Clinical trial NCT04353284
Conditions: COVID-19
Sponsor: Yale University
Start date: 2020-06-09; Completion date: 2021-04-22
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The rationale of the present clinical trial is that an orally available drug given to outpatients that could reduce the viral burden in the upper respiratory tract could forestall complications of SARS-CoV-2 infection and reduce transmission from one infected individual to another.

Detailed description:
The study is designed as a double-blind randomized controlled clinical trial to test the hypothesis that camostat mesylate, a serine protease inhibitor shown to inhibit SARS-COV-2 replication in vitro, inhibits SARS-COV-2 replication in early stage, laboratory-confirmed, COVID-19 ambulatory patients.

Camostat mesylate, a serine protease inhibitor used primarily for treating postoperative reflux esophagitis and for acute exacerbations of chronic pancreatitis. This drug, with more than 15 years clinical experience in Japan with a very safe clinical track record, will be studied as a repurposed drug based on published in vitro virus inhibition data and in vivo protective effects in a mouse model of SARS.

The primary objective of this study is to determine whether camostat mesylate reduces SARS-COV-2 viral load in early COVID-19 disease.

Arms: arm 1: Camostat mesylate 200mg taken 7 days. arm 2: Placebo taken for 7 days.
Interventions: intervention 1: Camostat Mesilate intervention 2: Placebo
Intervention descriptions: intervention 1: Camostat mesilate 200mg taken orally, 4 times daily, for 7 days. intervention 2: Placebo taken orally, 4 times daily, for 7 days.

Protocol documents:
Prot_SAP_000.pdf: 
 
Camostat mesylate in COVID-19 Outpatients 
Version 8.0 
Protocol #2000027971 
18 August 2020 
 
Page 1 of 47 
 
  
The Effect of Camostat Mesylate on COVID-19 
Infection in Ambulatory Patients:  
An Investigator-Initiated Randomized, Placebo-
Controlled, Phase IIa Trial 
Short title: Camostat mesylate in COVID-19 Outpatients  
 
Protocol Number: 2000027971 
 
National Clinical Trial (NCT) Identified Number:  NCT04353284 
Principal Investigator: Geoffrey Chupp, M.D. 
IND Sponsor: Geoffrey Chupp, M.D. 
FDA IND #: 150074 
 
Funded by: Yale University School of Medicine 
Version Number: 8.0 
18 August 2020 
 
 


 
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 4 
1 
PROTOCOL SUMMARY ................................................................................................................................... 4 
1.1 
Synopsis ...................................................................................................................................................... 4 
Title: .............................................................................................................................................................................. 4 
1.2 
Schema ....................................................................................................................................................... 5 
1.3 
Schedule of Activities (SoA) ..................................................................................................................... 7 
2 
INTRODUCTION ................................................................................................................................................ 8 
2.1 
Study Rationale .......................................................................................................................................... 8 
2.2 
Background ................................................................................................................................................. 8 
2.3 
Risk/Benefit Assessment ........................................................................................................................ 13 
2.3.1 
Known Potential Risks .................................................................................................................... 13 
2.3.2 
Known Potential Benefits ............................................................................................................... 13 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................................... 13 
3 
OBJECTIVES AND ENDPOINTS .................................................................................................................. 15 
4 
STUDY DESIGN ............................................................................................................................................... 17 
4.1 
Overall Design .......................................................................................................................................... 17 
4.2 
Scientific Rationale for Study Design .................................................................................................... 17 
4.3 
Justification for Dose ............................................................................................................................... 17 
4.4 
End of Study Definition ............................................................................................................................ 18 
5 
STUDY POPULATION .................................................................................................................................... 18 
5.1 
Inclusion Criteria ...................................................................................................................................... 18 
5.2 
Exclusion Criteria ..................................................................................................................................... 19 
5.3 
Lifestyle Considerations .......................................................................................................................... 19 
5.4 
Screen Failures ........................................................................................................................................ 19 
5.5 
Strategies for Recruitment and Retention ............................................................................................ 19 
6 
STUDY INTERVENTION ................................................................................................................................ 20 
6.1 
Study Intervention(s) Administration ..................................................................................................... 20 
6.1.1 
Study Intervention Description ...................................................................................................... 20 
6.1.2 
Dosing and Administration ............................................................................................................. 20 
6.2 
Preparation/Handling/Storage/Accountability ...................................................................................... 20 
6.2.1 
Acquisition and accountability ....................................................................................................... 20 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................................. 21 
6.2.3 
Product Storage and Stability ........................................................................................................ 22 
6.2.4 
Preparation ....................................................................................................................................... 22 
6.3 
Measures to Minimize Bias: Randomization and Blinding ................................................................. 23 
6.4 
Study Intervention Compliance .............................................................................................................. 23 
6.5 
Concomitant Therapy .............................................................................................................................. 23 
6.5.1 
Rescue Medicine ............................................................................................................................. 23 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL
 
23 
7.1 
Discontinuation of Study Intervention ................................................................................................... 24 
7.2 
Participant Discontinuation/Withdrawal from the Study ..................................................................... 24 
7.3 
Lost to Follow-Up ..................................................................................................................................... 24 
8 
STUDY ASSESSMENTS AND PROCEDURES .......................................................................................... 25 
8.1 
Efficacy Assessments ............................................................................................................................. 25 
8.2 
Safety and Other Assessments ............................................................................................................. 27 
8.3 
Adverse Events and Serious Adverse Events ..................................................................................... 27 


 
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8.3.1 
Definition of Adverse Events (AE) ................................................................................................ 28 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................................................... 28 
8.3.3 
Classification of an Adverse Event ............................................................................................... 28 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ........................................ 29 
8.3.5 
Adverse Event Reporting ............................................................................................................... 30 
8.3.6 
Serious Adverse Event Reporting ................................................................................................. 30 
8.3.7 
Reporting Events to Participants ................................................................................................... 30 
8.3.8 
Events of Special Interest .............................................................................................................. 30 
8.3.9 
Reporting of Pregnancy .................................................................................................................. 30 
8.4 
Unanticipated Problems .......................................................................................................................... 31 
8.4.1 
Definition of Unanticipated Problems (UP) .................................................................................. 31 
8.4.2 
Unanticipated Problem Reporting ................................................................................................. 31 
8.4.3 
Reporting Unanticipated Problems to Participants ..................................................................... 31 
9 
STATISTICAL CONSIDERATIONS ............................................................................................................... 32 
9.1 
Statistical Hypotheses ............................................................................................................................. 32 
9.2 
Sample Size Determination .................................................................................................................... 32 
9.3 
Populations for Analyses ........................................................................................................................ 32 
9.4 
Statistical Analyses .................................................................................................................................. 32 
9.4.1 
General Approach ........................................................................................................................... 32 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) .............................................................................. 33 
9.4.3 
Analysis of the Secondary Endpoint(s) ........................................................................................ 33 
9.4.4 
Safety Analyses ............................................................................................................................... 33 
9.4.5 
Baseline Descriptive Statistics ...................................................................................................... 33 
9.4.6 
Planned Interim Analyses .............................................................................................................. 34 
9.4.7 
Sub-Group Analyses ....................................................................................................................... 34 
9.4.8 
Tabulation of Individual participant Data ...................................................................................... 34 
9.4.9 
Exploratory Analyses ...................................................................................................................... 34 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .................................. 34 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ................................................................. 34 
10.1.1 
Informed Consent Process ............................................................................................................ 35 
10.1.2 
Study Discontinuation and Closure............................................................................................... 35 
10.1.3 
Confidentiality and Privacy ............................................................................................................. 36 
10.1.4 
Future Use of Stored Specimens and Data ................................................................................. 37 
10.1.5 
Key Roles and Study Governance ................................................................................................ 38 
10.1.6 
Safety Oversight .............................................................................................................................. 38 
10.1.7 
Clinical Monitoring ........................................................................................................................... 38 
10.1.8 
Quality Assurance and Quality Control ........................................................................................ 39 
10.1.9 
Data Handling and Record Keeping ............................................................................................. 40 
10.1.10 Protocol Deviations ......................................................................................................................... 40 
10.1.11 Publication and Data Sharing Policy ............................................................................................ 41 
10.1.12 Conflict of Interest Policy ................................................................................................................ 42 
10.2 
Additional Considerations ....................................................................................................................... 42 
10.3 
Abbreviations ............................................................................................................................................ 43 
10.4 
Protocol Amendment History ................................................................................................................. 45 
11 
REFERENCES ................................................................................................................................................. 47 
 
 
 


 
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STATEMENT OF COMPLIANCE 
 
This trial will be carried out in accordance with International Conference on Harmonisation Good Clinical Practice 
(ICH GCP) and the following:  
 
The trial will be conducted in accordance with International Conference on Harmonization Good Clinical Practice 
(ICH GCP). The Principal Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the Investigational New Drug (IND) sponsor, funding agency and documented 
approval from the Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard to 
the trial participants. All personnel involved in the conduct of this study have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to 
the IRB for review and approval. Approval of both the protocol and the consent form must be obtained before 
any participant is enrolled. Any amendment to the protocol will require review and approval by the IRB before 
the changes are implemented to the study. All changes to the consent form will be IRB approved; a 
determination will be made regarding whether a new consent needs to be obtained from participants who 
provided consent, using a previously approved consent form. 
1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
TITLE: 
The Effect of Camostat Mesylate on COVID-19 Infection in Ambulatory 
Patients: An Investigator-Initiated Randomized, Placebo-Controlled, Phase 
IIa Trial 
Study Description: 
 
Objectives: 
Primary Objective:  To determine whether camostat mesylate reduces 
SARS-COV-2 viral load in early COVID-19 disease. 
Secondary Objective: To determine the effect of camostat mesylate on 
COVID-19 symptom score. 
Endpoints: 
Primary Endpoint: 
1. Change (reduction) from baseline to day 4 in respiratory 
(Nasopharyngeal swab, saliva RT-PCR) log10 viral load. 
 
Secondary Endpoints:  
1. Change (reduction) from baseline to day 2 and to day 6 in 
respiratory (Nasopharyngeal swab, saliva RT-PCR) log10 viral load. 
2. Difference in rate of a positive COVID-19 test result at day 6, 14 
and 28 after enrollment 
3. Change of COVID-19 symptom score from baseline to day 6 and to 
14 
4. To assess the safety of camostat mesylate 200 mg po QID 
 
Exploratory Endpoints: 
1. Conversion of SARS-CoV-2 antigen detection (Quidel’s Sofia 
assay) from Nasopharyngeal specimens from baseline to days 6 
and 14;  there is no specific a priori power analysis for this 
exploratory outcome because this assay is new (under an FDA 
EUA) and has not been used for serial assessment of outpatients  
and this exploratory analysis will provide data regarding the 
performance of this test in our outpatient context. 


 
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2. To gain insight into whether clinical outcomes might improve after 
treatment with camostat mesylate 200 mg po QID but this study is 
not powered to  assess progression to hospitalization or other 
severe disease. 
Population: 
Male and female outpatients 18 and older with RT-PCR-confirmed COVID-
19 recruited and enrolled from  Yale New Haven Health System or 
referred/presenting for the study because of a positive COVID-19 test from 
an outside clinical laboratory. The subjects will not be stratified, hence will 
be undifferentiated as to general health status or geographic location. 
Phase: 
2  
Description of 
Sites/Facilities 
Enrolling Participants: 
Yale New Haven Health System  
  
Description of Study 
Intervention: 
Camostat mesylate 200mg po QID or placebo for 7 days  
  
Study Duration: 
1 year 
 
Participant Duration: 
4 weeks 
 
 
1.2 
SCHEMA 
 See below.   


 
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Flow diagram of randomized controlled trial 
 
 
Prior to  
Enrollment 
 
 
Visit 1 
Day 0 
 
 
 
 
 
 
 
 
Visits 2-4 
Days 2, 4, 6 
 
 
 
Visit 5 
Day 14+/-2 
 
 
 
 
Visit 6 
Day 28+/-2 
 
 
 
Total N=114:  Screen potential participants by inclusion and exclusion 
criteria; obtain relevant history, document all contacts with potential 
participants; refer to study site. 
At designated facility: Informed consent, randomization (after urine pregnancy test as indicated) 
A. Perform baseline assessments, study symptom assessment plus patient COVID-19-PRO daily for days 0-14, 28) 
 
B. Specimens to be collected. Nasopharyngeal swabs (2), saliva; research labs blood for CBC, chemistry, urine pregnancy 
test, research labs including serum, PBMC isolation, coagulation component measurements 
FINAL ASSESSMENT 
At designated facility 
 A. Perform followup assessment, in person (study symptom assessment plus patient COVID-19-PRO) 
B. Specimens to be collected. Nasopharyngeal swabs (2), saliva; research labs blood for CBC, chemistry, urine pregnancy 
test, research labs including serum, PBMC isolation, coagulation component measurements 
At designated facility 
 A. Perform followup assessment in person (study symptom assessment plus patient COVID-19-PRO) 
B. Specimens to be collected. Nasopharyngeal swabs (2), saliva; research labs blood for CBC, chemistry, urine pregnancy 
test, research labs including serum, PBMC isolation, coagulation component measurements 
Arm B (N=57) 
Arm A (N=57)  
At designated facility 
A. Perform followup assessments, days 2, 4, 6 in person (study symptom assessment plus patient COVID-19-PRO) 
B. Specimens to be collected. On day 4: required Nasopharyngeal swabs (2), saliva; on days 2 and 6, NP swabs optional but 
saliva required 
C. Provide 2 d of Camostat (8 x 200 mg capsules  or 8 placebo capsules) for days 2, 3 and 4, 5 and 6, 7; 200 mg po qid or 
matched placebo  
At in-person Visit 1 on Day 0: Randomize 
1:1 treatment (arm A) vs. placebo (arm B) 


 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
Procedures 
Enrollment, 
Study Visit 1, 
Day 0 
Study Visit 2 
Day 2 
Study Visit 3 
Day  4 
Study Visit 4 
Day  6 
Study Visit 5 
Day 14+/- 2 days 
Study Visit 6 
Day 28+/- 2 days 
Informed consent 
X 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
Administer study intervention: 
Subjects receive two days  
worth of drug/placebo on days 
0, 2, 4 and one day of 
drug/placebo on day 6  
X 
Drug/placebo 
For 2 days 
X 
Drug/placebo 
For 2 days 
X 
Drug/placebo 
For 2 days 
X 
Drug/placebo 
For 1 day 
 
 
Nasopharyngeal swabs, saliva 
for COVID-19 RT-PCR and 
antigen testing 
X 
X 
Swabs 
optional 
X 
X 
Swabs 
optional 
X 
X 
Physical exam: Vital signs, 
wt, pulse oximetry, other as 
clinically indicated 
X 
X 
X 
X 
X 
X 
Urine pregnancy test (as 
indicated) 
X 
 
 
 
 
 
Blood pregnancy test (as 
indicated) 
 
 
 
 
X 
 
Hematology and coagulation 
X 
 
 
 
X 
X 
Blood chemistries 
X 
 
 
 
X 
X 
Adverse event review and 
evaluation 
X 
X 
X 
X 
X 
X 
Concomitant medication 
review 
X 
X 
X 
X 
X 
X 
Blood for research 
biorespository 
X 
 
 
 
X 
X 
Complete Case Report Forms 
(CRFs) 
X 
X 
X 
X 
X 
X 
All subjects, regardless of study arm (blinded to subjects and investigators), will be tracked for their health status 
through daily phone calls from days 0 to day 14 with routine, scheduled daily phone calls by study staff to help 
participants fill out symptom scores on the standardized COVID-19-PRO instrument. Any subject reporting 
concerning symptoms, particularly chest pain, shortness of breath, extreme prostration, change in mental status 
will be referred to for emergency care. Subjects will be given a contact phone number of PI or designee to contact 
for any concerns. If there is complete resolution of symptoms at the day 14 visit, then phone calls will not be 
routinely continued  by our study staff to but subjects will be encouraged to call PI or designee for concerns or 
discussions. 
 


 
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2 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
SARS-CoV-2, one of a family of human coronaviruses, was initially identified in December 2019 in Wuhan 
city.1 This new coronavirus causes a disease presentation which has now been named COVID-19. The virus 
has subsequently spread throughout the world and was declared a pandemic by the World Health 
Organization on 11th March 2020. In the United States, as of 12 April 2020, there were 532,339 confirmed 
cases with 21,418 deaths, with an estimated case-fatality rate of 4% for identified cases. At this time, there is 
no approved specific treatment for COVID-19 nor any drug or vaccine that could be used to prevent COVID-
19. The current standard of care is limited to supportive treatment. The rationale of the present clinical trial is 
that an orally available drug given to outpatients that could reduce the viral burden in the upper respiratory 
tract could forestall complications of SARS-CoV-2 infection and reduce transmission from one infected 
individual to another. 
 
Success in this trial, which focuses on the biological outcome of reduced viral load in the respiratory tract, 
would then lead to scaled-up clinical trials, for treatment in hospital inpatients and as prophylaxis for those at 
risk for infection. Alternatively, if camostat mesylate does not reduce viral load in the respiratory tract, then 
this drug would not be pursued for further clinical study. 
 
2.2 
BACKGROUND  
Introduction 
SARS-CoV-2, one of a family of human coronaviruses, was initially identified in December 2019 in Wuhan 
city.2 This new coronavirus causes a disease presentation which has now been named COVID-19.3 The virus 
has subsequently spread throughout the world and was declared a pandemic by the World Health 
Organization on 11th March 2020. In the United States, as of 12 April 2020, there were 532,339 confirmed 
cases with 21,418 deaths, yielding an estimated case-fatality rate of 4% for identified cases (which is surely 
an underestimate). Therapy for COVID-19 and the current standard of care is supportive treatment. 
 
Patients infected with SARS-CoV can present with a range of symptoms from asymptomatic infection to severe 
respiratory failure, septic shock and multiple organ failure.3 The most common symptoms are fever, cough, 
myalgia and dyspnea, though some patients present with headache, dizziness, nausea and vomiting. Viral 
pneumonia occurs in severe disease and leads to severe acute respiratory failure. Overall estimation of 
mortality rates vary from 0.039 and 7%, depending on the efficiency of population-based RT-PCR testing and 
and host demographic and baseline clinical status. 
 
SARS-CoV-2 uses the angiotensin converting enzyme II (ACE2) as its cell entry receptor protein to access and 
infect human cells.4 The interaction between ACE2 and the spike protein is not in ACE2’s active site. This 
process critically uses the human epithelial cell (respiratory, gastrointestinal tract) surface-expressed serine 
protease TMPRSS2.4 Utilizing previous research on severe acute respiratory syndrome coronavirus (SARS-
CoV) and the closely related SARS-CoV-2 cell entry mechanism, it has been demonstrated that SARS-CoV-2 
cellular entry can be blocked by camostat mesylate (Foipan, Ono Pharmaceuticals) in vitro.5 In vivo, using a 
strain of SARS-Cov-1 adapted to causing lethal disease in a mouse model, camostat mesylate dosed at a 
concentration similar to the clinically achievable concentration in humans reduced mortality following SARS-CoV 
infection from 100% to 30-35% in this model. 
 
Rationale for choice of study drug 
Camostat mesylate is a proteolytic enzyme inhibitor that is used primarily in the treatment of postoperative reflux 
esophagitis and for acute, symptomatic exacerbations of chronic pancreatitis.5 It has been used clinically since 
at least 2006 and is widely used in Japan for chronic-pancreatitis associated pain. Importantly, camostat 
mesylate is very well tolerated and has no known drug-drug interactions. 
 
This randomized controlled trial will investigate the clinical effect of camostat mesylate on viral kinetics of SARS-
CoV-2 in newly diagnosed COVID-19 in ambulatory patients. There are two arms named A and B. Arm A is the 
camostat mesylate arm which will provide drug in identical appearance as placebo by overencapsulation. Patients 
in group A will receive 200 mg camostat mesylate to be taken four times daily. Arm B is the placebo arm and will 
be given YNHH research pharmacy-formulated placebo 4 times a day. All patients will receive treatment or 
placebo for a total of 7 days. 


 
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There is no clinical experience in using camostat mesylate in humans to treat SARS-CoV-2. Camostat mesylate, 
approved for clinical use in Japan since 2006, has been used there for more than two decades to treat reflux 
esophagitis and acute-on-chronic pancreatitis, and it displays very little toxicity (detailed below). In animal studies, 
treatment with comparable human dosing reduces mortality (100% to 35% within the study period of 13 days) in 
mice exposed to SARS-CoV. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Camostat mesylate inhibits TMPRSS2-mediated priming of the SARS-CoV-2 spike protein 
which prevents the virus from cell entry. Adapted from Clerkin et al. Circulation 2020 


 
Camostat mesylate in COVID-19 Outpatients 
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In another study, camostat was found to have an EC50 of 87nM in vitro,  a peak concentration achievable 
with oral camostat mesylate administration.6 
Camostat mesylate is immediately and extensively hydrolysed in plasma to 4-(4-guanidinobenzoyl-
oxy)phenylacetic acid (GBPA (FOY-251)), which is further degraded to 4-guanidinobenzoic acid (GBA). CM 
and GBPA have similar biological activity, while GBA is inactive. 
Indication of absorption fraction after oral dosing is not available. 
The Japanese manufacturer’s summary of product characteristics describes a study in five healthy, fasting 
adults of a single oral dose of 200 mg. For GBPA Tmax is 40 min, Cmax 87.1 ng/ml, AUC 10,400 ng*min/ml 
and T½ 100min. Another study of four patients with complete gastrectomy given a single dose of 100 mg 
shows similar plasma curve changes including Cmax 30 ng/ml. 
In another study, four healthy Caucasian males received a single dose of 40 mg camostat mesylate as 
intravenous infusion over 12 hours. The parent compound was not measurable in plasma, supportive of 
instantaneous degradation. PK parameters for the active metabolite, GBPA, were Tmax 300 min (after 
infusion start), Cmax 89.4 ng/ml, Css 83.6 ng/ml, AUC 966 ng.h/ml and T½ 1.0 hrs. 
In a study of pancreatic function, twelve healthy individuals (6M/6F, median age 24.5 yrs) were given 500 
mg four times daily for four weeks. Steady state concentration for GBPA at the end of week 1-4 were 19,600 
ng/ml, 18,600 ng/ml, 19,000 ng/ml and 14,400 ng/ml. 
Camostat mesylate is almost exclusively metabolized to GBPA and further on to GBA, by carboxyesterase 
and arylesterase. Neither parent compound nor metabolites affect CYP1A2, CYP2C9, CYP2C19, CYP2D6 
or CYP3A4. Excretion is mainly renal as GBA (>95%). 
The main metabolites of CM are renally eliminated, predominately 4-guanidinobenzoic acid (GBA) and to a 
much lesser extent 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA). After a single oral administration of 
200 mg in 5 healthy adults, the majority of these metabolites were excreted after 5-6 hours10. No PK studies 
have been located that have included patients with chronic kidney disease. However, the TACTIC trial, 
recruiting patients aiming at investigating the effect of CM against chronic pancreatitis in a western population, 
excludes patients with CKD stage IV (eGFR < 30 ml/min/1,73m2)15. This suggests that prior studies could 
potentially have documented the safety of CM use in patients with milder degrees of renal impairment. 
In PK simulation modeling provided recently by 
Ono Pharmaceuticals, the new FDA suggested 
dosing of 200 mg QID of camostat would yield the 
following curves and time of blood levels 
exceeding the 87 nM EC50. 
 
 
 
 
 
 
 
Interactions with other drugs 
There are no known interactions with other drugs and CM, GBA, GBPA. The drug and metabolites are not 
dependent on CYP metabolism. 
 


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Others 
- 
Edema 
Hypoglycemia 
- 
 
Table 1. Summary of Safety Data for Camostat Mesylate tablets 
Data summarized from the use of camostat mesylate for the indications of “Remission of acute symptoms of 
chronic pancreatitis” (83 ARs including abnormal lab.values observed in 69 (1.8%) of 3,806 patients) and 
“Postoperative reflux esophagitis” (75 ARs including abnormal lab.values observed in 57 (1.3%) of 4,224 
patients). 
Additional clinically significant ARs that may occur (incidences unknown*): 
Shock or anaphylactoid symptoms, thrombocytopenia, hepatic function disorder or jaundice, hyperkalaemia. 
*Incidence unknown: ADRs classified and collected from spontaneous reports. 
Two case reports have been found. One about autoimmune hepatitis that may have occurred following drug-
induced liver injury that may have been related to camostat treatment. Stopping the drug did not lead to 
complete remission, but low dose of corticosteroids completely cured the liver function17. Another case study 
reported eosinophilic pneumonia probably caused by 10 days treatment with camostat. The peripheral blood 
eosinophilia and eosinophilic infiltration into the alveolar space improved with the cessation of the drug18. 
Relevant monitoring of treatment is based on the knowledge about the reported clinically significant adverse 
reactions, which comprises: hyperkalemia, hepatic function disorder or jaundice, thrombocytopenia, 
eosinophilic pneumonia and shock/anaphylactic symptoms. 
Safety in patients with reduced renal output or end-stage renal disease 
Human data on camostat mesylate treatment and renal insufficiency. 
Three studies have been found in Medline and/or Embase that address the safety of camostat mesylate 
administration in patients with renal insufficiency: 
1. Onbe et al. J Diabet Complications 1991;5:167-8. 8 pts with nephrotic syndrome and diabetic nephropathy. 
CM 600 mg daily for 4 weeks. Reduced proteinuria, creatinine clearance stable throughout study. 
 
2. Ikeda et al. J Diabetes Complications 1999;13:56-8 
3 pts with nephrotic syndrome and diabetic nephropathy. CM 600 mg daily for 4 weeks. 
Reduced proteinuria, no side effects reported. 
 
3. Matsubara et al. Clin Nephrol 1989;32:119-23 
17 pts with heavy proteinuria caused by varous nephropathies. CM 600 mg daily for 4 weeks. 
Urine protein excretion diminished from week 2. No changes in serum creatinine during or after 
the study. 
Collectively, the above-mentioned studies demonstrate the safety profile of camostat mesylate 
administration in patients with varying degrees of renal insufficiency. The studies found no evidence 
of a negative effect of camostat mesylate on renal function. Camostat mesylate administration was 
also not associated with an increased risk of adverse drug reactions. 
 
In Japan, the approved doses for Foipan are 100 mg three times daily for postoperative reflux esophagitis 
and 200 mg three times daily for symptoms of chronic pancreatitis. We propose in the present study dosing 
at 200 mg po QID, for which Ono has obtained safety data in early clinical trials (see below).5 We will ask 
subjects to space out dosing over 24 hours as much as they can, taking sleep into account. 


 
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Much higher doses have been used in some studies without any severe adverse effects, i.e. 9 patients with 
severe oral carcinomas up to 7.2 g daily for several months as well as a study in healthy individuals of 2 g 
daily for four weeks.  
Since use of the compound in SARS-CoV-2 setting is unchartered territory, we will use doses that are safe 
within the limits of the SmPC for camostat mesylate. In cell lines, camostat seems able to inhibit the serine-
protease mediated maturation of the SARS Spike (S) protein. EC90 is about 5 uM and EC50 about 1 uM in 
that study. A more recent in vitro study showed an EC50 of 0.087 uM (87 NM).6 In a mouse model of SARS-
CoV-1 (the first SARS) virus, camostat mesylate (30 mg/kg x2) ameliorated progression to acute respiratory 
distress syndrome (ARDS). The reduction was from 100% to 35% lethality in the mouse model.8, 9 
The rationale for the duration of treatment with camostat mesylate (i.e. 200 mg QID daily for 7 days) is in 
part based on the current treatment guidelines for other lower respiratory tract viral infections and also the 
known viral kinetics of SARS-CoV-2 in COVID-19 patients. For influenza, the standard recommendation is 
Tamiflu (oseltamivir 75 mg x 2) for 5 days in adults. Because participants in the proposed camostat trial are 
enrolled very early after outpatient diagnosis, we anticipate that the majority of them will present with mild to 
moderate disease. Therefore, we propose to follow the treatment principles for other lower respiratory tract 
infections of similar disease severity. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 
KNOWN POTENTIAL RISKS  
The risks of camostat mesylate (FOIPAN) are based on the package insert provided by Ono Pharmaceutics for the 
approved drug.5 
 
In the first 7 days of participation in the study, minimal significant risks, either immediate or long-range risks to 
participants are anticipated from the physical, psychological, social, legal, economic, or other viewpoints by 
participating in the study that the Principal Investigator (PI) can foresee. Potential risks during the acute phase of 
COVID-19 infection and coming to the designated facility (outpatient study site) might be infection from others, or 
study personnel being exposed to active COVID-19 patients. These risks are mitigated by the participants being 
sampled by experienced staff wearing proper PPE and approved by EH&S during the first week of study 
participation, during which time they interact with study personnel obtaining respiratory swabs. Study personnel 
obtaining swabs will be dressed in YNHH system-approved PPE (N95 masks, goggles, face masks, gowns, 
gloves), and will change gowns, gloves, PPE sleeves between patients, as is standard practice. 
 
At days 14+/-2 and 28+/-2 days, participants will return to the study clinic and NP swabs and saliva will be 
obtained. Blood will be drawn for standard blood tests (CBC and chemistries) plus that for research use. A 
maximum total of 125 mL of blood will be obtained at these two time points. 
 
The guidance for maximum volume of blood draws that will be applied is for non-healthy adults, no more than 
2.5% total blood volume in 24-period and no more than 5% total blood volume in 30 days. 70mL/kg must be used 
to calculate the appropriate blood draw volume per patient. The two blood draws of maximum 125 mL each for a 
total of 250 over two weeks, plus 30 ccs per visit for Visits 1-4  for a study total of 370ccs is still within the 
allowable amount. 
 
 
 
2.3.2 
KNOWN POTENTIAL BENEFITS  
 
The anticipated potential benefits of receiving camostat mesylate treatment for patients with COVID-19 would be 
reduction of viral replication, which would be presumed to accelereate the reduction of COVID-19 disease 
symptomatology and reduce the contagiousness of the causative virus to others. 
 
2.3.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 


 
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According to what is known about COVID-19 disease and its potential for severe disease as well as transmission, 
and compared to the minimal risk of taking camostat mesylate, the potential benefits outweigh potential risks.  
 
Risk of the study design itself, focused on the highly transmissible virus SARS-SoV-2 causing COVID-19 disease, 
mitigates risk both to subject and to study personnel during the acute phase of the study (days 0-6) and at days 14 
and 28. 
 
 


 
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3 
OBJECTIVES AND ENDPOINTS 
  
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To determine whether camostat 
mesylate reduces SARS-COV-2 viral 
load within 2-3 days after 
laboratory-confirmed diagnosis of 
COVID-19 disease in ambulatory 
patients. 
 
Primary Endpoint:  
1. Change (reduction) from 
baseline to day 4  in 
respiratory (Nasopharyngeal 
swab, saliva RT-PCR) log10 
viral load . 
 
 
Per FDA 
recommendations and 
our own judgment, the 
timing of this primary 
endpoint was chosen 
because 
reduction of viral load 
in respiratory tract 
samples would be 
expected to be 
associated with anti-
viral activity of the 
study drug, and would 
be expected to be 
associated with 
continued reduction of 
viral load during drug 
administration, hence 
potential reduction 
severity of COVID-19 
disease and reduction 
of  transmission by 
reducing infectiousness 
of infected individual. 
 
If we are able to 
achieve a reduction in 
viral load   then a trial 
with clinical endpoints 
such as risk for 
progression to 
hospitalization and/or 
need for intensive unit 
care would be justified. 
 
Secondary 
 
 
1. To determine whether camostat 
mesylate reduces SARS-COV-2 viral 
load within 7 days after laboratory-
confirmed diagnosis of COVID-19 
disease in ambulatory patients. 
 
1. Change from baseline to day 2 and 
to day 6 in respiratory 
(Nasopharyngeal swab, saliva RT-
PCR) log10 viral load. 
 
2. Difference in rate of  positive 
COVID-19 test at day 6, 14 and 28  
 
As for the primary 
endpoints (above). 
 
We expect to see a 
time-dependent 
reduction of viral load, 
hence the second time 
point. 


 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
2. To determine the effect of 
camostat mesylate on COVID-19 
symptom score. 
 
 
 
3. To evaluate the safety of 
camostat mesylate 
 
4. Adverse events 
 
 
3. Change of COVID-19 symptom 
score from baseline, to days 6 and 14 
 
Assessment of safety by labs and 
history and physical, according to  
The Common Terminology Criteria 
for Adverse Events 
(CTCAE) Version 5.0. 
 
We expect to see a 
reduction in symptom 
score from baseline at 
day 6 and day 14 +/-2. 
 
If the secondary 
endpoints are not 
achieved,  then a trial 
to examine the effect 
of camostat mesylate 
on COVID-19 would not 
be justified. 
 
Tertiary/Exploratory  
 
 
To determine clinical outcome of  
COVID-19 treated with camostat 
mesylate 
 
To determine conversion of SARS-
CoV-2 antigen from positive at 
baseline to negative at days 6 and 
14. 
As an exploratory endpoint in 
comparing treatment to placebo 
groups, we will assess time to clinical 
improvement and risk for 
hospitalization.   
 
Quidel’s Sofia assay will be used for 
antigen detection. 
A tertiary objective not 
powered by this study. 
We will explore, 
however, whether the 
treatment group 
clinically improves or 
has a lower, neutral, or 
greater risk of 
hospitalization.  
 
As the Quidel assay has 
not been used for 
serial assessment of 
outpatients, this 
exploratory analysis 
will provide data 
regarding the 
performance of this 
test in our outpatient 
context 
 
 
 


 
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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial 
design. A description of the trial design should be consistent with the Protocol Synopsis (section 1.1) and Protocol 
Schema (section 1.2) and include: 
 
Hypothesis:  Camostat mesylate, a serine protease inhibitor shown to inhibit SARS-COV-2 replication in vitro and to reduce 
mortality in a mouse model of SARS, inhibits SARS-COV-2 replication in early stage, laboratory-confirmed, ambulatory 
COVID-19 patients.  
 
Trial phase: This is a phase II trial of camostat mesylate, a drug approved for clinical use in Japan for treatment of 
pancreatitis and postoperative reflux esophagitis. 
 
Trial design: Randomized, double-blind, placebo-controlled clinical trial  
 
Methods to minimize bias: Participants will be randomized equally to camostat mesylate or identical appearing placebo 
using a permuted-block design with variable block size. Actual treatment assignment will be concealed from the 
investigators and the participants. 
 
Number of study groups/arms and study intervention duration:  Two arms: Group A, study drug (camostat 
mesylate); Group B, placebo. Duration of study: 7 days. Duration of involvement by participants: 28 days. 
 
Number of Sites: one  
 
Name of study intervention: Camostat mesylate 
 
Stratification:  None  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The rationale for placebo is that there is no known effective treatment for COVID-19 disease. The natural history 
of viral shedding in infected patients  varies substantially among patients. Generally viral replication appears 
within about 5 days after exposure, and an asymptomatic phase may or may not be present for days prior to the 
onset of symptoms, most often described as progressive symptoms of fever, cough, malaise and shortness of 
breath. Because there is no available animal model in which to study the anti-SARS-CoV-2 viral effect of camostat 
mesylate, infected humans must be studied. Because respiratory viral burden varies substantially (orders of 
magnitude ranging from 102-109/swab) among COVID-19-affected individuals, in order to demonstrate an 
antiviral effect of any drug on SARS-CoV-2, serial samples and measurement of viral load on respiratory samples 
must be compared between placebo and experimental groups. We will also perform viral load testing on saliva 
because recent studies have suggested that saliva may be more reliable; however the nasopharyngeal swab 
remains the gold standard. Because enrollment will be based on an initial positive COVID-19 test on a 
nasopharyngeal swab and participants randomized in a double-blinded way, experimental and placebo groups 
are expected to be comparable without bias. 
 
4.3 
JUSTIFICATION FOR DOSE 
The standard dose of camostat mesylate as approved in Japan for patients with chronic pancreatitis is 
600mg/day (200 mg po tid). We will increase the dose to 800mg/day (200 mg po QID) which has been shown to 
be safe. This choice of dosage is consistent with PK simulation data (shown above) and Ono’s safety data as seen 
below, and the FDA IND approval letter suggested a dose of 800mg/day (200 mg po QID). The placebo control 
will be produced by the Yale New Haven Hospital research pharmacy to be a look-alike.  


 
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4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the study 
including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), Section 1.3. The 
end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial globally. 
 
5 
STUDY POPULATION 
 
 
5.1 
INCLUSION CRITERIA 
Consecutive participants testing positive for COVID-19 at the Sargent Drive testing center, any other YNHHS site, 
or external COVID-19 testing facility will be eligible for enrollment.  
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Be enrolled within 3 days of being notified of their first positive COVID-19 test result. 
2. Evidence of a recent active COVID-19 infection, as evidenced by the positive test results being associated 
with at least one COVID-19-compatible symptom such as fever, upper respiratory symptoms, cough, 
chills, loss of taste/smell, etc.(see  COVID-19-PRO symptom score sheet), or a recent high-risk exposure 
to COVID-19 
3. Provision of informed consent 
4. Stated willingness to comply with all study procedures and availability for the duration of the study  
5. Male or female, aged 18 and older 
6. Diagnosed with COVID-19 within past 3 days and not exhibiting manifestations requiring hospitalization 
such as extreme shortness of breath or severe prostration. Nurses at the study site will assess such 
severe conditions requiring hospitalization, which would preclude enrollment. 
7. Ability to take oral medication and be willing to adhere to the camostat mesylate regimen. 
8. For men and women of reproductive potential: use of condoms or other methods to ensure effective 
contraception with partner during study drug administration. 
9. Agreement to adhere to Lifestyle Considerations (birth control measures) throughout the 7-day duration 
of study drug administration. 
10. English and Spanish speaking subjects as well as patients speaking any language for which we can find 
appropriate translators will be enrolled. A short form with interpretation will be used for anyone 
speaking a language for which a translated informed consent form is not currently available  in 
accordance with local site IRB policies, including developing certified translations as necessary.  
 


 
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5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Presence of COVID-19 disease manifestations that would require referral for consideration of 
hospitalization. 
2. A previous positive COVID-19 test reported more than 7 days before,  which would indicate likelihood of 
non-culturable, nonreplicating virus 
3. A positive COVID-19 test without a known recent exposure that would indicate an active infection, hence 
an unknown chance of non-culturable, non-replicating virus being present (i.e., asymptomatic COVID-19 
infection of unknown duration) 
4. Known pregnancy or lactation; a positive urine pregnancy test done at the enrollment (day 0 visit) for 
women with child bearing potential. 
5. Known allergic reactions to components of camostat mesylate. 
 
With regard to inclusion or exclusion of women of child-bearing potential, women who tell us they know 
they are pregnant are excluded. All women of child-bearing potential who test positive for pregnancy by 
urine test at first visit are excluded. A day 14 followup blood pregnancy test will be done on appropriate 
enrolled women (i.e. those who had a negative urine pregnancy test on day 0 for further safety 
assessment. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Female subjects with potential for childbearing will be asked to maintain at least two forms of birth control 
during the 7 days of study drug/placebo administration, including but not limited to abstinence from sexual 
intercourse, condom use and/or using oral contraceptives. 
 
During this study, participants are asked to comply with State public health requirements and the U.S. Centers for 
Disease Control and Prevention in terms of social distancing and discontinuing home isolation ( 
https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-in-home-patients.html ), which will be provided in 
written form to participants. 
 
5.4 
SCREEN FAILURES 
 
The study design is expected to minimize screen failures because enrollment will be based on consecutively 
diagnosed COVID-19+ individuals. Screen failures are defined as participants who consent to participate in the 
clinical trial but are not subsequently randomly assigned to the study intervention or entered in the study. A 
minimal set of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Special circumstances must prevail for recruitment and retention in this study given the contagiousness potential 
of COVID-19. 
 


 
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Target study sample size: 114, with no pre-specified breakdown by gender, race, ethnicity, or age;  
 
Anticipated accrual rate: 1-5 participants weekly, may take longer 
 
Anticipated number of sites: one, Yale School of Medicine/Yale New Haven Health, New Haven, CT 
 
Source of participants: Persons with a positive SARS-CoV-2 test recorded at the clinical site, referral from 
healthcare personnel due to a positive SARS-CoV-2 test, or self-referral after receiving a positive SARS-CoV-2 test.  
 
How potential participants will be identified and approached: Participants who are diagnosed within the YNHH 
Health System will be identified via a daily JDAT data output that will identify new COVID-19 outpatients who 
have not opted out of being contacted for Yale research studies. Approved study personnel will use this list to 
identify subjects that fulfill inclusion criteria and are not excluded according to exclusion criteria, and then 
contact potential subjects to ask if they might be willing to participate in the study. If so, the study will be 
explained and the informed consent process initiated.  
 
Alternatively, physicians/APRNs/HCWs may refer a potential participant based on a new positive COVID-19 test, 
or patients may self-refer themselves for potential participation. 
 
Participants will be offered compensation . Free parking or reimbursement for parking will be provided for 
outpatient visits. Study site staff will make efforts to arrange and pay for safe transportation to and from the 
study site if a participant meeting eligibility criteria otherwise cannot make their appointments.  
 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 
STUDY INTERVENTION DESCRIPTION 
 
Study intervention: camostat mesylate 200mg po qid vs. placebo. Commercially available in Japan, but not in the 
United States. 
 
6.1.2 
DOSING AND ADMINISTRATION 
 
Camostat mesylate 200 mg po qid vs. placebo for 7 days. 
Two days of study drug or placebo will be provided every other day in the study clinic at the time of check-in, 
prior to being swabbed and obtaining saliva samples. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 
ACQUISITION AND ACCOUNTABILITY 
Ono Pharmaceutical, Japan, will provide Camostat mesylate 100 mg tablets as FOIPAN. The Yale New Haven 
Hospital research pharmacy will receive and store the drug within 15-30C range according to protocol storage 
requirements. 
 
Microcrystalline Cellulose NF (PH-102) for placebo formulation will be acquired from Fagron. 
Empty gelatin capsules Size 0, for over-encapsulation will be acquired from Fagron. 


 
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Before Ono Pharmaceutical can send the drug, an IND will be obtained from the FDA. 
 
The Sponsor-Investigator and the Yale New Haven Hospital research pharmacy will keep accountability records 
for all investigational products acquired, dispensed, used and disposed. 
 
6.2.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
Camostat mesylate will be provided by Ono Pharmaceuticals as 500 tablets/bottle in glass bottles. Each 
tablet contains 100 mg of Camostat mesylate. For study administration two tablets will be combined (by 
investigational pharmacy) into one 200 mg capsule (see page 23) and subjects will take one capsule qid of 
either study drug or placebo.  Placebo will be formulated to be similar in appearance to the study drug and 
provided in similar plastic containers. 
Chemical name: 4-[[4-[(Aminoiminomethyl)amino]benzoyl]oxy]benzeneacetic acid 2- 
(dimethylamino)-2-oxoethyl ester methanesulfonate. 
International Nonproprietary Name (INN): Camostat 
Molecular formula: C20H22N4O5 · CH4O3S 
Molecular weight: 494.52 
Structural formula


 
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6.2.3 
PRODUCT STORAGE AND STABILITY 
The study drug Camostat is stable at 25C and should be kept at ambient (15-30C) temperature 
for long term storage. For short term storage (up to 30 days) to facilitate daily dispensing of the 
drug it will be kept at ambient office or clinic temperature.   
 
Placebo for Camostat will also be stored at ambient (15-30C) temperature for long term storage. 
For short term storage (up to 30 days) to facilitate daily dispensing of the drug it will be kept at 
ambient office or clinic temperature. 
 
Drug will be stored in locked cabinets at ambient (15-30°C) temperature at all times other than 
during active dispensing. 
 
6.2.4 
PREPARATION 
 
Encapsulated Camostat 200 mg Capsules 
For blinding, two intact active camostat 100 mg tablets will be placed in a capsule shell, back 
filled with sufficient quantity of microcrystalline cellulose, and closed. The capsules are visually 
inspected and packed into polypropylene bottles. 
Placebo for Encapsulated Camostat 200 mg dose Capsules  
Matching placebo will be compounded, using a matching empty capsule filled with sufficient 
quantity of microcrystalline cellulose. The capsules are visually inspected and packed into 
polypropylene bottles. 
Assigned beyond use date is not later than the time remaining until the earliest expiration date 
of any ingredient or 6 months. 
Master formulation record and compounding record will be kept for the compounding. 
Compounding, packaging and labelling will be carried out by Investigational Drug Service 
Pharmacy, Yale-New Haven Hospital.  
Labeling: 
Camostat 200 mg dose Capsules (Active) 
 
Compounding Date:  
Lot:  
 
 
 
 
Exp Date:  
Qty:  
Protocol #  
Storage Condition (Room Temp 15-30°C) 
"Caution: New Drug--Limited by Federal (or United States) law to investigational use." 
 
Placebo for Camostat 200 mg Capsules  
 
Compounding Date: 
Lot:  
 
 
 
 
 
Exp Date: 
Qty: 
Protocol #  
Storage Condition (Room Temp 15-30 °C) 
"Caution: New Drug--Limited by Federal (or United States) law to investigational use." 
 


 
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Dispensing: 
For dispensing, 8 capsules of overencapsulated Camostat 200 mg per capsule or identically 
appearing Placebo for camostat mesylate 200 mg will be packaged in a polypropylene bottle and 
given to enrolled research participants every other day. The bottles will be labeled with 
dispensing label containing patient name, administration instructions, and provider information 
per state pharmacy regulations.  
 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Consecutive consenting COVID-19+ patients will be recruited as participants, who will be 
randomized equally to camostat mesylate or placebo using a permuted-block design with variable 
block size. Actual treatment assignment will be double-blind, concealed from the investigators 
and the participants. The YCCI statistical group (YCAS) will generate the randomization scheme 
and provide it to the pharmacy. Research pharmacy staff will prepare study drug and placebo for 
dispensing and assign and record which subject are assigned to receive them. The study site 
team will record what each participant receives according to assigned kit #. 
 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
The study design is built around obtaining respiratory swabs and saliva from participants. To 
encourage compliance with study protocol, study drug/placebo will be provided every other day 
(prior to swabbing and saliva collection) and verbal assessment of whether study drug/placebo 
was taken as prescribed will be done. 
 
Participants will have the option of not being swabbed again or providing saliva, even after 
receiving study drug, but lack of day 0 and 4 NP swabs would be a protocol deviation although 
they would be retained in intention to treat analysis. NP swabs are required at days 0, 4, 14, 28; 
optional swabs at days 2 and 6. Saliva will be collected at all study visits. 
 
6.5 
CONCOMITANT THERAPY 
 
Medications to be reported in the Case Report Form (CRF) are concomitant prescription 
medications (oral and parenteral), over-the-counter medications and supplements. There are no 
restrictions. We will track all concomitant medications that subjects take. 
 
6.5.1 
RESCUE MEDICINE 
 
Not applicable 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 


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Page 24 of 47 
 
7.1
DISCONTINUATION OF STUDY INTERVENTION 
Reasons why a study subjects may be withdrawn from the study intervention include, but are 
not limited to: 
 Subject request (withdrawal of consent) 
 Protocol violation, i.e. declining to take drug or be swabbed or providing saliva for viral 
load two times. 
 AE or reactions 
 Any condition, interaction, or contraindication where continued participation 
in the study will result in an unacceptable risk for the subject, as assessed by 
the Investigators or advisers 
 Discontinuation of the study by the Sponsor 
 Lost to follow-up 
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
 
x
Pregnancy 
 
x
Significant study intervention non-compliance  
 
x
If any clinical adverse event (AE) or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the participant 
 
x
Disease progression which requires discontinuation of the study intervention 
x
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
x
Participant unable to receive study intervention  
x
The reason for participant discontinuation or withdrawal from the study will be 
recorded on the Case Report Form (CRF). Subjects who provide informed consent and 
are randomized but do not receive the study intervention may be replaced. Subjects 
who sign the informed consent form, and are randomized and receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the 
study will be replaced. 
 
7.3
LOST TO FOLLOW-UP 
 


 
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A participant will be considered lost to follow-up if he or she fails to return for two  or more 
visits and is unable to be contacted by the study site staff; if a subject is hospitalized outside the 
YNHHS we  will attempt follow for clinical outcomes and concomitant medications. 
 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 
one day and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
Biological specimen collection and laboratory evaluations. 
On study days 0, 2 (NP swab optional, saliva required), 4 (NP swab and saliva both required) 
and 6 (NP swab optional, saliva required), 14+/-2 (NP swab and saliva both required) and 
28+/-2, (NP swab and saliva both required), samples will be obtained and analyzed by an 
FDA-authorized COVID-19 RT-PCR assay coordinated through the YNHH Clinical Virology 
Laboratory, and Yale Department of Pathology. Additional testing including antigen 
detection may be done on an NP swab, nasal swab or saliva. 
 
On study days 0, 14+/-2 and 28+/-2, blood will be collected for 1) clinical 
surveillance→complete blood count, blood chemistries and coagulation including 
electrolytes, BUN, creatinine, AST, ALT, total and direct bilirubin, HS-CRP, LDH and alkaline 
phosphatase, PT, INR, d-dimer, fibrinogen; 2) research testing including obtaining serum, 
plasma and  peripheral blood mononuclear cells for research studies. A maximum of 125 mL 
of blood will be requested to be collected on days 0, 14 and day 28 (total of 375 mL over 
four weeks)  for these purposes. 
 
Respiratory swab and saliva RT-PCR testing will be done by YNHHS or YNHHS-designated 
send-out laboratories. Quidel’s Sofia platform will be use at the study site  for antigen  
detection. Positivity and Ct values will be recorded and log10 viral loads back-extrapolated 
from log10 being equivalent to 3.3 Ct units or as determined using a concomitant standard 
curve. 
 


 
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Blood chemistries and CBCs (and an FDA-approved POC urine pregnancy test will be done on 
site prior to enrollment for appropriate women as required) will be done by YNHHS 
laboratories and recorded, and results reported to patients. 
 
Remaining blood samples will be stored in a biological specimen repository approved by 
Yale University as follows: 
 
Investigator: 
Stephanie Halene 
Type of Review: 
Modification/Update 
Title of Study: 
Specimen Repository for Hematologic Diseases 
IRB Protocol ID: 
1401013259 
Submission ID: 
MOD00029770 
Committee Name: 
IRB 0-Ad Hoc Committee 
 
        Final Approval Date: 3/29/2020 
        Expiration Date: 2/17/2021 
Remaining respiratory tract samples (NP swabs, saliva) processed by the YNHH Virology 
laboratory will be overlabelled with unique identifiers (to de-identify the samples) and 
conserved for future use in the Vinetz laboratory which has been approved to handle such 
COVID-19 specimens by EH&S.


 
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8.2 
SAFETY AND OTHER ASSESSMENTS 
At  study visits, vital signs including pulse oximetry will be obtained. Physical examination will not be 
performed routinely on participants unless dictated by signs or symptoms. Any patient experiencing 
symptoms requiring medical examination will be referred to hospital.. 
 
On all study days, participants will be asked to answer specific questions that relate to known potential 
adverse effects of camostat mesylate. The previously determined incidence of adverse effects (when 
drug administered for at least two weeks) are: 
 
Symptom 
0.1 to 0.5% 
<0.1% 
 
Rash 
0.4 
 
 
Pruritus 
0.2% 
 
 
Gastrointestinal 
 
0.1 to 0.5% 
(nausea, abdominal 
discomfort or 
fullness, diarrhea) 
Anorexia, vomiting, 
dry mouth, 
heartburn, abdominal 
pain, constipation 
 
 
Included in the informed consent form are concerns about rare side effects. Study personnel will 
specifically elicit whether there are symptoms concerning for severe allergy such as jaundice, 
anaphylaxis or anaphylactoid reactions will be determined on a daily basis by study personnel who will 
ask about such symptoms (yellow eyes, weakness, wheezing, shortness of breath, tongue swelling, 
hives, rash) during the first 7 days of the study. Laboratory evidence of adverse effects such as 
thrombocytopenia, hyperbilirubinemia, or hyperkalemia will only be able to be determined at day 14.  
 
Participants will be informed on study day 28 of all available research-specific study results to date. 
Results that return after day 28 will be communicated with the participant within 2 weeks of such 
results. If there are actionable results of routine/standard of care lab tests including CBC, chemistries 
and coagulation studies, they will be reported to participants in a timely manner, otherwise they will be 
discussed at the day 28 visit or if they become available after day 28, within 2 weeks of when new 
results become available. 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
The Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 will be used to characterize 
adverse events.  
 
The study involves a repurposed drug in routine clinical use in Japan and is an investigational new drug in 
the United States. 
 
The study involves the use of placebo in a population with diagnosed COVID-19, which is justified 
because there is no drug approved for its treatment, nor is there a current outpatient study for treatment 
of diagnosed COVID-19. 


 
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8.3.1 
DEFINITION OF ADVERSE EVENTS (AE) 
 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
Adverse events in this study will be assessed by verbal report, and specifically sought according to the 
approval package insert. 
 
8.3.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
 
8.3.3 
CLASSIFICATION OF AN ADVERSE EVENT 
 
 
8.3.3.1 
SEVERITY OF EVENT 
 
The Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 will be used to characterize 
adverse events.  
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious”. 


 
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8.3.3.2 
RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
8.3.3.3 
EXPECTEDNESS  
 
The PI and co-investigator team will be responsible for determining whether an adverse event (AE) is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the risk information previously described for the study intervention (i.e. 
the package insert approved in Japan). 
 
8.3.4 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 


 
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Study personnel will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit. Events will be followed for outcome information until resolution or stabilization. 
 
8.3.5 
ADVERSE EVENT REPORTING  
An external DSMB will be appointed to oversee this study, to assess safety and to  determine early 
evidence of efficacy or futility at a planned interim data examination. The PI and co-investigators will 
record all adverse events and report them to the sponsor according to the timetable for reporting specified 
in the protocol. 
All AEs will be reported to regulatory authorities, IRB, and investigators in accordance with all local 
applicable laws and regulations.  
 
8.3.6 
SERIOUS ADVERSE EVENT REPORTING  
 
The study clinician(s) will report to the Sponsor-Investigator within 24 hours of awareness of the event, 
any serious adverse event, whether or not considered study intervention related, including those listed in 
the protocol or package insert and must include an assessment of whether there is a reasonable 
possibility that the study intervention caused the event. Study endpoints that are serious adverse events 
(e.g., all-cause mortality) must be reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the study intervention and the event (e.g., death from 
anaphylaxis). In that case, the investigator must immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site investigator 
deems the event to be chronic or the participant is stable. Other supporting documentation of the event 
may be requested by the study sponsor and should be provided as soon as possible. 
 
The Sponsor-Investigator will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information and within 15 days for all other 
serious unexpected suspected adverse reactions (SUSARs), in an Investigational New Drug (IND) safety 
report. 
 
8.3.7 
REPORTING EVENTS TO PARTICIPANTS 
  
 Not applicable 
 
8.3.8 
EVENTS OF SPECIAL INTEREST  
 
Not applicable  
 
8.3.9 
REPORTING OF PREGNANCY  
 
Given that the duration of study drug administration is one week, a new pregnancy is unlikely to be 
reported. If so, the participant so reporting a new pregnancy will be stopped from receiving study 
drug/placebo. Other followup may be continued. 
 


 
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8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“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 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2 
 UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the lead principal investigator (PI). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within 2 days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within <insert timeline in 
accordance with policy> of the investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 2 days. 
 
8.4.3 
REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Not applicable to the study population. 


 
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9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
All tests performed will be tests of superiority. 
For the primary endpoint, we will test the hypothesis that camostat mesylate results in a significantly 
greater change from baseline to day 4 in respiratory (Nasopharyngeal swab, saliva RT-PCR) log10 viral 
load compared to placebo.  
Similarly, for secondary endpoints we will test the hypothesis that camostat mesylate will result in a 
significantly greater change from baseline to days 2 and 6 in respiratory (nasopharyngeal swab, saliva 
RT-PCR) log10 viral load compared to placebo; that camostat mesylate will reduce log10 of a positive 
COVID19 test at days 2 and 6 (optional swabs), rate of positive tests at days 6, 14 (required), and 28 
(required); and that camostat mesylate will result in lower symptom burden at days 6 and 14. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
The sample size calculation is based on the primary outcome of interest: change in log10 respiratory 
(nasopharyngeal swab, saliva swab RT-PCR) viral load from baseline to day 4 post-randomization. Given 
the limited data on the variability of the change in log10 viral load, we have powered the study based on 
detecting a moderate standardized effect size of 0.3 using an analysis of covariance (ANCOVA), 
adjusting for baseline log10 viral load. To put into context, one scenario that would produce a 0.3 
standardized effect size would be a change of 4 in log10 viral load in the camostat mesylate group 
compared to a change of 1 in log10 viral load in the placebo group assuming a standard deviation of 5.0. 
(NOTE: For ANCOVA, the effect size is the standard deviation of the treatment means divided by the 
pooled standard deviations of the observations.)  To be conservative we assume a R-squared of 0 
between the log10 viral RNA at 4-days and baseline log10 viral RNA.  With a power of 90%, and a type I 
error rate of 10% (2-sided), we would be able to detect the hypothesized 0.3 standardized effect size with 
98 total patients -  49 patients per group with a 1:1 randomization.  Increasing this sample size by 15%, 
5% for an efficacy and futility look at 50% information (i.e. when half of the patients have been enrolled) 
and 10% to account for loss to follow up, gives a total of 114 participants (57 per treatment arm). 
 
9.3 
POPULATIONS FOR ANALYSES 
 
Intention-to-Treat Analysis Dataset: Participants will be analyzed based on their treatment assignment.  
 
Per Protocol Analyses Dataset:  All participants completing the study who complied with the protocol.  
 
Safety Analysis Dataset: all study participants. 
 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 
GENERAL APPROACH 
All primary analyses will be performed as intent-to-treat analyses with a type I error rate of 10% (two-
sided).  Parametric distributional assumptions will be checked. If assumptions fail, other distributions will 
be considered prior to transformations and non-parametric methods. SAS (version 9.4) or the latest 
version of R (currently 3.6.3) will be used to analyze the data. 
 


 
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9.4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
The primary analysis will be according to intent-to-treat and conducted using ANCOVA, adjusting for 
baseline log10 viral load (or conversion from Ct value assuming 1 log10 = 3.3 Ct units). We will use the t-
statistic for the treatment effect to determine whether the treatment is statistically different from the 
placebo at the overall 10% level of significance, controlling for baseline log10 viral load. Because of the 
interim analysis (see below), a p-value of 0.06 (2-sided), corresponding to an efficacy boundary value of 
1.875 at the last look, will be used for the level of significance for the primary outcome at the final 
analysis.  In sensitivity analyses, we will also adjust for age and time since onset of symptoms. We will 
also conduct a per-protocol analysis as a secondary analysis. We will assess the missing mechanism and 
the impact of missing data. Sensitivity analyses under either missing at random or missing not at random 
will be considered, as appropriate. 
 
9.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Secondary outcomes of interest include: change in log10 respiratory (nasopharyngeal swab, saliva RT-
PCR) viral load from baseline (day 0) to days 2 and 6 post-randomization; log10 and risk for a positive 
COVID-19 test at day 6, 14 and 28; and change of COVID-19 symptom score from baseline (day 0), as 
measured at days 6 and 14 +/- 2 days after enrollment (day 0). The same ANCOVA analysis as proposed 
for the primary endpoint will be used to analyze two and six day change in log10 for the secondary 
endpoint. Risk for positive COVID19 test at day 6, 14 and 28 will be compared using an exact binomial 
distribution. Linear mixed models will be used to describe trajectories of change in the symptom score. 
The models will include fixed effects for treatment, time and the interaction of treatment and time. An 
unstructured covariance pattern will allow for correlation between repeated observations. Differences 
in means at each timepoint will be estimated along with 90% confidence intervals. All statistical tests 
will be conducted at 10% level of significance (two-sided) with no adjustment for multiple testing.  
 
The COVID-19 PRO daily self score tool, derived almost entirely from a validated  influenza symptom 
scoring. Tool (FLU-PRO)10 consists of 39 items that are answered daily. Items 1-33 are Likert scale 
questions (rated 0-4) where 0 = not at all,11, 12 and 4 = very much. These items are summed to score 
the severity of symptoms- where a total score of 132 would indicate the greatest severity of symptoms 
and a score of 0 would indicate no severity of symptoms. Items 34-38 are also Likert scale questions 
(rated 0-4) that measure the frequency of specific daily symptoms where 0 = 0 times and 4 = 4 times or 
more. These items are summed to score the frequency of symptoms- where the highest score for the 
frequency of symptoms (20) indicates the greatest burden of symptom frequency. The last question (39) 
asks patients for their highest temperature in Fahrenheit. 
 
9.4.4 
SAFETY ANALYSES 
Safety will be reported by treatment arm using descriptive statistics (means and standard deviations or 
frequencies and counts) and assessed by comparing the adverse events in the treatment group using 
Type I error of 5% (2-sided); no control for multiplicity will be done for safety outcomes.  We will 
consider Wilcoxon rank sum tests or two-sample t-tests for continuous outcomes and the exact binomial 
distribution for proportions. 
 
9.4.5 
BASELINE DESCRIPTIVE STATISTICS 


 
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Baseline characteristics (including demographic, lab, and clinical variables) will be presented by 
treatment group (camostat mesylate and placebo).  Means and standard deviations will presented for 
continuous variables and frequencies and proportions will be presented for categorical variables.  No 
inferential statistics will be presented. 
 
 
9.4.6 
PLANNED INTERIM ANALYSES  
 
Interim monitoring for safety, efficacy and futility will be conducted. When 50% of the participants have 
accumulated the primary endpoint, we will conduct an interim analysis to assess for efficacy and futility 
using the group sequential method with asymmetric boundaries.  We will use a Pocock boundary for 
efficacy and will consider stopping early for efficacy if the t-statistic for the treatment effect is greater 
than the critical value of 1.875; we propose stopping for futility if the drug is trending in the wrong 
direction, and have set a futility boundary value of -1. Safety will be assessed by comparing the rate of 
adverse events in the treatment group using Type I error of 5% (2-sided); no control for multiplicity will 
be done for safety outcomes. 
 
9.4.7 
SUB-GROUP ANALYSES 
 
Not applicable 
 
9.4.8 
TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Not applicable 
 
 
9.4.9 
EXPLORATORY ANALYSES 
Exploratory endpoints will include area under the log10 viral RNA curve; time to complete absence of 
symptoms the components of the symptom assessment scale (e.g. nose, throat, cough); and 
hospitalization. Also we are going to use Quidel’s Sofia’s antigen detection test in this study. Area under 
the curve (AUC) will only be calculated for participants with at least three follow-up log10 viral load 
measurements, and will account for the follow-up time. Mean AUC values will be compared using a two-
sample t statistic. Time to complete absence of symptoms will be analyzed using the Cox model and 
event-free rates determined by Kaplan-Meier. Individuals will be administratively censored at 28 days.  
Those who die will be censored at time of death. We will conduct sensitivity analyses using death as a 
semi-competing risk. Twenty-eight day hospitalization rates will be compared using an exact binomial 
distribution. We will also consider additional biomarkers (using similar methods as described for the 
primary and secondary outcomes) and the individual components of the symptoms (using similar methods 
as described above).  
 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 


 
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10.1.1 
INFORMED CONSENT PROCESS 
 
10.1.1.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS  
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and  documentation of informed consent is required prior to administering study 
intervention.  
 
10.1.1.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
Obtaining and documenting informed consent. Due to the contagiousness of COVID-19 patients and the 
desire to minimize face-to-face time between staff and subjects,  the process of obtaining written 
informed consent will be carried out as follows. 1) Prior to the first study visit, a member of the study 
team will contact, by telephone, the potential participant on the basis of a positive COVID-19 test and 
explain the study, according to the attached script. 2) The informed consent form will be provided by 
email if the participant has an active email address, or provided in paper form if the participant prefers 
at the first study visit for discussion. 3) On arrival to the first study visit, the participant will again provide 
verbal assent and will receive a written informed consent form. Verbal assent will be witnessed by a 
health care worker and/or a study researcher, recorded, and entered into the participant’s electronic 
medical record (EPIC). 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. 
 
Consent forms will be Institutional Review Board (IRB)-approved and the participant will be asked to 
read and review the document. The investigator will explain the research study to the participant and 
answer any questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and of their 
rights as research participants. Participants will have the opportunity to carefully review the written 
consent form and ask questions prior to signing. The participants should have the opportunity to discuss 
the study with their family or surrogates or think about it prior to agreeing to participate. Participants 
will be informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. A copy of the informed consent document will be given to the participants for their 
records. The informed consent process will be conducted and documented in the source document 
(including the date), and the form signed, before the participant undergoes any study-specific 
procedures. The rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study. 
 
 
10.1.2 
STUDY DISCONTINUATION AND CLOSURE 
 


 
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This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator, the Investigational New Drug 
(IND) sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the 
Principal Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), 
and sponsor and will provide the reason(s) for the termination or suspension. Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
10.1.3 
CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
 
 Language regarding long-term storage of samples and genetic testing have been included in the 
informed consent form. An opt-out check box is provided in the informed consent form, as well as the 
possibility that commercializable, for-profit products may result from their specimens, with no 
compensation to the subject.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 


 
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Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored in the Yale Center for Clinical Investigation’s Forte Electronic  Data Capture 
(EDC), which is 21 CFR Part 11 compliant. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by clinical sites and by 
the Yale Center for Clinical Investigation research staff will be secured and password protected. At the 
end of the study, all study databases will be de-identified and archived at the Yale Center for Clinical 
Investigation or its designate. 
 
 
10.1.4 
FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored in the PI’s private office. After the study is 
completed, the de-identified, archived data will be transmitted to and stored at at the Yale Center for 
Clinical Investigation and/or its designees, for use by other researchers including those outside of the 
study. Permission to transmit data to the Yale Center for Clinical Investigation and/or its designees will 
be included in the informed consent.  
 
Stored specimens will include nasopharyngeal swabs, saliva and blood and will be have coded identifiers 
with identities only known to study-approved personnel. No identifiers will be provided to researchers. 
The future use of these samples is intended to include possible genetic, immunological and virological 
analysis. Genetic studies may include single gene sequencing, whole genome sequencing, and T and B 
cell repertoire studies to look at genetic predisposition to COVID-19 and/or specificity of immune 
responses, including production of biologics derived from such studies, and for for-profit uses. These 
uses are described in lay terms in the informed consent form and include language that there will not be 
financial rights or compensation for genetic or immunological uses. 
 
After the study is completed, the de-identified, archived data stored at at the Yale Center for Clinical 
Investigation and/or its designees, will be made available for use by other researchers including those 
outside of the study.  
 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-
identified biological samples will be stored at the Biorepository supervised by Dr. Stephanie Halene at 
300 George St. with the same goal as the sharing of data with the YCCI. These samples could be used to 
research the causes of COVID-19, its complications and other conditions for which individuals viral 
infections are at increased risk, and to improve treatment. The Halene Biorepository will also be 
provided with a code-link that will allow linking the biological specimens with the phenotypic data from 
each participant, maintaining the blinding of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed.  
 
When the study is completed, access to study data and/or samples will be provided through the Halene 
Biorepository or Vinetz laboratory. 


 
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10.1.5 
KEY ROLES AND STUDY GOVERNANCE 
Provide the name and contact information of the Sponsor-Investigator. 
Sponsor-Investigator 
 
 
Geoffrey Chupp, M.D., 
Professor of Internal Medicine 
 
 
Yale School of Medicine 
Division of Pulmonary, Critical Care & 
Sleep Medicine 
 
 
300 Cedar Street TAC 441-B 
New Haven, CT 06520-8057 
 
 
203-737-5405 
 
 
geoffrey.chupp@yale.edu 
 
 
 
An independent COVID Data and Safety Monitoring Board (DSMB) will monitor data on an ongoing basis 
to ensure the continuing safety of the participants enrolled in this study and to review efficacy 
information. The COVID DSMB will perform periodic safety reviews throughout the study as outlined in 
the COVID DSMB charter. The board will also meet to review interim data. The COVID DSMB will consist 
of a minimum of four members including the chair, at least one infectious disease physician, at least one 
biostatistician and investigators with expertise in current clinical trials conduct and methodology. The 
COVID DSMB responsibilities, authorities, and procedures will be documented in a separate charter. 
 
 
10.1.6 
SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a collaboration between the PI and a DSMB . The DSMB 
will be independent from the study conduct and free of conflict of interest; measures will be in place to 
minimize perceived conflict of interest. The DSMB will meet according to a regular schedule to assess 
safety and efficacy data on each arm of the study. The PI and DSMB will operate under the rules of an 
approved charter that will be written and reviewed at the organizational meeting of the the PI and 
medical monitors. At this time, each data element that they need to assess will be clearly defined. The 
DSMB will provide input to the Yale School of Medicine via the PI. 
 
10.1.7 
CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
Monitoring for this study will be performed by the PI/Sponsor and an independent site monitor. 
  


 
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The Sponsor-Investigator-designated monitor(s) will conduct monitoring visits to ensure that clinical 
investigators and study team members are compliant with the protocol, ICH good clinical practice, 
federal, state and local regulations and institutional policies and procedures, that data are of high 
quality and integrity, and that the facilities and staffing are adequate for continued study participation. 
This will be performed by conducting monitoring visits including a site initiation visit, regularly scheduled 
interim monitoring visits while subjects are on study, and a site close-out visit at the site. Following each 
site visit, a visit report will be generated containing information on site activities and a summary of 
pertinent points and action items. The report will be provided with a follow-up letter. Site-specific data 
status reports will be distributed to the site regularly to outline planned, missing or incomplete case 
report forms and any outstanding data queries. 
 
During monitoring visits, the following may be reviewed: 
• 
Protection of the rights, safety and welfare of subjects through review of informed consent 
process and documentation, adverse events (AEs) and serious adverse events (SAEs) and safety 
procedures 
• 
Subject eligibility 
• 
Source verification 
• 
Protocol compliance 
• 
Deviations and Non-compliance 
• 
Investigator Site File 
• 
GCP compliance 
• 
Investigational Drug and Placebo Storage and Accountability (including quantity and disposal 
procedures) 
• 
Laboratory Facilities 
• 
Additional study supplies inventory and assessment 
• 
Study progress and/or follow-up on issues with Site Principal Investigator (PI) and relevant 
members of the study team 
 
The Sponsor-Investigator and the appointed independent clinical monitor will define the required study 
monitoring activities in a Study Monitoring Plan. 
 
 
10.1.8 
QUALITY ASSURANCE AND QUALITY CONTROL 
 
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan will be 
developed to describe the site’s quality management by the appointed Site Monitor. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 


 
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Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all source data/documents, and reports for the 
purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 
  
  
10.1.9 
DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.  
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study. Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into the Yale Center for Clinical Investigation’s Forte 
Electronic Data Capture (EDC), a 21 CFR Part 11-compliant data capture system.The data system 
includes password protection and internal quality checks, such as automatic range checks, to identify 
data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
 
10.1.9.2 
STUDY RECORDS RETENTION  
Study documents will be retained for 2 years after the last approval of a marketing application in an 
International Conference on Harmonisation (ICH) region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study intervention. These documents should be retained 
for a longer period, however, if required by local regulations. No records will be destroyed without the 
written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform the 
investigator when these documents no longer need to be retained. 
 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 


 
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noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within two working days of identification of the protocol deviation, or within one working 
days of the scheduled protocol-required activity. All deviations must be addressed in study source 
documents, reported to the IRB. Protocol deviations must be sent to the reviewing Institutional Review 
Board (IRB) per their policies, and to the Yale Center for Clinical Investigation data management staff for 
inclusion in the study database. The site investigator is responsible for knowing and adhering to the 
reviewing IRB requirements. Further details about the handling of protocol deviations will be included in 
the MOP. 
 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
Even though this study is not supported by the NIH, we will follow the National Institutes of Health (NIH) 
Public Access Policy, which ensures that the public has access to the published results of NIH funded 
research, even though this study is not funded by the NIH. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon 
acceptance for publication. 
 
Even though this study is not funded by the NIH, this study will comply with the NIH Data Sharing Policy 
and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials 
Registration and Results Information Submission rule. As such, this trial will be registered at 
ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. In 
addition, every attempt will be made to publish results in peer-reviewed journals. Data from this study 
may be requested from other researchers immediatelyafter the completion of the primary manuscript 
by contacting the Yale Center for Clinical Investigation.  
 
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use of these 
data for subsequent research. Large-scale data include genome-wide association studies (GWAS), single 
nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene 
expression data. 
 
 
 


 
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10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial. The study leadership 
in conjunction with the appropriate NIH Institute or Center will have established policies and procedures 
for all study group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest. 
 
 
10.2 ADDITIONAL CONSIDERATIONS 
Not applicable 
 
 
 


 
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10.3 ABBREVIATIONS 
The list below includes abbreviations utilized in this template. However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 


 
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NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 


 
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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale.  
 
Version 
Date 
Description of Change  
Brief Rationale 
6.0 
May 21, 
2020 
N/A – first version approved by IRB 
N/A 
7.1 
June 11, 
2020 
Increase dosing from TID to QID and 
change in primary endpoint 
evaluation from Day 2 to Day 4 
Operational changes as a result of 
institutional changes at Yale (eg 
different clinic) 
Clarifications of procedures 
Feedback from FDA 
 
Yale institutional operational 
refinements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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