this study is time to sustained recovery from acute COVID-19 
disease for all patients.  For high-risk patients, the first secondary endpoint is 
hospitalization or death.   In addition, patients will be followed using multiple additional 
clinical and laboratory assessments over time.  Viral shedding is a secondary endpoint.  
This is of importance in itself, as continuation of viral shedding increases the risk of 
spread of disease and impacts quality of life as the patient must spend longer in 
isolation.  Decreasing the duration of viral shedding will safely allow patients to resume 
normal activities earlier than otherwise possible. 
Because a) no oral therapy has demonstrated efficacy in treatment of COVID-19, and b) 
the existing treatments approved for outpatient use under EUA are antibody 
combinations indicated only for high risk patients and which require availability of facility 
for infusion therapy, use of a placebo comparator appears justified in the outpatient 
population in areas in which the antibodies are not available.  In addition, many patients 
opt not to receive antibody infusions despite their availability.  Therefore, patients in part 
B of the study will be stratified and outcomes will be analyzed according to antibody 
use. Two thirds of patients entered in part A of the study will receive active drug, and in 
part B, 60% will receive active drug.  Randomization 3:2 in part B will provide an 
incentive for participation in the study:  patients will have a 50% greater probability of 
receiving active drug than placebo.  This also provides a larger sample size for 
evaluation of safety than a 1:1 randomization.  Yet the shift from 1:1 to 3:2 
randomization increases the overall sample size by less than 10%. 
In part A of the study, upamostat will be administered at a dose of either 200 or 400 mg 
daily.  While both dose levels have been tolerated well in oncology studies, it appears 


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prudent to test two dose levels in this new population.  If both are tolerated similarly, the 
higher dose will be used in part B of the study.  If there are differences in tolerability, 
absent clinically significant differences in efficacy, the lower dose will be used in part B. 
As an early indication of pharmacologic activity, six parameters found to be associated 
with severity and outcome of COVID-19 disease will be assessed at multiple time points 
during the study:  oxygen saturation, C-reactive protein, lymphocyte counts, D-dimer, 
troponin and ferritin levels.  The primarily pharmacodynamic parameters, CRP, troponin 
and ferritin, will be followed only in territories in which they are readily available through 
a central lab which can standardize the results across sites.  Those analytes which are 
also safety parameters, oxygen saturation, D-dimer and lymphocyte counts, will be 
followed in all patients. 
Under this amendment, the study procedures have been modified taking into account 
experience with the first patients entered into the study, as well as reasons patients 
have declined to participate.  To date, symptoms have resolved in one to under three 
weeks.  Patients have been resistant to the heavy monitoring and questioning in the 
original protocol, resulting in reluctance to participate in the study, withdrawal of several 
patients and poor compliance with study procedures.  In order to enhance acceptability, 
accrual and compliance with the protocol, the duration of intensive vital sign monitoring 
is being reduced.  In addition, the definition of sustained recovery is modified to take 
into account the patient compliance issue and experience to date with those patients 
who have recovered.  If a substantial proportion of patients withdraws prior to the end of 
study because they feel better and the burden of study procedures is excessive, their 
efficacy results will be censored and those patients will be declared nonresponders. 
Temperature will be followed through 28 days after resolution of fever, if the patient is 
febrile, but with lower frequency from day 15 onward after resolution of fever. 
Hospitalization or death has been moved to become the first secondary endpoint.  FDA 
views this endpoint as that for which potential emergency use authorization is justified.   
 


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2. 
Objectives 
Primary  
Part A of the study:  determination of the safety and tolerability of two dose levels and 
selection of an upamostat dose for part B. Part B of the study:   
Primary objective:  in the entire patient population, comparison between upamostat and 
placebo in time to sustained recovery from symptomatic illness in all patients.  A patient 
will be considered to have recovered once he or she meets the following criteria: 
1) is afebrile (<38.0° C core temperature) for at least 48 hours without use of 
antipyretics; 
2) all symptoms have resolved or returned to pre-illness levels (e.g., if patient had 
respiratory compromise prior to the onset of COVID-19), except for: 
i. 
fatigue, anosmia, ageusia or dysgeusia, which may be persistent at a 
level similar to that during the acute illness, i.e., the same level per 
symptom questionnaire; 
ii. 
chest pain, cough or dyspnea, which if persistent must be at least one 
grade lower than at the start of treatment and no worse than grade 1 
(mild). 
Sustained recovery is recovery, per above definition, maintained for at least 14 or 28 
days, or through end of study, whichever comes first. The period required to confirm 
sustained recovery, 14 versus 28 days, will be assessed in part A of the study and a 
decision reached as to which period to use for definition of sustained recovery in part B. 
Symptoms to be followed and their grading are given in Appendix 2, Patient Diary. 
Secondary: 
Comparison between active and placebo of:  
1) Hospitalization or death from any cause by end of study, i.e, day 57.  The definition 
of high risk may be adjusted after part A and at the interim analysis in part B based 
on the incidence of hospitalization or death found in patients initially entered in the 
placebo group. 
2) In part A and at the interim analysis in part B, assessment of the risk of 
hospitalization or death as a function of the presence, number and severity of 
concerning conditions will be undertaken.  This information may be used to develop 
a definition of very high risk for calculation of the incidence of hospitalization or 
death in part B. 
3) Proportion of patients who are PCR-negative at days 8, 15, 29 and 57 from the start 
of treatment (landmark analyses)  
4) Time to resolution of individual disease-related symptoms present at baseline; 
5) Development of new disease-related symptoms and/or pneumonia on study; 
6) Changes in laboratory markers of disease severity, i.e., oxygen saturation, CRP, 
lymphocyte count, cardiac troponin, and D-dimer levels, from baseline to time points 
at which these are measured on study; 
7) Adverse events. 
 


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In addition to analysis within the entire study population, subgroup analyses for 
secondary endpoints 1, 3-6 will be performed in the high risk population.  Analysis for 
secondary endpoint 1 will focus primarily on the high risk and very high risk subgroups. 
 
Exploratory  
 
1) Percent of patients who have household contacts who have developed 
symptomatic, PCR or antigen-confirmed COVID-19 by day 57; 
2) Levels of serum IgM and IgG antibodies to SARS-CoV-2 at 57 days from the 
start of treatment. 


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3. 
Study Population 
A total of approximately 310-435 patients will be entered in this study. 
3.1 
Inclusion Criteria 
1. Patients with symptomatic, diagnostically confirmed COVID-19, per RT-PCR or 
antigen assay of respiratory tract sample. 
2. Patient must have either become symptomatic or found positive by RT-PCR or 
antigen assay within 5 days, whichever is greater, of randomization. 
3. Patients must have at least two symptoms of at least moderate severity on initial 
questionnaire.  Fatigue, anosmia, ageusia or dysgeusia may not be counted 
among the symptoms of at least moderate severity qualifying the patient for 
entry, 
Note:  patients should NOT be informed prior to completion of the questionnaire that 
presence of at least 2 symptoms of moderate severity is a criterion for study entry. 
4. Males and females ≥age 18 years. 
5. Oxygen saturation by pulse oximeter ≥92% on room air. 
6. Negative urine or serum pregnancy test (if woman of childbearing potential). 
7. Females of childbearing potential and males with female partners of childbearing 
potential must agree to use acceptable contraceptive methods during the study 
and for at least two months after the last dose of study medication. 
8. The patient must be able to complete the diary independently at baseline. 
9. The patient give informed consent based on an IRB-approved consent form. 
3.2 
Exclusion Criteria 
1. Patient is in need of acute hospitalization per clinician assessment. 
2. Pregnant or nursing women.   
3. Unwillingness or inability to comply with procedures required in this protocol. 
4. Patient requires supplemental oxygen. 
5. Patient is currently receiving, has received within the past 7 days or is expected 
to receive during the course of the study remdesivir, or other specific antiviral or 
anticytokine therapy for COVID-19, other than therapeutic monoclonal antibodies 
allowed or approved in the region in which the patient lives, or systemic 
corticosteroid equivalent to ≥20 mg daily prednisone/3 mg dexamethasone daily. 
6. Patient is currently receiving or has received within 30 days prior to screening 
any other investigational agent for any indication, including approved agents 
given for investigational indications (e.g., anti-cytokine treatments). 
7. 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. 


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4. 
Study Design 
4.1 
Overview 
This is a randomized, parallel-group double blind study of upamostat compared to 
placebo in patients with symptomatic COVID-19 who do not require immediate 
treatment with specific antiviral or anticytokine therapy.  The study uses phase 2/3 
operationally seamless design methodology for dose selection in phase 2 (part A) and 
inferentially independent confirmatory phase 3 study (part B). The phase 3 portion will 
include interim analysis for early termination for futility or increase in sample size, as 
indicated by initial results. 
In both parts of the study, patients who have a positive PCR or rapid antigen test for 
SARS-CoV-2 and meet inclusion and exclusion criteria will be stratified by age (≥65 vs 
<65 years). In part B, they will also be stratified based on presence of one or more 
concerning medical conditions and the additional factors shown below and then 
randomized to treatment with upamostat or placebo, according to randomization ratios 
specified below.  Concerning medical conditions are the following: 
• Age ≥65 years on date of randomization 
• Hypertension 
• Chronic lung disease (for example, chronic obstructive pulmonary disease, 
moderate-severe asthma, interstitial lung disease, cystic fibrosis and pulmonary 
hypertension) Diabetes 
• Obesity (BMI≥30) 
• Cardiovascular disease (including congenital heart disease, coronary artery 
disease, history of thrombotic events, including stroke and transient ischemic 
attacks [TIA])  
• Chronic renal disease 
• Immunosuppressive disease or immunosuppressive treatment  
• Sickle cell disease  
• Neurodevelopmental disorders (for example, cerebral palsy) or other conditions 
that confer medical complexity (for example, genetic or metabolic syndromes and 
severe congenital anomalies)  
• Having a medical-related technological dependence (for example, tracheostomy, 
gastrostomy, or positive pressure ventilation (not related to COVID-19)) 
All patients who live in regions in which one or more therapeutic monoclonal antibody 
combinations for outpatient treatment of COVID-19 are available will either be offered 
antibody, if provided at that facility, or given information as to where they can receive 
the antibodies. The patient may decide whether or not to take the antibody combination;  
receipt or refusal of antibody therapy will not affect the patient’s participation in this trial.  
If used, the antibody may be administered before or after the patient starts study 
medication.  However, the patient may not start study medication more than 5 days after 
onset of symptoms or receipt of laboratory diagnosis of COVID-19, whichever is longer. 
In part B, patients will be stratified based on  
1. The presence of none versus one or more of the above factors, 
2. Planned receipt vs nonreceipt of therapeutic monoclonal antibodies for 
COVID-19, 
3. Region in which patient is treated, 


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4. Whether the patient is at least 14 days after his or her last dose of COVID-19 
vaccine, 
and randomized to treatment as described below.   
Initially in part B, the proportion of patients in the low risk group, i.e., with no concerning 
conditions, will be limited to 30%.  This number and the definition of high risk, in terms 
of number and types of risk factors, may be revised at the time of the part A analysis 
and, in order to enroll a very high risk cohort, again at the interim analysis in part B. 
Part A 
Initially, a total of 60 patients will be randomized to one of three treatment groups, as 
follows: 
1. Upamostat 200 mg two capsules qd (n=20); 
2. Upamostat 200 mg one capsule and matching placebo one capsule qd (n=20) 
3. Placebo two capsules qd (n=20). 
In order to maintain blinding, patients will be given two bottles of medication and 
instructed to take one pill from each bottle each day. Both pills are to be taken at the 
same time. 
Part B  
After all part A subjects complete the study, further randomization into the study will be 
held until the part B dose regimen is selected and the high risk or very high risk 
population is further defined. Analysis of part A will be performed by a data and safety 
monitoring board (DSMB).  Assuming that there are no substantive negative safety 
signals to continuing with at least one dose level, a decision will be made regarding 
continuing with the current design and sample size or increasing the number of patients 
in part B to enable detection of a significant improvement in the incidence of 
hospitalization or death in the upamostat group as compared to placebo. 
If the decision is to continue as originally planned, an additional total of 250 patients, will 
be treated with the dose selected in part A or placebo.   If the decision is to power for 
detection of a significant effect on hospitalization or death, the sample size will be 
increased in accordance with the power calculations to be performed at that time. 
The DSMB decision-making process is further defined in section 4.7 of the protocol, 
below, and will be detailed in a separate DSMB charter.  As the results of part A will not 
be combined with those of part B, the analyses may be shared with the sponsor and 
study team. 
Based on results from part A, a dose for part B, either 200 mg (one capsule) or 400 mg 
(two capsules) daily will be selected.  Patients will then be randomized 3:2 to active 
drug or placebo at the schedule selected based on part A. If the study is powered for 
the symptom resolution endpoint, part B will have an event-driven design, requiring total 
of 201 endpoint-events (details in Section 7.1) The target sample size for this part is 250 
patients, 150 receiving active drug and 100 receiving placebo.  An interim analysis for 
early termination for futility or increase in sample size (up to maximum total 375), as 
indicated by comparative interim results will be performed after 50% of the primary 
endpoint recovery events are realized (details in section 4.8 and section 7.6). This 
interim analysis is estimated to occur when about 50% (125) of part B subjects have 
been enrolled and treated.   


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If the study is repowered to demonstrate a significant reduction in hospitalization or 
death, the timing of the part B interim analysis may be revised.  At the interim analysis, 
the incidence of hospitalization or death as a function of presence of concerning 
conditions will be assessed and the stratification or covariate weighting for the final 
analysis may be modified based on this analysis.  In addition, the sample size may be 
increased by 50% depending on results of the interim analysis. 
4.2 
Study Drug Administration  
4.2.1 Upamostat 
Upamostat will be administered as one or two 200 mg capsules once daily for 14 days, 
preferably at approximately the same time each day.  Medication should be 
administered with water and may be administered with or without food. 
4.2.2 Placebo 
Placebo will be administered as described above. 
4.2.3 Dose modifications 
Toxicity is an adverse event judged by the investigator to be possibly, probably or 
definitely related to study medication.  All grade 1 toxicities and adverse events and 
tolerable unrelated grade 2 adverse events can be treated according to standard clinical 
practice guidelines, without dose modification.  
See Table 2 for the Dose Modification Plan for patients experiencing ≥grade 2 toxicities. 
Table 2.  Dose Modification Plan for Treatment-Related Toxicities 
 
NCI CTC 5.0 Criteria 
Dose Modification Instructions 
Symptomatic toxicity (e.g., nausea, 
vomiting or diarrhea) or laboratory 
abnormalities (e.g, hypokalemia) 
≥grade 3 which can be reduced to 
≤grade 1 within 48 h with standard 
supportive measures 
No dose modification. 
Any intolerable grade 2 toxicity  
The investigator should consult the study sponsor 
regarding grade 2 toxicities that are considered 
intolerable by the patient or physician.   A dose 
reduction may occur with prior consultation with and 
approval by the study sponsor. 
Any toxicity ≥grade 3 other than the 
above   
Hold study drug.  
Assess patient at least every 3 days.  
If the toxicity improves to ≤ baseline within a week, 
restart study drug and reduce dose by one dose level 
(Table 3).  
If toxicity does not improve to ≤ baseline within one 
week, discontinue study drug.   
Omitted doses are not made up. 


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Patients may undergo two step-wise dose reductions, as shown in Table 3.  Only 
two dose reductions are allowed.  If the patient still has significant toxicity, as 
described in Table 2, after two dose reductions, treatment is to be stopped. 
Table 3.  Dose Levels 
Dose Level 
 
 
Starting dose 
1 cap daily  
2 caps qd 
Reduction 1 
1 cap q2 days 
1 cap qd 
Reduction 2 
Discontinue 
1 cap q2 days 
In part A of the study, patients may get two bottles of capsules with the same drug 
(active or placebo) or one bottle of each, active and placebo.  In order to dose reduce in 
that situation, the patient will be told to take one capsule from alternate bottles on 
alternate days, stopping at day 15, regardless of how many capsules are left.  
Generally, one capsule should remain at the end of the study, unless a capsule was 
accidentally damaged or lost. 
4.3 
Randomization and Blinding 
In part A of the study, patients will be stratified by age, <65 or ≥65, and randomized.   
In part B, they will be stratified by multiple factors, as described in section 4.1, above,  
and then randomized as described above.  Patients will be randomized using a 
centralized, automated randomization system, which will assign a blinded treatment kit 
to each patient.   
In part A, randomization will be done in a 1:1:1 ratio among each dose level and 
placebo with all patients receiving a kit that comprises 2 bottles of medication (active or 
placebo) and will be instructed to take one pill daily from each.  In part B, patients will be 
randomized 3:2 to active versus placebo.  They will receive one bottle of study 
medication.  Depending on whether the dose for part B is 200 or 400 mg daily, patient 
will be instructed to take either one or two capsules daily. 
4.4 
Concomitant Therapy 
All medications taken during the following periods are to be recorded in the case 
report form:   
• For 28 days prior to the signing of consent; 
• While the patient is on study medication and for 42 days thereafter. 
Patients should not take other antiviral treatments, other than monoclonal antibody 
infusions allowed under either EUA, NDA or similar mechanisms in countries 
outside the US, or any investigational agent for any indication while participating in 
the study. 
Patients may take other medications as necessary for concomitant conditions or 
for treatment of study therapy adverse effects.  In addition, patients whose 
condition worsens substantially at any time during the course of the study may 
receive treatment for COVID-19 per current local standard of care, including 
specific antiviral and anticytokine therapy. 


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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 Appendix 3 of the 
protocol.  These lists are based on the FDA website table: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-
drug-interactions-table-substrates-inhibitors-and-inducers#table2-1 
In particular, patients should 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. 
If several patients require symptomatic treatment of presumed upamostat-related 
toxicity, subsequent patients may receive prophylactic treatment.  If clinically 
necessary, routine use of prophylactic medications may be discussed with the 
sponsor. 
4.5 
Duration and Discontinuation of Treatment 
Treatment will continue for 14 days or  
a) the patient or physician decides that it is not in the patient’s best interest to 
continue, due to either deteriorating clinical condition or adverse event, whether 
or not due to study medication.  
b) the patient decides for any reason to discontinue therapy and/or withdraw from 
the study. 
If the patient is still virus positive at 14 days, treatment will be stopped, but follow-up will 
continue for 42 days.  The patient will still be included in analysis for recovery and all 
other study endpoints.  All patients will be followed through day 57 from the start of 
treatment, regardless of the duration of treatment. 
4.6 
Replacement of Patients 
Patients who are randomized but not treated will be replaced.  Replacement patients 
will be given new randomization assignments; they will not receive the assignment of 
the replaced patient.   
Patients who receive any study medication but discontinue with or without subsequent 
collection of data will not be replaced. 
4.7 
Discontinuation of Study 
All serious adverse events and grade 4 or 5 adverse events will be reviewed by the 
sponsor and the DSMB on an ongoing basis.  Treatment will be unblinded to the DSMB 
for all grade 5 adverse events regardless of putative causation, and the DSMB may 
recommend to the Sponsor unblinding treatment of additional patients reviewed.  The 
DSMB may request unblinding for grade 4 adverse events if, in their judgment, they 
may be related to study medication and the toxicity poses a risk to subsequent patients. 


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Based on review of serious, grade 4, and grade 5 adverse events, the DSMB may at 
any point in the study recommend termination or revision of the study if they feel that 
toxicity poses a risk to subsequent patients. 
4.8 
Data and Safety Monitoring Board 
A data and safety monitoring board (DSMB) will be convened for oversight of the study.  
A DSMB charter will be written as a separate document.   
Preliminary review:  The DSMB will be informed by the Sponsor on an ongoing basis of 
each patient whose study medication dose is reduced or discontinued due to toxicity.  
DSMB members may request an early review of all patients if warranted by the type, 
severity or frequency of toxicities resulting in dose reduction or drug discontinuation. 
Initial full review:  The DSMB will review data after the 60 patients have completed 
treatment (part A), with regard to the following: 
a) Adverse events requiring dose modification or discontinuation of treatment 
overall and those considered at least possibly related to study medication; 
b) Serious adverse events deemed at least possibly related to study medication; 
c) Serious adverse events of any cause;  
d) Exacerbation of COVID-19 disease, including hospitalization or death; 
e) Effect of treatment on oxygen saturation, C-reactive protein, lymphocyte count 
and D-dimer (pharmacodynamic markers); 
f) Additional efficacy parameters available at that time, including time to sustained 
recovery 
g) Correlations between comorbidities and hospitalization or death. 
A statistically significant difference in any of these parameters is unlikely with a limited 
early data set.  However, the DSMB in conjunction with the sponsor will determine using 
their clinical judgement if, based on the safety profile of the two active arms, the 
tolerability is substantially lower at 400 mg as compared to 200 mg daily. 
 
A. If the DSMB determines that safety of both dose levels is similar, accrual in part B 
will proceed with the 400 mg daily schedule. 
B. If safety is more favorable with the 200 mg daily regimen, accrual in part B will 
proceed with the 200 mg daily schedule. 
Efficacy will be analyzed in part A but, unless there is a marked difference between the 
two active dose levels, will not be used to decide on dosing in part B.  Similarly, 
pharmacodynamic parameters will be analyzed but not used to decide on dosing. 
At the end of part A, incidence of hospitalization or death will be analyzed as a function 
of the presence of one or more concerning conditions.  The definition of high risk for 
purposes of the hospitalization/mortality endpoint in part B may be adjusted based on 
findings in part A. 
Interim analysis in part B:  If the study proceeds as originally powered, the DSMB will 
again be convened after approximately half the required information on the primary 
endpoint has been observed, i.e., 101 recovery events out of a total planned 201 
events. 
The DSMB will review the same parameters as were reviewed at the first meeting and 
also the primary efficacy endpoint. 


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The DSMB will make a recommendation to continue to the planned target number of 
events, stop the study for futility, or enlarge the study if efficacy results fall in the 
predefined promising zone.   
Classifica-
tion of 
primary 
endpoint 
result at 
interim 
Description 
DSMB 
recommendation 
Comment 
Futility 
zone 
Results indicate definite futility 
if the study proceeds to the 
planned size 
Stop the trial 
Statistical 
futility rule is 
not binding. 
Unfavor-
able zone 
Results do not meet the futility 
criteria above; however result is 
still disappointing 
Continue the study to 
planned end 
As long as 
tolerability is 
reasonable 
Promising 
zone 
Result show a trend toward 
clinical benefit, but initially 
planned sample size does not 
provide enough power to 
demonstrate statistical 
superiority.  
Increase study size up 
to 50% larger than 
planned. 
Favorable 
zone 
Interim results sufficiently 
favorable that the trial 
continues to the planned end 
without the need to increase 
the trial size 
Continue the study to 
planned end 
 
Early stopping for superior efficacy is not planned. 
If the study is repowered for the hospitalization or death endpoint, the timing of the part 
B interim analysis may be revised.  The definition of high risk for purposes of the 
hospitalization/mortality endpoint may again be adjusted based on the part B interim 
analysis in order to achieve an expected 15% or greater incidence of hospitalization or 
death among the high risk or very high risk control group.  Other assessments will be 
conducted as shown in the table above, focusing on the hospitalization or death 
endpoint. 
 


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5. 
Study Evaluations 
5.1 
Schedule of Evaluations 
Study procedures are shown in Table 1, after the synopsis, and further described in the 
notes to that table on the following page.  
Patients are to be screened and started on treatment within 5 days of onset of 
symptoms or demonstration of positive PCR or rapid antigen test, whichever is longer.   
5.2 
Description of Study Procedures 
Most study procedures are standard clinical and clinical laboratory procedures.   
SARS-CoV-2 Testing 
Two baseline SARS-CoV-2 tests will be obtained at the start of the study: a test 
performed locally to determine eligibility, and an RT-PCR test run in a central laboratory 
and which allows quantification.   
If the patient has a positive result from a PCR or antigen test performed within 5 days of 
the planned start of treatment (not just screening day if treatment is to start a day or 
more after screening), a repeat PCR/antigen assay need not be performed.  The results 
must be on an official laboratory report, not word of mouth or doctor’s note.  A copy of 
the outside PCR report must be retained by the site as a source document. 
If at screening, the patient has not had a positive PCR or antigen test, a rapid test (PCR 
or antigen) may be performed at the site to determine eligibility.  After consent, a 
second specimen must be taken for shipment to a central laboratory for quantitative 
PCR and sequencing. 
Once a patient has qualified for the study (positive local test for COVID-19 PCR or 
antigen, determined by the questionnaire to have sufficient symptomatology, and the 
patient meets all other inclusion/exclusion criteria), the patient is randomized to 
treatment and the telemetry devices set up.   
• Optimally, the screening, randomization and set-up of devices will all occur the same 
day in the clinic or ER.   
• If all procedures cannot be completed the same day, medication can be provided 
and devices set up the following day, either by visit of study personnel to the 
patient’s home or a return visit by the patient to the facility. 
In the event of discrepant results between the rapid PCR/antigen test and standard 
PCR, results of the rapid PCR/antigen test will determine eligibility, i.e., a patient will not 
be declared ineligible if the central laboratory PCR is subsequently found to be 
negative. 
Instructions for obtaining and handling samples for SARS-CoV-2 PCR testing are found 
in Appendix 1 of the protocol. 
Study Medication 
Study medication will usually be provided to the patient on the initial day of evaluation.  
In a situation where final eligibility is not determined prior to the patient’s leaving the 
clinic or on the first day of hospitalization, study medication may be provided after the 
baseline visit, either by the home health staff member who will be seeing the patient or 
at a return visit to the facility. 


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Therapeutic monoclonal antibody combinations 
In regions in which these are available, they will either be administered at the 
investigative site or patients will be informed as to where they can receive the 
antibodies.  Use of the antibodies will be discussed with each patient in regions in which 
they are available.  It is the patient’s decision whether or not to receive the antibody 
combination. 
Other Tests and Procedures 
Patients will complete a smartphone-based diary at baseline and daily from day 2 (the 
second treatment day) through day 28 and days 1, 3 and 5 each subsequent week 
during the study.  This will collect symptom information, adverse events, and study and 
concomitant medication administration.  A patient who is unable to enter the diary data 
independently at baseline should not be enrolled in this study.  If, however, the patient 
becomes physically unable to complete the diary during the course of the study, he or 
she may dictate responses to a caregiver or other companion; that the caregiver is 
completing the diary should be noted. If the patient is unable to respond to the 
questions during the course of the study, that should be so noted.  A caregiver or 
companion should not complete the diary using assumed responses.  The patient will 
be deemed not to have recovered on any day when he or she is unable to provide 
responses to the diary questions.  If difficulties in use of the smartphone-based diary 
system occur, paper forms may be substituted for individual patients or in regions in 
which the smartphone-based system does not function properly. 
If the baseline diary is completed on treatment day 1, rather than prior to treatment day 
1, the patient should not complete the diary again that evening.  The information to be 
collected is shown in Appendix 2. 
At the baseline visit, patients will receive a kit which contains devices for remote patient 
monitoring.  The kit includes: 
• Electronic thermometer  
• Pulse oximeter 
• 6-lead ECG   
The ECG device may be kept by the site personnel or by the patient, depending on 
convenience and logistics at each site. 
All devices are FDA-cleared (i.e., approved via 510K pathway). 
Patients and caregivers will be trained on use of all devices at their baseline visit  and 
will be given additional documentation at the time of the baseline visit.   
In addition, home health or clinic staff will obtain all vital signs independently of patient 
measurements, to verify that data are being collected accurately.  ECGs are scheduled 
only for days when home health or clinic visits occur, and will be conducted by medical 
personnel, not by the patient. 
Home visits will be conducted on days 8, 15 (or end of treatment if prior to day 15), and 
29 of the study.  Alternatively, at the mutual convenience of study staff and patients, one 
or more of the visits for days 8, 15 and 29 may be conducted in the facility.  Televisits, 
either audio or audio and video, will be conducted on days 3, 22 and 43.  On day 3, in 
addition to collecting general information about the patient’s condition, use of the 
devices provided will be reviewed.  


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At the day 57 clinic visit, consenting patients will undergo testing for serum alpha-1-
antitrypsin level and whole blood glucose-6-phosphate dehydrogenase (G6PD) 
deficiency.  Consent may be obtained by the investigator either at the day 43 televisit or 
the day 57 clinic visit. 
This is a multinational study.  In some locations, performance of certain pharmacology 
and other specialty tests, e.g., troponin and ferritin levels may not be feasible due to 
logistic constraints. In addition, obtaining multiple consents for genetic testing (alpha-1-
antitrypsin, G6PD) may be problematic and their performance logistically difficult.  
Accordingly, these tests may not be obtained in all regions. 
Visit windows, in relation to day 1 (first treatment day): 
Day 3:  every attempt should be made to conduct the visit on that day.  If 
impossible due to communication or logistic issues, it may be conducted up to 
one day later, i.e., on day 4. 
Days 8 and 15:  ±2 days 
Days 22, 29, 43 and 57: ±4 days 
5.3 
Unscheduled Visit 
If, in the Investigator’s opinion, a patient should be seen outside of the proposed visit 
schedule, then an unscheduled visit may be performed.  Additional eCRFs will be 
provided to accommodate such visits.  Venue of and activities at these visits will depend 
upon the investigator’s concerns. The investigator will record the reason(s) for the 
unscheduled visit as well as the information gathered at that visit. 
 


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6. 
Safety Reporting 
All subjects will be assessed regularly for potential adverse events (AEs) occurring from 
the time the subject receives the first dose of study medication, through study day 57.  . 
6.1 
Terminology 
An Adverse Event (AE) is defined as any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related.  An AE (may also 
be referred to as an adverse experience) can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal (investigational or marketed) 
product, whether or not considered related to the medicinal (investigational or marketed) 
product and from any route of administration, formulation, or dose, including an 
overdose. Worsening of baseline signs, symptoms or concomitant illnesses are also 
considered adverse events. 
Exacerbation of COVID-19-related signs and symptoms are considered lack of efficacy, 
rather than adverse events.  All signs and symptoms will be followed, but will be 
analyzed as part of the efficacy rather than safety analyses. 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose 
results in any of the following outcomes:   
death;  
is a life-threatening adverse event (defined as 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); 
requires in-patient hospitalization or causes prolongation of existing hospitalization; 
a persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
a congenital anomaly/birth defect; 
is an important medical event.  This is defined as a medical event that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the other serious outcomes 
listed in the definition above.  Examples of such events include, but are not limited 
to, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization. 
If either the sponsor or investigator believes that the event is serious, the event must be 
considered serious and be evaluated by the Sponsor for expedited reporting. 
A suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. 
A suspected adverse reaction is considered unexpected if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed.    


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6.2 
Assessment of Causal Relationship 
The following categories and definitions for assessing the causal relationship of an 
event to the investigational product(s) are provided as a guide for evaluating adverse 
events reported in this study to determine “suspected adverse reactions” that require 
expedited reported to regulatory agencies if they are unexpected, i.e., SUSARs, 
suspected unexpected serious adverse reactions.  In addition to the assessment below, 
the aggregate number of occurrences will be considered to decide whether the event is 
a reportable event and requires an IND safety report. 
Table 4.  Relationship of Study Medication to Adverse Events 
Unrelated 
The study drug almost certainly (or certainly) did not cause the event.  Guidelines: 
There is no reasonable temporal relationship of the event to the administration of drug; 
The pattern is inconsistent with that known for the drug; and/or 
There is another obvious etiology. 
Probably 
not 
related 
It is more likely that the event is due to another etiology than due to the study drug.  
Guidelines: 
There is no reasonable temporal relationship of the event to the administration of drug; 
The pattern is inconsistent with that known for the drug; and/or 
There is another more likely etiology. 
Possibly 
related 
It is approximately equally likely that the event is due to the study drug as it is due to another 
etiology.  Guidelines: 
There is a reasonable temporal relationship of the event to the study drug; 
The drug seems as likely as other etiologies to have caused the effect 
Probably 
related 
It is more likely that the event is due to the study drug than due to another etiology.  
Guidelines: 
There is a reasonable temporal relationship of the event to the study drug; 
The event may be consistent with a known pattern of drug (or drug class) effects; 
The drug seems more likely than other etiologies to cause the effect; 
The adverse event diminished upon cessation of study drug exposure or reduction in 
dose; and/or 
The adverse event worsened or recurred upon unintentional re-exposure to the study drug 
(Intentional rechallenge for the purpose of assigning causality should not be performed.) 
Definitely 
related 
The evidence is compelling that the study drug caused the adverse event.  Guidelines: 
There is a reasonable temporal relationship of the event to the study drug; 
The event is consistent with a known pattern of drug (or drug class) effects; 
The drug is far more likely than other etiologies to have caused the effect; 
The adverse event diminished upon cessation of study drug exposure or reduction in 
dose; 
The adverse event worsened or recurred upon unintentional re-exposure to the study drug 
(Intentional rechallenge for the purpose of assigning causality should not be performed.) 
Unknown 
The data are inadequate to assign any of the above causal relationship categories to the 
study drug. 
 
6.3 
Adverse Event Grading and Coding 
AEs will be coded, grouped and tabulated by MedDRA preferred terms by body system 
organ class.  The MedDRA version current at study initiation will be used for the entire 
study. 


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Adverse events will be graded according to US National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE] v5.0. The following are the 
general criteria for severity grading: 
Grade                Description 
1 
 
Mild 
2 
 
Moderate   
3                   Severe   
4                   Life-threatening or disabling  
5                 Fatal  
The NCI CTCAE v5.0 can be downloaded in pdf format at:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_8.5x11.pdf 
6.4 
Handling of Serious Adverse Events 
Adverse events classified as serious must be recorded on the AE page of the CRF and 
require expeditious handling and reporting to the sponsor to comply with regulatory 
requirements.  These SAEs will include deaths, regardless of their causal relationship to 
investigational product.  All SAEs must be reported using the Serious Adverse Event 
Report form.  To the extent possible, the descriptive terminologies and other SAE 
attributes entered on the SAE report form should approximate similar information in the 
CRF.  The completed SAE report form with supporting documentation must be provided 
to the sponsor within 24 hours of the study site personnel’s initial notification/awareness 
of the event.  All telephone communication regarding SAE must be followed by a written 
report.  Duly authorized study site personnel may sign completed SAE report forms; 
however, it is recommended that the investigator sign each final SAE report. 
Collection of complete information concerning SAEs is extremely important.  Thus, 
follow-up information that becomes available as the SAE evolves, as well as supporting 
documentation (e.g. hospital discharge summaries, additional lab and test results, 
autopsy reports, etc.), should be collected subsequently, if not available at the time of 
the initial report, and immediately sent to sponsor using the same procedure as the 
initial SAE report. Information on the SAE must be in sufficient detail to allow for a 
complete medical assessment of the case and independent determination of causality. 
For ease of analysis, worldwide standardization, and regulatory reporting, the sponsor 
will code each reported adverse event or symptom to its corresponding preferred term 
and body system/organ class in the MedDRA dictionary version adopted for the study. 
The principal investigator will be responsible for assessing severity based on the 
intensity of the event as it presented using the criteria listed in section 6.3, above. 
All SAE reports must be sent to the study medical monitor and the sponsor’s 
regulatory/clinical affairs contact: 


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Medical Monitor:   
 
 
 
Terry Plasse, MD 
 
 
 
 
 
 
Mobile phone:  +972-50-588-7376 or  
   +1-917-913-7315 
 
 
 
 
 
 
e-mail:  terry@redhillbio.com 
 
Pharmacovigilance officer:   
 
Sanan Smith 
Email: sasmith@fhiclinical.com 
Phone: + 1 919 544 7040 x1234 
Additional pharmacovigilance contacts 
will be provided for ex-US sites 
As required, all investigators will be notified of all AE reports that are determined to be 
serious, unexpected, and related (by the reporting investigator or sponsor) to the 
investigational product.  The notification will be in the form of a Safety Update (Dear 
Doctor Letter). 
The notification is considered an addendum to the current Investigator’s Brochure; 
therefore, upon receiving such notices, the investigator must review and immediately 
submit a copy to the IRB according to local regulations.  The notification must be 
retained within the Investigator’s Brochure.  The investigator and IRB will determine if 
the informed consent requires revision. 
6.5 
Laboratory Test Abnormalities 
All new abnormal laboratory findings and those abnormal at baseline which change 
significantly (i.e., by at least one toxicity grade as defined in the National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v5.0) are 
considered AEs.  Laboratory AEs for which there is no clinical intervention will be 
recorded only on the laboratory data pages of the eCRF.  Laboratory AEs not listed in 
the NCI CTCAE v5.0 will be considered as grade 1 (mild) if there is no clinical effect or 
intervention.  Laboratory values outside the normal range for certain parameters will not 
be considered AEs if they are generally not considered as indicating an abnormality; 
this includes such parameters as liver enzymes which are below the normal range.  If 
there is a clinical sequela or intervention, the laboratory abnormality is to be graded 
according to the criteria used for clinical AEs, described above. 
The NCI CTCAE v5.0 can be downloaded in pdf format at:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_8.5x11.pdf 
6.6 
Other Safety Considerations 
Patients will be followed for a total of 8 weeks from the start of study medication.  After 
the enrolment visit until the end of study visit, direct contacts between study personnel 
and patients may be entirely by home and televisits.  Alternatively, at the mutual 
convenience of patients and study staff, one or more of the interim visits may be held at 
the investigative site  In some instances, in particular for significant exacerbations of 
disease or adverse events regardless of relationship to study medication, the patient will 
come to the medical facility for an in-person assessment.   
All AEs must be recorded and followed until resolution or for at least 28 days after 
discontinuation of study medication, whichever comes first. 


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Any clinically significant changes noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded on the AE page 
of the CRF. 


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7. 
Data Analysis and Statistical Considerations 
This section of the protocol describes the statistical analysis as it is foreseen at the time 
of planning the study. A fully detailed Statistical Analysis Plan (SAP) will be produced 
and finalized after finalizing the protocol and before breaking the blind of the study for 
interim analysis. 
The SAP will be reviewed after analysis of data from part A.  Modifications may be 
made to the analyses planned for part B based on that review.  The revisions will be 
finalized before reaching the interim analysis point for part B. 
7.1 
Sample Size Considerations 
Part A 
In the first part of this study, two different dose levels of upamostat will be tested; 
randomization will be 1:1:1 to the two upamostat dose levels and placebo.  
The objective of this part is to evaluate the tolerability of two dosing levels of upamostat 
in order to select the dose level that will be evaluated in the confirmatory Part B of the 
study.  
The sample size for part A, consisting of 20 subjects per each arm (placebo, upamostat 
200 mg qd, upamostat 400 mg qd) was not chosen for statistical power consideration, 
as there are no formal statistical inferences planned. The size of this part is judged 
adequate for the tolerability assessment. 
Part B 
After accrual to the first part of the study is completed and a determination as to which 
active arm to continue into the next part of the study is made, accrual will continue at a 
3:2 ratio, active:placebo.  A minimum total of 250 patients will be accrued to part B, 150 
to the active arm using the regimen selected in part A of the study and 100 to placebo. 
The sample size currently shown for part B was determined based on the primary 
endpoint, time to sustained recovery from COVID-19 illness, as defined in the primary 
objective. It was calculated that in order to detect a hazard ratio for sustained 
recovery=1.5 comparing the active group to placebo group with 3:2 allocation ratio, a 
total of 201 recovery events are required, to provide 80% power using a log-rank test at 
a two-sided significance level of 0.05. Assuming 80% sustained recovery rate in the 
control arm by end of follow-up (assumed equal follow-up of 57 days for all enrolled 
patients), it was calculated that in order to achieve the required number of events, the 
minimum number of patients enrolled will be 250 in total. As this study is defined as an 
operationally seamless phase 2/3 study, subjects from the part A of the study will not be 
combined with those in part B for the efficacy analysis. Therefore the target enrollment 
for part B is the total number of required subjects, namely 250 subjects in total, 150 and 
100 for the active and placebo groups, respectively. 
The target number of events for this event-based part B portion is 201, taking into 
account a non-binding futility analysis that will be performed when 50% of the 
information (primary events) have been realized.  
Sample size re-assessment 
In light of the limited information currently regarding time to sustained recovery and 
incidence of hospitalization or death expected in the control arm, and /or to address the 


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possibility that the magnitude of upamostat effect may be smaller than the relatively 
large target effect size but is still trending in the right direction and is big enough to be of 
clinical relevance, sample size re-assessment will be performed. 
The sample size of 250 subjects was predicted to be sufficient to provide the required 
total 201 ‘recovery’ events (assuming 80% sustained recovery rate by study day 57, in 
the control arm). The study design plan for part B is to continue recruitment until there 
are at least 201 subjects with a “recovered” status, if more than 250 subjects are 
needed for this.  
If part A results suggest that the initial assumptions above should be altered, an 
updated target number of events and/or number of subjects will be predefined for part 
B. 
In part B, sample size re-estimation, the results of which will be unblinded only to the 
DSMB, will take place when about 50% of target primary endpoint recovery or 
hospitalization or death events have been realized, to allow increasing the target event 
size by 50% (that is to a maximum of 301), thus requiring an associated increase of the 
sample by 50% (that is to a maximum of 375 subjects), only in the case that interim 
results falls within a “promising zone”, as strictly defined in Chen et al, 2004, and Mehta 
and Pocock, 2011. Using this approach, a valid (using the conventional statistic for the 
final analysis, and the type-1 error not inflated) increase in sample size following an 
unblinded comparative look is allowed when the observed interim treatment effect, 
although smaller than hoped for, is still trending in the right direction and is of clinical 
relevance.  
To safeguard study integrity, the pre-specified rules will be documented separately, in 
the DSMB charter.  
 
If at the end of part A, the study is repowered to achieve statistical significance for the 
hospitalization or death endpoint, the incidence of this endpoint in the treatment groups 
in part A as well as literature data will be considered in determining the sample size for 
part B. This will take into account not only overall results of part A but also results in 
patients who are defined as high risk.  It is understood that these calculations are based 
on a very small database, which may prove to be very imprecise.   
If part B of the study is repowered, the timing of the interim analysis may be adjusted.  
At the interim analysis, the incidence of hospitalization or death in the high risk group, 
defined as patients with one or more of the concerning conditions listed in Section 4.1, 
may be modified.  A higher risk group may be defined in order to establish an adequate 
incidence level of hospitalization or death in a well-defined subgroup to ensure the study 
is adequately powered for the analysis of this endpoint in a meaningful patient 
population. This may result in a revised sample size and limiting or redefining 
recruitment in the different subgroups. Sample size reassessment for the primary 
endpoint will only be conducted if the revised sample size is lower than the maximum 
sample size proposed for the primary endpoint as above. 
7.2 
Analysis Datasets 
The primary and most secondary efficacy analyses will be performed on the modified 
intent to treat (mITT) population, defined as all randomized patients who receive any 
treatment.  A per protocol (PP) analysis will be performed on patients with no major 
protocol violations and who receive at least one week of study medication or the reason 


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for stopping medication is worsening COVID-19 or development of AEs.  In these 
analyses patients will be analyzed according to their randomized treatment.  Analysis 
for the first secondary endpoint, hospitalization or death, will be performed primarily on 
a subset of the mITT population, the high risk or very high risk subset to be defined at 
the end of part A and redefined at the interim analysis of part B. 
Formal efficacy analyses will be performed using part B enrolled subjects, the efficacy 
data from part A subjects will be descriptively summarized separately. 
Safety analyses will be performed on all patients who receive any study medication in 
parts A and B combined, according to the treatment actually received. 
7.3 
Study Population and Demographics 
Demographic and pretreatment patient characteristics, including disease parameters 
and comorbidities, will be summarized with appropriate descriptive statistics, by study 
part, overall and by treatment group.  The descriptive statistics will include sample size, 
mean, standard deviation, median, minimum, and maximum for continuous variables 
and number and percentages for discrete variables. 
7.4 
Efficacy Analyses 
7.4.1 Analysis of the primary efficacy endpoints 
The primary endpoint of the study is time to sustained recovery from COVID-19 illness, 
as defined in section 2 of the protocol.  The first secondary endpoint , incidence of 
hospitalization or death, will primarily be assessed in the high risk or very high risk 
population.   
Time to sustained recovery is the number of days from first dose of study medication 
until the day on which patient is recovered and remains recovered for at least 14 days 
or until end of study, whichever comes first. The definition of “sustained” may be 
modified, as noted above, at the end of part A. First date of recovery will be defined as 
the latest time among the events below: 
1) Start date of the period during which the patient is afebrile for at least 48 hours 
without use of antipyretics; 
2) First date when all symptoms have resolved or returned to pre-illness levels (e.g., 
if patient had baseline respiratory compromise), except for  
a. fatigue, anosmia, ageusia or dysgeusia, which may be persistent at levels 
similar to the acute illness, or  
b. dyspnea, cough or chest pain, which, if persistent, must be at least one 
grade lower than baseline and no worse than grade 1 (mild). 
Time will include the first day of study medication and the day on which patient is 
declared to have recovered.   
Patients who have reached day 57 from the start of treatment but have not recovered 
will be censored at day 57. In addition, several situations override the above definition of 
recovery: 
• Patients lost to follow-up during treatment or follow-up (before recovering) will be 
censored at day 57.  


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• Patients who recover per the definition above but are subsequently hospitalized for 
any reason and are in hospital at day 57 will be censored at day 57. 
• Patients who die before recovery will be censored at day 57, the end of follow-up, 
reflecting the most unfavorable possible outcome for this endpoint.   
Calculation of time to sustained recovery requires completion of the symptom diary.  If 
a patient is hospitalized, he or she will be considered as not recovered on those days, 
regardless of the reason for hospitalization.  
Supportive analysis will be performed to include recovery from viral shedding in the 
definition of recovered event. In this analysis time to recovery will be the latest between 
the two events above and time of first negative nose viral swab.  
The comparison of the time to sustained recovery between active and placebo groups 
will be performed using stratified log-rank test, at 5% significance level. The stratification 
factors used for randomization will be used. Kaplan-Meier plots of time to sustained 
recovery will be provided along with median estimates and hazard ratio (HR) will be 
estimated along with 95% confidence interval using stratified Cox regression model. 
Estimates of cumulative incidence of sustained recovery at certain time points (for 
example days 15, 29, 43 or 57) for each group, along with 95% confidence interval will 
be tabulated.  
More details on statistical analyses of the primary endpoint and sensitivity analyses will 
be provided in the SAP.  These will address the following aspects:  
• Using the PP population and ITT population 
• To account for the possibility of errors in values of stratification factors used for 
randomization, the primary analysis will supportively be repeated using the 
correct values. 
• Comparison between the treatment and control groups when controlling for 
possible imbalance in important baseline factors will be analysed by evaluating 
the HR obtained from estimating a multiple proportional hazards Cox regression 
model.  
Subgroups to be analyzed, such as various risk categories, will be enumerated in the 
SAP. Handling of missing data will be described in the SAP. 
7.4.2 Analysis of the secondary efficacy endpoints   
Comparison between active treatment and placebo of the following secondary efficacy 
endpoints will be performed: 
1) Incidence of hospitalization or death:  the primary assessment of this endpoint 
will be among patients in the high risk group.  This has been defined preliminarily 
above.  The group may be redefined and recruitment restricted based on 
analysis at the end of part A and again in the interim analysis of part B. 
Additional secondary endpoints include: 
2) The proportion of patients who are PCR-negative at each time point assessed, 
days 8, 15, 29 and 57 from the start of treatment (landmark analysis); 
3) Time to resolution of individual disease-related symptoms present at baseline; 
4) Development of new disease-related symptoms or pneumonia on study; 


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5) Changes in laboratory markers of disease severity, i.e., oxygen saturation, CRP, 
lymphocyte count and D-dimer levels, from baseline to time points at which 
these are measured on study; 
 
The time frame for all endpoints unless otherwise stated is from Day 1 (day of first dose 
of study medication) through study Day 57.  The time to event endpoints will be analyzed 
using the methods described for the primary endpoint above.  
Binary (Yes/No) endpoints (development of pneumonia, hospitalization and mortality) will 
be summarized using counts and percentages for each group. A 95% confidence interval 
will be constructed for each proportion. Population-level risk differences will be used to 
estimate treatment effect.  More specific details will be provided in the SAP.  
Changes from baseline in continuous variables will be summarized by descriptive 
statistics and analyzed using repeated-measures model. Data will be log transformed, as 
needed. 
7.4.3 Type 1 error control 
The overall type 1 error for the study is 5%, which will be used for the efficacy analysis of 
the dose level assessed in part B of the study. As data from part A of the study will not be 
used for the main, part B efficacy analysis, no correction for multiplicity or selection is 
needed.  
The unblinded comparative size re-estimation (ubSSR) at the time of part B interim 
analysis will follow the rules that increase sample size only if comparative results falls in 
a pre-defined ‘promising zone’.  Building on the theoretical work of Chen, DeMets and 
Lan (2004) and Mehta and Pocock (2011), it has been shown that the ‘Promising Zone 
approach’ allow type 1 error to be preserved with the use of conventional final analysis 
test statistic, that is without need for statistical adjustment. To safeguard study integrity, 
all details regarding the pre-defined ubSSR rules will be documented separately. 
The interim analysis will allow only early stopping for futility (non-binding), and not for 
efficacy, therefore no inflation of type one error is associated with study early stopping 
criteria.  
To protect the overall 5% type I error arising from secondary endpoint multiplicity, all the 
secondary endpoints will be interpreted inferentially only if a statistically significant 
treatment effect (p-value ≤0.05) is detected in the primary endpoint for the study.  
The order of the secondary endpoints defines an hierarchy according to which these 
endpoints will be sequentially tested, where an endpoint can be inferentially interpreted 
only if the previous endpoint was statistically significant.  The hierarchy of endpoints will 
be finalized after Part A data are available but before unblinding of Part A and will be 
documented in the SAP. 
7.5 
Safety Analyses 
The safety and tolerability of upamostat will be determined by reported AEs, physical 
examinations, vital signs, and laboratory tests. Patients who receive any study 
medication, even a partial dose, or who immediately vomit the study medication are 
considered evaluable for safety. 


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As noted above, exacerbation of COVID-19-related signs and symptoms are considered 
lack of efficacy, rather than adverse events. Therefore, hospitalization or death from 
COVID-19 will be considered in the efficacy rather than safety analyses, although all 
hospitalizations and deaths, regardless of cause, will be included in the overall statistics 
for these events.  COVID-19-related events will be followed similarly to serious adverse 
events, but not counted in the analyses thereof. 
In part A of the study, safety data will be analyzed per the outline in section 4.8, above, 
to determine which treatment regimen to carry into part B of the study. 
As possible, summaries will be provided for dose level that will be used in both study 
parts combining data from both parts. Similarly, placebo safety data will be combined. 
The unselected dose level data will be presented separately. 
7.5.1 Adverse Events 
The NCI-CTCAE v5.0 system will be used to grade new or worsening clinical and 
laboratory abnormalities.  New laboratory abnormalities for which there are no CTCAE 
v5.0 criteria will be assigned grade 1 if there were no clinical effects or interventions, 
and according to the criteria in section 6.5 if there were clinical effects and/or 
interventions. AEs will be grouped and tabulated by MedDRA preferred terms by system 
organ class.  
The Medical Dictionary for Regulatory Activities (MedDRA) version current at time of 
study initiation will be used to classify all AEs with respect to system organ class and 
preferred term.  
Summary tables of AEs and SAEs will be prepared by system organ class, preferred 
term and severity for each treatment group. AEs that lead to premature discontinuation 
from the treatment or to death will be listed separately via data listings.   
7.5.2 Clinical Safety Laboratory Tests 
Laboratory tests and change from baseline at each time point will be tabulated by 
treatment groups.  No inferential testing will be performed to compare the differences 
between the treatment groups. 
7.5.3 Other Parameters 
The results from physical examination will be presented in the subject data listings. Vital 
signs and physical findings will be shown in listings, but no calculations or study report 
tables will be generated.  Findings on physical examination, including vital signs, which 
constitute clinically significant changes will be listed as adverse events.  
Concomitant medications will be summarized and presented, as will be detailed in the 
SAP.  
7.6 
Interim Analyses   
Once treatment and follow-up of the first 60 patients (part A) is completed, data will be 
reviewed by the DSMB for safety, as described in section 4.8, above, and a decision 
made regarding which regimen to continue into part B of the study. As the study is 
defined as ‘operationally seamless’ such that efficacy data from part A will not be used 
both for the dose selection and the confirmatory analysis, the Sponsor may take part in 
that decision and be exposed to the comparative part A data. 


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At that time, the parameters being studied and the analysis plan will be reviewed and 
may be adjusted based on findings in part A before initiating part B. 
A second analysis and DSMB review will be conducted in part B, at one of the time 
points described above, depending on whether the study is powered for the sustained 
recovery endpoint or the hospitalization or death endpoint. 
To safeguard study integrity and to minimize operational bias from the planned interim 
analysis, the following operational procedures will take place (Mehta and Pocock, 2011; 
FDA Guidance for Industry on Adaptive Designs for Clinical Trials of Drugs and 
Biologics, November 2019): 
• The unblinded independent statistician who is not otherwise involved in the study will 
perform the interim analyses calculations.  
• The DSMB charter will describe what the interim analysis report should contain, who 
may have access to that report, the precise rules for increasing the sample size, and 
the procedure to be followed in making the sample size recommendation to the 
sponsor.  
• The unblinded sample size increase will use a discretized fixed decision rather than 
a continuous adaptation decision to limit the option of back-calculation of treatment 
effect. 
• Procedure for notifications to be followed by DSMB if recommendation to stop study 
or to increase sample size will be specified. For example, if the sample size is 
increased after an interim analysis, trial sites would not be notified of the specific 
targeted final sample size. 
 


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8. 
Study Medications 
Upamostat will be provided in 200 mg capsules.  Patients will receive an adequate 
supply of medication for 14 days. Medication is to be stored at room temperature, 15-
25°C (59-77°F).   
Matching placebo for upamostat will also be provided in blinded fashion.  
For part A of the study, the two bottles provided will be labeled A and B.  Patients will be 
instructed to take one capsule from each bottle each day.  For patients in the 200 mg 
daily group, i.e., receiving different medications in bottles A and B, active and placebo 
will be randomized between the two bottles so that A or B will not automatically signify 
either active or placebo.  If dose is reduced, patients will be instructed to take one pill 
from alternate bottles each day. 


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9. 
Investigator Responsibilities 
9.1 
Compliance with Declaration of Helsinki and Good Clinical Practices 
The study will be performed in accordance with the Declaration of Helsinki (1964) as 
revised, most recently in Seoul (2008), US FDA, as well as regulations in other 
countries in which patients may be accrued, and the ICH Guideline for Good Clinical 
Practice, E6(R2).  The investigator will ensure that all those concerned with conducting 
the study (such as pharmacists, research nurses and co-investigators) are provided with 
copies of the protocol and all safety information prior to the start of the study. 
9.2   Institutional Review Board (IRB)/Ethics Committee (EC) Review and Approval 
The investigator is responsible for obtaining IRB/EC approval to conduct this study 
(including IRB/EC approval of the Informed Consent form) and for ensuring continuing 
review as required by the IRB/EC.  Written confirmation of this approval and periodic 
review must be provided to the sponsor prior to the start of the study and at appropriate 
intervals. 
9.3   Informed Consent 
The investigator will inform subjects as to the nature, expected duration and purpose of 
the study, the administration of the study medication, and the hazards involved, as well 
as the potential benefits that may come from treatment with this investigational drug.  
Informed consent must be obtained in accordance with US Code of Federal Regulations 
(21 CFR Part 50), and other national regulations, if study is conducted at sites outside 
the US.   
The subject will be informed that his/her medical records will be subject to review by the 
sponsor and possibly by a representative of the Food and Drug Administration, as well 
as national regulatory authorities, for patients treated outside the US.  Subjects will be 
informed that they are free to refuse participation in this clinical investigation, and if they 
should participate, it will be made clear to them that they may withdraw from this study 
at any time without prejudicing further care. Informed consent must be obtained from 
every subject prior to study entry. This will be kept by the investigator and will be subject 
to review by the sponsor; it will also be available to the subject. 
9.4   Confidentiality 
All information provided to the investigator relevant to the study medication, as well as 
information obtained during the course of the study, will be regarded as confidential.  
The investigator and members of his/her research team agree not to disclose or publish 
such information in any way to any third-party without prior written permission from the 
sponsor, except as required by law. 
9.5   Source Documentation 
The investigator will allow inspections of the study site and documentation by clinical 
research and audit personnel from the sponsor, external auditors or representatives of 
regulatory authorities.   The purpose of these inspections is to verify and corroborate the 
data collected on the case report forms.  In order to do this direct access to the subjects’ 
medical or clinic records is necessary.  The investigator will ensure that certain 
information is contained in the medical or clinic records of the subject and that the 
entries are signed and dated, as follows: 


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• sufficient data to allow verification of the entry criteria in terms of past and present 
medical and medication histories; 
• a note on the day the subject entered the study describing the study number, the 
drug being evaluated, the study number assigned to that subject and a statement 
that consent was obtained; 
• a note of each subsequent study visit including any concerns about adverse events 
or abnormal laboratory data and their resolution; 
• notes of all concomitant medication taken by the subject including start and stop 
dates; 
• a note of when the subject terminated from the study, the reason for termination and 
the subject’s general condition at termination; 
• a copy of the signed informed consent form should be kept in the medical records of 
each subject during the clinical phase of the study (thereafter it will be archived with 
the study file). 
9.6   Drug Accountability 
The investigator agrees to supervise the maintenance of records of the receipt, 
dispensing and return or destruction of study material supplied by the sponsor.  
Destruction of any material must be witnessed and documented in writing.  The 
dispensing record must make it clear which subject received which material. 
9.7   Data Monitoring and Collection 
Suitably qualified and trained clinical research personnel of the sponsor will visit the 
study center one or more times during or after the study for monitoring purposes and to 
assist the research staff with any queries they may have. 
Due to the nature of the illness being treated and the data collected, some or all 
monitoring at certain sites may be performed remotely. 
9.8   Case Report Forms, Investigator’s Study File and Record Retention 
All case report forms and supporting source documentation must be available to the 
sponsor during monitoring visits. 
Prior to review of the case report forms by the sponsor’s representative and forwarding 
of the case report forms to the sponsor, they should be reviewed for completeness and 
legibility by the investigator or a member of the research team. 
The investigator will maintain all records relating to the study (including copies of case 
report forms) for at least 2 years after written notification by the sponsor that the 
investigational drug program has been either completed or terminated, or that a New 
Drug Application (NDA) has been approved by the FDA.  Should the investigator retire, 
relocate, or for other reasons withdraw from the responsibility of keeping the study 
records, custody must be transferred to a person who will accept that responsibility, and 
the sponsor must be notified in writing of the name and address of said person. 
9.9   Non-Protocol Research 
No investigational procedures other than those outlined in this protocol may be 
undertaken on the subjects in this study without the prior written permission of the 
subject, the sponsor and the IRB/EC. 


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10. 
Sponsor Responsibilities 
10.1   General 
The sponsor agrees to adhere to US FDA Guidelines on Good Clinical (Research) 
Practices and with the ICH Guideline for Good Clinical Practice, E6(R2).  The sponsor 
has a legal responsibility to report fully to regulatory authorities the results of this study.  
It is the sponsor’s responsibility to obtain appropriate regulatory approval to perform the 
study. 
10.2   Case Report Forms 
Case report forms will be provided by the sponsor or, upon agreement with the sponsor, 
forms generated by the investigative site may be used.  The electronic data collection 
system used will be compliant with applicable aspects of 21 CRF Part 11, ICH 
guidelines, GCP and HIPAA. 
10.3 Data Monitoring and Collection 
Suitably qualified and trained clinical research personnel of the sponsor will visit the 
study centers.  Due to the nature of the research and the issues surrounding travel at 
this time, on-site monitoring may not occur until after completion of the study. Case 
report forms and source documentation will be available for review during monitoring 
visits to the center.  The function of this monitoring is to ensure compliance with the 
protocol, adherence to regulatory and good clinical (research) practice obligations, 
proper maintenance of records including drug accountability records, correct 
administration of study medications including storage conditions and accurate reporting 
of adverse events.   
10.4   Audit 
The sponsor has an obligation to audit a proportion of studies; this is usually undertaken 
by a department other than the clinical research department.  Therefore the sponsor, an 
independent auditor or a regulatory authority may wish to audit the study site and 
documentation and these audits may take place as the study is running or up to several 
years later. 
10.5   Confidentiality 
The sponsor will not keep any material on file bearing any subject’s name, and the 
subject’s confidentiality will be maintained at all times. 
 
 


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11. 
Protocol Modifications 
If necessary during the course of the study, the protocol may be modified by the 
sponsor in consultation with the investigator.  Except in the case of modifications to 
resolve an imminent safety issue, any protocol modification or revision must be 
reviewed and approved by the investigator’s IRB/EC prior to implementation. 
 


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12. 
Publication 
RedHill will provide unblinded data to a publications committee for publication of the 
results of this study once completed and all data have been cleaned and the blind 
broken.  The publications committee will be constituted according to the guidelines 
developed by the Company.  If deemed necessary by the Company for protection of 
proprietary information prior to patent filing, the investigators agree to delay for 60 days 
before any presentation or publication is submitted. 
 


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13. 
References 
Abe M, Tahara M, Sakai K, Yamaguchi H, Kanou K, Shirato K, Kawase M, Noda M, 
Kimura H, Matsuyama S, Fukuhara H, Mizuta K, Maenaka K, Ami Y, Esumi M, Kato A, 
Takeda M. TMPRSS2 Is an Activating Protease for Respiratory Parainfluenza Viruses. J 
Virol. 2013 Nov;87(21):11930-5. 
Bertram S, Glowacka I, Muller MA, Lavender H, Gnirss K, Nehlmeier I, Niemeyer D, He 
Y, Simmons G, Drosten C, Soilleux EJ. Jahn O, Steffen I, Pohlmann S. Cleavage and 
activation of the severe acute respiratory syndrome coronavirus spike protein by human 
airway trypsin-like protease. J Virol. 2011 Dec;85(24):13363-72.  
CDC COVID Data Tracker:  https://covid.cdc.gov/covid-data-tracker/#cases_totalcases.  
Downloaded 9/20/20. 
Chen YH, DeMets DL, Lan KK. Increasing the sample size when the unblinded interim 
result is promising. Stat Med 2004;23:1023–38. 
Gandhi RT, Lynch JB, del Rio C.  Mild or moderate COVID-19.  New Eng J Med 2020; 
online ahead of print. 
Han C, Duan C, Zhang S, Spiegel B, Shi H, Wang W, Zjang L, Lin R, Liu J, Ding Z, Hou 
X.  Digestive symptoms in COVID-19 patients with mild disease severity:  clinical 
presentation, stool viral RNA testing, and outcomes.  Am J Gastroenterol 2020;115:916-
23. 
Massarweh A, Eliakim-Raz N, Stemmer A, Levy-Barda A, Yust-Katz S, Benouaich-
Amiel A, Ben-Zvi H, Moskovits N, Brenner B, Bishara J, Yahav D, Tadmor B, Zaks T, 
Stemmer SM.  Evaluation of seropositivity following BNT162b2 messenger RNA 
vaccination for SARS-CV-2 in patients undergoing treatment for cancer.  JAMA Oncol 
2021 published online. 
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Stat Med 2011;30: 3267–84 
Meyer JE, Brocks C, Graefe H, Mala C, Thans N, Burgle M, Rempel A, Rotter H, 
Wollenberg B, Lang S. The oral serine protease inhibitor WX-671 – First experience in 
patients with advanced head and neck carcinoma. Breast Care 2008;3:20-4. 
Oguntuyo KY, Stevens CS, Siddiquey MNA, Schilke RM, Woolard D, Zhang H, Acklin 
JA, Ikegame S, Huang C-T, Lim JK, Cross RW, Geisbert TW, Ivanov SS, Kamil JP, Lee 
B.  In plain sight:  the role of alpha-1-antitrypsin in COVID-19 pathogenesis and 
therapetucs.  bioRxiv, 2020. 
Oldenburg E, Schar CR, Lange EL, Plasse TF, Abramson DT, Towler EM, Levitt M, 
Fathi R, Jensen JK.  New potential therapeutic applications of WX-UK1, as a specific 
and potent inhibitor of human trypsin-like proteases.  Proc Amer Assn Cancer Res 
2018;abstract 784. 
Pruijssers AJ, George AS, Schafer A, Leist SR, Gralinski LE, Dinnon KH III, Yount BL, 
Agostini ML, Stevens LJ, Chapell JD, Lu X, Hughes TM, Gully K, Martinzez DR, Brown 
AJ, Graham RL, Perry JK, Du Pont V, Pitts J, Ma B, Babusis D, Murakami E, Feng JY, 
Bilello JP, Porter DP, Cihlar T, Baric RS, Denison MR, Sheahan TP. Remdesivir 
potently inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing 
the SARS-CoV-2 RNA polymerase in mice. bioRxiv 2020. 32 (3); 107940. 


Upamostat for Treatment of COVID-19 
Amendment 4 
15 June, 2021 
CONFIDENTIAL: PROPRIETARY INFORMATION 
58 
Tsujimura S, Saito K, Nakayamada S, Tanaka Y.  Bolus infusion of human urinary 
trypsin inhibitor improves intractable interstitial pneumonia in patients with connective 
tissue diseases.  Rheumatol 2008;47:907-13. 
van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, 
Tamin A, Harcourt JL, Thornburg NJ, Gerber SI, Lloyd-Smith JO, de Wit E, Munster VJ. 
Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J 
Med. 2020 Mar 17. 
van Gerwen M, Alsen M, Little C, Barlow J, Genden E, Naymagon L, Tremblay D.  Risk 
factors and outcomes of COVID-19 in New York City;  a retrospective cohort study.  J 
Med Virol 2021;93:907-15. 
Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, Tan W. Detection of SARS-CoV-2 in 
different types of clinical specimens.     J Amer Med Assn 2020;epub ahead of print. 
Williamson EJ Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, Curtis HJ, 
Mehrkar A, Evans D, Inglesby P, Cockburn J, McDonald HI, MacKenna B, Tomlinson L, 
Douglas IJ, Rentsch CT, Mathur R, Wong AUS Grieve R Harrison D, Forbes H, 
Schultze A, Croker R, Parry J, Hester F, Harper S, Perera F, Evans SJW, Smeeth L, 
Goldacre B.  Factors associated with COVID-19-related death using OpenSAFELY.  
Nature 2020;584:430-46. 
World Health Organization.  WHO R&D Blueprint:  novel coronavirus.  2020.  
Downloaded 3/20/20:  https://www.who.int/blueprint/priority-diseases/key-action/COVID-
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf?ua=1 
Wu Z, McGoogan JM.  Characteristics of and important lessons from the coronavirus 
disease 2019 (COVID-19) outbreak in China.  Summary of a report of 72314 cases from 
the Chinese Center for Disease Control and Prevention.  J Amer Med Assn 
2020;323:1239-42. 
Yamada H, Le QT, Kousaka A, Higashi Y, Tsukane M, Kido H. Sendai virus infection 
up-regulates trypsin I and matrix metalloproteinase-9 triggering viral multiplication and 
matrix degradation in rat lungs and lung L2 cellls.  Arch Virol 2006;151:2529-37. 
Yamane D, McGivern DR, Wauthier E, Yi M, Madden VJ, Welsch C, Antes I, Wen Y, 
Chugh PE, McGee CE, Widman DG, Misumi I, Bandyopadhyay S, Kim S, Shimakami T, 
Oikawa T, Whitmire JK, Heise MT, Dittmer DP, Kao CC, Pitson SM, Merrill AH Jr, Reid 
LM, Lemon SM. Regulation of the hepatitis C virus RNA replicase by endogenous lipid 
peroxidation. Nat Med. 2014 Aug;20(8):927-35. 
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei 
Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B.  Clinical course and risk factors for 
mortality of adult inpatients with COVID-19 in Wuhan, China:  a retrospective cohort 
study.   
Zhou C, Gao C, Xie Y, Xu M. COVID-19 with spontaneous pneumomediastinum. Lancet 
2020;395:1054-62. 
Zmora P, Hoffman M, Kollmus H, Moldenhauer A-S, Danov O, Braun A, Winkler M, 
Schughart K, Pohlmann S. TMPRSS11A activates the influenza A virus hemagglutinin 
and the MERS coronavirus spike protein and is insensitive against blockade by HAI-1. J 
Biol Chem. 2018 Sep 7;293(36):13863-13873. 


Upamostat for Treatment of COVID-19 
Amendment 4 
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CONFIDENTIAL: PROPRIETARY INFORMATION 
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Appendices 
Appendix 1. Nasal Mid-Turbinate (NMT) Specimen Collection 
US CDC-recommended procedure on next two pages.  
 


Upamostat for Treatment of COVID-19 
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Upamostat for Treatment of COVID-19 
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Appendix 2.  Patient diary 
Patient-Reported COVID-19 Sign and Symptom Diary (PRO-COVID-19) 
General information (not to be included in the actual questionnaire): Questions 
and response options are sorted into four separate domains based on affected system 
including: body/systemic, respiratory, gastrointestinal and nose/mouth/throat. 
Instructions 
This questionnaire asks about the impact of COVID-19 on your health.  Please respond 
as accurately as possible.   
Domain 1: Body/Systemic 
1) At their worst, what was the severity of your CHILLS OR SHIVERING over the last 
24 hours?  Chills and shivering are a feeling of coldness or shaking while not in a 
cold environment. 
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
 
2) At its worst, what was the severity of FEELING HOT OR FEVERISH over the last 24 
hours?    
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
 
3) At their worst, what was the severity of your MUSCLE OR BODY ACHES over the 
last 24 hours?    
 
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
 


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4) At their worst, what was the severity of your HEADACHES over the last 24 hours?     
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
 
5) At its worst, what was the severity of your TIREDNESS OR FEELING OF LOW 
ENERGY over the last 24 hours?     
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
 
6) At its worst, what was the severity of your CHEST PAIN over the last 24 hours?  
This picture shows the location of your chest.  
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
 
Domain 2: Respiratory 
7) At its worst, what was the severity of your DIFFICULTY BREATHING over the last 
24 hours?     
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
 
8) At its worst, what was the severity of your COUGH over the last 24 hours?  
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
Chest


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63 
 
Domain 3: Gastrointestinal 
9)  At its worst, what was the severity of your ABDOMINAL PAIN over the last 24 
hours?  This picture shows the location of your abdomen.   
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
 
10) At its worst, what was the severity of your NAUSEA over the last 24 hours?  Nausea 
is the feeling of needing to vomit, commonly referred to as throwing up.  
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
 
11) At its worst, what was the severity of your LOSS OF APPETITE over the last 24 
hours?  Loss of appetite is not wanting to eat or drink.  
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
 
12) How many times did you have DIARRHEA in the last 24 hours?  Diarrhea is having 
loose or watery and more frequent bowel movements.  
⃝      I did not have diarrhea at all 
⃝      1-2 times 
⃝      3-4 times 
⃝      5 or more times 
 
Abdomen 


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64 
13) How many times did you have VOMIT (THROW UP) in the last 24 hours?  Vomiting 
is expelling stomach contents  through your mouth.  
⃝      I did not vomit at all 
⃝      1-2 times 
⃝      3-4 times 
⃝      5 or more times 
 
Domain 4: Nose & Throat 
14) At its worst, what was the severity of your SORE THROAT over the last 24 hours?  
A sore throat may be painful or feel scratchy or irritated.  
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
 
15) At its worst, what was the severity of your STUFFY OR RUNNY NOSE over the last 
24 hours?   
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
 
16) Rate your SENSE OF SMELL in the last 24 hours 
⃝      My sense of smell is the same as usual 
⃝      My sense of smell is less than usual 
⃝      I have no sense of smell 
 
17) Rate your SENSE OF TASTE in the last 24 hours 
⃝      My sense of taste is the same as usual 
⃝      My sense of taste is less than usual 
⃝      I have no sense of taste 
 


Upamostat for Treatment of COVID-19 
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65 
GLOBAL 
1) In the past 24 hours, have you returned to your USUAL HEALTH 
(before your COVID-19 illness)? 
 
⃝      Yes 
⃝      No 
 
2) In the past 24 hours, have you returned to your USUAL ACTIVITIES 
(before your COVID-19 illness)?  
 
⃝      Yes 
⃝      No 
 
3) In the past 24 hours, what was the severity of your OVERALL COVID-
19-RELATED SYMPTOMS at their worst?  
 
⃝      None 
⃝      Mild 
⃝      Moderate 
⃝      Severe 
 
Additional Health and Medication Assessments  
1. In the past 24 hours, have you experienced any other changes in health 
that have not already been reported? 
 
⃝     Yes 
⃝     No 
∗ Answering “Yes” will trigger a short free-text box to describe issue, and a 
note to contact study staff if medical assistance is required immediately.  
 
2. Please enter each medication (other than the study medication) you have 
taken for COVID-related symptoms today, including the amount taken over 
the past 24 hours. 
 
I didn’t take any medication for COVID-19-related symptoms today. ☐  
OR 
Medication name:   _____________________________ 
 
Dose per tablet/capsule (of primary ingredient):  _____________________   
 
Number of doses taken over past 24 hours (since you last filled out the questionnaire):  
 
_____________ 


Upamostat for Treatment of COVID-19 
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Did you take any additional medications for COVID-19?  Yes:  ☐    No: ☐   
 
Answering yes will trigger another set of lines to list additional medication, dosage and 
number of doses. 
 
3. What time did you take your study medication today? 
Enter time: HH:MM AM/PM 
☐Check this box if study medication was not taken 
(If time entered): 
3a. How many capsules did you take? 
⃝     1 capsule 
⃝     2 capsules 
 
 
 
 


Upamostat for Treatment of COVID-19 
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Appendix 3.  CYP3A4 Strong inhibitors and sensitive substrates 
Strong inhibitors 
 
boceprevir 
clarithromycin  
cobicistat  
danoprevir and ritonavir 
elvitegravir and ritonavir 
grapefruit juice  
idelalisib  
indinavir and ritonavir 
itraconazole 
ketoconazole  
lopinavir and ritonavir 
nefazodone  
nelfinavir  
paritaprevir and ritonavir 
and (ombitasvir and/or 
dasabuvir) 
posaconazole  
ritonavir  
saquinavir and ritonavir 
telaprevir  
tipranavir and ritonavir 
telithromycin  
troleandomycin 
voriconazole
 
Sensitive substrates 
 
alfentanil  
avanafil  
budesonide  
buspirone  
conivaptan  
darifenacin  
darunavir  
dasatinib  
dronedarone  
ebastine  
eletriptan  
eplerenone  
everolimus  
felodipine  
ibrutinib  
indinavir  
lomitapide  
lovastatin  
lurasidone  
maraviroc  
midazolam  
naloxegol  
nisoldipine  
saquinavir  
simvastatin  
sirolimus  
tacrolimus  
tipranavir  
triazolam  
vardenafil  
quetiapine  
sildenafil  
ticagrelor  
tolvaptan
 
Source:  FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors 
and Inducers.  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-
and-drug-interactions-table-substrates-inhibitors-and-inducers#table2-1  Downloaded 
11/23/20. 

SAP_001.pdf: 
 
Study:  RHB-107-01 
 
Page 1 of 28 
Part A Statistical Analysis Plan (Version 2.0) 
  
 
 
 
 
 
 
PHASE 2/3 STUDY OF UPAMOSTAT, A SERINE PROTEASE INHIBITOR, OR 
PLACEBO FOR TREATMENT OF COVID-19 DISEASE 
 
Protocol Number: RHB-107-01 
 
IND Number: 151472 
 
Protocol Version: Amendment 4:   15 June 2021 
 
Sponsor Name: RedHill Biopharma   
 
Statistical Analysis Plan for Part A, Version 2.0 
SAP Version Date: 13 January 2022 
 
 
 
 
 
 
 
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Study: RHB-107-01
Page 2 of 28
Part A Statistical Analysis Plan (Version 2.0)
STATISTICAL ANALYSIS PLAN APPROVAL PAGE
Document Information
Version 
2.0
Document Date 
13 January 2022
Prepared for 
RedHill Biopharma
Prepared by 
Mario Chen, FHI 360
Sponsor Approver details
Name 
Terry Plasse, MD
Job Role 
Medical Director
Company 
RedHill Biopharma
Signature
Date of signature
Other Approver details
Name 
Mario Chen
Job Role 
Director of Biostatistics and Data Sciences
Company 
FHI 360
Signature
Date of signature
DocuSign Envelope ID: 721B2720-71FA-4FD1-B348-452230398518
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Study:  RHB-107-01 
 
Page 3 of 28 
Part A Statistical Analysis Plan (Version 2.0) 
  
 
 
STUDY SUMMARY 
Title: 
Phase 2/3 Study of Upamostat, a Serine Protease inhibitor, or Placebo for 
Treatment of COVID-19 Disease  
Design:  
A 2-part, multicenter, Phase 2/3, randomized, double-blind, placebo-
controlled, parallel group study to evaluate the safety and efficacy of 
upamostat in adult patients with COVID-19 disease who do not require 
inpatient care. 
Investigational Drug:  
Upamostat (RHB-107) 
Reference Treatment:  Matching capsule will be used as placebo treatment 
Population:  
Patients with positive PCR test for SARS-CoV-2 and symptomatic COVID-19 who 
do not require inpatient care. 
Study Duration: 
The enrollment is expected to start in January 2020; each subject is expected 
to stay in the study for 57 days:  14 days treatment;  total 57 days treatment 
plus follow-up, regardless of duration of treatment.  
Primary Objectives:  
 Part A of the study:  determination of the safety and tolerability of two dose       
 
 levels and selection of an upamostat dose for part B. 
Part B of the study:  comparison between upamostat and placebo in time to 
sustained recovery from symptomatic illness.   
Primary Endpoints:  
Part A:  safety and adverse event profile of upamostat at two dose levels 
compared to placebo 
Part B:  Time to sustained recovery from acute COVID-19 disease  
Secondary Objectives:  Comparison between active and placebo of  
1) Hospitalization or death from any cause by end of study, i.e, day 57. 
2) In part A and at the interim analysis in part B, assessment of the risk of hospitalization or death 
as a function of the presence, number and severity of concerning conditions will be undertaken.  
This information may be used to develop a definition of very high risk for calculation of the 
incidence of hospitalization or death in the high risk/very high risk population in part B. 
3) Proportion of patients who are PCR-negative at days 8, 15, 29 and 57 from the start of 
treatment (landmark analyses)  
4) Time to resolution of individual disease-related symptoms present at baseline; 
5) Development of new disease-related symptoms and/or pneumonia on study; 
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Part A Statistical Analysis Plan (Version 2.0) 
  
 
 
6) Changes in laboratory markers of disease severity, i.e., oxygen saturation, CRP, lymphocyte 
count, cardiac troponin, and D-dimer levels, from baseline to time points at which these are 
measured on study; 
7) Adverse events; 
In addition to analysis within the entire study population, subgroup analyses for secondary endpoints 1, 
3-6 will be performed in the high risk population. Analysis for secondary endpoint 1 will focus primarily 
on the high risk and very high risk subgroups. 
Where procedures and analyses described in the SAP differ from those in the protocol, those in the SAP 
take precedence. 
This document focuses on analysis of part A of the study.  Based on results of part A, study parameters 
including analysis parameters may be modified for part B.  Changes from the current protocol and SAP 
will be formalized in amendments to the protocol and SAP, respectively. 
 
 
 
 
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Part A Statistical Analysis Plan (Version 2.0) 
  
 
 
LIST of ABBREVIATION and SPECIALIST TERM 
Abbreviation 
Description 
AE 
Adverse Event 
BUN     
Blood urea nitrogen 
CoV 
Coronaviruses 
COVID-19 
Coronavirus-2019 
CSR 
Clinical Study Report 
DSMB 
Data and Safety Monitoring Board 
ECG      
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
HR 
Hazard Ratio 
INR 
International Normalized Ratio 
IWRS 
Interactive Web-based randomization System 
ITT 
Intent-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
PP 
Per Protocol 
RS 
Randomization Statistician 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS 
Severe Acute Respiratory Syndrome 
SOC 
System Organ Class 
ubSSR 
Unblinded Sample Size Re-estimation 
 
 
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Part A Statistical Analysis Plan (Version 2.0) 
  
 
 
TABLE OF CONTENTS 
1. 
Introduction ........................................................................................................................................ 7 
2. 
Study Objectives .................................................................................................................................. 8 
2.1 
Primary Objectives .................................................................................................................. 8 
2.2 
Secondary Objectives .............................................................................................................. 8 
2.3 
Exploratory .............................................................................................................................. 8 
3. 
Study Design and Procedures ............................................................................................................. 9 
4. 
General Analytic Considerations ....................................................................................................... 12 
4.1 
Missing Data .......................................................................................................................... 12 
4.2 
 Covariate Adjustment .......................................................................................................... 12 
4.3 
Test Size and Confidence Levels ............................................................................................ 12 
4.4 
Type 1 error control .............................................................................................................. 12 
4.6 
Safety data ............................................................................................................................ 12 
5. 
Randomization, Allocation Concealment and Blinding ..................................................................... 13 
5.1 
Randomization ...................................................................................................................... 13 
5.2 
Allocation Concealment and Blinding ................................................................................... 13 
5.3  
Blinded Data Review ............................................................................................................. 13 
5.4  
Study Size and Power ............................................................................................................ 14 
6. 
Analysis Populations.......................................................................................................................... 15 
7. 
Data and Safety Monitoring Board Meeting Scope and Time Point ................................................. 16 
8. 
Participant Disposition Analysis ........................................................................................................ 18 
9. 
Demographics and Baseline Characteristics ..................................................................................... 18 
10. 
Medical History ................................................................................................................................. 18 
11. 
Analysis of Study Treatment Dosage ................................................................................................ 18 
12. 
Analysis of Primary Efficacy Endpoint ............................................................................................... 19 
13. 
Analysis of Secondary Efficacy Endpoints ......................................................................................... 21 
14. 
Analysis of Exploratory Endpoints ..................................................................................................... 22 
15. 
Safety Analysis ................................................................................................................................... 22 
16. 
Additional Safety Analysis ................................................................................................................. 23 
16.1  
Clinical Safety Laboratory Tests ........................................................................................ 24 
16.2  
Other Parameters ............................................................................................................. 24 
16.3  
Analysis of Concomitant Medication ................................................................................ 24 
17. 
Subgroup Analysis ............................................................................................................................. 24 
18. 
Change from Analysis Specified in the Corresponding Protocol Version ......................................... 25 
19. 
References ......................................................................................................................................... 26 
 
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Part A Statistical Analysis Plan (Version 2.0) 
  
 
 
1. Introduction 
This statistical analysis plan (SAP) expands the summary analysis plan in Section 7 Data Analysis 
and Statistical Considerations of the study protocol “Phase 2/3 Study of Upamostat, a Serine 
Protease Inhibitor, or Placebo for Treatment of COVID-19 Disease ” authored by the sponsor (RedHill 
Biopharma Ltd.) approved amendment 4 version dated June 15, 2021. This is the first version of the 
SAP and there are no changes to track from a previous version.  This SAP is intended for analysis of 
part A of the study.  The SAP for part B will be finalized after analysis of data from part A and an 
SAP for analysis of part B of the study generated.  Modifications may be made to the analyses 
planned for part B based on that review as allowed in the approved protocol or based on protocol 
amendments made after Part A analysis. Based on the current protocol, changes that may be 
made after Part A analysis are highlighted in bold and italicized throughout this SAP. The SAP for 
part A will be approved by the sponsor before unblinding of Part A data. Deviations from this SAP 
will be documented in the part A analysis report. Changes after approval of version 1.0 of the SAP 
are summarized in the appendix. 
The scope of analysis provided in this part A SAP includes plans for analysis after all subjects 
enrolled in Part A complete treatment or discontinue early and complete follow-up. The analysis of 
part A in this SAP is divided into first and second tier analyses. The first-tier analysis is prioritized to 
allow to proceed to part B expeditiously. Where procedures and analyses described in the SAP differ 
from those in the protocol, those in the SAP take precedence. 
 
 
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Part A Statistical Analysis Plan (Version 2.0) 
  
 
 
2. Study Objectives  
2.1 
Primary Objectives 
• 
Part A of the study:  determination of the safety and tolerability of two dose levels and 
selection of an upamostat dose for part B. 
2.2 
Secondary Objectives 
Items 1, 2, 4, 6 and 8, below, are first-tier secondary objectives, to be analyzed initially.  Items 3, 5 and 7 
are second tier objectives, which may be reported subsequently.  Both exploratory objectives are 
second tier. 
Comparison between active treatment group and placebo of  
1) Time to sustained recovery from symptomatic illness; 
2) Hospitalization or death from any cause by end of study, i.e, day 57; 
3) Assessment of the risk of hospitalization or death as a function of the presence, number and 
severity of concerning conditions will be undertaken.  This information may be used to develop 
a definition of very high risk for calculation of the incidence of hospitalization or death in part B. 
4) Proportion of patients who are PCR-negative at days 8, 15, 29 and 57 from the start of 
treatment (landmark analyses); 
5) Time to resolution of individual disease-related symptoms present at baseline; 
6) Development of new disease-related symptoms and/or pneumonia on study; 
7) Changes in laboratory markers of disease severity, i.e., oxygen saturation, CRP, lymphocyte 
count, cardiac troponin and D-dimer levels, from baseline to time points at which these are 
measured on study; 
8) Adverse events. 
2.3 
Exploratory 
1) Percent of patients who report household contacts who have developed symptomatic, PCR-
confirmed COVID-19 by day 57; 
2) Levels of anti-SARS-CoV-2 serum IgM and IgG at 57 days from the start of treatment. 
 
 
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Part A Statistical Analysis Plan (Version 2.0) 
  
 
 
3. Study Design and Procedures 
This is a randomized, parallel-group double blind study of upamostat compared to placebo in 
patients with symptomatic COVID-19 who do not require immediate treatment with specific 
antiviral or anticytokine therapy.  The study uses phase 2/3 operationally seamless design 
methodology for dose selection in phase 2 (part A) and inferentially independent confirmatory 
phase 3 study (part B). The phase 3 portion will include interim analysis for early termination for 
futility or increase in sample size, as indicated by initial results. 
In both parts of the study, patients who have a positive pre-study PCR or rapid antigen test for 
SARS-CoV-2 and meet inclusion and exclusion criteria will be stratified by age (≥65 vs <65 years). In 
part B, they will also be stratified based on presence of one or more concerning medical conditions 
and the additional factors shown below and then randomized to treatment with upamostat or 
placebo, according to randomization ratios specified below.  Concerning medical conditions are the 
following: 
• 
Age ≥65 years on date of randomization 
• 
Hypertension 
• 
Chronic lung disease (for example, chronic obstructive pulmonary disease, moderate-severe 
asthma, interstitial lung disease, cystic fibrosis and pulmonary hypertension) Diabetes 
• 
Obesity (BMI≥30) 
• 
Cardiovascular disease (including congenital heart disease, coronary artery disease, history of 
thrombotic events, including stroke and transient ischemic attacks [TIA])  
• 
Chronic renal disease 
• 
Immunosuppressive disease or immunosuppressive treatment  
• 
Sickle cell disease  
• 
Neurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer 
medical complexity (for example, genetic or metabolic syndromes and severe congenital 
anomalies)  
• 
Having a medical-related technological dependence (for example, tracheostomy, gastrostomy, 
or positive pressure ventilation (not related to COVID-19)) 
All patients who live in regions in which one or more therapeutic monoclonal antibody 
combinations for outpatient treatment of COVID-19 are available will either be offered antibody, if 
provided at that facility, or given information as to where they can receive the antibodies. The 
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patient may decide whether or not to take the antibody combination;  receipt or refusal of antibody 
therapy will not affect the patient’s participation in this trial.  If used, the antibody may be 
administered before or after the patient starts study medication.  However, the patient may not 
start study medication more than 5 days after onset of symptoms or receipt of laboratory diagnosis 
of COVID-19, whichever is longer. 
In part B, patients will be stratified based on  
1. The presence of none versus one or more of the above factors, 
2. Planned receipt vs nonreceipt of therapeutic monoclonal antibodies for COVID-19, 
3. Region in which patient is treated, 
4. Whether the patient is at least 14 days after his or her last dose of COVID-19 vaccine, 
and randomized to treatment as described below.   
In part B, the proportion of patients in the low risk group, i.e., with no concerning conditions, 
may be limited to 30%.  This number and the definition of high risk, in terms of number and types of 
risk factors, may be revised at the time of the part A analysis  in order to enroll a sufficiently high 
risk cohort in Part B. 
In Part A, a total of approximately 60 patients meeting the criteria for per protocol analysis will 
be randomized to one of three treatment groups, as follows: 
1. Upamostat 200 mg two capsules qd (n=20); 
2. Upamostat 200 mg one capsule and matching placebo one capsule qd (n=20) 
3. Placebo two capsules qd (n=20). 
In part A, in order to maintain blinding, patients will be given two bottles of medication and 
instructed to take one pill from each bottle each day. Both pills are to be taken at the same time. 
After all part A subjects complete the study, further randomization into the study will be held 
until the part B dose regimen is selected and the high risk or very high risk population is further 
defined. Analysis of part A will be reviewed by a data and safety monitoring board (DSMB).  
Assuming that there are no substantive negative safety signals to continuing with at least one dose 
level, a decision will be made regarding continuing with the current design and sample size or 
increasing the number of patients in part B to enable detection of a significant improvement in the 
incidence of hospitalization or death in the upamostat group as compared to placebo. 
If the decision is to continue as originally planned, an additional total of 250 patients, will be 
treated with the dose selected in part A or placebo.   If the decision is to power for detection of a 
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significant effect on hospitalization or death or to revise in order to have adequate power to detect 
a difference in time to sustained recovery based on the data from part A, the sample size will be 
increased in accordance with the power calculations to be performed at that time. 
The DSMB decision-making process is further defined in section 7 below and detailed in a 
separate DSMB charter.  As the results of part A will not be combined with those of part B, the 
analyses may be shared with the sponsor and study team. 
Based on results from part A, a dose for part B, either 200 mg (one capsule) or 400 mg (two 
capsules) daily will be selected.  Patients will then be randomized 3:2 to active drug or placebo at 
the schedule selected based on part A. If the study is powered for the symptom resolution endpoint 
and the sample size is unchanged from that currently in the protocol, part B will have an event-
driven design, requiring total of 201 endpoint-events (details in Section 7.1) The target sample size 
for this part is 250 patients, 150 receiving active drug and 100 receiving placebo.  An interim analysis 
for early termination for futility or increase in sample size (up to maximum total 375), as indicated 
by comparative interim results will be performed after 50% of the primary endpoint recovery events 
are realized (details below). This interim analysis is estimated to occur when about 50% (125) of part 
B subjects have been enrolled and treated.   
If the study is repowered to demonstrate a significant reduction in hospitalization or death, the 
timing of the part B interim analysis may be revised.  At the interim analysis, the incidence of 
hospitalization or death as a function of presence of concerning conditions will be assessed and the 
stratification or covariate weighting for the final analysis may be modified based on this analysis.  In 
addition, the sample size may be increased by 50% depending on results of the interim analysis. 
 
 
 
 
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4. General Analytic Considerations 
4.1 
Missing Data 
In general, no imputation of missing data will be done unless specified in the definition of the endpoints 
below. Rules for censoring for time to event endpoints will also be described in detail in the definitions 
below. Additional rules for imputation of missing data may be determined during blind review of the data 
and documented prior to unblinding. 
4.2 
 Covariate Adjustment  
In part B only, primary analyses will adjust for stratification factors used in the randomization, but strata 
may be combined if they are too small. Additional covariate adjustments may be done in sensitivity and 
exploratory analyses. The stratification factors used in the randomization or covariates of interest will be 
investigated via the subgroup analysis as detailed below.  
4.3 
Test Size and Confidence Levels 
Analysis for Part A data will be only descriptive. More formal analysis will be done with data from Part B. 
Unless otherwise noted, all reported confidence intervals will be computed at the 95% confidence level, 
and all p-values will be assessed at the two-sided 0.05 significance level, with pre-specified multiplicity 
adjustment (see section on control of type I error below).  
4.4 
Type 1 error control 
The overall type 1 error for the study is 5%, which will be used for the efficacy analysis of the dose level 
assessed in part B of the study. As data from part A of the study will not be used for the main, part B 
efficacy analysis, no correction for multiplicity or selection is needed.  
The order of the secondary endpoints defines a hierarchy according to which these endpoints will be 
sequentially tested, where an endpoint can be inferentially interpreted only if the previous endpoint was 
statistically significant. The hierarchy of endpoints will be finalized after Part A data are available. If the 
hierarchy is changed from the order specified above, the SAP will be amended, and the decision 
documented in this SAP. 
4.6 
Safety data 
If not further specified, the system organ class (SOC) and preferred term for adverse events analysis will 
be summarized using Medical Dictionary for Regulatory Activities (MedDRA). The MedDRA version 
current at study initiation will be used for the entire study. Severity grade will be defined by US National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.  
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QTcB and QTcF results from baseline standard 12-lead ECG’s and Alivecor 6-lead ECGs performed the 
same day will be compared.  For calculation of shifts, only Alivecor 6-lead ECGs will be used. 
5. Randomization, Allocation Concealment and Blinding 
5.1 
Randomization 
In part A, patients will be stratified by age, <65 or ≥65, then randomization will be done in a 
1:1:1 ratio among each dose level and placebo with all patients receiving 2 bottles of medication (active 
or placebo) and will be instructed to take one pill daily from each.  
The randomization sequence will be developed by a qualified FHI Randomization Statistician (RS) 
who is not otherwise involved in the study using a validated program written in SAS®.  
5.2 
Allocation Concealment and Blinding 
The randomization statistician will prepare an electronic randomization list containing 
treatment assignments following the randomization sequence to be sent electronically to the Interactive 
Web Response System (IWRS) vendor, Clinical One. 
After a participant has completed all baseline procedures per protocol prior to randomization 
and is determined to be eligible for the study, site staff will perform online randomization through 
Clinical One IWRS. Site staff will remain blinded and will be trained in proper randomization and 
unblinding procedures. 
5.3  
Blinded Data Review 
Prior to scheduled study unblinding and final data cleaning, the data may be reviewed in a 
blinded fashion per the sponsor’s or safety monitoring stakeholder’s request. Based on analysis needs, 
the lead statistician will develop specific listings for this review and will document the sponsor or 
stakeholders’ decisions prior to unblinding. These reviews may include (but not necessarily be restricted 
to) violations of inclusion/exclusion criteria and/or data points. More specifically, Protocol violations will 
include those documented by the study team as well as violations that can be detected directly from the 
data base. Decisions on inclusion into each analysis population, missing data, and final imputation of 
endpoints will be done during this blinded review. Blinded data review may also include clinical 
evaluation of safety data for reasonableness or to issue clinical queries to the site if needed. Any 
decisions affecting analysis will be described in internal documentation and the CSR. 
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5.4  
Study Size and Power 
Part A 
In the first part of this study, two different dose levels of upamostat will be tested; 
randomization will be 1:1:1 to the two upamostat dose levels and placebo.  
The objective of this part is to evaluate the tolerability of two dosing levels of upamostat in order to 
select the dose level that will be evaluated in the confirmatory Part B of the study.  
The sample size for part A, consisting of 20 subjects per each arm (placebo, upamostat 200 mg 
qd, upamostat 400 mg qd) was not chosen for statistical power consideration, as there are no formal 
statistical inferences planned. The size of this part is judged adequate for the tolerability assessment. 
Part B 
After accrual to the first part of the study is completed and a determination as to which active 
arm to continue into the next part of the study is made, accrual will continue at a 3:2 ratio, 
active:placebo.  A minimum total of 250 patients will be accrued to part B, 150 to the active arm using 
the regimen selected in part A of the study and 100 to placebo. 
The sample size for part B was determined based on the primary endpoint, time to sustained 
recovery from COVID-19 illness, as defined in the primary objective. It was calculated that in order to 
detect a hazard ratio for sustained recovery=1.5 comparing the active group to placebo group with 3:2 
allocation ratio, a total of 201 sustained recovery events are required, to provide 80% power using a log-
rank test at a two-sided significance level of 0.05. Assuming 80% sustained recovery rate in the control 
arm by end of follow-up (assumed equal follow-up of 57 days for all enrolled patients), it was calculated 
that in order to achieve the required number of events, the minimum number of patients enrolled will 
be 250 in total. As this study is defined as an operationally seamless phase 2/3 study, subjects from the 
part A of the study will not be combined with those in part B for the efficacy analysis. Therefore, the 
target enrollment for part B is the total number of required subjects, namely 250 subjects in total, 150 
and 100 for the active and placebo groups, respectively. These targets may be adjusted after analysis of 
Part A. 
The target number of events for this event-based part B portion is 201, taking into account a 
non-binding futility analysis and sample size-re-assessment that will be performed when 50% of the 
information (primary events) have been realized (See section 8 below for more details).  
If at the end of part A, the study is repowered to achieve statistical significance for the 
hospitalization or death endpoint, the incidence of this endpoint in the treatment groups in part A as 
well as literature data will be considered in determining the sample size for part B. This will take into 
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account not only overall results of part A but also results in patients who are defined as high risk.  It is 
understood that these calculations are based on a very small database, which may prove to be very 
imprecise.   
If part B of the study is repowered, the timing of the interim analysis may be adjusted.  At the 
interim analysis, the incidence of hospitalization or death in the high risk group, defined as patients with 
one or more of the concerning conditions listed in Section 3 above, may be modified.  A higher risk 
group may be defined in order to establish an adequate incidence level of hospitalization or death in a 
well-defined subgroup to ensure the study is adequately powered for the analysis of this endpoint in a 
meaningful patient population. This may result in a revised sample size and limiting or redefining 
recruitment in the different subgroups. Sample size reassessment for the primary endpoint will only be 
conducted if the revised sample size is lower than the maximum sample size proposed for the primary 
endpoint as above 
6. Analysis Populations  
The following analysis populations will be used when performing statistical analyses: 
• 
Screened Population includes all subjects who are screened.  
• 
Randomized Population includes all subjects who are enrolled and randomized in the study. In 
these analyses, patients will be analyzed according to their randomized treatment. 
• 
Modified Intent to Treat (mITT) Population includes all randomized patients who receive any 
study treatment. The primary and secondary efficacy analyses will be performed on the 
modified intent to treat (mITT) population. In these analyses, patients will be analyzed according 
to their randomized treatment. 
• 
Per Protocol Population includes patients with  
A. no major protocol violations which may affect study outcome and  
B. who receive at least one week of study medication unless the reason for stopping 
medication is worsening COVID-19 or development of AEs.  
Analysis using the per protocol (PP) population will be done according to treatment actually received.  
Table 2 lists the major protocol violations (also known as major protocol deviations) which remove 
patients from the per protocol population. The final list of PVs will be reviewed during blinded data 
review and additional PVs may be determined to be major and added to the list of exclusions. 
• 
Safety Population includes all patients who receive any study medication. Safety analyses will be 
performed according to the treatment actually received. 
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Table 1.  Summary of Planned Analysis, by Population 
Analysis 
Screened 
Rando
mized  
mITT Safety 
PP 
Participant Disposition 
√ 
 
 
 
 
Demographics and Baseline 
 
√ 
√ 
√ 
√ 
Medical History 
 
 
 
√ 
 
Study Treatment Dosage 
 
 
 
√ 
 
Primary Efficacy 
 
 
√ 
 
√ 
Secondary Efficacy Endpoints 
 
 
√ 
 
√ 
Exploratory Endpoints 
 
 
√ 
 
√ 
Safety 
 
 
 
√ 
 
Additional Safety 
 
 
 
√ 
 
Concomitant Medications  
 
 
 
√ 
 
Subgroup Analysis 
 
 
√ 
 
√ 
 
Table 2.  Major protocol Deviations/Violations Affecting Outcome 
Did not meet inclusion/exclusion criteria 
Forbidden medication which may affect outcome taken 
Started drug >5 days after onset of symptoms or positive SARS-CoV-2 diagnosis 
Missed >3 days of treatment over the 14-day period unless patient was hospitalized, or this was an 
investigator-directed dose reduction or hold.    
Failure to complete symptom diary for ≥7 consecutive days (one full week continuously) through day 
29 or early discontinuation, excluding days patient is hospitalized. 
 
7. Data and Safety Monitoring Board Meeting Scope and Time Point 
A data and safety monitoring board (DSMB) will be convened for oversight of the study.  A DSMB charter 
is maintained as a separate document.   
Preliminary review:  The DSMB will be informed by the Sponsor on an ongoing basis of each patient 
whose study medication dose is reduced or discontinued due to toxicity.  DSMB members may request 
an early review of all patients if warranted by the type, severity or frequency of toxicities resulting in 
dose reduction or drug discontinuation. 
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Initial full review:  The DSMB will review data after the first 60 patients have completed treatment and 
follow-up (part A), with regard to the following: 
a) Adverse events requiring dose modification or discontinuation of treatment overall and those 
considered at least possibly related to study medication; 
b) Serious adverse events deemed at least possibly related to study medication; 
c) Serious adverse events of any cause;  
d) Exacerbation of COVID-19 disease, including hospitalization; 
e) Effect of treatment on oxygen saturation, C-reactive protein, lymphocyte count and D-dimer 
(pharmacodynamic markers); 
f) Additional efficacy parameters available at that time, including time to sustained recovery, as 
defined above. 
In addition to the safety data, proportions of subjects screened, enrolled, and length of follow-up will be 
provided by site for the Enrolled Population. Screening failure reasons will be summarized. Furthermore, 
subject disposition based on the Randomized Analysis Population, including subject status. Dose 
administration status overall and by treatment arm will be provided for the Safety Population.  
Baseline information, demographics, treatment status, primary reason for early termination, and 
baseline laboratory values will be tabulated and summarized for the Safety Population.  
A statistically significant difference in any of these parameters is unlikely with a limited early data set.  
However, the DSMB in conjunction with the sponsor will determine using their clinical judgement if, 
based on the safety profile of the two active arms, the tolerability is substantially lower at 400 mg as 
compared to 200 mg daily. 
A. If the DSMB determines that safety of both dose levels is similar, accrual in part B will proceed with 
the 400 mg daily schedule. 
B. If safety is more favorable with the 200 mg daily regimen, accrual in part B will proceed with the 200 
mg daily schedule. 
Efficacy will be analyzed in part A but, unless there is a marked difference between the two active dose 
levels, will not be used to decide on dosing in part B.  Similarly, pharmacodynamic parameters will be 
analyzed but not used to decide on dosing. 
The Safety population will be used for safety analysis in this Part A DSMB analysis. Modified ITT 
population will be used for efficacy endpoints. 
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After all part A subjects complete the study, further randomization into the study will be held until the 
part B dose regimen is selected and the high risk or very high risk population is further defined. Analysis 
of part A will be reviewed by a data and safety monitoring board (DSMB).   Assuming that there are no 
substantive negative safety signals to continuing with at least one dose level, a decision will be made 
regarding continuing with the current design and sample size or increasing the number of patients in 
part B to enable detection of a significant improvement in the incidence of hospitalization or death in 
the upamostat group as compared to placebo. 
8. Participant Disposition Analysis 
Analysis population: Screened population. The frequency and percentage of subjects screened, enrolled, 
randomized, and who fail each eligibility criterion will be tabulated based on screened population.  The 
number of subject enrolled and randomized at each site will be tabulated by treatment arm using the 
randomized analysis set. 
The subject final status, including frequency and percentage of subjects who complete the study, are 
lost to follow-up, or terminate early along with primary reason for discontinuation based on CRF will be 
tabulated using randomized analysis set and by treatment arm.     
The frequency of protocol deviations will be summarized with frequency tabulations by treatment arm 
using randomized analysis set. Furthermore, all protocol deviations classified as major and/or significant 
with respect to the evaluation of the primary endpoints will be listed individually. 
9. Demographics and Baseline Characteristics 
Analysis population: Randomized, mITT, PP, and Safety Populations. Baseline demographic and baseline 
characteristics information (age, gender, height, weight, race, ethnicity) will be summarized by 
treatment group.  
10. Medical History 
Analysis population: Safety population. Medical history data separated by active status will be 
summarized using frequency tabulations by the Medical Dictionary for Regulatory Activities (MedDRA) 
system organ class and preferred term as for demographic data. 
11. Analysis of Study Treatment Dosage 
Analysis population: Safety population. All planned and actual doses (mg/day) will be listed and 
summarized descriptively for each study day and treatment arm, including the number of expected and 
actual subjects with study drug administered.  
The individual listings will be provided to support the descriptive analysis. 
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12. Analysis of Primary Efficacy Endpoint 
Analysis population: The primary efficacy analysis will be done using the mITT population and will be 
repeated on the PP population. Efficacy analysis for Part A will be only descriptive. Analysis with 
statistical testing will be done with data from Part B only. 
Time to sustained recovery is the number of days from first dose of study medication until the day on 
which patient is recovered and remains recovered for at least 28 days or until end of study, whichever 
comes first. The period required to confirm sustained recovery, 14 versus 28 days, will be assessed in 
part A of the study and a decision reached as to which period to use for definition of sustained 
recovery in part B. First date of sustained recovery will be defined as the latest time among the events 
below:  
1) Start date of the period during which the patient is afebrile (<38 oC core or rectal/37.5 oC 
oral or forehead) for at least 48 hours1; 
2) First date when all symptoms have resolved or returned to pre-illness levels (e.g., if patient 
had baseline respiratory compromise), except for  
a. fatigue, anosmia, ageusia or dysgeusia, which may be persistent at levels similar to 
the acute illness (through day 7), or  
b. dyspnea, cough or chest pain, which, if persistent, must be at least one grade lower 
than baseline and no worse than grade 1 (mild). 
Time to sustained recovery will include the first day of study medication and the day on which patient is 
declared to have recovered.   
Patients who have reached day 57 from the start of treatment but have not recovered will be censored 
at day 57. In addition, several situations override the above definition of recovery: 
• 
Patients lost to follow-up during treatment or follow-up (before recovering) will be censored at day 
57.  
• 
Patients who recover per the definition above but are subsequently hospitalized for any reason and 
are in hospital at day 57 will be censored at day 57. 
• 
Patients who die before recovery will be censored at day 57, the end of follow-up, reflecting the 
most unfavorable possible outcome for this endpoint.   
 
1 Use of antipyretics will not be considered in the assessment of sustained recovery as defined in the 
protocol. Please see appendix for more details regarding this change  
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Calculation of time to sustained recovery requires completion of the symptom diary and determination 
that patient is afebrile. Before recovery is first documented, patients with missing symptom data will be 
considered as not recovered (i.e., last observation carried forward).  If the diary is not completed on a 
given day after first meeting the definition of recovery as above, the recovery will still be considered 
sustained if symptom data is missing only intermittently. We will consider missing as intermittent if 
symptom data is missing for at most 4 consecutive days during the 28-day period when symptoms are 
expected to be recorded daily or 3 consecutive reporting days in the weeks after Day 28 when 
symptoms are recorded thrice a week until the end of study. If data gaps are longer than defined above, 
recovery will be considered as not sustained during these periods, and sustained recovery may be fully 
documented at a later time.  If a patient is hospitalized, he or she will be considered as not recovered 
on those days, regardless of the reason for hospitalization.  However, once a patient has completed the 
observation period defining sustained recovery (either 14 or 28 days), subsequent diary data gaps will 
not be considered as loss of sustained recovery status.  
The comparison of the time to sustained recovery between active and placebo groups will be performed 
using log-rank test, at 5% significance level. The stratification factors used for randomization may be 
used if sample size per stratum is adequate. Kaplan-Meier plots of time to sustained recovery will be 
provided along with median estimates and hazard ratio (HR) will be estimated along with 95% 
confidence interval using stratified Cox regression model. Estimates of cumulative incidence of sustained 
recovery at certain time points (for example days 15, 29, 43 or 57) for each group, along with 95% 
confidence interval will be tabulated. 
12.1 Correction of measured temperature to core temperature  
The initial 10 patients’ temperatures were measured with a biosticker adherent to the patient’s chest.  
This provided data on surface temperature.  This is not corrected to core temperature.  In order to 
correct the measured biosticker temperature to core temperature, the biosticker temperatures closest 
in time to the oral temperature measurements performed by study staff (i.e., at each study visit) will be 
compared.  The mean [median] difference across all patients for whom there are measurements will be 
calculated and then applied to correct the temperatures measured orally.  Oral temperature is 0.5° C 
lower than the core (rectal) temperature, so the ultimate correction will be the mean [median] 
difference between biosticker and oral temperature plus 0.5° C. 
To correct from measured oral or forehead temperature to core temperature, add 0.5° C to the 
measured temperature. 
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13. Analysis of Secondary Efficacy Endpoints  
Analysis population: Analysis will be performed using the mITT and PP populations. 
Analysis will be performed not only of symptom resolution and occurrence of new symptoms in 
aggregate, but also by individual symptoms assessed by investigators as related to COVID-19.  This 
includes both the symptoms in the questionnaire and additional, less common symptoms which are 
recorded on the AE reports but attributed to COVID-19.  
Items 1, 2, and 4 below are first-tier secondary objectives, to be analyzed initially.  Items 3, and 5 are 
second tier objectives, which may be reported subsequently.  Comparison between active treatment 
and placebo of the following secondary efficacy endpoints will be performed: 
1) Incidence of hospitalization or death:  the primary assessment of this endpoint will be among 
patients in the high risk group.  This has been defined preliminarily above.  The group may be 
redefined and recruitment for part B restricted based on analysis at the end of part A. 
Specific COVID-19 symptoms resulting in hospitalization will be tabulated by SOC, PT and 
severity.  Depending on the number of patients hospitalized, this may be shown either as a 
table or listing. 
Specific main COVID-19 symptoms resulting in death will be listed per patient. 
2) The proportion of patients who are PCR-negative at each time point assessed, days 8, 15, 29 
and 57 from the start of treatment (landmark analysis); 
3) Time to resolution of individual disease-related symptoms present at baseline; 
COVID-19 symptoms, derived from the symptom questionnaires and those events entered as 
related to COVID-19 on the AE tables will be summarized as well using MedDRA classification by 
SOC, PT and severity as  new COVID-19 symptoms and those worsening on study by at least one 
grade 
4) Development of new disease-related symptoms or pneumonia on study; 
5) Changes in laboratory markers of disease severity, i.e., oxygen saturation, CRP, lymphocyte 
count and D-dimer levels, from baseline to time points at which these are measured on study. 
The time frame for all endpoints unless otherwise stated is from Day 1 (day of first dose of study 
medication) through study Day 57.  The time to event endpoints will be analyzed using the methods 
described for the primary endpoint above.  
Binary (Yes/No) endpoints (i.e., development of pneumonia diagnosed clinically, hospitalization and 
mortality) will be summarized using counts and percentages for each group. A 95% confidence interval 
will be constructed for each proportion. For endpoints other than mortality, (e.g, development of new 
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disease-related symptom on study), analysis will treat death before the event of interest as the most 
unfavorable possible outcome for this endpoint. Additional rules for handling missing data will be 
determined during blind review of the data and documented prior to unblinding. 
Changes from baseline in laboratory markers (continuous variables) will be summarized by descriptive 
statistics. For oxygen saturation, which is measured twice daily throughout the study period, patterns will 
be presented visually. The median value for each subject from the preceding week will be used (e.g., for 
the Day 8, the median SpO2 value for Days 2-8 will be used). The daily SpO2 will be the subject’s median 
of the 14 values collected (morning and evening). The morning and evening SpO2 will be the median of 
the 7 values at that time of day. Descriptive tables will be done for Days 1, 15, 22, 29, 36, 43, 50, 57.  
14. Analysis of Exploratory Endpoints 
Analysis population: Analysis of exploratory endpoints will be performed using the mITT and PP 
populations. There are two exploratory endpoints in the study. First, the percent of patients who have 
household contacts who have developed symptomatic, PCR-confirmed COVID-19 by day 57 will be 
summarized using counts and percentages for each group. This will be done in the second tier analysis.  
15. Safety Analysis 
Analysis population: Safety population. The safety and tolerability of upamostat will be determined by 
reported AEs, physical examinations, vital signs, and laboratory tests. Patients who receive any study 
medication, even a partial dose, or who immediately vomit the study medication are considered 
evaluable for safety. 
As noted above, exacerbation of COVID-19-related signs and symptoms are considered lack of efficacy, 
rather than adverse events.  Hospitalization or death from COVID-19 will be considered in the efficacy 
rather than safety analyses.  These events will be followed similarly to serious adverse events, but not 
counted in the analyses thereof. 
In part A of the study, safety data will be analyzed per the outline in section 7, above, to determine 
which treatment regimen to carry into part B of the study. 
All subjects will be assessed regularly for potential adverse events occurring from the time the subject 
receives the first dose of the study medication until 56 days after the first dose of study medication. AEs 
collected will include AEs which newly started on or after the first dosing of the study drug or an existing 
condition being worse on or after the first dosing of the study drug. 
A treatment-related AE is defined as an AE which is considered to be of suspected relationship to the 
study drug. Adverse events with missing relationship to study drug other than laboratory data-derived 
AEs will be assessed as treatment-related. 
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The following summaries will be provided: 
• 
AEs will be summarized as follows, overall and by SOC and PT: 
o 
All AEs 
o 
All related AEs 
o 
AEs leading to discontinuation of treatment 
o 
AEs with toxicity grade >=3 
o 
Serious AEs 
o 
Related Serious AEs 
o 
AEs that led to death 
o 
AEs leading to dose modification 
All AEs will be summarized by maximum toxicity grade, SOC, and PT.  
If a subject experiences multiple AEs under the same PT (SOC), then the subject will be counted only 
once for that PT (SOC). If a subject experiences the same AE more than once with different toxicity 
grade, the event with the highest grade will be tabulated in “by maximum toxicity grade” tables.  
All newly abnormal laboratory findings and those abnormal at baseline which change significantly (i.e., 
by at least one toxicity grade as defined in the National Cancer Institute Common Terminology Criteria 
for Adverse Events [NCI CTCAE] v5.0) are considered AEs.  Laboratory AEs for which there is no clinical 
intervention will be abstracted from the laboratory data.  Laboratory AEs not listed in the NCI CTCAE 
v5.0 will be considered as grade 1 (mild) if there is no clinical effect or intervention.  Laboratory values 
outside the normal range for certain parameters will not be considered AEs if they are generally not 
considered as indicating an abnormality; this includes such parameters as liver enzymes and creatinine 
which are below the normal range.  If there is a clinical sequela or intervention, the laboratory 
abnormality is to be entered in an adverse event report and graded according to the criteria used for 
clinical AEs. 
No missing data will be imputed for this part of the analysis, nor will formal hypothesis testing be 
performed. For safety analysis with adverse events, the observation with highest severity within the 
study day during treatment period will be used.   
Subject level listing of AEs, vital signs, and laboratory assessments will be provided. 
16. Additional Safety Analysis 
Analysis population: These additional safety analyses will be done using the Safety population. 
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Part A Statistical Analysis Plan (Version 2.0) 
  
 
 
16.1  
Clinical Safety Laboratory Tests 
Laboratory tests and change from baseline at each time point will be tabulated by treatment groups.  No 
inferential testing will be performed to compare the differences between the treatment groups.  This is 
a second-tier analysis. 
16.2  
Other Parameters 
The results from physical examination will be presented in the subject data listings. Vital signs and 
physical findings will be shown in listings, but no calculations or study report tables will be generated.  
Findings on physical examination, including vital signs, which constitute clinically significant changes will 
be listed as adverse events. This will be done in the second-tier analysis. 
Supplemental oxygen and ventilator use will be tabulated by treatment arm and overall population. This 
is applicable only for hospitalized patients; the relevant information will be obtained from hospital 
records of these patients. This will be prioritized in the first-tier analysis. 
The result of rRT-PCR will be tabulated by positive or negative and, for positives, by viral load at each 
time point assessed and over time.  This will be prioritized in the first-tier analysis. 
16.3  
Analysis of Concomitant Medication  
Prior medications are defined as medications taken within 28 days of the Screening Visit until the start 
of study drug. In addition, COVID-19 vaccinations are recorded in the concomitant medication listings, 
regardless of how long prior to study entry the vaccinations were received.  Concomitant medications 
are defined as medications with a start date and time after the start of the Day 1 study drug. 
Frequency summaries of prior and concomitant medications coded with WHO drug dictionary (version 
Mar2020) will be provided by treatment group.  
At each level of subject summarization, a subject is counted once if the subject reported one or more 
medications. A listing, including reason for use, duration, frequency and dosage of concomitant and 
prior medication will be provided. 
Only prior COVID-19 vaccination will be a first-tier analysis. 
17. Subgroup Analysis 
Analysis populations: These analyses will be done using the mITT and PP populations. The primary efficacy 
endpoint, the first secondary endpoint of death/hospitalization, and other secondary endpoints by 
subgroups including sex (male/female), BMI (≥30, <30), age, (>65, ≤ 65), presence of additional concerning 
conditions (none, 1 or more or by specific conditions), whether the patient has received the last primary 
vaccination at least 14 days prior to study entry,  whether patient plan to use an antiviral antibody 
treatment as assessed at baseline, and study region (US vs non-US).  
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Part A Statistical Analysis Plan (Version 2.0) 
  
 
 
 
18. Change from Analysis Specified in the Corresponding Protocol Version 
The use of antipyretics will not be included in the assessment of the primary endpoint of sustained 
recovery as stated in the protocol. This is noted in the endpoint definition above and additional details 
of this change are provided in the appendix.. 
 
 
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Part A Statistical Analysis Plan (Version 2.0) 
  
 
 
19. References 
Chen YH, DeMets DL, Lan KK. Increasing the sample size when the unblinded interim result is promising. 
Stat Med 2004;23:1023–38. 
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a practical 
guide with examples. Stat Med 2011;30: 3267–84. 
Steingrimsson, Hanley, & Rosenblum. (2017). Improving precision by adjusting for prognostic baseline 
variables in randomized trials with binary outcomes, without regression model assumptions. 
Contemporary Clinical Trials, 54, 18-24. 
 
 
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Part A Statistical Analysis Plan (Version 2.0) 
  
 
 
20.  
Appendix. Changes to analysis plan after approval of version 1.0 
20.1 Changes implemented in version 2.0 
Changes in version 2.0 were implemented prior to any unblinding of any team members. 
20.1.1 Definition of primary endpoint of sustained recovery 
Change: Use of antipyretics will not be considered to discount that the participant may be afebrile as 
reported in symptom diary.  
Justification: After a review of the concomitant medication by the medical director, it was determined 
that antipyretics were not consistently reported in detail, and in some instances the same drugs, which 
are both antipyretics and analgesics, were used for indications other than fever. For example, 
considering a participant as not having been recovered from fever because s/he has taken an 
antipyretic/analgesic without either previous signs or symptoms of fever previously was not 
appropriate. 
This constitutes a deviation from the definition and, therefore, analysis, as stated in the protocol 
(Amendment 4 dated 15 June 2021) 
Clarification: Temperature data from the biosticker for the first 10 participants will not be used to 
determine if a participant is febrile. 
Justification: Temperature data from the biostickers for the first 10 patients was compared with the 
temperatures measured by study staff at patient contacts.  It was found that correlation between 
manually measured temperatures and data collected from the biostickers at the times that patients had 
temperatures taken was poor.  Accordingly, temperatures measured by the biostickers will not be used 
for determination of recovery from symptomatic COVID; only the diary data will be used.   
Clarification: The definition of recovery specifically notes that fatigue, anosmia and ageusia/dysgeusia 
may be persistent, defined as being “at a level similar to that during the acute illness”. For analysis, we 
have defined “at a level similar to that during the acute illness” as follows:  severity of each symptom is 
graded as 0, 1, 2 or 3 for questionnaire responses none, mild, moderate or severe, respectively.  The 
median grade for responses during the first 7 days of study (which may contain fewer than 7 responses 
if the patient missed one or more days) will be calculated.  As long as the individual symptom is no 
worse than the median value during the first week, it will not be considered in determining the date of 
recovery.  
Addition: Additional knowledge of the course of COVID-19 has been gained over the past year and a 
half, since the protocol definition of recovery was written.  Accordingly, several sensitivity analyses using 
different definitions of recovery may be undertaken. Examples include: 
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Page 28 of 28 
Part A Statistical Analysis Plan (Version 2.0) 
  
 
 
1. First day at which there are no moderate or severe symptoms and ≤2 mild symptoms or 
symptoms worse than pre-COVID-19 illness, for at least 14 days or until last observation on 
study, whichever comes first.  This will be calculated two ways: including and excluding sense of 
taste and smell. 
2. First day at which there are no symptoms and no occurrence of any symptoms for at least 14 
days or until last observation on study, whichever comes first.  This will be calculated two ways: 
including and excluding sense of taste and smell. 
3. First day at which the global assessment of symptoms is none and the global usual health 
response is yes, both continuing for at least 14 days or last observation on study, whichever 
comes first. 
Justification:  as noted in the amended procedure, considerable knowledge regarding resolution of 
COVID-19 symptoms and the occurrence of “long COVID” has been accumulated since the protocol was 
written.  Accordingly, in this pilot analysis which is preparatory to a larger, definitive study, we want to 
consider several potential ways to look at the data, in order to optimize definition of the endpoint to be 
used for the pivotal study. 
20.1.2 Modified intent-to-treat (mITT) population 
Change: A small edit to the definition was made to clarify that the mITT population will include all 
randomized patients who receive any study treatment regardless of receipt of antibody treatments. The 
definition now reads:  
Modified Intent to Treat (mITT) Population includes all randomized patients who receive any 
study treatment. 
 
 
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Certificate Of Completion
Envelope Id: 721B272071FA4FD1B348452230398518
Status: Completed
Subject: Please DocuSign: RHB-107-01 Part A SAP_v2.0_13Jan2022.pdf
Project/Charge Code: 150026.001.699.001
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Certificate Pages: 5
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Timothy Asmar
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