Clinical trial NCT04358549
Conditions: COVID-19
Sponsor: Fujifilm Pharmaceuticals U.S.A., Inc.
Start date: 2020-04-17; Completion date: 2020-10-30
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To determine the effect of favipiravir + SOC v. SOC on COVID-19 viral clearance.

Detailed description:
This is an open label, randomized, controlled, multicenter Phase 2 proof-of-concept study of favipiravir in hospitalized subjects with Corona Virus Disease (COVID) -19. Subjects will be randomized within their study site and stratified by the severity of their disease to receive either favipiravir + standard of care (SOC) or SOC alone.

The dose regimen will be 1800 mg favipiravir bis in die (BID) plus SOC or SOC alone on Day 1 followed by 1000 mg BID favipiravir (800 mg BID for subjects with Child-Pugh A liver impairment) plus SOC or SOC for the next 13 days.

The study will have 14 days of treatment and 46 days of follow-up.

Approximately 50 patients are planned to be enrolled in the trial at approximately 8 study sites in the US.

Arms: arm 1: Day 1: favipiravir 1800 mg BID plus Standard of Care (SOC) Days 2-14: 1000 mg BID plus SOC. For subjects with Child-Pugh A liver impairment: Days 2-14: 800 mg BID plus SOC arm 2: Standard of Care for 14 days
Interventions: intervention 1: Favipiravir intervention 2: Standard of Care
Intervention descriptions: intervention 1: Favipiravir to be administered as an oral tablet or made into a slurry for subjects who cannot swallow tablets intervention 2: Standard of Care for individual study site as determined by each hospital's protocol

Protocol documents:
Prot_000.pdf: 
FUJIFILM Pharmaceuticals U.S.A., Inc. 
 
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Confidential and Proprietary 
 
Page 1 of 43 
 
 
 
Open Label, Randomized, Controlled Phase 2 Proof-of-Concept 
Study of the Use of Favipiravir Compared to Standard of Care  
in Hospitalized Subjects with COVID-19 
 
 
 
 
PROTOCOL NUMBER: 
FAVI-COV-US201 
 
IND NUMBER: 
 
148286 
 
 
INVESTIGATIONAL   
favipiravir 
PRODUCT: 
 
 
PROTOCOL VERSION 
Version 6.0 
/DATE:  
15July2020 
 
 
 
SPONSORED BY: 
 
FUJIFILM Pharmaceuticals U.S.A., Inc. 
 
 
 
One Broadway, Cambridge, MA 02142 
 
 
 
USA 
 
 
 
CONTACT 
Sponsor’s Representative: 
INFORMATION: 
Moriyoshi Maeda 
 
Email: mmaeda@fujifilm.com 
 
 
Acting Chief Medical Officer 
 
Carol Epstein, MD 
 
Email: carol@biologics.com 
 
Mobile phone: +1 617-548-2221 
 
 
Confidentiality Statement 
This document is the confidential and proprietary information of FUJIFILM Pharmaceuticals U.S.A., 
Inc. (FPHU) The confidential information in this document is provided to you as a Potential Investigator 
or consultant for review by you, your staff and the applicable Institutional Review Board. You may 
disclose the contents of this document only to study personnel under your supervision or to your 
Institutional Review Board who need to know the purpose of this clinical trial for approval decisions. 
Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from FPHU. 


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FUJIFILM PHARMACEUTICALS U.S.A., INC. 
PROTOCOL FAVI-COV-US201 APPROVAL 
 
Version 6.0, 15July2020 
 
 
 
(SIGNATURES ON FILE AT FPHU) 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
___________________ 
Mikihiko Kato 
 
 
 
 
 
Date (MM/DD/YYYY) 
FUJIFILM Pharmaceutical U.S.A., Inc. 
 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
___________________ 
Carol Epstein, M.D.  
 
 
 
 
Date (MM/DD/YYYY) 
Acting Chief Medical Officer  
 
 
 
 
 
FUJIFILM Pharmaceutical U.S.A., Inc. 
 
 
 
 
_______________________________ 
 
 
___________________ 
 
John Balser, Ph.D. 
 
 
 
 
 
Date (MM/DD/YYYY) 
President and Chief Biostatistician 
Veristat 
 
 
 
 
 
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
 
 
Protocol Title:  
Open Label, Randomized, Controlled Phase 2 Proof-of-Concept Study 
of the Use of Favipiravir v. Standard of Care in Hospitalized Subjects 
with COVID-19 
 
Protocol Number: 
FAVI-COV-US201 
 
 
Protocol Version/Date:  Version 6.0 
15July2020 
 
 
Sponsor Name:  
FUJIFILM Pharmaceuticals U.S.A., Inc. 
 
 
One Broadway, Cambridge, MA 02142 
 
 
USA 
 
 
 
 
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) 
 
 
 
 
 


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TABLE OF CONTENTS 
1 
SYNOPSIS ...............................................................................................................................8 
2 
INTRODUCTION ................................................................................................................14 
2.1 
Background Information ............................................................................................14 
2.2 
Preclinical and In Vitro Experiences ........................................................................15 
2.3 
Clinical Experience .....................................................................................................15 
2.4 
In Vitro Therapeutic Levels .......................................................................................16 
2.5 
Phase 1 Study Steady State Exposure .......................................................................16 
2.6 
Rationale for 14-day Dosing Regimen .......................................................................18 
2.7 
Rationale for the Current Study ................................................................................18 
3 
DESIGN .................................................................................................................................19 
4 
OBJECTIVES .......................................................................................................................19 
4.1 
Primary Objective .......................................................................................................19 
4.2 
Secondary Objectives ..................................................................................................19 
5 
SUBJECT POPULATION ...................................................................................................20 
5.1 
Inclusion Criteria ........................................................................................................20 
5.2 
Exclusion Criteria .......................................................................................................20 
5.3 
Removal of Subjects from Treatment .......................................................................21 
5.4 
Individual Stopping Rule ............................................................................................22 
6 
STUDY TREATMENT - FAVIPIRAVIR ..........................................................................22 
6.1 
Study Drug ...................................................................................................................22 
6.2 
Standard Dose .............................................................................................................22 
6.3 
Administration of Favipiravir ....................................................................................22 
6.3.1 Outpatient Favipiravir Dosing ..........................................................................23 
6.4 
Drug Accountability ....................................................................................................23 
6.5 
Treatment Compliance ...............................................................................................23 
6.6 
Treatment Precautions ...............................................................................................23 
6.7 
Prohibited Concomitant Therapy ..............................................................................23 
7 
STUDY PROCEDURES ......................................................................................................24 
7.1 
Day 1 (PRE-DOSE) .....................................................................................................24 
7.2 
Day 1 (FIRST DOSE AND POST-DOSE) ................................................................25 
7.3 
Days 2 and 14 ...............................................................................................................26 
7.4 
Days 3, 8 and 11 ...........................................................................................................26 
7.5 
Days 15 and 29 (Follow-up) or Early Termination ..................................................27 
7.6 
Days 45 and 60 (Additional Safety Follow-up) .........................................................27 
7.7 
Day of Discharge from Hospital.................................................................................28 


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8 
EFFICACY, PHARMACOKINETICS AND SAFETY ASSESSMENTS ......................28 
8.1 
Efficacy Assessments ...................................................................................................28 
8.2 
Required Resistance Testing ......................................................................................29 
8.3 
Pharmacokinetics/Pharmacodynamics Assessments ...............................................29 
8.4 
Safety Assessments ......................................................................................................29 
8.4.1 Adverse Events..................................................................................................30 
8.4.2 Definition of an Adverse Event.........................................................................30 
8.4.3 Evaluating and Reporting of Adverse Events ...................................................31 
8.4.4 Serious Adverse Events (SAEs) ........................................................................32 
8.4.5 Definition of Serious Adverse Events ...............................................................32 
8.4.6 SAE Reporting Requirements to the Sponsor ...................................................32 
8.5 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................33 
8.5.1 Reporting SUSARs to the FDA: IND Safety Reports ......................................33 
8.6 
Clinical Laboratory Abnormalities and Other Abnormal Assessments ................34 
8.7 
Handling of Overdose .................................................................................................34 
9 
STATISTICAL METHODS ................................................................................................34 
9.1 
General Considerations ..............................................................................................34 
9.2 
Sample size justification .............................................................................................35 
9.3 
Demographic and Baseline Characteristics ..............................................................35 
9.4 
Analysis Populations ...................................................................................................35 
9.5 
Stratification, Subgroup Analysis and Pooled Analysis ..........................................36 
9.6 
Efficacy Endpoint Analysis ........................................................................................36 
9.7 
Safety Analysis .............................................................................................................37 
10 RECORDING AND COLLECTION OF DATA ...............................................................37 
10.1 Case Report Form .......................................................................................................37 
10.2 Study Files and Subject Source Documents .............................................................38 
10.3 Monitoring ...................................................................................................................38 
10.4 Audit .............................................................................................................................38 
10.5 Retention of Data.........................................................................................................39 
11 ETHICS .................................................................................................................................39 
11.1 Ethics Committee ........................................................................................................39 
11.2 Subject Information and Consent .............................................................................39 
12 GENERAL CONSIDERATIONS .......................................................................................39 
12.1 Discontinuation of the Study ......................................................................................39 
12.2 Use of Information and Publication ..........................................................................39 
13 SCHEDULE OF ASSESSMENTS ......................................................................................41 
Appendix A: Subject Status Scales .....................................................................................43 


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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 


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NO 
Nitrous Oxide 
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 
Open Label, Randomized, Controlled, Phase 2 Proof-of-Concept Study 
of the Use of Favipiravir v. Standard of Care in Hospitalized Subjects 
with COVID-19 
Design 
This is an open label, randomized, controlled, multicenter Phase 2 proof-
of-concept study of favipiravir in hospitalized subjects with COVID-19.  
Subjects will be randomized within their study site and stratified by the 
severity of their disease to receive either favipiravir + standard of care 
(SOC) or SOC alone. 
The dose regimen will be 1800 mg favipiravir BID plus SOC or SOC 
alone on Day 1 followed by 1000 mg BID favipiravir (800 mg BID for 
subjects with Child-Pugh A liver impairment) plus SOC or SOC for the 
next 13 days. 
The study will have 14 days of treatment and 46 days of follow-up. 
Objectives 
Primary Objective 
To determine the effect of favipiravir + SOC v. SOC on viral clearance.  
Secondary Objectives 
1. To determine the clinical benefit of administering favipiravir plus 
SOC compared to SOC alone [assessed using a study-specific 6-
point ordinal scale adapted from the WHO Master Protocol (V2.0 
24FEB20) COVID-19 7-point ordinal scale] on Day 15 in adult 
patients hospitalized with COVID-19. 
2. To determine if the treatment effect on the 6-point ordinal scale, on 
Day 15, is reasonably likely to reflect clinical benefit, such that it 
can be used as the primary clinical outcome endpoint in a similar 
study that is double-blinded, by assessment of the relationship of the 
scale to changes in clinical and symptom outcomes, including time 
to clinical recovery, occurrence of fever, cough, dyspnea, reduction 
in oxygen requirements, and other measures. 
3. To explore the clinical effect of favipiravir + SOC v. SOC as 
measured by the National Early Warning Score 2 (NEWS2) system. 
4. To determine the safety of favipiravir plus SOC compared to SOC 
alone, in this population. 
5. To explore the PK of this dose regimen of favipiravir in this patient 
population. 
Endpoints 
Primary Endpoint:  
Time to viral clearance. 
Secondary Endpoints:  
1. Status of Clinical recovery as measured by the study-specific 6-point 
ordinal scale at Day 15. 


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2. Time to Clinical Recovery (TTCR) as assessed up to 29 days and 
defined as: 
a. The time (in hours) from initiation of study treatment (favipiravir 
+ SOC or SOC alone) until normalization of fever, respiratory 
rate, and oxygen saturation, and alleviation of cough, sustained 
for at least 72 hours; or discharge. 
b. Normalization and alleviation criteria are defined as: 
i. Fever – ≤ 37.2 °C oral, 
ii. Respiratory rate – ≤ 24/minute on room air, 
iii. Oxygen saturation – SpO2 > 94% on room air, 
iv. Cough – mild or absent on a patient reported scale of severe, 
moderate, mild, absent. 
3. Clinical effect as measured by the National Early Warning Score 2 
(NEWS2) system. 
4. All-cause mortality as assessed daily up to 29 days and at final 
follow up on Day 60. 
5. Frequency of respiratory progression as assessed up to 29 days (daily 
and per SOC at each site) and defined as: 
a. SpO2 ≤ 94% on room air or PaO2/FiO2 < 300mmHg, and 
b. requirement for supplemental oxygen, or 
c. more advanced ventilator support. 
6. Time to defervescence (in those with fever at enrollment) as assessed 
daily up to 29 days and at Day 60 (if possible). 
7. Time to cough reported as mild or absent (in those with cough at 
enrollment rated severe or moderate) as assessed daily up to 29 days 
and on Day 60. 
8. Time to dyspnea reported as mild or absent (on a scale of severe, 
moderate, mild absent, in those with dyspnea at enrollment rated as 
severe or moderate) as assessed daily up to 29 days and on Day 60 
(if possible). 
9. Frequency of requirement for supplemental oxygen or non-invasive 
ventilation as assessed daily up to 29 days and on Day 60. 
10. Time to SARS-CoV-2 RT-PCR negative in upper respiratory tract 
specimen as assessed up to 29 days. 
11. Change in SARS-CoV-2 viral load in upper respiratory tract 
specimen as assessed by area under viral load curve as assessed up to 
29 days. 
12. Frequency of requirement for mechanical ventilation as assessed up 
daily to 29 days and at Day 60 
13. Safety of favipiravir + SOC v. SOC alone as assessed daily up to 
29 days and at Day 60. 
14. C-reactive protein (CRP) over time. 
15. Population PK analysis of favipiravir with assessment of maximum 
plasma concentration (Cmax), minimum plasma concentration (Cmin), 
and AUC(0-24h) on Days 1, 2, 8 and 14. 


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Study Sites 
Approximately 8 sites in the U.S.A. 
Planned 
Enrollment  
Approximately 50 subjects; randomized 1:1 
Study Population 
Adults who are hospitalized for treatment of confirmed COVID-19 
Subject Entry 
Criteria 
Inclusion Criteria (all questions must be answered YES) 
1. 
Adults (18 to 80 years old): 
a. within 72 hours of their hospitalization for infection with 
SARS-CoV-2, AND, 
b. within 72 hours of the latest PCR positive result and within 
7 days of the 1st PCR positive result for SARS-CoV-2. (The 
latest PCR could be the only PCR result.), AND, 
c. within 10 days of onset of any COVID-19 symptoms.  
2. 
Subject or their legal representative understands the requirements of 
the study and provides written informed consent prior to 
undergoing any treatment-related procedures. 
3. 
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). 
4. 
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 


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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 pregnancy test at screening. 
f. 
Has not had unprotected sexual intercourse within the past 
month. 
Exclusion Criteria (all questions must be answered NO) 
1. 
Subject has a concomitant bacterial respiratory infection unless 
cleared by the Sponsor 
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. 
2. 
Subject has a history of abnormalities of uric acid metabolism 
unless cleared by the Sponsor. 
3. 
Subject has a history of hypersensitivity to an anti-viral nucleoside-
analog drug targeting a viral RNA polymerase. 
4. 
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. 
Per the conclusions of The Randomised 
Evaluation 
of 
COVID-19 
therapy 
(RECOVERY) 
trial 
(https://www.medrxiv.org/content/10.1101/202
0.06.22.20137273v1; 
accessed 
13Jul2020), 
dexamethasone 6 mg daily (PO or IV) for 10 
days 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. 
5. 
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, 


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vascular, or endocrinologic disease states requiring medication dose 
adjustments within the last 30 days). 
6. 
Has previously received favipiravir within the past 30 days. 
7. 
Has renal insufficiency requiring hemodialysis or continuous 
ambulatory peritoneal dialysis (CAPD) or glomerular filtration rate 
of less than 20 mL/min. 
8. 
Has liver impairment greater than Child-Pugh A. (NOTE: Child-
Pugh A subjects will have the maintenance dose decreased to 800 
mg BID). 
9. 
Has a history of alcohol or drug abuse in the previous 6 months. 
10. Has a psychiatric disease that is not well controlled where 
controlled is defined as: stable on a regimen for more than one year. 
11. Has taken another investigational drug within the past 30 days. 
12. Is on another antiviral or is participating in a clinical trial for the 
treatment of COVID-19. 
13. Subject is on ventilator at the time of study entry. 
14. Is deemed by the Investigator to be ineligible for any reason. 
Treatment 
Regimen for 
Favipiravir 
(Standard dose) 
• Favipiravir tablets will be administered orally. If necessary, a slurry 
may be administered by nasogastric tube. 
• The regimen begins with loading doses of 1800 mg BID on Day 1 
(the first 24 hours of treatment at t =0 and t = 12 hours) then 
maintenance dosing of 1000 mg BID from Day 2 (beginning 24 hours 
after the start of therapy). 
• Patients with Child-Pugh liver impairment of grade A will have their 
maintenance dose decreased to 800 mg BID. 
• The total duration of treatment is expected to be 14 days. 
• The dose regimen may be altered, after consultation between the 
treating physician and the Sponsor, depending on the clinical 
condition of the patient. 
Duration of Study 
Participation 
Subjects will participate in the study for up to 60 days: 14 days treatment 
(or as discussed with the Sponsor) and 46 days follow up. 
Statistical 
Methods  
• This study is intended to be exploratory. Based upon available data, a 
two-arm study of approximately 50 total subjects will be sufficient to 
provide reasonable assurance that the endpoints chosen for a 
confirmatory trial will elucidate treatment differences between 
favipiravir and a control. Statistical significance testing will be used 
to assess the relative strength of evidence of the primary and 
secondary endpoints. 
• Randomization will be stratified by: 
• Site 
• Severity of illness at enrollment: 


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o Critical disease: 
 Requires supplemental oxygen delivered by non-
rebreather mask or high-flow cannula, OR 
 Use of invasive or non-invasive ventilation, OR 
 Requiring treatment in an intensive care unit, use of 
vasopressors, extracorporeal life support. 
o Severe disease: 
 Evidence of pneumonia on chest x-ray or CT scan, or 
chest auscultation (rales, crackles), OR 
 SpO2 ≤ 93% on room air OR PaO2/FiO2 < 300 mmHg, 
OR 
 Requires supplemental oxygen by nasal canula, simple 
face mask, or other similar oxygen delivery device. 
o Mild-moderate disease: SpO2 > 94% and respiratory rate < 24 
breaths/min without supplemental oxygen 
• There is no planned interim analysis. 
Individual 
Stopping Rule 
A subject should be removed from favipiravir treatment if one of the 
following criteria is met: 
• AST or ALT > 8 × ULN 
• ALT or AST > 3 × ULN AND total bilirubin > 2 × ULN 
• AST or ALT > 3 × ULN AND patient has right upper quadrant pain 
or eosinophilia 
• Uric acid > 20 mg/dL 
Study 
Measurements: 
Efficacy, Safety 
and PK 
Primary Efficacy Measurement: 
Presence of virus in the nasopharyngeal and oropharyngeal samples taken 
on Days 1, 3, 8, 11, 15 and 29 (if hospitalized and when able to return to 
clinic after discharge). Swabs will also be obtained on day of discharge 
from hospital if discharge occurs before Day 15. 
Secondary Measurements (Efficacy, Safety and PK): 
1. Clinical improvement of hospitalized subjects with COVID-19 
receiving either favipiravir + SOC or SOC alone as defined by the 
following study-specific 6-point ordinal scale at Day 15 
a. Not hospitalized 
b. Hospitalized, not requiring supplemental oxygen 
c. Hospitalized, requiring supplemental oxygen 
d. Hospitalized, on non-invasive ventilation or high flow oxygen 
devices 
e. Hospitalized, on invasive mechanical ventilation or ECMO 
f. Death 
2. Status on the 6-point ordinal scale assessed daily while 
hospitalized and at each outpatient visit until Day 60. 
3. NEWS2 assessed daily while hospitalized and at each outpatient visit 
until Day 60. 


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4. Patient status assessed daily while hospitalized and at each outpatient 
visit until Day 60 via Study-specific Symptom Status and the ECOG 
Performance Status questionnaires (see Appendix A). 
5. Duration of supplemental oxygen (if applicable). 
6. Duration of mechanical ventilation (if applicable). 
7. Duration of hospitalization. 
8. Date and cause of death (if applicable). 
9. Safety as assessed by: 
a. Observed and reported adverse events. 
b. Hematology and chemistry laboratories on Days 1; 3, 8, 11, 15 
and 29 (if hospitalized and when able to return to clinic after 
discharge)  
c. Physical Examination at screening, Day 15 and Day 29. 
d. Vital signs daily while hospitalized and at each outpatient visit 
until Day 60 
10. Qualitative and quantitative PCR and TCID50 in nasopharyngeal 
and oropharyngeal swabs on Days 1 (pre-dose); 3, 8, 11, 15 and 29 
(if hospitalized and when able to return to clinic after discharge). 
Swabs will also be obtained on day of discharge from hospital if 
discharge occurs before Day 15. 
11. Blood for determination of antibodies to SARS-CoV-2 will be 
obtained on Days 1, 15 and 29 (if hospitalized and when able to 
return to clinic after discharge). 
12. Blood 6.0 ml for PK in patients randomized to favipiravir is obtained 
pre-dose (within 30 minutes prior to dosing) and post-dose (45 to 75 
minutes following dosing) on Day 1 and trough levels on Days 2, 8 
and the last day of favipiravir treatment (Day 14 unless subject 
leaves the study before completing treatment) and peak levels on 
Days 3 and 11 post-dosing. 
To gather these measurements – subjects will undergo 9 planned 
venipunctures  
 
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). 


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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 corona virus COVID-19, which causes disease 
ranging from mild, cold-like symptoms to acute respiratory failure and death. Epidemiologic 
studies are underway to determine whether individuals can be asymptomatic and transmit 
disease.  There is currently no available treatment for COVID-19. 
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 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 


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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 
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 
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. 


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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. 
Below is the same graph for US317, the second pivotal trial in the program. 


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2.6 
Rationale for 14-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. 
• (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 the influenza studies.  Patients with influenza have recovered more quickly than placebo 
controls. 
People who have been hospitalized to treat acute respiratory symptoms in the US have no proven 
option other than supportive care, which includes mechanical ventilation, oxygen therapy and 
treatment of co-infections and organ failure if needed. The safety profile of favipiravir is well-
established. It is generally safe and well-tolerated with the exception of transient elevations of 


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uric acid that resolve with cessation of dosing. 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 
This is an open label, randomized, controlled, multicenter Phase 2 study of favipiravir in 
hospitalized subjects with COVID-19. Subjects will be randomized within their study site and 
stratified by the severity of their disease to receive either favipiravir + standard of care (SOC) or 
SOC alone (See Section 9.5 for details). 
SOC will be site-specific and based on what each site is currently using for COVID-19 patients. 
The dose regimen will be 1800 mg favipiravir BID plus SOC or SOC alone on Day 1 followed 
by 1000 mg BID favipiravir (800 mg BID for subjects with Child-Pugh A liver impairment) plus 
SOC or SOC for the next 13 days. 
The study will have 14 days of treatment and 46 days of follow-up. 
4 OBJECTIVES 
4.1 
Primary Objective 
• To determine the effect of favipiravir + SOC v. SOC on viral clearance 
4.2 
Secondary Objectives  
1. To determine the clinical benefit of administering favipiravir plus SOC compared to SOC 
alone [assessed using a study-specified 6-point ordinal scale adapted from the WHO Master 
Protocol (V2.0 24FEB20) COVID-19 7-point ordinal scale] in adult patients hospitalized 
with COVID-19. 
2. To determine if the treatment effect on the 6-point ordinal scale, on Day 15, is reasonably 
likely to reflect clinical benefit, such that it can be used as the primary clinical outcome 
endpoint in a similar study that is double-blinded, by assessment of the relationship of the 
scale to changes in clinical and symptom outcomes, including time to clinical recovery, 
occurrence of fever, cough, dyspnea, reduction in oxygen requirements, and other measures. 
3. To explore the clinical effect of favipiravir + SOC v. SOC as measured by the NEWS2 
system. 
4. To determine the safety of favipiravir plus SOC compared to SOC alone, in this population. 
5. To explore the PK of this dose regimen of favipiravir in this patient population. 


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5 SUBJECT POPULATION 
5.1 
Inclusion Criteria 
All criteria must be confirmed as “YES”: 
1. Adults (18 to 80 years old): 
a. within 72 hours of their hospitalization for infection with SARS-CoV-2, AND, 
b. within 72 hours of the latest PCR positive result and within 7 days of the 1st PCR positive 
result for SARS-CoV-2. (The latest PCR could be the only PCR result.), AND, 
c. within 10 days of onset of any COVID-19 symptoms. 
2. Subject or their legal representative understands the requirements of the study and provides 
written informed consent prior to undergoing any treatment-related procedures. 
3. 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).  
4. 
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 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 unless cleared by the Sponsor. 


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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. 
2. Subject has a history of abnormalities of uric acid metabolism unless cleared by the Sponsor. 
3. Subject has a history of hypersensitivity to an anti-viral nucleoside-analog drug targeting a 
viral RNA polymerase 
4. 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. Per the conclusions of The Randomised Evaluation 
of 
COVID-19 
therapy 
(RECOVERY) 
trial 
(https://www.medrxiv.org/content/10.1101/2020.06.22.20137
273v1; accessed 13Jul2020), dexamethasone 6 mg daily (PO 
or IV) for 10 days 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. 
5. 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 requiring medication dose adjustments within the last 30 days). 
6. Has previously received favipiravir within the past 30 days. 
7. Has renal insufficiency requiring hemodialysis or continuous ambulatory peritoneal dialysis 
(CAPD). 
8. Has liver impairment greater than Child-Pugh A.  (NOTE: Child-Pugh A subjects will have 
the maintenance dose decreased to 800 mg BID). 
9. Has a history of alcohol or drug abuse in the previous 6 months. 
10. Has a psychiatric disease that is not well controlled where controlled is defined as: stable on a 
regimen for more than one year. 
11. Has taken another investigational drug within the past 30 days. 
12. Is on another antiviral or is participating in a clinical trial for the treatment of COVID-19. 
13. Is on a ventilator at the time of study entry. 
14. 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: 


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• 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. 
5.4 
Individual Stopping Rule 
In addition to the above, a. subject should be removed from favipiravir treatment if one of the 
following criteria is met: 
• AST or ALT > 8 × ULN 
• ALT or AST > 3 × ULN AND total bilirubin > 2 × ULN 
• AST or ALT > 3 × ULN AND patient has right upper quadrant pain or eosinophilia 
• Uric acid > 20mg/dL 
A subject whose treatment is terminated should remain in the study for appropriate follow up 
assessments. 
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. 
6.2 
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 1000 mg twice daily BID (Ideally 12 hours apart but 10–16 hours is allowed) on Days 
2–14 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 800 mg BID on 
Days 2 through 14.  
6.3 
Administration of Favipiravir 
 
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. 
If a subject cannot swallow the tablets, a slurry may be administered by nasogastric (NG) or 
orogastric (OG) tube. (Instructions for preparing the slurry are provided in the pharmacy 
instructions.). If an NG or OG tube cannot be placed, the favipiravir tablets can be crushed and 
administered in a “masking” substance such as apple sauce or cranberry juice. 


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Subjects who vomit during or immediately after dosing, should not be re-dosed. 
The Investigator must consult with the Sponsor Medical Monitor prior to adjusting the dose 
level, regimen, or route of dosing. 
6.3.1 Outpatient Favipiravir Dosing 
It is possible that some subjects may improve sufficiently to be discharged from the hospital 
prior to Day 14. If this happens, subjects in the favipiravir + SOC arm, will be dispensed 
sufficient favipiravir to ensure continued dosing until their next study visit. Subjects will also be 
given a Diary Card to record the date and time they take their dose. 
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. 
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 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, 


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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). 
For hospitalized subjects on the favipiravir + SOC arm, site staff will be reminded to consider 
the above prior to prescribing concomitant medications. 
The following message appears on the Diary Card given to subjects that are discharged with 
favipiravir to take at home (see Section 6.3.1): 
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 while you were in the hospital, 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 13: 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 4.c, obtain urine or 
blood pregnancy test and proceed it result is negative. 
• Measure and record vital signs (BP, HR, Temp, Resp). 
NOTE: vital signs to be recorded and entered in the EDC every day while subject is in the 
hospital and on return study visits after discharge. 
• 
Perform Physical exam (may be done by the Principal Investigator or their designee)  
• 
Assess and record baseline clinical status according to the following study-specific 6-point 
scale:  
1. Not hospitalized 
2. Hospitalized, not requiring supplemental oxygen 
3. Hospitalized, requiring supplemental oxygen 
4. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
5. Hospitalized, on invasive mechanical ventilation or ECMO 


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6. Death 
NOTE: Clinical Status to be recorded and entered in the EDC every day while subject is in 
the hospital and on return study visits after discharge. 
• Assess and record NEWS2 (See charts by clicking this link: 
https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2 
NOTE: NEWS2 assessment to be recorded and entered in the EDC every day while subject 
is in the hospital and on return study visits after discharge. 
• Assess and record ECOG Performance Status and Study-specific Symptom Status (see 
Appendix A). 
NOTE: ECOG Performance Status and Study-specific Symptom Status to be collected and 
recorded every day while the subject is in the hospital and on return study visits after 
discharge. 
• Collect nasopharyngeal and oropharyngeal swabs for virologic testing. (See Virology 
Laboratory Manual.) 
• Collect blood samples for: 
o Antibodies to SARS-CoV-2. 
o Hematology and clinical chemistry laboratory analyses 
• Collect and record SpO2 by Finger Sensor 
NOTE: SpO2 to be recorded and entered in the EDC every day while subject is in the 
hospital and on return study visits after discharge. 
• Perform subject randomization (via EDC) to establish treatment arm (favipiravir + SOC or 
SOC alone). 
• For subjects randomized to favipiravir: Collect blood sample for PK prior to first dose (refer 
to PK laboratory manual for handling and shipping instructions). 
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) at time 0. 
Following First Dose: 
• For subjects randomized to favipiravir, collect blood sample for PK within 45 to 75 minutes 
post-dose 
• Measure and record vital signs (BP, HR, Temp, Resp). 
• Collect and record SpO2 by Finger Sensor 
• Administer second dose (1800 mg) at time 0 + 12 hours. 
• Perform limited PE to focus on heart and lungs (may be done by the Principal Investigator or 
their designee). 
NOTE: to be done every day while the subject is in the hospital and on return study visits 
after discharge 
• Collect and record adverse events (see Section 8.4 for detailed instructions) 


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7.3 
Days 2 and 14 
• Measure and record vital signs (BP, HR, Temp, Resp). 
• Perform a limited PE to focus on heart and lungs. 
• 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). 
• For subjects randomized to favipiravir collect blood sample for PK analysis at 30 minutes 
prior to any dose 
• Collect and record adverse events (see Section 8.4 for detailed instructions) 
• Collect and record SpO2 by Finger Sensor 
• Assess and record clinical status according to the following study-specific 6-point scale: 
1. Not hospitalized 
2. Hospitalized, not requiring supplemental oxygen 
3. Hospitalized, requiring supplemental oxygen 
4. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
5. Hospitalized, on invasive mechanical ventilation or ECMO 
6. Death 
• Assess and record NEWS2  
• Assess and record ECOG Performance Status and Study-specific Symptom Status (see 
Appendix A). 
• Collect and record adverse events (see Section 8.4 for detailed instructions). 
7.4 
Days 3, 8 and 11 
• 
Collect blood samples for hematology and clinical chemistry laboratory analyses 
• 
On Day 8 ± 1 day only: For subjects randomized to receive favipiravir, collect blood 
samples for PK trough analysis at 30 minutes prior to any dose 
• 
On Days 3 and 11 ± 1 day: For subjects randomized to receive favipiravir, collect blood 
samples for PK peak analysis at 45-75 minutes after any dose. 
• 
Measure and record vital signs (BP, HR, Temp, Resp). 
• 
Perform a limited PE to focus on heart and lungs. 
• 
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). 
• 
Collect and record SpO2 by Finger Sensor 
• 
Assess and record clinical status according to the study-specific 6-point scale: 
1. Not hospitalized 
2. Hospitalized, not requiring supplemental oxygen 
3. Hospitalized, requiring supplemental oxygen 
4. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
5. Hospitalized, on invasive mechanical ventilation or ECMO 
6. Death 
• Assess and record NEWS2  
• Collect nasopharyngeal and oropharyngeal swabs for virologic testing.  
• Collect and record adverse events (see Section 8.4 for detailed instructions). 
• Assess and record ECOG Performance Status and Study-specific Symptom Status (see 
Appendix A). 


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7.5 
Days 15 and 29 (Follow-up) or Early Termination 
• Perform a limited PE to focus on heart and lungs. 
• 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 blood samples for: 
o Antibodies to SARS-CoV-2. 
o Hematology and clinical chemistry laboratory analyses 
• Assess and record clinical status according to the following study-specific 6-point scale: 
1. Not hospitalized 
2. Hospitalized, not requiring supplemental oxygen 
3. Hospitalized, requiring supplemental oxygen 
4. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
5. Hospitalized, on invasive mechanical ventilation or ECMO 
6. Death 
• Assess and record NEWS2  
• Collect nasopharyngeal and oropharyngeal swabs for virologic testing.  
• Collect and record adverse events (see Section 8.4 for detailed instructions). 
• Assess and record ECOG Performance Status and Study-specific Symptom Status (see 
Appendix A).  
Note: Day 15 visit procedures may be conducted on Day 14 if patient is discharged before 
Day 15. 
7.6 
Days 45 and 60 (Additional Safety Follow-up) 
Follow up assessment of general health and well-being may be done while the subject remains 
hospitalized or by phone if the subject has been released from the hospital and is unable to return 
for the study visit. 
• Measure and record vital signs (BP, HR, Temp, Resp). 
• Perform a limited PE to focus on heart and lungs. 
• 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). 
• Collect and record SpO2 by Finger Sensor 
• Assess and record clinical status according to the following study-specific 6-point scale: 
1. Not hospitalized 
2. Hospitalized, not requiring supplemental oxygen 
3. Hospitalized, requiring supplemental oxygen 
4. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
5. Hospitalized, on invasive mechanical ventilation or ECMO 
6. Death 
• 
Assess and record NEWS2 
• 
Administer the ECOG Performance Status questionnaire. (See Appendix A) 
• 
Administer the Study-specific Symptom Status questionnaire. (See Appendix A) 


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• 
Collect and record adverse events (see Section 8.4 for detailed instructions). 
NOTE: if the visit is conducted by phone, vital signs, limited PE, SpO2, and NEWS2 will not be 
evaluated. 
7.7 
Day of Discharge from Hospital 
• Some subjects may be well enough for discharge from the hospital prior to completing the 
full 14 days of treatment. In these cases, the following procedure should be followed 
• FOR ALL SUBJECTS (regardless of treatment assignment) 
o The study staff will collect nasopharyngeal and oropharyngeal swabs, regardless of which 
study day the subject is discharged (e.g., samples should be collected on subjects 
discharged from the hospital on Study Day 4 even though they will have had this 
procedure on Study Day 3, per protocol.) 
• FOR SUBJECTS TAKING FAVIPIRAVIR 
o The study staff will request the pharmacy to dispense the appropriate number of tablets 
for the subject to take between the time of discharge and the next scheduled study visit 
plus one extra day in case the visit must be changed.  Prior to each study visit, the study 
staff will request a “refill” of favipiravir tablets to be taken by the subject between the 
time of the current visit and the subsequent visit. (See Pharmacy Instructions for details 
of dispensing.) 
o To assist the subject with compliance, dosing instructions will be provided along with the 
favipiravir. 
o Subjects will be reminded that the Rx bottle MAY NOT BE RETURNED TO (LEFT 
AT) THE SITE. To avoid contamination, each subject will bring the bottle and unused 
drug to their visit and show the contents of the bottle to the study staff conducting the 
visit. Once the drug has been counted, the subject will be instructed to dispose of the pills 
by placing them in a separate bag and putting the bag in the on-site trash. 
o NOTE: the site may make modifications to this procedure if needed to comply with local 
rules for non-contamination of the site. 
o When a subject completes dosing (either by completing all 14 days of dosing or by 
leaving the study) the pharmacy will send the Subject IP accountability log to the 
Sponsor for verification with the EDC and compliance with the protocol. 
8 EFFICACY, PHARMACOKINETICS AND SAFETY ASSESSMENTS 
8.1 
Efficacy Assessments 
Efficacy will be assessed by the following measurements:  
• Presence of virus in the nasopharyngeal and oropharyngeal samples taken on Days 1, 3, 8, 
11, 15 and 29 (if hospitalized and when able to return to clinic after discharge). Swabs will 
also be obtained on day of discharge from hospital if discharge occurs before Day 15. 
• Clinical improvement of hospitalized subjects with COVID-19 receiving either favipiravir + 
SOC or SOC alone as defined by the following study-specific 6-point ordinal scale at Day 15 


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1. Not hospitalized 
2. Hospitalized, not requiring supplemental oxygen 
3. Hospitalized, requiring supplemental oxygen 
4. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
5. Hospitalized, on invasive mechanical ventilation or ECMO 
6. Death 
• Status on the study specific 6-point ordinal scale assessed daily while hospitalized 
and at each outpatient visit until Day 60. 
• NEWS2 assessed daily while hospitalized and at each outpatient visit until Day 60. 
• Patient status assessed daily while hospitalized and at each outpatient visit until Day 60 via 
Study-specific Symptom Status and the ECOG Performance Status questionnaires (see 
Appendix A). 
• Duration of supplemental oxygen (if applicable). 
• Duration of mechanical ventilation (if applicable). 
• Duration of hospitalization. 
• Date and cause of death (if applicable). 
• PCR and TCID50 in nasopharyngeal and oropharyngeal swabs on Days 1, 3, 8, 
11, 15 and 29 (if hospitalized and when able to return to clinic after discharge), 
and on day of discharge if hospital discharge occurs before Day 15. 
• Blood for determination of antibodies to SARS-CoV-2 obtained on Days 1, 15 and 29 (if 
hospitalized and when able to return to clinic after discharge). 
8.2 
Required Resistance Testing 
Resistance testing, as required in clinical trials of anti-viral drugs will be performed using one of 
the swabs, at each time point that nasopharyngeal and oropharyngeal swabs are taken. 
8.3 
Pharmacokinetics/Pharmacodynamics Assessments 
• 6.0 mL of blood will be collected for PK sampling on: 
o Day 1 pre- and post-dosing (1st dose) 
o Days 2, 8 and 14 pre-dosing (any dose) 
o Days 3 and 11 post-dosing (any dose) 
• 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 


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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) 
Lactic dehydrogenase (LDH) 
Glucose 
Albumin 
Total protein 
Bicarbonate 
Phosphate 
Sodium 
Potassium 
Chloride 
Calcium 
Total cholesterol 
Urate 
C-reactive protein 
D-dimer 
 
NOTES: 
• All clinical laboratory assessments listed above (hematology and chemistry) will be 
conducted at each site’s local 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 9 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 46 days post-treatment (Day 60). 
In the favipiravir + SOC arm: Adverse event solicitation and recording will begin immediately 
following the first dose of favipiravir and will include only on-treatment (treatment emergent) 
events. Any changes to a subject’s health that occur between the signing of the informed consent 
and dosing will be recorded as updates to the subject’s medical history. 
In the SOC alone arm: Adverse event solicitation and recording will begin following the 
completion of all baseline assessments. 
Subjects will be instructed to report AEs during the study and staff will query subjects regarding 
AEs throughout the study. The Investigator (and/or designee) must document all AEs reported 
through completion of the Day 60 visit. Any subject who is withdrawn from the study due to an 
AE shall be followed until the event has resolved or stabilized or, if in the favipiravir arm, 14 
days after last dose. The Investigator will document available follow-up information on the 
subject’s source documentation and CRF. 
8.4.2 Definition of an Adverse Event 
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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 SOC alone arm, must be 
recorded as an AE or SAE (if applicable), on the Adverse Event eCRF and SAE form, as 
applicable. The Investigator must follow all AEs until the AE resolves, or until the 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 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 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 
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 
• 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 by the 
Principal 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 


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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). 
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 Day 60 
(which is 46 days after the last planned study drug administration) must be reported to the 
Sponsor as soon as the site becomes aware of them. Any SAEs occurring after Day 60 (more 
than 46 days after last planned 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 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. 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. 
8.4.6 SAE Reporting Requirements to the Sponsor 
The procedure for reporting SAEs, regardless of causal relationship, is as follows: 


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• Within 24 hours of the 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 will distribute completed SAE forms, which may be used to notify the IRB 
when applicable, via a secure internet-based document depository. 
• The Investigator should notify the IRB of Serious Adverse Events occurring at the site and 
other adverse reports received from the Sponsor in accordance with local procedures. 
The 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. 
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 an 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 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. 
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 


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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 Investigator learns of the event and are 
counted in calendar days – not business days. Therefore, it is important that the 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 
9.1 
General Considerations  
This study is intended to support a Phase 3 registrational trial in this patient population by 
providing information on the treatment effect on an unambiguous indicator of antiviral activity, 
i.e., the time to viral clearance, as well as to estimate the treatment effect on a number of 
important clinical and symptomatic disease correlates. Proof of concept will be established by a 
significant treatment effect on the primary endpoint of time to viral clearance. Based upon 
available data, a two-arm study of approximately 50 total subjects will be sufficient to provide 
reasonable assurance that the endpoints chosen for a confirmatory trial will elucidate treatment 
differences between favipiravir + SOC and SOC. Statistical significance testing will be used to 
assess the relative strength of evidence of the primary and secondary endpoints; given that this 
trial is intended as a proof of concept, a two-sided alpha-level of 0.10 will be used for 
significance testing. 
It is important to ensure that reasonable certainty is achieved in the conclusions reached for key 
secondary endpoints, therefore key secondary endpoints will be adjusted for multiple statistical 
testing through a gatekeeping hierarchical methodology, as follows: Statistical significance for 
the first secondary endpoint, according to the order outlined in the endpoints section of this 
protocol, will be declared only if the primary endpoint has previously reached statistical 
significance. Subsequent endpoint analyses in the order presented will be declared significant 


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only if the previous endpoint in order has reached statistical significance. All analyses of 
secondary endpoints will also be conducted at the two-sided alpha-level of 0.10. The order of 
secondary endpoint analysis will be the following: the study-specific 6-point ordinal scale; time 
to clinical recovery; reduction in disease symptoms; reduction in oxygen/ventilation 
requirements. 
Tabulations will be produced for appropriate demographic, baseline, efficacy, pharmacokinetic, 
and safety parameters. For categorical variables, summary tabulations of the number and 
percentage of subjects within each category (with a category for missing data) of the parameter 
will be presented. For continuous variables, the number of subjects, mean, median, standard 
deviation (SD), minimum, and maximum values will be presented, as well as 2-sided 95% 
confidence intervals (CIs). Summaries of categorical data will include counts and percentages, 
along with 2-sided 95% CIs. Kaplan Meier methods will be used to summarize the time-to-event 
endpoints, including 25th, 50th (median), and 75th percentiles with associated 2-sided 95% CIs, 
as well as percentage of events and censored observations. 
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. 
9.2 
Sample size justification 
Approximately 50 subjects will be enrolled. The primary endpoint analysis will consist of a log-
rank test of the difference in treatment groups in the time to viral clearance. Based on a recent 
publication: 
(https://www.sciencedirect.com/science/article/pii/S2095809920300631?via%3Dihub) 
it is assumed that the median time to clearance for favipiravir would be approximately 4 days, 
and the median time for SOC would likely be approximately 11 days; this latter estimate may in 
fact be conservative since SOC is not as likely to reduce viral load as well as the control in the 
above referenced study. Using two-sided alpha of 0.10 and power of 90% (appropriate for a trial 
to be used as the justification for a confirmatory, fully-powered blinded and randomized Phase 3 
study), and a fixed per-subject observation period of 15 days, an approximate sample size of 25 
subjects per arm (total size of 50) would be required.  
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: 
• Intent-to-treat (ITT) population – All subjects randomized to treatment. Subjects in the ITT 
population will be analyzed based on the treatment to which they were randomized, 
irrespective of what treatment they actually received. This population was selected for the 
analysis of the primary and secondary endpoints in order to maintain the benefits of 


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randomization and avoid the potential bias associated with the non-random loss of the 
participant. 
• Safety population – All ITT subjects who received either favipiravir + SOC, or SOC alone. 
Subjects in the safety population will be analyzed based on the actual treatment they 
received, irrespective of the treatment to which they were randomized. It is anticipated that 
the safety population will be the same as the ITT population. 
• Modified intent-to-treat (MITT) – All subjects of the safety population that have an 
assessment of viral shedding after randomization and are confirmed COVID-19 positive. 
Subjects in the MITT population will be analyzed based on the treatment to which they were 
randomized, irrespective of what treatment they actually received. 
• Per protocol (PP) population – All MITT subjects who adhere to relevant study procedures 
and have an outcome assessment. Further specific details defining the analyses to be 
performed on this population will be described in the SAP. 
• PK population (PK) – All subjects in the safety population that have at least one result that 
can be used in the PK summaries. 
9.5 
Stratification, Subgroup Analysis and Pooled Analysis 
The stratification factors used in randomization, critical v. severe v. mild/moderate disease as 
defined above based on supplemental oxygen requirements, SpO2 status etc., will be accounted 
for in the efficacy analyses. The stratification factor may be deleted from the statistical model if 
the interaction is not significant at the 0.10 level. Efficacy data will be pooled across study sites 
for analysis, after visual inspection of summary results reveals similarity across study sites. 
Efficacy results may also be summarized within each randomization stratum for exploratory 
purposes. 
9.6 
Efficacy Endpoint Analysis 
The primary endpoint of time to viral clearance will be analyzed with the log-rank test for 
treatment difference and summarized using the Kaplan-Meier methodology as noted above. Viral 
load results from day of discharge as available will also be included in the analysis of viral 
clearance. 
The key secondary endpoint of status of clinical recovery as measured by the study-specific 6-
point ordinal scale at Day 15 will be analyzed using ordinal categorical data methods, since it is 
unlikely that linear differences exist between the elements of the scale (for example, a 1-point 
difference in magnitude may not apply to each increment on the scale). As an exploratory 
analysis, sequential binary analysis will be performed, based on successive classification of a 
subject into categories of less than or greater/equal to each ordinal item on the scale. 
Longitudinal analysis of the 6-point scale over time on study will also be performed to 
investigate temporal patterns of improvement. 
Time to event endpoints will be analyzed using similar methods as used for the primary 
endpoint; these will include time to: clinical recovery; defervescence; cough mild or absent; 
dyspnea mild or absent; SARS-CoV-2 RT-PCR negative in upper respiratory tract. 
Categorical endpoints will be analyzed using categorical data analysis methods; continuous data 
will be analyzed using analysis of variance with treatment and strata as factors. 


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Missing efficacy data in a trial of hospitalized patients is generally unlikely, and great care will 
be taken at each study site to ensure that all outcome assessments are obtained as planned in this 
protocol. However, as treatment of COVID-19 subjects evolves, it is clear some subjects will be 
discharged from the hospital prior to Day 15.  Subjects are asked to return for follow up visits on 
Days 29, 45 and 60.  This requirement is presenting challenges for subjects and in order to 
ensure that in cases where the subject does not return for their follow up visits, an additional 
swabbing has been added on the day of hospital discharge (See Section 7.7).  Should missing 
data occur for the primary endpoint, time to viral clearance, such patients will be included in the 
log-rank analysis as censored observations. Missing clinical outcome data will be evaluated 
using a variety of methods, including multiple imputation, worst-value assignment, and other 
methods, to be completely outlined in the statistical analysis plan. 
9.7 
Safety Analysis 
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 Day 60. 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 RECORDING AND COLLECTION OF DATA 
10.1 Case Report Form 
The Investigator or designee will record all data collected on the electronic Case Report Form 
(eCRF) provided for that purpose. 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. 


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10.2 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. 
10.3 Monitoring 
Due to the restrictions imposed on clinical and hospital visits by the COVID-19 pandemic, all 
monitoring of this study will be conducted remotely. Monitors will work with the Study 
Coordinator at each site to determine times for “joint” remote monitoring – meaning that the 
monitor and the SC will review data together over the telephone. 
Remote 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 
Investigator will cooperate in the monitoring process by ensuring the availability of the eCRFs, 
source documents and other necessary documents at the time of remote monitoring and by 
prompt attention to any matters brought to his/her attention by the monitor. 
10.4 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 
Investigator and 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. 


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10.5 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. 
11 ETHICS 
11.1 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. 
11.2 Subject Information and Consent 
It is the responsibility of the 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 consider whether or not to participate in the study. A copy of the ICF, signed and dated by the 
subject/representative 
and 
the 
Investigator 
(or 
designee), 
must 
be 
given 
to the 
subject/representative. Confirmation of 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. 
12 GENERAL CONSIDERATIONS 
12.1 Discontinuation of the Study 
The Sponsor reserves the right to discontinue the study at any time for any reason. 
12.2 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 


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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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13 SCHEDULE OF ASSESSMENTS 
 
 
 
ASSESSMENT 
HOSPITALIZED 
FOLLOW UP 
Outpatient or Hospitalized 
 
DAY 1 
PRE-DOSE 
DAY 1 
POST-DOSE 
DAY 2 
DAY 3 
DAY 8 
Day 11 
DAY 14 
DAY 15  
(-1 to + up 
to 2 days) 
DAY 29 ±  
2 days 
DAYS 45 
and 60 ±  
2 days8 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 10 
X 
  
  
  
   
  
   
 
 
 
Limited Physical Exam3 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
Review12 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Review of Entry Criteria 
X 
 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, Temp, 
Resp)3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory 
Exams1,2.,9 
X 
 
 
X 
X 
X 
 
X 
X 
 
Blood for antibodies to 
SARS-CoV-2 
X 
 
 
 
 
 
 
X 
X 
 
Blood for PK Sampling 
X4 
X4 
X5 
 X6 
X5 
X6 
X5 
 
 
 
SpO2 by Finger Sensor3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine or Blood Pregnancy 
Test 
 X 
 
 
 
 
 
 
 
 
 
Nasopharyngeal and 
Oropharyngeal Swabs for 
Viral RNA, PCR and 
TCID50 
X 
 
 
X11 
X11 
X11 
 
X 
X 
 
Clinical Status – 6-point 
Ordinal Scale 3 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
National Early Warning 
Score (NEWS2)3 
X 
 
X 
X 
X 
X 
 
X 
X 
X 


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1. Hematology, Chemistry (See Section 8.4). 
2. May use results of labs taken at the hospital as part of SOC if done no more than 24 hours prior. 
3. To be measured every day while hospitalized and at each clinic visit after hospital discharge through Day 60 
a. 
Vital signs  
b. Clinical Status 6-point scale  
c. 
NEWS2 
d. ECOG Performance status  
e. 
Study-specific symptom status  
f. 
Adverse Events  
g. SpO2  
h. Limited PE (heart and lungs) 
4. PK on Day 1 prior to favipiravir dosing and between 45 to 75 minutes post-first dose. 
5. PK trough samples to be taken approximately 30 minutes prior to any dose. 
6. PK peak samples to be taken between 45 to 75 minutes post-dose 
7. Maintenance dose for CP score A is 800 mg BID. 
8. Days 45 and 60 may be completed in the hospital, outpatient clinic, or by phone 
9. Subjects will undergo 9 planned venipunctures. 
10. To be completed by PI or designee 
11. Days 3, 8, 11 Nasopharyngeal and Oropharyngeal Swabs for Viral RNA, PCR and TCID50 may be done +/- 1 day from their scheduled day. Swabs will also 
be obtained on day of discharge from hospital if discharge occurs before Day 15. 
12. To be checked throughout hospitalization and at clinic visits and changes only recorded as applicable. 
 
 
DAY 1 
PRE-DOSE 
DAY 1 
POST-DOSE 
DAY 2 
DAY 3 
DAY 8 
Day 11 
DAY 14 
DAY 15  
(-1 to + up 
to 2 days) 
DAY 29 ±  
2 days 
DAYS 45 
and 60 ±  
2 days8 
ECOG Performance Status3 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Study Specific Symptom 
Status3 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Investigational Product 
Dosing  
 
Favipiravir Dosing Days 1-14 
(1800 mg BID on Day 1000 mg BID Days 2-14)7 
 
 
 
Solicitation of Treatment-
Emergent Adverse Events3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Release from the Study 
 
 
 
 
 
 
 
  
  
X 


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Appendix A: Subject Status Scales 
 
 
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% of 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 
 
Symptom 
Present? Y/N 
Severity: 
Mild, Moderate, Severe 
Feeling Feverish 
 
 
Dyspnea 
 
 
Cough 
 
 
Use of Antibiotic 
 
 
 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
Open Label, Randomized, Controlled Phase 2 Proof-of-Concept Study of the 
Use of Favipiravir Compared to Standard of Care in Hospitalized Subjects 
with COVID-19 
Protocol FAVI-COV-US201 
 
Protocol Number: 
Protocol Version and Date: 
FAVI-COV-US201 
Version 6.0: 15 July 2020 
Name of Test Drug: 
Favipiravir 
Phase: 
Phase 2 
Methodology: 
Open-label, Randomized, Controlled, Proof-of-Concept 
Sponsor: 
FUJIFILM Pharmaceuticals U.S.A., Inc. 
One Broadway, Cambridge, MA 02142 
Sponsor Representative: 
Moriyoshi Maeda 
mmaeda@fujifilm.com 
Sponsor Representative: 
 
Carol Epstein, MD 
Acting Chief Medical Officer 
carol@biologics.com 
+1 617-548-2221 
Analysis Plan Date: 
15 December 2020 
Analysis Plan Version: 
Final Version 3.0 
 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of 
FUJIFILM Pharmaceuticals U.S.A., Inc. and any unauthorized use or disclosure of such 
information without the prior written authorization of FUJIFILM Pharmaceuticals 
U.S.A., Inc. is expressly prohibited. 


FUJIFILM Pharmaceuticals U.S.A., Inc. 
Statistical Analysis Plan, Protocol FAVI-COV-US201 
15 December 2020, Final Version  3.0 
 
CONFIDENTIAL 
2
APPROVAL SIGNATURE PAGE 
Protocol Title: 
Open Label, Randomized, Controlled Phase 2 Proof-of-
Concept Study of the Use of Favipiravir Compared to Standard 
of Care in Hospitalized Subjects with COVID-19 
Sponsor: 
FUJIFILM Pharmaceuticals U.S.A., Inc. 
One Broadway, Cambridge, MA 02142  
USA 
Protocol Number: 
FAVI-COV-US201  
Document Date / Version: 
15 December 2020 / Final Version 3.0 
Veristat, Inc. Author: 
134 Turnpike Road, Suite 200 
Southborough, MA  01772 
Approval Signature 
Job Title 
 
 
 
 


FUJIFILM Pharmaceuticals U.S.A., Inc. 
Statistical Analysis Plan, Protocol FAVI-COV-US201 
15 December 2020, Final Version  3.0 
 
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Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidances and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments.  All changes to the 
planned analyses will be described in the clinical study report. 
Sponsor Signatory: 
FUJIFILM Pharmaceuticals U.S.A., Inc. 
One Broadway, Cambridge, MA 02142  
USA  
 
 
Approval Signature 
Job Title 
 
 


FUJIFILM Pharmaceuticals U.S.A., Inc. 
Statistical Analysis Plan, Protocol FAVI-COV-US201 
15 December 2020, Final Version  3.0 
 
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TABLE OF CONTENTS 
1. 
Information From the Study Protocol ......................................................................... 10 
1.1. 
Introduction and Objectives ............................................................................. 10 
1.1.1. 
Introduction ........................................................................................... 10 
1.1.2. 
Study Objectives ................................................................................... 10 
1.2. 
Study Design ....................................................................................................... 11 
1.2.1. 
Synopsis of Study Design ..................................................................... 11 
1.2.2. 
Randomization Methodology ............................................................... 12 
1.2.3. 
Removal of Subjects from Treatment ................................................... 12 
1.2.4. 
Stopping Rules ...................................................................................... 13 
1.2.5. 
Study Procedures .................................................................................. 13 
1.2.6. 
Efficacy, Pharmacokinetic, and Safety Parameters .............................. 17 
1.2.6.1. Efficacy Parameters ............................................................... 17 
1.2.6.2. Pharmacokinetic Parameters .................................................. 17 
1.2.6.3. Safety Parameters................................................................... 18 
2. 
Subject Population ......................................................................................................... 19 
2.1. 
Population Definitions ....................................................................................... 19 
2.2. 
Protocol Violations ............................................................................................. 19 
3. 
General Statistical Methods .......................................................................................... 20 
3.1. 
Sample Size Justification ................................................................................... 20 
3.2. 
Efficacy Endpoints and Hypothesis Testing .................................................... 20 
3.3. 
General Methods ................................................................................................ 20 
3.4. 
Computing Environment................................................................................... 21 
3.5. 
Baseline Definitions ............................................................................................ 21 
3.6. 
Methods of Pooling Data ................................................................................... 21 
3.7. 
Adjustments for Covariates .............................................................................. 21 
3.8. 
Subpopulations ................................................................................................... 22 
3.9. 
Withdrawals, Dropouts, Loss to Follow-up ..................................................... 22 
3.10. Missing, Unused, and Spurious Data ............................................................... 22 
3.10.1. 
Efficacy Data ........................................................................................ 22 
3.10.2. 
Adverse Event Data .............................................................................. 22 
3.10.3. 
Prior and Concomitant Medication ....................................................... 23 


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3.11. Visit Windows..................................................................................................... 23 
3.12. Interim Analyses ................................................................................................ 24 
4. 
Study Analyses ............................................................................................................... 25 
4.1. 
Subject Disposition............................................................................................. 25 
4.2. 
Demographics and Baseline Characteristics ................................................... 25 
4.3. 
Efficacy Evaluation ............................................................................................ 25 
4.3.1. 
Analysis of the Primary Efficacy Endpoint .......................................... 25 
4.3.2. 
Analysis of Secondary Efficacy Endpoints .......................................... 26 
4.3.2.1. Analysis of Clinical Status via the Study-Specific 6-point 
Ordinal Scale ......................................................................... 26 
4.3.2.1.1. Sensitivity Analysis .................................................27 
4.3.2.2. Time to Clinical Recovery ..................................................... 27 
4.3.2.3. Progression/Reduction in Disease Symptoms ....................... 28 
4.3.2.3.1. Respiratory Progression ..........................................28 
4.3.2.3.2. Time to Defervescence ............................................29 
4.3.2.3.3. Time to Mild/Absent Cough ...................................29 
4.3.2.3.4. Time to Mild/Absent Dyspnea ................................29 
4.3.2.3.5. ECOG Performance Status ......................................29 
4.3.2.4. Analysis of the National Early Warning Score ...................... 29 
4.3.2.5. Reduction in Oxygen/Ventilation Requirements ................... 30 
4.3.2.6. Duration of Supplemental Oxygen, Non-Invasive Ventilation, 
Mechanical Ventilation, ECMO, Hospitalization, and Time in 
ICU ........................................................................................ 30 
4.3.2.7. All-Cause Mortality ............................................................... 31 
4.3.2.8. Time to SARS-CoV-2 TCID50 Negative .............................. 31 
4.3.2.9. Change in SARS-CoV-2 Viral Load...................................... 31 
4.3.2.10. Neutralizing Antibodies ......................................................... 32 
4.4. 
Pharmacokinetic Evaluations ........................................................................... 32 
4.5. 
Safety Analyses ................................................................................................... 32 
4.5.1. 
Study Drug Exposure ............................................................................ 32 
4.5.2. 
Adverse Events ..................................................................................... 33 
4.5.3. 
Laboratory Data .................................................................................... 33 
4.5.4. 
Vital Signs and Physical Examination .................................................. 34 


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4.5.5. 
Prior and Concomitant Medications ..................................................... 34 
5. 
Changes to Planned Analyses ....................................................................................... 35 
6. 
References ....................................................................................................................... 36 
 


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15 December 2020, Final Version  3.0 
 
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TABLES INCLUDED IN THE TEXT 
 
 
Table 1-1 
Schedule of Assessments................................................................................................. 14 
Table 3-1 
Post-Baseline Analysis Visit Designations ..................................................................... 24 
Table 4-1 
Normalization and Alleviation Criteria ........................................................................... 28 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate transaminase 
BCG 
Bacillus Calmette-Guérin 
BID 
Twice daily 
CI 
Confidence interval 
COVID-19 
Coronavirus disease of 2019 
CRF 
Case report form 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECMO 
Extracorporeal membrane oxygenation 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
FCS 
Fully conditional specification 
FiO2 
Fraction of inspired oxygen 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IEC 
Institutional Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LOCF 
Last Observation Carried Forward 
MAR 
Missing at random 
mITT 
Modified intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NEWS2 
National Early Warning Score 2 
PaO2 
Pressure of oxygen 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PMM 
Predicted mean Matching 
PP 
Per protocol 
Rel Day 
Relative study day 
RM ANOVA 
Repeated measures analysis of variance 


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Abbreviation 
Definition 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SD 
Standard deviation 
SOC 
Standard of care 
SpO2 
Oxygen saturation 
TCID50 
Median Tissue Culture Infectious Dose at 50% cell infection 
TEAE 
Treatment-emergent adverse event 
TTCR 
Time to clinical recovery 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 


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1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1. 
Introduction and Objectives 
1.1.1. 
Introduction 
Favipiravir is a small molecule, novel antiviral 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, severe acute respiratory 
syndrome and the novel coronavirus 2 (SARS-CoV-2), the novel coronavirus that causes the 
coronavirus disease of 2019 (COVID-19).  
There is a global pandemic caused by SARS-CoV-2, threatening the lives of many and resulting 
in the need for well-tolerated molecular agents to speed cessation of viral shedding and 
ultimately recovery from COVID-19. SARS-CoV-2 causes disease ranging from mild, cold-like 
symptoms to acute respiratory failure and death. Epidemiologic studies are underway to 
determine whether individuals can be asymptomatic and transmit disease. There is currently no 
available approved treatment for COVID-19. People who have been hospitalized to treat acute 
respiratory symptoms in the US have no proven option other than supportive care, which 
includes mechanical ventilation, oxygen therapy, and treatment of coinfections and organ failure 
if needed. 
Evidence from nonclinical (cell culture) experiments and recently reported clinical experience in 
China indicates that favipiravir may have clinical benefit in subjects infected with SARS-CoV-
2. Prior influenza research indicated faster cessation of viral shedding and faster recovery for 
subjects treated with favipiravir than with placebo control. The safety profile of favipiravir is 
well-established. It is generally safe and well-tolerated except for transient elevations of uric 
acid that resolve with cessation of dosing. 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 subjects with COVID-19 treated with favipiravir as compared to control. Data 
from this trial are expected to support the planning and execution of a larger study to 
demonstrate clinical benefit. The information gathered from this study will also help define the 
safety profile of favipiravir during the global pandemic and enable expansion into other subject 
populations such as those who have been exposed but who are not yet ill. 
1.1.2. 
Study Objectives 
The primary objective of this study is to determine the effect of favipiravir plus standard of care 
(SOC) vs SOC on viral clearance.  
The secondary objectives of the study are as follows: 
• To determine the clinical benefit of administering favipiravir plus SOC compared to 
SOC alone (assessed using a study-specified 6-point ordinal scale adapted from the 


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World Health Organization [WHO] Master Protocol [V2.0 24FEB20] COVID-19 7-
point ordinal scale) in adult subjects hospitalized with COVID-19. 
• To determine if the treatment effect on the 6-point ordinal scale, on Day 15, is 
reasonably likely to reflect clinical benefit such that it can be used as the primary clinical 
outcome endpoint in a similar study that is double-blinded, by assessment of the 
relationship of the scale to changes in clinical and symptom outcomes, including time to 
clinical recovery, occurrence of fever, cough, dyspnea, reduction in oxygen 
requirements, and other measures. 
• To explore the clinical effect of favipiravir + SOC vs SOC as measured by the National 
Early Warning Score 2 (NEWS2) system. 
• To determine the safety of favipiravir plus SOC compared to SOC alone in this 
population. 
• To explore the pharmacokinetics (PK) of this dose regimen of favipiravir in this subject 
population. 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objective(s). Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided. The statistical analyses 
and summary tabulations described in this SAP will provide the basis for the results sections of 
the clinical study report (CSR) for this trial. 
This SAP will also outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 
1.2. 
Study Design 
1.2.1. 
Synopsis of Study Design 
This study is an open label, randomized, SOC-controlled, multicenter Phase 2 study of 
favipiravir in hospitalized subjects with COVID-19. Subjects will be randomized within their 
study site and stratified by the severity of disease to receive either favipiravir + SOC or SOC 
alone.  
Standard of care will be site-specific and based on what each site is currently using for treatment 
of hospitalized COVID-19 patients.  
The dose regimen will be 1800 mg favipiravir twice daily (BID) plus SOC or SOC alone on 
Day 1 followed by 1000 mg BID favipiravir (800 mg BID for subjects with Child-Pugh A liver 
impairment) plus SOC or SOC for the next 13 days.  
Subjects are planned to have 14 days of treatment and 46 days of follow-up. 


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1.2.2. 
Randomization Methodology 
Subjects will be evaluated for eligibility during Day 1, prior enrollment in the study or starting 
treatment. The randomization procedure will be performed centrally using the electronic data 
capture (EDC) system, IBM Clinical Development.  
Approximately 50 subjects are planned to be randomized at a 1:1 ratio to receive either 
favipiravir + SOC or SOC alone. Randomization will be stratified by site and severity of illness 
at enrollment. Severity of illness at enrollment will be graded (i.e., critical disease, severe 
disease, or mild//moderate disease) as follows: 
• Critical disease: 
o Requires supplemental oxygen delivered by non-rebreather mask or high-flow 
cannula, OR 
o Requires use of invasive or non-invasive ventilation, OR 
o Requires treatment in an intensive care unit, use of vasopressors, extracorporeal life 
support (i.e., extracorporeal membrane oxygenation [ECMO]). 
• Severe disease: 
o Evidence of pneumonia on chest x-ray or computed tomography (CT) scan, or chest 
auscultation (rales, crackles), OR 
o Peripheral capillary oxygen saturation (SpO2) ≤ 93% on room air OR partial 
pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) < 300 mmHg, OR 
o Requires supplemental oxygen by nasal canula, simple face mask, or other similar 
oxygen delivery device. 
• Mild/moderate disease: SpO2 > 94% and respiratory rate ≤ 24 breaths/min without 
supplemental oxygen 
The randomization will target balance within stratum. This does not guarantee balance overall; 
however, utilizing a block size of 2, as well as with sufficient sample size within strata, balance 
will be approximately maintained while pooling across sites.  
1.2.3. 
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. 


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• The subject is withdrawn at the discretion of the Investigator for medical reasons or non- 
compliance. 
1.2.4. 
Stopping Rules 
A subject should be removed from favipiravir treatment if one of the following criteria is met:  
• Alanine transaminase (ALT) or aspartate transaminase (AST) > 8 × upper limit of 
normal (ULN) 
• ALT or AST > 3 × ULN AND total bilirubin > 2 × ULN 
• ALT or AST > 3 × ULN AND subject has right upper quadrant pain or eosinophilia 
• Uric acid >20 mg/dL 
A subject whose treatment is terminated should remain in the study for appropriate follow-up 
assessments. 
1.2.5. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1-1. 
 


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Table 1-1 
Schedule of Assessments 
ASSESSMENT 
HOSPITALIZED 
FOLLOW-UP 
Outsubject or Hospitalized 
 
DAY 1 
PRE-DOSE 
DAY 1 
POST-DOSE 
DAY 2 
DAY 3 
DAY 8 
Day 11 
DAY 14 
DAY 15 + 
(-1 to + up 
to 2 days 
DAY 29 ±  
2 days 
DAY 45 
and 60 ± 2 
days8 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical/Surgical 
History 
X 
 
 
 
 
 
 
 
 
 
Physical Exam10 
X 
 
 
 
 
 
 
 
 
 
Limited Physical 
Exam3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications Review12 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Review of Entry 
Criteria 
X 
 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, 
Temp, Resp)3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory 
Exams1,2,9 
X 
 
 
X 
X 
X 
 
X 
X 
 
Blood for antibodies to 
SARS-CoV-2 
X 
 
 
 
 
 
 
X 
X 
 
Blood for PK Sampling 
X4 
X4 
X5 
X6 
X5 
X6 
X5 
 
 
 
SpO2 by Finger Sensor3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine or Blood 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
Nasopharyngeal and 
Oropharyngeal Swabs 
for Viral RNA, PCR 
X 
 
 
X11 
X11 
X11 
 
X 
X 
 


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ASSESSMENT 
HOSPITALIZED 
FOLLOW-UP 
Outsubject or Hospitalized 
 
DAY 1 
PRE-DOSE 
DAY 1 
POST-DOSE 
DAY 2 
DAY 3 
DAY 8 
Day 11 
DAY 14 
DAY 15 + 
(-1 to + up 
to 2 days 
DAY 29 ±  
2 days 
DAY 45 
and 60 ± 2 
days8 
and TCID50 
Clinical Status – 6-
point Ordinal Scale3 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
National Early Warning 
Score (NEWS2)3 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
ECOG Performance 
Status3 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Study Specific 
Symptom Status3 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Investigational Product 
Dosing 
 
Favipiravir Dosing Days 1-14 
(1800mg BID on Day 1000mg BID Days 2-14)7 
 
 
 
Solicitation of 
Treatment-Emergent 
Adverse Events3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Release from the Study 
 
 
 
 
 
 
 
 
 
X 
1. Hematology, Chemistry (See Protocol Section 8.4).  
2. May use results of labs taken at the hospital as part of SOC if done no more than 24 hours prior.  
3. To be measured every day while hospitalized and at each clinic visit after hospital discharge through Day 60  
 
a. Vital signs 
 
b. Clinical Status 6-point scale 
 
c. NEWS2 
 
d. ECOG Performance status 
 
e. Study-specific symptom status 
 
f. Adverse Events 
 
g. SpO2 
 
h. Limited PE (heart and lungs) 
4. PK on Day 1 prior to favipiravir dosing and between 45 to 75 minutes post-first dose.  


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5. PK trough samples to be taken approximately 30 minutes prior to any dose.  
6. PK peak samples to be taken between 45 and 75 minutes post-dose. 
7. Maintenance dose for CP score A is 800mg BID.  
8. Days 45 and 60 may be completed in the hospital, outsubject clinic or by phone. 
9. Subjects will undergo 9 planned venipunctures. 
10. To be completed by PI or designee. 
11. Days 3, 8, 11 Nasopharyngeal and Oropharyngeal Swabs for Viral RNA, PCR, and TCID50 may be done +/- 1 day from their scheduled day. Swabs will also be obtained on 
day of discharge from hospital if discharge occurs before Day 15. 
12. To be checked throughout hospitalization and at clinic visits and changes only recorded as applicable. 
 
 


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1.2.6. 
Efficacy, Pharmacokinetic, and Safety Parameters 
1.2.6.1. 
Efficacy Parameters 
Efficacy will be measured through the following parameters: 
For Primary Endpoint: 
• PCR in the nasopharyngeal and oropharyngeal samples taken on Days 1, 3, 8, 11, 15 and 
29. Swabs will also be obtained on day of discharge from hospital if discharge occurs 
before Day 15. 
For Secondary Endpoint:  
• Clinical improvement of hospitalized subjects with COVID-19 receiving either 
favipiravir + SOC or SOC alone as defined by the following study-specific 6-point 
ordinal scale assessed daily while hospitalized and at each outpatient visit until Day 60.. 
1. Not hospitalized  
2. Hospitalized, not requiring supplemental oxygen  
3. Hospitalized, requiring supplemental oxygen  
4. Hospitalized, on non-invasive ventilation or high flow oxygen devices  
5. Hospitalized, on invasive mechanical ventilation or ECMO  
6. Death  
• NEWS2 assessed daily while hospitalized and at each outpatient visit until Day 60.   
• Vital signs (BP, HR, RR, BT, SpO2) measured daily while hospitalized and at each 
outpatient visit until Day 60.   
• Patient status assessed daily while hospitalized and at each outpatient visit until Day 60 
via Study-specific Symptom Status and ECOG Performance Status questionnaires 
• Period of each respiratory assistance (if applicable).  
• Period of hospitalization.  
• Period of intensive care unit (if applicable). 
• Date and cause of death (if applicable).  
• TCID50 in nasopharyngeal and oropharyngeal swabs on Days 1, 3, 8, 11, 15 and 29. 
Swabs will also be obtained on day of discharge from hospital if discharge occurs before 
Day 15. 
Note: Since TCID50 for SARS-CoV-2 is not yet proven to be sensitive for detection 
of the virus and is still under development for that purpose, analyses using TCID50 
will not be conducted if TCID50 for SARS-CoV-2 is not detectable enough. 
• Blood for determination of antibodies to SARS-CoV-2 obtained on Days 1, 15 and 29.  
1.2.6.2. 
Pharmacokinetic Parameters 
The PK measurement in blood samples taken on Days 1, 2, 3, 8, 11 and 14.  


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1.2.6.3. 
Safety Parameters 
Abnormal clinical laboratory values that are clinically significant and all reported adverse 
events (AEs) will be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. 
Safety will be assessed by the following: 
• Observed and reported AEs (including solicited and unsolicited events)  
• Hematology and chemistry laboratories on Days 1, 3, 5, 8, 11, 15 and 29; if coagulation 
laboratory assays are ordered as part of the SOC, the results will be recorded 
• Limited physical examination assessed daily while hospitalized and at each outpatient 
visit until Day 60. 
 
 
 


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2. 
SUBJECT POPULATION 
2.1. 
Population Definitions 
The following subject populations will be evaluated and used for presentation and analysis of 
the data: 
• Intent-to-treat (ITT) population – All subjects randomized to treatment. Subjects in the 
ITT population will be analyzed based on the treatment to which they were randomized, 
irrespective of what treatment they actually received. This population was selected for 
the analysis of the primary and secondary endpoints in order to maintain the benefits of 
randomization and avoid the potential bias associated with the non-random loss of the 
participant.  
• Safety population – All ITT subjects who received either favipiravir + SOC or SOC 
alone. Subjects in the safety population will be analyzed based on the actual treatment 
they received, irrespective of the treatment to which they were randomized. It is 
anticipated that the safety population will be the same as the ITT population.  
• Modified intent-to-treat (mITT) – All subjects of the ITT population that have a post-
baseline assessment of viral shedding and at least one PCR positive result for SARS-
CoV-2 in any protocol-required swab samples. Note that results recorded as less than the 
lower limit of quantification (LLOQ) are considered to be negative. Subjects in the 
mITT population will be analyzed based on the treatment to which they were 
randomized, irrespective of what treatment they actually received. 
• Per protocol (PP) population – All mITT subjects who adhere to relevant study 
procedures (i.e. have no major protocol deviation that would be expected to affect 
efficacy assessments) and have an outcome assessment.  
• PK population (PK) – All subjects in the safety population that have at least one result 
that can be used in the PK summaries.  
The ITT population is the primary population for the analysis of efficacy parameters; the mITT 
and PP populations will be used for supportive inferences concerning efficacy. The PK 
population is the primary population for the analysis of PK parameters. The Safety population is 
the primary population for the analysis of safety endpoints. 
2.2. 
Protocol Violations 
All protocol violations will be presented in a data listing. 


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3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
Approximately 50 subjects will be enrolled. The primary endpoint analysis will consist of a log-
rank test of the difference in treatment groups in the time to viral clearance. Based on a recent 
publication  
(https://www.sciencedirect.com/science/article/pii/S2095809920300631?via%3Dihub),  
it is assumed that the median time to clearance for favipiravir would be approximately 4 days, 
and the median time for placebo would likely be approximately 11 days. This latter estimate 
may be conservative since SOC is not as likely to reduce viral load as well as the control in the 
above referenced study. Using two-sided alpha of 0.10 and power of 90% (appropriate for a trial 
to be used as the justification for a confirmatory, fully-powered, blinded and randomized Phase 
3 study), and a fixed per-subject observation period of 15 days, an approximate sample size of 
25 subjects per arm (total size of 50) is required.  
3.2. 
Efficacy Endpoints and Hypothesis Testing 
The primary efficacy endpoint is time to viral clearance by PCR, measured on Days 1, 3, 8, 11 
(while hospitalized); and days 15 and 29 (if able to return to clinic or still hospitalized). 
Contrary to what is included in the study protocol, the hierarchical testing of key secondary 
endpoints will not be performed. For more information please refer to Section 5.  
All analyses will be conducted at the two-sided alpha-level of 0.10. P-values for all analyses 
other than the primary efficacy endpoint will be presented for the purposes of ‘descriptive 
significance’ only. 
3.3. 
General Methods 
All data listings that contain an evaluation date will contain a relative study day (Rel Day). 
Pre-treatment and on-treatment study days are numbered relative to the day of the first dose of 
study medication which is designated as Day 1.  The preceding day is Day -1, the day before 
that is Day -2, etc.  
All output will be incorporated into Microsoft Word, or Adobe Acrobat PDF files, sorted and 
labeled according to the International Council for Harmonisation (ICH) recommendations, and 
formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, PK, and safety 
parameters. For categorical variables, summary tabulations of the number and percentage of 
subjects within each category (with a category for missing data) of the parameter will be 
presented along with 2-sided 90% confidence intervals (CIs). For continuous variables, the 
number of subjects, mean, median, standard deviation (SD), minimum, and maximum values 
will be presented, as well as 2-sided 90% CIs. Time-to-event data will be summarized using 
Kaplan-Meier methodology using 25th, 50th (median), and 75th percentiles with associated 2-


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sided 90% CIs, as well as percentage of censored observations. Where appropriate, p-values will 
be reported. 
Assuming raw or derived variables are to ‘x’ decimal places, the data will be presented as 
follows: 
• Range to x decimal places 
• Mean and median to (x+1) decimal places 
• SD to (x+2) decimal places 
• (x+2) should not be greater than 4 decimal places 
• percentages may be calculated without a decimal place or with (x+1) decimal place 
Formal statistical hypothesis testing will be performed on the primary and secondary efficacy 
endpoints as described in Section 4 with all tests conducted at the 2-sided, 0.10 level of 
significance.  
Data will be presented by subject and summarized by treatment group.   
3.4. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software Version 9.4, 
unless otherwise noted. Medical history and adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) Version 23.0. Concomitant medications will be 
coded using the WHO Drug Dictionary Version March 2020. 
3.5. 
Baseline Definitions 
For all analyses, baseline will be defined as the most recent measurement prior to the first 
administration of study drug for patients on favipiravir. For patients on SOC, baseline will be 
defined as the closest (either before or after) measurement to randomization. 
For the purpose of time-to-event analyses, treatment start date is used as the origin point for 
patients on favipiravir, while randomization date is used for patients on SOC.  
3.6. 
Methods of Pooling Data 
Efficacy data will be pooled across study sites for analysis.  
3.7. 
Adjustments for Covariates 
For the analyses of durations of supplemental oxygen, non-invasive/mechanical ventilation, 
Extracorporeal Membrane Oxygenation (ECMO), hospitalization, and ICU, baseline SpO2 level 
will act as a covariate in all analysis of covariance (ANCOVA) models. Disease severity, as 
defined in Section 1.2.2, will be accounted for in all efficacy analyses. Other factors may be 
accounted for if deemed relevant. 


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3.8. 
Subpopulations 
Subgroup analyses on dexamethasone usage (Yes/No) will be performed on the primary 
efficacy analyses, as well as on select secondary efficacy analyses. Other subgroups of interest 
may be analyzed for exploratory purposes.  
3.9. 
Withdrawals, Dropouts, Loss to Follow-up 
Subjects who are withdrawn or discontinue from the study will not be replaced. 
3.10. 
Missing, Unused, and Spurious Data 
3.10.1. 
Efficacy Data 
Should missing data occur for time-to-event endpoints, such subjects will be included in the log-
rank analysis as censored observations as specified in Section 4.3.1. 
Missing clinical outcome data for secondary efficacy endpoints (other than time-to-event) will 
be handled by a multiple imputation model that contains the following variables: baseline and 
post-baseline parameter values, and disease severity, stratified by treatment group. Imputation 
of missing data will be conducted under a working assumption of missing at random (MAR), 
meaning that the propensity for a data point to be missing is not related to the missing data, but 
it is related to some of the observed data.  
The imputations will be performed for post-baseline visits. The Fully Conditional Specification 
(FCS) method will be used, given its natural handling of both ordinal and nominal variables 
(Liu & De 2015). Predicted Mean Matching (PMM) (using a linear prediction model to obtain 
predicted values and k=5 for randomly drawing from kth nearest observed values to the predicted 
value) will be implemented under FCS (Schenker & Taylor 1996). One hundred (100) datasets 
will be imputed in order to estimate the treatment effect, where the median value across the 
imputed datasets will be used for subjects with missing endpoints. 
3.10.2. 
Adverse Event Data 
When tabulating AE data, partial start dates will be handled as follows: 
• If the year, month, and day are all missing, then set the onset day to the date of the first 
dose. 
• If the month and day are missing, and the year is: 
o the same as the year of first dose, then set the onset day as the first day of 
the month of the first dose; 
o earlier than the year of first dose, then set the onset day as December 31; 
o after the year of the first dose, then set the onset day as January 1. 


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• If only the day is missing, then 
o if the month/year is the same as the first dose, then set the onset day as 
the date of first dose; 
o if the month/year is earlier than the month/year of the first dose, then set 
the onset day as the last day of the month; 
o if the month/year is later than the month/year of the first dose, then set the 
onset day as the first day of the month. 
Partial end dates will only be imputed if the year is non-missing: 
• If the month and day are missing, and the year is the same as the year of the last dose 
then set the end day as the last day of the month of the first dose. Otherwise, set the end 
date as December 31. 
• If only the day is missing, then set the end day as the last day of the month. 
If the imputed start date is later than the imputed end date then set the imputed start date to the 
imputed end date. 
3.10.3. 
Prior and Concomitant Medication 
When tabulating prior/concomitant medication data, partial start dates will be handled as 
follows: 
• If the year, month, and day are all missing, then set the start date to the date of first dose. 
• If the month and day are missing and the year is earlier than the year of the first dose, 
then set the start date to December 31. Otherwise, set the start date to January 1. 
• If only the day is missing, if the month/year is earlier than the month/year of the first 
dose then set the start date to the first day of the month. Otherwise, set the start date to 
the last day of the month. 
Partial end dates will only be imputed if the year is non-missing: 
• If the month and day are missing then set the end date to December 31. 
• If only the day is missing, then set the end day as the last day of the month. 
If the imputed start date is later than the imputed end date then set the imputed start date to the 
imputed end date. 
3.11. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. However, analysis 
visits will be derived based on study day for all by-visit summaries and analyses. Analysis visit 
designations are detailed in Table 3-1. 


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Table 3-1 
Post-Baseline Analysis Visit Designations  
Analysis Visit 
Analysis Visit 
Range 
Day 1 
Day 1 
Day 2 
Day 2 
Day 3 
Days 3-5 
Day 8 
Days 6-9 
Day 11 
Days 10-12 
Day 15 
Days 13-17 
Day 21 
Days 18-24 
Day 29 
Days 25-33 
Day 45 
Days 34-52 
Day 60 
Days 53-70 
In the event there are multiple assessments within a given analysis range, the value closest to the 
target day (understood to be the day identified in the analysis visit) will be chosen. If more than 
one measurement are the same distance from the target day, the earlier visit will be chosen.  
In data listings, the relative day of all dates will be presented.  
3.12. 
Interim Analyses 
No interim analyses are planned for this study. 


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4. 
STUDY ANALYSES 
4.1. 
Subject Disposition 
Subject disposition will be tabulated by treatment group and include the number randomized, 
the number treated, the number in each population for analysis, and the number who completed 
the treatment (who reached Day 14 for SOC alone), the number who completed the study (i.e., 
reached Day 29 visit), and the number who discontinued treatment and discontinued study and 
reason(s) for withdrawal.  
A by-subject data listing of treatment and study completion information including the reason for 
treatment discontinuation and study discontinuation, if applicable, will be presented. 
4.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be tabulated by treatment group. Age (years), 
race, gender, ethnicity, and smoking status use will be summarized using descriptive statistics. 
In addition, the number of subjects with Child-Pugh A liver impairment, and the number of 
patients who received a bacillus Calmette-Guérin (BCG) vaccine will be provided. Baseline 
disease characteristics will also be summarized; these include the number of subjects in each 
stratification level (based on disease severity), the number of subjects who require each type of 
respiratory assistance, the number of subjects who had antibodies to SARS-CoV-2 at baseline, 
SpO2 at baseline, and days from symptom onset, from PCR positivity, and from start of 
hospitalization to randomization. Demographic and baseline data for each subject will be 
provided in data listings. 
Medical history will be coded using MedDRA v23.0 and presented by system organ class and 
preferred term by treatment group. If a subject had more than one medical history event within a 
system organ class, the subject is counted once for each preferred term and once for the system 
organ class. Medical history data will also be provided in by-subject listings. 
Demographic and baseline characteristics summary tabulations will be produced for the ITT 
population.  
4.3. 
Efficacy Evaluation 
4.3.1. 
Analysis of the Primary Efficacy Endpoint 
The primary endpoint of time to viral clearance will be analyzed with the log-rank test for 
treatment difference based on a two-sided alpha-level of 0.10 and summarized using Kaplan-
Meier methodology. The time to viral clearance (in days) is defined as the time of Negative or 
Lower Limit of Quantification (LLOQ) results (without any quantitative results after that) as 
measured by PCR for SARS-CoV-2 via scheduled nasopharyngeal and oropharyngeal swab 
samples minus the date of first dose + 1.  
Subjects who have no evidence of viral clearance will be censored at the time of the last PCR 
measurement with the following conditions: 


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• Patients whose symptoms worsen (defined as an increase of ≥ 1 point on the 6-point 
Ordinal Scale from baseline) on the day of the last PCR measurement, or who die 
will be censored at Day 29, 
• Patients who are lost to follow-up will be censored on the day of the last PCR 
measurement. 
 
The median time to viral clearance will be estimated based on the Kaplan-Meier estimator; 
additional summary statistics will be presented, including the 25th and 75th percentiles, 90% CIs 
(the log-log transformation) on the median and other percentiles and proportion of censored 
subjects. Viral clearance rates at Days 3, 8, 11, 15, and 29 will also be presented.  
The analysis of the primary efficacy endpoint will be done using the ITT population.  
The primary analysis will be supplemented with a sensitivity analysis, using a stratified log-rank 
test, where the treatment difference based on a two-sided alpha-level of 0.10 will be 
summarized and stratified by disease severity. 
The analysis will also be repeated by the dexamethasone usage subgroup, where patients will be 
categorized as having received dexamethasone if they received it at any time prior to the last 
viral clearance assessment.  
Kaplan-Meier curves will be provided for the overall ITT population. By-subject data listings of 
viral clearance data will also be provided. 
4.3.2. 
Analysis of Secondary Efficacy Endpoints 
4.3.2.1. 
Analysis of Clinical Status via the Study-Specific 6-point Ordinal Scale  
The first secondary endpoint of clinical status as measured by the study-specific 6-point ordinal 
scale at Day 15 will be analyzed by fitting a cumulative odds model, using the most appropriate 
approach. Clinical status will be modelled as the dependent variable (ordered from 1 to 6, as 
defined in Section 1.2.6.1), and treatment group and disease severity as independent variables; 
other factors may be added for exploratory purposes. Subjects with missing Day 15 data will 
have their clinical status imputed in the following manner: 
1) If patients were discharged prior to Day 15, then their clinical status will be imputed to 
‘Not Hospitalized’ at Day 15 
2) If patients died prior to Day 15, then their clinical status will be imputed to ‘Death’ at 
Day 15 
3) If there is no evidence of hospital discharge or death, clinical status at Day 15 will be 
imputed using the multiple imputation method described in Section 3.10.1 


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The odds ratios and their 90% CI will be provided. As described in Section 3.2, a test at the two-
sided alpha level of 0.10 will be performed for descriptive purposes.  
Longitudinal analysis of the 6-point scale over time at each visit will be performed in a similar 
manner. Clinical status will be modelled as the dependent variable and treatment group, disease 
severity, visit, and the visit/treatment group interaction term as independent variables. The 
overall treatment odds ratio and their 90% CI will be provided, along with by-visit odds ratios 
and 90% CI.  
Analyses using the study-specific 6-point scale will be done using the ITT population.  
The analysis will also be repeated by the dexamethasone usage subgroup, where patients will be 
categorized as having received dexamethasone if they received it at any time prior the Day 15 
analysis visit assessment.  
 
Stacked bar charts over time will be generated to graphically display the proportion of patients 
in each level of the 6-point scale by treatment group for the ITT population. 
 
By-subject data listings will be provided. 
 
4.3.2.1.1. Sensitivity Analysis 
The following sensitivity analyses are planned for supportive inference using the ITT 
population: 
1) The status of clinical recovery at Day 15 analysis will be repeated using the single 
imputation method of Last Observation Carried Forward (LOCF) rather than the 
multiple imputation approach described in Section 3.10.1 
2) Clinical status will be dichotomized over time, where subjects will be classified as either 
improved (Yes) or declined/no change (No) based on the 6-point scale result from the 
baseline visit. Subjects who are discharged or deceased over time will not contribute to 
subsequent timepoints. The treatment effect will be analyzed via generalized linear 
mixed models using SAS PROC GLIMMIX, with improvement in clinical status 
(yes/no) as the dependent variable, and treatment group, disease severity, and visit as 
independent variables. Least-squares means of the treatment group effect on the logit 
scale (difference on the log odds) will be utilized for analysis, where the odds ratio and 
corresponding 90% CI will be provided  
4.3.2.2. 
Time to Clinical Recovery  
The time to clinical recovery (TTCR) assessed up to 29 days will be analyzed in a similar 
manner as the primary efficacy endpoint. TTCR is defined as the time (in days) from initiation 
of study treatment (favipiravir + SOC or SOC alone) until normalization of fever, respiratory 
rate, oxygen saturation, and alleviation of cough, sustained for at least 72 hours; or hospital 
discharge. The normalization and alleviation criteria are presented in Table 4-1.  


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Table 4-1 
Normalization and Alleviation Criteria 
Parameter 
Criteria 
Fever 
≤37.2 ºC 
Respiratory Rate 
≤24 breaths/minute on room air 
Oxygen Saturation 
SpO2 > 94% on room air 
Cough 
Mild or absent on a subject-reported scale of severe, moderate, mild, absent 
Subjects with no evidence of clinical recovery will be censored at last assessment of the 
parameter that is not be recovered. The censoring rules as provided in Section 4.3.1 will also be 
employed. In addition, if a subject achieves TTCR and then discontinues from the study during 
the 72 hour confirmation period, it will be censored at the discontinuation. If a subject achieves 
TTCR and then discharge, it will be confirmed as recovered at the time of achieving TTCR. 
The difference between treatment groups will be analyzed using a log-rank test at the two-sided 
alpha level of 0.10, where the p-value will be presented for descriptive purposes (and using a 
stratified log-rank test by disease severity as a sensitivity analysis). 
Analyses of TTCR will be done on the ITT population. Only patients with at least one abnormal 
result (among the four symptoms listed in Table 4-1) at baseline (or within 72 hours post 
baseline) will be included in the analysis. 
Kaplan-Meier curves will be provided for the overall ITT population. By-subject data listings 
will also be provided. 
In addition, the analysis will be performed with stratification by disease severity. 
The analysis will also be repeated by the dexamethasone usage subgroup, where patients will be 
categorized as having received dexamethasone if they received it at any time prior to the last 
assessments of normalization and alleviation criteria.  
4.3.2.3. 
Progression/Reduction in Disease Symptoms  
All the analyses below will be done on the ITT population with the same methodology as the 
analysis of time to clinical recovery in Section 4.3.2.2.  
The analyses of time to defervescence, mild/absent cough, and mild/absent dyspnea will also be 
performed stratified by disease severity.  
In addition to the specified analyses, all data will be provided via by-subject data listings.  
4.3.2.3.1. Respiratory Progression 
The frequency of respiratory progression as assessed up to Day 29 will be tabulated by 
treatment group. Respiratory progression is defined as: 
SpO2 ≤94% on room air or PaO2/FiO2 < 300 mmHg, and 


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a. Requirement for supplemental oxygen, or 
b. More advanced ventilator support  
The treatment effect will be analyzed via generalized linear mixed models using SAS PROC 
GLIMMIX, with respiratory progression (Yes/No) as the dependent variable, and treatment 
group, disease severity, age (in years), and visit as independent variables. Least-squares means 
of the treatment group effect on the logit scale (difference on the log odds) will be presented, 
along with a 90% CI and a descriptive p-value from a two-sided alpha-level test. 
4.3.2.3.2. Time to Defervescence 
Summary statistics of time to defervescence assessed up to 29 days, if possible, will be 
presented by treatment group. Time to defervescence is defined as the time (in days) from 
initiation of study treatment (favipiravir + SOC or SOC alone) until normalization of fever, 
described as an oral temperature ≤37.2 ºC, or discharge. Only subjects with fever at study entry 
or within the first 72 hours will contribute to this analysis.  
A Kaplan-Meier curve will be provided for the overall ITT population, where subjects will be 
censored at the last assessment of the parameter if no defervescence is observed. 
4.3.2.3.3. Time to Mild/Absent Cough 
Time to mild/absent cough will be analyzed in a similar fashion to time to defervescence. Only 
subjects with reported moderate or severe cough at study entry or within the first 72 hours will 
contribute to this analysis. Subjects will be censored at the last assessment of the parameter if no 
mild/absent cough is observed. 
4.3.2.3.4. Time to Mild/Absent Dyspnea 
Time to mild/absent dyspnea will be analyzed in a similar fashion to time to defervescence. 
Only subjects with reported moderate or severe dyspnea at study entry or within the first 72 
hours will contribute to this analysis. Subjects will be censored at the last assessment of the 
parameter if no mild/absent dyspnea is observed. 
4.3.2.3.5. ECOG Performance Status 
ECOG performance status will be tabulated over time by treatment group.   
4.3.2.4. 
Analysis of the National Early Warning Score  
The time to aggregate NEWS2 score of ≤ 2 (sustained for at least 72 hours) or hospital 
discharge will be analyzed up to Day 29 in a similar manner as the time to TTCR described in 
Section 4.3.2.2. Only patients with a score >2 at baseline or within 72 hours post baseline will 
contribute to the analysis. Subjects will be censored at last assessment of the parameter if there 
are no events of ≤ 2 aggregate scores. The censoring rules as provided in Section 4.3.1 will also 
be employed. In addition, if a subject achieves the event and then discontinues from the study 


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during the 72-hour confirmation period, it will be censored at the discontinuation. If a subject 
achieves the event and then discharge, it will be confirmed as reach the event at the time of 
aggregate NEWS2 score of ≤ 2; Kaplan-Meier curves will be provided for the overall ITT 
population. 
In addition, the analysis will be performed with stratification by disease severity. 
Additionally, descriptive statistics of mean changes from baseline in aggregate NEWS2 scores 
to post-baseline visits will be provided by treatment group. This analysis will be performed 
using the ITT population. Only patients with at least one-post baseline measurement will be 
included. 
By-subject data listings will be provided. 
4.3.2.5. 
Reduction in Oxygen/Ventilation Requirements 
The frequency of requirement for any supplemental oxygen or ventilation (non-invasive, 
mechanical, or ECMO), as assessed daily up to 29 days and on Day 45 and 60, if possible, will 
be analyzed in a similar fashion as respiratory progression in Section 4.3.2.3.1.  
In addition, the frequency of requirement for any ventilation requirement (non-invasive, 
mechanical or ECMO) and either mechanical ventilation or ECMO will be analyzed in the same 
manner as above.  
The analyses on oxygen/ventilation requirements will be performed using the ITT population. 
4.3.2.6. 
Duration of Supplemental Oxygen, Non-Invasive Ventilation, Mechanical 
Ventilation, ECMO, Hospitalization, and Time in ICU 
The total duration (in days) of any respiratory assistance (supplemental oxygen, non-invasive 
ventilation, mechanical ventilation, ECMO), hospitalization, and ICU will be analyzed using an 
ANCOVA model, investigating the difference in means between the treatment groups. The 
difference in mean durations between treatment groups will be provided, along with 90% CI. 
All durations are counted from randomization. In addition, the total time on any ventilation 
assistance (non-invasive/mechanical ventilation, ECMO), and either mechanical ventilation or 
ECMO will be analyzed using an ANCOVA model as above. 
The exact duration will be counted. But, it was initiated prior to study enrollment, duration will 
be calculated from treatment start date for patients on favipiravir and randomization date for 
patients on SOC. The maximum value of these durations will not exceed 60 days  
The analyses above will be performed using the ITT population. 
Box plots for the total duration of any respiratory assistance and hospitalization will be provided 
by treatment group. By-subject data listings for each parameter will also be provided. 


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4.3.2.7. 
All-Cause Mortality 
All-cause mortality will be analyzed by investigating the relationship between all-cause 
mortality and treatment group. An adjusted relative risk analysis will be done using a stratified 
Cochran-Mantel-Haenszel test; the cross-tabulation of all-cause mortality and treatment group 
will be stratified by disease severity. The adjusted relative risk will be provided, along with a 
90% CI. 
All-cause mortality will be analyzed using the ITT population. 
A by-subject data listing will be provided.  
4.3.2.8. 
Time to SARS-CoV-2 TCID50 Negative 
Time to SARS-CoV-2 TCID50 negative in upper respiratory tract will be analyzed in a similar 
fashion as the primary efficacy endpoint. Time to SARS-CoV-2 TCID50 negative is defined as 
the time (in days) from initiation of study treatment (favipiravir + SOC or SOC alone) until a 
negative assessment in upper respiratory tract specimen.  
Time to SARS-CoV-2 TCID50 negative will be performed on the mITT population. 
Note: Since TCID50 for SARS-CoV-2 is not yet proven to be sensitive for detection of the virus 
and is still under development for that purpose, analyses using TCID50 will not be conducted if 
TCID50 for SARS-CoV-2 is not detectable enough. 
4.3.2.9. 
Change in SARS-CoV-2 Viral Load 
The change in SARS-CoV-2 viral load in upper respiratory tract specimen as assessed by area 
under viral load curve (quantitative PCR) as assessed up to 29 days. The area under the curve 
(AUC) over time for a given subject will be calculated, using the linear trapezoidal rule, as the 
sum of the maximum viral load for each day up through Day 29. Lower Limit of Quantification 
(LLOQ) result is considered as negative. An analysis of treatment group differences will be 
performed on the change in viral load using ANOVA model, with treatment group and disease 
severity as fixed factors.  
The change in SARS-CoV-2 viral load will be analyzed by comparing the change between 
treatment groups using a mixed model with repeated measures (MMRM). This analysis will 
assess whether or not there is a difference in estimated change from baseline values between 
active treatment and SOC by visit using least squares means estimates from the MMRM.SAS 
PROC MIXED will be used to fit an MMRM with change from baseline in SARS-CoV-2 viral 
load as the response variable and the following covariates and fixed effects: 
• Baseline SARS-CoV-2 viral load (covariate) 
• Treatment group (fixed effect) 
• Visit (fixed effect, time will be defined in terms of Visits) 
• Time by Treatment Interaction (Time*Treatment) 


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The covariance structure for the repeated measures in this model will be unstructured (UN). If 
UN does not converge for the model, a first-order autoregressive (AR(1)) covariance structure 
will be used. 
Changes in viral load will be analyzed using the mITT population. 
 By-subject data listings will also be provided.  
4.3.2.10. 
Neutralizing Antibodies 
Summaries of neutralizing antibody titers will be presented over time by treatment group using 
descriptive statistics. Antibody titer results will be summarized for each dilution at which 50% 
neutralization was observed. 
The analysis of antibody titers will be performed using the ITT populations. 
By-subject data listings will also be provided.  
4.4. 
Pharmacokinetic Evaluations 
All PK data analysis will be conducted using the PK population. 
Maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), and AUC(0-
24h) on Days 1, 2, 3, 8, 11 and 14 will be calculated. Plasma PK parameters will be summarized 
and plotted using descriptive statistics, as appropriate.   
4.5. 
Safety Analyses 
Safety analyses will be conducted using the Safety population. 
4.5.1. 
Study Drug Exposure  
Duration of study drug exposure will be calculated as the number of days subjects were 
administered study drug and will be summarized for the favipiravir arm using descriptive 
statistics.  
Total drug received (in mg) will be summarized for the favipiravir arm. Percent compliance will 
be summarized for each subject from the date of first dose through the last dose of study drug 
per the following definition:  
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 (%) = 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑟𝑟𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 (𝑚𝑚𝑚𝑚) 
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 (𝑚𝑚𝑚𝑚) × 100% 
For subjects who withdrew/discontinued treatment prematurely, the amount of drug planned 
will be calculated based on the period of treatment up to their withdrawal/termination.  
Each Study drug administration per patient will be provided in data listings.  


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4.5.2. 
Adverse Events 
All AEs will be coded using the MedDRA v23.0 coding system and displayed in tables and data 
listings using system organ class and preferred term. Missing and partial dates will be handled 
as described in Section 3.10.2.  
Treatment-emergent AEs (TEAEs) will be defined as those occurring coincident with start of 
treatment through Day 60.  
 
In the favipiravir + SOC arm: Adverse event solicitation and recording will begin immediately 
following the first dose of favipiravir and will include only on-treatment (treatment-emergent) 
events. Any changes to a subject’s health that occur between the signing of the informed 
consent and dosing will be recorded as updates to the subject’s medical history.  
 
In the SOC alone arm: Adverse event solicitation and recording will begin following the 
completion of all baseline assessments.  
 
Clinical events related to the progression of COVID-19 will not be considered AEs. 
Adverse events are summarized by subject incidence rates; therefore, in any tabulation, a subject 
contributes only once to the count for a given AE in both SOC and preferred term. 
The number and percentage of patients with any TEAE, with any TEAE assessed by the 
Investigator as related to treatment, with any serious TEAE, and with any treatment-emergent 
serious AE (SAE) potentially related to treatment will be summarized by treatment group and 
overall. 
All AEs occurring on-study will be listed in subject data listings. 
By-subject listings also will be provided for the following: subject deaths, SAEs, and AEs 
leading to treatment/study discontinuation.  
4.5.3. 
Laboratory Data 
Clinical laboratory values will be expressed in SI units. 
All laboratory data will be provided in data listings. 
Abnormal clinical laboratory values that are clinically significant will be graded according to 
the CTCAE version 5.0. A listing of all abnormal laboratory values will be provided.  
Shift tables for hematology and chemistry parameters from baseline to worst value will be 
provided by treatment group and overall. All unscheduled visits, if any, will contribute to the 
last or worst value.  


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4.5.4. 
Vital Signs and Physical Examination 
The actual values and changes from baseline to each on-study evaluation will be summarized 
for vital signs by treatment group and overall.  
Vital sign measurements will be presented for each subject in a data listing. 
4.5.5. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO Drug Dictionary.  
The use of prior and concomitant medications will be included in a by-subject data listing. 


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5. 
CHANGES TO PLANNED ANALYSES 
The following are changes between the protocol-defined statistical analyses and those presented 
in this statistical analysis plan: 
• The hierarchical testing of the key secondary endpoints has been removed, given that this 
study is a Proof of Concept study that is not meant to act as a pivotal or confirmatory study 
for marketing authorization.  
All changes from procedures outlined in the protocol and procedures outlined in this SAP will 
be summarized in the study report.  Decisions to deviate from planned analyses will be 
documented at the time they are made. 


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6. 
REFERENCES 
Liu, Y., & De, A. (2015). Multiple Imputation by Fully Conditional Specification for Dealing 
with Missing Data in a Large Epidemiologic Study. International journal of statistics in medical 
research, 4(3), 287–295. 
Schenker, N., and Taylor, J. M. G. (1996). “Partially Parametric Techniques for Multiple 
Imputation.” Computational Statistics and Data Analysis 22:425–446