Clinical trial NCT04346628
Conditions: Sars-CoV2 COVID-19
Sponsor: Stanford University
Start date: 2020-07-12; Completion date: 2021-04-16
Enrollment: 149 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the efficacy of oral favipiravir plus standard of care treatment (SOC) compared with placebo plus SOC in reducing the duration of shedding of SARS-CoV2 virus in patients with mild or asymptomatic COVID-19.

Detailed description:

Arms: arm 1: In addition to SOC, participants will receive favipiravir for 10 days, and be evaluated for health outcomes through day 28. arm 2: In addition to SOC, participants will receive placebo to match favipiravir for 10 days, and be evaluated for health outcomes through day 28.
Interventions: intervention 1: Favipiravir intervention 2: Placebo intervention 3: Standard of care treatment
Intervention descriptions: intervention 1: Favipiravir administered orally, 1800 mg on the first dose (day 1) followed by 800 mg twice daily for the next 9 days (days 2-10). intervention 2: Placebo to match favipiravir administered orally through day 10. intervention 3: Standard of care treatment for COVID-19 infection

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
A Phase 2 Randomized, Double Blinded, Placebo Controlled Study of Oral 
Favipiravir Compared to Standard Supportive Care in Subjects with Mild or 
Asymptomatic COVID-19 
Study Protocol and Statistical Analysis Plan 
NCT04346628 
February 18, 2021 


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Confidential 
 
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A Phase 2 Randomized, Double Blinded, Placebo Controlled Study of Oral Favipiravir 
Compared to Standard Supportive Care in Subjects with Mild or Asymptomatic COVID-19  
 
 
 
PROTOCOL NUMBER: 
IND 
 
IND#:  
 
 
INVESTIGATIONAL   
Favipiravir (T-705) 
PRODUCT: 
 
 
PROTOCOL VERSION / DATE: 
Version 9: 18Feb2021 
 
 
Amendment Version 8: 12Feb2021 
 
Amendment Version 7: 30Oct2020 
 
Amendment Version 6: 07Oct2020 
 
Amendment Version 5: 29Sep2020 
 
Amendment Version 4: 04Aug2020 
 
Amendment Version 3: 29Jul2020 
 
Amendment Version 2: 17Jul2020 
 
Original Version 1: 30Jun2020 
 
 
SPONSORED BY: Dr. Yvonne Maldonado, M.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CONTACT INFORMATION:  
Dr. Yvonne Maldonado, M.D.  
Professor of Pediatric Epidemiology and Population Health  
Chief, Division of Pediatric Infectious Diseases 
Stanford University School of Medicine 
Medical Director, Infection Prevention & Control and Attending Physician 
Lucile Packard Children's Hospital at Stanford  
Email: bonniem@stanford.edu 
 
Chaitan Khosla, Ph.D. 
Baker Family co-Director, Stanford ChEM-H 
Professor of Chemistry and Chemical Engineering 
Stanford University  
Email: khosla@stanford.edu  
 
Sponsor’s Representative: 
, Pharm. D. 
Senior VP, Regulatory Affairs 
Veristat LLC 
 
Email: 
  
 
 
Multi-Site Coordinator: 
, MPH, MSED 
Study Startup Operations Associate 
Email: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Protocol Title:  
A Phase 2 Randomized, Double Blinded, Placebo Controlled Study 
of Oral Favipiravir Compared to Standard Supportive Care in Subjects 
with Mild or Asymptomatic COVID-19  
Protocol Number: 
      PIND 
 
Protocol Version/Date:  Version 8 / 18Feb2021 
 
 
Sponsor Name: Dr. Yvonne Maldonado, M.D. 
Professor of Pediatric Epidemiology and Population Health  
Chief, Division of Pediatric Infectious Diseases,  
Medical Director, Infection Prevention & Control and Attending Physician 
Email: bonniem@stanford.edu 
 
Declaration of Investigator 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct 
the described trial in compliance with all stipulations of the protocol, regulations and ICH E6 
Guideline for Good Clinical Practice (GCP). 
  
 
Principal Investigator Name:  __________________________________________ 
                                                         
 
 
Principal Investigator Signature:  _______________________________________ 
                                                            
 
Date:  ___________________ 
          Date (MM/DD/YYYY)                                               
 
Statement of Compliance 
The signature below provides the necessary assurance that this study will be conducted 
according to all stipulations of the protocol including statements regarding confidentiality, and 
according to local legal and regulatory requirements, US federal regulations, and ICH E6(R2) 
GCP guidelines. 
 
Site Investigator Name:  __________________________________________ 
                                                            
 
 
Site Investigator Signature:  _______________________________________ 
                                                            
 
Date:  ___________________ 
          Date (MM/DD/YYYY)                                               
 


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TABLE OF CONTENTS 
1 
SYNOPSIS ...............................................................................................................................8 
2 
INTRODUCTION ................................................................................................................15 
2.1 
Background Information ............................................................................................15 
2.2 
Preclinical and In Vitro Experiences ........................................................................15 
2.3 
Clinical Experience .....................................................................................................16 
2.4 
In Vitro Therapeutic Levels ........................................................................................16 
2.5 
Phase 1 Study Steady State Exposure .......................................................................17 
2.6 
Rationale for 14-day Dosing Regimen .......................................................................18 
2.7 
Rationale for the Current Study ................................................................................19 
3 
DESIGN .................................................................................................................................19 
3.1    Study Design .................................................................................................................19 
3.2    Study Sites ....................................................................................................................20 
4 
OBJECTIVES .......................................................................................................................20 
4.1 
Primary Objective .......................................................................................................20 
4.2 
Secondary Objectives ..................................................................................................20 
5 
SUBJECT POPULATION ...................................................................................................21 
5.1 
Inclusion Criteria ........................................................................................................21 
5.2 
Exclusion Criteria .......................................................................................................22 
5.3 
Removal of Subjects from Treatment .......................................................................23 
5.4     Compensation ……………………………………………………………………….24 
6 
STUDY TREATMENT - FAVIPIRAVIR ..........................................................................24 
6.1 
Study Drug ...................................................................................................................24 
6.2 
Administration of Favipiravir or placebo .................................................................24 
6.3 
Outpatient Favipiravir Dosing ...................................................................................24 
6.4 
Drug Accountability ....................................................................................................25 
6.5 
Treatment Compliance ...............................................................................................25 
6.6 
Treatment Precautions ...............................................................................................25 
6.7 
Prohibited Concomitant Therapy ..............................................................................25 
7 
STUDY PROCEDURES ......................................................................................................26 
7.1 
Day 1 (PRE-DOSE) .....................................................................................................26 
7.2 
Day 1 (FIRST DOSE AND POST-DOSE) ................................................................27 
7.3 
Days 5, 10,  28 (Follow-up) or Early Termination ...................................................27 
8 
EFFICACY, PHARMACOKINETICS AND SAFETY ASSESSMENTS ......................28 
8.1 
Efficacy Assessments ...................................................................................................28 
8.2 
Required Resistance Testing ......................................................................................28 


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8.3 
Pharmacokinetics/Pharmacodynamics Assessments ...............................................28 
8.4 
Safety Assessments ......................................................................................................29 
8.4.1 Adverse Events .................................................................................................29 
8.4.2 Definition of an Adverse Event.........................................................................30 
8.4.3 Evaluating and Reporting of Adverse Events ...................................................30 
8.4.4 Serious Adverse Events (SAEs) ........................................................................31 
8.4.5 Definition of Serious Adverse Events ...............................................................31 
8.4.6 SAE Reporting Requirements to the Sponsor ...................................................32 
8.5 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................32 
8.5.1 Reporting SUSARs to the FDA: IND Safety Reports ......................................33 
8.6 
Clinical Laboratory Abnormalities and Other Abnormal Assessments ................33 
8.7 
Handling of Overdose .................................................................................................33 
9 
STATISTICAL METHODS ................................................................................................33 
9.1 
General Considerations ..............................................................................................33 
9.2 
Sample size justification .............................................................................................34 
9.3 
Demographic and Baseline Characteristics ..............................................................34 
9.4 
Analysis Populations ...................................................................................................34 
9.5 
Stratification, Subgroup Analysis and Pooled Analysis ..........................................34 
9.6 
Efficacy Endpoint Analysis ........................................................................................35 
9.7 
Safety Analysis .............................................................................................................36 
10 INTERIM ANALYSIS .........................................................................................................36 
11 RECORDING AND COLLECTION OF DATA ...............................................................37 
11.1 Case Report Form .......................................................................................................37 
11.2 Study Files and Subject Source Documents .............................................................37 
11.3 Monitoring ...................................................................................................................37 
11.4 Audit .............................................................................................................................38 
11.5 Retention of Data ........................................................................................................38 
12 ETHICS .................................................................................................................................38 
12.1 Ethics Committee ........................................................................................................38 
12.2 Subject Information and Consent .............................................................................38 
13 GENERAL CONSIDERATIONS .......................................................................................39 
13.1 Discontinuation of the Study ......................................................................................39 
13.2 Use of Information and Publication ..........................................................................39 
14 SCHEDULE OF ASSESSMENTS ......................................................................................40 
 
 


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List of Abbreviations 
 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AO 
Aldehyde oxidase 
AST 
Aspartate aminotransferase 
BID 
“bis in dies” / Twice a day 
BMI 
Body mass index 
CAPD 
Continuous ambulatory peritoneal dialysis 
CI 
Confidence interval(s) 
COVID-19  
Corona Virus Disease 2019  
CRP 
C-reactive Protein 
EC50 
Half maximal effective concentration 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
FPHU 
FUJIFILM Pharmaceuticals, U.S.A. Inc. 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization 
IEC 
Institutional ethics committee 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IUD 
Intra-uterine device 
MedDRA 
Medical dictionary for regulatory activities 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
MITT 
Modified intent-to-treat 
NEWS2 
National early warning score 2 
NO 
Nitrous Oxide 


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PaO2 
Partial pressure of oxygen 
PCR 
Polymerase chain reaction 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
RNA 
Ribo-nucleic acid 
RT-PCR 
Reverse transcriptase polymerase chain reaction 
SAE 
Serious adverse event 
SARS-CoV-2 
Severe acute respiratory syndrome corona virus 2 
SD 
Standard deviation 
SOC 
Standard of care 
SPO2 
Peripheral capillary oxygen saturation 
SUSAR 
Suspected unexpected serious adverse reaction 
TCID50 
Median tissue culture infectious dose 
TEAE 
Treatment-emergent adverse event 
TTCR 
Time to clinical recovery 
WHO 
World Health Organization 


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1 SYNOPSIS 
Title 
A Phase 2 Randomized, Double Blinded, Placebo Controlled Study of 
Oral Favipiravir Compared to Current Standard of Care in Subjects with 
Mild or Asymptomatic COVID-19 
Design 
This is a Phase 2 Double Blinded, Placebo Controlled Study evaluating 
the efficacy, safety and pharmacokinetics of favipiravir in adult subjects 
with PCR-positive, mild or asymptomatic COVID-19 infections. The 
study is a multicenter trial that will be conducted in up to 5 sites 
nationwide.  
Subjects will be randomized to receive either favipiravir + current 
Standard of Care (SOC) or placebo + SOC.  
For those subjects in the favipiravir + SOC arm, the dose regimen will be 
1800 mg BID favipiravir on the first dose (day 1) followed by 800 mg 
BID for the next 9 days (days 2-10).   
NOTE: 600 mg BID for subjects with Child-Pugh A liver impairment on 
days 2-10. 
Subjects in the SOC arm will receive placebo.  
The total anticipated duration of the study for each patient is 28 days. 
Objectives 
Primary Objective 
To evaluate the efficacy of oral favipiravir plus SOC compared with 
placebo plus SOC in reducing the duration of shedding of SARS-CoV2 
virus in patients with mild or asymptomatic COVID-19.  
Secondary Objectives 
1. To evaluate the efficacy of oral favipiravir compared with placebo 
in reducing the onset or duration of symptoms, hospitalizations, or 
ED visits in patients with mild or asymptomatic COVID-19. 
2. To assess the safety and tolerability of favipiravir in this subject 
population. 
3. To assess the development of antibodies against SARS-CoV-2  
4. To evaluate any changes in the PK profile of favipiravir and its 
major metabolite M1 in this subject population 
Endpoints 
Primary Endpoint: 
Time until cessation of shedding of SARS-CoV-2 virus, defined as the 
time in days from randomization to the first of two consecutive negative 
RT-PCR results of self-collected nasal swabs. 
Secondary Endpoints 
1. Nucleic acid (RT-PCR) from oropharyngeal swabs collected on 
Days 1, 5, 10, and 28 


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2. Clinical worsening of COVID-19 in symptomatic subjects 
(clinical worsening defined the development of respiratory distress 
or symptoms that require hospitalization) or development of 
COVID-19 symptoms in asymptomatic subjects  
3. Adverse events AEs and clinical laboratory tests for systemic 
safety including hematology and clinical chemistry 
4. Development of antibodies to SARS-CoV-2  
5. Time until cessation of symptoms (cessation of symptoms 
defined as absence of symptoms for at least 24 hours for those 
with mild symptoms).  
6. Absence of development of any symptoms among those 
enrolled with asymptomatic infection.   
7. Population PK analysis of favipiravir with assessment of 
maximum plasma concentration (Cmax) and minimum plasma 
concentration (Cmin) on Days 1, 5 and 10 
Study Sites 
Stanford University School of Medicine 
Planned 
Enrollment  
180 (90 in the favipiravir + SOC group and 90 in the placebo + SOC 
group) 
Study Population 
Adults with confirmed SARS-CoV-2 who are asymptomatic or 
experiencing mild to moderate symptoms 
Subject Entry 
Criteria 
Inclusion Criteria (all questions must be answered YES) 
1. Adults (18-80) 
2. Diagnosis of COVID-19 disease:  
a. If symptomatic, but without signs of respiratory distress (as 
defined by SpO2 <=94% on room air, RR >=24, HR 
>=110), with FDA-cleared molecular diagnostic assay 
positive for SARS-CoV-2 within 72 hours from initial 
swab to the time of commencing informed consent: Mild 
disease is defined as having at least 1 of the following: 
i. Fever (>98.7F) 
b. Cough/Shortness of breath/dyspnea 
c. Fatigue 
d. Headache/Body aches  
e. Joint pain 
f. Chest pressure 
g. GI symptoms including nausea, vomiting, and/or 
diarrhea 
h. Abdominal pain 
i. Sore throat 
j. Nasal congestion 
k. Chills 
l. Runny nose 
 


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m. New loss of taste or smell 
n. Abdominal pain 
o. Rash 
The date of onset of the first of the above symptoms 
will be documented. 
p. If asymptomatic, initial diagnosis obtained no more than 
72 hours from initial swab to the time of commencing 
informed consent 
3. Subject or their legal representative understands the requirements 
of the study and provides written informed consent prior to 
undergoing any treatment-related procedures. 
4. If male, subject must fulfill one of the following criteria: 
a. Be sterile (e.g., have had a vasectomy at least 6 months 
prior to Day 1 dosing), OR, 
b. Agree not to donate sperm during the study and for seven 
days following the last dose of study medication, AND, 
c. Agree to strictly adhere to the following contraceptive 
measures during the study and for seven days following the 
last dose of study medication: 
i. Abstain from sexual intercourse  
ii. Use a condom during sexual intercourse with a 
female of child-bearing potential. In addition, the 
female partner must use another form of 
contraception (e.g. intrauterine device [IUD], 
diaphragm with spermicide, oral contraceptives, 
injectable progesterone, or subdermal implants). 
5. If female, subject must fulfill one of the following criteria: 
a. Be unable to bear children (have not had a period for ≥ 12 
consecutive months, have had her uterus or ovaries 
removed, or have had a tubal ligation), OR, 
b. Must ensure that their male partner is incapable of 
fathering a child (e.g., has had a vasectomy at least 6 
months prior to study entry), OR,  
c. If she is of childbearing potential will strictly adhere to the 
following contraceptive measures during the study and for 
seven days following the last dose of study medication: 
i. Abstain from sexual intercourse, OR, 
ii. Must ensure that their male partner agrees to use a 
condom during sexual intercourse and agree to use 
an approved method of contraception (e.g., IUD, 
diaphragm with spermicide, oral contraceptives, 
injectable progesterone, or subdermal implants). 


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d. Agrees to stop breast-feeding prior to first dose of study 
drug and through seven days after completing therapy. 
e. Has a negative urine pregnancy test at screening. 
6. Subject agrees to maintain home or other quarantine as 
recommended by the study physician, except to visit the study site 
as required by the protocol. 
7. Subject agrees to take daily nasal swabs (anterior nares) for Day 1 
to Day 10 and Day 14, 21, and 28 using the study provided 
materials, and mail via FEDEX each sample on the day collected.  
8. Subject agrees to record daily symptoms, temperature, oxygen 
saturation, and pulse using the study provided materials.  
9. Subject agrees to return to the study site for follow-up visits on Day 
5, 10, and 28. The study site will be staffed by trained healthcare 
providers wearing full personal protective equipment and study site 
equipment will be disinfected between patients according to the 
same protocols as a clinical setting. Subjects will be wearing masks, 
will be appropriately spaced, and the number of subjects assessed 
at each time will be limited. 
10. Members of the same household may participate in the study as long 
as the inclusion and exclusion criteria are met.  
 
Exclusion Criteria (all questions must be answered NO) 
11. Subject has a concomitant bacterial respiratory infection as 
documented by a respiratory culture with microbiologic growth. 
NOTE: Subjects on empirical antibiotic treatment 
for possible but unproven bacterial pneumonia, but 
who are positive for SARS-CoV-2, are allowed in 
the study.  
12. Subject has a history of abnormalities of uric acid metabolism. 
13. Subject has a history of hypersensitivity to an anti-viral 
nucleoside-analog drug targeting a viral RNA polymerase. 
14. Subject has any of the following abnormal laboratory test results 
at screening: 
a. Platelet count <100,000 cells/mm3 
b. Absolute lymphocyte count <500 cells/mm3 
c. Hemoglobin <11 g/dL for women and <12 g/dL for men 
d. Serum creatinine concentration ≥1.5× ULN 
e. Confirmed creatinine clearance (CrCl) < 50 mL/min by 
Cockcroft-Gault 
f. Serum uric acid >20 mg/dL 
g. Subject is using adrenocorticosteroids (except topical or 
inhaled preparations or oral preparations equivalent to or 


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less than 10 mg of oral prednisone) or immunosuppressive 
or immunomodulatory drugs (e.g., immunosuppressants, 
anticancer drugs, interleukins, interleukin antagonists or 
interleukin receptor blockers). 
NOTE: Clinical screening laboratory 
evaluations will be performed locally by the 
site or site-designated laboratory. Treatment 
of study participants following institutional 
COVID-19 treatment policies or guidelines, 
including the use of immunomodulatory 
medications, is permitted. This excludes 
treatment with agents that have the potential 
for direct antiviral activity, including 
convalescent plasma and NO, and co-
enrolment into other clinical studies that 
evaluate investigational agents for COVID-19. 
15. Subject has a serious chronic disease (e.g., human 
immunodeficiency virus [HIV], cancer requiring chemotherapy 
within the preceding 6 months, and/or moderate or severe hepatic 
insufficiency and/or unstable renal, cardiac, pulmonary, 
neurologic, vascular, or endocrinologic disease states per 
investigator judgement). 
16. Has previously received favipiravir within the past 30 days. 
17. Has renal insufficiency requiring hemodialysis or continuous 
ambulatory peritoneal dialysis (CAPD). 
18. Has liver impairment greater than Child Pugh A. 
19. Has a history of alcohol or drug abuse in the previous two years. 
20. Has a psychiatric disease that is not well controlled where 
controlled is defined as: stable on a regimen for more than one 
year. 
21. Has taken another investigational drug within the past 30 days. 
22. Is deemed by the Investigator to be ineligible for any reason.  
Randomization 
Following consent, those subjects meeting all entry criteria will be 
randomized in a 1:1 ratio.  
Treatment Arm: favipiravir + SOC 
Control Arm: placebo + SOC 
Randomization will be stratified by age (>=50 and <50 years old) and sex. 
Treatment 
Regimen for 
Favipiravir 
(Standard dose) 
• Favipiravir and placebo tablets will be administered orally.  
• The regimen begins with loading doses of 1800 mg BID on Day 1 
(the first 24 hours of treatment at t =0 and t = 8-12 hours) (3600 


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mg/day). Then maintenance dosing of 800 mg BID (1600 mg/day) 
from Day 2 (beginning 18-24 hours after the loading dose on Day 1). 
• 
Patients with Child-Pugh liver impairment of grade A will have their 
maintenance dose decreased to 600 mg BID 
• The total duration of treatment is expected to be 10 days. 
Duration of Study 
Participation 
The total anticipated duration of the study for each patient is up to 28 
days. 
Statistical 
Methods  
To address our primary objective, time until viral shedding cessation will 
be compared between the two treatment arms using a two-sided Wald test 
derived from a Cox proportional hazards model adjusted for age and sex 
and stratified by site. The test will be performed at the two-sided alpha = 
0.05 level of significance. The hazard ratio for shedding cessation will be 
estimated, along with its 95% confidence interval, from a Cox 
proportional hazards model. If the proportional hazards assumption is not 
met, we will consider an extended Cox model that relaxes the 
proportional hazards assumption. The log rank test will also be 
performed. 
The distribution of viral shedding cessation will be estimated using the 
Kaplan-Meier method, and Kaplan-Meier curves will be presented for 
each treatment arm. Time to shedding cessation along with 95% 
confidence intervals will be presented for each treatment arm.  
 
The rate of hospitalizations and ED visits will be estimated along with 
95% confidence intervals by each arm. In addition, we will compare 
between arms the time to each of respiratory failure, hospitalization or 
deaths and the corresponding composite of all such events using Kaplan-
Meier methods. The frequency of adverse events and serious adverse 
events will be tabulated by type and by treatment arm. AEs will be 
compared by arm using the Chi-squared test or Fisher’s exact test, as 
appropriate, in the safety analysis set. 
 
An interim analysis for safety and overwhelming efficacy will be 
performed once 50% of patients have 24 hours of follow-up complete. 
Enrollment will pause once 50% of patients have received treatment and 
will remain paused until the DSMC makes their recommendation after 
their safety review. 
Individual 
Stopping Rule 
A subject should be removed from favipiravir treatment if one of the 
following criteria is met: 
• AST or ALT > 8 x ULN 
• ALT or AST > 3 x ULN AND total bilirubin > 2X ULN 
• AST or ALT > 3 x ULN AND patient has right upper quadrant pain 
or eosinophilia 


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• Uric acid >20mg/dL 
A subject whose treatment is terminated should remain in the study for 
appropriate follow up assessments. 
Study 
Measurements: 
Efficacy, Safety 
and PK 
Primary Measurement (Efficacy): 
1. Time to first of two negative tests based on nasal swab for RT-
PCR taken daily from Day 1 to Day 10, and Days 14, 21, and 28.  
Secondary Measurements (Safety, Efficacy and PK): 
2. Oropharyngeal swab for nucleic acid (RT-PCR) taken Day 1, 5, 
10, and 28.  
3. Symptom improvement or worsening: Subjects will fill in a diary 
daily, recording the following symptoms:  
a. Cough 
b. Sore throat 
c. Headache 
d. Nasal congestion 
e. Body aches and pains 
f. Fatigue 
g. Oral temperature taken after 4 pm and at least four hours 
after ingesting the most recent antipyretic (acetaminophen 
or NSAID) 
h. Dyspnea 
i. Shaking chills 
j. New loss of taste or smell 
k. GI symptoms including nausea, vomiting, and/or diarrhea 
l. Chest pain 
4. Safety as assessed by:  
a. Observed and reported adverse events 
b. Clinical laboratory evaluations of blood on Days 1, 5, 10, 
and 28 
c. Physical Examination at screening (pre-dose Day 1), Days 
10, and 28 
d. Daily vital signs: pulse oximetry, heart rate, and 
temperature.  
5. Optional Blood for determination of antibodies to SARS-CoV-2 
will be obtained on Days 1 and 28. Collection of blood for 
antibodies is optional for sites. 
6. Optional Blood for PK obtained pre-dose (within 30 minutes prior 
to dosing) and post-dose (45 to 75 minutes following dosing) on 
Days 1, 5 and 10. Collection of PK is optional for sites. 
7. Optional Stool samples for determination of viral load in stool 
and microbiome characterization will be obtained in the following 


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windows Day 1±5, 14±7, and 28±7. Collection of stool is optional 
for sites. 
 
2 INTRODUCTION 
2.1 
Background Information 
Favipiravir, a small molecule, is a novel anti-viral agent discovered by FUJIFILM Toyama 
Chemical Co., Ltd. It is a broad-spectrum antiviral that includes activity against all RNA virus 
families tested, including rabies, Ebola, Lassa, and coronaviruses. It has been in clinical trials for 
influenza, Severe Fever with Thrombocytopenia virus, Ebola, and has been used under 
compassionate release for Ebola, rabies, Lassa fever, norovirus and COVID-19. As of the date of 
this protocol, three Chinese studies exploring its use against COVID-19 have been posted to the 
Chinese Clinical Trial Registry website (http://www.chictr.org.cn/showprojen.aspx?proj=49042 
http://www.chictr.org.cn/showprojen.aspx?proj=49015 
http://www.chictr.org.cn/showprojen.aspx?proj=49013). 
Results from one study have been reported as demonstrating that viral PCR titers fall faster in 
patients treated with favipiravir plus interferon as compared with patients treated with interferon 
plus lopinavir/ritonavir. 
Host cellular enzymes convert favipiravir to T-705 ribosyl triphosphate (T-705RTP), which 
selectively inhibits viral RNA polymerase. Based on its potent and selective inhibitory activities 
against a broad spectrum of influenza A, B, and C viruses, including strains poorly susceptible to 
amantadine hydrochloride or oseltamivir phosphate, favipiravir has been approved in Japan for the 
treatment of uncomplicated influenza, when currently available anti-influenza medications are not 
sufficient.  Favipiravir has been tested against the novel coronavirus SARS-CoV2, which causes 
disease ranging from mild, cold-like symptoms to acute respiratory failure and death.  
Epidemiologic studies suggest that individuals can be asymptomatic and transmit disease.  The only 
available treatment for COVID-19 illness is remdesivir but it’s use is currently limited to 
hospitalized patients with severe disease under an emergency use authorization from the FDA. 
2.2 
Preclinical and In Vitro Experiences 
Preclinical and animal studies indicate that favipiravir is effective against RNA viruses causing a 
variety of disorders. 
Preclinical and animal studies show no direct suppression of white blood cell types or 
immunosuppression by favipiravir. This contrasts with strong immunosuppressive effects of 
ribavirin and other antiviral agents.   
Genotoxicity studies indicate that favipiravir does not pose a clinical genotoxic risk, however, based 
on the results of embryo-fetal toxicity studies, favipiravir is not recommended for use in pregnant 
females, those who may become pregnant, or those who are nursing. A human testicular toxicity 
study was run to determine if there are effects on human spermatogenesis. No abnormality in 
testicular function tests was observed; however, this study was performed at doses less than those 
to be used in this study. Due to the effect on embryo-fetal development seen in animals, and the 
presence of favipiravir in semen for several days after the end of therapy, the recommendation is 


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for male and female contraception for seven days following the end of treatment, in the dose 
regimen for influenza. Details of the reproductive toxicity studies may be found in the Investigator’s 
Brochure. 
Favipiravir is both metabolized by, and inhibits, aldehyde oxidase (AO). A potential interaction 
exists between favipiravir and drugs oxidatively metabolized by the AO pathway, where blood 
concentration of these drugs or favipiravir may be increased. Similarly, a potential interaction exists 
between favipiravir and drugs inhibiting AO activity, where blood concentration of favipiravir may 
be increased. Similarly, a potential interaction exists between favipiravir and drugs inhibiting AO 
activity, where blood concentration of favipiravir may be increased. Favipiravir should not be used 
with pyrazinamide. 
2.3 
Clinical Experience 
Overall, more than 40 clinical studies with favipiravir have been conducted globally, mainly in the 
US and Japan. Recently, China has begun studying favipiravir in patients with severe influenza as 
well as COVID-19.  More than 3100 study subjects have received at least one dose of favipiravir 
manufactured by Toyama Chemical. Favipiravir has been well tolerated in studies in adults and 
elderly subjects with uncomplicated influenza. A consistent safety profile composed of relatively 
low frequencies of mild to moderate adverse events (AEs) clustering around the system organ 
classes of gastrointestinal disorders, investigations, and infections and infestations has been 
characterized. Mild to moderate transient, asymptomatic elevations in serum uric acid and mild to 
moderate diarrhea are the two most common AEs known to occur with favipiravir. In double blind 
studies, the adverse event profile of favipiravir and placebo were similar with the exception of 
elevations of uric acid. Details can be found in the Investigator’s Brochure. 
Favipiravir has been used in an open label study in patients with Ebola, (2400 mg twice eight hours 
apart, followed by 1200 mg 8 hours later and then 1200 mg BID for the following 9-13 days). 
Although conclusions about efficacy cannot be reached because of the lack of a concurrent control 
group, favipiravir at this regimen appeared to be well tolerated.  A study in Japan in patients with 
Severe Fever with Thrombocytopenia administered 1800 mg BID Day 1 followed by 800 mg BID 
for the next 13 days.  It has also been used under compassionate use in patients with rabies or other 
unusual RNA virus illnesses 
2.4 
In Vitro Therapeutic Levels 
Recent in vitro experiments indicate that therapeutic levels for SARS-CoV-2 should be achievable, 
as illustrated in the following table:  
Virus 
USAMRIID 
Literature 
 
IC50 (µg/ml) 
SARS-CoV-2 
 
9.71 (EC50) 
Influenza 
 
< 42 
SFTS 
 
< 43 
Lassa (Josiah) 
10 
4.644 
Marburg 
9.9 
 
MERS-CoV 
35.2 
 
Ebola 
66 
475 and 10.56 
1. 
Wang, et al, Cell Research 2020 p1-3 


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2. 
Sleeman, et al, Antimicrob Agents Chemo 2010 54 p2517 
3. 
Baba, et al, Antivir Chem Chemother 2017 25 p83 
4. 
Oestereich, et al, J Infect Dis 2016 213 p934 
5. 
Smithers, et al, Antivir Res 2014 104 p153 
6. 
Oestereich, et al, Antivir Res 2014 105 p17 
Unpublished data from different labs report EC50s of 32 and >15.7 ug/mL for SARS-CoV-
2.  Several other labs have reported that the same cell lines and viral strains of influenza 
can result in up to four-fold differences in susceptibility on different days (data on file).  
The optimal cell lines for studying SARS-CoV-2 has not been determined, and no animal 
models have been developed as yet. Additional experiments are being planned. 
2.5 
Phase 1 Study Steady State Exposure 
In a Phase 1 study in Japan, steady state exposures above the influenza target were achieved, which 
should cover the necessary exposure for SARS-CoV-2.  
 
Similar to the PK profile above, the studies in the global influenza program using 5-days of 
treatment, demonstrated a similar PK profile, albeit with lower exposures. Below is the graph from 
US316, one of the US pivotal trials, a five-day study of 1800 mg BID Day 1 followed by 800 mg 
BID Days 5.  As can be seen, the mean daily trough levels were above the target level of 20 ug/ml. 


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Below is the same graph for US317, the second pivotal trial in the program. 
 
2.6 
Rationale for 10-day Dosing Regimen 
A Chinese study reported that patients in the control group (Ketruda plus aerosolized interferon) 
shed virus for a mean of 11 days, and the mean time to clearance in the group on favipiravir plus 
interferon was four days.  Therefore, a mean time treatment duration of 14 days was chosen in case 
interferon plus favipiravir was more effective than favipiravir alone, given the safety data 
supporting treatment of 10 days and beyond.   


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• (https://www.sciencedirect.com/science/article/pii/S2095809920300631) 
2.7 
Rationale for the Current Study 
There is a global pandemic caused by the SARS-CoV-2 virus, which threatens the lives of many 
and the economic stability of the world.  Therapeutic approaches are badly needed, and an orally 
available, well tolerated small molecule agent could play a critical part in preventing and 
ameliorating COVID-19. 
Evidence from non-clinical (cell culture) experiments and recently reported clinical experience in 
China, indicates that favipiravir may have clinical benefit in patients infected with SARS-CoV-2. 
Favipiravir has been shown to be active against all families of RNA viruses in which it has been 
tested.  Clear antiviral activity (faster cessation of viral shedding) has been demonstrated in 
influenza studies.  Patients with influenza treated with favipiravir have recovered more quickly than 
placebo controls.   
People with COVID-19 who are asymptomatic or experiencing mild to moderate symptoms that do 
not require hospitalization have no proven option other than supportive care. The safety profile of 
favipiravir is well-established.  It is generally safe and well-tolerated with the exception of transient 
elevations of uric acid that resolve with cessation of dosing. Furthermore, reducing viral shedding 
may decrease household and community transmission of SARS-CoV2. Thus, the risk to benefit 
assessment of treatment with favipiravir in the face of COVID-19 is clearly in favor of potential 
study subjects. 
This study will assess the time course of cessation of viral shedding, and gather clinical benefit 
information, in patients with COVID-19 treated with favipiravir as compared to control.  Data from 
this trial is expected to support a larger study which will demonstrate clinical benefit and serve as 
a pivotal trial for approval.  The information gathered from this study will also help define the 
safety profile in this setting and enable expansion into other patient populations such as those who 
have been exposed but who are not yet ill.  This could have a significant impact on public health. 
3 DESIGN 
3.1 
Study Design 
This is a Phase 2 Double Blinded and Placebo Controlled Study evaluating the safety, 
pharmacokinetics, and efficacy of favipiravir in adult subjects with PCR-positive, asymptomatic, 
or mild COVID-19 infections. 
Subjects will be randomized to receive either favipiravir + current local Standard of Care (SOC) or 
placebo + SOC. SOC at Stanford is defined as methods Stanford University Healthcare is using for 
COVID-19 patients at the time of study initiation. Each site’s local SOC to be defined and shared 
with Sponsor prior to study initiation.   
For those subjects in the favipiravir + SOC arm, the dose regimen will be 1800 mg BID favipiravir 
on the first dose (day 1) followed by 800 mg BID for the next 9 days (days 2-10).   NOTE: 600 mg 
BID for subjects with Child-Pugh A liver impairment on days 2-10. 
Subjects in the SOC arm will receive placebo. The total anticipated duration of the study for each 
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3.2 
Study Sites 
This study is being supported by the Stanford Innovative Medicines Accelerator (IMA), Clinical 
Trials Research Unit (CTRU), and the Stanford Center for Clinical Research. This study may be 
performed at up to 5 sites nationally.  
Each investigator or group of investigators at a clinical site must obtain Institutional Review Board 
(IRB) approval for this protocol and submit all required regulatory documents (including any 
protocol specific documents) to their respective IRB as required per institution. Sites can submit 
through a Stanford-designated central IRB for this trial. All subsequent mentions of IRB related 
activity in this document will reflect whichever choice they decide, be it local or central IRB. 
Requirements for site selection and site registration: Sites will be evaluated by Stanford team 
and the main PI prior to selection or activation. 
Stanford requires documentation that verifies IRB-approval for this protocol, informed 
consent documents, and associated documents prior to recruitment, screening, and enrollment 
of subjects, and any IRB-approvals for continuing review or amendments. 
 
Please refer to the MOP for information on:  
• Requesting and submitting regulatory documents 
• Patient enrollment & randomization 
• Randomization notification 
• Requesting study drug 
• Withdrawals 
• Lost to follow-up 
• Protocol deviations 
• Data submissions 
 
4 OBJECTIVES 
4.1 
Primary Objective 
To evaluate the efficacy of oral favipiravir plus SOC compared with placebo plus SOC in reducing 
the duration of shedding of SARS-CoV2 virus in patients with mild or asymptomatic COVID-19 
disease. 
4.2 
Secondary Objectives  
1. To evaluate the efficacy of oral favipiravir plus SOC compared with placebo plus SOC in 
reducing the duration of symptoms, hospitalizations, or ED visits in patients with mild or 
asymptomatic COVID-19 disease. 
2. To assess the safety and tolerability of favipiravir in this subject population. 
3. To assess the development of antibodies against SARSCoV-2  
4. To evaluate any changes in the PK profile of favipiravir and its major metabolite M1 in this 
subject population 
5. To determine the viral load and duration of viral shedding in stool as measured by RT-PCR. 


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6. To characterize microbiome signatures of infection by next-generation sequencing.  
5 SUBJECT POPULATION 
5.1 
Inclusion Criteria 
The following criteria must be confirmed as “YES” except optional PK, antibody, and stool sample 
collection: 
1. Adults (18 to 80 years old inclusive) 
2. Diagnosis of COVID-19 disease:  
a. If symptomatic without signs of respiratory distress (as defined by SpO2 >=94% on 
room air, RR <=20, HR <=100), with FDA-cleared molecular diagnostic assay 
positive for SARS-CoV-2 within 72 hours from swab to the time of commencing 
informed consent. Mild disease is defined as having at least 1of the following: 
i.  Fever (>98.7F) 
b. Cough/Shortness of breath/dyspnea 
c. Fatigue 
d. Headache/Body aches  
e. Joint pain 
f. Chest pressure 
g. GI symptoms including nausea, vomiting, and/or diarrhea 
h. Abdominal pain 
i. Sore throat 
j. Nasal congestion 
k. Chills 
l. Runny nose 
m. New loss of taste or smell 
n. Abdominal pain 
o. Rash 
p. If asymptomatic, initial diagnosis obtained no more than 72 hours from initial swab 
to the time of commencing informed consent 
3. Subject or their legal representative understands the requirements of the study and provides 
written informed consent prior to undergoing any treatment-related procedures. 
4. Subject agrees to take daily nasal swabs (anterior nares) for Day 1 to Day 10 and Day 14, 21, 
and 28 using the study provided materials, and mail via FEDEX each sample on the day 
collected.  
5. Subject agrees to record daily symptoms, temperature, oxygen saturation, and pulse using the 
study provided materials.  
6. Subject agrees to obtain stool samples after the Day 1 visit, and 1-3 days before the Day 14 and 
Day 28 timepoints and agrees to bring the sample back in the provided stool collection kit to 
their subsequent appointment and to optionally mail in 4-month sample. Collection of stool is 
optional for sites. 
7. Subject agrees to return to the study site for follow-up visits on Day 5, 10, and 28. The study 
site will be staffed by trained healthcare providers wearing full personal protective equipment 
and study site equipment will be disinfected between patients according to the same protocols 


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as a clinical setting. Subjects will be wearing masks, will be appropriately spaced, and the 
number of subjects assessed at each time will be limited. 
8. Subject agrees to maintain home or other quarantine as recommended by the study physician, 
except to visit the study site as required by the protocol.  
9. Members of the same household may participate in the study as long as the inclusion and 
exclusion criteria are met.  
10. If male, subject must: 
a. Be sterile (e.g., have had a vasectomy at least 6 months prior to Day 1 dosing), OR, 
b. Agree not to donate sperm during the study and for seven days following the last dose of 
study medication, AND, 
c. Agree to strictly adhere to the following contraceptive measures during the study and for 
seven days following the last dose of study medication: 
i. Abstain from sexual intercourse. 
ii. Use a condom during sexual intercourse with a female of child-bearing potential. In 
addition, the female partner must use another form of contraception (e.g. intrauterine 
device [IUD], diaphragm with spermicide, oral contraceptives, injectable progesterone, 
or subdermal implants).  
11. If female, subject must: 
a. Be unable to bear children (have not had a period for ≥ 12 consecutive months, have had 
her uterus or ovaries removed, or have had a tubal ligation), OR, 
b. Must ensure that their male partner is incapable of fathering a child (e.g., has had a 
vasectomy at least 6 months prior to study entry), OR,  
c. If she is of childbearing potential will strictly adhere to the following contraceptive 
measures during the study and for seven days following the last dose of study medication: 
i. Abstain from sexual intercourse, OR, 
ii. Must ensure that her male partner agrees to use a condom during sexual intercourse and 
agree to use an approved method of contraception (e.g., IUD, diaphragm with 
spermicide, oral contraceptives, injectable progesterone, or subdermal implants).  
d. Agrees to stop breast-feeding prior to first dose of study drug and through seven days after 
completing therapy. 
e. Has a negative urine pregnancy test at screening. 
f. Has not had unprotected sexual intercourse within the past month. 
5.2 
Exclusion Criteria 
All criteria must be confirmed as “NO”: 
1. Subject has a concomitant bacterial respiratory infection, as defined by positive respiratory 
culture 
2. Subject has a history of abnormalities of uric acid metabolism unless cleared  
3. Subject has a history of hypersensitivity to an anti-viral nucleoside-analog drug targeting a viral 
RNA polymerase 
4. Subject has any of the following abnormal laboratory test results at screening: 
a. Platelet count <100,000 cells/mm3 
b. Absolute lymphocyte count <500 cells/mm3 


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c. Hemoglobin <11 g/dL for women and <12 g/dL for men 
d. Serum creatinine concentration ≥1.5× ULN 
e. Confirmed creatinine clearance (CrCl) < 50 mL/min by Cockcroft-Gault  
f. Serum uric acid >20mg/dL 
5. Subject is using adrenocorticosteroids (except topical or inhaled preparations or oral 
preparations equivalent to or less than 10 mg of oral prednisone) or immunosuppressive or 
immunomodulatory drugs (e.g., immunosuppressants, anticancer drugs, interleukins, 
interleukin antagonists or interleukin receptor blockers). 
NOTE: Treatment of study participants following institutional COVID-19 treatment 
policies or guidelines, including the use of immunomodulatory medications, is 
permitted. This excludes treatment with agents that have the potential for direct 
antiviral activity, including convalescent plasma and NO, and co-enrolment into 
other clinical studies that evaluate investigational agents for COVID-19. 
6. Subject has a serious chronic disease (e.g., human immunodeficiency virus [HIV], cancer 
requiring chemotherapy within the preceding 6 months, moderate or severe hepatic 
insufficiency and/or unstable renal, cardiac, pulmonary, neurologic, vascular, or endocrinologic 
disease states per investigator judgement). 
7. Has previously received favipiravir within the past 30 days. 
8. Has renal insufficiency requiring hemodialysis or continuous ambulatory peritoneal dialysis 
(CAPD). 
9. Has liver impairment greater than Child-Pugh A.  (NOTE: Child-Pugh A subjects will have the 
maintenance dose decreased to 800 mg BIID). 
10. Has a history of alcohol or drug abuse in the previous 6 months. 
11. Has a psychiatric disease that is not well controlled where controlled is defined as: stable on a 
regimen for more than one year. 
12. Has taken another investigational drug within the past 30 days. 
13. Is deemed by the Investigator to be ineligible for any reason. 
5.3 
Removal of Subjects from Treatment 
The participation of a subject in the study or the administration of treatment may be terminated at 
any time for one of the following reasons: 
• The subject desires to discontinue study treatment. 
• The subject withdraws consent to participate in the study. 
• The subject is unwilling or unable to comply with the safety procedures. 
• The subject is discovered to be pregnant.  
• The subject experiences a medical emergency that necessitates withdrawal. 
• The subject is withdrawn at the discretion of the Investigator for medical reasons or non- 
compliance. 
• AST or ALT > 8 x ULN 
• ALT or AST > 3 x ULN AND total bilirubin > 2X ULN 
• AST or ALT > 3 x ULN AND patient has right upper quadrant pain or eosinophilia 


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• Uric acid >20mg/dL CrCl < 30  
A subject whose treatment is terminated should remain in the study for appropriate follow up 
assessments whenever possible. 
5.4 
Compensation  
Compensation, if any, may be determined locally and in accordance with local IRB requirements 
and approval.  
 
6 STUDY TREATMENT - FAVIPIRAVIR 
6.1 
Study Drug 
Favipiravir will be provided in 200 mg tablet form to be stored at controlled room temperature 
(15°C to 30°C [59°F to 86°F]) and shielded from light. Matching placebo will be provided in tablet 
form to be stored at controlled room temperature (15°C to 30°C [59°F to 86°F]) and shielded from 
light.  
Standard Dose 
Subjects randomized to the favipiravir + SOC arm will be administered loading doses of 1800 mg 
BID (ideally 12 hours apart but 10-16 hours is allowed) on Day 1, and then maintenance dosing of 
800 mg twice daily BID (Ideally 12 hours apart but 10- 16 hours is allowed) on Days 2-10 beginning 
24 hours after the first dose. Day 1 is deemed to be the first 24 hours after enrollment into the study, 
with time 0 (time of first dose) occurring as soon as possible after the subject’s eligibility has been 
confirmed.   
An exception to the above maintenance dose will be made for those subjects entering the study with 
a Child-Pugh liver impairment of grade A who will receive favipiravir 600 mg BID on Days 2 
through 10.  
Subjects randomized to the placebo + SOC arm will be administered placebo BID (ideally 12 hours 
apart but 10-16 hours is allowed) on Day 1, and then maintenance dosing twice daily BID (Ideally 
12 hours apart but 10- 16 hours is allowed) on Days 2-10 beginning 24 hours after the first dose. 
Day 1 is deemed to be the first 24 hours after enrollment into the study, with time 0 (time of first 
dose) occurring as soon as possible after the subject’s eligibility has been confirmed.   
6.2 
Administration of Favipiravir or placebo 
 
Favipiravir is provided as 200 mg tablets and dosed orally. Favipiravir is rapidly and completely 
absorbed after oral administration of the 200 mg immediate release tablets. 
Subjects who vomit during or immediately after dosing, should not be re-dosed. 
6.3 
Outpatient Favipiravir Dosing 
Subjects in the favipiravir + SOC arm, will be dispensed sufficient favipiravir to ensure continued 
dosing until their next study visit.  Subjects in the placebo+ SOC arm, will be dispensed sufficient 
placebo to ensure continued dosing until their next study visit.  Subjects in both arms will also be 
given a Diary Card to record the date and time they take their dose. 


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Subjects will also be instructed that if they miss a dose, they should follow the guidelines: 
1) If more than 1/2 the time until their next dose has elapsed, they SHOULD NOT take the 
dose. They should just take the next dose at the normal scheduled time. 
2) If less than 1/2 the time until their next dose has elapsed, they should take the missed dose 
immediately.  
3) In both cases, they should then return to their regular dosing schedule. 
4) The intention is to complete a 10-day course of medication.   If, because of missed doses, 
there are leftover doses after completing their PM dose on Day 10, bring all additional doses 
to their next study visit.     
6.4 
Drug Accountability 
The Investigator must maintain adequate records showing the receipt, dispensation, or other 
disposition of favipiravir including the date, quantity and identification of subjects (study ID) who 
received favipiravir. Drug supplies will be inventoried and accounted. Unused supplies of all 
favipiravir will be returned to the Sponsor (or designee) or destroyed on site in accordance with 
local procedures upon approval of the Sponsor. 
6.5 
Treatment Compliance 
All doses of study drug will be administered by site staff while in the hospital. If the patient is 
discharged while still on drug, the pharmacy will provide bottles of favipiravir for outpatient use 
(Exact dispensing instructions for outpatients will be described in the pharmacy instructions). 
Assessment for compliance with each dose will be monitored and recorded in accordance with site 
standard operating procedures. 
6.6 
Treatment Precautions 
An overdose is defined as any dose of study drug given to a subject or taken by a subject that 
exceeds the dose described in this document. In the event of an overdose, the subject should be 
treated symptomatically, and the Sponsor informed. 
6.7 
Prohibited Concomitant Therapy 
The following may interact with favipiravir and risks and benefits should be carefully considered 
prior to treatment with the following: 
• Any other anti-viral medication whether investigational or approved. 
• Any drugs known to significantly inhibit AO activity (e.g., pyrazinamide, amitriptyline, 
chlorpromazine, clomipramine, clozapine, erythromycin, ketoconazole, nortriptyline, 
quetiapine, raloxifene, perphenazine, promethazine, propafenone, tamoxifen, thioridazine). 
• Any drugs metabolized by the AO pathway (e.g., famciclovir, hydralazine, lamivudine, 
sulindac, zaleplon, ziprasidone).  
• Drugs with possible drug-drug interactions (concomitant medications requiring particular 
attention – see the Investigator Brochure). 
The following message appears on the daily questionnaire given to subjects with favipiravir to take 
at home: 


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Favipiravir can slightly increase the concentration of acetaminophen (Tylenol) in the 
blood.  Do not take more than 3000 mg (do not forget to include any acetaminophen that 
could be in over-the-counter preparations) in a 24-hour period as long as you are taking 
favipiravir. 
There are possible interactions of favipiravir with other drugs.  During the time that you 
remain on favipiravir, do not take any medications or supplements that you were not taking 
before you started the trial, without getting approval first from the study doctor.    
Favipiravir can cause you to be mildly sensitive to sunlight.  Please avoid excessive 
exposure to sunlight or artificial ultraviolet light (tanning machines) while you are on 
favipiravir. 
7 STUDY PROCEDURES 
Refer also to Section 14: Schedule of Assessments 
7.1 
Day 1 (PRE-DOSE)  
• Obtain informed consent. 
• Verify eligibility per the inclusion and exclusion criteria. (See Sections 5.1 and 5.2) 
o Review and record medical history, including tobacco use, to ensure there are no 
exclusionary illnesses. 
o Review and record concomitant medications for possible prohibited medications.  (See 
Section 6.7) 
• If subject is female of child-bearing potential and meets inclusion criteria 11.c, obtain urine 
pregnancy test and proceed it result is negative. 
• Measure and record vital signs (BP, HR, Temp, Resp).  
• Collect and record SPO2 by Finger Sensor 
• Perform Physical exam (may be done by the Principal Investigator or their designee)  
• Complete baseline symptom survey to establish severity of symptoms (if present)  
• Collect oropharyngeal swab for virologic testing (RT-PCR) and resistance analysis.  
• Collect two nasal swabs for antigen testing and molecular viability testing. 
• Collect blood samples for 
o Uric acid 
o CRP 
o Hematology and clinical chemistry laboratory analyses (samples collected within 48 hours 
of enrollment are acceptable): 
o Resistance analysis 
o Optional: Antibodies to SARS-CoV-2. 
o Optional: Biobanking 
o Optional: Pre-dose PK 


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• Perform subject randomization (via EDC) to establish treatment arm (favipiravir + SOC or 
placebo + SOC). 
• Explain in home procedures for the study (self-sampling of nasal swabs, temperature, SPO2, 
completing the daily questionnaire and the optional collection of stool sample).  
• Provide supplies to research subject and review the calendar of return visits. 
• Optional: Explain that stool sample from first bowel movement after enrollment should be 
collected in Zymo fecal tube and brought back to Day 5 follow-up visit. If the first bowel 
movement sample cannot be collected, it is permitted to collect a subsequent bowel movement 
sample.  
7.2 
Day 1 (FIRST DOSE AND POST-DOSE) 
NOTE: Day 1 is deemed to be the first 24 hours after enrollment into the study, with time 0 (time 
of first dose) occurring as quickly as possible after the subject’s eligibility has been confirmed.  
• Administer first dose (1800 mg favipiravir or placebo) at time 0. 
Following First Dose: 
• Monitor patient for 30 minutes after their first dose. 
• Optional: Take a blood sample 45 to 75 minutes following the first dose for post-dose PK 
analysis 
7.3 
Days 5, 10, 28 (Follow-up) or Early Termination (Window of +1 or -1 day allowed on 
Days 5 and 28. Window of -1 allowed for Day 10.) 
• Conduct and record the results of a Physical Exam (Day 5, 10, 28). 
• Review and record concomitant medications (Note: if there have been changes in concomitant 
medications during the study, determine whether the change is due to an AE). 
• Measure and record vital signs (BP, HR, Temp, Resp). 
• Collect and record SPO2 by Finger Sensor 
• Collect oropharyngeal swab for virologic testing (RT-PCR) and resistance analysis.  
• Collect and record adverse events (see Section 8.4 for detailed instructions).  
• Collect nasal swab for antigen testing and molecular viability testing (day 1, 5, 10) 
• Collect blood samples for: 
o Hematology and clinical chemistry laboratory analyses (Day 5, 10, 28) 
o Urine for repeat pregnancy test (Day 5)  
o Optional: Antibodies to SARS-CoV-2. (28) 
o Optional: Biobanking (28) 
o Optional: Blood for PK and resistance analysis obtained pre-dose (within 30 minutes prior 
to dosing) and post-dose (45 to 75 minutes following dosing) (Days 5 and 10).  
• Optional: Provide Zymo fecal stool collection kit: one on Day 1, two on Day 10, and 28. 


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• Optional: Collect stool samples on Day 5, 14, 28, and patient sends in sample at 4 months post 
enrollment date.   
8 EFFICACY, PHARMACOKINETICS AND SAFETY ASSESSMENTS 
8.1 
Efficacy Assessments 
Primary Measurement (Efficacy): 
1. Nasal swab for PCR taken daily from Day 1 to Day 10, and Days 14, 21, and 28.  
Secondary Measurements (Efficacy): 
1. Nucleic acid (RT-PCR) from oropharyngeal swabs collected on Days 1, 5, 10, and 28. 
2. Symptom improvement or worsening: Subjects will fill in a diary daily, recording the 
following symptoms:  
a. Cough/Shortness of breath/dyspnea 
b. Fatigue 
c. Headache/Body aches  
d. Joint pain 
e. Chest pressure 
f. GI symptoms including nausea, vomiting, and/or diarrhea 
g. Abdominal pain 
h. Sore throat 
i. Nasal congestion 
j. Chills 
k. Runny nose 
l. Oral temperature taken after 4 pm and at least four hours after ingesting the most 
recent antipyretic (acetaminophen or NSAID) 
m.  
n. New loss of taste or smell 
o. Abdominal pain 
p. Rash 
3. Blood for determination of antibodies to SARS-CoV-2 will be obtained on Days 1, 14, and 
28. 
4. Number of subject hospitalizations, emergency department visits, incidence of respiratory 
failure, deaths, and proportions of subjects alive, not hospitalized, and free of respiratory 
failure on day 28 
8.2 
Required Resistance Testing 
Resistance testing, as required in clinical trials of anti-viral drugs will be performed at each time 
point that oropharyngeal swabs are taken. 
8.3 
Pharmacokinetics/Pharmacodynamics Assessments 
6.0mL of blood may be collected for PK obtained pre-dose (within 30 minutes prior to dosing) and 
post-dose (45 to 75 minutes following dosing) on Days 1, 5 and 10. These collections are optional. 
 


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Kits for each PK draw and instructions for handling and shipping are provided by the PK analysis 
laboratory. 
8.4 
Safety Assessments 
Abnormal clinical laboratory values that are clinically significant and all reported adverse events 
will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0.  
Safety will be assessed by the collection of observed and reported adverse events, physical exams, 
vital signs and the following clinical laboratory tests: 
• Hematology 
Hemoglobin (Hgb)  
Hematocrit (Hct) 
Platelet count 
Red blood cell count 
White blood cell count with differential 
• Chemistry 
Blood Urea Nitrogen (BUN) 
Creatinine 
Total bilirubin 
Alkaline Phosphatase 
Aspartate transaminase (AST) 
Alanine transaminase (ALT) 
Gamma-glutamyl transferase (GGT) 
Albumin 
Glucose 
Bicarbonate 
Total protein 
Sodium 
Phosphate 
Chloride 
Potassium 
 
Calcium 
C-reactive protein 
Urate 
 
 
NOTES:  
• All clinical laboratory assessments listed above (hematology and chemistry) will be 
conducted at the Stanford University Medical Center clinical laboratory. 
• If coagulation assays are ordered as part of the SOC, the results should be added to the EDC. 
Including PK and Clinical Laboratory Testing, subjects will undergo up to 7 planned venipunctures 
during this study. 
8.4.1 Adverse Events 
Treatment-emergent AEs will be defined as those occurring coincident with start of treatment 
through 28 days post-treatment. 
Subjects will be instructed to report AEs during the study and staff will query subjects regarding 
AEs throughout the study. The Site Investigator (and/or designee) must document all AEs reported 
through completion of the Day 28 visit. Any subject who is withdrawn from the study due to an AE 
shall be followed until the event has resolved or stabilized or 14 days after last dose, if in the 


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favipiravir arm. The Site Investigator will document available follow-up information on the 
subject’s source documentation and CRF 
8.4.2 Definition of an Adverse Event 
The FDA Safety Guidance, referencing 21CFR312.32(a), defines an Adverse Event as follows: 
Adverse event means any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related.    
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug and does not imply any judgment about causality.  An 
adverse event can arise with any use of the drug (e.g., off-label use, use in combination with 
another drug) and with any route of administration, formulation, or dose, including an 
overdose.   
Adverse Events are NOT: 
• Clinical events related to the progression of COVID-19. 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion).  
The condition that leads to the procedure is the AE. 
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions). 
8.4.3 Evaluating and Reporting of Adverse Events 
All AEs (i.e. a new event or an exacerbation of a pre-existing condition) that occur after dosing 
with favipiravir and after completion of baseline assessments in the Placebo + SOC arm, must be 
recorded as an AE or SAE (if applicable), on the Adverse Event eCRF and SAE form, as applicable.  
The Site Investigator must follow all AEs until the AE resolves, or until the Site Investigator and/or 
the Medical Monitor determine the event is chronic or clinically stable.  If an AE remains 
unresolved at the conclusion of the study, the Site Investigator and Medical Monitor will make a 
clinical assessment to determine whether continued follow-up of the AE is warranted.  All subjects 
who have received at least one exposure to study therapy will be evaluated for safety of study 
treatment. 
The Site Investigator should attempt to establish a diagnosis of the event based on signs, symptoms 
and/or other clinical information.  In such cases, the diagnosis should be documented as the AE and 
not the individual signs/symptoms. 
All AEs must be promptly documented on the Adverse Event eCRF and assessed by the Site 
Investigator.  Details of the event must include the dates of onset and resolution, severity, 
relationship to study drug, seriousness, and whether the event caused the subject to withdraw from 
the study, outcome and timing with regard to administration of the study drug.  
Severity: Severity should be graded and recorded as follows: 
• Mild: Awareness of event but easily tolerated 
• Moderate: Discomfort enough to cause interference with usual activity 


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• Severe: Inability to carry out usual activity, incapacitating, requires medical intervention 
Relationship: The relationship of the Adverse Event to the study drug will be determined initially 
by the Site Investigator, and assessed using the following definitions: 
• Related: There is a distinct temporal relationship between the event onset and administration 
of the study drug.  There is a known reaction to agent or chemical group or predicted by known 
pharmacology.  The event cannot be explained by subject’s clinical state or other factors. 
• Unrelated:  Evidence exists that the AE has an etiology other than the study drug (e.g., pre-
existing condition, underlying disease, intercurrent illness, or concomitant medication). 
Final determination of relatedness will be made by the Sponsor. 
Expectedness: Whether or not the event was excepted or unexpected. Further details on this can 
be found in section 8.5. 
These criteria, in addition to good clinical judgment, should be used as a guide for determining the 
causal assessment.  If it is felt that the event is not related to study drug therapy, then an alternative 
explanation should be provided. 
8.4.4 Serious Adverse Events (SAEs) 
All SAEs as defined below and that occur after the first dose of favipiravir and up to 46 days post-
dose must be reported to the Sponsor as soon as the site becomes aware of them.  Any SAEs 
occurring more than 46 days after last study drug administration and considered at least possibly 
drug-related must also be reported. 
8.4.5 Definition of Serious Adverse Events  
An SAE is an AE from this study that results in any of the following outcomes:  
• Death (even if caused by COVID-19 all deaths are recorded as SAEs) 
• Life-threatening situation (subject is at immediate risk of death) 
• Inpatient hospitalization or prolongation of existing hospitalization  
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a subject who received study drug 
NOTE: Important medical events that may not result in death, be immediately life-threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
A life-threatening AE is defined as any adverse experience that places the subject in the view of the 
Site Investigator, at immediate risk of death from the event as it occurred.  This does not include 
an event that might have led to death, if it had occurred with greater severity. 
 “Inpatient hospitalization” means the subject has been formally admitted to a hospital for medical 
reasons, for any length of time with a minimum one overnight stay.  Presentation and care within 
an emergency department does not necessarily constitute an SAE.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization, it is an SAE. 


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8.4.6 SAE Reporting Requirements to the Sponsor 
The procedure for reporting SAEs, regardless of causal relationship, is as follows: 
• Within 24 hours of the Site Investigator’s knowledge of an SAE, the site must notify the 
Sponsor by phone call to their site monitor, medical monitor or other Sponsor representative. 
They should also immediately complete the AE eCRF and select “Serious”. 
• This initial reporting of an SAE should contain as much information as is available to the 
Investigator.  Submission of the SAE via the EDC should not be delayed in order to collect 
additional information to complete the form.  
• Follow-up SAE reports may be generated in cases in which additional information becomes 
available.  Hospital records, autopsy reports, and other documents may become available and 
scanned copies can be provided to the Sponsor when applicable.  The follow-up SAE report 
should describe whether the event has resolved or continues, if and how it was treated, whether 
the blind was broken or not, and whether the subject continued or withdrew from study 
participation. 
• The Sponsor (or designee) will distribute completed SAE forms, which may be used to notify 
the IRB when applicable, via a secure internet-based document depository. 
• The Site Investigator should notify the IRB of Serious Adverse Events occurring at the site and 
other adverse reports received from the Sponsor in accordance with reporting requirements of 
the governing IRB.  
The Site Investigator must take all therapeutic measures necessary for resolution of the SAE.  Any 
medications necessary for treatment of the SAE must be recorded onto the concomitant medication 
section of the subject’s eCRF.  However, treatment medication should only be recorded in the 
narrative description section of the SAE form. 
8.5 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
A SUSAR carries specific and time-based reporting requirements for the Sponsor of a clinical trial. 
Thus, after a Site Investigator reports an SAE, the FDA expects the Sponsor will determine whether 
it meets the definition of a SUSAR. 
A SUSAR is defined according to 3 criteria:  
1. The AE is deemed a “suspected adverse reaction” if there is a reasonable possibility that the 
study drug caused the AE.  A “reasonable possibility” means there is evidence to suggest a 
causal relationship between the drug and adverse event. 
2. The AE is “Serious” if it meets the definition of an SAE provided in section 8.4.5 
3. The AE is deemed “unexpected” if it is not listed in the Investigator’s Brochure (IB) or if in the 
IB, has not been reported at the severity observed. 
In cases where the Sponsor deems a SUSAR has occurred, it must file an IND Safety Report with 
the FDA.  FPHU will require the assistance and cooperation of the Site Investigator and staff to 
provide accurate and complete information on the subject and observed SAE so that reporting 
requirements to the FDA can be met. 


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8.5.1 Reporting SUSARs to the FDA: IND Safety Reports 
IND safety reports are used to submit reports of SUSARs to the FDA.  There are 2 types of reports:  
• A “15-day report” is used when the reported SAE is a SUSAR and requires that as much 
information as is available to the investigator and the sponsor, be submitted to the FDA in on 
the appropriate form. For US trials, the appropriate form is the FDA Form 3500A also 
commonly known as a “MedWatch” form. 
• A “7-day report” is used when the SUSAR is considered to be fatal or life-threatening. 
The 7-day and 15-day timelines begin the day that the Sponsor determines the information qualifies 
for reporting and are counted in calendar days – not business days.  Therefore, it is important that 
the Site investigator carefully follow the reporting requirements described in section 8.4.6. 
8.6 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Laboratory abnormalities are usually not recorded as AEs unless considered to be clinically 
significant by the site clinician.  An abnormal laboratory result will be considered an AE if it 
induces clinical signs or symptoms, if the abnormality is of a degree that requires active 
management (e.g. discontinuation of the study drug, dose modification) or when the event is 
requiring treatment or other therapeutic intervention (e.g. iron supplements, blood transfusion, etc.). 
The Investigator will evaluate the relationship of any significantly abnormal result to protocol 
treatment and clinical condition, if possible.  All clinically significant abnormal laboratory results 
will be followed until they return to normal or become stabilized.  
8.7 
Handling of Overdose 
An overdose is defined as any dose greater than the highest daily dose included in this document. 
Any overdose must be recorded. If the overdose is associated with an AE, that AE must be recorded, 
assessed for seriousness, and reported as an SAE. 
9 STATISTICAL METHODS 
Complete details of all statistical analyses, including methods for handling missing data, will be 
included in a formal statistical analysis plan (SAP), to be completed as soon as possible after study 
initiation. 
9.1 
General Considerations  
For the primary comparison, the following will be tested: 
• Null hypothesis: time to cessation of oral shedding is equal in control and treatment; 
• Alternative hypothesis: time to cessation of oral shedding differs between control and 
treatment. 
Hypothesis tests will be two sided and conducted at an overall alpha = 0.05 level of significance. 
 
The number of hospitalizations and emergency department visits will be estimated for each arm, 
with 95% confidence intervals. The frequency of adverse events and serious adverse events will be 


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tabulated by type and by treatment arm. AEs will be compared by arm using the Chi-squared test 
or Fisher’s exact test, as appropriate, in the safety analysis set. 
 
9.2 
Sample size justification 
Approximately 180 patients will be enrolled. 
Assuming 1:1 randomization and the use of a two-sided log rank test at the alpha=0.04999 level 
of significance for the final analysis, 79 events will provide 80% power to detect a hazard ratio 
of 2.03. This leaves alpha=0.00001 to check for overwhelming efficacy after 60 participants have 
completed 24 hours of follow-up. Assuming the control and treatment arm median cessation of 
shedding is 14 and 7 days, respectively, a two-month accrual period, a two-week follow-up 
period after randomization of the last patient, and a drop out of 10% in the control arm, it is 
estimated that the total sample size required to achieve 79 events is 120 (60 patients in each 
arm). We assume 33% of patients will test negative for SARS-CoV-2 virus by RT-PCR on Day 
1, thus the total sample size required to be randomized is 180 (120/0.67). The assumption of 33% 
is based on calculations performed after the DSMB recommended a sample size re-estimation to 
account for the patients who test negative at baseline and do not contribute meaningfully to the 
primary analysis. 
 
9.3 
Demographic and Baseline Characteristics 
Summary statistics will be provided per treatment group for demographic (e.g., age, height, weight, 
body mass index [BMI], race, gender) and other initial subject characteristics (e.g., medical history, 
concomitant diseases) will be provided per treatment group and for the total group. The ITT 
population will be used for the summaries. 
9.4 
Analysis Populations 
The following analysis populations will be defined for the study: 
The intent-to-treat (ITT) population will include all randomized patients. Patients will be analyzed 
according to their assigned treatment arm. All efficacy analyses will be completed in the ITT 
population. 
 
The safety population will include all patients who receive study treatment. Patients will be 
analyzed according to actual treatment received. All safety analyses will be completed in the safety 
population. 
 
9.5 
Stratification, Subgroup Analysis and Pooled Analysis 
Following consent, those subjects meeting all entry criteria will be randomized in a 1:1 ratio  
Treatment Arm: favipiravir + SOC 
Control Arm: placebo + SOC 
Randomization will be stratified by age (>=50 and <50 years old) and sex.  


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Members of the same household may participate in the study as long as the inclusion and exclusion 
criteria are met. Because this is a double-blind, placebo-controlled trial, subjects from the same 
household will be randomized just as any other subject. 
9.6 
Efficacy Endpoint Analysis 
Descriptive analyses 
Descriptive statistics (proportions for categorical variables, means, medians, standard deviations, 
and interquartile ranges for continuous variables) will be reported for all key patient variables, 
including baseline and demographic characteristics, use of medications, compliance, and study 
completion status.  Data that are missing on key patient characteristics and the outcome will be 
fully described, including any patterns of missingness (i.e., any relationships between missingness 
of a variable and patient characteristics). 
 
A CONSORT diagram displaying the number of patients screened, eligible, and consented along 
with reasons for ineligibility will be provided. Graphical tools such as histograms, boxplots, and 
scatterplots will be created to assess quality of data and to display patterns over time. 
Primary efficacy analysis 
Time until shedding cessation will be compared between the two treatment arms using a Cox 
proportional hazards model adjusted for age and sex and stratified by site. The test will be 
performed at the alpha = 0.05 level of significance. The hazard ratio for shedding cessation will be 
estimated, along with its 95% confidence interval, from a Cox proportional hazards model. If the 
proportional hazards assumption is not met, we will consider an extended Cox model that relaxes 
the proportional hazards assumption. 
 
The distribution of shedding cessation will be estimated using the Kaplan-Meier method, and 
Kaplan-Meier curves will be presented for each treatment arm. Time to shedding cessation at the 
end of the study period along with 95% confidence intervals will be presented for each treatment 
arm.  
Secondary efficacy analyses 
The distribution of cessation of symptoms will be estimated using the Kaplan-Meier method, and 
Kaplan-Meier curves will be presented for each treatment arm. Time to cessation of symptoms at 
the end of the study period along with 95% confidence intervals will be presented for each treatment 
arm. The hazard ratio for cessation of symptoms will be estimated, along with its 95% confidence 
intervals, from a Cox proportional hazards model. Time to cessation of symptoms will be 
determined by analysis of daily questionnaires. Resolution of symptoms requires that symptoms 
are mild or absent for at least 24 hours.  
 
The number of hospitalizations, emergency department visits, incidence of respiratory failure, 
deaths, and proportions of subjects alive, not hospitalized, and free of respiratory failure will be 
estimated for each arm, with 95% confidence intervals. Respiratory failure is defined as the need 
for mechanical ventilation, ECMO, non- invasive ventilation, or high-flow oxygen 
 


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Our analyses will use multiple imputation methods that assume data are missing at random by 
including all baseline characteristics, treatment assignment, and reasons for missingness in the 
imputation model. This approach will be applied to any analysis involving endpoints or key 
variables where any missing data occurs in order to adhere to the ITT principle. Assumptions 
regarding missingness will be addressed in sensitivity analyses.  
9.7 
Safety Analysis 
 
The frequency of adverse events and serious adverse events will be tabulated by type and by 
treatment arm. AEs will be compared by arm using the Chi-squared test or Fisher’s exact test, as 
appropriate, in the safety analysis set. 
 
The original exact terms in the electronic data capture (EDC) system used by Investigators to 
identify AEs other than symptoms of COVID-19 will be fully described and coded according to the 
Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs will be defined 
as those occurring coincident with start of treatment and through 28 days post-treatment. TEAEs 
will be summarized overall and by treatment group and by MedDRA body organ system and 
preferred term, severity, relatedness, and seriousness. 
An overall summary of TEAEs will be presented by treatment, with subject counts and percentages 
of subjects with the event. This summary will include subjects with any TEAE, any treatment-
related TEAE, any serious TEAE, any treatment-related serious TEAE, TEAEs leading to study 
infusion discontinuation, treatment-related TEAEs leading to study infusion discontinuation, 
TEAEs leading to death, and treatment-related TEAEs leading to death. The difference in 
proportions between treatment groups in each of these categories will be calculated. 
 
Summaries of changes over time in laboratory parameters, as well as counts and percentages of 
laboratory parameters that are Low, Normal, and High compared to the reference ranges will be 
presented by treatment at each visit and time point. Shift tables will be presented for laboratory 
parameters with defined severity grades.  
10 INTERIM ANALYSIS 
An interim analysis for safety and overwhelming efficacy will be performed once 50% of patients 
have 24 hours of follow-up complete. Enrollment will pause once 50% of patients have received 
treatment and will remain paused until the DSMC makes their recommendation after their safety 
review. The DSMC will meet one or two days after enrollment is paused to review the safety data 
collected within the first 24 hours of follow-up on all enrolled patients. We additionally expect 
blood count labs collected at day 5 to be available in approximately 25% of patients at the time of 
the DSMC review.  
 
The DSMC will also review the efficacy data on all randomized participants at this meeting. The 
interim efficacy analysis will use the same methods as are planned for the final analysis using the 
ITT analysis. Based on the results of the interim analysis, the DSMC will either recommend to the 
sponsor to terminate the study for overwhelming efficacy (p<0.00001 at the interim analysis), 


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terminate the study for safety concerns, modify the study, or continue the study as planned. No 
formal stopping rules for futility are planned. 
 
11 RECORDING AND COLLECTION OF DATA 
11.1 Case Report Form 
The Investigator or designee will record all data collected on the electronic Case Report Form 
(eCRF) provided for that purpose. For this study, REDCAP cloud will be the eCRF. The site will 
be suitably trained on the use of the eCRF and appropriate site personnel will be provided electronic 
signatures. 
All site entries will be made in a secured web site and the Principal Investigator will review the 
record for completeness.  Upon completion of the review, the PI will sign electronically in the 
signature page of the eCRF.  
The Investigator or designee will make necessary eCRF corrections.  The investigator must 
authorize the corrections to the entered data on eCRF. 
Specific instructions on use of the EDC system and guidelines for data entry and correction will be 
provided to the sites. 
11.2 Study Files and Subject Source Documents 
Subject confidentiality is strictly held in trust by the participating investigators, research staff, the 
Sponsor and their designees.  This confidentiality is extended to cover testing of biological samples 
in addition to the clinical information relating to subjects.  Authorized representatives of the 
Sponsor 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 subjects in this study.  Any data, specimens, forms, reports, and other records that leave the site 
will be identified only by a subject identification number to maintain confidentiality. 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to 
be fully documented and the study data to be subsequently verified.  These documents include 
Investigators’ Study Files and original subject clinical source documents generated at the study site.  
The term “original” means the first recording of the data. 
The Investigator will ensure the site master files are maintained, including the study protocol and 
its amendments, IRB and regulatory approvals with associated correspondence, informed consents, 
study drug records, staff curriculum vitae, all correspondence, and other appropriate documents. 
Subject clinical source documents may include, but are not limited to, subject hospital/clinic 
records, physicians’ and nurses’ notes, appointment books, laboratory reports, ECGs, radiographs, 
and consultant letters.  The Investigator must assure that all original source documents are available 
to support monitoring activities. 
11.3 Monitoring 
Due to the restrictions imposed on clinical and hospital visits by the COVID-19 pandemic, most 
monitoring activities of this study will be conducted remotely. Monitors will work with the site 


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study staff at each site to determine times for “joint” remote or in-person monitoring – meaning 
that the monitor and the site study staff will review data together. 
Monitoring will be conducted according to the applicable ICH and GCP guidelines to ensure 
protocol adherence, quality of data, drug accountability, compliance with regulatory requirements 
and continued adequacy of the investigational site and its facilities.  The site study staff will 
cooperate in the monitoring process by ensuring the availability of the eCRFs, source documents 
and other necessary documents at the time of monitoring and by prompt attention to any matters 
brought to their attention by the monitor. 
11.4 Audit 
ICH guidelines for GCP require independent inspection of clinical program activities.  Such 
inspections may be performed at any time - before, during and/or after the study.  The site 
Investigator and site study staff are responsible for maintaining the site master file containing all 
study-related regulatory documentation as outlined by the Sponsor that will be suitable for 
inspection at any time by the Sponsor, its designees, and/or regulatory agencies.  The Investigator 
understands and agrees to give access to the necessary documentation and files. 
11.5 Retention of Data 
All records connected with this clinical study will be retained for at least two years following the 
date of an approved marketing application [21 CFR 312.62(c)]; or at least three years from the 
formal discontinuation of favipiravir development; or seven years from the end of the study, 
whichever is longer.  All local laws regarding retention of records must also be followed.  Study 
sites are required to retain all records until written notification allowing destruction is received from 
the Sponsor. 
12 ETHICS 
12.1 Ethics Committee 
A properly constituted, valid IRB/IEC must review the treatment plan and procedures, the 
Investigator’s informed consent document, and related subject information. It is the responsibility 
of the Investigator to ensure that all aspects of institutional review are conducted in accordance 
with current regulations governing the jurisdiction where the study is conducted. The Sponsor (or 
designee) must receive a letter documenting IRB/IEC approval that specifically identifies the title 
of the treatment plan, subject information sheet, and ICF. 
12.2 Subject Information and Consent 
It is the responsibility of the site Investigator to ensure that written informed consent is obtained 
from the subject or legal representative before any activity or procedure is undertaken that is not 
part of routine care. The informed consent must comply with local regulations. 
The background of the study, the procedures, the potential benefits and risks of the treatment, and 
the fact that treatment is voluntary for the subject must be explained to the subject or legal 
representative. The subject or representative must be given sufficient time to consider whether to 
receive compassionate treatment. A copy of the ICF, signed and dated by the subject/representative 
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a subject’s informed consent must also be documented in the subject’s medical record prior to any 
treatment with favipiravir. 
Each consent form should contain an authorization allowing the Investigator and the Sponsor (or 
designee) to use and disclose protected health information (PHI) (i.e., subject-identifiable health 
information) in compliance with local law. The signed consent form will be retained with the 
treatment records. 
13 GENERAL CONSIDERATIONS 
13.1 Discontinuation of the Study 
The Sponsor reserves the right to discontinue the study at any time for any reason. 
13.2 Use of Information and Publication 
All information concerning favipiravir, Sponsor operations, patent applications, formulas, 
manufacturing processes, basic scientific data, formulation, and other information supplied by the 
Sponsor to the Investigator and not previously published is considered confidential and remains the 
sole property of the Sponsor. The Investigator agrees to use this information only to treat this patient 
and will not use it for other purposes without written consent of the Sponsor. 
The information obtained in this study will be used by the Sponsor in connection with the continued 
development and, if approved, commercialization of favipiravir. Thus, Sponsor may disclose such 
information as required to other clinical Investigators, contractors, and government regulatory 
agencies. 
Publication or other public presentation of results from this study and related information is subject 
to the provisions of the Clinical Trial Agreement between Sponsor and the Study Site. 


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14 SCHEDULE OF ASSESSMENTS 
 
Day Assessment 
in the study 
clinic  
 
Administration 
of study drugs 
Self-
collected 
nasal swab 
and self-
assessment) 
 
 
Oropharyngeal 
swab 
Blood 
collected by 
phlebotomy 
for clinical labs 
(CBC, Chem 7, 
LFTs, uric acid, 
CRP)A, B 
Blood 
collected by 
phlebotomy 
for 
biobanking/ 
immunology 
studies C 
Blood 
collected by 
phlebotomy 
for PK, pre- 
and post- 
dose C 
Urine for 
pregnancy 
test 
(serum if 
needed) 
Stool 
self-
collected 
using 
Zymo 
fecal kit, 
C  
Collect 
nasal 
swabs for 
antigen 
testing 
 
Collect 
nasal swab 
for 
molecular 
testing 
1 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense 
stool kit 
X 
X 
2 
 
X 
X 
 
 
 
 
 
 
 
 
3 
 
X 
X 
 
 
 
 
 
 
 
 
4 
 
X 
X 
 
 
 
 
 
 
 
 
5 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
6 
 
X 
X 
 
 
 
 
 
 
 
 
7 
 
X 
X 
 
 
 
 
 
 
 
 
8 
 
X 
X 
 
 
 
 
 
 
 
 
9 
 
X 
X 
 
 
 
 
 
 
 
 
10 
X 
X 
X 
X 
X 
 
X 
 
Dispense  
two stool 
kits 
X 
X 
14 
 
 
X 
 
 
 
 
 
X 
 
 
21 
 
 
X 
 
 
 
 
 
 
 
 
28 
X 
 
X 
X 
X 
X 
 
 
X, 
Dispense 
stool kit 
 
 
Appendix A: Subject Status 
  
A: Blood for uric acid and CRP required at Day 1 while results for CBC/Chem 7/LFTs can be within 48 hours of enrollment 
B: Local lab ranges will be submitted by sites for review prior to initiation 
C: Collection of biobanking, PK, and stool are optional for sites. 
 


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1. ECOG Performance Status 
 
 
GRADE ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature
e.g., light housework, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% off
waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:649-655. 
 
 
 
2. Study Specific Symptom Status Scale 
 
See symptom survey