Clinical trial NCT04470544
Conditions: Severe Acute Respiratory Syndrome
Sponsor: Alan Bryce
Start date: 2020-07-28; Completion date: 2022-01-20
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To determine if the reduction in TMPRSS2 activity via direct inhibition with Camostat mesilate combined with standard of care (SOC) treatment will increase the proportion of patients alive and free from respiratory failure at Day 28 in SARS-CoV-2 as compared to SOC treatment with placebo.

Detailed description:

Arms: arm 1: Standard of Care will be defined by the investigators in collaboration with the sponsor on the basis of the best available evidence at the time of study initiation with placebo. arm 2: Patient will receive SOC tablets and Camostat mesilate 200 mg four times a day after each meal with Standard of Care treatment.
Interventions: intervention 1: Camostat Mesilate intervention 2: Standard of Care
Intervention descriptions: intervention 1: Given PO intervention 2: At Investigator discretion

Protocol documents:
Prot_SAP_000.pdf: 
Mayo Clinic 
 
 
RECOVER: Phase 2 Randomized, Double-Blind Trial TREating hospitalized patients with COVID-19 
with Camostat MesilatE, a TMPRSS2 Inhibitor 
Amendment 3 – March 3, 2023 
 
Summary of Changes 
Protocol section updated 
Nature of change 
Title Page 
• Updated Document History to reflect Version 3 
Section 4.0, Test Schedule 
• Footnote ‘o’ added to allow remote monitoring after 
day 1 for patients discharged from the hospital 
Section 7.0, Protocol Treatment 
• Section 7.1 updated to allow NG tube as a potential 
route for Camostat or Placebo 
Section 8.0, Adverse Event (AE) 
Monitoring and Reporting 
• 8.4.1 updated to send reports to Ono 
• 8.6 pregnancy reporting added 
Section 9.0, Biospecimens 
• 9.1 Table updated allowing all specimen collection to 
be mandatory on day 1, optional on all other days 
• 9.2 Mayo Clinic Florida will assemble kits for their 
site 
• 9.2.6 Specimens that are drawn during the evening 
hours (Monday through Wednesday) can be shipped 
the next morning 
• 9.3.2 Mayo Clinic Florida will store specimens and 
ship batch at end of study enrollment to Mayo Clinic 
Arizona 
Section 11.0, Drug Information 
• 11.1.4 Updated to allow NG tube as a potential route 
for Camostat or Placebo 
Section 13.0, Statistical Considerations and 
Methodology 
• 13.4 Primary analysis updated for clarification on 
minimizing loss to follow-up 
• 13.7 Stopping rule updated to specify the stopping 
rule criteria will be evaluated separately for each 
treatment arm 
Editorial and administrative changes have been made throughout the protocol but do not affect the 
scientific content or meaning. 
A replacement protocol is provided. Please replace the current copy with the one attached. 
 
Please keep this summary of changes with your protocol 


CAM20CV 
Amendment 3 
 
 
 
RECOVER: Phase 2 Randomized, Double-Blind Trial TREating hospitalized patients with COVID-19 
with Camostat MesilatE, a TMPRSS2 Inhibitor 
 
 
FDA IND 
Sponsor/Principal Investigator: 
 
 
 
 
 
 
 
Co-Investigators: 
 
 
 
Statistician: 
 
 
IND #: 150171 
 
 
Drug Availability: 
Drug Company Supplied: Camostat mesilate or placebo 
 
Commercial: Remdesivir 
 
√ Study contributor(s) not responsible for patient care 
 
Research Coordinating Center 
 
 
 
 
 
Document History 
(Effective Date) 
 
Version 1.0 
April 28, 2020 
Version 2.0 
June 12, 2020 
Version 2.1 
July 29, 2020 
Version 3.0 
March 2, 2023 


3 
3 
 
 
 


4 
4 
 
 
 
Table of Contents 
Schema .......................................................................................................................................................... 5 
1.0 
Background ........................................................................................................................................ 6 
2.0 
Goals .................................................................................................................................................. 7 
3.0 
Patient Eligibility ............................................................................................................................... 8 
4.0 
Test Schedule ..................................................................................................................................... 9 
5.0 
Stratification Factors ........................................................................................................................ 10 
6.0 
Registration/Randomization Procedures .......................................................................................... 11 
7.0 
Protocol Treatment .......................................................................................................................... 13 
8.0 
Adverse Event (AE) Monitoring and Reporting .............................................................................. 14 
9.0 
Biospecimens ................................................................................................................................... 20 
10.0 
Treatment/Follow–up Decision at Evaluation of Patient ................................................................. 22 
11.0 
Drug Information ............................................................................................................................. 24 
12.0 
Treatment Evaluation Criteria .......................................................................................................... 29 
13.0 
Statistical Considerations and Methodology .................................................................................... 30 
14.0 
Records and Data Collection Procedures ......................................................................................... 37 
15.0 
Bibliography .................................................................................................................................... 39 
Appendix I: Clinical Safety Labs ................................................................................................................ 40 
 


5 
5 
 
 
1:1 randomization 
Schema 
 
 
 
 
Hospitalized patients with 
SARS-CoV-2 infection 
 
 
(Control) 
Placebo + SOC* 
 
(Experimental) 
Camostat + SOC* 
 
 
 
 
 
 
*As the Standard of Care (SOC) is rapidly evolving, the control arm will be at the discretion of 
the treating physician and in accordance with institutional standards. Institutions will be 
responsible for obtaining SOC medications. The following SOC medications will not be 
provided by this study. 
• 
Remdesivir 
• 
Anticoagulation of hospitalized patients per institutional standard 


6 
6 
 
 
 
 
1.0 
Background 
 
COVID-19 infections caused by SARS-CoV-2 have overwhelmed health care systems around the 
globe due to the profound respiratory failure that is characteristic of severe disease and which 
constitutes the primary reason for death1. Immune responses to SARS-CoV-2 infection follow a 
two phase pattern. In the first phase, adaptive immune responses are protective and lead to mild 
disease. However, if immunity is impaired or otherwise deficient, severe cases are associated with 
Lymphopenia and a cytokine storm at which point the immune response is maladaptive and leads 
to acute respiratory distress syndrome (ARDS) and pulmonary failure.2,3 
COVID-19 is a Coronavirus that is similar to the pathogen (SARS-CoV) which caused the SARS 
epidemic of 2002-2003. Research into SARS-CoV demonstrated the potential role of TMPRSS2 
in the pathogenicity of that disease and in particular the link to pulmonary manifestations. 
Previous work has shown that the SARS S (spike) protein is proteolytically processed by 
TMPRSS2. SARS S is cleaved into several fragments upon coexpression of TMPRSS2 (cis- 
cleavage) and upon contact between SARS S-expressing cells and TMPRSS2-positive cells 
(trans-cleavage)4. SARS S protein is associated with inhibition of antibody mediated 
neutralization of the virus, and thus promotes viral spreading. TRMPSS2 is also a coreceptor for 
SAR-CoV (with ACE2), and is thus associated with SARS-CoV infectivity, shedding, and 
resistance to protective antibodies. Like SARS, SARS-CoV-2 has been shown to use the ACE2 
and TMPRSS2 receptors for cell entry.5 
Camostat is a serine protease inhibitor that is currently approved in Japan for the treatment of 
chronic pancreatitis and reflux esophagitis. It exhibits anti TMPRSS2 activity in cell line studies3. 
Camostat successfully abrogated SARS S cleavage, inhibited cell entry, and decreased viral 
replication. 
There is currently no proven therapy for COVID-19 infection. Multiple trials are currently active, 
with multiple agents having shown some promise based on small case series. These include 
hydroxychloroquine and azithromycin. 
A key national priority in the current pandemic as well as for the individual patients is to decrease 
the need for ICU admissions and ventilator support. Current projections estimate a national 
shortage of over 19,000 ICU beds and 31,000 ventilators at the peak of the infection6. In a case 
series of 138 hospitalized patients with SARs-CoV-2 pneumonia in Wuhan, 26% required 
admission to the ICU2. Therefore, any intervention that can lessen the need for respiratory support 
will improve survival both by helping the patient under treatment and by reducing the availability 
of limited resources for other patients. 
Remdesivir has recently received emergency use authorization from the US FDA as a treatment 
for hospitalized patients with severe cases of COVID-19. In its letter authorizing emergency use, 
the FDA describes remdesivir as “a direct acting antiviral drug that inhibits viral RNA synthesis.” 
Based on review of the topline data from the randomized, double-blinded, placebo-controlled trial 
conducted by NIAID (NCT04280705) and from the Gilead-sponsored open-label trial that 
evaluated different durations of remdesivir (NCT04292899), it is reasonable to believe that the 
known and potential benefits of RDV outweigh the known and potential risks of the drug for the 
treatment of patients hospitalized with severe COVID-19.”7 The EUA is based on preliminary 


7 
7 
 
 
 
 
data from the National Institute of Allergy and Infectious Diseases (NIAID) sponsored Adaptive 
COVID-19 Treatment Trial (ACTT) indicate that patients who received remdesivir had a median 
time to recovery of 11 days compared with 15 days for those who received placebo(p<0.001). 
The mortality rate was 8.0% for the group receiving remdesivir versus 11.6% for the placebo 
group (p=0.059)8. 
 
Other drugs that are frequently used for patients admitted with COVID -19 include 
anticoagulation, tocilizumab, and convalescent plasma. The use of convalescent plasma is based 
on an EUA and is currently being tested in a clinical trial. 
 
2.0 
Goals 
 
2.1 
Primary Objective 
To determine if the reduction in TMPRSS2 activity via direct inhibition with Camostat 
mesilate combined with standard of care (SOC) treatment will increase the proportion of 
patients alive and free from respiratory failure at Day 28 in SARS-CoV-2 as compared to 
SOC treatment with placebo. 
2.2 
Secondary Objectives include the following: 
 
2.2.1 
To determine if reduction in TMPRSS2 activity via direct inhibition with 
Camostat mesilate combined with SOC treatment will increase the proportion of 
patients alive and free of ventilator use or ECMO at Day 28 as compared to SOC 
treatment combined with placebo. 
2.2.2 
To determine if the combination of Camostat mesilate combined with SOC 
treatment will result in a decreased mortality rate at 28 and 56 days as compared 
to SOC treatment combined with placebo. 
2.2.3 
To determine if time to clinical improvement is reduced in patients receiving 
SOC treatment combined with Camostat mesilate as compared to SOC treatment 
combined with placebo. 
2.2.4 
To determine if Camostat mesilate combined with SOC treatment is associated 
with overall improved clinical status at Days 14 and 28 as compared to SOC 
treatment combined with placebo. 
2.2.5 
To determine if Camostat mesilate combined with SOC treatment is associated 
with a reduced length of stay in the hospital as compared to SOC treatment 
combined with placebo. 
2.2.6 
To determine if Camostat mesilate combined with SOC treatment is associated 
with reduced duration of: 
a) mechanical ventilation or ECMO use, 
 
b) non-invasive ventilation or high-flow oxygen use, and 


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8 
 
 
 
 
c) supplemental oxygen use as compared to SOC treatment combined with 
placebo. 
2.2.7 
To compare the safety and toxicity profile of Camostat mesilate combined with 
SOC treatment as compared to SOC treatment combined with placebo. 
2.2.8 To determine if treatment with Camostat mesilate combined with SOC treatment 
is associated with decreased incidence of thrombotic events and bleeding 
complications as compared to SOC treatment combined with placebo. 
2.3 
Exploratory Objectives 
 
2.3.1 
To determine changes in viral load over the course of treatment as determined by 
assays of nasopharyngeal secretions, oral secretions, stool, and serum. 
 
3.0 
Patient Eligibility 
 
3.1 
Inclusion Criteria 
 
3.1.1 
Laboratory confirmed SARS-CoV-2 infection 
 
3.1.2 
Admitted to hospital for management of SARS-CoV-2 
 
3.1.3 
Age ≥18 
 
3.1.4 
Subject or legal representative able to give informed consent 
 
3.1.5 
Ability to take all study drugs 
 
3.1.6 
Respiratory status of 3 or greater on the WHO ordinal scale 
 
3.1.7 
ALT or AST ≤5 x ULN 
 
3.1.8 
Creatinine clearance ≥50 mL/min using the Cockroft-Gault formula 
 
3.1.9 
Willingness to provide mandatory specimens for correlative research and 
banking (see Section 6.0 and 9.0). 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Women who are pregnant or breastfeeding 
 
3.2.2 
Known hypersensitivity to the study drug, the metabolites or formulation 
excipient 


9 
9 
 
 
 
 
 
4.0 
Test Schedule 
 
Baseline/Prior to 
Registration 
Randomized Treatment Period 
(Day 1-Day 14) 
Follow-Up Evaluation 
Day 0 (≤ 2 days) 
Day 1 (1st 
Dose ) 
Day 2- 
13(l) 
Day 14 
Day 28(k) 
Day 56(k) 
Informed Consent(a) 
X 
Complete medical and 
surgical history 
X 
Update of medical history 
X 
Record medications and 
therapies(b) 
X 
Record Concomitant 
medications 
X 
X 
X 
X 
X 
Height(c) 
X 
Body weight 
X 
X 
Comprehensive physical 
examination(d), (o) 
X 
X 
X 
X 
Targeted physical 
examination(e), (o) 
X 
X 
X 
Vital Signs(f), (o) 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
Chest CT 
X 
X 
CBC with differential(g) 
X 
X 
X 
X 
Comprehensive metabolic 
panel(g) 
X 
X 
X 
X 
Procalcitonin, IL-6, ferritin, 
azotemia, Ca, triglycerides, 
glucose, LDH, GGT, CPK, 
D-dimer, PT/INR, 
fibrinogen, and troponin 
X 
X 
X 
X 
Thrombotic Events(m) 
X 
X 
X 
X 
Renal profile(g) 
X 
X 
X 
X 
X 
Urinalysis with 
microscopic(g) 
X 
X 
Serum pregnancy test for 
WCBP 
X 
X 
X 
Urine pregnancy test for 
WCBP 
X 
Ordinal 
Scale Assessment(h) 
X 
X 
X 
X 
X 
PCR based COVID-19 
test(i) 
X 
Only Day 7 
X 
X 
X 
SpO2 by pulse oximetry 
with FiO2(j) 
X 
X 
X 
X 
X 
X 
Blood sample for future 
analysis (See Section 9.0)R 
X 
Only Day 7 
X 
X 
X 
Blood Sample for GBPA 
(See Section 9.0)R 
X 
Only Day 7 
X 
X 
X 


10 
10 
 
 
 
 
Stool (See Section 9.0)n, R 
X 
Only Day 7 
X 
X 
Saliva (See Section 9.0)R 
X 
Only Day 7 
X 
X 
PBMC (See Section 9.0)R 
X 
X 
Nasal Pharyngeal (See 
Section 9.0) 
X 
Only Day 7 
X 
X 
X 
Adverse Event Evaluation 
X 
X 
X 
X 
X 
a. ICF must be signed prior to performing Baseline evaluations. 
b. Record medications and therapies taken or received within 30 days prior to Baseline (or longer for 
investigational drugs for which 5 half-lives of the drug exceed 30 days). 
c. If subject is able to stand. 
d. Comprehensive physical examination will include the following organ or body system assessments: 
skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular; abdomen (liver, spleen); lymph 
nodes; and extremities, as well as an abbreviated neurological exam. 
e. Targeted physical examination will specifically target the pulmonary system, as well as any areas of 
concern from the medical history or noted on the prior physical examination or indicated by subject 
systems or other findings as determined by the Investigator or designee. 
f. BP, pulse rate, respiration rate, and temperature. Vital signs will be measured at Baseline, and twice 
daily at least 8 hours apart while hospitalized, and once daily as an outpatient. Timing of assessments 
in accordance with institutional SOP for hospitalized patients. 
g. See Appendix I for a list of specific CBC with differential, comprehensive metabolic panel, renal 
profile, and urinalysis with microscopic tests. 
h. See Section 12.0 for description of scale. 
i. 
Collect nose or throat swab to measure for the presence or absence of SARS-SoV-2 by a PCR based 
COVID-19 test. The swabbing site (nose or throat) used for the Baseline evaluation should be 
maintained for all subsequent assessments of the study. If only one nostril will be sampled, use the 
same nostril for collections. 
j. 
SpO2 determined by pulse oximetry with simultaneous recording of FiO2 to be recorded twice daily 
at least 8 hours apart while hospitalized, and once daily as an outpatient. Timing of assessments in 
accordance with institutional SOP for hospitalized patients. 
k. A + 3 day window will be allowed. 
l. 
Patients who are discharged prior to Day 14 will not need to come into the clinic to follow Day 1-14 
Test Schedule. Patients will be called by Study Team for remote evaluation and will resume visits on 
Day 14 unless needing to be seen sooner. 
m. Assess as clinically indicated by the treating physician. 
n. Stool samples can be ± 1 day and will be collected only if patient is able to produce. 
o. Since patients may improve and be discharged from the hospital at any point during the study period, 
remote monitoring without an in-person exam may be utilized for all Physical exam and assessments 
after day 1 in accordance with institutional SOP. 
 
 
R Research Funded 
 
5.0 
Stratification Factors 
 
5.1 
Age: ≥65 vs. <65 years 
 
5.2 
Clinical status ordinal score at enrollment: 3-4 (hospitalized with mild disease) vs. 
Score 5 (hospitalized with severe disease) 


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11 
 
 
 
 
 
 
 
 
6.0 
Registration/Randomization Procedures 
 
6.1 
Registration Procedures 
 
6.1.1 
To register a patient, access the Research Registration Application at 
 The Research Registration Application is available 24 
hours a day, 7 days a week. Back up and/or system support contact information is 
available on the website. If unable to access the website, contact Research 
Registration Office at 
between the 
hours of 8 a.m. and 4:30 p.m. Central Time (Monday through Friday). 
Access and training instructions for the Research Registration Application are 
available on the Office of Clinical Trials web page 
 
 
6.1.2 
Verification of materials 
 
Prior to accepting the registration, registration/randomization application will 
verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected 
health information 
 
6.1.3 
Documentation of IRB approval 
 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients. 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
 If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
 
6.1.4 
Correlative Research 


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12 
 
 
 
 
 
6.1.4.1 Mandatory 
 
A mandatory correlative research component and banking is part of this 
study, the patient will be automatically registered onto this component 
(see Sections 3.0, and 9.0). 
 
6.1.5 
Banking 
 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) 
for future research of SARS-CoV-2 infection. 
• 
Patient has/has not given permission to store and use his/her sample(s) 
for future research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) 
to researchers at other institutions. 
 
6.1.6 
Pretreatment 
 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.1.7 
Treatment 
 
Treatment cannot begin prior to registration and must begin ≤ 5 days after 
registration. 
 
6.1.8 
Kits are available on site. 
 
6.2 
Randomization Procedures 
 
6.2.1 
The factors defined in Section 5.0, together with the registering membership (site 
of institution) will be used as stratification factors. 
6.2.2 
After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 
treatment groups using the Pocock and Simon dynamic allocation procedure 
which balances the marginal distributions of the stratification factors between the 
treatment groups.11 
All patients must be registered before starting therapy. Under no circumstances 
will non-registered patients be retrospectively eligible for the study. 
6.3 
Procedures for Double-Blinding the Treatment Assignment 


13 
13 
 
 
 
 
6.3.1 
After the treatment assignment has been ascertained by the 
registration/randomization application, the patient’s treatment assignment (SOC 
treatment + Camostat mesilate OR SOC treatment + placebo) will be 
electronically sent to McKesson’s Clinical Research Services. Upon receipt of 
orders, McKesson will send per patient supplies to participating institutions. The 
Camostat mesilate/placebo will be prepared and labeled by McKesson. 
 
7.0 
Protocol Treatment 
 
7.1 
Patients will be randomized to either the control arm (placebo) or the treatment arm 
(camostat). 
Control Therapy Placebo combined with SOC: Patients will be randomized 1:1 to 
camostat or placebo taken as 2 tablets four times daily on an empty stomach at least 30 
minutes before each meal, 2 hours since the last meal, and at bedtime. Remdesivir will be 
administered once daily IV for 5 or 10 days. Remdesivir must be obtained commercially. 
Remdesivir will not be supplied for this study. Other management decisions are left to the 
discretion of the treating physicians and may include any medicines deemed necessary 
and appropriate such as anticoagulation. 
 
 
 
Agent 
Dose Level 
Route 
Day 
Camostat or 
placebo 
200 mg four times daily 
on an empty stomach 30 
minutes before each meal, 
2 hours since last meal, 
and at bedtime 
PO/NG € 
1-14 
Remdesivir¥ 
200 mg 
IV 
1 
Remdesivir¥ 
100 mg 
IV 
2, 3, 4, 5 (5 day 
course) 
OR 
2, 3, 4, 5, 6, 7, 8, 9, 
10 (10 day course 
per local provider 
recommendation§ 
Anticoagulation 
Per institutional standard 
¥ The suggested dose is for adults and pediatric patients weighing ≥ 40 kg. 


14 
14 
 
 
 
 
§ A treatment course of 10 days is recommended for adults and pediatric patients 
requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation. 
A treatment course of 5 days is recommended for adults and pediatric patients not 
requiring invasive mechanical ventilation and/or ECMO. If a patient does not 
demonstrate clinical improvement, treatment may be extended for up to 5 additional days 
(i.e. a total of 10 days). 
€ Doses may be administered via NG tube by dissolving tablets in 55 ml of warm water 
until tablets dissolve into solution. Resulting solution can be administered via NG tube. 
Note, if a patient is on continuous tune feedings, camostat doses must be held. 
7.2 
Dose Modifications 
 
Treatment discontinuation in the event of investigator assessed treatment 
associated toxicity rather than dose reduction. 
Missed doses should not be replaced. Rather, treatment should resume with the 
next scheduled dose. Doses missed due to clinical inability to administer the dose 
(e.g. patient is undergoing a procedure at the scheduled time) shall not be 
counted as a protocol deviation and should simply be recorded as “unable to give 
dose”. 
7.3 
Breaking Codes in Double-Blinded Studies 
 
7.3.1 
In the event of an emergency, email the Research Registration Office at 
to break the code on Monday through Friday, 8:00 
a.m. to 4:30 p.m. Central Time. If the code must be broken after hours, 
assume the patient was assigned to active treatment and treat 
accordingly. Send an email to the Research Registration Office 
informing them of the need to un-blind a patient. Provide your contact 
information so that the personnel can respond to the email the next 
business day. 
7.3.2 
If, in the judgment of the attending physician, it would be helpful for the 
future clinical care of the individual patient, the code may be broken 
after the patient has completed the study. That is, after the patient has 
been fully evaluated and all evaluation information has been recorded by 
the attending physician and the patient (if appropriate), the Research 
Registration Office may be emailed at 
to find out 
which study therapy the patient was receiving. 
 
8.0 
Adverse Event (AE) Monitoring and Reporting 
 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure 


15 
15 
 
 
 
 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug. 
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. 
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming 
aware of the event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, 
but that for a specific protocol are being reported via expedited means in order to 
facilitate the review of safety data (may be requested by the FDA or the sponsor). 
 
8.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site: 
 
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial. 
 
b. Identify the grade and severity of the event using the CTCAE version 5.0. 
 
c. Determine whether the event is expected or unexpected (see Section 8.2). 
 
d. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 


16 
16 
 
 
 
 
 
e. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 8.4). 
 
f. Determine if other reporting is required (see Section 8.5). 
 
g. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 8). 
 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA Lowest 
Level Term (LLT). 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as serious 
AE which is defined in the table in Section 8.4. 
 
8.2 
Expected vs. Unexpected Events 
 
Expected events - are those described within the Section 11.0 of the protocol, the study 
specific consent form, and the investigator brochure, (if an investigator brochure is not 
required, otherwise described in the general investigational plan). 
 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
11.0 of the protocol, the study specific consent form, or in the investigator brochure (or 
are not listed at the specificity or severity that has been observed); if an investigator 
brochure is not required or available, is not consistent with the risk information described 
in the general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
 
 
8.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug/device and the adverse event. 
 
8.4 
Expedited Adverse Event Reporting Requirements for IND/IDE Agents 
 
8.41 Expedited Reporting via the Adverse Event Expedited Report Form for Adverse 
Events That Occur Within 30 Days1 of the Last Dose of the Investigational Agent 


17 
17 
 
 
 
 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening adverse event 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH 
E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within the 
timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥ 
24 hrs 
7 Calendar Days 
24-Hour; 3 Calendar Days 
Not resulting in 
Hospitalization 
≥ 
24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, followed 
by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of learning 
of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded 
UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above applies after this 
reporting period. 
Effective Date: May 5, 2011 
Special Instructions: 
 
• 
Follow site-specific reporting guidelines. 
• 
Submit the Adverse Event Expedited Report Form to the SAE Coordinator email 
The SAE Coordinator will forward to Ono at 
within 24 hours of receiving. 
• 
The SAE Coordinator will forward to IND Coordinator 
 
as appropriate. The IND Coordinator will assist the sponsor-investigator in notifying the FDA 
if required. 
8.5 
Other Required Reporting 


18 
18 
 
 
 
 
8.5.1 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
 
 
8.5.2 
Submit via appropriate Case Report Forms the following AEs experienced by a 
patient and not specified in Section 8.5: 
 
8.5.2.1 Grade 1 and 2 AEs deemed possibly, probably, or definitely related to the 
study treatment or procedure. 
 
8.5.2.2 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure 
 
8.5.2.3 Grade 5 AEs (Deaths) 
 
8.5.2.3.1 
Any death within 56 days after registration on the trial must 
be submitted as a Grade 5 AE, with a CTCAE type and 
attribution assigned. 


19 
19 
 
 
 
 
8.6 
Pregnancy 
 
The investigator should report all pregnancies, including those of partners of male 
patients, within 24 hours to ACCRU at 
The SAE 
Coordinator will forward to Ono at 
 within 24 hours of being 
notified. 
 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn infant’s 
parent or legal guardian before any data collection can occur. A consent form will need to 
be submitted to the IRB for these subjects if a pregnancy occurs. If informed consent is 
not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion the mother is the patient. In cases where 
the child/fetus experiences a serious adverse event other than fetal death, the child/fetus 
is the patient. 
 
NOTE: When submitting ACCRU Adverse Event Report reports for “Pregnancy”, 
“Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure of the fetus to the 
investigational agent(s) should be documented in the “Description of Event” section. 
Include any available medical documentation. 


20 
20 
 
 
 
 
 
 
9.0 
Biospecimens 
 
9.1 
Summary Table of Research Blood/Blood Products to Be Collected for This Protocol 
 
 
Specimen 
Purpose 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Day 1 
Day 7 
Day 14 
Day 28 
Day 56 
Process
at site?
(Yes or
No)1,2 
 
 
 
-C1 
☒ Correlative 
☐ Banking 
Mandatory 
on day 1, 
optional all 
other days 
Nasal 
Pharyngeal 
Swab 
1 
X 
X 
X 
X 
X 
N 
 
 
 
-C2 
☒ Correlative 
☐ Banking 
Mandatory 
on day 1, 
optional all 
other days 
Whole blood 
SST (red 
and black 
marble top) 
8.5mL (1) 
X 
X 
X 
X 
X 
N 
 
 
C33 
☒ Correlative 
☐ Banking 
Mandatory 
on day 1, 
optional all 
other days 
Stool 
Brown and 
white bottle 
25mL 
X 
X 
X 
X 
N 
 
 
 
-C4 
☒ Correlative 
☐ Banking 
Mandatory 
on day 1, 
optional all 
other days 
Saliva 
Oragene 
1 
X 
X 
X 
X 
N 


21 
21 
 
 
 
 
 
Specimen 
Purpose 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Day 1 
Day 7 
Day 14 
Day 28 
Day 56 
Process
at site?
(Yes or
No)1,2 
 
 
 
-C5 
☒ Correlative 
☐ Banking 
Mandatory 
on day 1, 
optional all 
other days 
PBMC, 
plasma 
Na Heparin 
(green top) 
10mL 
X 
X 
N 
1. All samples will be processed and stored by Arizona BAP. 
2. All Mayo sites using RLIMS must add MCA processing instructions to RLIMS builds. 
3. Stool samples can be ± 1 day and will be collected only if patient is able to produce. 
 
9.2 
Kits will be used for this study. 
 
9.2.1 
Kits will be supplied by the MCA Biospecimen Accessioning and Processing 
Shared Resource (BAP). 
 
NOTE: Mayo Clinic Florida BAP will assemble the kits for specimen collection 
at Mayo Clinic Florida. 
 
9.2.2 
The kit contains supplies and instructions for collecting, processing and shipping 
specimens. 
 
9.2.3 
Participating institutions may obtain kits by emailing the Supply Order Form to 
the number listed on the form (D: ARZ Biobank). Because we are charged for all 
outgoing kits, a small, but sufficient, supply of the specimen collection kits 
should be ordered prior to patient entry. Supply Order Forms must be filled in 
completely and legibly for quick processing. 
 
9.2.4 
Kits will be sent via Fed Ex Ground at no additional cost to the participating 
institutions. Allow at least two weeks to receive the kits. 
 
9.2.5 
Kits will not be sent via rush delivery service unless the participating institution 
provides their own Fed Ex account number or alternate billing number for 
express mail. Cost for rush delivery of kits will not be covered by the study. 
 
9.2.6 
Specimens must be collected and shipped Monday – Thursday ONLY. MCA 
may collect Monday-Friday. Specimens that are drawn during the evening 
hours (Monday through Wednesday) can be shipped the next morning. 
 
9.3 
Shipping Specimens 


22 
22 
 
 
 
 
9.3.1 
Verify ALL section of the Blood Specimen Submission Form (see Forms 
Packet), BAP Requisition Form (provided in kit), and specimen collection labels 
are completed and filled in correctly. 
 
9.3.2 
Specimens must be shipped the same day they are drawn/collected. 
 
NOTE: Mayo Clinic Florida will process and store specimens at Mayo Clinic 
Florida Biobank and then ship specimens in batch to Mayo Clinic Arizona at the 
end of study enrollment. 
 
 
9.3.3 
Ship all samples via Priority Overnight service. The nasal pharyngeal swabs, 
saliva, Na Heparin, SST tubes and brown and white stool bottles will be shipped 
in a dual-temperature shipping container. Place the refrigerated SST red and 
black marble top and the brown and white stool container with a properly 
prepared cold pack in one compartment. See kit instructions for specific details 
for cold pack preparation (i.e., frozen or refrigerated) and proper packing of 
blood and cold pack to avoid freezing of specimen. Place the nasal pharyngeal 
swab, Oragene saliva samples, and NA Heparin green top tube with an ambient 
cool pack in the other compartment of the dual-temperature shipping container. 
 
9.3.4 
Ship specimens via Priority Overnight service. Do not send samples on 
weekends or just prior to federal holidays. 
 
9.3.5 
The BAP kits will include a smart shipper label (3x5 white barcoded label) 
affixed to the shipping boxes. The smart shipper label is a pre-addressed return 
label, which replaces the need for an airbill. Shipping costs will be covered by 
the funding sponsor if the shipping box provided with the BAP kit is used for 
shipping specimens to BAP Receiving. 
 
Recipient Name: BAP 
Company Name: Mayo Clinic 
Address Line 1: 5779 E. Mayo Blvd. 
Address Line 2: MCSB C-303 
City: Phoenix 
State: AZ 
Zip: 85054 
Phone: (480) 342-4036 
 
9.3.6 
BAP Arizona will receive the samples, accession and process and store the 
samples as indicated at MCA BAP. Samples will be processed and stored per the 
protocol and then sent weekly in batches to: 
 
 
 
 
10.0 
Treatment/Follow–up Decision at Evaluation of Patient 


23 
23 
 
 
 
 
10.1 
Continuation of treatment 
Patients who are responding and show signs of clinical improvement to treatment per the 
investigator’s judgement will continue treatment per protocol. 
10.2 
Clinical deterioration 
Patients who develop clinical deterioration while receiving therapy will go to the clinical 
follow-up phase. 
10.3 
Off protocol treatment 
Follow the table below for patient follow-up after patient goes off protocol treatment. 
 
 
CFU=Clinical Follow-Up 
 
Reason Off Treatment 
Go to CFU, or end 
follow-up 
Treatment (Intervention) Completed Per Protocol Criteria 
CFU 
Patient Withdrawal/Refusal After Beginning Protocol Therapy 
(Intervention) 
CFU 
Adverse Events/Side Effects/Complications 
CFU 
Clinical deterioration During Active Treatment (Intervention) 
CFU 
Alternative Therapy 
No follow-up 
Patient Off-Treatment (Intervention) For Other Complicating 
Disease 
CFU 
Death On Study 
No follow-up 
Other 
CFU 
Clinical deterioration Before Active Treatment (Intervention) 
No follow-up 
Patient Withdrawal/Refusal Prior To Beginning Protocol Therapy 
(Intervention) 
No follow-up 
 
 
10.4 
Clinical Follow-up occurs at Day 28 and Day 56 after registration unless patient 
withdrawal has occurred. 
If the patient has achieved clinical improvement, the patient will be observed at 56 days, 
from time of registration. 
10.5 
Ineligible 
 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
• 
If the patient received treatment, the patient may continue treatment at the discretion 
of the physician as long as there are not safety concerns. The patient will continue in 
the Active Monitoring/Treatment phase of the study, as per section 4.0 of the 
protocol. 
• 
If the patient never received treatment, on-study material must be submitted. Clinical 


24 
24 
 
 
 
 
Follow-up will be required per Section 4.0 of the protocol. 
 
10.6 
Major violation 
 
A patient is deemed a major violation, if protocol requirements regarding treatment of the 
initial therapy are severely violated that evaluability for primary end point is 
questionable. If the patient received treatment, the patient may continue treatment at the 
discretion of the physician as long as there are no safety concerns. The patient will 
continue in the Active Monitoring/Treatment phase of the study, as per section 4.0 of the 
protocol, and all data submission should continue per protocol. If the patient does not 
continue with treatment, the patient will go off treatment and be followed in Clinical 
Follow-up. 
10.7 
Cancel 
 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the Off Treatment form must be 
submitted. No further data submission is necessary. 
 
11.0 
Drug Information 
 
11.1 
Camostat mesilate (Foipan®): 
 
11.1.1 Background: Camostat mesilate is a serine protease inhibitor that is currently 
approved in Japan for pancreatitis and reflux esophagitis. Camostat mesilate acts 
promptly on kinin formation, fibrinolytic, coagulation and complementary 
systems to immediately inhibit enzyme activities and their abnormal increases. 
For the purposes of this study, camostat mesilate also exhibits anti- 
transmembrane serine protease 2 (TMPRSS2) activities. It can also void severe 
acute respiratory syndrome (SARS) S cleavage, inhibit cell entry and decrease 
viral replication. 
11.1.2 Formulation: Camostat mesilate is available as a 100 mg film coated tablet. Each 
tablet also contains hydroxypropylcellulose, carmellose calcium, magnesium 
stearate, polyoxyethylene (105) polyoxyethylene (5) glycol, and lactose hydrate. 
11.1.3 Preparation and storage: Camostat mesilate are packaged in bottles of 28 tablets. 
The recommended storage condition for camostat mesilate film coated tablets is 
15° to 30°C. 
11.1.4 Administration: Camostat mesilate tablets should be taken by mouth or via 
nasogastric tube four times daily on an empty stomach at least 30 minutes before 
each meal, 2 hours since last meal, and at bedtime. For nasogastric 
administration, place tablets into 55 ml of room temperature water until tablets 
dissolve into solution. Once tablets have dissolved, deliver the solution to 


25 
25 
 
 
 
 
patients via nasogastric tube. If a patient is receiving continuous tube feedings, 
camostat dosing must be held while on continuous tube feedings. 
 
 
11.1.5 Pharmacokinetic information: 
 
Absorption: After a single dose of camostat mesilate at 200 mg, Tmax values 
were 40 minutes with a maximum of 87.1 ng/mL 
Protein binding: Protein binding to human serum was 25.8-28.2% 
 
Metabolism: Carboxylate ester moiety of camostat mesilate is hydrolyzed to an 
active metabolite 4-(4-guanidinobenzoyloxy) phenylacetate, which is further 
hydrolyzed to 4-guanidinobenzoic acid. Camostat mesilate is mainly hydrolyzed 
by carboxyesterase and 4-(4-guanidinobenzoyloxy) phenylacetate by arylesterase 
(in vitro). Camostat mesilate and its metabolite 4-(4-guanidinobenzoyloxy 
phenylacetate did not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6 and 
CYP3A4 (in vitro). 
Half-life elimination: Mean half-life is 100 minutes +/- 40 minutes. 
 
Excretion: Urinary excretion rates at 5-6 hours post administration were 20% and 
0.8%, respectively, and little was further recovered in urine during later periods. 
11.1.6 Potential Drug Interactions: Camostat mesilate did not appreciably inhibit 
CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 (in vitro). 
11.1.7 Known potential toxicities: 
 
Clinically significant toxicities: 
• 
Shock or anaphylactic symptoms 
• 
Thrombocytopenia 
• 
Hepatic function disorder or jaundice 
• 
Hyperkalemia 
 
Toxicities ≥ 0.1 to < 0.5%: 
Hypersensitivity: Rash, pruritus 
Gastrointestinal: Nausea, abdominal discomfort, abdominal fullness, diarrhea 
Hepatic: Increased AST (GOT), ALT (GPT) 
 
Toxicities < 0.1%: 
Hematologic: Leukopenia, erythrocytopenia 
Gastrointestinal: Anorexia, vomiting, dry mouth, heartburn, 
abdominal pain, constipation 
Renal: Increased BUN, increased creatinine 
Other: Edema, hypoglycemia 


26 
26 
 
 
 
 
Incidence unknown: Eosinophilia 
 
11.1.8 Drug procurement: Ono Pharmaceutical Co., Ltd. will supply the drug to 
McKesson Specialty Pharmacy’s Clinical Research Services. After the patient is 
registered, McKesson will receive an electronic order with the patient’s treatment 
assignment. Upon receipt of orders, McKesson will send per patient supplies to 
participating institutions. The Camostat mesilate will be prepared and labeled by 
McKesson. 
11.1.9 Temperature excursions that occur at the site should be reported by the site by 
contacting McKesson Speciality Pharmacy at 
 
 
11.2 
Placebo for camostat 
 
11.2.1 Formulation: Placebo will be available as a film coated tablet. Each tablet 
contains D-mannitol, low substituted hydroxypropyl cellulose, and magnesium 
stearate. The film coating contains hydroxypropyl methylcellulose and purified 
water. 
11.2.2 Preparation & storage: The recommended storage condition for placebo film 
coated tablets is 15° to 30°C. 
11.2.3 Administration: Take by mouth four times daily on an empty stomach at 
least 30 minutes before each meal, 2 hours since last meal, and at bedtime. 
11.2.4 Drug Procurement: Ono Pharmaceutical Co., Ltd. will supply the drug to 
McKesson Specialty Pharmacy’s Clinical Research Services. After the patient is 
registered, McKesson will receive an electronic order with the patient’s treatment 
assignment. Upon receipt of orders, McKesson will send per patient supplies to 
participating institutions. The placebo will be prepared and labeled by 
McKesson. 
11.2.5 Temperature excursions that occur at the site should be reported by the site by 
contacting McKesson Speciality Pharmacy at 
 


27 
27 
 
 
 
 
11.3 
Remdesivir (GS-5734, Veklury®)) 
 
11.3.1 Background: Remdesivir is a nucleotide prodrug that is intracellularly 
metabolized into an analog of adenosine triphosphate that inhibits viral RNA 
polymerases and has broad activity against members of the filoviruses [i.e. Ebola 
virus, Marburg virus, CoVs (SARS-CoV, MERS-CoV) and paramxoviruses 
(respiratory syncytial virus, Nipha virus, and Hendra virus)]. 
11.3.2 Formulation: Remdesivir for Injection, 100 mg, is a preservative-free, white to 
off-white or yellow lyophilized solid containing 100 mg of remdesivir. It requires 
reconstitution and then further dilution prior to administration by intravenous 
infusion. The inactive ingredients are 3 g betadex sulfobutyl ether sodium and 
may include hydrochloric acid and/or sodium hydroxide for pH adjustment. 
 
 
Remdesivir injection contains 100 mg/20 mL (5 mg/mL) as a sterile, 
preservative-free, clear, colorless to yellow solution in a single-dose clear glass 
vial. It requires dilution prior to administration by intravenous infusion. The 
inactive ingredients are 6 g betadex sulfobutyl ether sodium, Water for Injection, 
USP, and may include hydrochloric acid and/or sodium hydroxide for pH 
adjustment. 
11.3.3 Preparation and storage: Remdesivir for Injection should be stored refrigerated at 
at 2˚C to 8 ˚C [36 ˚F to 46 ˚F] prior to use. 
 
There are differences in the way the two formulations are prepared. 
Carefully follow the product-specific preparation instructions below. 
Remdesivir for Injection 100 mg lyophilized powder is to be reconstituted with 
19 mL of Sterile Water for Injection. Immediately shake the vial for 30 seconds. 
Allow the contents of the vial to settle for 2 to 3 minutes. A clear, colorless to 
yellow solution, free of visible particulates, should results. If the contents are not 
completely dissolved, repeat the process of shaking for 30 seconds and allowing 
contents to settle for 2 to 3 minutes. Following reconstitution, each vial contains 
5 mg/mL remdesivir concentrated solution with sufficient volume to allow 
withdraw of 20 mL (100 mg of remdesivir). 
 
Remdesivir should be diluted into 100 to 250 mL 0.9% NaCL prior to 
administration by intravenous infusion. Invert 20 times to mix. Remdesivir for 
injection is recommended to be reconstituted and diluted within the same day as 
administration. The prepated infusion solution is stable for 24 hours at room 
temperature (20°C to 25°C [68°F to77°F]) or 48 hours at refrigerated temperature 
(2°C to 8°C [36°F to 46°F]).Any unused remdesivir should be discarded. 


28 
28 
 
 
 
 
11.3.4 Administration: Infuse intravenously over 30 minutes. The infusion time may be 
extended up to 120 minutes. Flush the tubing with 30 mL of 0.9% NaCL post- 
remdesivir infusion. 
11.3.5 Pharmacokinetic information: 
 
Protein binding: Remdesivir: 88% to 93.6%; GS-441524: 2%; GS-704277: 1% 
Half-life elimination: Remdesivir: ~1 hour; GS-441524: 27 hours; GS704277: 
1.3 hours 
Excretion: Urine: Remdesivir: 10%; GS-441524: 49%; GS-704277: 2.9%; 
Feces: Remdesivir: not detected; GS-441524: 0.5%; GS-704277: not detected 
 
11.3.6 Potential Drug Interactions: Due to potential antagonism based on data from cell 
culture experiments, concomitant use of remdesivir with chloroquine phosphate 
or hydroxychloroquine sulfate is not recommended. 
Drug-drug interaction trials have not been conducted in humans. Remdesivir and 
its metabolites are in vitro substrates and/or inhibitors of certain drug 
metabolizing enzymes and transporters. The clinical relevance of these 
assessments has not been established. 
11.3.7 Known potential toxicities: 
 
Common known potential toxicities ≥ 10%: 
Endocrine & metabolic: Increased serum glucose 
Renal: Decreased creatinine clearance 
 
Less common known potential toxicities 1-10%: 
Dermatologic: Skin rash 
Gastrointestinal: Nausea 
Hematologic & oncologic: Decreased hemoglobin, lymphocytopenia, prolonged 
prothrombin time 
Hepatic: Increased ALT, increased AST 
Hypersensitivity: Hypersensitivity reaction 
Frequency not defined: 
Hepatic: Increased serum alkaline phosphatase 
Hypersensitivity: Anaphylaxis, angioedema 
Local: Erythema at injection sites 
Miscellaneous: Infusion related reaction 
 
Postmarketing: 
Cardiovascular: Bradycardia, heart failure, hypotension 
Hepatic: Acute hepatic failure 
 
11.3.8 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 


29 
29 
 
 
 
 
12.0 
Treatment Evaluation Criteria 
 
The ordinal scale used for assessment of the clinical and respiratory status on each day of the study is 
included below. Each day, the worst (i.e., highest ordinal) score from the previous day will be recorded, 
i.e., on Day 3, the highest ordinal score from Day 2 is obtained and recorded for Day 2. The scale is as 
defined by the WHO as follows7: 
 
 
 
Patient State 
Descriptor 
Score 
Uninfected 
No Clinical or Virological Evidence of 
Infection 
0 
Ambulatory 
No Limitation of activities 
1 
Limitation of activities 
2 
Hospitalized, Mild Disease 
Hospitalized, no oxygen therapy 
3 
Oxygen by mask or nasal prongs 
4 
Hospitalized, Severe Disease 
Non-invasive ventilation or high flow 
oxygen 
5 
Intubation and Mechanical Ventilation 
6 
Ventilation + additional organ support- 
pressors, RRT, ECMO 
7 
Dead 
Death 
8 
 
 
In addition, patients will be stratified at baseline based on the ordinal scale below. A score of 3-4 is 
associated with hospitalized with mild disease versus score of 5 is associated with severe disease. 
The primary outcome assessment for efficacy will be evaluated based on the number of patients who are 
alive AND respiratory failure-free at Day 28 after study entry. 
Respiratory failure at Day 28 will be defined by clinical diagnosis of respiratory failure corresponding to 
a score of 5-8 on the above ordinal scale at Day 28. Specifically, respiratory failure is defined by meeting 
any of the following criteria: 
 
• 
Requiring ICU admission, 
• 
mechanical ventilation, 
• 
ECMO, 
• 
non-invasive ventilation, 
• 
or high flow oxygen devices, 


30 
30 
 
 
 
 
13.0 
Statistical Considerations and Methodology 
 
13.1 
Statistical Design 
 
The study design will be a randomized (1:1 ratio), double-blinded, placebo-controlled 
phase II trial of 264 patients. Randomization will be stratified based on age (< 65 years 
versus >= 65 years) and disease severity at study entry (hospitalized with mild disease 
versus hospitalized with moderate/severe disease). The purpose of this study is to 
evaluate the efficacy of Camostat mesilate in addition to SOC treatment as compared to 
SOC treatment combined with placebo with respect to clinical status on Day 28. The 
proportion of patients alive AND free from respiratory failure at Day 28 will be the 
primary outcome. 
Patients will be analyzed according to their randomization assignment. All patients 
meeting eligibility criteria who received at least1 dose of study drug will be included in 
the analysis. 
Formal interim analysis will be conducted after the first 66 patients (33 treated in the 
treatment arm and 33 in the control group) have completed the 28 Day assessment period. 
Safety analyses will be done to assess occurrence of any differences in adverse events 
between the treatment arms. A second interim analysis will occur after 132 patients (66 
in the treatment arm and 66 in the control group) have completed the 28 Day assessment 
period. 
13.2 
Accrual Time and Study Duration 
 
We expect to accrue approximately 20 patients a week across the clinical trial sites. With 
a total sample size of 264 and a follow-up duration of 56 days for all patients, accrual will 
require approximately 14 weeks with a total study duration of 22 weeks. The primary 
endpoint will be evaluable after 28 days of follow-up in all patients. 
13.3 
Study Endpoints 
 
13.3.1 Primary Endpoint: 
 
The primary endpoint will be evaluated based on the number of patients who are alive 
AND free from respiratory failure at Day 28 after study entry divided by the number of 
total patients enrolled for each treatment arm. A respiratory failure event is defined in the 
Treatment evaluation criteria section 12.0. 
13.3.2 Secondary Endpoints 
 
1.  Proportion of patients alive AND free of ventilator use or ECMO at Day 28: The 
proportion will be evaluated based on the number of patients who are alive AND free of 
ventilator use or ECMO (clinical status score of 5 or less) at Day 28 after study entry 
divided by the number of total patients enrolled for each treatment arm. 
2.  Time to death: Time to death will be measured as the number of days from the date of 
randomization/study entry until death date. Deaths due to any cause will be considered an 


31 
31 
 
 
 
 
event. All-cause mortality rate at 28 and 56 days after study entry will be evaluated. If the 
patient is lost to follow-up or withdraws from the study early, or doesn’t experience a 
death event, they will be censored at Day 28. 
3.  Time to clinical improvement: Clinical improvement will be defined as a 2 or more 
point decrease on the WHO ordinal scale (see Section 12.0). Time to clinical 
improvement will be calculated as the number of days from study entry until the earliest 
date of clinical improvement as defined above. The number of patients who achieve 
clinical improvement by Day 14 and 28 will be evaluated. In addition, time to clinical 
improvement will also be assessed. 
4.  Clinical status at Days 14 and 28: Evaluation of the distribution of clinical status 
scores by the ordinal scale will be done at days 14 and 28. 
5.  Length of Hospitalization Stay: This will be defined as the time from randomization/ 
study entry until the time of hospital discharge. Time in the ICU will be described in 
number of days spent receiving ICU care, if applicable. 
6.  Duration of Mechanical ventilation / ECMO: Ventilator / ECMO days will be defined 
as the number of days where the clinical status score is equal to 6 or 7 for those subjects 
who have a baseline score of 6-7 at study entry. Total number of days will be the sum of 
all reported days, regardless of whether the days occur consecutively or in disjoint 
intervals. 
 
7.  Duration of non-invasive ventilation / high-flow oxygen: Non-invasive ventilation / 
high-flow oxygen days will be defined as the number of days where the clinical status 
score is equal to 5 for those with a baseline score of 5 at study entry. Total number of 
days will be the sum of all reported days, regardless of whether the days occur 
consecutively or in disjoint intervals. 
 
8.  Days of supplemental oxygen use: Oxygen days will be defined as the number of days 
where the clinical status score is equal to 4-7 for those who have a clinical status score 
greater than or equal to 4 at study entry. Total number of days will be the sum of all 
reported days, regardless of whether the days occur consecutively or in disjoint intervals. 
 
9.  Occurrence of adverse events related to treatment: Adverse Events will be recorded 
and graded according to CTCAE version 5.0 criteria. Occurrence of grade 3 or higher 
adverse events and SAEs will be assessed between arms. 
10.  Development of thrombosis / bleeding complications: Incidence of arterial and 
venous thrombosis or bleeding complications will be described in both treatment groups. 
 
 
13.3.3 Exploratory Endpoint(s) 
 
1. Time to Viral Clearance: Viral clearance will be assessed at days 1, 7, 14, 28, 56 after 
study entry and the proportion of patients having viral clearance at each of these days will 
be estimated as the proportion of patients who are documented as having non-detectable 


32 
32 
 
 
 
 
viral shedding divided by the total number of patients in each treatment arm. Serum and 
nasopharyngeal assays will be used for this analysis. 
13.4 
Planned Analyses 
 
Primary Analysis 
 
Frequency distributions and chi-square tests will be used to screen for major imbalances 
in the two randomization groups for qualitative variables; graphical displays including 
box plots and summary statistics (e.g., mean, median, standard deviation, ranges, etc.) 
will be used for quantitative variables with t-tests (after appropriate transformations if 
necessary to meet the assumptions of the methods). 
 
The primary outcome will include the number of patients who are alive AND free from 
respiratory failure at Day 28 divided by the total number of patients in each arm. This 
endpoint will be analyzed in a binary fashion using properties of the binomial distribution 
and will be compared between randomized arms by the use of independent samples Z-test 
for proportions and a 95% confidence interval will be constructed for the difference 
between arms. Proportions will also be compared using Cochran-Mantel-Haenszel tests, 
including the stratification factors of age and baseline disease severity. Multivariable 
logistic regression models will be used to assess the influence of treatment while 
controlling for covariates of interest (gender, symptom onset, comorbidities) along with 
stratification factors. Primary analysis for this efficacy outcome will include all 
participants who are randomized and received at least 1 dose of study treatment. 
Participants will be analyzed according to the treatment to which they were randomized. 
 
Efforts to minimize loss to-follow-up will be considerable. However, small amounts of 
missing data may occur. In such cases, participants without Day 28 outcome data will be 
excluded from the analysis. Sensitivity analyses will evaluate the impact of making 
different assumptions about the missing observations. 
 
Interim analyses: Two interim analyses will be conducted after 25% and 50% of patients 
have completed the 28 day study period. The interim analysis will include the below 
stopping rules for efficacy and futility based on a Lan-DeMets spending function with 
O’Brien-Fleming boundaries. Occurrence of adverse events will also be evaluated at the 
interim analysis. 
 
Accrual 
Control 
arm (#) 
Camostat 
arm (#) 
Total 
number 
(#) 
Efficacy 
boundary 
(Z scale) 
Alpha 
spent 
Futility 
boundary 
(Z scale) 
Beta 
spent 
25% 
33 
33 
66 
+/- 4.33 
0.001 
+/- 0.007 
0.002 
50% 
66 
66 
132 
+/- 2.96 
0.003 
+/- 0.34 
0.04 
100% 
132 
132 
264 
+/- 1.97 
0.05 
+/- 1.97 
0.20 
 
 
13.5 
Secondary Analyses 
 
1.  Proportion of patients alive AND free of ventilator use / ECMO at Day 28: The 
proportion will be evaluated based on the number of patients who are alive AND free of 


33 
33 
 
 
 
 
ventilator use or ECMO at Day 28 after study entry divided by the number of total 
patients enrolled for each treatment arm. The proportion of patients who have this event 
will be analyzed similarly to the primary endpoint. Comparisons will be done by use of 
independent samples Z-test for proportions and a 95% confidence interval will be 
constructed for the difference between groups. The Cochran-Mantel-Haenszel test will 
be used to include stratification factors. Multivariable logistic regression models will be 
used to assess the influence of treatment arm on while adjusting for other factors of 
interest. 
2. Time to death and Mortality rate: The Kaplan-Meier method will be used evaluate 
differences in the distributions of time-to-death between treatment arms. Rates of 
mortality at day 28 and day 56 mortality will be estimated. Patients lost to follow-up or 
who withdraw early will be considered censored at their last assessment date for the Day 
28 rate. The stratified log-rank test will be used to compare differences in distributions of 
time to death based on stratification factors. Cox proportional hazards model will be used 
to compare treatment arms with inclusion of stratification factors or adjustment for 
covariates of interest. 
3. Time to clinical improvement: Time to clinical improvement will be evaluated using 
Kaplan-Meier methods and Cox regression models. Rates of clinical improvement at days 
14 and 28 will be estimated. Time to clinical improvement will be assessed after all 
patients have reached day 14 and 28; no clinical improvement at day 14 or 28 or death 
before day 14 or 28 will be considered as right censored. Hazard ratios with 95% 
confidence intervals will be calculated by the Cox proportional-hazards model. 
Covariates of interest will be included in regression models. 
 
4. Clinical status at Days 14 and 28: The distribution of the clinical status will be 
summarized by arm at days 14 and 28. A proportional odds model with treatment arm 
and disease severity at baseline as covariates will be used to evaluate whether the odds of 
improvement on the ordinal scale are higher for the treatment arm as compared to 
control. 
 
5. Length of Stay: Length of stay will be defined as the time from study entry until the 
time of hospital discharge and the number of days hospitalized will be compared between 
groups by use of non-parametric Wilcoxon rank-sum test. The proportions of patients 
who require an ICU admission will be compared between randomized groups by the use 
of independent samples Z-test for proportions and a 95% confidence interval will be 
constructed for the difference between groups. In addition, time in the ICU will be 
described in number of days spent receiving ICU care, if applicable. 
6.  Duration of Mechanical ventilation / ECMO: Duration of ventilator / ECMO use will 
be summarized by medians or quartiles by arm for those subjects who have a baseline 
score of 6-7 at study entry. 
 
7.  Duration of non-invasive ventilation / high-flow oxygen: Duration of non-invasive 
ventilation / high-flow oxygen will be summarized by medians and quartiles by arm for 
those patients who have a clinical status score of 5 at study entry. 


34 
34 
 
 
 
 
8.  Duration of supplemental oxygen use: Duration of supplemental oxygenation use will 
be summarized by medians and quartiles by arm for those patients who have a clinical 
status score greater than or equal to 4 at study entry. 
 
9.  Occurrence of adverse events related to treatment: Analyses for safety will include all 
participants who are randomized and received at least 1 dose of study treatment. 
Participants will be grouped according to the treatment to which they were randomized. 
Events will be summarized on the basis of the date of onset for the event. The maximum 
grade for each type of adverse event will be recorded for each patient. Frequency tables 
of adverse events will be constructed based on maximum grade for each treatment arm. 
Overall adverse event rates, rates of grade 3 or higher events and serious adverse events 
will be compared between treatment groups using Chi-square or Fisher’s exact test. 
10.  Development of thrombosis / bleeding complications: Incidence of arterial and 
venous thrombosis or bleeding complications will be described and compared by 
treatment arms by use of chi-square or Fisher’s exact test. 
 
Subgroup analyses for the primary and secondary analyses will examine the treatment 
effect across the following subgroups of interest. Forest plots with odds ratio and 95% 
confidence intervals will be presented along with interaction tests. 
 
• Duration of symptoms prior to enrollment: <= Median versus > Median number of 
days, 
• Comorbidities, presence of Hypertension/CHF/COPD/coronary artery disease: Yes 
versus No, 
• Age: <65 versus >= 65 years, 
• Sex: Female versus Male, 
• Baseline severity of disease: Mild/moderate versus Severe disease 
Exploratory Analysis 
Time to Viral Clearance: Viral clearance will be assessed at days 1,7, 14, 28 and 56 after 
study entry and the viral clearance rate at each of these days will be estimated as the 
proportion of patients who are documented as having non-detectable viral shedding 
divided by the total number of patients in that treatment arm. The rates at each time point 
will be compared using chi-square tests to assess differences between treatment arms 
Missing Data Considerations 
 
All efforts will be made to minimize the occurrence of missing data. Subjects who 
discontinue treatment in either arm will be encouraged to remain in the study and to 
continue with follow-up visits for key outcomes at Day 28 and 56. 
 
For time to event outcomes, subjects who are lost to follow-up or withdrawal from the 
study prior to Day 28 and prior to observing/experiencing the event will be censored at 
the time of their last observed assessment. 
 
For duration of non-invasive ventilation/high-flow oxygen, ventilation/ECMO or 
supplemental oxygen, subjects will be considered to have the event of interest until Day 


35 
35 
 
 
 
 
28 if they have the event of interest at their last follow-up assessment day before Day 28 
in the case of lost to follow-up or patient withdrawal. Likewise, if they do not have the 
event of interest at their last follow-up assessment, they will be considered to not have 
this event through Day 28. 
 
If the subject is discharged and no further hospitalization data are available, then the 
subject will be assumed to not have been readmitted to the hospital. 
 
13.6 
Sample Size 
 
Randomization will be done according to a 1:1 ratio. Based on data from Wang et al(9) , 
82% of patients treated with Remdesivir were alive and free from respiratory failure at 
day 28. In the preliminary report of Remdesivir for the treatment of COVID-19 in 1059 
hospitalized patients, approximately 70% of patients treated with Remdesivir were alive 
and free from respiratory failure at Day 15; Day 28 data are not yet available(12). Using an 
expected proportion of 80% for the SOC control arm, this study would require 132 
patients in each arm (total of 264 patients). Sample sizes of 132 in each arm achieves 
80% power to detect a difference between the group proportions of 12% for the primary 
endpoint. The proportion in the treatment arm is assumed to be 80% under the null 
hypothesis and 92% under the alternative hypothesis. The proportion in the SOC arm is 
80%. The test statistic used is the two-sided Z-Test with unpooled variance. The 
significance level of the test is 0.05 (two-sided). 
 
13.7 
Data & Safety Monitoring 
 
The study chair(s) and the study statistician will review the study every week to identify 
accrual, adverse event, and any endpoint problems that might be developing. A Data 
Safety Monitoring Board (DSMB) will be formed to monitor the conduct of this study 
and for reviewing safety data. 
The DSMB will be comprised of disease experts who are not investigators or involved 
with the study. The DSMB will review the study safety data and interim analysis based 
on reports provided by the Statistical Office. 
Adverse Event Stopping Rules: The stopping rules specified below are based on the 
knowledge available at study development. The stopping rule applies to the overall study. 
We note that the Adverse Event Stopping Rule may be adjusted in the event of either (1) 
the study re-opening to accrual or (2) at any time during the conduct of the trial and in 
consideration of newly acquired information regarding the adverse event profile of the 
treatment(s) under investigation. The study team may choose to suspend accrual because 
of unexpected adverse event profiles that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we observe events 
considered at least possibly related to study treatment (i.e. an adverse event with attribute 
specified as “possible”, “probable”, or “definite”) that satisfy the following: 
 
• 
 If 3 or more of the first 10, or 30% or more of patients thereafter (in either 
treatment arm) experience a grade 3 or higher toxicity considered at least 
possibly related to study treatment. 


36 
36 
 
 
 
 
• 
The stopping rule criteria will be evaluated separately for each treatment arm. 
 
13.8 
Results Reporting 
 
At study activation, this study will have been registered within the “ClincialTrials.gov” 
website. The Primary and Secondary Endpoints along with other required information for 
this study will be reported on 
 For purposes of timing of the 
Results Reporting, the initial estimated completion date for the Primary Endpoint of this 
study is 28 days after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time the last patient registered has been 
followed for at least 28 days. 
 
13.9 
Inclusion of Women and Minorities 
 
13.9b 
This study will be available to all eligible patients, regardless of race, gender, or ethnic 
origin. 
 
13.9c 
There is no information currently available regarding differential effects of this regimen 
in subsets defined by race, gender, or ethnicity, and there is no reason to expect such 
differences to exist. Therefore, although the planned analysis will, as always, look for 
differences in treatment effect based on racial and gender groupings, the sample size is 
not increased in order to provide additional power for subset analyses. 
13.9d 
The geographical region served by Mayo Clinic has a population which includes 
approximately 30% minorities. Based on the burden of COVID in our community, we 
expect about 30% of patients will be classified as minorities by race and about 40% of 
patients will be women. Expected sizes of racial by gender subsets are shown in the 
following table: 
 
Accrual Estimates by Gender/Ethnicity/Race 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
21 
32 
53 
Not Hispanic or Latino 
84 
127 
211 
Ethnic Category: Total of all subjects* 
105 
159 
264 
Racial Category 
American Indian or Alaskan Native 
31 
48 
79 
Asian 
5 
8 
13 
Black or African American 
6 
23 
39 
Native Hawaiian or other Pacific Islander 
0 
0 
0 


37 
37 
 
 
 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
White 
53 
80 
133 
Racial Category: Total of all subjects* 
105 
159 
264 
 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central American, or 
other Spanish culture or origin, regardless of race. The term “Spanish origin” can also be used 
in addition to “Hispanic or Latino.” 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original peoples 
of North, Central, or South America, and who maintains tribal affiliations or community 
attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast Asia, 
or the Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, 
Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: Individuals from the 
Philippine Islands have been recorded as Pacific Islanders in previous data collection 
strategies.) 
Black or African American – a person having origins in any of the black racial groups of 
Africa. Terms such as “Haitian” or “Negro” can be used in addition to “Black or African 
American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the original 
peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle East, or 
North Africa. 
 
 
 
14.0 
Records and Data Collection Procedures 
 
14.1 
Submission Timetable 
 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
 
14.2 
CRF completion 
 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave® clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on the 
organization roster at the enrolling site. 
 
NOTE: Due to the design and length of study, treatment and follow-up data will be 


38 
38 
 
 
 
 
collected cumulatively on like forms and not divided into Treatment and Follow-up 
folders. Any questions regarding form completion and content should be directed to the 
Data Manager. 
 
14.3 
Site responsibilities 
 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
registration number, and protocol number. All PHI must be redacted from any 
documentation. 
 
14.4 
Supporting documentation 
 
Upload a copy of documentation of clinical improvement or clinical deterioration in 
RAVE on the Supporting Documentation Form. 
 
Baseline: The following documents are required for diagnosis and eligibility verification: 
(Imaging report (if available), Lab report, Clinic note, COVID viral assays, etc.). These 
documents should be submitted within 14 days of registration. 
 
Treatment/Follow-up: The following documents are required: (Imaging report, Lab 
report, Clinic note, etc.) 
 
At patient progression or restaging for evidence of response: (Imaging report, Lab report, 
Clinic note, etc.) 
 
14.5 
Labeling of materials 
 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
registration number, and protocol number. Patient’s name must be removed. 


39 
39 
 
 
 
 
15.0 
Bibliography 
 
 
1. 
Jingchun F, Xiaodong L, Weimin P, Mark WD, Shisan B. Epidemiology of 2019 Novel 
Coronavirus Disease-19 in Gansu Province, China, 2020. Emerging Infectious Disease journal. 
2020;26(6). 
2. 
Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 
Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020. 
3. 
Shi Y, Wang Y, Shao C, et al. COVID-19 infection: the perspectives on immune responses. Cell 
Death Differ. 2020. 
4. 
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 
and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020. 
5. 
Wang Q, Li W, Liu XS, et al. A hierarchical network of transcription factors governs androgen 
receptor-dependent prostate cancer growth. Mol Cell. 2007;27(3):380-392. 
6. 
Evaluation IfHMa. COVID-19 Projections. 2020. 
7. 
Ashley Rhoades M, RAC. Food and Drug Administration (FDA) issue an Emergency Use 
Authorization (EUA) for emergency use of remdesivir for the treatment of hospitalized 2019 
coronavirus disease (COVID-19) patients. In: Administration UFaD, ed2020. 
8. 
NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19 [press 
release]. National Institutes of Health2020. 
9. 
Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, 
double-blind, placebo-controlled, multicentre trial. The Lancet. 2020. 
10. 
Organization WH. WHO R&D Blueprint: Novel Coronavirus. COVID-19 Therapeutic Trial 
Synopsis. In:2020. 
11. 
Pocock SJ, Simon R. Sequential Treatment Assignment with Balancing for Prognostic Factors in 
the Controlled Clinical Trial. Biometrics 31(1):103-115, 1975 Mar. 
12. 
Beigel, John H. “Remdesivir for the Treatment of Covid-19 — Preliminary Report.” New 
England Journal of Medicine, 22 May 2020, 10.1056/nejmoa2007764. 


40 
40 
 
 
 
 
Appendix I: Clinical Safety Labs 
 
 
The CBC with differential, comprehensive metabolic panel, and urinalysis tests listed below will be 
performed at each visit specified in the Test Table (Section 4.0). A renal profile is a subset of the 
comprehensive metabolic panel, and includes sodium, potassium, chloride, carbon dioxide (total), BUN, 
creatinine, BUN: creatinine ratio, glucose, and eGFR. 
 
CBC with Differential 
Comprehensive Metabolic Panel 
Urinalysis 
Hematocrit 
Alanine aminotransferase 
Color 
Hemoglobin 
Aspartate aminotransferase 
Clarity 
Mean corpuscular hemoglobin 
Alkaline phosphatase 
pH 
Mean corpuscular hemoglobin concentration 
BUN 
Specific gravity 
Mean corpuscular volume 
Creatinine 
Bilirubin 
Mean platelet volume 
BUN:creatinine ratio 
Glucose 
Platelet count 
eGFR* 
Ketones 
Red blood cell distribution width 
Bilirubin, total 
Leukocytes 
Red blood cell count 
Carbon dioxide, total 
Nitrite 
White blood cell count 
Calcium 
Blood (hemoglobin) 
White blood cell differential 
Chloride 
Protein 
(% & absolute): 
Potassium 
Urobilinogen 
Basophils 
Sodium 
Red blood cells 
Eosinophils 
Glucose 
White blood cells 
Lymphocytes 
Albumin 
Epithelial cells 
Monocytes 
Globulin, total 
Bacteria, yeast, & parasites 
Neutrophils 
Albumin:globulin ratio 
Casts 
Protein, total 
Crystals 
Cholesterol, total 
Triglycerides 
Uric acid 
*eGFR will be calculated as follows: eGFR (mL/min/1.73 m2) = 175 × (serum creatinine in mg/dL)-1.154 × 
(age in years)-0.203 × (0.742 if female) × (1.212 if African American)