Conditions: Covid19
Keywords: AVIGAN Favipiravir COVID-19 Phase 3
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 353
Healthy volunteers: no

Brief summary:
This is a prospective, interventional, multi-centre, phase III, randomized, double blind, placebo-controlled, parallel design trial to evaluate the efficacy, safety and tolerability of favipiravir as adjunct ('add on') to supportive care, in comparison to placebo with supportive care, in the acute treatment of patients who have tested positive for SARS-CoV-2 and presenting with moderate to severe COVID-19.

This study will be conducted in two parts; Stage I - Main study and Stage II - Extended Follow up.

Detailed description:
Stage I - Main Study:

All the eligible patients will be randomized to receive either favipiravir + supportive care or placebo + supportive care. The treatment duration with the IMP will be for a period of 10 consecutive days. If the patient is discharged before Day 10, the patient will be required to continue the remainder of the treatment course of the assigned IMP at home. Patients in both the groups will receive supportive care, as appropriate. The duration of supportive care will be based upon Investigator's judgement and as per individual patient's requirement. The study data collection period will be up to 28 (+2) days.

Day 10 will be considered as the End of treatment (EOT) assessment.

1. If the patient remains in the hospital until Day 10, the EOT will be performed at the site and all the scheduled assessments for Day 10 will be performed
2. If the patient is discharged before Day 10, the EOT can be performed either as an onsite visit or will be performed at the patient's home :

   1. On-site visit: If the patient is able to visit the hospital on Day 10, procedures for an unscheduled visit will be performed.

      OR
   2. At home: If the patient is unable to visit the hospital for the EOT, study nurse or phlebotomist will visit the patient at his/her residence to collect blood sample for safety assessments. A telephonic follow up will be performed to enquire on treatment emergent AEs experienced, concomitant medication and COVID-19 associated symptom for assessment of clinical relapse.

Day 28 will be considered the end of study visit. If patient is discharged from the hospital before Day 28, the assessments mentioned in the end of study visit (Day 28) will be performed before the patient is discharged. After discharge, telephonic follow up will be performed on Day 10 (applicable only for patients who are discharged earlier than Day 10 and if patients are unable to visit the site for EOT on Day 10), Day 14, Day 21 and Day 28. The telephonic follow up will be as applicable for the individual patient, depending upon the actual day when (s)he is discharged. A 2-day window period is allowed for telephonic follow up.

In case the patient remains admitted in the hospital beyond Study Day 28, the end of study assessments will be performed for the patient on Day 28 (+2) days.

Stage I of the study will be completed when the 'Day 28' assessment is completed either as an in-patient assessment if the patient is still hospitalized, or as a telephonic follow up assessment if the patients are discharged earlier to Day 28.

Once all the patients complete the Stage I of the study, the database would be locked, and analysis will be performed.

Stage II - Extended Follow Up:

All the patients will be followed up for AEs or for 'clinical relapse' of COVID 19. Two telephonic follow up assessments will be performed on Day 42 and Day 60. An additional visit to the hospital (for further assessment) may be scheduled for such patients, if required.

Arms:
arm 1: Frequency: Twice daily (morning and evening) Dosage Form: Tablets. Tablet Strength 200 mg. Dosage: 1,800 mg BID on Day 1 + 800 mg BID for next 9 days (maximum). On Day 1, the second dose will be administered with at least a 4-hour interval from administration of the first dose. arm 2: Frequency: Twice daily (morning and evening) Dosage Form: Tablets Dosage: 9 tablets for BID on Day 1 + 4 tablets BID for next 9 days (maximum). On Day 1, the second dose will be administered with at least a 4-hour interval from administration of the first dose.

Interventions: intervention 1: AVIGAN intervention 2: Placebo Comparator
Intervention descriptions: intervention 1: Patients will be randomized to the favipiravir + supportive care group in a 1:1 ratio intervention 2: Patients will be randomized to the placebo + supportive care group in a 1:1 ratio

Protocol document:
Prot_000.pdf: 
Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 1 of 146 
 
Confidential 
CLINICAL STUDY PROTOCOL 
 
A Multi-center, Randomized, Double Blind, Placebo Controlled Clinical Trial Evaluating 
the Efficacy and Safety of Favipiravir in Moderate to Severe COVID-19 Patients 
 
Investigational 
Medicinal 
Product: 
AVIGAN® (Favipiravir or 6-fluoro-3-hydroxypyrazine-2-carboxamide) 
Sponsor: 
Dr. Reddy’s Laboratories Limited 
8-2-337, Road No. 3 
Banjara Hills, Hyderabad 
Telangana 500034, India 
 
Co-sponsor 
G Response Aid FZCO (“GRA”) 
Emirates Financial Tower, 
South Tower, Unit 704, 
Sheikh Zayed Road, Dubai, UAE 
 
Protocol 
Number: 
CVD-04-CD-001 
Study Code: 
NV-05-983-2020 
Version No.: 
Final Version 5.0 
Date: 
06 Jan 2021 
 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 2 of 146 
 
Confidential 
PROTOCOL APPROVAL PAGE 
 
 
A Multi-center, Randomized, Double Blind, Placebo Controlled Clinical Trial Evaluating 
the Efficacy and Safety of Favipiravir in Moderate to Severe COVID-19 Patients. 
 
 
PROTOCOL NO.: CVD-04-CD-001 
 
STUDY CODE: NV-05-983-2020 
 
EudraCT Number: 2020-005485-34 
 
 
Protocol Title: 
A Multi-center, Randomized, Double Blind, Placebo Controlled Clinical 
Trial Evaluating the Efficacy and Safety of Favipiravir in Moderate to 
Severe COVID-19 Patients  
Protocol Number: 
CVD-04-CD-001 
This study will be conducted according to the Guidelines of the World Medical Association 
Declaration of Helsinki in its revised edition (Brazil, 2013), the International Council for 
Harmonisation (ICH) guidelines for current Good Clinical Practice (cGCP) 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 3 of 146 
 
Confidential 
Sponsor Signatory  
 
Sagar Munjal, MD, MS 
Vice President & Head-Clinical Development, 
Operations and Medical Affairs 
Proprietary Products Group 
Dr. Reddy’s Laboratories, Inc. 
107 College Road East 
Princeton, NJ 08540 
 
Signature 
 
Date 
 
 
Sponsor Study Lead and Medical Monitor 
 
Srinivas Shenoy B., MD 
Director - Clinical Development, 
Proprietary Products Group 
Dr Reddy’s Laboratories, Inc. 
107 College Road East 
Princeton, NJ 08540 
 
Signature 
 
Date 
 
 
Co-sponsor Signatory 
 
Mr. Mitch Wilson 
Chief Executive Officer 
G Response Aid FZCO (“GRA”) 
Emirates Financial Tower, 
South Tower, Unit 704, 
Sheikh Zayed Road, Dubai, UAE 
 
Signature 
 
Date 
 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Dr. Reddy’s Laboratories, Limited. The information is 
provided to you in confidence, which is requested under an agreed upon and signed Confidentiality and Disclosure 
Agreement. Do not give this document or any copy of it or reveal any proprietary information contained in it to any 
third party (other than those in your organization who are assisting you in this work and are bound by the 
Confidentiality and Disclosure Agreement) without the prior written permission of an authorized representative of Dr. 
Reddy’s Laboratories, Limited. 
 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B
06-Jan-2021 | 9:08 PM IST
06-Jan-2021 | 9:14 PM IST
06-Jan-2021 | 8:09 AM PST


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 4 of 146 
 
Confidential 
DEPARTMENTS AND FACILITIES 
 
Sponsor: 
Dr. Reddy’s Laboratories Limited 
8-2-337, Road No. 3 
Banjara Hills, Hyderabad 
Telangana 500034, India 
 
Co-sponsor 
G Response Aid FZCO (“GRA”) 
Emirates Financial Tower, 
South Tower, Unit 704, 
Sheikh Zayed Road, Dubai, UAE 
 
Sponsor’s Authorized 
Representative: 
Sagar Munjal, MD, MS 
Vice President & Head-Clinical Development, Operations 
and Medical Affairs 
Proprietary Products Group 
Dr. Reddy’s Laboratories, Inc. 
107 College Road East 
Princeton, NJ 08540 
 
Co-sponsor’s Authorized 
Representative: 
 
Mr. Mitch Wilson 
Chief Executive Officer 
G Response Aid FZCO (“GRA”) 
Emirates Financial Tower, 
South Tower, Unit 704, 
Sheikh Zayed Road, Dubai, UAE 
Sponsor Study Lead and 
Medical Monitor 
(Sponsor): 
Srinivas Shenoy B., MD 
Director - Clinical Development, 
Proprietary Products Group 
Dr Reddy’s Laboratories, Inc. 
107 College Road East 
Princeton, NJ 08540 
Email ID : srinivasshenoyb@drreddys.com  
Mobile no. : 0016099550249 
Study Consultant 
Richard Kaszynski MD, PhD 
rkaszynski.md.phd@gmail.com  
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 5 of 146 
 
Confidential 
Principal Investigators 
Salman Khalifa Al-Sabah MD MBA FACS FRCS(c) 
Jaber Al-Ahmad Al-Sabah Hospital 
Khalid Ben AbdulAziz Street  
South Surra 
Kuwait  
Post code: 47781  
E-mail: salman.k.alsabah@gmail.com  
 
Mohammad S. M. D. AlHumaidan MBBS, FAAP, 
FRCPC.  
Mishref Field Hospital 
Mubarak Al-Abdullah Street 
Mishref 
Kuwait 
Post code: 90005  
E-mail: alhumaidan77@yahoo.com  
 
Dr. Nawal AlKaabi 
Sheikh Khalifa Medical city 
Al Karamah street – Al Tibbiya W13-01 – Abu Dhabi 
E-mail: Nalkaabi@seha.ae  
 
Dr.Naela M. Al Mazeedi 
Farwaniya Hospital 
PO box 13373, Farwaniya 81004 
Kuwait, Farwaniya 
Phone-(+965) 99735376 
E-mail: naela@doctor.com   
 
Bulgaria: 
Principal Investigators and Site details will be provided in 
the European Clinical Trials Registry 
 
Contract Research 
Organization (CRO): 
ECRON ACUNOVA LIMITED  
Mobius Towers  
SJR-i-Park  
EPIP Whitefield  
Bangalore – 560 066  
India  
 
CLINIC DESIGN MPM LTD 
4, Philip Kutev Str 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 6 of 146 
 
Confidential 
Office Building, fl. 2 and 3 
1407 Sofia 
Bulgaria 
Project Manager (EA): 
Deepanjana Sengupta 
Project Manager 
Ecron Acunova Limited,  
Mobius Towers, SJR I-Park, 
EPIP Zone, Whitefield 
Bangalore - 560 066, India  
Telephone No.: +91 80 66915700 
E-mail: deepanjana.s@navitaslifesciences.com  
Medical Monitor (EA): 
Dr Sudheer Balaraju 
Head – Medical and Safety 
Ecron Acunova Limited,  
Mobius Towers, SJR I-Park, 
EPIP Zone, Whitefield 
Bangalore - 560 066, India  
Telephone No.: +91 80 4351 5700 
E-mail: sudheer.balaraju@navitaslifesciences.com  
Fax No.: +91 80 43515719 
Protocol Author: 
Dr. Farzana Banu  
Associate Manager – Medical Writing  
Ecron Acunova Limited,  
Mobius Towers, SJR I-Park, 
EPIP Zone, Whitefield 
Bangalore - 560 066, India 
Telephone No.: +91 80 4351 5700  
Email: farzana.banu@navitaslifesciences.com  
Fax No.: +91 80 43515719 
Biostatistician: 
 
Rajeshkumar Gajendran, 
Principal Biostatistician,  
2nd Floor, A1, Gateway Office Parks Rd, Balaji  
Nagar, New Perungalathur, Chennai,  
Tamil Nadu 600063 
Telephone No: 044 4590 9000 
E-mail: rajeshkumar.g@navitaslifesciences.com  
Data Management: 
Shantha Lakshmi 
Senior Project Database Manager 
Ecron Acunova Limited,  
Mobius Towers, SJR I-Park, 
EPIP Zone, Whitefield 
Bangalore - 560 066, India  
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 7 of 146 
 
Confidential 
Telephone No.: +91 990 218 2288 
E-mail: Shantha.lakshmi@navitaslifesciences.com  
Fax No.: +91 80 4351 5731  
Clinical Laboratories: 
Jaber Laboratory  
South Surra  
Jaber Al-Ahmad Al-Sabah Hospital  
Kuwait  
E-mail: mohammad.alghounaim@gmail.com  
phone: +965 97333099 
Mishref Lab  
Mishref Field Hospital (Mishref) 
Kuwait City, 90005, Kuwait  
The New Kuwait German Laboratory,  
2nd Floor, Block 3, Street 6, Aknan Tower,  
Salmiya, Kuwait 
E-mail: dr.najla@igckwt.com 
 
Bulgaria: 
Local Site Laboratory  
 
 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 8 of 146 
 
Confidential 
 
PROTOCOL SYNOPSIS 
EudraCT Number 
2020-005485-34 
Protocol Number: 
CVD-04-CD-001 
Investigational Medicinal 
Product: 
AVIGAN® (Favipiravir) tablets 
Active Ingredient(s)/INN: Favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide) 
Study Sponsor 
Dr. Reddy’s Laboratories Limited 
8-2-337, Road No. 3 
Banjara Hills, Hyderabad 
Telangana 500034, India 
Study Title: 
A Multi-center, Randomized, Double Blind, Placebo 
Controlled Clinical Trial Evaluating the Efficacy and Safety 
of Favipiravir in Moderate to Severe COVID-19 Patients 
Study Phase: 
Phase III 
Indication Under 
Investigation: 
Acute treatment of moderate to severe COVID-19 caused 
by SARS-CoV-2 infection 
Study Objectives: 
Primary Objective: 
• To evaluate the efficacy of oral favipiravir in 
improving the time to resolution of hypoxia in 
moderate to severe COVID-19 patients 
Secondary Objectives 
• To evaluate the efficacy of oral favipiravir in 
improving the clinical and virological outcomes in 
moderate to severe COVID-19 patients 
• To assess the tolerability and safety of favipiravir in 
the targeted study population 
Study Design: 
• Prospective 
• Interventional 
• Randomized (ratio 1:1) 
• Double-blind 
• Placebo-controlled 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 9 of 146 
 
Confidential 
• As adjunct (‘add on’) to Supportive Care  
• Parallel assignment to treatment groups 
This study will be conducted in two parts; Stage I – Main 
study and Stage II – Extended Follow up. Once all the 
patients complete the Stage I of the study, the database will 
be locked, and analysis will be performed. Patients will enter 
Stage II of study after they complete the Day 28 assessment. 
Inclusion/Exclusion 
Criteria: 
Inclusion Criteria:  
Patients must satisfy all the following criteria to be 
included in the study: 
1. Male and female patients aged 21 to 80 years (both 
inclusive) 
2. Patients who have tested positive for SARS-CoV-2 
by 
Reverse 
Transcriptase-Polymerase 
Chain 
Reaction (RT-PCR) assay using a respiratory tract
sample 
(either 
nasopharyngeal 
swab 
OR 
oropharyngeal swab OR nasal aspirate OR trachea-
bronchial aspirate) collected within 72 hours prior to 
randomization 
3. Patients should be hospitalized 
4. Patients having ‘moderate’ or ‘severe’ COVID-19* 
with a score of > 4 on the 10-point ordinal scale of 
clinical status used by WHO in the SOLIDARITY 
trial at baseline assessment [i.e., patients with blood 
oxygen saturation (SpO2) <95% at rest on room air 
at sea level and requiring supplemental oxygen].  
 
*Note: This includes patients clinically assigned as: 
I. ‘moderate’ COVID-19 
a. symptoms which could include fever, cough, 
sore throat, malaise, headache, muscle pain, 
gastrointestinal symptoms or shortness of 
breath with exertion and/or clinical signs, 
such as respiratory rate ≥20 breaths per 
minute or heart rate ≥90 beats per minute 
AND 
b. blood oxygen saturation (SpO2) of 94% at 
rest on room air at sea level  
II. ‘severe’ COVID-19 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 10 of 146 
 
Confidential 
a. symptoms which could include any symptom 
of moderate illness or shortness of breath at 
rest, or respiratory distress and/or clinical
signs, such as respiratory rate ≥30 per minute 
or heart rate ≥125 per minute 
AND 
b. blood oxygen saturation (SpO2) ≤93% on 
room air at sea level or PaO2/FiO2 <300 
 
*The above-mentioned definitions of COVID-19 severity are 
adapted from the FDA Guidance document COVID-19: 
Developing Drugs and Biological Products for Treatment or 
Prevention - Guidance for Industry Final Document dated May 
2020 
5. Female patients of childbearing potential* 
a. Must have a negative serum pregnancy test at 
screening.  
b. Should not be lactating; and not planning to 
become pregnant/breast feed during the 
treatment period and for 7 days after the last 
dose of study medication. 
c. Should commit to the use of TWO forms of 
study-acceptable 
contraception 
methods, 
including a barrier method (eg. diaphragm) 
along with one or more of the following 
methods of contraception for the duration of 
the treatment period and for 7 days after the 
last dose of study medication:  
i) 
hormonal 
methods 
[insertable, 
injectable, 
transdermal, 
or 
combination 
oral 
(estrogen+ 
progestin)] or  
ii) intrauterine contraceptive device  
Note: Female patients who are sexually abstinent
or whose male sexual partner has 
undergone vasectomy at least three months 
prior to the start of study treatment in the 
trial may be enrolled at the Investigator’s 
discretion, 
provided 
that 
they 
are 
counseled to remain sexually inactive for 
the duration of the study and understand 
the possible risks involved in getting 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 11 of 146 
 
Confidential 
pregnant during the study. Patients must 
also agree to use TWO forms of study-
acceptable contraception methods should 
they become sexually active during the 
treatment period and for 7 days after the 
last dose of study medication. 
*Note: 
A 
female patient 
is 
considered 
of 
childbearing potential unless she is  
a. postmenopausal for at least 12 months prior 
to study product administration, or 
b. without a uterus and/or both ovaries; or has 
been surgically sterilized (ie, tubal ligation 
or has a fallopian tube blocking coil) for at 
least 6 months prior to study product 
administration.  
6. Male patients should agree to abstain from sexual 
intercourse or to use double-barrier contraception 
(e.g. condom with spermicide) for the duration of the
treatment period in the study and for at least 7 days 
after receiving the last dose of study medication. 
Male patients should also avoid semen donation or 
providing semen for in-vitro fertilization during the 
above-mentioned duration. 
7. Able and willing to provide informed consent 
8. Able to understand the trial requirements and comply 
with trial medications and assessments in the opinion 
of the Investigator 
9. Should not have received investigational treatment 
from participation in another clinical trial within 30 
days prior to randomization in the current trial and 
agrees not to participate in other clinical studies 
during the entire study period 
Exclusion Criteria: 
Patients who meet any of the following criteria will be 
disqualified from entering the study: 
1. Critically ill patients, defined as those who are 
candidates 
for 
endotracheal 
intubation 
and 
mechanical ventilation,  Extracorporeal Membrane 
Oxygenation (ECMO) , or clinical diagnosis of 
respiratory failure (i.e., clinical need for one of the 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 12 of 146 
 
Confidential 
preceding therapies, but preceding therapies not able 
to be administered in setting of resource limitation) 
and those with shock (defined by systolic blood 
pressure (BP) <90 mm Hg, or diastolic BP 
<60 mm Hg or requiring vasopressors) or multi-
organ dysfunction/failure, at baseline 
Note: The above-mentioned definition of ‘critically ill’ 
COVID-19 patients is as defined in the FDA Guidance 
document COVID-19: Developing Drugs and Biological
Products for Treatment or Prevention - Guidance for
Industry Final Document dated May 2020 
2. Patients in whom the first onset of symptoms/ signs 
suggestive of COVID-19 illness was observed >10 
days earlier to the baseline assessment and 
randomization 
3. Patients who have used interferon beta 1-a 
(IFN-β 1-a) preparations or drugs with reported anti-
viral 
action 
against 
SARS-CoV-2 
(hydroxychloroquine sulfate, phosphate, lopinavir-
ritonavir combination drugs, ciclesonide, nafamostat 
mesylate, camostat mesylate) within 9 days after 
development of fever (≥37.5°C) 
Note: The above-mentioned exclusion criterion is not 
applicable in case of patients with history of human 
immunodeficiency virus infection or infective hepatitis 
in whom use of anti-viral drugs or interferons are 
prescribed for treatment of the underlying condition and 
who are currently receiving one or more of these 
medications (as maintenance treatment) at the time of 
randomization. The infection episode in question is a 
relapse of, or reinfection with SARS-CoV-2. 
4. Patients suspected to have a complication of 
congestive cardiac failure based on Investigator’s 
clinical judgement 
5. Patients 
with 
moderate 
and 
severe 
hepatic 
dysfunction equivalent to Grade B and Grade C in 
the Child-Pugh classification respectively 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 13 of 146 
 
Confidential 
6. Patients with alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) levels > 5 times
upper limit of normal (ULN) at screening evaluation 
7. Patients with renal impairment requiring dialysis 
8. Patients with serum uric acid higher than the ULN at 
screening evaluation 
9. Patients with history of hereditary xanthinuria 
10. Patients who have been diagnosed with xanthine 
urinary calculus 
11. Patients with a history of gout or patients who are 
currently being treated for gout 
12. Patients who are taking immunosuppressants  
13. Patients who were administered Favipiravir in the 
past 30 days 
14. Patients with known hypersensitivity reaction to 
Favipiravir 
Study Duration: 
This study will be conducted in two parts; Stage I – Main 
study and Stage II – Extended Follow up 
Stage I – Main Study: 
It is estimated that the duration of the patient participation in 
the Stage I of the study will not exceed 33 days, including a 
maximum of 3 days of screening period, a treatment period 
of 10 days and a study data collection period of 28 (+2) days 
Study treatments Favipiravir/Placebo will be administered 
over 10 consecutive days. If the patient is discharged before 
Day 10, the patient will be required to continue the 
remainder of the treatment course at home. However, the
above-mentioned treatment period will be shortened if it is 
necessary to discontinue administration of the study drug 
due to AEs or other circumstances.  
The patients will be discharged when the Principal 
Investigator or a medically qualified Sub Investigator judges 
that the patient is fit for discharge.  
Day 10 will be considered as the End of treatment (EOT) 
assessment.  
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 14 of 146 
 
Confidential 
1. If the patient remains in the hospital until Day 10, the 
EOT will be performed at the site and all the 
scheduled assessments for Day 10 will be performed. 
2. If the patient is discharged before Day 10, the EOT 
can be performed either as an onsite visit or will be 
performed at the patient’s home. 
a. On-site visit: If the patient is able to visit the 
hospital on Day 10, procedures for an 
unscheduled visit will be performed. 
OR  
b. At home: If the patient is unable to visit the 
hospital for the EOT, study nurse or phlebotomist 
will visit the patient at his/her residence to collect 
blood sample for safety assessments. A
nasopharyngeal swab or oropharyngeal swab 
will be collected from the patient and sent for 
detection (qualitative) of SARS-CoV-2 RNA by 
RT-PCR assay based on Investigator’s discretion 
for individual patients. A telephonic follow up 
will be performed to enquire on treatment 
emergent 
AEs 
experienced, 
concomitant 
medication and COVID-19 associated symptom 
for assessment of clinical relapse. 
Day 28 will be considered the end of study visit.  
If patient is discharged from the hospital before Day 28, the 
assessments mentioned in the end of study visit (Day 28)
will be performed before the patient is discharged. After 
discharge, telephonic follow up will be performed on Day 
10 (applicable only for patients who are discharged earlier 
than Day 10 and if patients are unable to visit the site for
EOT on Day 10), Day 14, Day 21 and Day 28. The 
telephonic follow up will be as applicable for the individual 
patient, depending upon the actual day when (s)he is 
discharged. A 2-day window period is allowed for 
telephonic follow up. 
In case the patient remains admitted in the hospital beyond 
Study Day 28, the end of study assessments will be 
performed for the patient on Day 28 (+2) days. 
Stage II – Extended Follow Up: 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
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The duration of the patient participation in the Stage II of the 
study will not exceed 34 days. Two telephonic follow up 
assessments will be performed on Day 42 and Day 60. The 
patients will be followed up for AEs or for ‘clinical relapse’ 
of COVID 19. An additional visit to the hospital (for further 
assessment) may be scheduled for such patients, if required. 
A 2-day window period is allowed for telephonic follow up. 
Administration of Study 
Treatments  
Treatment group: Favipiravir + Supportive care 
Patients assigned to the ‘Favipiravir + Supportive care’ 
treatment group will receive AVIGAN® (favipiravir) 200 mg 
tablets at a dose of 1800 mg (9 tablets) orally twice daily
(BID) on Day 1, followed by 800 mg (4 tablets) orally BID
for 9 days. 
On Day 1, the second dose will be administered with at least 
a 4-hour interval from administration of the first dose. 
If the patient is discharged from hospital before Day 10, the 
patient will be required to continue the remainder of the 
treatment course of Favipiravir at home. 
Control group: Placebo + Supportive care 
Patients assigned to the ‘Placebo + Supportive care’ 
(control) treatment group will receive matching placebo, 9
tablets orally twice daily (BID) on Day 1, followed by 4
tablets orally BID for 9 days. 
On Day 1, the second dose will be administered with at least 
a 4-hour interval from administration of the first dose. 
If the patient is discharged from hospital before Day 10, the 
patient will be required to continue the remainder of the 
treatment course of Placebo at home. 
Patients in both the groups will receive supportive care,
including symptomatic treatments. The Investigator may be 
guided by Management of COVID-19 as per the current 
local guidance or institutional practice, in his/her choice of 
supportive care for individual patients. Based on the 
individual patient’s requirement, supportive care may be 
given for a longer period than favipiravir/matching placebo 
in the study. 
Planned Sample Size: 
Based on review of published literature, a hazard ratio of 
1.25 is reported (adjusted for the stratification in 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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randomization) for time to clinical improvement in COVID-
19 patients receiving anti-viral interventions. The hazard 
ratio of 1.25 is also assumed to be constant throughout the 
study as per the assumptions of the Cox proportional hazards 
regression model with the expected average probability of 
the event over the course of the study to be 0.9 and 0.8 in test 
and control group respectively. Inequality testing of the 
hazard ratio using the Cox proportional hazards regression 
model with 371 subjects in Favipiravir group and 371 
subjects in Placebo group achieves 80% power at the 0.05 
significance level for an actual hazard ratio of 1.25 assuming 
the hazard ratio is 1 under the null hypothesis and that the 
total number of events achieved is 631. Based on the above
assumption and considering the dropout rate to be 5%, 
overall, 390 patients will be randomized in each treatment 
group. i.e. 780 patients in total to be randomized in the study. 
The sample size is estimated using nQuery version 8.5.0.0 
using Cox proportional hazard regression. 
Sample size will be re-estimated based on the analysis of 
results for the primary endpoint observed during interim 
analyses. . Details of the interim analysis and futility 
assessment are provided in the Statistical Analysis Plan 
(SAP) for the Interim Analysis. 
Study Endpoints: 
Stage I: 
Efficacy Endpoints: 
Primary Efficacy Endpoint: 
1. Time to resolution of hypoxia (Time frame: Up to 28 
days) 
This endpoint will be considered to have been met when the 
patient has attained a score of 4 or lower on the 10-point
ordinal scale of clinical status and either of a) or b), and c) is
met: 
a) Score is ≤ 4 on consecutive assessments over the next 
5 days, if patient continues to remain in hospital (i.e., 
has not been discharged). 
OR 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
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b)  Patient was discharged before five consecutive 
assessments (after reaching a score of 4). 
AND 
c) The patient has survived and has not been re-
admitted to hospital for COVID-19 management 
through Day 28. 
Secondary Efficacy Endpoints: 
1. Time to discharge from hospital. 
2. Time (no. of days) from randomization to the earliest
time when ALL COVID-19 associated symptoms 
(fever, chills, cough, sore throat, malaise, headache, 
muscle pain, gastrointestinal symptoms- specifically 
diarrhoea and vomiting, shortness of breath or 
dyspnoea) are scored by the Investigator/trained 
study personnel as either ‘0=absent’ or ‘mild =1’ in 
assessments over a period of 24 hours, when assessed
from baseline to Day 28 or discharge from hospital 
(if discharge happens earlier than Day 28).  
3. Percentage of patients with score of either ‘0=absent’ 
or ‘mild =1’ over a period of 24 hours, for ALL 
COVID-19 associated symptoms, by Days 4, 7, 10, 
14, 21 and 28 or discharge (if discharge happens 
earlier than one or more of the above-mentioned 
timepoints)  
Note: Symptoms evaluated are fever, chills, cough, sore 
throat, malaise, headache, muscle pain, gastrointestinal 
symptoms- 
specifically, 
diarrhoea 
and 
vomiting, 
shortness of breath or dyspnoea. The Investigator/trained 
study personnel will assess (including by enquiry with the 
patient, as necessary) and score the severity of each 
COVID-19 associated symptom on a 5-point Likert-type 
scale (0= absent, 1= mild, 2=moderate, 3= severe, 4= 
very severe/critical).  
4. Time to improvement in EACH of the symptoms of 
fever, chills, cough, sore throat, malaise, headache, 
muscle pain, gastrointestinal symptoms- specifically 
diarrhoea and vomiting, shortness of breath or 
dyspnoea by at least 1 grade over baseline.  
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Note: Severity of symptoms will be evaluated once daily 
(preferably at or around the same clock time) on each day 
that the patient is admitted in the hospital. The
Investigator/trained 
study 
personnel 
will 
assess 
(including by enquiry with the patient, as necessary) and 
score the severity of each COVID-19 associated symptom 
on a 5-point Likert-type scale (0= absent, 1= mild, 
2=moderate, 3= severe, 4= very severe/critical). The 
improvement observed must be sustained at evaluations 
over a period of 24 hours, in order for this secondary 
efficacy endpoint to be reached. 
5. Percentage of patients reporting a clinical relapse of 
COVID-19 when assessed from day of discharge to 
27 days after the day of randomization (Day 28). 
Note: ‘Clinical relapse’ is defined as either the 
reappearance or worsening of severity (over the 
assessment on the day of discharge) of one or more of the 
above-mentioned COVID-19 associated symptoms, or the 
appearance of any of these symptoms (due to COVID-19 
infection) for the first time after discharge. This endpoint 
will be assessed only for those patients that were 
discharged before Day 28.  
6. Time (no. of days) to negative conversion of 
detectable SARS-CoV-2 viral RNA in the RT-PCR 
assays of respiratory sample, from randomization. 
7. Percentage of patients showing negative conversion 
of detectable SARS-CoV-2 viral RNA in the 
RT-PCR assays of respiratory sample on Days 5, 10 
and 28 or discharge (if discharge happens earlier than 
one or more of the above-mentioned timepoints)  
8. Changes over time in patient’s clinical status on the
10-point ordinal scale used in the SOLIDARITY trial 
by WHO 
a. Changes in the 10-point ordinal scale score 
from baseline until discharge   
b. Proportion of patients in whom clinical status 
score of 4 (‘hospitalized, no oxygen 
required’) or lower has been attained by Days 
4, 7, 10, 14, 21 and 28 or discharge (if 
discharge happens earlier than one or more of 
the above-mentioned timepoints) 
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Protocol No.: CVD-04-CD-001  
 
 
 
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Clinical Study Protocol  
 
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c. Time (no. of days) from randomization to 
clinical status score improvement by 1 and by 
2 points (from baseline)  
d. Proportion of patients for whom clinical 
status score improvement by 1 and by 2 
points has been attained by Days 4, 7, 10, 14, 
21 and 28 or discharge (if discharge happens 
earlier than one or more of the above-
mentioned timepoints) 
9. Changes over time in patient’s clinical status on the
8-point ordinal scale  
a. 
Time (no. of days) from randomization to 
attain clinical status score of 4 or lower  
b. Proportion of patients in whom clinical
status score of 4 or lower has been attained 
by Days 4, 7, 10, 14, 21 and 28 or discharge 
(if discharge happens earlier than one or 
more of the above-mentioned timepoints) 
c. 
Time (no. of days) from randomization to 
attain clinical status score of 3 or lower  
d. Proportion of patients in whom clinical
status score of 3 or lower has been attained 
by Days 4, 7, 10, 14, 21 and 28 or discharge 
(if discharge happens earlier than one or 
more of the above-mentioned timepoints) 
e. 
Time (no. of days) from randomization to 
clinical status score improvement by 1 and 
by 2 points (from baseline)  
f. 
Proportion of patients for whom clinical 
status score improvement by 1 and by 2 
points has been attained by Days 4, 7, 10, 14, 
21 and 28 or discharge (if discharge happens 
earlier than one or more of the above-
mentioned timepoints) 
10. Changes over time in findings on chest X-ray  
11. Changes over time in the National Early Warning 
Score-2 (NEWS) 
12. Percentage of patients requiring, until Day 28 or 
discharge from hospital (if discharge happens 
earlier) 
a. Management in intensive care unit  
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
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Clinical Study Protocol  
 
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b. High Flow Nasal Oxygen or Non-invasive
mechanical ventilation 
c. Invasive mechanical ventilation 
13. Time (no. of days) from randomization to: 
a. Management in intensive care unit  
b. High Flow Nasal Oxygen or Non-invasive
mechanical ventilation 
c. Invasive mechanical ventilation 
over an assessment period from randomization 
until Day 28 or discharge from hospital (if 
discharge happens earlier) 
14. Duration (no. of days) the patient requires: 
a. Management in intensive care unit  
b. Oxygen supplementation 
c. High Flow Nasal Oxygen  
d. Non-Invasive Mechanical Ventilation 
e. Invasive mechanical ventilation 
over an assessment period from randomization 
until Day 28 or discharge from hospital (if 
discharge happens earlier) 
15. Percentage of patients: 
a. dying from any cause 
b. dying from a COVID-19 associated complication 
over an assessment period from randomization 
until Day 28 or discharge from hospital (if 
discharge happens earlier) 
Safety endpoints: 
1. Number (and percentage) of patients reporting 
treatment emergent adverse events (TEAEs) (by 
MedDRA system organ class and preferred term) 
2. Changes of parameters at each assessment during the 
study/follow-up period, compared to baseline for: 
▪ Vital signs: body temperature, heart rate, 
respiratory rate, systolic/diastolic BP and oxygen 
saturation.  
▪ Clinical laboratory assessments: hematology, 
serum chemistry, urinalysis. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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▪ 12-lead ECG: Changes in heart rate, PR, QRS, 
QT and QTcB intervals. 
Stage II 
Efficacy endpoint: 
1. Percentage of patients reporting a clinical relapse of 
COVID-19 when assessed from day of discharge to 
59 days after the day of randomization (Day 60). 
Note: ‘Clinical relapse’ is defined as either the reappearance or 
worsening of severity (over the assessment on the day of 
discharge) of one or more of the above-mentioned COVID-19 
associated symptoms, or the appearance of any of these symptoms 
(due to COVID-19 infection) for the first time after discharge. 
2. Proportion of patients 
a. With disease worsening and requires: 
• Admission to ICU 
• High flow nasal oxygen 
• Non-invasive mechanical ventilation 
• Invasive mechanical ventilation 
                AND 
b. Dying 
 until Day 60 (regardless of whether patients are 
discharged from hospital before Day 28 or not) 
Safety Endpoint: 
1. Number (and percentage) of patients reporting 
treatment emergent adverse events (TEAEs) (by 
MedDRA system organ class and preferred term) 
Secondary endpoints may be modified, or additional 
secondary endpoints may be defined in the SAP. 
Statistical Analyses: 
Unless otherwise specified, the primary efficacy analysis 
will be done using Intention to Treat (ITT) population. The 
statistical significance level is 0.05 by one sided or two-
sided test, wherever appropriate. Mean/ Median (and other 
general statistics estimates such as Inter Quartile range, SD, 
min, max etc.) and the 95% CI for the estimates of the mean 
will be provided for the applicable efficacy endpoints. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Endpoints will be analysed descriptively and inferentially 
wherever necessary.  
All AEs and TEAEs will be summarized in terms of severity, 
relationship to study treatment, action taken and patient 
outcome. The number and the proportion of patients who 
experienced AEs will be computed by treatment group, 
classified by Medical Dictionary for Regulatory Activities 
(MedDRA version 23.0) Primary System Organ Class and 
Preferred Terms. The AE data will be summarized using 
safety population. 
Detailed description on the statistical methods will be 
explained in the Statistical Analysis Plan which will be 
finalized before study database lock of Stage I of the study. 
If there is a discrepancy in the planned analysis between the 
protocol and SAP, the SAP takes precedence. 
An independent data monitoring committee (DMC) will 
review the results of the interim analyses to assess the 
efficacy and safety data emerging from the trial. The details 
of the interim analysis or futility assessment will be included 
in a separate Interim Analysis Plan, appended to the DMC 
charter. Sample size will be re-estimated based on the 
analysis of results for the primary endpoint observed during 
interim analyses. Details of the interim analysis and futility 
assessment are provided in the Statistical Analysis Plan 
(SAP) for the Interim Analysis. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
TABLE OF CONTENTS 
 
1 
INTRODUCTION AND BACKGROUND INFORMATION ..................................................................... 32 
1.1 
NAME OF INVESTIGATIONAL PRODUCT ................................................................................................... 34 
1.1.1 
Description ........................................................................................................................................... 34 
1.1.2 
Intended Use under Investigation ......................................................................................................... 34 
1.1.3 
Nonclinical Studies ............................................................................................................................... 34 
1.1.4 
Clinical Experience .............................................................................................................................. 35 
1.2 
STUDY RATIONALE ................................................................................................................................. 36 
1.3 
RISKS AND BENEFITS FOR STUDY PATIENTS ........................................................................................... 38 
1.4 
ROUTE, DOSAGE, DOSAGE REGIMEN, TREATMENT PERIOD .................................................................... 38 
1.5 
COMPLIANCE STATEMENT, ETHICS AND REGULATORY COMPLIANCE .................................................... 38 
1.5.1 
Patient Confidentiality .......................................................................................................................... 39 
1.5.2 
Informed Consent Procedure ................................................................................................................ 39 
1.5.3 
Regulatory Compliance ........................................................................................................................ 40 
2 
STUDY OBJECTIVES AND HYPOTHESES .............................................................................................. 41 
2.1 
STUDY OBJECTIVES ................................................................................................................................ 41 
3 
STUDY DESIGN .............................................................................................................................................. 42 
3.1 
OVERALL STUDY DESIGN ....................................................................................................................... 42 
3.1.1 
Study Type ............................................................................................................................................. 42 
3.1.2 
Treatment Groups ................................................................................................................................. 43 
3.1.3 
Study Endpoints .................................................................................................................................... 45 
3.1.4 
Duration of the Study ............................................................................................................................ 48 
3.1.5 
Duration of Patient Participation ......................................................................................................... 49 
3.1.6 
Completion or Discontinuation of the Clinical Study and Discontinuation of Administration of the Study 
Drug (Completion or Discontinuation by Individual Patient) ........................................................................... 50 
4 
STUDY POPULATION................................................................................................................................... 52 
4.1 
ENROLLMENT.......................................................................................................................................... 52 
4.1.1 
Inclusion Criteria .................................................................................................................................. 52 
4.1.2 
Exclusion Criteria ................................................................................................................................. 54 
4.2 
REMOVAL OF PATIENTS FROM THERAPY................................................................................................. 55 
4.2.1 
Withdrawal Procedures ........................................................................................................................ 55 
4.2.2 
Patient Replacement ............................................................................................................................. 55 
4.2.3 
Patient Re-screening Procedures ......................................................................................................... 55 
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Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
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5 
TREATMENTS ADMINISTERED ............................................................................................................... 56 
5.1 
INVESTIGATIONAL PRODUCT(S) .............................................................................................................. 56 
5.1.1 
Method of Assigning Patients to Treatments ........................................................................................ 57 
5.1.2 
Method of Assessing Treatment Compliance ........................................................................................ 57 
5.1.3 
Labeling and Packaging ....................................................................................................................... 58 
5.1.4 
Preparation ........................................................................................................................................... 58 
5.1.5 
Drug Accountability .............................................................................................................................. 59 
5.1.6 
Blinding and Unblinding ...................................................................................................................... 60 
5.1.7 
Dosing Schedule, Selection and Timing of dosing ................................................................................ 60 
5.1.8 
Instructions for Patients ....................................................................................................................... 60 
5.1.9 
Concomitant Medications ..................................................................................................................... 61 
5.1.10 Drug-Drug Interaction ......................................................................................................................... 61 
5.1.11 Prohibited concomitant drugs .............................................................................................................. 62 
5.1.12 Rescue Medications .............................................................................................................................. 62 
6 
STUDY PROCEDURES .................................................................................................................................. 63 
6.1 
STAGE I – MAIN STUDY .......................................................................................................................... 63 
6.1.1 
Visit 1 - Screening (Day -3 to Day -1) .................................................................................................. 63 
6.1.2 
Visit 2- Randomization/Baseline Visit [Day 1 (Pre-dose and post-dose)] ............................................ 64 
6.1.3 
Study Period (Day 2 to Day 27) ............................................................................................................ 64 
6.1.4 
End of Study-Day 28 (+2 days) or discharge or study discontinuation whichever is earlier ............... 66 
6.1.5 
Telephonic follow up on Day 10, Day 14, Day 21 and Day 28, as applicable for the individual patient
 
66 
6.2 
STAGE II – EXTENDED FOLLOW UP ......................................................................................................... 67 
6.2.1 
Telephonic Follow Up on Day 42 (+2 days) and Day 60 (+2 days) .................................................... 67 
6.3 
MEASUREMENTS AND EVALUATIONS ...................................................................................................... 67 
6.3.1 
Stage I – Main Study ............................................................................................................................. 67 
6.3.2 
Stage II - Extended Follow Up ............................................................................................................. 73 
6.4 
PROTOCOL DEVIATIONS .......................................................................................................................... 80 
7 
EVALUATION CRITERIA ............................................................................................................................ 81 
7.1 
EFFICACY EVALUATION CRITERIA .......................................................................................................... 81 
7.1.1 
Stage I ................................................................................................................................................... 81 
7.1.2 
Stage II .................................................................................................................................................. 89 
7.2 
SAFETY EVALUATION CRITERIA ............................................................................................................. 89 
7.2.1 
Stage I ................................................................................................................................................... 89 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
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7.2.2 
Stage II .................................................................................................................................................. 90 
8 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ........................................................ 91 
9 
SAFETY ASSESSMENTS .............................................................................................................................. 92 
9.1 
ADVERSE EVENTS ................................................................................................................................... 92 
9.1.1 
Definitions ............................................................................................................................................ 92 
9.2 
SERIOUS ADVERSE EVENT REPORTING ................................................................................................... 97 
9.2.1 
SUSARs ................................................................................................................................................. 98 
9.3 
EXPOSURE IN UTERO DURING CLINICAL STUDIES ................................................................................... 99 
9.4 
CLINICAL LABORATORY EVALUATIONS .................................................................................................. 99 
9.5 
RT-PCR (QUALITATIVE) ...................................................................................................................... 101 
9.6 
VITAL SIGNS ......................................................................................................................................... 101 
9.7 
ELECTROCARDIOGRAMS ....................................................................................................................... 101 
9.8 
PHYSICAL EXAMINATION FINDINGS ...................................................................................................... 102 
9.9 
OTHER SAFETY ASSESSMENTS .............................................................................................................. 102 
10 
OTHER ASSESSMENTS .............................................................................................................................. 102 
11 
STATISTICAL METHODS ......................................................................................................................... 103 
11.1 
ANALYSIS SETS ..................................................................................................................................... 103 
11.2 
GENERAL STATISTICAL CONSIDERATIONS ............................................................................................ 103 
11.2.1 Missing data ....................................................................................................................................... 103 
11.3 
STUDY POPULATION DATA ................................................................................................................... 104 
11.4 
EFFICACY ANALYSES ............................................................................................................................ 104 
11.4.1 Primary Efficacy Analyses .................................................................................................................. 104 
11.4.2 Secondary Efficacy Analyses .............................................................................................................. 104 
11.4.3 Exploratory Efficacy Analyses ............................................................................................................ 104 
11.5 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES .......................................................................... 105 
11.6 
SAFETY ANALYSES ............................................................................................................................... 105 
11.6.1 Adverse Event Analyses ...................................................................................................................... 105 
11.6.2 Clinical Laboratory Evaluation Analyses ........................................................................................... 105 
11.6.3 Vital Sign Analyses ............................................................................................................................. 105 
11.6.4 Electrocardiogram Analyses ............................................................................................................... 105 
11.6.5 Physical Finding Analyses .................................................................................................................. 105 
11.6.6 Other Safety Analyses ......................................................................................................................... 105 
11.7 
OTHER ANALYSES ................................................................................................................................ 105 
11.8 
INTERIM ANALYSES .............................................................................................................................. 106 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
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CONFIDENTIAL 
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11.9 
INDEPENDENT DATA MONITORING COMMITTEE ................................................................................... 106 
11.10 
SAMPLE SIZE DETERMINATION ............................................................................................................. 106 
12 
DATA INTEGRITY AND QUALITY ASSURANCE ................................................................................ 107 
12.1 
STUDY MONITORING PLAN ................................................................................................................... 107 
12.2 
DATA COLLECTION ............................................................................................................................... 108 
12.3 
DATA MANAGEMENT ............................................................................................................................ 108 
12.4 
STUDY DOCUMENTATION AND STORAGE .............................................................................................. 109 
12.5 
RECORD KEEPING ................................................................................................................................. 110 
12.6 
AUDITS AND INSPECTIONS .................................................................................................................... 110 
12.7 
TRAINING OF STAFF .............................................................................................................................. 110 
12.8 
CHANGES TO THE PROTOCOL ................................................................................................................ 110 
12.9 
PROTOCOL DEVIATIONS AND VIOLATIONS: CONDITION WHERE THE STUDY WILL BE TERMINATED .... 111 
13 
FINANCING AND INSURANCE ................................................................................................................ 112 
13.1 
FINANCES .............................................................................................................................................. 112 
13.2 
REIMBURSEMENT, INDEMNITY, AND INSURANCE .................................................................................. 112 
14 
ETHICAL CONSIDERATIONS .................................................................................................................. 113 
14.1 
IRB/IEC REVIEW AND COMMUNICATIONS ........................................................................................... 113 
14.2 
INFORMED CONSENT PROCESS .............................................................................................................. 113 
14.3 
STATEMENT OF PATIENT CONFIDENTIALITY INCLUDING OWNERSHIP OF DATA ................................... 114 
14.4 
TERMINATION OF STUDY ...................................................................................................................... 114 
15 
PUBLICATION POLICY ............................................................................................................................. 115 
16 
SPECIAL CONSIDERATIONS ................................................................................................................... 116 
16.1 
PROCEDURES IN CASE OF MEDICAL EMERGENCY ................................................................................. 116 
16.2 
INVESTIGATOR’S RESPONSIBILITIES ...................................................................................................... 116 
17 
REFERENCES ............................................................................................................................................... 117 
18 
APPENDICES ................................................................................................................................................ 119 
 
 
 
 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
LIST OF IN-TEXT TABLES 
Table 1: Investigational Medicinal Product Details ...........................................................56 
Table 2: Study Assessment Schedule ................................................................................74 
Table 3: The 10-point ordinal scale used in the WHO SOLIDARITY trial for assessment 
of patients’ clinical status ...................................................................................................83 
Table 4: Modified 8-point ordinal scale of Clinical Status ................................................84 
Table 5: Consolidation and density scoring in the Radiographic Assessment of Lung 
Edema (RALE) score .........................................................................................................84 
Table 6: National Early Warning Score 2 (NEWS-2) .......................................................86 
Table 7: Clinical / Diagnostic Laboratory Tests ..............................................................100 
 
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LIST OF IN-TEXT FIGURES 
Figure 1: Schematic diagram of study design ....................................................................44 
 
LIST OF APPENDICES 
Appendix I COVID-19: Developing Drugs and Biological Products for Treatment or 
Prevention - Guidance for Industry ..................................................................................120 
Appendix II: Ethical Principles for Medical Research Involving Human Subjects ........139 
Appendix III: INVESTIGATOR’S DECLARATION ....................................................146 
 
 
 
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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ACTT-1 
Adaptive COVID-19 Treatment Trial-1 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALT 
Alanine Transaminase/Alanine Aminotransferase 
AO 
Aldehyde Oxidase 
AST 
Aspartate Transaminase/Aspartate Aminotransferase 
AUC 
Area Under the Plasma Concentration-Time Curve  
AUCτ 
AUC during repeated dose intervals 
BD/BID 
Bis In Die (Twice Daily) 
BP 
Blood Pressure 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Maximum Observed Plasma Concentration 
Cmin 
Minimum observed Plasma Concentration 
COVID-19 
Novel Corona Virus Disease 2019 
CYP 
Cytochrome P-450 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCEA 
Common Terminology Criteria for Adverse Events 
DIC 
Diffuse Intravascular Coagulation 
DMC 
Data Monitoring Committee 
DMP 
Data Management Plan 
EC50 
Drug Concentration Producing 50% of Maximum Effect  
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation  
eCRF 
Electronic Case Report Form 
ENT 
Ear Nose Throat 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FiO2 
Fraction of Inspired Oxygen 
FPV 
Favipiravir 
GCP 
Good Clinical Practice 
GOT 
Glutamic Oxaloacetic Transaminase 
GPT 
Glutamic Pyruvic Transaminase 
Hb 
Haemoglobin 
IB 
Investigator’s Brochure 
IC50 
Drug Concentration Producing 50% of Maximum Inhibition 
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ABBREVIATION 
DEFINITION 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee  
Ig 
Immunoglobulin 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board  
ITT 
Intention to Treat 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
IFN 
Interferon 
JP321 
Japanese Phase III clinical study 
LAR 
Legally Acceptable Representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS-CoV 
Middle East Respiratory Syndrome Coronavirus  
mITT 
Modified Intention to treat 
MOI 
Multiplicity of Infection 
NEWS 
National Early Warning Score 
NIV 
Non-invasive Ventilation 
OTC 
Over the Counter 
PaO2 
Partial Pressure of Oxygen 
PIC 
Patient Identity Code 
PP 
Per Protocol 
PPS 
Per Protocol Set 
RBC 
Red Blood Corpuscles  
RdRp 
RNA-dependent RNA Polymerase  
RNA 
Ribonucleic Acid 
RT-PCR 
Reverse Transcriptase – Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAF 
Safety Population  
SAP 
Statistical Analysis Plan 
SARS‐CoV‐2 
Severe Acute Respiratory Syndrome Coronavirus 2  
SFTS 
Severe Fever with Thrombocytopenia Syndrome 
SOC 
System Organ Class 
SpO2 
Peripheral Capillary Oxygen Saturation 
T-705RMP 
Favipiravir ibofuranosyl-5′-monophosphate 
T-705RTP 
Favipiravir ibofuranosyl-5′-triphosphate 
TEAE 
Treatment Emergent Adverse Event 
WBC 
White Blood Corpuscles 
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ABBREVIATION 
DEFINITION 
WHO 
World Health Organization 
WHO-DG 
World Health Organization Drug Global 
XO 
Xanthine oxidase 
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1 
INTRODUCTION AND BACKGROUND INFORMATION 
Background Information 
The novel corona virus disease 2019 (COVID-19) is a global pandemic. COVID-19 is caused by 
severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). As of 29 June 2020, there have 
been 9,962,193 confirmed cases of COVID-19, including 498,723 deaths in 216 countries 
worldwide.1  
The human-to-human transmission occurs through respiratory droplets with an incubation period 
ranging from 2 to 14 days. Fever, fatigue, dry cough, myalgia, dyspnoea, expectoration and 
diarrhea are the common symptoms reported among patients with the COVID-19 infection.2 In 
addition to the respiratory system, this virus can infect the digestive system, the urinary system 
and the hematological system.3 Inflammatory reactions occur in the all organs of the body, the 
microvascular system is damaged, leading to abnormal activation of the coagulation system, which 
pathologically manifests as generalised small vessel vasculitis and extensive micro thrombosis.3 
There is direct viral invasion of cardiomyocytes, hypoxia due to severe pneumonia leading to 
ischemic cardiac tissue, or an overwhelming inflammatory response leading to cytokine storm and 
myocardial dysfunction.4 COVID-19 predispose to both venous and arterial thromboembolic 
disease due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular 
coagulation (DIC).5  
The common laboratory abnormalities in patients with COVID-19 infection includes increased 
counts / levels of neutrophils, D-dimer, C-reactive protein, lactate dehydrogenase, alanine 
transaminase (ALT), aspartate aminotransferase (AST), creatinine, creatine kinase, IgG and IgM. 
Decreased counts / levels of lymphocyte, platelet and albumin are also observed. The symptoms 
of SARS-CoV and Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections are 
similar to SARS-CoV-2 infection. The severity of the infection in patients with confirmed SARS-
CoV-2 can be identified using radiological images of the lungs. The different abnormalities 
observed in the lungs of patients including ground-glass opacities, consolidation, centrilobular 
nodules, architectural distortion, bronchial wall thickening, vascular enlargement, traction 
bronchiectasis, reticulation, crazy paving pattern, intrathoracic lymph node enlargement and 
subpleural bands, that cause pulmonary discomfort and require rapid diagnosis and treatment.6 
The main transmission routes for SARS-CoV-2 are respiratory droplets and close contact such as 
touching an infected person or the surfaces and fomites that the infected person has either touched, 
or on which large virus-containing droplets expired by the infected person have landed.7  
SARS-CoV-2, a single-stranded positive sense RNA virus, targets cells through the viral structural 
spike (S) protein embedded in the viral membrane (M) that binds to the angiotensin-converting 
enzyme 2 receptor on target host cells. Following receptor binding, the virus particle uses host cell 
receptors and endosomes to enter cells. Once inside the cell, viral polyproteins are synthesized that 
encode for the replicase-transcriptase complex. The virus then synthesizes ribonucleic acid (RNA) 
via its RNA-dependent RNA polymerase (RdRp). Structural proteins are synthesized leading to 
completion of assembly and release of viral particles.8  
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Clinical Study Protocol  
 
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Within six days of the onset of symptoms, patients with COVID-19 infections demonstrate high 
viral loads in their upper and lower respiratory tract. A nasopharyngeal swab and/or an 
oropharyngeal swab are often recommended for screening or diagnosis of early infection. For late 
detection and monitoring of patients with severe COVID-19 pneumonia, sputum or 
bronchoalveolar lavage should be used for collecting lower respiratory tract specimens.9  
Clinical care of suspected patients with SARS-CoV-2 infection focuses on recognition of the 
disease condition at the earliest, isolation and adoption of proper infection control measures, and 
delivery of optimized supportive care toward the suspected/confirmed cases. For preventive 
measure, the WHO guideline “Clinical management of severe acute respiratory infection when 
novel coronavirus (COVID-19) infection is suspected” mainly focuses on avoiding close contact 
with persons suffering from acute respiratory infections, frequent hand washing, and avoidance of 
unwanted contact with wild animals. In case of patients with respiratory distress, the patient is to 
be evaluated for the presence of shock. Empirical antimicrobial coverage is to be given to cover 
the likely causative organisms, which may be responsible for severe acute respiratory infection. 
Special concern is to be given for other comorbid conditions. In case of hypoxemic respiratory 
failure, it needs to be managed aggressively with high-flow nasal oxygen or noninvasive 
ventilation or by endotracheal intubation and positive pressure ventilation as required. Special 
concern is to be taken for the identification and management of septic shock.10  
The following drugs are being utilized as COVID-19 treatment in various clinical trials worldwide 
with varied results.  
Selected Repurposed Drugs: Agents previously used to treat SARS and MERS 
• Chloroquine phosphate 
• Hydroxychloroquine sulfate 
• Lopinavir/ritonavir 
• Ribavirin 
• Oseltamivir  
• Umifenovir (Arbidol) 
Investigational agents 
• Remdesivir 
• Favipiravir  
Adjunctive therapy8 
• Systematic corticosteroids 
• Cytokines or Immunomodulators (Tocilizumab) 
• IV immunoglobulin 
In the current study, Investigator may be guided by the current local guidance for COVID-19 
management or by the institutional practice, in his/her choice of supportive care for individual 
patients. The duration of supportive care will be based Investigator’s judgement and as per 
individual patient’s requirement.  
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1.1 
Name of Investigational Product 
AVIGAN® (Favipiravir) tablets 
1.1.1 Description 
Favipiravir (Favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide), also known as T-705, is a 
selective nucleic acid (purine) analog that is converted to Favipiravir ibofuranosyl-5′-
monophosphate (T-705RMP) and Favipiravir ibofuranosyl-5′-triphosphate (T-705RTP) by 
cellular kinases. Favipiravir is a novel nucleic acid (pyrazine molecule) analogue that interferes 
with viral ribonucleic acid (RNA) replication.11 T-705RTP is recognized as a substrate by the viral 
RNA-dependent RNA polymerase (RdRP), and it selectively inhibits the latter. 
1.1.2 Intended Use under Investigation 
Favipiravir is being developed for the treatment of acute, uncomplicated, mild to moderate 
COVID-19 illness and to potentially reduce transmission by abbreviating the duration of viral 
shedding. An in-vitro study by Wang et al12 found that SARS-CoV-2 was inhibited by 
favipiravir in Vero E6 cells with an EC50 of 61.88 µM. Favipiravir also inhibits growth in cells of 
pathogenic viruses from ten different RNA virus families and has been shown to be effective in 
animal models for RNA viral diseases including those caused by new and old world arenaviruses, 
Chikungunya virus, rabies virus, and Ebola virus. It has been used in compassionate use cases to 
treat people with Jamestown Canyon virus, Lassa fever, Ebola, norovirus and rabies.11 
1.1.3 Nonclinical Studies 
Nonclinical studies, single oral dose toxicity studies, repeated oral dose toxicity studies, 
genotoxicity studies and reproductive and developmental toxicity studies have been conducted 
using various species. Based on the results of these toxicity studies, it was identified that there are 
possibilities that adverse events (AEs) such as hepatic function disorder, renal impairment, 
anaemia symptoms, loss of appetite, queasy/vomiting, tissue discoloration, and testicular toxicity 
could occur in clinical studies. 
Early embryonic deaths (in rats) and teratogenicity (in monkeys, mice, rats and rabbits) have been 
observed in animal studies with exposure levels similar to or lower than the clinical exposure. 
Also, the in vitro anti-viral effect of favipiravir on SARS-CoV-2 was confirmed. Vero E6 cells 
were infected with nCoV-2019BetaCoV/Wuhan/WIV04/2019 with a multiplicity of infection 
(MOI) of 0.05 in the presence of various concentrations of favipiravir. The virus copy number in 
the cell supernatant was evaluated via quantitative real-time reverse transcription-polymerase 
chain reaction, and the emergence of virus nucleoproteins in immunofluorescence microscopy 
over 48 hours after infection was visualized for confirmation. The EC50 of favipiravir was 61.88 
μM) 12. 
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1.1.4 Clinical Experience 
JP 120 study was a 22-Day repeated dose study on favipiravir investigation of the 
pharmacokinetics, safety and tolerability in healthy subjects. In the JP120 study, favipiravir was 
administered at 1,800/800 mg BID, which is the same dosage as in this clinical study, in repeated 
doses for 22 days, the maximum observed plasma concentration (Cmax) was approximately 65 
μg/mL after the first dose on Day 1 and approximately 100 μg/mL after the first dose on Day 12 
and after administration on Day 22. The area under the plasma concentration-time curve (AUC) 
was approximately 720 μg·hr/mL after the first dose on Day 1, the AUC during repeated dose 
intervals (AUCτ) after the first dose on Day 12 and after administration on Day 22 was 
approximately 950 μg·hr/mL. The Cmin remained at approximately 56 to 75 μg/mL after the second 
dose on Day 1 and onward. 
Also, in the JP120 study, there were no serious adverse events (SAEs) including death or any 
significant AEs. The incidence of AEs was 100% (8/8 subjects, 16 events) in the favipiravir group 
and 1/2 subjects (1 event) in the placebo group. The incidence of AEs that occurred was as follows. 
In the favipiravir group: blood uric acid increase was 100% (8/8 subjects, 8 events), alanine 
aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, and white blood 
cells urine positive were each 25.0% (2/8 subjects, 2 events), and abdominal pain upper and rash 
were each 12.5% (1/8 subjects, 1 events). In the placebo group: the incidence of protein urine 
present was 1/2 subjects (1 event). The AEs that occurred in the JP120 study were all AEs for 
which a causal relationship with the investigational drug cannot be ruled out, except for white 
blood cells urine positive, which occurred in the favipiravir group. All AEs that occurred were 
mild in severity and resolved without any treatment. Based on the above, the safety and tolerability 
of favipiravir administered for 22 days were confirmed. 
In the Japanese Phase III clinical study (JP321), in which favipiravir was administered at 1,800/800 
mg BID, which is the same dosage as in this clinical study, in repeated doses for 10 days in patients 
with severe fever with thrombocytopenia syndrome (SFTS), three AEs (SFTS) that resulted in 
death occurred in three patients and six other SAEs (liver function test increased, Factor XIII 
deficiency, sepsis, myocarditis, seizure and respiratory arrest, one event each) in five patients. All 
these AEs, except for liver function test increased and seizure, were judged by the Principal 
Investigator to be unrelated to the study drug. The incidence of AEs was 86.7% (26/30 patients, 
116 events). Adverse events with an incidence of ≥ 10% were hyperglycemia and hyperuricemia 
each in 23.3% (7/30 patients), insomnia and blood uric acid increased each in 20.0% (6/30 
patients), constipation and rash each in 16.7% (5/30 patients), back pain in 13.3% (4/30 patients), 
oral candidiasis, SFTS, hypertriglyceridemia and pneumonia aspiration each in 10.0% (3/30 
patients). The incidence of AEs for which a causal relationship with the study drug could not be 
ruled out was 70.0% (21/30 patients, 40 events). Adverse events with an incidence of ≥ 10% were 
hyperuricemia in 23.3% (7/30 patients), blood uric acid increased in 20.0% (6/30 patients), and 
hypertriglyceridemia in 10.0% (3/30 patients). 
In a prospective, randomized, controlled, open-label study13 conducted on adult patients with 
COVID-19, 116 patients received Favipiravir (twice daily) and 120 patients received Umifenovir 
(thrice daily) plus standard care. Favipiravir was started with 1600 mg on the first day followed 
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by 600 mg for the following days upto a maximum of 10 days. In the comparator arm Umifenovir 
was given at 200 mg combined with standard care for 7 days. On Day 7, the clinical recovery rate 
in Favipiravir group was 71/116 and Umifenovir group was 62/120. There was no significant 
difference between the 2 groups. In Favipiravir group there was a significant improvement with 
respect to relief for fever and cough. But there was an increase in serum uric acid observed in 16 
patients receiving Favipiravir.  
Favipiravir was compared with Lopinavir/Ritonavir an open label study on patients with confirmed 
COVID-19. Oral Favipiravir (1600 mg twice daily on first day followed by 600 mg twice daily for 
the following days until Day 14) was given to 35 patients. In the control arm, 45 patients received 
oral tablet with combination of Lopinavir (400 mg)/Ritonavir (100 mg) twice daily for 14 days. 
Both the groups received interferon (IFN)-α by aerosol inhalation (5 million U twice daily). Viral 
clearance rate was shorter and improvement in chest imaging was significant in Favipiravir group 
compared to control group.14  
An observational study on Favipiravir registered 2,158 COVID-19 cases. These patients received 
orally 1800 mg Favipiravir twice daily on first day followed by 800 mg twice daily for the 
successive days for a mean duration of 11 days. The clinical improvement rates were 79% on Day 
7 and 92.4% on Day 14 in patients aged 59 years or younger. The same were 55% and 73.8% 
respectively in patients aged 60 years or older.15  
 
1.2 
Study Rationale 
Favipiravir is an antiviral drug that was discovered by FUJIFILM Toyama Chemical Co., Ltd. 
(previously, Toyama Chemical Co., Ltd.). At the time of initial registration, its indication was 
limited to “novel or re-emerging influenza virus infection (only for cases in which other anti-
influenza virus agents were not effective or were insufficiently effective),” and the drug was 
approved for marketing in Japan in March 2014. The mechanism of action of favipiravir is that the 
ribosyl triphosphate form (T-705RTP) converted in vivo selectively suppresses the viral RNA 
polymerase, and it has been shown in preclinical studies tobe effective on RNA viruses in addition 
to the influenza virus. Favipiravir has been reported to have an effect in vitro and in vivo against 
Ebola virus and viruses of the families Arenaviridae and Bunyaviridae, which are RNA viruses 16, 
17, 18. 
There is a Licensing agreement between Fujifilm and Dr Reddy’s Laboratories and Global 
Response Aid on development, manufacture and sale of Favipiravir tablets. Fujifilm authorises Dr 
Reddy’s Laboratories and Global Response Aid to implement clinical studies targeting COVID-
19 patients in India and Middle East and other regions where infections has been spreading. 
The novel coronavirus19 (SARS-CoV-2) first reported in China at the end of 2019 is an RNA virus, 
which belongs to the family Coronaviridae, order Nidovirales 20. When infected with this virus, 
fever and acute respiratory symptoms including cough and dyspnea develop, 19 and when the 
condition is exacerbated, pneumonia develops. COVID-19 is a multi-system disease that results 
from uncontrolled immune reaction (‘cytokine storm’) and clotting in smaller blood vessels.21 
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Clinical Study Protocol  
 
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CONFIDENTIAL 
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Confidential 
The drug concentration producing 50% of maximum effect (EC50) of favipiravir on SARS-CoV-2 
using Vero E6 cells reported by Wang et al. in the journal Cell Research was 61.88 μM12. This 
corresponded to 9.72 μg/mL and was almost equivalent to the drug concentration producing 50% 
of maximum inhibition (IC50) of 10.5 μg/mL (67 μM) 18 against Ebola virus. 
In a clinical study conducted in Ebola virus-infected patients in Sierra Leone, 22favipiravir was 
administered at 1,600 mg twice a day (BID) on Day 1 and 600 mg BID from Day 2 
(1,600/600 mg BID), which are the current approved doses for influenza virus infections, for 3 to 
11 days. The survival rate with favipiravir (except for patients who were transferred to other 
hospitals within 2 days after the treatment initiation) was 56.4% while with the conventional 
therapy (historical control) it was 35.3% (except for patients who were transferred to other 
hospitals within 2 days after the treatment initiation), demonstrating a significant difference (p = 
0.027). Following co-administration of interferon alpha-1b with favipiravir to COVID-19 patients 
in Shenzhen, China, the median time to elimination of SARS-CoV-2 was 4 days. The rate of 
improvement in findings from chest imaging was 56.25% (18/32 patients) on Day 9 and 91.43% 
(32/35 patients) on Day 14. Co-administration of interferon alpha-1b with favipiravir showed 
earlier therapeutic effect compared with that of co-administration of interferon alpha-1b with a 
lopinavir-ritonavir combination drug 14. 
In a 22-day multiple dose study (JP120)11 in which favipiravir was administered at 1,800 mg BID 
on Day 1 and 800 mg BID from Day 2 (1,800/800 mg BID) to Japanese healthy adult males aged 
20 to ≤ 39 years, the peak plasma concentration of favipiravir remained at approximately 87 to 
104 μg/mL on Day 5 and onward and the minimum plasma concentration after peak (Cmin) 
remained at approximately 56 to 75 μg/mL following the second dose on Day 1 and onward. This 
value was higher than the abovementioned EC50 of favipiravir, 9.72 μg/mL, on SARS-CoV-2 even 
taking into consideration the human protein binding ratio of favipiravir, which is approximately 
55%. These results showed that favipiravir may be effective in COVID-19 patients. 
Based on the fact a positive signal is seen with 1800/800 mg dose in COVID-19 patients with 
Favipiravir and safety has been established with this regimen for upto 22 days, 1800/800 mg dose 
has been chosen for the phase III study. 
There is no established treatment method for COVID-19, and a continuous increase in the number 
of COVID-19 patients is a concern based on epidemiological surveys to date. Given the relatively 
high contagiousness of SARS-CoV-2 and continuous outbreaks, the development of a treatment 
that is effective for COVID-19 is urgent. This clinical study was planned because if the therapeutic 
efficacy of favipiravir against COVID-19 in humans is demonstrated, it can significantly 
contribute to the treatment of COVID-19. 
Patients will be randomized to each treatment group and the study will be conducted in a ‘double-
blind’ fashion in order to minimize bias. The study will compare the safety and efficacy of 
favipiravir when administered as adjunct (‘add-on’) to supportive care as per local guidance to that 
of placebo added on to supportive care, and will enroll moderate to severe COVID-19 patients 
(those having a blood oxygen saturation < 95% at rest and requiring Oxygen supplementation). 
Given that there is currently no established treatment for moderate to severe COVID-19, it is 
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reasonable to use placebo as control, while using supportive care as per local guidance and 
management practices in both treatment groups as appropriate, to ensure patients receive the 
medical care they need. 
 
1.3 
Risks and Benefits for Study Patients 
Many medicinal treatments for COVID-19 disease are being administered off-label, or in the 
experimental setting. In this study, we are evaluating one such potential treatment, favipiravir, 
which has demonstrated some indirect and direct evidence of efficacy in the management of 
COVID-19 patients over and above the standard of care in accordance with the institutional 
guidelines.  
Patients will have clinical assessments, assays for detection of the SARS-CoV-2, other clinical 
laboratory evaluations and chest imaging performed, at more than one time points during the 
course of this study, at no cost to them, and may benefit from close medical oversight in the course 
of safety assessments in the trial. Finally, they would have altruistic satisfaction of having directly 
contributed to medical scientific research against an infectious disease that has emerged as a major 
current challenge to the human race, as well their immediate personal health. 
The risks to the study patients from study participation are that, they could possibly experience 
one or more adverse effects from any medications used as and from favipiravir such as blood uric 
acid increased, diarrhea, neutrophil count decreased, aspartate aminotransferase (AST) increased, 
alanine aminotransferase (ALT)increased. 
Serious adverse events reported in subjects taking this drug are hepatic function abnormality, 
hematochezia, colitis, seizure and acute kidney injury. It is not known if all are attributable 
favipiravir administration. 
The clinically significant adverse reactions of similar (anti-influenza) drugs requiring particular 
attention include shock, anaphylaxis, pneumonia, hepatitis fulminant, hepatic function disorder, 
jaundice, TEN, oculomucocutaneous syndrome (Stevens-Johnson syndrome), acute renal failure, 
neurological and psychiatric symptoms (consciousness disturbed, abnormal behavior, delirium, 
hallucination, delusion, convulsion, etc.), and colitis hemorrhagic. 
1.4 
Route, Dosage, Dosage Regimen, Treatment Period 
AVIGAN® (Favipiravir) is supplied as 200 mg tablets to be administered orally. The proposed 
dosing regimen for this study is 1,800 mg twice a day (BID) for 1 day followed by 800 mg BID 
for a maximum of 9 days. 
1.5 
Compliance Statement, Ethics and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that have their 
origin in the Declaration of Helsinki, the International Council for Harmonization (ICH) 
consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and applicable 
regulatory requirement(s) of Food and Drug Administration (FDA) GCP Regulations: Code of 
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Clinical Study Protocol  
 
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Federal Regulations (CFR) Title 21, parts 11, 50, 54, 56 and 312 as appropriate and/or local 
regulations.  
An approval must be obtained from applicable regulatory agencies and ethics committees.  
Patient’s written informed consent will be taken prior to any study procedure being conducted. 
1.5.1 Patient Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all patients taking part in the 
study, in accordance with GCP and local and applicable data protection regulations. 
The Investigator must ensure that the patient’s anonymity is maintained. On the electronic Case 
Report Forms (eCRFs) or other documents submitted to Sponsor/CRO, patients should be 
identified by a unique patient identifier as designated by the Sponsor. Documents that are not for 
submission to Sponsor/CRO (eg, signed Informed Consent Forms [ICF]) should be kept in strict 
confidence by the Investigator. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the Investigator 
and institution permit authorized representatives of the Sponsor companies or CRO, of the 
Regulatory agency(s), and the Independent Ethics Committee (IEC) or Institutional Review Board 
(IRB) direct access to review the patient’s original medical records for verification of study-related 
procedures and data. The Investigator is obligated to inform the patient that his/her study-related 
records will be reviewed by the above named representatives without violating the confidentiality 
of the patient. 
1.5.2 Informed Consent Procedure 
Before a patient’s participation in the study, it is the Investigator’s responsibility to obtain freely 
given consent, in writing, from the patient or legally acceptable representative (LAR) after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study 
and before any protocol-specific screening procedures or any study drugs are administered. The 
written ICF should be prepared in the local language(s) of the potential patient population. 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki. The consent form and any revision(s) should be 
approved by the IEC or IRB prior to being provided to potential patients. 
The patient’s written informed consent should be obtained prior to his/her participation in the 
study, and should be documented in the patient’s medical records, as required by 21 CFR Part 
312.62. The ICF should be signed and personally dated by the patient or a legally acceptable 
representative, and by the person who conducted the informed consent discussion (not necessarily 
the Investigator). The original signed ICF should be retained in accordance with institutional 
policy, and a copy of the signed consent form should be provided to the patient or legal 
representative. The date and time (if applicable) that informed consent was administered to the 
patient/legal representative should be recorded on the Case Report Form. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 40 of 146 
 
Confidential 
If the patient or legally acceptable representative cannot read, then according to ICH GCP 
Guideline, Section 4.8.9, an impartial witness should be present during the entire informed consent 
discussion. This witness should sign the ICF after the patient or the legally acceptable 
representative has orally consented to the patient’s participation and, if possible, signed the ICF. 
By signing the ICF, the witness attests that the information in the ICF and any other written 
information was adequately explained to and apparently understood by the patient or the legally 
acceptable representative and that informed consent was freely given by the patient or the legally 
acceptable representative. 
1.5.3 Regulatory Compliance 
The study protocol, patient information and consent form, the Investigator’s Brochure, any written 
instructions to be given to the patient, available safety information, patient recruitment procedures 
(eg, advertisements), information about payments and compensation available to the patients, and 
documentation evidencing the Investigator’s qualifications should be submitted to the IEC or IRB 
for ethical review and approval according to local regulations, prior to the study start. The written 
approval should identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the Statistical Analysis Plan (SAP). 
The Investigator must submit and, where necessary, obtain approval from the IEC or IRB and/ or 
Sponsor for all subsequent protocol amendments and changes to the informed consent document 
or changes of the investigational site, facilities or personnel. The Investigator should notify the 
IEC or IRB of deviations from the protocol or SAEs occurring at the site and other AE reports 
received from the Sponsor or Contract Research Organization (CRO) in accordance with local 
procedures. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 41 of 146 
 
Confidential 
2 
STUDY OBJECTIVES AND HYPOTHESES 
2.1 
Study Objectives 
Primary Objective: 
• To evaluate the efficacy of oral favipiravir in improving the time to resolution of hypoxia 
in moderate to severe COVID-19 patients 
Secondary Objectives 
• To evaluate the efficacy of oral favipiravir in improving the clinical and virological 
outcomes in moderate to severe COVID-19 patients 
• To assess the tolerability and safety of favipiravir in the targeted study population 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 42 of 146 
 
Confidential 
3 
STUDY DESIGN 
3.1 
Overall Study Design 
3.1.1 Study Type 
This is a prospective, interventional, multi-centre, phase III, randomized, double blind, placebo-
controlled, parallel design trial to evaluate the efficacy, safety and tolerability of favipiravir as 
adjunct (‘add on’) to supportive care, in comparison to placebo with supportive care, in the acute 
treatment of patients who have tested positive for SARS-CoV-2, presenting with moderate to 
severe COVID-19 and require hospitalization.  
This study will be conducted in two parts; Stage I – Main study and Stage II – Extended Follow 
up.  
Stage I – Main Study:  
All the eligible patients will be randomized to receive either favipiravir + supportive care or 
placebo + supportive care. The treatment duration with the IMP will be for a period of 10 
consecutive days. If the patient is discharged before Day 10, the patient will be required to continue 
the remainder of the treatment course of the assigned IMP at home. Patients in both the groups 
will receive supportive care, as appropriate. The duration of supportive care will be based 
Investigator’s judgement and as per individual patient’s requirement. The study data collection 
period will be up to 28 (+2) days.  
Day 10 will be considered as the End of treatment (EOT) assessment.  
1. If the patient remains in the hospital until Day 10, the EOT will be performed at the site 
and all the scheduled assessments for Day 10 will be performed (details mentioned in 
Section 6.3.1.3).  
2. If the patient is discharged before Day 10, the EOT can be performed either as an onsite 
visit or will be performed at the patient’s home (details mentioned in Section 6.3.1.4). 
a. On-site visit: If the patient is able to visit the hospital on Day 10, procedures for an 
unscheduled visit will be performed. 
OR  
b. At home: If the patient is unable to visit the hospital for the EOT, study nurse or 
phlebotomist will visit the patient at his/her residence to collect blood sample for safety 
assessments. A nasopharyngeal swab or oropharyngeal swab will be collected from the 
patient and sent for detection (qualitative) of SARS-CoV-2 RNA by RT-PCR assay 
based on Investigator’s discretion for individual patients. A telephonic follow up will 
be performed to enquire on treatment emergent AEs experienced, concomitant 
medication and COVID-19 associated symptom for assessment of clinical relapse. 
Day 28 will be considered the end of study visit.  
If patient is discharged from the hospital before Day 28, the assessments mentioned in the end of 
study visit (Day 28) will be performed before the patient is discharged. After discharge, telephonic 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 43 of 146 
 
Confidential 
follow up will be performed on Day 10 (applicable only for patients who are discharged earlier 
than Day 10 and if patients are unable to visit the site for EOT on Day 10), Day 14, Day 21 and 
Day 28. The telephonic follow up will be as applicable for the individual patient, depending upon 
the actual day when (s)he is discharged. A 2-day window period is allowed for telephonic follow 
up. 
In case the patient remains admitted in the hospital beyond Study Day 28, the end of study 
assessments will be performed for the patient on Day 28 (+2) days. 
Stage I of the study will be completed when the ‘Day 28’ assessment is completed either as an in-
patient assessment if the patient is still hospitalized, or as a telephonic follow up assessment if the 
patients are discharged earlier to Day 28. 
Once all the patients complete the Stage I of the study, the database would be locked, and analysis 
will be performed.  
Stage II – Extended Follow Up: 
All the patients will be followed up for AEs or for ‘clinical relapse’ of COVID 19. Two telephonic 
follow up assessments will be performed on Day 42 and Day 60. An additional visit to the hospital 
(for further assessment) may be scheduled for such patients, if required. A 2-day window period 
is allowed for telephonic follow up. 
3.1.2 Treatment Groups 
The study population will consist of patients of either sex, aged between 21 and 80 years (both 
inclusive) that have tested positive for SARS-CoV-2 by Reverse Transcriptase -Polymerase Chain 
Reaction (RT-PCR) assay using a respiratory tract sample (nasopharyngeal swab or oropharyngeal 
swab or nasal aspirate or tracheobronchial aspirate) and clinically assessed to have moderate to 
severe COVID-19. The study will be conducted in Middle East and Europe. An adequate number 
of patients will be screened in order to randomize 780 patients into two treatment groups at a 1:1 
ratio, so as to have approximately 390 patients in favipiravir + supportive care group and 390 
patients in placebo + supportive care group. 
An interim analysis and/or assessment futility and/or harm will be performed. An independent data 
monitoring committee (DMC) will review the results of the interim analysis to assess the efficacy 
and safety data emerging from the trial. The details of the interim analysis and/or futility/harm 
assessment will be included in a separate Interim Analysis Statistical Analysis Plan (SAP), that 
will be appended to the DMC charter. Sample size will be re-estimated based on the analysis of 
results for the primary endpoint observed during interim analyses. Details of the interim analysis 
and futility assessment are provided in the Statistical Analysis Plan (SAP) for the Interim Analysis. 
If there is a discrepancy in the planned analysis between the protocol and SAP, the SAP takes 
precedence.  
The study population will consist of patients admitted/ requiring admission in hospital. Figure 1 
provides a schematic overview about the study design. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 44 of 146 
 
Confidential 
Figure 1: Schematic diagram of study design 
 
The screening period will be for a maximum of 3 days. Although the duration of screening period 
is for a maximum of 3 days, once the results of the screening assessments are available and the 
patient successfully fulfils the eligibility criteria for the study, the Day 1 visit will be scheduled.  
On Day 1, once the pre-dose assessments are completed and the patient is found to be eligible to 
participate in the study, patients will receive either favipiravir + supportive care or placebo + 
supportive care as per the randomization schedule. Given the current pandemic situation, wherein 
patients reporting to the hospital sites with a suspicion of COVID-19 are undergoing specific 
evaluations/ investigations as part of their medical care which overlap those that are mentioned as 
part of screening procedure for this study, these specific investigations conducted within 72 hours 
prior to Randomization/Baseline Visit (Visit 2 /Day 1) may be accepted for determining study 
eligibility and not repeated again as part of Screening Procedure. Refer to Section 6 for further 
details. 
In both the treatment groups, patients will receive favipiravir/matching placebo for 10 consecutive 
days. If the patient is discharged from hospital before Day 10, the patient will be required to 
continue the remainder of the treatment course of favipiravir/matching placebo at home. Changes 
V1 
V2 
V3 
Treatment period (until Day 10) 
(Supportive care may be continued 
beyond Day 10) 
Screening  
(Day -3 to 
Day -1) 
Up to 72 
hours 
Favipiravir  
+ Supportive Care  
Placebo  
+ Supportive Care 
Day 10 
Randomization 
End of Study  
(Stage I) 
Day 1 
Day 60 
V
1
V
1
Stage I – Main Study*  
(until Day 28) 
V
1
V
1
Stage II – Extended Follow Up period for relapse 
(from Day 29 to 60 days after start of study treatment) 
Day 28 
Day 42 
Telephonic FU 1 
Telephonic FU 2 
V4 
V5 
Database 
lock 
* If patient is discharged from the hospital before Day 28, a telephonic follow up will be performed on Day 10 
(applicable only for patients who are discharged earlier than Day 10 and if patients are unable to visit the site for 
EOT on Day 10), Day 14, Day 21 and Day 28 as applicable for the individual patient. 
End of Treatment 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 45 of 146 
 
Confidential 
to the medications used in supportive care are permitted during the treatment period. The 
Investigator will record all changes to the medications (medication, dose, frequency, regimen, 
route of administration) in the dedicated eCRF page. As per Investigator’s clinical discretion, 
supportive care may be continued for individual patients beyond Study Day 10, as necessary; 
however, favipiravir/matching placebo will not be continued beyond Study Day 10 under any 
circumstance. Stage I of the study will be completed on Day 28. Stage II of the study will be 
extended follow up for safety and clinical relapse until Day 60. 
3.1.3 Study Endpoints 
3.1.3.1 Stage I 
3.1.3.1.1 Efficacy Endpoints  
Primary Efficacy Endpoint: 
Time to resolution of hypoxia (Time frame: Up to 28 days) 
This endpoint will be considered to have been met when the patient has attained a score of 4 or 
lower on the 10-point ordinal scale of clinical status and either of a) or b), and c) is met: 
a) Score is ≤ 4 on consecutive assessments over the next 5 days, if patient continues to remain 
in hospital (i.e., has not been discharged). 
OR 
b) Patient was discharged before five consecutive assessments (after reaching a score of 4). 
AND 
c) The patient has survived and has not been re-admitted to hospital for COVID-19 
management through Day 28. 
 Secondary Efficacy Endpoints: 
1. Time to discharge from hospital 
2. Time (no. of days) from randomization to the earliest time when ALL COVID-19 
associated symptoms (fever, chills, cough, sore throat, malaise, headache, muscle pain, 
gastrointestinal symptoms – specifically diarrhoea and vomiting, shortness of breath or 
dyspnoea) are scored by the Investigator/trained study personnel as either ‘0=absent’ 
or ‘mild =1’ in assessments over a period of 24 hours, when assessed from baseline to 
Day 28 or discharge from hospital (if discharge happens earlier than Day 28).  
3. Percentage of patients with score of either ‘0=absent’ or ‘mild =1’ over a period of 24 
hours, for ALL COVID-19 associated symptoms, by Days 4, 7, 10, 14, 21 and 28 or 
discharge (if discharge happens earlier than one or more of the above-mentioned 
timepoints)  
Note: Symptoms evaluated are fever, chills, cough, sore throat, malaise, headache, muscle pain, 
gastrointestinal symptoms- specifically, diarrhoea and vomiting, shortness of breath or dyspnoea. 
The Investigator/trained study personnel will assess (including by enquiry with the patient, as 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 46 of 146 
 
Confidential 
necessary) and score the severity of each COVID-19 associated symptom on a 5-point Likert-type 
scale (0= absent, 1= mild, 2=moderate, 3= severe, 4= very severe/critical).  
4. Time to improvement in EACH of the symptoms of fever, chills, cough, sore throat, 
malaise, headache, muscle pain, gastrointestinal symptoms- specifically diarrhoea and 
vomiting, shortness of breath or dyspnoea by at least 1 grade over baseline.  
Note: Severity of symptoms will be evaluated once daily (preferably at or around the same clock 
time) on each day that the patient is admitted in the hospital. The Investigator/trained study 
personnel will assess (including by enquiry with the patient, as necessary) and score the severity 
of each COVID-19 associated symptom on a 5-point Likert-type scale (0= absent, 1= mild, 
2=moderate, 3= severe, 4= very severe/critical). The improvement observed must be sustained at 
evaluations over a period of 24-hours, in order for this secondary efficacy endpoint to be reached. 
5. Percentage of patients reporting a clinical relapse of COVID-19 when assessed from 
day of discharge to 27 days after randomization (Day 28). 
Note: ‘Clinical relapse’ is defined as either the reappearance or worsening of severity (over the 
assessment on the day of discharge) of one or more of the above-mentioned COVID-19 associated 
symptoms, or the appearance of any of these symptoms (due to COVID-19 infection) for the first 
time after discharge. This endpoint will be assessed only for those patients that were discharged 
before Day 28. 
6. Time (no. of days) to negative conversion of detectable SARS-CoV-2 viral RNA in the 
RT-PCR assays of respiratory sample, from randomization. 
7. Percentage of patients showing negative conversion of detectable SARS-CoV-2 viral 
RNA in the RT-PCR assays of respiratory sample on Days 5, 10 and 28 or discharge 
(if discharge happens earlier than one or more of the above-mentioned timepoints)  
8. Changes over time in patient’s clinical status on the 10-point ordinal scale used in the 
SOLIDARITY trial by WHO 
a. Changes in the 10-point ordinal scale score from baseline until discharge   
b. Proportion of patients in whom clinical status score of 4 (‘hospitalized, no 
oxygen required’) or lower has been attained by Days 4, 7, 10, 14, 21 and 28 or 
discharge (if discharge happens earlier than one or more of the above-
mentioned timepoints) 
c. Time (no. of days) from randomization to clinical status score improvement by 
1 and by 2 points (from baseline)  
d. Proportion of patients for whom clinical status score improvement by 1 and by 
2 points has been attained by Days 4, 7, 10, 14, 21 and 28 or discharge (if 
discharge happens earlier than one or more of the above-mentioned timepoints) 
 
9. Changes over time in patient’s clinical status on the 8-point ordinal scale  
a. Time (no. of days) from randomization to attain clinical status score of 4 or lower  
b. Proportion of patients in whom clinical status score of 4 or lower has been attained 
by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier than one 
or more of the above-mentioned timepoints) 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 47 of 146 
 
Confidential 
c. Time (no. of days) from randomization to attain clinical status score of 3 or lower  
d. Proportion of patients in whom clinical status score of 3 or lower has been attained 
by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier than one 
or more of the above-mentioned timepoints) 
e. Time (no. of days) from randomization to clinical status score improvement by 1 
and by 2 points (from baseline)  
f. Proportion of patients for whom clinical status score improvement by 1 and by 2 
points has been attained by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge 
happens earlier than one or more of the above-mentioned timepoints) 
10. Changes over time in findings on chest X-ray  
11. Changes over time in the National Early Warning Score-2 (NEWS)  
12. Percentage of patients requiring, until Day 28 or discharge from hospital (if discharge 
happens earlier) 
a. Management in intensive care unit  
b. High Flow Nasal Oxygen or Non-invasive mechanical ventilation 
c. Invasive mechanical ventilation 
13. Time (no. of days) from randomization to: 
a. Management in intensive care unit  
b. High Flow Nasal Oxygen or Non-invasive mechanical ventilation 
c. Invasive mechanical ventilation 
over an assessment period from randomization until Day 28 or discharge from hospital 
(if discharge happens earlier) 
14. Duration (no. of days) the patient requires: 
a. Management in intensive care unit  
b. Oxygen supplementation 
c. High Flow Nasal Oxygen 
d. Non-invasive mechanical ventilation 
e. Invasive mechanical ventilation 
over an assessment period from randomization until Day 28 or discharge from hospital 
(if discharge happens earlier) 
15. Percentage of patients: 
a. dying from any cause 
b. dying from a COVID-19 associated complication 
over an assessment period from randomization until Day 28 or discharge from hospital 
(if discharge happens earlier) 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
3.1.3.1.2 Safety endpoints 
1. Number (and percentage) of patients reporting treatment emergent adverse events 
(TEAEs) (by MedDRA system organ class and preferred term) 
2. Changes of parameters at each assessment during the study/follow-up period, 
compared to baseline for: 
▪ Vital signs: body temperature, heart rate, respiratory rate, systolic/diastolic blood 
pressure (BP) and oxygen saturation.  
▪ Clinical laboratory assessments: hematology, serum chemistry, urinalysis. 
▪ 12-lead ECG: Changes in heart rate, PR, QRS, QT and QTcB intervals. 
3.1.3.2 Stage II 
3.1.3.2.1 Efficacy Endpoints: 
1. Percentage of patients reporting a clinical relapse of COVID-19 when assessed from day 
of discharge to 59 days after randomization (Day 60). 
Note: ‘Clinical relapse’ is defined as either the reappearance or worsening of severity (over the 
assessment on the day of discharge) of one or more of the above-mentioned COVID-19 associated 
symptoms, or the appearance of any of these symptoms (due to COVID-19 infection) for the first 
time after discharge.  
2. Proportion of patients 
a. With disease worsening and requires: 
• Admission to ICU 
• High flow nasal oxygen 
• Non-invasive mechanical ventilation 
• Invasive mechanical ventilation 
            AND 
b. Dying  
until Day 60 (regardless of whether patients are discharged from hospital before Day 28 or not) 
 
3.1.3.2.2 Safety Endpoints: 
1. Number (and percentage) of patients reporting treatment emergent adverse events (TEAEs) 
(by MedDRA system organ class and preferred term) 
Secondary endpoints may be modified, or additional secondary endpoints may be defined in the 
SAP. 
3.1.4 Duration of the Study 
The overall duration of the study from First-patient-First-Visit to Last-Patient-Last-Follow-up, 
including the recruitment period will be approximately 5 months. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
3.1.5 Duration of Patient Participation 
It is estimated that the total duration of the patient participation in the current study will not exceed 
67 days.  
Stage I: The duration of the patient participation in the Stage I of the study will not exceed 33 days, 
including a maximum of 3 days of screening period, a treatment period of 10 consecutive days and 
a study data collection period of 28 (+2) days.  
Study treatments Favipiravir/Placebo will be administered over 10 consecutive days. If the patient 
is discharged before Day 10, the patient will be required to continue the remainder of the treatment 
course at home. However, the above-mentioned treatment period will be shortened if it is necessary 
to discontinue administration of the study drug due to AEs or other circumstances.  
The patients will be discharged when the Principal Investigator or a medically qualified Sub 
Investigator judges that the patient is fit for discharge.  
Day 10 will be considered as the EOT assessment.  
1. If the patient remains in the hospital until Day 10, the EOT will be performed at the site 
and all the scheduled assessments for Day 10 will be performed (details mentioned in 
Section 6.3.1.3).  
2. If the patient is discharged before Day 10, the EOT can be performed either as an onsite 
visit or will be performed at the patient’s home (details mentioned in Section 6.3.1.4). 
c. On-site visit: If the patient is able to visit the hospital on Day 10, procedures for an 
unscheduled visit will be performed. 
OR  
d. At home: If the patient is unable to visit the hospital for the EOT, study nurse or 
phlebotomist will visit the patient at his/her residence to collect blood sample for safety 
assessments. A nasopharyngeal swab or oropharyngeal swab will be collected from the 
patient and sent for detection (qualitative) of SARS-CoV-2 RNA by RT-PCR assay 
based on Investigator’s discretion for individual patients. A telephonic follow up will 
be performed to enquire on treatment emergent AEs experienced, concomitant 
medication and COVID-19 associated symptom for assessment of clinical relapse. 
Day 28 will be considered the end of study visit.  
If patient is discharged from the hospital before Day 28, the assessments mentioned in the end of 
study visit (Day 28) will be performed before the patient is discharged. After discharge, telephonic 
follow up will be performed on Day 10 (applicable only for patients who are discharged earlier 
than Day 10 and if patients are unable to visit the site for EOT on Day 10), Day 14, Day 21 and 
Day 28. The telephonic follow up will be as applicable for the individual patient, depending upon 
the actual day when (s)he is discharged. A 2-day window period is allowed for telephonic follow 
up. 
In case the patient remains admitted in the hospital beyond Study Day 28, the end of study 
assessments will be performed for the patient on Day 28 (+2) days. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
Stage II:  
The duration of the patient participation in the Stage II of the study will not exceed 34 days. Two 
telephonic follow up assessments will be performed on Day 42 and Day 60. The patients will be 
followed up for AEs or for ‘clinical relapse’ of COVID 19. An additional visit to the hospital (for 
further assessment) may be scheduled for such patients, if required. A 2-day window period is 
allowed for telephonic follow up. 
3.1.6 Completion or Discontinuation of the Clinical Study and Discontinuation of 
Administration of the Study Drug (Completion or Discontinuation by Individual 
Patient) 
3.1.6.1 Study Discontinuation 
3.1.6.1.1 Study discontinuation criteria 
When a patient meets any of the following criteria, the Principal Investigator or a Sub-Investigator 
will discontinue the patient from the study. 
a. The patient requests withdrawal from the clinical study 
b. The patient died 
c. The patient is lost to follow-up 
d. The patient is otherwise deemed ineligible to continue in the study by the Principal 
Investigator or a Sub-Investigator (e.g adverse event or pregnancy)  
e. Upon request by the CRO or Sponsor Medical Monitor (with appropriate justification) 
3.1.6.1.2 Study discontinuation procedures 
If the patient is discontinued from the clinical study based on criteria mentioned in Section 
3.1.6.1.1, the Principal Investigator or a Sub-Investigator is to take appropriate action and conduct 
the assessments scheduled for Day 28 as specified in Section 6.3.1.5 before the patient is 
discharged. 
The date of discontinuation from the clinical study, the reason for discontinuing the patient from 
clinical study, and other details are to be investigated. One of applicable reason for discontinuation 
from the list below will be entered in the eCRF. 
When the patient misses the scheduled visits, the Principal Investigator or a Sub-Investigator will 
confirm the patient’s condition using methods such as telephone calls and mail and encourage the 
patient to visit the site. A follow-up investigation regarding the subsequent course of symptoms, 
and the presence or absence of AEs, will also be conducted within the scope of the patient’s 
cooperation, and the results will be recorded. When a follow-up investigation is impossible 
(because of a change of residence or other factors), such situations will also be recorded. A patient 
will be called ‘lost to follow-up’ if there is no response from the patient even after 3 documented 
telephone contact attempts on 3 different days.  
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 51 of 146 
 
Confidential 
3.1.6.2 Study Treatment Discontinuation   
3.1.6.2.1 Study treatment discontinuation criteria 
When a patient meets any of the following criteria, the Principal Investigator or a Sub-Investigator 
will discontinue administering the study drug to that patient. 
a. The patient requests withdrawal from the clinical study 
b. If the patient requests discontinuation of administration of the study drug  
c. The patient died 
d. The patient is lost to follow-up 
e. If an AE occurs and the Principal Investigator or a medically qualified Sub-Investigator 
judges that continuing with the administration of the study drug would not be in the interest 
of patient’s safety or well-being  
f. If a patient experiences a serious adverse event assessed by Investigator and/or Medical 
Monitor to be reasonably causally related to the IMP (FPV/Placebo) 
g. If a patient becomes pregnant while receiving IMP (FPV/Placebo) 
h. If patient’s serum uric acid or hepatic transaminases levels are assessed as Grade 3 severity 
by National Institutes of Health (NIH) National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE)23, at any timepoint during the 
treatment period  
i. If a patient is otherwise deemed ineligible to continue in the study by the Principal 
Investigator or a Sub-Investigator 
j. Upon request by the CRO or Sponsor Medical Monitor (with appropriate justification) 
3.1.6.2.2 Study treatment discontinuation procedures 
If the study drug administration is discontinued based on Section 3.1.6.2.1, the Principal 
Investigator or a Sub-Investigator need to take appropriate action. The date of, and reasons for, 
discontinuing administration of the study drug and the details (including actions taken after 
discontinuation of drug administration and the outcome, if the study drug was discontinued due to 
an AE) are to be investigated and captured in the eCRF. One of applicable reason for 
discontinuation from the list below will be entered in the eCRF. 
Even if the administration of study treatment is stopped, patients will be encouraged to continue 
in the study and provide the applicable scheduled assessments, as specified in Section 6.3 until the 
patients are discharged, as long as they do not meet the criteria for study discontinuation.  
 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 52 of 146 
 
Confidential 
4 
STUDY POPULATION 
The study population will consist of patients of either sex, 21 to 80 years of age, who test positive 
for SARS-CoV-2 by RT-PCR assay using a respiratory tract sample (nasopharyngeal swab or 
oropharyngeal swab or nasal aspirate or tracheobronchial aspirate), have moderate to severe 
clinical presentations of COVID-19 and require hospitalization. An adequate number of patients 
will be screened to randomize 780 patients in a 1:1 ratio, so as to have approximately 390 patients 
in favipiravir + supportive care group and 390 patients in placebo + supportive care group.  
4.1 
Enrollment 
Patients are eligible for enrolment into the study if they meet all the inclusion criteria and do not 
meet any of the exclusion criteria. 
4.1.1 Inclusion Criteria 
Patients must satisfy all the following criteria to be included in the study: 
1. Male and female patients aged 21 to 80 years (both inclusive) 
2. Patients who have tested positive for SARS-CoV-2 by RT-PCR assay using a respiratory 
tract sample (either nasopharyngeal swab OR oropharyngeal swab OR nasal aspirate OR 
tracheobronchial aspirate) collected within 72 hours prior to randomization 
3. Patients should be hospitalized 
4. Patients having moderate or severe COVID-19* with a score of > 4 on the 10-point ordinal 
scale of clinical status used by WHO in the SOLIDARITY trial, at baseline assessment 
[i.e., patients with blood oxygen saturation (SpO2) <95% at rest on room air at sea level 
and requiring supplemental oxygen].  
 
*Note: This includes patients clinically assigned as: 
I. 
‘moderate’ COVID-19 
a. symptoms which could include fever, cough, sore throat, malaise, headache, 
muscle pain, gastrointestinal symptoms or shortness of breath with exertion 
and/or clinical signs, such as respiratory rate ≥20 breaths per minute or heart rate 
≥90 beats per minute  
AND 
b. blood oxygen saturation (SpO2) of 94% at rest on room air at sea level 
 
II. 
‘severe’ COVID-19 
a. 
symptoms which could include any symptom of moderate illness or shortness of 
breath at rest, or respiratory distress and/or clinical signs, such as respiratory rate 
≥30 per minute or heart rate ≥125 per minute 
AND 
b. 
blood oxygen saturation (SpO2) ≤93% on room air at sea level or PaO2/FiO2 
<300* 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 53 of 146 
 
Confidential 
The above-mentioned definitions of COVID-19 severity are adapted from the FDA Guidance document 
COVID-19: Developing Drugs and Biological Products for Treatment or Prevention - Guidance for 
Industry Final Document dated May 202024 
5. Female patients of childbearing potential* 
a. must have a negative serum pregnancy test at screening  
b. should not be lactating; and not planning to become pregnant/breast feed during 
the treatment period and for 7 days after the last dose of study medication. 
c. should commit to the use of TWO forms of study-acceptable contraception 
methods, including a barrier method (eg. diaphragm) along with one or more of the 
following methods of contraception for the duration of the treatment period and for 
7 days after the last dose of study medication:  
i) 
hormonal 
methods 
[insertable, 
injectable, 
transdermal, 
or 
combination oral (estrogen+ progestin)] or  
ii) 
intrauterine contraceptive device  
Note: Female patients who are sexually abstinent or whose male sexual partner 
has undergone vasectomy at least three months prior to the start of study treatment 
in the trial may be enrolled at the Investigator’s discretion, provided that they are 
counseled to remain sexually inactive for the duration of the study and understand 
the possible risks involved in getting pregnant during the study. Patients must also 
agree to use TWO forms of study-acceptable contraception methods should they 
become sexually active during the treatment period and for 7 days after the last 
dose of study medication. 
*Note: A female patient is considered of childbearing potential unless she is: 
a. postmenopausal for at least 12 months prior to study product administration, or 
b. without a uterus and/or both ovaries or has been surgically sterilized (ie, tubal ligation 
or has a fallopian tube blocking coil) for at least 6 months prior to study product 
administration.  
6. Male patients should agree to abstain from sexual intercourse or to use double-barrier 
contraception (e.g. condom with spermicide) for the duration of the treatment period in the 
study and for at least 7 days after receiving the last dose of study medication. Male patients 
should also avoid semen donation or providing semen for in-vitro fertilization during the 
above-mentioned duration. 
7. Able and willing to provide informed consent 
8. Able to understand the trial requirements and comply with trial medications and 
assessments in the opinion of the Investigator 
9. Should not have received investigational treatment from participation in another clinical 
trial within 30 days prior to randomization in the current trial and agrees not to participate 
in other clinical studies during the entire study period 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 54 of 146 
 
Confidential 
4.1.2 Exclusion Criteria 
Patients who meet any of the following criteria will be disqualified from entering the study: 
1. Critically ill patients, defined as those who are candidates for endotracheal intubation and 
mechanical ventilation, Extracorporeal Membrane Oxygenation (ECMO), or clinical 
diagnosis of respiratory failure (i.e., clinical need for one of the preceding therapies, but 
preceding therapies not able to be administered in setting of resource limitation) and those 
with shock (defined by systolic BP <90 mm Hg, or diastolic BP <60 mm Hg or requiring 
vasopressors) or multi-organ dysfunction/failure at baseline 
Note: The above-mentioned definition of ‘critically ill’ COVID-19 patients is as defined in the 
FDA Guidance document COVID-19: Developing Drugs and Biological Products for 
Treatment or Prevention - Guidance for Industry Final Document dated May 202024 
2. Patients in whom the first onset of symptoms/signs suggestive of COVID-19 illness was 
observed >10 days earlier to the baseline assessment and randomization 
3. Patients who have used interferon beta 1-a (IFN-β-1a) preparations or drugs with reported 
anti-viral action against SARS-CoV-2 (hydroxychloroquine sulfate, chloroquine 
phosphate, lopinavir-ritonavir combination drugs, ciclesonide, nafamostat mesylate, 
camostat mesylate) within 9 days after development of fever (≥37.5°C) 
Note: The above-mentioned exclusion criterion is not applicable in case of patients with history 
of human immunodeficiency virus infection or infective hepatitis in whom use of anti-viral 
drugs or interferons are prescribed for treatment of the underlying condition and who are 
currently receiving one or more of these medications (as maintenance treatment) at the time of 
randomization. The infection episode in question is a relapse of, or reinfection with SARS-
CoV-2 
4. Patients suspected to have a complication of congestive cardiac failure based on 
Investigator’s clinical judgement 
5. Patients with moderate and severe hepatic dysfunction equivalent to Grade B and Grade C 
in the Child-Pugh classification respectively 
6. Patients with ALT and AST levels > 5 times upper limit of normal (ULN) at screening 
evaluation 
7. Patients with renal impairment requiring dialysis 
8. Patients with serum uric acid higher than the ULN at screening evaluation 
9. Patients with history of hereditary xanthinuria 
10. Patients who have been diagnosed with xanthine urinary calculus 
11. Patients with a history of gout or patients who are currently being treated for gout 
12. Patients who are taking immunosuppressants  
13. Patients who were administered Favipiravir in the past 30 days 
14. Patients with known hypersensitivity reaction to Favipiravir 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 55 of 146 
 
Confidential 
4.2 
Removal of Patients from Therapy 
4.2.1 Withdrawal Procedures 
Patients who drop out will be asked about the reason(s) for their discontinuation and about the 
presence of any AEs. If a patient withdraws consent or is discontinued from the study before 
completion, every effort should be made to complete the assessments scheduled for Day 28. The 
PI must provide a written report on the appropriate eCRF page describing the reason for 
discontinuation. The primary reason for the discontinuation must also be recorded in patient’s 
medical record along with eCRF. Adverse events should be followed up and all investigational 
products should be returned by the patient.  
If the Principal Investigator or a medically qualified Sub-Investigator judges that the patient is fit 
for discharge, the assessment specified on Day 28 (Section 6.3.1.5) will be performed.  
4.2.2 Patient Replacement 
Patients who drop out from the study after enrolment will not be replaced. 
4.2.3 Patient Re-screening Procedures 
Not applicable. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 56 of 146 
 
Confidential 
5 
TREATMENTS ADMINISTERED 
5.1 
Investigational Product(s) 
The Investigator must ensure that the investigational medicinal products (IMP) will be used only 
in accordance with the protocol. The IMP will be manufactured complying with all required 
regulations. Sufficient quantities of the IMP will be supplied to the clinical study facility by the 
Sponsor. Batch numbers and expiration dates will be filed in the study documents when available. 
See the Table 1 below for ingredient list of each product.  
Table 1: Investigational Medicinal Product Details 
 
Treatment 
Comparator 
Active Ingredient 
Favipiravir (+ supportive care a) 
Placebo (+ supportive care a) 
Brand name 
AVIGAN® (T-705) 
Placebo 
Dosage form 
Tablets 
Tablets 
Strength 
200 mg 
Not Applicable 
Dosage 
1,800 mg BID on Day 1 + 800 mg 
BID for next 9 days (maximum) 
On Day 1, the second dose will be 
administered with at least a 4-hour 
interval from administration of the 
first dose. 
9 tablets for BID on Day 1 + 4 tablets 
BID for next 9 days (maximum) 
On Day 1, the second dose will be 
administered with at least a 4-hour 
interval from administration of the 
first dose. 
Frequency 
Twice daily (morning and evening) 
Twice daily (morning and evening) 
Route of 
administration b 
Oral 
Oral 
Supplied by c 
FUJIFILM Toyama Chemical Co., 
Ltd. 
4-1, Shimookui 2-chome, Toyama-
shi, Toyama (Japan) - 930-8508 
FUJIFILM Toyama Chemical Co., 
Ltd. 
4-1, Shimookui 2-chome, Toyama-shi, 
Toyama (Japan) - 930-8508 
a Patients in both the groups will receive supportive care, as appropriate. The Investigator may be guided 
by the current local guidance for COVID-19 management or by the institutional practice, in his/her 
choice supportive care for individual patients. The duration of supportive care will be based 
Investigator’s judgement and as per individual patient’s requirement.  
COVID 
management 
guidelines 
of 
Kuwait: 
https://www.moh.gov.kw/UserRefs/Technical%20Dept/AdultC19.pdf  
COVID 
management 
guidelines 
of 
United 
Arab 
Emirates: 
https://covidaba.com/wp-
content/uploads/2020/06/National-Guidelines-for-Clinical-Management-and-Treatment-of-COVID-19-
Version-4-1-June-2020.pdf  
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 57 of 146 
 
Confidential 
 
Treatment 
Comparator 
b During the study period, in case of patient’s clinical status deteriorates as to require invasive mechanical 
ventilation and patient is not able to take IP orally, IP can be powdered and administered as a suspension 
in water through Ryle’s tube, if patient continues in the study as per Investigator’s judgement. 
c Dr. Reddy Ltd. is an Authorised Licensee of Avigan (Favipiravir) with FUJIFILM. 
Note: For the purpose of this trial, Investigational Medicinal Product/ IMP refers to favipiravir and 
matching placebo. The use of terms study medication / study drug / study treatment is non-standard and in 
certain contexts may refer to IMP and the medications prescribed as part of supportive care (including 
symptomatic treatments) for individual patients. 
5.1.1 Method of Assigning Patients to Treatments  
A total of 780 eligible patients will be assigned randomly to one of two treatment groups in 1:1 
ratio, so as to have approximately 390 patients in favipiravir + supportive care group and 390 
patients in placebo + supportive care group.  Details of the interim analysis and futility assessment 
are provided in the Statistical Analysis Plan (SAP) for the Interim Analysis. 
Patients will be randomized to the favipiravir + supportive care group or placebo + supportive care 
group in a 1:1 ratio and a conditional stratification will be performed to include at least 15% of 
female patients, at least 30% of patients with either category of baseline disease severity (i.e., 
moderate and severe) and at least 30% of patients aged more than 50 years randomized in each of 
the treatment groups. If there is an impact on the patient recruitment rate due to limits enforced by 
the stratification of patients based on the category of baseline disease severity, a decision may be 
made to waive the stratification based on disease severity. The percentage of stratification may be 
adjusted according to the re-estimated sample size. The randomization schedule will be generated 
by CRO statistical team, in SAS, (version 9.4 or higher), according to CRO’s standard operating 
procedures (SOPs).  
All patients who sign an IRB/IEC approved informed consent form and authorization for the use 
and disclosure of protected health information will be assigned a unique patient identity code (PIC) 
consisting of 03-digit center/site code and three digits (004) patient specific code. The 
randomization code will be captured separately as an additional identity.  
5.1.2 Method of Assessing Treatment Compliance 
Compliance to study treatment will be assessed every day the treatment is administered.  
If patient is in the hospital for 10 days, compliance will be assessed by supervised administration/ 
intake history of all supportive medications and the IMP dose (as per the prescribed regimen) and 
also by periodic IMP pill counts. Patients judged to be non-compliant will be counselled on the 
importance of daily intake of study medication, as prescribed. Patients who are repeatedly or 
severely non-compliant may be discontinued, at Investigator’s discretion. 
If the patient is discharged before Day 10, the patient will be required to continue the remainder 
of the IMP treatment course at home. The compliance for the medication taken at home will be 
evaluated based on the details in the patient diary. The patients will be counselled on the 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 58 of 146 
 
Confidential 
importance of daily intake of study medication, as prescribed, and instructed to comply to 
instructions provided by study personnel on how and when to s(he) should take IMP (and any SoC 
medications) at the time of discharge.  
The number of days the treatment was taken overall and the number of days the treatment was 
taken in compliance with the prescribed regimen (for supportive care) and the protocol (for IMP) 
will be assessed.  
This information will be recorded in the eCRF. 
5.1.3 Labeling and Packaging 
It will be the Sponsor’ responsibility to provide the IMP (favipiravir and placebo). Packaging and 
labelling will be done in accordance with the principle of Good Manufacturing Practice (GMP) 
and the applicable national and/or local regulatory requirements by the Sponsor/designated vendor. 
The following general information will be provided on the clinical trial supply label: 
• Protocol Number 
• Product Name and Strength 
• Brief Instructions for use  
• Storage Instructions 
• Batch or Lot # 
• Expiry date 
• Supplier of drug 
Cautionary Statement – “For clinical trial purpose only” 
Note: Sponsor will not supply any medications that are prescribed as part of supportive care for the 
patients.  
5.1.4 Preparation 
A pharmacist or designated site staff personnel, delegated by the Investigator, will dispense 
sufficient IMP to each individual patient.  
When the patient is at the site, a delegated pharmacist/ staff personnel will maintain comprehensive 
and accurate records of the dispensing and dose administration for the IMP dispensed and dosed 
to each individual patient, date and time of dispensing of each dose of IMP, any IMP units that 
were dispensed but not dosed to patients, at each designated treatment administration timepoint. 
Details of medication administered as part of supportive care (medication name [brand and 
generic] dosage form, strength, dose, frequency, route of administration, time[s] of 
administrations) will also be recorded on a daily basis for each individual patient or Investigator 
decides no further supportive treatment is necessary for the individual patient, whichever is earlier. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 59 of 146 
 
Confidential 
(This would also include any medication that might be used to treat one or more of the core 
symptoms of COVID-19 ([eg. analgesics or antipyretics])  
If the patient is discharged before Day 10, the remaining treatment course will be continued at 
home. Delegated pharmacist/ staff personnel will dispense the study drug to each individual patient 
to be taken at home at the time of discharge. Delegated pharmacist/ staff personnel will maintain 
comprehensive and accurate records of the dispensing of IMP.  
Note: Any IMP units that was dispensed but not dosed to patients at a designated timepoint (for whatever 
reason) should not be re-dispensed in the trial. Instead such IMP units should be labelled appropriately 
and stored separately (from undispensed IMP) at the site, until return to Sponsor/ CRO/ designated vendor 
for destruction. 
5.1.5 Drug Accountability 
When IMP shipment is received, the Investigator or designated site staff personnel (preferably a 
pharmacist) will check the amount and condition of the IMP (including temperature during transit), 
check drug expiration date, and sign the Receipt of Shipment Form provided. The Receipt of 
Shipment Form should be scanned by the site and shared with Sponsor/CRO/designated vendor. 
The original Form will be retained at the site. In addition, the Investigator or designee shall contact 
site clinical research associate (CRA) as soon as possible if there is a problem with the shipment. 
An Investigator designated site staff personnel, preferably a pharmacist outside the isolation ward, 
will be responsible for study drug accountability, reconciliation, and record maintenance. In 
accordance with all applicable regulatory requirements, the designated site staff (study pharmacist) 
will maintain accurate study drug accountability records throughout the course of the study. An 
electronic or manual drug accountability log for recording the receipt, dispensing and return of 
study drug will be maintained to document the amount of drug received, and the amount of drug 
used in the study. Study medication requests, receipts and dispensing records as well as study 
medication inventory forms will be examined and reconciled during and at the end of the study by 
the Sponsor/CRO/designated vendor personnel. The reconciliation can happen remotely whilst 
checking scanned documents and electronic documents and possibly with on-site monitoring visit, 
as appropriate.  
If the patient is discharged before Day 10, the details of treatment regimen completed at home will 
captured in the patient diary and transcribed to the eCRF and IMP accountability log. If the patients 
continue to be on supportive care, the details of medication administered as part of supportive care 
will enquired during the telephonic follow up and also be recorded in the eCRF. The IMP 
accountability will also be checked using the empty blisters and unused IMP returned during the 
Day 10 visit.  
All unused or partially used IMP must be returned to the Sponsor/designated vendor at the end of 
the study for destruction. Reconciliation between the amounts of IMP supplied, used and returned 
to the Sponsor/designated vendor must be performed and any discrepancies accounted for. This 
reconciliation will be logged on the study IMP reconciliation form, signed and dated. The study 
drug destroyed on site, if any and as appropriate, will be documented in the study files. A Drug 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 60 of 146 
 
Confidential 
Accountability electronic or manual record will be provided for the study drug and should be 
maintained. The details for the Drug accountability will be included within the Clinical Monitoring 
Plan. 
5.1.6 Blinding and Unblinding 
This will be a double-blind randomized study. All investigators, patients, site personnel, Sponsor 
and CRO study team (except persons involved in preparation of the codes and the safety 
monitoring group and unblinded biostatistician involved in the interim analysis and to present data 
to DMC for closed sessions), will be blinded to the medication codes. The medication codes will 
not be available to the investigators, patients, site personnel, Sponsor and CRO study team (except 
persons involved in preparation of the codes and the safety monitoring group) until completion of 
the study and final data review (clinical database lock) except in case of an emergency. 
A treating physician may request unblinding of study medication for an individual patient, if it is 
essential for the clinical management of the patient’s health, or to ensure safety. If a treating 
physician requires unblinding of study medication on a patient, e.g. for management of a SAE, the 
investigators will be able to access this information via IWRS. The Sponsor and CRO medical 
monitor should be contacted immediately (preferably before unblinding takes place).  
As back up to the IWRS, sealed envelopes containing the randomized study treatment (Favipiravir 
or Placebo) for each patient in the trial will be held in the secure custody (under ‘lock and key’) 
by a designated third party vendor, who would be accessible round the clock to the Investigator in 
case unblinding of treatment becomes necessary for individual patients (in the event of a medical 
emergency where knowledge of the treatment administered is essential). 
The date and reason for unblinding has to be documented in the source document (medical record) 
and CRF, accordingly. The CRO medical monitor or designee is required to contact and inform 
the Sponsor regarding unblinding of the patient’s treatment. 
5.1.7 Dosing Schedule, Selection and Timing of dosing 
Dosing schedule of study medications is mentioned under Section 5.1. 
5.1.8 Instructions for Patients 
Patients will be instructed as follows: 
1. Patients have to take the medicines regularly, as per the treatment group they are assigned 
and the dosage regimen prescribed. 
2. Patients have to comply with all other requirements of the study protocol. 
3. Patients must try and adhere to any oral or written instructions provided by the Investigator 
on how the study treatment is to be taken.  
4. Patients should inform the Investigator if they believe they are not able to tolerate study 
medication or develop severe side effects. 
5. Patients must inform the Investigator or site staff if they develop any side effects or 
experience any symptoms after discharge and until Day 60. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 61 of 146 
 
Confidential 
6. If the patient is discharged before Day 10, the patients will be dispensed the remainder of 
the treatment course to be taken at home. Patients will be instructed to return the empty 
blister and unused IMP to the site.  
5.1.9 Concomitant Medications 
Concomitant treatment with other medications (other than the investigational products and 
prohibited medications) for the control of AEs or other conditions identified during screening 
(medical history) are permitted during the study. 
The medications provided to treat the core symptoms of COVID-19 (e.g., analgesics or 
antipyretics) will be recorded daily, including name of medication, dose, unit, frequency, route 
and date(s) of administration in a separate module in the eCRF. 
5.1.10 Drug-Drug Interaction 
Favipiravir is not metabolized by cytochrome P-450 (CYP). It is metabolized by aldehyde oxidase 
(AO) and partially metabolized by xanthine oxidase (XO). Also, it inhibits AO and CYP2C8, but 
no CYP-induction has been observed. 
Favipiravir may show drug-drug interactions with the following medications and caution must be 
exercised when co-administering favipiravir with these drugs. 
1. Pyrazinamide 
Pyrazinamide additively promotes reabsorption of uric acid in the renal tubular, increasing 
blood uric acid levels. 
2. Repaglinide 
Inhibition of CYP2C8 by favipiravir increases blood concentrations of repaglinide, 
increasing the risk of adverse reactions associated with repaglinide. 
3. Theophylline 
Theophylline increases the blood concentration of favipiravir via XO, increasing the risk 
of adverse reactions associated with favipiravir. 
4. Famciclovir 
Inhibition of AO by favipiravir may reduce famciclovir’s efficacy. 
5. Sulindac 
Inhibition of AO by favipiravir may reduce sulindac’s efficacy. 
Patients should not be administered or take acetaminiphen/paracetamol at doses of ≥ 3000 mg per 
day whilst receiving favipiravir. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 62 of 146 
 
Confidential 
5.1.11 Prohibited concomitant drugs 
Use of the following medications is prohibited during the study period because they may affect 
the efficacy evaluation of the study drug. 
1. Other drugs under development for treatment of COVID-19 
2. Interferon alpha or beta preparations 
3. Drugs with anti-viral effect (those that directly inhibit the virus grown and multiplication) 
are not permitted eg., zanamivir, oseltamivir, lopinavir/ritonavir, ribavirin, umifenovir, etc.  
4. The following drugs whose anti-viral action against SARS-CoV-2 has been reported  
a. Hydroxychloroquine sulfate, chloroquine phosphate 
b. Ciclesonide 
c. Nafamostat mesylate 
d. Camostat mesylate 
Exceptions will be made in case of patients with human immunodeficiency virus infection or 
infective hepatitis, in whom use of anti-viral drugs or interferons are prescribed for treatment of 
the underlying condition and these medications may be permitted.  
5.1.12 Rescue Medications 
Acute deterioration of disease conditions has been reported in some COVID-19 patients. In such 
cases, further treatment management will be as per the Principal Investigator’s or a medically 
qualified Sub-Investigator’s discretion and hospital protocol or practice for treating COVID-19.  
Study treatment with the IMPs (Favipiravir/Placebo) will be permanently discontinued before 
starting treatment with convalescent plasma. In such cases, the Principal Investigator or a Sub-
Investigator will record assessment specified in Section 6.3.1.5 in accordance with Section 
3.1.6.2.2. 
Study treatment with the IMPs can be continued with rescue treatment like remdesivir, and IL-6 
pathway antagonists like tocilizumab. The details of rescue medication (medication, dose, route, 
start date, frequency of administration, end date etc.) will be captured.  
The use of low molecular weight heparin, vasopressors, rehydration fluids is allowed as per 
patient’s clinical status and local management guidelines/hospital practice. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
6 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided in Table 2. All study assessments (with the 
exception of telephonic follow up assessments on Study days 10, 14, 21, 28 (as applicable) and on 
Days 42 and 60) will be performed on an in-patient basis. 
6.1 
Stage I – Main Study 
6.1.1 Visit 1 - Screening (Day -3 to Day -1) 
An adequate number of patients will be screened to ensure enrolment of 780 patients into the study. 
The duration of screening period will be from Day -3 to Day -1. The Principal Investigator or his 
designee will explain the nature of the study, give full details and obtain a written informed consent 
from the patient prior to their participation in any study related procedures.  
All inclusion/exclusion criteria will be assessed. Demographic characteristics including age, 
gender, nationality, race, height and weight will be assessed. A detailed medical history will be 
elicited regarding symptoms and prior medical/surgical therapies in the past 1 year prior to date of 
screening. Prior medications will include all medications that the patient has received in the past 
1 month prior to date of screening and those which are still ongoing will be recorded at this visit. 
COVID-19 associated symptom severity assessment will be performed. A respiratory tract sample 
(nasopharyngeal swab or oropharyngeal swab or nasal aspirate or tracheobronchial aspirate) will 
be collected from the patient and sent for detection (qualitative) of SARS-CoV-2 RNA by RT-
PCR assay. The patient’s clinical severity will be assessed. The clinical status by WHO 10-point 
ordinal scale, 8-point ordinal scale and NEWS-2 score will be evaluated and recorded. Safety 
assessments [vital signs, complete physical examination, serum pregnancy test for women of 
childbearing potential, 12-lead ECG, clinical laboratory evaluations (hematology, serum 
biochemistry, urinalysis)] will be performed. Chest X-ray will be performed at this visit. AEs 
reported after signing the informed consent and before receiving the first dose of study drug will 
be recorded as pre-treatment AEs.  
Although the duration of screening period is for a maximum of 3 days, once the results of the 
screening assessments are available and the patient successfully fulfills the eligibility criteria for 
the study, the next visit (Day 1) will be scheduled.  
Screening investigations, including clinical laboratory evaluations (hematology, serum 
biochemistry, urinalysis, serum pregnancy test), chest X ray, ECG and RT-PCR assay for detection 
of SARS-CoV-2 RNA, performed within 72 hours prior to Randomization/Baseline Visit (Visit 2 
/Day 1) can be considered for eligibility assessments. This sample/investigation might have been 
collected/performed as a part of routine work up at the hospital for detection/ evaluation of 
COVID -19 prior to patient having signed the informed consent for participation in the current 
trial. The sample/investigation collection/performed date and time will be considered for 
calculating the time gap between screening procedures and day of randomization. If any 
evaluations which are part of the screening procedures according to the protocol, have not been 
conducted previously, then those investigations would need to be performed for confirming the 
eligibility status. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
However, if there is delay in randomizing the patient (i.e., time gap between sample collection / 
investigation and randomization is greater than 72 hours), then all the investigations mentioned 
under screening will be performed again to check the eligibility status.  
If the patients do not meet the eligibility criteria, they will be considered as screen failures. The 
Investigator will maintain a log of all the patients screened for study participation and will record 
the reason(s) for screen failure. 
6.1.2 Visit 2- Randomization/Baseline Visit [Day 1 (Pre-dose and post-dose)] 
The patients who successfully pass the screening tests and meet the eligibility criteria will be 
enrolled in the study and will be randomized to one of the two treatment groups by IWRS. 
The clinical status by WHO 10-point ordinal scale, 8-point ordinal scale, NEWS-2 score and 
COVID-19 associated symptom severity assessment (i.e., presence or absence, and if present, the 
severity of individual COVID-19 related symptoms) will be evaluated and recorded. To confirm 
patient eligibility for randomization (i.e., whether or not [s]he meets inclusion criterion no. 4), the 
patient’s blood oxygen saturation (SpO2) will be measured once at rest on room air (i.e., without 
O2 supplementation). In case of patients with ‘severe’ ( or suspicion of ‘severe’) COVID-19 
disease at baseline, for whom it is not possible to record the SpO2 on room air, the estimated SpO2 
/ FiO2 ratio (as a surrogate for PaO2/ FiO2 ratio) while receiving supplemental oxygen will be used 
for determining eligibility. Safety assessments (vital signs, partial physical examination, 12-lead 
ECG will be performed. A chest X-ray will be performed. Pre-treatment AEs will be recorded. 
Patients will be administered the study medication as per the treatment group to which (s)he is 
allocated to by the IWRS system. On Day 1, the second dose will be administered with at least a 
4-hour interval from administration of the first dose. Treatment emergent AEs and concomitant 
medication will be recorded. 
The status of each individual patient with respect to admission to the Intensive care unit (ICU) of 
the hospital (with date of admission), supplemental oxygen (standard or high flow) and mechanical 
ventilation will be collected. 
The investigations (chest X ray and 12 lead ECG) mentioned in Visit 2 - Randomization/Baseline 
Visit can be waived off if Randomization/Baseline Visit (Visit 2) is being performed on the same 
day of screening or if the investigations were performed within 72 hours before 
Randomization/Baseline Visit. 
6.1.3 Study Period (Day 2 to Day 27) 
The study period will be for a duration of 28 consecutive days. The patients will be discharged 
when the Principal Investigator or a medically qualified Sub Investigator judges that the patient is 
fit for discharge. All assessments mentioned in Section 6.3.1.5 will be completed before the patient 
is discharged from the hospital.  
The below assessments will be performed as applicable until discharge or Day 28, whichever is 
earlier.  
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 65 of 146 
 
Confidential 
The clinical status by WHO 10-point ordinal scale and 8-point ordinal scale, NEWS-2 score and 
COVID-19 associated symptom severity assessment will be evaluated and recorded every day 
during the study period (until discharge or Day 28, whichever is earlier). Vital signs will be 
assessed, partial physical examination will be performed every day (until discharge or Day 28, 
whichever is earlier).  
A respiratory tract sample (nasopharyngeal swab or oropharyngeal swab or nasal aspirate or 
tracheobronchial aspirate or bronchial lavage) will be collected from the patient and sent for 
detection (qualitative) of SARS-CoV-2 RNA by RT-PCR on Day 5, Day 10 or discharge (if 
discharge happens earlier than one or more of the above-mentioned assessment timepoints).  
Safety assessments [clinical laboratory evaluations (hematology, serum biochemistry, urinalysis)] 
and 12-lead ECG will be performed on Day 4, Day 7, Day 10, Day 14 and Day 21 or discharge (if 
discharge happens earlier than one or more of the above-mentioned assessment timepoints). Chest 
X-ray will be performed on Day 4, Day 7, Day 10 and Day 14 or discharge (if discharge happens 
earlier than one or more of the above-mentioned assessment timepoints).  
Treatment emergent AEs and concomitant medication will be recorded every day. 
The status of each individual patient with respect to admission to the Intensive care unit (ICU) of 
the hospital (with dates of admission and discharge), details of supplemental oxygen received 
(standard and/or high flow) and details of any mechanical ventilation will be collected every day 
during the study period (until discharge or Day 28, whichever is earlier).  
In case the patient is hospitalized until Day 10, the IMP (Favipiravir/Placebo) will be dispensed 
for each individual patient in the morning and evening on every study day for 10 days. Patient will 
take/ be administered the dispensed IMP and treatment compliance will be assessed in the morning 
and evening on every study day for 10 consecutive days.  
If the patient is discharged before Day 10, the required IMP (Favipiravir/Placebo) to complete the 
remainder of the IMP treatment course will be dispensed to patient at the time of discharge. The 
patient will be required to continue the remainder of the IMP treatment course at home. The 
compliance will be evaluated based on details recorded in the patient diary. 
End of Treatment (EOT) assessment: 
The EOT assessment will be performed on Day 10 (+2 days). A window period of 2 days is 
applicable only if the patient is discharged before Day 10. 
1. If the patient remains in the hospital until Day 10, the EOT will be performed at the site 
and all the scheduled assessments for Day 10 will be performed (details mentioned in 
Section 6.3.1.3).  
2. If the patient is discharged before Day 10, the EOT can be performed either as an onsite 
visit or will be performed at the patient’s home. 
a. On-site visit: If the patient is able to visit the hospital on Day 10, procedures for an 
unscheduled visit will be performed. Empty blister packs and /or unused IMP will 
be collected. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 66 of 146 
 
Confidential 
OR  
b. At home: If the patient is unable to visit the hospital for the EOT, study nurse or 
phlebotomist will visit the patient at his/her residence to collect blood sample for 
safety assessments. A nasopharyngeal swab or oropharyngeal swab will be 
collected from the patient and sent for detection (qualitative) of SARS-CoV-2 RNA 
by RT-PCR assay based on Investigator’s discretion for individual patients. Empty 
blister packs and /or unused IMP will be collected. A telephonic follow up will be 
performed to enquire on treatment emergent AEs experienced, concomitant 
medication and COVID-19 associated symptom for assessment of clinical relapse. 
6.1.4 End of Study-Day 28 (+2 days) or discharge or study discontinuation whichever is 
earlier 
The end of study assessments will be performed on Day 28 or earlier if the patient is discontinued 
from study or is considered fit for discharge earlier. If the Principal Investigator or a Sub-
Investigator judges that the patient is fit for discharge, patient should undergo assessments 
scheduled for End of Study – Day 28 (+2 days) visit.  
The clinical status by WHO 10-point ordinal scale and 8-point ordinal scale, NEWS-2 score and 
COVID-19 associated symptom severity assessment will be evaluated. Vital signs will be assessed, 
and partial physical examination will be performed. A respiratory tract sample (nasopharyngeal 
swab or oropharyngeal swab or nasal aspirate or tracheobronchial aspirate or bronchial lavage) 
will be collected from the patient and sent for detection (qualitative) of SARS-CoV-2 RNA by RT-
PCR assay. Safety assessments [serum pregnancy test for female patients of child-bearing 
potential, 12-Lead ECG, clinical laboratory evaluations (hematology, serum biochemistry, 
urinalysis)] will be performed. A chest X-ray will be performed. Treatment emergent AEs and 
concomitant medication will be recorded. 
The status of each individual patient with respect to admission to the Intensive care unit (ICU) of 
the hospital (with date of discharge, if discharged from ICU), details of supplemental oxygen 
received (standard and/or high flow), and details of any mechanical ventilation will be collected. 
Note: Principal Investigator or a medically qualified Sub Investigator may discharge a patient if 
(s)he considers the patient to be clinically fit and eligible (per applicable National Regulations/ 
Hospital practice) for discharge. After discharge, a telephonic follow up will be performed on Day 
10, Day 14, Day 21 and Day 28 (as applicable for the individual patient, depending on the actual 
day of his/her discharge). 
6.1.5 Telephonic follow up on Day 10, Day 14, Day 21 and Day 28, as applicable for the 
individual patient  
For patients who are discharged before Day 28, a telephonic follow up assessment will be 
performed on Day 10 (applicable only for patients who are discharged earlier than Day 10 and if 
patients are unable to visit the site for EOT on Day 10), Day 14, Day 21 and Day 28 as applicable 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 67 of 146 
 
Confidential 
for the individual patient (window period for telephonic follow up is +2 days from scheduled day 
of follow up). The patients will be followed-up for: 
a. safety reasons (eg. follow-up on AEs),  
b. to report a clinical relapse of COVID-19 (the patient will be asked if they have had any of 
the symptoms of COVID 19 after they were discharged).  
An additional visit to the hospital (for further assessment) may be scheduled for such patients, if 
required. Details of concomitant medication will be recorded. The assessments to be performed at 
an unscheduled visit are mentioned in Section 6.3.2.3 and Table 2. 
 
6.2 
Stage II – Extended Follow Up 
6.2.1 Telephonic Follow Up on Day 42 (+2 days) and Day 60 (+2 days) 
During the extended follow up period, the patients will be followed up for AEs or for ‘clinical 
relapse’ of COVID 19. An additional visit to the hospital (for further assessment) may be scheduled 
for such patients, if required. Details of concomitant medication will be recorded. The assessments 
to be performed at an unscheduled visit are mentioned in Section 6.3.2.3 and Table 2. 
During the telephonic follow up, the patients will be followed-up for the following reasons: 
a) safety reasons (eg. follow-up on AEs),  
b) to report a clinical relapse of COVID-19 (the patient will be asked if they have had any of 
the symptoms of COVID-19 after they were discharged).  
 
6.3 
Measurements and Evaluations 
6.3.1 Stage I – Main Study 
6.3.1.1 Visit 1: Screening Visit (Day -3 to Day -1)  
• Written informed consent. 
• Demographic data (age, gender, nationality, race, height and weight) 
• Medical history 
• Collection of respiratory tract sample (nasopharyngeal swab or oropharyngeal swab 
or nasal aspirate or tracheobronchial aspirate) for detection (qualitative) of 
SARS-CoV-2 (by RT-PCR assay)* 
• Serum Pregnancy Test (only for female patients of childbearing potential)* 
• Complete physical examination  
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
• Vital signs (SpO2, body temperature, systolic BP, diastolic BP, pulse rate, and 
respiratory rate) 
• Clinical Status by WHO 10-point ordinal scale 
• Clinical Status by 8-point ordinal scale 
• NEWS-2 score 
• Severity of COVID-19 associated symptoms  
• Prior medications 
• Chest X-ray* 
• 12-Lead ECG* 
• Clinical Laboratory assessments (haematology, serum biochemistry and 
urinalysis)* 
• Pre-treatment AEs 
• Apply Inclusion and Exclusion Criteria  
*Note: Screening investigations, including clinical laboratory evaluations (hematology, serum 
biochemistry, urinalysis, serum pregnancy test), chest X ray, ECG and RT-PCR assay for detection 
of SARS-CoV-2 RNA, performed within 72 hours prior to Randomization Day (Day 1) can be 
considered for eligibility assessments. Refer to Section 6.3.1.1 for further details.  
6.3.1.2 Visit 2: Randomization/Baseline Visit (Day 1)  
• Clinical Status by 10-point ordinal scale 
• Clinical Status by 8-point ordinal scale 
• NEWS-2 score 
• Blood oxygen saturation (SpO2) measurement at rest on room air (i.e., without O2 
supplementation) or alternatively SpO2/ FiO2 will be estimated if the patient is on 
supplemental oxygen, for confirmation of patient eligibility 
• Presence/ Absence, and if present, then COVID-19 associated symptom severity 
assessment 
• ICU admission status, supplemental oxygen and mechanical ventilation details 
• Partial physical examination  
• Vital signs  
• Chest X-ray* 
• 12 Lead ECG* 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 69 of 146 
 
Confidential 
• Pre-treatment AEs 
• Randomization of patients 
• Dosing and compliance assessment 
• Treatment emergent AEs  
• Concomitant medication 
*Note: The investigations (chest X ray and 12 lead ECG) mentioned in Visit 2 - 
Randomization/Baseline Visit can be waived off if Randomization/Baseline Visit (Visit 2) is being 
performed on the same day of screening or if the investigations were performed within 72 hours 
before Randomization/Baseline Visit. 
6.3.1.3 Study period: (Day 2 to Day 27 or discharge, whichever is earlier) 
• Clinical Status by 10-point ordinal scale (assessment to be performed once daily on 
each study day until Day 27 or discharge) 
• Clinical Status by 8-point ordinal scale (assessment to be performed once daily on 
each study day until Day 27 or discharge) 
• NEWS-2 score (assessment to be performed once daily on each study day until Day 
27 or discharge) 
• COVID-19 associated symptom severity assessment (assessment to be performed 
once daily on each study day until Day 27 or discharge)  
• ICU admission status, supplemental oxygen (standard and/or high flow) and 
mechanical ventilation details (to be collected once daily on each study day until Day 
27 or discharge) 
• Partial physical examination  
• Vital signs  
• Treatment emergent AEs  
• Concomitant medication  
• Dosing (two times in a day) of IMP and assessment of treatment compliance, on each 
study day until Day 10 or discharge. (Note: If the patient is discharged before Day 
10, the patient will be required to continue the remainder of the IMP treatment 
course at home. The compliance will be evaluated based on the details in the patient 
diary) 
• Collection of a respiratory tract sample (nasopharyngeal swab or oropharyngeal swab 
or nasal aspirate or tracheobronchial aspirate or bronchial lavage) for detection 
(qualitative) of SARS-CoV-2 (by RT-PCR assay) on Day 5 and Day 10 or discharge 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 70 of 146 
 
Confidential 
(if discharge happens earlier than one or more of the above-mentioned assessment 
timepoints) 
• Clinical Laboratory assessments (haematology, serum biochemistry and urinalysis) 
on Day 4, Day 7, Day 10, Day 14 and Day 21 or discharge (if discharge happens 
earlier than one or more of the above-mentioned assessment timepoints) 
• 12 Lead ECG on Day 4, Day 7, Day 10, Day 14 and Day 21 or discharge (if discharge 
happens earlier than one or more of the above-mentioned assessment timepoints) 
• Chest X-ray on Day 4, Day 7, Day 10 and Day 14 or discharge (if discharge happens 
earlier than one or more of the above-mentioned assessment timepoints) 
6.3.1.4 End of treatment assessment [Day 10 (+2 days)] 
1. If the patient remains in the hospital until Day 10, the EOT will be performed at the site 
and all the scheduled assessments for Day 10 mentioned in Section 6.3.1.3 will be 
performed. 
2. If the patient is discharged before Day 10, the EOT can be performed either as an onsite 
visit or will be performed at the patient’s home. 
a. On-site visit:  
If the patient is able to visit the hospital on Day 10, procedures for an unscheduled visit 
will be performed. 
• COVID-19 associated symptom severity assessment 
• Collection of a respiratory tract sample (nasopharyngeal swab or oropharyngeal 
swab or nasal aspirate or tracheobronchial aspirate or bronchial lavage) for 
detection (qualitative) of SARS-CoV-2 (by RT-PCR assay)* 
• Partial physical examination*  
• Vital signs*  
• Chest X-ray* 
• 12 Lead ECG* 
• Clinical Laboratory assessments (haematology, serum biochemistry and 
urinalysis)* 
• Treatment emergent AEs 
• Concomitant medication*  
• ICU admission status, supplemental oxygen (standard and/or high flow) and 
mechanical ventilation details* 
• Return of empty blister packs and /or unused IMP 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 71 of 146 
 
Confidential 
* Assessments maybe performed at Investigator’s discretion for individual patients for evaluation 
of patient safety or follow up of adverse events. 
OR  
b. At home:  
If the patient is unable to visit the hospital for the EOT, the below procedures will be 
performed. 
• Study nurse or phlebotomist will visit the patient at his/her residence  
• Blood sample collection for clinical laboratory assessments (haematology, serum 
biochemistry)  
• A nasopharyngeal swab or oropharyngeal swab will be collected from the patient 
and sent for detection (qualitative) of SARS-CoV-2 RNA by RT-PCR assay based 
on Investigator’s discretion for individual patients 
• Collection of empty blister packs and /or unused IMP 
• A telephonic follow up will be performed to assess the below 
o Treatment emergent AEs 
o COVID-19 associated symptom enquiry for assessment of clinical relapse 
o Concomitant medication 
 
6.3.1.5 Visit 3: End of Study-Day 28 (+2 days) or discharge or study discontinuation 
whichever is earlier 
• Serum Pregnancy Test (only for female patients of childbearing potential) 
• Clinical Status by 10-point ordinal scale 
• Clinical Status by 8-point ordinal scale 
• NEWS-2 score 
• COVID-19 associated symptom severity assessment  
• ICU admission status, supplemental oxygen (standard and/or high flow) and 
mechanical ventilation details  
• Collection of a respiratory tract sample (nasopharyngeal swab or oropharyngeal swab 
or nasal aspirate or tracheobronchial aspirate or bronchial lavage) for detection 
(qualitative) of SARS-CoV-2 (by RT-PCR assay)  
• Partial physical examination  
• Vital signs  
• Chest X-ray 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 72 of 146 
 
Confidential 
• 12 Lead ECG 
• Clinical Laboratory assessments (haematology, serum biochemistry and urinalysis) 
• Treatment emergent AEs 
• Concomitant medication  
 
6.3.1.6 Telephonic follow up on Day 10, Day 14, Day 21 and Day 28, as applicable for the 
individual patient  
For patients who are discharged before Day 28, a telephonic follow up assessment will be 
performed on Days 10 (applicable only for patients who are discharged earlier than Day 10 and if 
patients are unable to visit the site for EOT on Day 10), 14, 21 and 28 as applicable for the 
individual patient (window period for telephonic follow up is +2 days from scheduled day of 
follow up).  
• Treatment emergent AEs 
• COVID-19 associated symptom enquiry for assessment of clinical relapse 
• Concomitant medication 
6.3.1.7 Unscheduled Visit: If further assessment is found to be necessary on Telephonic 
Follow up 
• COVID-19 associated symptom severity assessment 
• Collection of a respiratory tract sample (nasopharyngeal swab or oropharyngeal swab 
or nasal aspirate or tracheobronchial aspirate or bronchial lavage) for detection 
(qualitative) of SARS-CoV-2 (by RT-PCR assay)* 
• Partial physical examination*  
• Vital signs*  
• Chest X-ray* 
• 12 Lead ECG* 
• Clinical Laboratory assessments (haematology, serum biochemistry and urinalysis)* 
• Treatment emergent AEs 
• Concomitant medication*  
• ICU admission status, supplemental oxygen (standard and/or high flow) and 
mechanical ventilation details* 
* Assessments maybe performed at Investigator’s discretion for individual patients for evaluation 
of patient safety or follow up of adverse events. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 73 of 146 
 
Confidential 
6.3.2 Stage II - Extended Follow Up 
6.3.2.1 Telephonic follow up on Day 42 (+2 days) 
• Treatment emergent AEs 
• COVID-19 associated symptom enquiry for assessment of clinical relapse 
• Concomitant medication 
6.3.2.2 Telephonic follow up on Day 60 (+2 days) 
• Treatment emergent AEs 
• COVID-19 associated symptom enquiry for assessment of clinical relapse 
• Concomitant medication 
6.3.2.3 Unscheduled Visit: If further assessment is found to be necessary on Telephonic 
Follow up 
• COVID-19 associated symptom severity assessment 
• Collection of a respiratory tract sample (nasopharyngeal swab or oropharyngeal swab 
or nasal aspirate or tracheobronchial aspirate or bronchial lavage) for detection 
(qualitative) of SARS-CoV-2 (by RT-PCR assay)*  
• Partial physical examination*  
• Vital signs*  
• Chest X-ray* 
• 12 Lead ECG* 
• Clinical Laboratory assessments (haematology, serum biochemistry and urinalysis)* 
• Treatment emergent AEs 
• Concomitant medication*  
• ICU admission status, supplemental oxygen (standard and/or high flow) and 
mechanical ventilation details* 
* Assessments maybe performed at Investigator’s discretion for individual patients for evaluation 
of patient safety or follow up of adverse events. 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 74 of 146 
 
Confidential 
Table 2: Study Assessment Schedule 
Assessments 
STAGE I – Main Study1 
Data
base 
Lock 
Stage II – 
Extended 
Follow Up2 
Unsche
duled 
Visit 
 
Scree
ning3 
Randomization 
(Baseline)4 
 
EOT5 
 
End of 
Study 
Day 
-3 
to -1 
(72 
hrs) 
1  
(Pre-
dose) 
1 (Post-
dose) 
On all 
days 
until 
discha
rge 
On 
all 
days 
until 
Day 
10 
4 
5 
7 
10 
14 
21 
28 or 
dischar
ge 
42 
60  
Window Period 
N/A 
0 
0 
N/A 
N/A 
0 
0 
0 
0/+2 
0/+2 
0/+2 
0/+2 
 
+2 
+2 
 
 
1 Stage I of the study includes a treatment period of 10 consecutive days and a study data collection period until Day 28. The treatment period may be shortened if 
it is necessary to discontinue administration of the study drug due to AEs or other circumstances. Principal Investigator or a medically qualified Sub Investigator 
may discharge a patient, if (s)he considers the patient to be clinically fit and eligible (per applicable National Regulations/ Hospital practice) for discharge. After 
discharge, telephonic follow up will be performed on Days 10, 14, 21 and 28 (as applicable for the individual patient, depending on actual day of discharge). For 
patients who remain admitted in the hospital until Study Day 28, the End of Study assessments will be performed on Day 28. A window period of 2 days will be 
allowed for the telephonic follow ups. 
2 During the Stage II of the study, the patients will be followed up for AEs or for ‘clinical relapse’ of COVID 19, on Day 42 and Day 60. An additional visit to the 
hospital (for further assessment) may be scheduled for such patients, if required. A window period of 2 days will be allowed for the telephonic follow ups. 
3 Screening investigations, including clinical laboratory evaluations (hematology, serum biochemistry, urinalysis, serum pregnancy test), chest X ray, ECG and 
RT-PCR assay for detection of SARS-CoV-2 RNA, performed within 72 hours prior to Randomization Day (Day 1) can be considered for eligibility assessments. 
Refer to Section 6.1.1 for further details. 
4 The investigations (chest X ray and 12 lead ECG) mentioned in Visit 2 - Randomization/Baseline Visit can be waived off if Randomization/Baseline Visit (Visit 
2) is being performed on the same day of screening or if the investigations were performed within 72 hours before Randomization/Baseline Visit. Refer to 
Section 6.1.2 for further details 
5 The EOT assessment will be performed on Day 10 (+2 days). If the patient remains in the hospital until Day 10, the EOT will be performed at the site and all the 
scheduled assessments for Day 10 will be performed.  If the patient is discharged before Day 10, the EOT can be performed either as an onsite visit or will be 
performed at the patient’s home (refer to Section 6.3.1.4). 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 75 of 146 
 
Confidential 
Assessments 
STAGE I – Main Study1 
Data
base 
Lock 
Stage II – 
Extended 
Follow Up2 
Unsche
duled 
Visit 
 
Scree
ning3 
Randomization 
(Baseline)4 
 
EOT5 
 
End of 
Study 
Day 
-3 
to -1 
(72 
hrs) 
1  
(Pre-
dose) 
1 (Post-
dose) 
On all 
days 
until 
discha
rge 
On 
all 
days 
until 
Day 
10 
4 
5 
7 
10 
14 
21 
28 or 
dischar
ge 
42 
60  
(Days)6 
Obtaining informed 
consent  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline patient 
characteristics7 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test8  
●  
 
 
 
 
 
 
 
 
 
 
● 
 
 
 
 
Assessment 
of 
inclusion/exclusion 
criteria 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Measurement of 
Blood Oxygen 
Saturation at rest on 
room air (without 
oxygen 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 If patient is discharged before Day 28, a telephonic follow up assessment will be performed on Days 10 (applicable only for patients who are discharged earlier 
than Day 10 and if patients are unable to visit the site for EOT on Day 10), 14, 21 and 28 (as applicable for the individual patient). A window period for telephonic 
follow up will be +2 days from scheduled day of follow up.  
7 Includes age, gender, nationality, race, height and weight. 
8 Pregnancy test only for female subjects of childbearing potential. Serum pregnancy will be performed at Screening and End of Study (Day 28 or discharge, 
whichever is earlier).  
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 76 of 146 
 
Confidential 
Assessments 
STAGE I – Main Study1 
Data
base 
Lock 
Stage II – 
Extended 
Follow Up2 
Unsche
duled 
Visit 
 
Scree
ning3 
Randomization 
(Baseline)4 
 
EOT5 
 
End of 
Study 
Day 
-3 
to -1 
(72 
hrs) 
1  
(Pre-
dose) 
1 (Post-
dose) 
On all 
days 
until 
discha
rge 
On 
all 
days 
until 
Day 
10 
4 
5 
7 
10 
14 
21 
28 or 
dischar
ge 
42 
60  
supplementation) or 
SpO2/ FiO2 estimated 
on supplemental 
oxygen for 
confirmation of 
eligibility 
Randomization 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing 
and 
complian
ce status9 
Morning 
 
 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
Evening 
 
 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 
associated symptom 
severity assessment 10 
● 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
●11 
 
9 IMPs will be administered twice daily (in the morning and evening) from Day 1 to Day 10. If the patient is discharged before Day 10, the patient will be required 
to continue the remainder of the IMP treatment course at home. Dosing compliance status will be checked for 10 days. Compliance will be assessed daily assessment 
if the patient is the hospital or based on the details in the patient diary and the empty blister packs and / unused IMP in case of patients discharged before study 
Day 10. 
10 COVID-19 associated symptom severity assessment will be done on all days (Day 1 up to Day 28 or until discharge, whichever is earlier).  
11 COVID-19 associated symptom severity assessment will be done and recorded in case of patients in whom the follow up (unscheduled) visit was necessitated 
for reporting of clinical relapse 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 77 of 146 
 
Confidential 
Assessments 
STAGE I – Main Study1 
Data
base 
Lock 
Stage II – 
Extended 
Follow Up2 
Unsche
duled 
Visit 
 
Scree
ning3 
Randomization 
(Baseline)4 
 
EOT5 
 
End of 
Study 
Day 
-3 
to -1 
(72 
hrs) 
1  
(Pre-
dose) 
1 (Post-
dose) 
On all 
days 
until 
discha
rge 
On 
all 
days 
until 
Day 
10 
4 
5 
7 
10 
14 
21 
28 or 
dischar
ge 
42 
60  
RT-PCR 
(qualitative)12 
● 
 
 
 
 
 
● 
 
● 
 
 
● 
 
 
 
● 
Clinical Status by 10-
point ordinal scale 
(SOLIDARITY 
SCALE)13 
● 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Status by 8-
point ordinal scale 14 
● 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
NEWS-2 score15 
● 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 Qualitative RT-PCR assay for detection of SARS-CoV-2 RNA in a respiratory tract sample will be performed at Screening, on Day 5, Day 10 and Day 28, or 
discharge (i.e., if the patient happens to be discharged before one or more of the mentioned timepoints, then the sample will be collected at discharge). No sample 
will be collected from patients at any timepoint after discharge, EXCEPT if individual patients are scheduled for an additional (unscheduled) visit, either to follow 
up on an AE or to report a possible ‘clinical relapse’ of COVID-19 or based on Investigator’s discretion during the Day 10 - home visit. A sample for RT-PCR will 
be collected during the unscheduled visit in such cases. 
13 Clinical Status by 10-point ordinal scale (SOLIDARITY SCALE) will be assessed once daily at screening, on all days (Day 1 up to Day 28 or until discharge, 
whichever is earlier). 
14 Clinical Status by 8-point ordinal scale will be assessed once daily at screening, on all days (Day 1 up to Day 28 or until discharge, whichever is earlier). 
15 NEWS-2 score will be assessed once daily on all days (Day 1 up to Day 28 or until discharge, whichever is earlier). 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 78 of 146 
 
Confidential 
Assessments 
STAGE I – Main Study1 
Data
base 
Lock 
Stage II – 
Extended 
Follow Up2 
Unsche
duled 
Visit 
 
Scree
ning3 
Randomization 
(Baseline)4 
 
EOT5 
 
End of 
Study 
Day 
-3 
to -1 
(72 
hrs) 
1  
(Pre-
dose) 
1 (Post-
dose) 
On all 
days 
until 
discha
rge 
On 
all 
days 
until 
Day 
10 
4 
5 
7 
10 
14 
21 
28 or 
dischar
ge 
42 
60  
Clinical Laboratory 
Evaluations 
(Hematology, Serum 
Biochemistry, 
Urinalysis) 
● 
 
 
 
 
● 
 
● 
● 
● 
● 
● 
 
 
 
● 
Chest X-ray 
● 
● 
 
 
 
● 
 
● 
● 
● 
 
● 
 
 
 
● 
12-lead ECG 
● 
● 
 
 
 
● 
 
● 
● 
● 
● 
● 
 
 
 
● 
Vital signs16 
● 
● 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
● 
Complete Physical 
Examination17  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Partial 
Physical 
Examination18  
 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
Hospitalization 
period19 
● 
● 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Medications 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16 Vital signs will be assessed on all days (Day 1 to Day 28 or until discharge, whichever is earlier). Includes SpO2, body temperature (axillary), systolic BP, 
diastolic BP, pulse rate, and respiratory rate. Vital signs will be measured at pre-dose only on Day 1 and at least twice, morning and afternoon, daily from Day 2 
to Day 28 or until discharge, whichever is earlier. 
17 Includes general appearance, skin, head, neck, ENT, heart, lungs, abdomen, extremities, neurological, musculoskeletal, and lymph nodes 
18 Includes general appearance, ENT, heart, lungs and lymph nodes. 
19 The patients will be discharged when the Principal Investigator or a medically qualified Sub Investigator judges that the patient is fit for discharge. If the patient 
is discharged before Day 10, the remaining treatment course will be continued at home. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 79 of 146 
 
Confidential 
Assessments 
STAGE I – Main Study1 
Data
base 
Lock 
Stage II – 
Extended 
Follow Up2 
Unsche
duled 
Visit 
 
Scree
ning3 
Randomization 
(Baseline)4 
 
EOT5 
 
End of 
Study 
Day 
-3 
to -1 
(72 
hrs) 
1  
(Pre-
dose) 
1 (Post-
dose) 
On all 
days 
until 
discha
rge 
On 
all 
days 
until 
Day 
10 
4 
5 
7 
10 
14 
21 
28 or 
dischar
ge 
42 
60  
Concomitant 
Medications 
 
● 
● 
● 
 
 
 
 
 
● 
● 
● 
 
● 
● 
● 
Pre-treatment 
Adverse Events 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Emergent 
Adverse events 
 
 
● 
● 
 
 
 
 
 
● 
● 
● 
 
● 
● 
●20 
ICU 
admission 
status, supplemental 
oxygen 
and 
mechanical 
ventilation details 21 
 
 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
Clinical relapse22 
 
 
 
 
 
 
 
 
● 
● 
● 
● 
 
● 
● 
 
 
 
 
20 Treatment Emergent Adverse Events will be assessed and recorded in case of patients in whom the follow up (unscheduled) visit was necessitated for follow up 
of an adverse event/reporting of a new Treatment Emergent Adverse Event after discharge. 
21 Will be evaluated on all days during the study period (until Day 28 or discharge, whichever is earlier) and also may be evaluated when patient retiurns for 
additional visit  
22 Patients will be asked if they experience any COVID-19 symptoms after discharge. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
6.4 
Protocol Deviations 
The Investigator shall conduct the study in compliance with the study protocol. Waivers to deviate 
from the protocol will not be granted neither by the Sponsor nor by the Medical Lead of the CRO 
acting on behalf of the Sponsor. All protocol deviations occurring will be tracked in the clinical 
database and classified as major or minor protocol deviations. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
7 
EVALUATION CRITERIA 
7.1 
Efficacy Evaluation Criteria 
7.1.1 Stage I 
7.1.1.1 Evaluation Criteria for the Primary Endpoint 
Primary Efficacy Endpoint: 
1. Time to resolution of hypoxia (Time frame: Up to 28 days) 
This endpoint will be considered to have been met when the patient has attained a score of 4 or 
lower on the 10-point ordinal scale of clinical status and either of a) or b), and c) is met: 
a) Score is ≤ 4 on consecutive assessments over the next 5 days, if patient continues to remain 
in hospital (i.e., has not been discharged). 
OR 
b) Patient was discharged before five consecutive assessments (after reaching a score of 4). 
AND 
c) The patient has survived and has not been re-admitted to hospital for COVID-19 
management through Day 28. 
 . 
7.1.1.2 Evaluation Criteria for the Secondary Endpoints  
1. Time to discharge from hospital. 
2. Time (no. of days) from randomization to the earliest time when ALL COVID-19 
associated symptoms (fever, chills, cough, sore throat, malaise, headache, muscle pain, 
gastrointestinal symptoms – specifically diarrhoea and vomiting, shortness of breath or 
dyspnoea) are scored by the Investigator/trained study personnel as either ‘0=absent’ or 
‘mild =1’ in assessments over a period of 24 hours, when assessed from baseline to Day 
28 or discharge from hospital (if discharge happens earlier than Day 28). 
3. Percentage of patients with score of either ‘0=absent’ or ‘mild =1’ over a period of 24 
hours, for ALL COVID-19 associated symptoms, by Days 4, 7, 10, 14, 21 and 28 or 
discharge (if discharge happens earlier than one or more of the above-mentioned 
timepoints)  
Note: Symptoms evaluated are fever, chills, cough, sore throat, malaise, headache, muscle pain, 
gastrointestinal symptoms- specifically, diarrhoea and vomiting, shortness of breath or dyspnoea. 
The Investigator/trained study personnel will assess (including by enquiry with the patient, as 
necessary) and score the severity of each COVID-19 associated symptom on a 5-point Likert-type 
scale (0= absent, 1= mild, 2=moderate, 3= severe, 4= very severe/critical). 
4. Time to improvement in EACH of the symptoms of fever, chills, cough, sore throat, 
malaise, headache, muscle pain, gastrointestinal symptoms- specifically diarrhoea and 
vomiting, shortness of breath or dyspnoea by at least 1 grade over baseline.  
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
Note: Severity of symptoms will be evaluated once daily (preferably at or around the same clock 
time) on each day that the patient is admitted in the hospital. The Investigator/trained study 
personnel will assess (including by enquiry with the patient, as necessary) and score the severity 
of each COVID-19 associated symptom on a 5-point Likert-type scale (0= absent, 1= mild, 
2=moderate, 3= severe, 4= very severe/critical). The improvement observed must be sustained at 
evaluations over a period of 24hours, in order for this secondary efficacy endpoint to be reached. 
5. Percentage of patients reporting a clinical relapse of COVID-19 when assessed from day 
of discharge to 27 days after the day of randomization (Day 28). 
Note: ‘Clinical relapse’ is defined as either the reappearance or worsening of severity (over the 
assessment on the day of discharge) of one or more of the above-mentioned COVID-19 associated 
symptoms, or the appearance of any of these symptoms (due to COVID-19 infection) for the first time 
after discharge. This endpoint will be assessed only for those patients that were discharged before Day 
28.  
6. Time (no. of days) to negative conversion of detectable SARS-CoV-2 viral RNA in the 
RT-PCR assays of respiratory sample, from randomization 
7. Percentage of patients showing negative conversion of detectable SARS-CoV-2 viral RNA 
in the RT-PCR assays of respiratory sample on Days 5, 10 and 28 or discharge (if discharge 
happens earlier than one or more of the above-mentioned time points)  
Patients who have tested positive for SARS-CoV-2 on a RT-PCR assay will be enrolled in this 
study. The RT-PCR assay will be evaluated at screening, on Day 5, Day 10, and Day 28, or 
discharge (i.e., if the patient happens to be discharged before one or more of the mentioned 
timepoints, then the sample will be collected at discharge). No sample will be collected from 
patients at any timepoint after discharge, EXCEPT if individual patients are scheduled for an 
additional (unscheduled) visit, either to follow up on an AE or to report a possible ‘clinical relapse’ 
of COVID-19. A sample will be collected during the unscheduled visit in such cases.  
8. Changes over time in patient’s clinical status on the 10-point ordinal scale used in the 
SOLIDARITY trial by WHO 
a. Changes in the 10-point ordinal scale score from baseline until discharge   
b. Proportion of patients in whom clinical status score of 4 (‘hospitalized, no oxygen 
required’) or lower has been attained by Days 4, 7, 10, 14, 21 and 28 or discharge (if 
discharge happens earlier than one or more of the above-mentioned timepoints) 
c. Time (no. of days) from randomization to clinical status score improvement by 1 and 
by 2 points (from baseline)  
d. Proportion of patients for whom clinical status score improvement by 1 and by 2 points 
has been attained by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens 
earlier than one or more of the above-mentioned timepoints) 
 
For the SOLIDARITY trial, a COVID-19 specific ordinal scale has been developed by WHO to 
assess the clinical status of the patient at baseline and to monitor over time the changes of the 
clinical status. Table 3 shows the scores assigned on an ordinal level to each status. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
Table 3: The 10-point ordinal scale used in the WHO SOLIDARITY trial for assessment of 
patients’ clinical status 
Score 
Description  
0 
Uninfected, no viral RNA 
1 
Asymptomatic, viral RNA detected 
2 
Symptomatic, independent 
3 
Symptomatic, Assistance Needed 
4 
Hospitalized: no oxygen therapy 
5 
Hospitalized, on oxygen 
6 
Hospitalized, Oxygen by NIV or high-flow 
7 
Mechanical ventilation, p/f>150 or s/f >200 
8 
Mechanical ventilation, p/f<150 or s/f<200 OR vasopressors 
9 
Mechanical ventilation, p/f<150 AND vasopressors, dialysis, or ECMO 
10 
Death 
 
Note: Score categories 3,2,1 and 0 apply even if the patient continues to remain in the hospital.  
9. Changes over time in patient’s clinical status on the 8-point ordinal scale  
a. Time (no. of days) from randomization to attain clinical status score of 4 or lower  
b. Proportion of patients in whom clinical status score of 4 or lower has been attained 
by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier than one 
or more of the above-mentioned timepoints) 
c. Time (no. of days) from randomization to attain clinical status score of 3 or lower  
d. Proportion of patients in whom clinical status score of 3 or lower has been attained 
by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier than one 
or more of the above-mentioned timepoints) 
e. Time (no. of days) from randomization to clinical status score improvement by 1 
and by 2 points (from baseline)  
f. Proportion of patients for whom clinical status score improvement by 1 and by 2 
points has been attained by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge 
happens earlier than one or more of the above-mentioned timepoints) 
The 8-point ordinal scale of Clinical Status is adapted from the one used in the Adaptive COVID-
19 Treatment Trial- 1 (ACTT-1) that formed basis of approval for Veklury® (Remdesivir or RDV) 
in moderate to severe COVID-19 in the United States. Table 4 shows the scores assigned on an 
ordinal level to each status. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
Table 4: Modified 8-point ordinal scale of Clinical Status 
Category Score 
Clinical Status Category Description  
1 
Not hospitalized, no limitation of activities 
2 
Not hospitalized, limitation of activities 
3 
Hospitalized, not requiring supplemental oxygen and no longer requiring 
ongoing medical care* 
 (used if hospitalization was extended for infection-control reasons) 
4 
Hospitalized, not requiring supplemental oxygen but requiring ongoing medical 
care (COVID-19– related or other medical conditions) 
5 
Hospitalized, requiring any supplemental oxygen 
6 
Hospitalized, requiring non-invasive ventilation or use of high-flow oxygen 
devices 
7 
Hospitalized, receiving invasive mechanical ventilation or extracorporeal 
membrane oxygenation (ECMO) 
8  
Death 
*Patients receiving vitamins, minerals or other supplements, symptomatic treatments (e.g. analgesics, 
antitussives), treatments for non-COVID-19 related ailments and antibiotics or treatment for secondary 
infections will not be considered as requiring ‘ongoing medical care’  
10. Changes over time in findings on chest X-ray 
Chest X-ray will be performed at screening, on Days 1 (pre-dose), 4, 7, 10, 14, and Day 28 or 
discharge or Study Discontinuation, whichever is earlier. 
The Principal Investigator or a Sub-Investigator will assess improvement in chest images. 
Radiographic Assessment of Lung Edema (RALE) score will be used to evaluate the changes in 
the chest X-ray. Each radiograph will be divided into quadrants, defined vertically by the vertebral 
column and horizontally by the first branch of the left main bronchus. Each quadrant will be 
assigned a consolidation score from 0–4 to quantify the extent of alveolar opacities, based on the 
percentage of the quadrant with opacification and a density score from 1–3 to quantify the overall 
density of alveolar opacities, unless the consolidation score for that quadrant was 0. The density 
score (1=hazy, 2=moderate, 3=dense) allows for more quantitative assessment of the density of 
opacification by quadrant. To calculate the final RALE score, the product of the consolidation and 
density score for each quadrant will be summed for a final RALE score ranging from 0 (no 
infiltrates) to 48 (dense consolidation in >75% of each quadrant).25  
Table 5: Consolidation and density scoring in the Radiographic Assessment of Lung 
Edema (RALE) score 
Consolidationa 
Consolidation score 
Extent of alveolar opacities 
0 
None 
1 
<25% 
2 
25 to 50% 
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Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
3 
50 to 75% 
4 
> 75% 
Densityb 
Density score 
Density of alveolar opacities 
1 
Hazy 
2 
Moderate 
3 
Dense 
Final RALE Score 
Right Lung 
Left Lung 
Upper Quadrant 
Consolidation score × Density score = Q1 score 
Upper Quadrant 
Consolidation score × Density score = Q3 score 
Lower Quadrant 
Consolidation score × Density score = Q2 score 
Lower Quadrant 
Consolidation score × Density score = Q4 score 
Total RALE = Q1 + Q2 + Q3 + Q4 
a Consolidation is scored for each quadrant 
b Density is scored for each quadrant that has a consolidation score ≥1  
11. Changes over time in the National Early Warning Score-2 (NEWS) on  
NEWS-2 is the latest version of the National Early Warning Score (NEWS), first produced in 2012 
and updated in December 2017, which advocates a system to standardise the assessment and 
response to acute illness. In this second edition, NEWS has received further improvements to 
become the early warning system for identifying acutely ill patients – including those with sepsis 
– in hospitals.  
Table 6 shows the NEWS-2 chart in which the specific variables will be scored. 
The NEWS-2 is based on a simple aggregate scoring system in which a score is allocated to 
physiological measurements, already recorded in routine practice, when patients present to, or are 
being monitored in hospital. Six simple physiological parameters form the basis of the scoring 
system: 
1. Respiration rate 
2. Oxygen saturation 
3. Systolic blood pressure 
4. Pulse rate 
5. Level of consciousness or new confusion* 
6. Temperature 
*The patient has new-onset confusion, disorientation and/or agitation, where previously their mental state 
was normal – this may be subtle. The patient may respond to questions coherently, but there is some 
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Study code: NV-05-983-2020 
  
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
confusion, disorientation and/or agitation. This would score 3 or 4 on the GCS (rather than the normal 5 
for verbal response), and scores 3 on the NEWS system. 
A score is allocated to each parameter as they are measured, with the magnitude of the score 
reflecting how extremely the parameter varies from the norm. The score is then aggregated and 
uplifted by 2 points for people requiring supplemental oxygen to maintain their recommended 
oxygen saturation. 
Table 6: National Early Warning Score 2 (NEWS-2) 
Variable 
Points 
Respiratory rate, breaths per 
minute 
≤8 
3 
9-11 
1 
12-20 
0 
21-24 
2 
≥25 
3 
SpO2 (on 
room 
air 
or 
supplemental) 
≤91% 
3 
92-93% 
2 
94-95% 
1 
≥96% 
0 
SpO2 (if 
patient 
has 
hypercapnic 
respiratory 
failure) 
≤83% 
3 
84-85% 
2 
86-87% 
1 
88-92%, ≥93% on room air 
0 
93-94% on supplemental oxygen 
1 
95-96% on supplemental oxygen 
2 
≥97% on supplemental oxygen 
3 
Room air or supplemental 
oxygen 
Supplemental oxygen 
2 
Room air 
0 
Temperature 
≤35.0°C (95°F) 
3 
35.1-36.0°C (95.1-96.8°F) 
1 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
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Variable 
Points 
36.1-38.0°C (96.9-100.4°F) 
0 
38.1-39.0°C (100.5-102.2°F) 
1 
≥39.1°C (102.3°F) 
2 
Systolic BP, mmHg 
≤90 
3 
91-100 
2 
101-110 
1 
111-219 
0 
≥220 
3 
Pulse, beats per minute 
≤40 
3 
41-50 
1 
51-90 
0 
91-110 
1 
111-130 
2 
≥131 
3 
Consciousness 
Alert 
0 
New-onset 
confusion 
(or 
disorientation/agitation), 
responds to voice, responds to pain, or unresponsive 
3 
Note: Interpretation of NEW score: 
NEW Score 
Clinical 
risk 
Frequency 
of 
monitoring 
Response 
0-4 
Low 
Minimum every 12 
hrs if score of 0 
Minimum every 4-6 
hrs if score 1-4 
Assessment by a competent registered nurse or 
equivalent, to decide change in frequency of 
clinical monitoring or escalation of care 
Score of 3 in any 
individual 
parameter 
Low-
medium 
Minimum every hr 
Urgent review by a ward-based doctor, to decide 
change in frequency of clinical monitoring or 
escalation of care 
5-6 
Medium 
Urgent review by a ward-based doctor or acute 
team nurse, to decide if critical care team 
assessment is needed 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
NEW Score 
Clinical 
risk 
Frequency 
of 
monitoring 
Response 
≥7 
High 
Continuous 
monitoring of vital 
signs 
Emergent assessment by a clinical team or 
critical care team and usually transfer to higher 
level of care 
 
12. Percentage of patients requiring, until Day 28 or discharge from hospital (if discharge 
happens earlier) 
a. Management in intensive care unit  
b. High Flow Nasal Oxygen or Non-invasive mechanical ventilation 
c. Invasive mechanical ventilation 
13. Time (no. of days) from randomization to: 
a. Management in intensive care unit  
b. High Flow Nasal Oxygen or Non-invasive mechanical ventilation 
c. Invasive mechanical ventilation 
over an assessment period from randomization until Day 28 or discharge from hospital (if 
discharge happens earlier) 
14. Duration (no. of days) the patient requires: 
a. Management in intensive care unit  
b. Oxygen supplementation 
c. High Flow Nasal Oxygen  
d. Non-invasive mechanical ventilation 
e. Invasive mechanical ventilation 
over an assessment period from randomization until Day 28 or discharge from hospital (if 
discharge happens earlier) 
15. Percentage of patients: 
a. dying from any cause 
b. dying from a COVID-19 associated complication 
over an assessment period from randomization until Day 28 or discharge from hospital (if 
discharge happens earlier) 
Details about management in the intensive care unit, patients requiring supplemental oxygen, 
(standard or by high flow nasal cannula) non-invasive and invasive mechanical ventilation will 
be collected daily during the study along with the duration that these are required.  
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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7.1.2 Stage II 
7.1.2.1 Evaluation Criteria for the Efficacy Endpoint 
1. Percentage of patients reporting a clinical relapse of COVID-19 when assessed from day 
of discharge to 59 days after the day of randomization (Day 60). 
Note: ‘Clinical relapse’ is defined as either the reappearance or worsening of severity (over the assessment 
on the day of discharge) of one or more of the above-mentioned COVID-19 associated symptoms, or the 
appearance of any of these symptoms (due to COVID-19 infection) for the first time after discharge. 
2. Proportion of patients 
a. With disease worsening and requires: 
• Admission to ICU 
• High flow nasal oxygen 
• Non-invasive mechanical ventilation 
• Invasive mechanical ventilation 
                 AND 
b. Dying 
 until Day 60 (regardless of whether patients are discharged from hospital before Day 28 or not) 
 
7.2 
Safety Evaluation Criteria 
7.2.1 Stage I 
1. Number (and percentage) of patients reporting treatment emergent adverse events (TEAEs) 
(by MedDRA system organ class and preferred term) 
The AEs and SAEs occurring throughout the study will be collected irrespective of whether they 
are related to investigational product or not and will be presented as per the System Organ Class 
(SOC). The number of patients with treatment-emergent AEs will be collected and summarized 
based on the SOC and preferred term. 
2. Changes of parameters at each assessment during the study/follow-up period, compared to 
baseline for: 
▪ Vital signs: body temperature, heart rate, respiratory rate, systolic/diastolic BP and 
oxygen saturation.  
▪ Clinical laboratory assessments: hematology, serum chemistry, urinalysis. 
▪ 12 Lead ECG: Changes in heart rate, PR, QRS, QT and QTcB intervals. 
Vital signs will be measured at screening, at pre-dose only on Day 1 and at least twice, morning 
and afternoon, daily from Day 2 to Day 28 or discharge or discontinuation form the study. 
Laboratory assessments will be performed at screening, Day 4, Day 7, Day 10, Day 14, Day 21, 
and Day 28 or discharge or discontinuation. 12-Lead ECG will be performed at screening, Day 1 
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Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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(pre-dose), Day 4, Day 7, Day 10, Day 14, Day 21 and Day 28 or discharge (if discharge happens 
earlier than one or more of the above-mentioned assessment timepoints or study discontinuation 
(whichever is earlier). Pre-dose measurement will act as the baseline for vital signs, laboratory 
assessments and 12-Lead ECG parameters. The changes in these parameters will be compared 
between the treatment groups for each of these assessments. 
7.2.2 Stage II 
1. Number (and percentage) of patients reporting treatment emergent adverse events (TEAEs) 
(by MedDRA system organ class and preferred term) 
The AEs and SAEs occurring throughout the study will be collected irrespective of whether they 
are related to investigational product or not and will be presented as per the System Organ Class 
(SOC). The number of patients with treatment-emergent AEs will be collected and summarized 
based on the SOC and preferred term. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
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8 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
Not applicable.  
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Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
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CONFIDENTIAL 
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9 
SAFETY ASSESSMENTS 
9.1 
Adverse Events 
All clinical AEs occurring after the patient signs the Informed Consent Form and up to Day 60 or 
study discontinuation, whichever is earlier whether observed by the Investigator or reported by the 
patient, will be recorded on the AE electronic case report form (eCRF) page. All SAEs are to be 
reported according to the procedures in Section 9.2 SAE Reporting-Procedure for Investigators. 
Pre-planned procedure or hospitalization for pre-existing conditions which do not worsen in 
severity should not be reported as SAEs (see Section 9.1.1 for Definitions). 
At each visit, the Investigator will determine whether any AEs have occurred by evaluating the 
patient. Adverse events may be directly observed, reported spontaneously by the patient or by 
questioning the patient at each study visit. Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms. All laboratory values must be appraised by 
the Investigator as to clinical significance. All post-baseline abnormal laboratory values 
considered clinically significant by the Investigator must be recorded in the AE page of the eCRF. 
Investigator should follow patients with AEs until the event has resolved or the condition has 
stabilized. In case of unresolved AEs including significant abnormal laboratory values at the end 
of study assessment, these events will be followed up until resolution or until they become 
clinically not relevant. 
9.1.1 Definitions 
9.1.1.1 Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. 
An AE is therefore any unfavorable and unintended sign (an abnormal ophthalmic finding, for 
example), symptom (including physical, psychological or behavioral effect), or disease temporally 
associated with the use of a medicinal (investigational or marketed) product, experienced by a 
patient during their participation in an investigational study, in conjunction with the use of the drug 
or biologic, whether or not considered product-related. 
This includes any untoward signs, symptoms, illness or clinically significant laboratory test 
abnormality that has appeared or worsened during the course of the clinical trial, experienced by 
the patient from the time of signing the informed consent until completion of the study. Throughout 
the patient’s participation in the study, any new clinically significant findings/abnormalities that 
meet the definition of an AE must be recorded and documented as an AE. 
9.1.1.2 Serious Adverse Event (SAE) 
A serious adverse event is defined as any untoward medical occurrence that at any dose: 
• Results in death, 
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Clinical Study Protocol  
 
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• Is life-threatening, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, 
• Is a congenital anomaly/birth defect, or 
• Is an important medical event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the patient was 
at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe.  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situation, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient’s safety or may 
require intervention to prevent one of the other outcomes listed in the definition above. Examples 
include allergic bronchospasm, convulsions, and blood dyscrasias or development of drug 
dependency or drug abuse. 
Note: 
• 
A procedure is not an AE or SAE, but the reason for the procedure may be an AE. 
• 
Pre-planned surgeries or hospitalizations for pre-existing conditions which do not worsen in severity 
are not SAEs. 
• 
Routine treatment or monitoring of the studied indication not associated with deterioration in 
condition should not be considered as SAE. For example, in the patient population for the current 
study, administration of supplemental oxygen should not in itself be considered as SAE, unless it is 
associated with a significant deterioration in subject’s condition (such as development of ARDS 
and/or respiratory failure requiring invasive mechanical ventilation).  
• 
. Hospitalization or prolongation of hospitalization for technical, practical, or social reasons, in 
absence of an AE should not be considered as SAE. 
• 
Abnormal clinically significant laboratory values should not be reported as SAEs, unless they lead to 
prolongation of hospitalization on their own, while the underlying disease condition merited a 
discharge from the hospital. 
Adverse Event Reporting Period 
The study period during which AEs must be reported is defined as the period from the time patient 
signs the Informed Consent Form to Day 60 or study discontinuation, whichever is earlier. If 
follow up is required beyond Day 60 for safety related reasons, additional visit(s) may be scheduled 
for individual patients. 
Medical History Condition 
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Clinical Study Protocol  
 
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A medical history condition is any clinically significant medical/surgical condition already present 
at the time of informed consent.  
Pre-treatment Adverse Events 
Any clinically significant abnormality between the time of informed consent and intake of the first 
dose of the study drug in the trial, which meets the definition of AE, should be recorded as a pre-
treatment AE (or non-Treatment Emergent Adverse Event). Any new clinically significant event 
or worsening of existing medical history condition between the time of informed consent and 
intake of the first dose of the study drug in the trial, which meets the definition of AE will also be 
considered as pre-treatment AE. 
Treatment Emergent Adverse Events 
All AEs recorded after the first dose of study drug (on Day 1) until Day 30 or study discontinuation, 
whichever is earlier will be considered as Treatment Emergent Adverse Events (TEAEs). Disease 
signs, symptoms and/or laboratory abnormalities already existing prior to the use of the product 
will not be considered as adverse experiences after treatment (TEAEs) unless they reoccur after 
the patient has recovered from the pre-treatment condition or they represent an exacerbation in 
intensity or frequency, or the character of the condition worsens during the study period.  
Post Treatment Adverse Events  
All AEs recorded after Day 30 until Day 60 or study discontinuation, whichever is earlier will be 
considered as post treatment AEs. 
Physical Examination Findings 
At screening assessment, any clinically significant abnormality detected on physical examination 
should be recorded as a pre-existing condition. During the visits that fall within the treatment 
period and after the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an AE must be recorded and documented as an AE.  
Abnormal Laboratory Values 
A clinically significant laboratory abnormality should be documented as an AE if any one of the 
following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
• The abnormality suggests a disease and/or organ toxicity, then the underlying 
condition should be captured as an AE. 
• The abnormality is of a degree that requires active management; e.g. change of 
dose, discontinuation of the drug, more frequent follow-up assessments, further 
diagnostic investigation, etc. 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
Lab abnormalities found during the screening assessments will not be considered as AE but will 
be used by the Investigator in determining eligibility of the individual patient for study 
participation and included as part of the medical history. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as a SAE. Any condition responsible for surgery should be documented as an AE if the 
condition meets the criteria for an AE.  
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
AE in the following circumstances: 
a) Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a pre-existing condition. Surgery should not be reported as an 
outcome of an AE if the purpose of the surgery was elective or diagnostic and the 
outcome was uneventful. 
b) Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
c) Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical Investigator. 
9.1.1.3 AE Severity 
The intensity or severity of AEs will be done by two methods: 
a. The severity of the respective AEs will be graded using the NIH NCI CTCAE Version 5.0. 
Published: November 27, 201723. 
b. Additionally, the following definitions should be used to assess severity of AEs: 
• Grade 1 Mild: asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.  
• Grade 2 Moderate: minimal, local or non-invasive intervention indicated; limiting 
age appropriate instrumental Activities of Daily Living (ADL)*.  
• Grade 3 Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self care ADL**.  
• Grade 4: Life-threatening consequences; urgent intervention indicated.  
• Grade 5: Death related to AE. 
Activities of Daily Living (ADL)  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
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Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
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**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
9.1.1.4 Causality Assessment 
The relationship between an AE and the study drugs will be determined by the Investigator on 
the basis or his/her medical/ pharmacological knowledge and clinical judgment and the following 
definitions: 
• Not Related: The event is clearly due to extraneous causes (e.g., diseases, environment, 
etc.) (specify if known) or, the event is most probably produced by other factors such as 
the patient’s clinical state, therapeutic interventions, or concomitant therapy and does not 
follow a known response pattern to the study product. 
• Possibly Related: The event is temporally related to study product use but can be 
explained by another etiology. Information on the effect of study product withdrawal may 
be lacking. 
• Probably Related: The event is temporally related to study product use and is consistent 
with known effects of the study product and/or improves upon withdrawal of the study 
product. 
• Definitely Related: The event follows a reasonable temporal sequence from the time of 
study product administration and/or follows a known response pattern to the study 
product, and could not have been produced by other factors such as the patient’s clinical 
state, therapeutic intervention, or concomitant therapy, and either occurs immediately 
following study product administration or improves on stopping the product, or there is a 
positive reaction at the application site 
9.1.1.5 Action Taken Regarding the Study Product 
The action taken regarding the study product will be categorized as below; 
Grading 
Category 
Definition 
1 
None 
No change in study drug dosage was made 
2 
Discontinued Permanently 
The study product was permanently stopped 
3 
Reduced 
The dosage of study product was reduced 
4 
Interrupted 
The study product was temporarily stopped. 
5 
Increased 
The study product dosage was increased 
9.1.1.6 Adverse Event Outcome 
The outcome of the AE will be categorized as below; 
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Protocol No.: CVD-04-CD-001  
 
 
 
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Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
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Grading Category 
Definition 
1 
Recovered/Resolved 
The patient fully recovered from the AE with no residual 
effect observed 
2 
Recovered/Resolved 
with 
Sequelae 
The residual effects of the AE are still present and 
observable. 
Identify sequelae/residual effects 
3 
Not Recovered/Not Resolved 
The AE itself is still present and observable 
4 
Fatal 
The AE resulted in death of the patient or contributed 
significantly to it 
5 
Unknown 
The outcome of the AE in the patient is not known or cannot 
be determined. 
9.1.1.7 Other Action Taken for Event 
The other action taken for the AE will be categorized as below; 
Grading 
Category 
Definition 
1 
None 
No treatment was required 
2 
Medication required 
Prescription and/or OTC medication was required to 
treat the AE 
3 
Hospitalization or prolongation 
of hospitalization required 
Hospitalization was required or prolonged due to the 
AE, whether or not medication was required 
4 
Other 
 
 
9.2 
Serious Adverse Event Reporting 
Procedure for Investigator 
All serious adverse events (SAEs) should be reported immediately to the CRO (at the below 
mentioned e-mail address), who will relay it to Sponsor. The Investigator will report the SAEs 
using SAE form via email, regardless of the Investigator’s determination of causality at least within 
24 hours of the Investigator becoming aware of the event on dedicated SAE Reporting Form. 
SAE Reporting Contact Information 
DRLPV@navitaslifesciences.com 
 
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Clinical Study Protocol  
 
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In particular, if the SAE is fatal or life-threatening, the CRO must be notified immediately, 
irrespective of the extent of available AE information. This timeframe also applies to additional 
(follow-up) information that becomes available on previously forwarded SAE reports. 
At a minimum, the Investigator must provide the following information: protocol number, site ID, 
patient initials, patient number and date of event initiation, event term and causality in the initial 
SAE form. 
The Investigator is obligated to pursue and provide information to Sponsor and the responsible 
CRO on all SAEs in accordance with the timeframes for reporting specified above. In addition, an 
Investigator may be requested by Sponsor and the responsible CRO to obtain specific additional 
follow-up information in an expedited fashion. This information may be more detailed than that 
captured on eCRF. In general, this will include a description of the SAE, which should be provided 
in sufficient detail so as to allow for a complete medical assessment of the case and independent 
determination of possible causality. Information on other possible causes of the event, such as 
concomitant medications and illnesses must be provided. In the case of a subject death, a summary 
of available autopsy findings must be submitted as soon as possible to Sponsor or its designated 
representative. 
The initial reports should be followed promptly by detailed written reports. The initial and follow-
up reports should identify patients by unique code numbers assigned to the trial patients rather than 
by the patients’ names, personal identification numbers, and/or addresses.  
All SAEs will be followed until event resolution or stabilization (for chronic events), if possible, 
even when a subject is withdrawn from treatment. For chronic events that does not fully resolve 
until years later, the outcome should be reported as “resolved with sequelae” as soon as the event 
has stabilized or returned to baseline. Follow-up information for the SAE should be actively sought 
and submitted as the information becomes available. 
All pre-treatment events (see Section 9.1.1) which are assessed as being serious according to the 
criteria listed in Section 9.1.1.2 , have to be reported in the same way. 
Procedure for Sponsor/CRO 
Sponsor will follow expedited reporting procedures according to local and international 
regulations as appropriate. The Sponsor will promptly notify SAE to the applicable regulatory 
authorities, Ethics Committee and other investigators of the trial within applicable timelines as per 
the applicable regulatory requirement. 
9.2.1 SUSARs 
Procedure for Investigator 
Investigator will inform the responsible CRO (who in turn will inform the Sponsor) about the 
occurrence of the SAE via email within 24 hours of the occurrence of the SAE. The investigator 
should comply with the local regulatory requirements related to the reporting of unexpected serious 
adverse drug reactions (SUSARs) to the regulatory authority and IRB. 
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Clinical Study Protocol  
 
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Procedure for Sponsor 
In case of fatal or life threatening unexpected ADRs will be notified to regulatory agencies as soon 
as possible or no later than 7 calendar days. The follow up report will be submitted within 8 
additional calendar days after the first knowledge by the Sponsor that a case qualifies. 
 
In case of serious, unexpected reactions (ADRs) that are not fatal or life-threatening will be filed 
as soon as possible but no later than 15 calendar days after first knowledge by the Sponsor that the 
case meets the minimum criteria for expedited reporting. 
For unexpected SAE, the Sponsor considers the Investigator’s causality assessment but submits an 
IND safety report to the applicable regulatory authority for those events for which the Sponsor 
determines there is a reasonable possibility that the drug caused the event (a Suspected Adverse 
Reaction), regardless of the investigator’s causality assessment. 
 
9.3 
Exposure In Utero During Clinical Studies 
If a patient becomes pregnant during the treatment period or within 7 days after the last dose of 
study treatment, she must not receive additional study drug or treatment and must be promptly 
discontinued from the study. The patient must be followed up until the outcome of the pregnancy 
is known (i.e., delivery, elective termination, or spontaneous abortion). If the pregnancy results in 
the birth of a child, additional follow-up information may be requested. 
The Investigator must notify the responsible CRO (at the below mentioned e-mail address) within 
24 hours of first learning of the occurrence of pregnancy using the Pregnancy Notification Form 
providing as much information as possible. The Investigator must notify the responsible CRO 
about reported complications within 24 hours using the same procedure. Outcome of pregnancy, 
once known by the Investigator, must also be reported to the responsible CRO within 24 hours 
using the Pregnancy Outcome Form. Pregnancy communications will be directed to: 
Pregnancy Reporting Contact Details Email 
DRLPV@navitaslifesciences.com 
CRO who will relay pregnancy notifications to Sponsor. Please note that pregnancy in and of itself 
is not an AE or SAE. Pregnancy should not be entered into the CRF as an AE unless the 
Investigator suspects an interaction between the study treatment and contraceptive method. 
Pregnancy will be documented as the reason for study discontinuation. 
CRO will direct the pregnancy communication to Sponsor (Pharmacovigilance and Medical 
Monitor) as soon as it is received. 
9.4 
Clinical Laboratory Evaluations 
All laboratory values outside the normal range will be evaluated for clinical significance by the 
Investigator and annotated as clinically significant or not clinically significant. Patients with values 
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outside of the normal range (at the screening visit) may continue in the study at the Investigator’s 
discretion, provided they do not meet any of the exclusion criteria of the study. 
Laboratory tests mentioned in Table 7 will be evaluated at the local laboratory as described in 
Section 6.3. 
When a change in a laboratory test value constitutes an AE, the event should be followed-up until 
the change resolves or improves even after the end of the study period, within the scope of the 
patient’s cooperation. 
Table 7: Clinical / Diagnostic Laboratory Tests 
Haematology 
Serum chemistry 
Urine analysis 
▪ Haemoglobin 
▪ Haematocrit  
▪ Total WBC count  
▪ Differential WBC count 
▪ Platelet count 
▪ RBC count 
▪ Absolute neutrophil count 
 
▪ 
Total Cholesterol 
▪ 
Triglycerides 
▪ 
Total Protein 
▪ 
Albumin 
▪ 
Albumin/Globulin 
ratio 
▪ 
Blood Urea Nitrogen 
▪ 
Uric acid 
▪ 
Creatinine 
▪ 
Total Bilirubin 
▪ 
Aspartate 
aminotransferase 
(AST) 
▪ 
Alanine 
aminotransferase 
(ALT) 
▪ 
Gamma-glutamyl 
transferase 
▪ 
Alkaline phosphatase 
▪ 
Lactate 
dehydrogenase 
▪ 
Creatine Kinase 
▪ 
Calcium 
▪ 
Phosphate 
▪ 
Sodium 
▪ 
Potassium 
▪ 
Chloride 
▪ 
C-Reactive Protein 
▪ 
Glucose 
▪ 
D-dimer 
▪ 
Ferritin 
▪ Colour  
▪ Transparency  
▪ pH 
▪ Specific gravity 
▪ Protein 
▪ Glucose 
▪ Ketone bodies 
▪ Bilirubin  
▪ Blood 
▪ Nitrite 
▪ Urobilinogen 
▪ Microscopic examination 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 101 of 146 
 
Confidential 
 
9.5 
RT-PCR (Qualitative) 
Sample collection 
The respiratory tract sample will be collected through nasopharyngeal swab or oropharyngeal swab 
or nasal aspirate or tracheobronchial aspirate (or bronchial lavage at post-baseline assessments) 
for the RT-PCR (qualitative) assay for SARS-CoV-2 RNA. The sample will be collected at 
screening, on Day 5, Day 10 and Day 28, or discharge (i.e., if the patient happens to be discharged 
before one or more of the mentioned timepoints, then the sample will be collected at discharge). 
No sample will be collected from patients at any timepoint after discharge, EXCEPT if individual 
patients are scheduled for an additional (unscheduled) visit, either to follow up on an AE or to 
report a possible ‘clinical relapse’ of COVID-19 or based on Investigator’s discretion during the 
Day 10 - home visit. A sample will be collected during the unscheduled visit in such cases. The 
time of sample collection will be recorded. 
However, the test may be performed on other days at the Principal Investigator’s or a Sub-
Investigator’s discretion. 
Testing of samples 
The test will be performed at the site laboratory, if the site laboratory is not capable of performing 
RT-PCR assay, the testing will be conducted in an approved laboratory. 
9.6 
Vital Signs  
SpO2, body temperature (axillary), systolic BP, diastolic BP, pulse rate, and respiratory rate will 
be measured at pre-dose only on Day 1 and at least twice, morning and evening, daily from Day 2 
to Day 28 or discharge or discontinuation form the study (whichever is earlier), and the results will 
be recorded with time of measurement (one measurement of each vital sign is accepted at Study 
Discontinuation). If more than one measurement is performed in both the morning and evening, 
the worst value will be recorded. SpO2 will be measured without oxygen therapy as much as 
possible. If SpO2 is measured under oxygen therapy, it should be recorded. If body temperature is 
≤ 37.4°C, whether the measurement in question occurred within 4 hours after the use of antipyretic 
analgesic drugs should be recorded. 
9.7 
Electrocardiograms 
12-lead electrocardiogram (ECG) will be recorded with the patient at rest in the supine position at 
screening, once daily (preferably at the same time on each day) on Day 1, Day 4, Day 7, Day 10, 
Day 14, Day 21 and Day 28 or discharge (if discharge happens earlier than one or more of the 
above-mentioned assessment timepoints) or Study Discontinuation, whichever is earlier, and heart 
rate (HR), RR, PR, QRS, QT and QTcB intervals, and the presence or absence of clinically 
significant abnormalities will be recorded. Changes in ECG parameters will be recorded as AEs if 
the Investigator judges these as being clinically significant. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 102 of 146 
 
Confidential 
9.8 
Physical Examination Findings 
The Physical Examination will be performed, and results will be documented at visits as described 
in Section 6.3. Changes to physical examination from screening to end of trial will be recorded as 
AEs if the Investigator judges these as being clinically significant. 
A complete physical examination includes general appearance, skin, head, neck, ENT, heart, lungs, 
abdomen, extremities, neurological, musculoskeletal, and lymph nodes.  
A partial physical examination includes general appearance, ENT, heart, lungs and lymph nodes. 
9.9 
Other Safety Assessments 
Serum pregnancy test will be conducted in case of women of childbearing potential at screening 
and End of Study (Day 28 or discharge, whichever is earlier). 
10 OTHER ASSESSMENTS 
Not applicable. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 103 of 146 
 
Confidential 
11 STATISTICAL METHODS 
11.1 Analysis Sets 
Four Analysis populations will be considered for this study which are defined as below. 
Screened Population: All participants who signed the informed consent form. 
Safety Population (SAF): All randomized patients who received at least one dose of the study 
medication. 
Intention-to-treat (ITT): All randomized patients who received at least one dose of the study 
medication. 
Modified Intention to treat (mITT): All randomized patients who received at least one dose of 
the study medication and has at least one post dose primary efficacy endpoint assessment available.  
(Note: If there is a greater than 5% difference in the number of patients in the ITT and mITT 
populations, then analyses for mITT population will be provided additionally)  
Per protocol set (PPS): All patients included in the ITT who complete the study without major 
protocol deviation which would affect the primary endpoint of the study. 
11.2 General Statistical Considerations 
Adverse events and medical history will be classified using standard Medical Dictionary for 
Regulatory Activities (MedDRA Version 23.0) terminology. Prior and concomitant medications 
(including medications which are a part of supportive care) will be coded with the World Health 
Organization Drug Global (WHO-DG, version March 1, 2020) dictionary as applicable. 
Unless otherwise specified, the primary efficacy analysis will be done using ITT population. The 
statistical significance level is 0.05 by one sided or two-sided test, wherever appropriate. Mean/ 
Median estimate (and other general statistics such as Inter quartile range, SD, min, max) and the 
95% CI for the estimates of the mean will be provided for the applicable efficacy endpoint. 
Endpoints will be analysed descriptively and inferentially wherever necessary. Details of the 
statistical methods will be described in the SAP, which will be finalized before study database lock 
of Stage I of the study. 
Description of statistics:  
The primary indicators collected in this study will be described by appropriate statistical methods. 
To briefly mention, Quantitative indicators will be described by arithmetic mean, standard 
deviation, median, inter quartile range, maximum, minimum etc.; qualitative indicators will be 
described by frequency and percentage.  
11.2.1 Missing data 
Efficacy 
Missing data imputation will be done for the for the primary endpoint analysis. Method to be used 
will described on SAP.  
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 104 of 146 
 
Confidential 
Furthermore, a sensitivity analysis will be done for the method of handling missing values, if the 
number of missing values is substantial. 
Safety 
No imputation will be done on missing safety data, unless for partially incomplete dates for remote 
events such as AE, concomitant medication etc. The detailed information on imputing partial dates 
will be detailed in SAP. 
11.3 Study Population Data 
The safety data will be analysed using safety population; the summaries for disposition will be 
presented using screened population; demographics and other baseline characteristics will be 
presented using safety and ITT population and efficacy analysis will be analysed using ITT and 
PP population as required. 
11.4 Efficacy Analyses 
11.4.1 Primary Efficacy Analyses 
Analysis of the primary endpoint: 
The time from the start of administration of the study drug to time to resolution of hypoxia as 
described in the Section 3.1.3.1.1 will be compared between the treatment groups using the Cox 
proportional hazard model with age, gender and disease severity (moderate and severe) as factors 
and baseline WHO ordinal score at the start of administration of the study drug as baseline 
covariates. The hazard ratio and its corresponding 95% confidence interval (CI) and p-value will 
be obtained from the above Cox proportional hazard model; Also Median time, Inter quartile range 
estimate etc. will be presented and Kaplan-Meier plot will be plotted. All the efficacy analysis 
mentioned will be performed using ITT and PP population.  
For censored patients who died of any cause, discontinued or were lost to follow-up due to 
treatment-related adverse events or lack of efficacy, they will be censored at Day 28. However, 
censored patients who discontinued or were lost to follow-up for reasons that were independent of 
the study medication will be censored at the day of discontinuation of lost to follow-up.  Censored 
patients who were still in the study follow-up at the time of the analysis will be censored at the last 
day of available follow-up data.  
11.4.2 Secondary Efficacy Analyses 
All the secondary endpoints will be analysed descriptively and inferentially wherever necessary 
and more details on statistical analysis will be explained in the SAP. If there is a discrepancy in 
the planned analysis between the protocol and SAP, the SAP takes precedence. 
11.4.3 Exploratory Efficacy Analyses 
Based on the data availability and feasibility, exploratory analysis may be planned if required for 
this study and will be detailed in the SAP. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 105 of 146 
 
Confidential 
11.5 Pharmacokinetic/Pharmacodynamic Analyses 
Not applicable  
11.6 Safety Analyses 
11.6.1 Adverse Event Analyses 
All AEs and TEAEs will be summarized in terms of severity, relationship to study treatment, action 
taken and patient outcome. The number and the proportion of patients who experienced AEs will 
be computed by treatment arm, classified by Medical Dictionary for Regulatory Activities 
(MedDRA version 23.0) Primary System Organ Class and Preferred Terms. The AE data will be 
summarized using safety population. 
11.6.2 Clinical Laboratory Evaluation Analyses 
Continuous Laboratory data will be summarized using descriptive statistics, such as arithmetic 
mean, standard deviation, median, minimum and maximum values; while the categorical variable 
will be summarized using frequency and percentage. Descriptive statistical summaries will be 
generated for each assessment timepoint as well as change from baseline at each timepoint 
Clinically significant abnormal lab data will be summarized using frequency and percentage.  
The lab data will be summarized using safety population. 
11.6.3 Vital Sign Analyses 
Descriptive statistics such as arithmetic mean, standard deviation, median, minimum and 
maximum values will be summarized for vital sign parameters using Safety population. Clinically 
significant abnormal vital data will be summarized using frequency and percentage. Descriptive 
statistical summaries will be generated for each assessment timepoint as well as change from 
baseline at each timepoint 
11.6.4 Electrocardiogram Analyses 
Descriptive statistics, such as arithmetic mean, standard deviation, median, minimum and 
maximum values will be provided for the continuous variables and the number of observations 
and percentage will be provided for the categorical variables. Descriptive statistical summaries 
will be generated for each assessment timepoint as well as change from baseline at each timepoint 
The 12 Lead ECG analysis will be summarized using safety population. 
11.6.5 Physical Finding Analyses 
The physical examination findings will be summarized by number of observation and percentage 
using safety population  
11.6.6 Other Safety Analyses 
Other safety analysis if required will be detailed in the SAP 
11.7 Other Analyses 
Other analysis if required will be detailed in the SAP. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 106 of 146 
 
Confidential 
11.8 Interim Analyses 
Based on the data availability and feasibility, an interim analyses and/or assessment for futility 
and/or harm will be performed. During the interim analyses and/or assessment for futility and/or 
harm, re-estimation of sample size will be considered. The details of the interim analysis and 
futility/harm assessment will be included in a separate SAP for Interim analyses, appended to the 
DMC charter. If there is a discrepancy in the planned analysis between the protocol and SAP, the 
SAP takes precedence.  
 
11.9 Independent Data Monitoring Committee 
An independent data monitoring committee will review the results of the interim analyses to assess 
the efficacy and safety data emerging from the trial. The details appended to the DMC charter of 
the interim analysis and/or futility and/or harm assessment will be included in a separate SAP. If 
there is a discrepancy in the planned analysis between the protocol and SAP, the SAP takes 
precedence. 
11.10 Sample Size Determination 
Based on review of published literature,26 a hazard ratio of 1.25 is reported (adjusted for the 
stratification in randomization) for time to clinical improvement in COVID-19 patients receiving 
anti-viral intervention. The hazard ratio of 1.25 is also assumed to be constant throughout the study 
as per the assumptions of the Cox proportional hazards regression model with the expected average 
probability of the event over the course of the study to be 0.9 and 0.8 in test and control group 
respectively. Inequality testing of the hazard ratio using the Cox proportional hazards regression 
model with 371 subjects in Favipiravir group and 371 subjects in Placebo group achieves 80% 
power at the 0.05 significance level for an actual hazard ratio of 1.25 assuming the hazard ratio is 
1 under the null hypothesis and that the total number of events achieved is 631. Based on the above 
assumption and considering the dropout rate to be 5%, overall, 390 patients will be randomized in 
each treatment group. i.e. 780 patients in total to be randomized in the study. The sample size is 
estimated using nQuery version 8.5.0.0 using Cox proportional hazard regression. 
Sample size will be re-estimated based on the analysis of results for the primary endpoint observed 
during interim analyses. Details of the interim analysis and futility assessment are provided in the 
Statistical Analysis Plan (SAP) for the Interim Analysis. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 107 of 146 
 
Confidential 
12 DATA INTEGRITY AND QUALITY ASSURANCE 
The Investigator/investigational site will permit study-related in-person or remote monitoring, 
audits, IRB/IEC review and regulatory inspections by providing direct access to source documents 
and remote access to source data. Direct access includes permission to examine, analyze, verify 
and reproduce any records and reports that are important to the evaluation of a clinical study. 
Remote access to source data is applicable when on site access is not possible or restricted. 
This will be carried out giving due consideration to applicable data protection and medical 
confidentiality. 
 
12.1 Study Monitoring Plan 
Before the first patient is recruited into the study, the monitor(s) of CRO will remotely review and 
confirm the selection of clinical study facilities to: 
• Determine the adequacy of the clinical study facility 
• Discuss with the Investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence and other responsibilities 
During the progress of the study, the monitor(s) from CRO will have regular telephonic contacts, 
online discussions with the clinical study facility, or an in-person visit (if permissible and 
necessary) at agreed interval depending on the requirement and the situation to: 
• Provide information and support to Investigator(s) 
• Confirm the continued adequacy of the clinical study facility 
• Confirm that the investigational team is adhering to the protocol, GCP, and applicable 
regulatory requirements 
• Perform remote source data review (a comparison of the data in the CRFs with the 
patient’s medical records, and other records relevant to the study). 
• Check that the data are being accurately and completely recorded in the CRFs, and that 
drug accountability checks are being performed 
• Verify the protection of the rights and wellbeing of the patients 
During these remote contacts, online discussions or in-person visit (if permissible), CRFs and 
supporting documentation or scanned copies with redacted patient details as per agreement related 
to the study will be reviewed and any discrepancies or omissions or any other issues will be 
resolved. The monitor or another CRO representative will be available between discussions or visit 
if the Investigator(s) or other staffs need information or advice. 
After each remote monitoring contact or in person study visit, the monitor will prepare a 
monitoring report. A follow up letter will be prepared and sent to the Investigator for activities 
done and the resolution plan, if any. These activities will be as per the current version of the 
monitoring plan. A trial monitoring plan will be formulated and agreed upon between the Sponsor, 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 108 of 146 
 
Confidential 
CRO, clinical manager, monitors (and sites, if applicable) before the first patient is enrolled into 
the trial. 
The Principal Investigator or Sub-Investigator will also ensure that the monitor or other 
compliance or quality assurance reviewer is given access to all the above noted study-related 
documents as appropriate. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these remote monitoring or online discussion or in-person visits are addressed and 
documented. 
12.2 Data Collection 
The study eCRF is the primary data collection instrument for the study. Data will be collected 
using eCRFs that are specifically designed for this study. The eCRFs are used to record study data 
and are an integral part of the study and subsequent reports. Therefore, the eCRFs must be 
completed for each patient enrolled according to the patient’s source data and as this study is being 
conducted in a pandemic situation available documentation method will be utilized. All the eCRF 
entries should be made according to the instructions given in the Investigator’s Remote Data 
Capture manual. Corrections to electronic forms will be automatically documented via the 
software’s “audit trail”.  
If applicable, patients are to be identified by birth date and patient number. Data requested should 
be first recorded on the source document or any documentation facility as appropriate/agreed at 
investigational site and then on the eCRF; however considering the pandemic situation and in order 
not to hinder patient management, it may be agreed upon to utilize eCRF entries as source 
documents, for specific parameters. Data will be entered at the site by the appropriately designated 
and trained site personnel.  
Each entered eCRF must be approved by the site Investigator, verified against the patient’s source 
documents by the CRA/monitor and reviewed by Data Management prior to locking the database. 
Once all the eCRFs for a patient have been completed, approved, verified, reviewed and cleaned, 
the patient's eCRFs will be locked. 
The Investigator e-signs according to the study data flow. 
eCRF completion should be kept current to enable the monitor to review the patient’s status 
throughout the course of the study. eCRF will be completed, reviewed and signed off or e-signed 
by the Investigator.  
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.3 Data Management 
Data management will be handled by CRO. CRO shall ensure that clinical study data collected 
throughout the trial are complete, accurate and of the highest quality and shall be performed in 
accordance with applicable International Conference on Harmonization (ICH) guidelines and 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 109 of 146 
 
Confidential 
regulations. All the source documents will be maintained at the study site for audit and monitoring 
purposes. 
Data Management Plan (DMP) shall include all general and study-specific data management 
processes and will identify the applicable processes, the people responsible for performing it, all 
relevant SOPs to be used and what is expected as output/ documentation. 
eCRFs shall be made available to the site. Clinical data discrepancies will be identified, and data 
queries shall be resolved depending on the type of query as described in the DMP. Types of data 
to be coded will include, AEs and medications. Adverse events will be coded using the MedDRA 
adverse experience coding dictionary. Medications will be coded using the WHO-DG.  
Periodic reviews of the safety database and the clinical database will occur to ensure consistency 
between the databases. If there are any amendments to the protocol in future having an impact on 
the data points collected on the eCRFs, these would be considered for eCRF modifications as per 
the protocol requirements. 
12.4 Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons to whom he/she 
has delegated study duties. All persons authorized to make entries and/or corrections on case report 
forms will be included on the Signature List. 
Source documents are original documents, data, and records from which the patient’s case report 
form data are obtained. These include but are not limited to hospital records, clinical and office 
charts, progress notes, laboratory reports and pharmacy records, X-rays, and correspondence. As 
the Investigator is managing a pandemic situation, so as not to inconvenience site personnel and 
hinder patient management, it maybe be agreed upfront to utilize an e-Source platform and/or to 
utilize eCRF entries as source documents, for specific parameters as mentioned in the Monitoring 
plan. 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (Trial Master File) of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable regulatory authorities. 
Essential documents include: 
• Any Patient files as appropriate containing informed consents, and supporting copies of 
source documentation (if kept and as agreed) 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of relevant essential documents required prior to commencing a clinical study, and all 
correspondence to and from the IEC/IRB and the Sponsor 
• Records related to the Investigational Product(s) including acknowledgment of receipt at 
site, accountability records and final reconciliation and applicable correspondence 
In addition, all original source documents supporting entries in the case report forms must be 
maintained and be readily available.  
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 110 of 146 
 
Confidential 
In accordance with the applicable regulatory requirement(s), the confidentiality of records that 
could identify patients must be protected, respecting the privacy and confidentiality rules. 
12.5 Record Keeping 
Records of patients’ source documents, monitoring logs, inventory of investigational product, 
regulatory documents (e.g. protocol and amendments, IRB/EC correspondence and approvals, 
approved and signed informed consent forms, Investigator’s Agreement, clinical supplies receipts, 
distribution and return records), and other Sponsor correspondence pertaining to the study must be 
kept in traceable appropriate study files at the site for 5 years from study completion.  
Source documents include all recordings and observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical study. These 
records will be retained in a secure file for at least 5 years from study completion at the sites. Prior 
to transfer or destruction of these records Sponsor/CRO must be notified in writing and be given 
the opportunity to further store such records. 
In the event that the Investigator withdraws from the study (e.g., relocation, retirement), the records 
shall be transferred to a mutually agreed upon designee (e.g., another Investigator, IRB). Notice 
of such transfer will be given in writing to the Sponsor. 
12.6 Audits and Inspections 
Authorized representatives of the Sponsor, a regulatory authority, an IEC or an IRB may visit the 
center to perform audits or inspections, including source data verification. During this visit, they 
will be allowed access to CRFs, source documents and other study files. The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP and any applicable regulatory 
requirements. The Investigator should contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection at his or her center. 
12.7 Training of Staff 
The PI will maintain a record of all individuals involved in the study (medical, nursing and other 
staff) with support from CRO. He or she will ensure that appropriate training relevant to the study 
(including the current version of study protocol) is given to all of these staff members, and that 
any new information of relevance to the performance of this study is forwarded to the staff 
involved. There will be training and information on all study related processes through online 
remote trial initiation. 
12.8 Changes to the Protocol 
The study shall be conducted as described in this approved protocol. Any significant deviation 
must be documented in the eCRF. All revisions of the protocol will be discussed with the Sponsor 
or Sponsor’ representatives. The study procedures will not be changed without the mutual 
agreement of Investigators, CRO and the Sponsor. Administrative changes also require the mutual 
agreement of Investigators, CRO and the Sponsor. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 111 of 146 
 
Confidential 
In the event a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) 
prior to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to: 
• IRB/IEC for review and approval/favorable opinion 
• Sponsor/CRO 
• Regulatory Authority(ies), if required by local regulations 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to the Sponsor/CRO. If it is necessary for the study protocol to be amended, the amendment 
or a new version of the study protocol (Amended Protocol) must be provided to or approved by 
IEC, and if applicable, also the regulatory authority, before implementation. In the event an 
Amendment substantially alters the study design or increases the potential risk to the patient:  
1. The consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion;  
2. The revised form must be used to obtain consent from patients currently enrolled in the 
study if they are affected by the Amendment; and  
3. The new form must be used to obtain consent from new patients prior to enrollment. 
The Sponsor or CRO will distribute amendments and new versions of the protocol to the Principal 
Investigator or designee, who in turn is responsible for the distribution of these documents to 
IRB/IEC. 
12.9 Protocol Deviations and Violations: Condition Where the Study will be Terminated 
After a patient is enrolled into the trial and is noticed to be noncompliant with inclusion and 
exclusion criteria, the same will be documented as a protocol violation(s). During the conduct of 
the trial process if deviation(s) are noticed from the norm mentioned in the protocol, the same will 
be documented as protocol deviation(s).  
The severity of the protocol violation and protocol deviation will be graded as minor if the 
violation/deviation is not altering the integrity of the study plan or its safety and efficacy outcome, 
as major if the violation/deviation is altering the integrity of the study plan or its safety and efficacy 
outcome. 
The Sponsor reserve the right to terminate the study at any time and bear the responsibility for 
informing applicable regulatory authorities. Whereas the Principal Investigator reserves the right 
to discontinue the study for safety reasons at any time and bears the responsibility to inform the 
IEC. The reason for this termination will be provided to the patients. 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 112 of 146 
 
Confidential 
13 FINANCING AND INSURANCE 
13.1 Finances 
Prior to starting the study, the Principal Investigator and/or institution will sign a clinical study 
agreement with the Sponsor or CRO as agreed. This agreement will include the financial 
information agreed upon by the parties. 
13.2 Reimbursement, Indemnity, and Insurance 
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 113 of 146 
 
Confidential 
14 ETHICAL CONSIDERATIONS 
This study will be consistent with Good Clinical Practice (GCP) and applicable regulatory 
requirements and will be conducted in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki. 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the patient informed consent must receive IRB/IEC approval/favorable opinion prior to 
initiation of the study. Freely given written informed consent must be obtained from every patient 
prior to clinical trial participation. The rights, safety and well-being of the trial patients are the 
most important considerations and should prevail over interests of science and society. Study 
personnel involved in conducting this trial should be qualified by education, training, and 
experience to perform their respective task(s). This trial will not use the services of study personnel 
where sanctions have been invoked or where there has been scientific misconduct or fraud (e.g., 
loss of medical licensure, debarment). 
Systems with procedures will be implemented to assure the quality of every aspect of the study. 
14.1 IRB/IEC Review and Communications 
This protocol and any amendments will be submitted to Institutional Review Board (IRB) or 
Institutional Ethics Committee (IEC) in agreement with local regulations, for formal approval of 
the study to be conducted. The opinion of the IRB/ IEC concerning the conduct of the study will 
be made in writing to the Investigator and a copy of this decision will be provided to the Sponsor 
before commencement of this study. The Investigator will provide a list of IRB/IEC members and 
their affiliate to the Sponsor. 
14.2 Informed Consent Process 
The Principal Investigator(s) at each center will ensure that the patient/LAR is given full and 
adequate oral and written information about the nature, purpose, possible risk and benefits of the 
study. The procedures to be carried out and the possible potential hazards will be described to the 
patients/LAR in a language which the patient/LAR comprehends. The patient/LAR will be 
required to read and sign the consent form summarizing the discussion prior to enrolment in the 
study. A copy of the written informed consent form will be given to the patient/LAR, which 
describes the study procedures including the clinical/laboratory tests and the possible potential 
hazards in nontechnical terms in conformity with regulatory requirements. If the patient/LAR is 
unable to read, an impartial witness should be present during the entire informed consent 
discussion. After the written informed consent form and any other written information to be 
provided to patient/LAR is read and explained to the patient/LAR in a language understood by 
him/her and if the patient/LAR has orally consented to his participation in the screening/study, the 
witness should sign and personally date the consent form. By signing the consent form, the witness 
attests that the information in the consent form and any other written information was accurately 
explained to and apparently understood by the patient/LAR and that the informed consent was 
freely given by the patient/LAR. The ICF will be signed and dated by the patient/LAR and the PI 
or designee. 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 114 of 146 
 
Confidential 
The consent form will include a statement that the Sponsor or designated Sponsor’ representatives) 
and regulatory authorities will have direct access to patient records. The Investigator must have 
the IRB/IEC’s written approval/favorable opinion of the written informed consent form and any 
other information to be provided to the patients prior to the beginning of the study. 
The ICF provided to patients or the patient’s legally acceptable representative, should be revised 
whenever important new information becomes available that is relevant to the patient’s consent, 
and they should receive IRB/IEC approval/favourable opinion prior to use. Any updates to the 
consent form and any updates to the written information will be provided to the patient during a 
patient’s participation in the trial.  
14.3 Statement of Patient Confidentiality Including Ownership of Data 
The records of the patient’s medical history, physical examination, laboratory results and any other 
information or data generated during the study will be made available to the Sponsor, CRO or their 
designees (auditors, monitors), ethics committee, and will be made available to applicable drug 
regulatory bodies of countries, formulary committees of hospitals, at the opinion of the Sponsor. 
A pre-condition for entry into this study will be patient’s agreement to release all of the above-
mentioned documentation and data for any lawful purpose. In such cases, the patients name will 
be removed from all documentation to ensure anonymity.  
 
14.4 Termination of Study 
The Sponsor and the Institutional Review Board/ Independent Ethics Committee reserve the right 
to terminate the study at any time. The reason for this termination will be provided to the patients. 
The Principal Investigator reserves the right to discontinue the study for safety reasons at any time. 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 115 of 146 
 
Confidential 
15 PUBLICATION POLICY 
The results of the study including all obtained data will be the property of the Sponsor. 
However, the Investigator and CRO may seek permission to publish results of the study from the 
Sponsor. Unpublished data cannot be disclosed to any third party by the Investigators or CRO 
without written approval of the Sponsor. Any formal publication of data collected as a result of 
the study will be considered a joint publication by the Investigators and the appropriate Sponsor 
personnel. Authorship will be determined by mutual agreement. 
All clinical trials should be registered in a public trials registry. It is the responsibility of the 
Sponsor or designee to register this trial in an acceptable registry such as www.clinicaltrials.gov. 
Results might also be published in a peer-reviewed journal and authorship issues should be 
discussed and agreed upon early in the process between the Principal Investigator, sub-Investigator 
and Sponsor. 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 116 of 146 
 
Confidential 
16 SPECIAL CONSIDERATIONS 
16.1 Procedures in Case of Medical Emergency 
In a medical emergency requiring immediate attention, study staff will apply appropriate medical 
intervention, according to current standards of care. Regulatory authorities and IEC will be notified 
of the event(s) when applicable. 
16.2 Investigator’s Responsibilities 
The Investigators responsibilities involves the following- 
1. Monitor and record all AE(s), which includes SAE(s), regardless of the severity or 
relationship to IP. 
2. Determine the seriousness, relationship, and severity of each event. 
3. Determine the onset and resolution dates of each event. 
4. Complete an SAE form for each SAE and e-mail it to the CRO/Sponsor within 24 hours of 
the study site staff becoming aware of the event. 
5. Pursue SAE follow-up information actively and persistently. Follow-up information must 
be reported to the CRO/Sponsor within 24 hours of the study site staff becoming aware of 
the information and to IEC within 7 working days. 
6. Ensure all AE and SAE reports are supported by documentation in the patient’s medical 
records. 
7. Notification of the Institutional Review Board/ Independent Ethics Committee must be sent 
to the Sponsor or designee in a timely manner. 
8. During and following the patient’s participation in the trial, the Investigator should ensure 
that adequate medical care is provided to the participant for any AEs. 
 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 117 of 146 
 
Confidential 
17 REFERENCES 
1. Coronavirus 
disease 
(COVID-19) 
Pandemic. 
Available 
online 
from: 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019. 
[Accessed 
on 
29 Jun 2020]. 
2. Gasmi A, Noor S, Tippairote T, Dadar M, Menzel A, Bjørklund G. Individual risk 
management strategy and potential therapeutic options for the COVID-19 pandemic. Clin 
Immunol. 2020; 215:108409. 
3. Song JC, Wang G, Zhang W, et al. Chinese expert consensus on diagnosis and treatment 
of coagulation dysfunction in COVID-19. Mil Med Res. 2020;7(1):19. Published 2020 Apr 
20. 
4. Tan W, Aboulhosn J. The cardiovascular burden of coronavirus disease 2019 (COVID-19) 
with a focus on congenital heart disease [published online ahead of print, 2020 Mar 28]. 
Int J Cardiol. 2020;309:70‐77. 
5. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications 
in critically ill ICU patients with COVID-19 [published online ahead of print, 2020 Apr 
10]. Thromb Res. 2020;S0049-3848(20)30120-1. 
6. Ozma MA, Maroufi P, Khodadadi E et al. Clinical manifestation, diagnosis, prevention 
and control of SARS-CoV-2 (COVID-19) during the outbreak period. Infez Med. 
2020;28(2):153–165. 
7. Morawskaa L, Caob J. Airborne transmission of SARS-CoV-2: The world should face the 
reality. Environment International. Volume 139, June 2020. 
8. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for 
Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020 Apr 13. 
9. Tang Yw, Schmitz JE, Persing DH, Stratton CW. The Laboratory Diagnosis of COVID-19 
Infection: Current Issues and Challenges. J Clin Microbiol. 2020;JCM.00512-20. 
10. Sarma P, Prajapat M, Avti P et al. Therapeutic options for the treatment of 2019-novel 
coronavirus: An evidence-based approach. EDITORIAL. The Indian Journal of 
Pharmacology, Jan-Feb 2020, Volume 52, Issue 1, Page 1-5. 
11. FUJIFILM Pharmaceuticals U.S.A., Inc. Favipiravir Investigator’s Brochure–twelfth 
Edition, dated 20 Mar 2020. 
12. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine 
effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 
2020;30:269-71. 
13. Chen C, Huang J, Cheng Z, Zhang Y, Cheng Z et al. Favipiravir versus arbidol for COVID-
19: 
a 
randomized 
clinical 
trial. 
Available 
online 
from: 
https://doi.org/10.1101/2020.03.17.20037432. [Accessed on 06 Jul 2020]. 
14. Cai Q, Yang M, Liu D, et al. Experimental Treatment with Favipiravir for COVID-19: An 
Open-Label Control Study [published online ahead of print, 2020 Mar 18]. Engineering 
(Beijing). doi:10.1016/j.eng.2020.03.007 
15. Favipiravir Observational Study Group. Preliminary Report of the Favipiravir 
Observational 
Study 
in 
Japan. 
Available 
online 
from 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 118 of 146 
 
Confidential 
http://www.kansensho.or.jp/uploads/files/topics/2019ncov/covid19_casereport_en_20052
9.pdf [Accessed on 06 Jul 2020]  
16. Gowen BB, Wong MH, Jung KH, Sanders AB, Mendenhall M, Bailey KW, et al. In vitro 
and in vivo activities of T-705 against arenavirus and bunyavirus infections. Antimicrob 
Agents Chemother. 2007;51:3168-76. 
17. Mendenhall M, Russell A, Smee DF, Hall JO, Skirpstunas R, Furuta Y, et al. Effective oral 
favipiravir (T-705) therapy initiated after the onset of clinical disease in a model of 
arenavirus hemorrhagic Fever. PLoS Negl Trop Dis. 2011;5:e1342. 
18. Oestereich L, Lüdtke A, Wurr S, Rieger T, Rieger T, Muñoz-Fontela C, et al. Successful 
treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal 
model. Antiviral Res. 2014;105:17-21. 
19. Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health 
concern. Lancet. 2020;395:470-3. 
20. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The 
species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV 
and naming it SARS-CoV-2. Nat Microbiol. 2020 Mar 2. PubMed PMID: 32123347. 
21. Catanzaro M, Fagiani F, Racchi M, Corsini E, Govoni S, Lanni C. Immune response in 
COVID-19: addressing a pharmacological challenge by targeting pathways triggered by 
SARS-CoV-2. Signal Transduct Target Ther. 2020; 5: 84. 
22. Bai CQ, Mu JS, Kargbo D, Song YB, Niu WK, Nie WM, et al. Clinical and Virological 
Characteristics of Ebola Virus Disease Patients Treated With Favipiravir (T-705)-Sierra 
Leone, 2014. Clin Infect Dis. 2016;63:1288-94. 
23. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. National Institutes of 
Health. National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0. Published: November 27, 2017. Available online from 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_8.5x11.pdf [Accessed on 03 Aug 2020] 
24. FDA. COVID-19: Developing Drugs and Biological Products for Treatment or Prevention 
Guidance 
for 
Industry. 
May 
2020. 
Available 
online 
from 
https://www.fda.gov/media/137926/download [Accessed on 29 Jun 2020]. 
25. Warren MA, Zhao Z, Koyama T et al. Severity scoring of lung oedema on the chest 
radiograph is associated with clinical outcomes in ARDS. Thorax. 2018;73(9):840-846. 
26. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe 
COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 
2020; 395(10236): 1569–1578. 
 
 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 119 of 146 
 
Confidential 
18 APPENDICES 
Appendix I: COVID-19: Developing Drugs and Biological Products for Treatment or Prevention 
- Guidance for Industry 
Appendix II: Declaration of Helsinki 
Appendix III: Investigator’s Declaration 
 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
Page 120 of 146 
 
Confidential 
Appendix I COVID-19: Developing Drugs and Biological Products for Treatment or 
Prevention - Guidance for Industry 
 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


 
 
COVID-19: Developing 
Drugs and Biological 
Products for Treatment or 
Prevention 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2020 
Clinical/Medical
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


 
 
COVID-19: Developing 
Drugs and Biological 
Products for Treatment or 
Prevention 
Guidance for Industry 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
and/or 
 
Office of Communication, Outreach, and Development 
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2020 
Clinical/Medical
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Contains Nonbinding Recommendations 
 
Preface 
 
Public Comment 
 
This guidance is being issued to address the Coronavirus Disease 2019 (COVID-19) public 
health emergency. This guidance is being implemented without prior public comment because 
the Food and Drug Administration (FDA or the Agency) has determined that prior public 
participation for this guidance is not feasible or appropriate (see section 701(h)(1)(C) of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR 10.115(g)(2)). This guidance 
document is being implemented immediately, but it remains subject to comment in accordance 
with the Agency’s good guidance practices. 
 
Comments may be submitted at any time for Agency consideration.  Submit written comments to 
the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852. Submit electronic comments to https://www.regulations.gov.  
All comments should be identified with the docket number FDA-2020-D-1370 and complete title 
of the guidance in the request. 
 
Additional Copies 
 
Additional copies are available from the FDA webpage titled “Coronavirus Disease 2019 
(COVID-19),” available at https://www.fda.gov/emergency-preparedness-and-response/mcm-
issues/covid-19-related-guidance-documents-industry-fda-staff-and-other-stakeholders, and the 
FDA webpage titled “Search for FDA Guidance Documents,” available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. You may also send 
an e-mail request to COVID19-productdevelopment@fda.hhs.gov to receive an additional copy 
of the guidance. Please include the docket number FDA-2020-D-1370 and complete title of the 
guidance in the request. 
 
Questions 
For questions about this document, contact Eithu Lwin, 301-796-0728, 
Eithu.Lwin@fda.hhs.gov. 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I. 
INTRODUCTION............................................................................................................. 1 
II. 
BACKGROUND ............................................................................................................... 2 
III. 
DISCUSSION .................................................................................................................... 3 
A. 
Population ....................................................................................................................................... 3 
B. 
Trial Design .................................................................................................................................... 6 
C. 
Efficacy Endpoints ......................................................................................................................... 8 
D. 
Safety Considerations .................................................................................................................. 10 
E. 
Statistical Considerations ............................................................................................................ 11 
APPENDIX .................................................................................................................................. 13 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Contains Nonbinding Recommendations 
1 
COVID-19: Developing Drugs and Biological Products for 
1 
Treatment or Prevention 
2 
Guidance for Industry1 
3 
 
4 
 
5 
 
6 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
7 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
8 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
9 
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
10 
title page 
11 
 
12 
 
13 
 
14 
I. 
INTRODUCTION 
15 
 
16 
FDA plays a critical role in protecting the United States from threats such as emerging infectious 
17 
diseases, including the Coronavirus Disease 2019 (COVID-19) pandemic. FDA is committed to 
18 
providing timely guidance to support response efforts to this pandemic. 
19 
 
20 
FDA is issuing this guidance to assist sponsors in the clinical development of drugs2 for the 
21 
treatment or prevention of COVID-19. Preventative vaccines3 and convalescent plasma4 are not 
22 
within the scope of this guidance. 
23 
 
24 
This guidance is intended to remain in effect for the duration of the public health emergency 
25 
related to COVID-19 declared by the Department of Health and Human Services (HHS), 
26 
including any renewals made by the HHS Secretary in accordance with section 319(a)(2) of the 
27 
Public Health Service (PHS) Act. However, the recommendations described in the guidance are 
28 
expected to assist the Agency more broadly in its continued efforts to assist sponsors in the 
29 
clinical development of drugs for the treatment of COVID-19 beyond the termination of the 
30 
                                                 
1 This guidance has been prepared by the Office of New Drugs and the Office of Biostatistics in the Center for Drug 
Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and 
Drug Administration. 
 
2 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless 
otherwise specified. 
 
3 Clinical trials of preventative vaccines raise different and additional considerations, including those pertaining to 
subject selection, safety monitoring, and effectiveness evaluation.  We encourage developers of preventative 
vaccines to contact the Office of Vaccines Research and Review in CBER. 
 
4 FDA has issued guidance to provide recommendations to health care providers and investigators on the 
administration and study of investigational convalescent plasma collected from individuals who have recovered 
from COVID-19 (COVID-19 convalescent plasma) during the public health emergency, available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigational-covid-19-convalescent-
plasma. 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Contains Nonbinding Recommendations 
2 
COVID-19 public health emergency and reflect the Agency’s current thinking on this issue. 
31 
Therefore, within 60 days following the termination of the public health emergency, FDA 
32 
intends to revise and replace this guidance with any appropriate changes based on comments 
33 
received on this guidance and the Agency’s experience with implementation. 
34 
 
35 
Given this public health emergency related to COVID-19 declared by HHS, this guidance is 
36 
being implemented without prior public comment because FDA has determined that prior public 
37 
participation for this guidance is not feasible or appropriate (see section 701(h)(1)(C) of the 
38 
Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR 10.115(g)(2)). This guidance 
39 
document is being implemented immediately, but it remains subject to comment in accordance 
40 
with the Agency’s good guidance practices. 
41 
 
42 
In general, FDA’s guidance documents, including this guidance, do not establish legally 
43 
enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a 
44 
topic and should be viewed only as recommendations, unless specific regulatory or statutory 
45 
requirements are cited. The use of the word should in Agency guidance means that something 
46 
is suggested or recommended, but not required. 
47 
 
48 
 
49 
II. 
BACKGROUND 
50 
 
51 
There is currently an outbreak of respiratory disease caused by a novel coronavirus. The virus 
52 
has been named SARS-CoV-2 and the disease it causes has been named Coronavirus Disease 
53 
2019 (COVID-19). On January 31, 2020, HHS issued a declaration of a public health 
54 
emergency related to COVID-19, effective January 27, 2020, and mobilized the Operating 
55 
Divisions of HHS.5 In addition, on March 13, 2020, the President declared a national 
56 
emergency in response to COVID-19.6 
57 
 
58 
COVID-19 can range from mild to severe disease, the latter including pneumonia, severe acute 
59 
respiratory syndrome, multi-organ failure, and death. The incubation period for SARS-CoV-2 is 
60 
thought to be as long as 14 days, with a median time of 4 to 5 days from exposure to symptom 
61 
onset.7 There are currently no FDA-approved drugs to treat COVID-19. Clinical management 
62 
includes symptomatic and supportive care, such as supplemental oxygen, mechanical ventilation, 
63 
and extracorporeal membrane oxygenation (ECMO) when indicated. 
64 
 
65 
                                                 
5 Secretary of Health and Human Services Alex M. Azar, Determination that a Public Health Emergency Exists. 
(Jan. 31, 2020, renewed April 21, 2020), available at 
https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx. 
 
6 Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) 
Outbreak (March 13, 2020), available at https://www.whitehouse.gov/presidential-actions/proclamation-declaring-
national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/. 
 
7 See the Centers for Disease Control and Prevention Interim Clinical Guidance for Management of Patients with 
Confirmed Coronavirus Disease (COVID-19), available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-
guidance-management-patients.html. 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Contains Nonbinding Recommendations 
3 
This guidance describes FDA’s current recommendations regarding phase 2 or phase 3 trials for 
66 
drugs under development to treat or prevent COVID-19.8 This guidance focuses on the 
67 
population, trial design, efficacy endpoints, safety considerations, and statistical considerations 
68 
for such clinical trials. This guidance does not provide general recommendations on early drug 
69 
development in COVID-19, such as use of animal models. Drugs should have undergone 
70 
sufficient development before their evaluation in phase 2 or phase 3. FDA is committed to 
71 
supporting all scientifically sound approaches to attenuating the clinical impact of COVID-19. 
72 
Sponsors engaged in the development of drugs for COVID-19 should also see the guidance for 
73 
industry and investigators COVID-19 Public Health Emergency: General Considerations for 
74 
Pre-IND Meeting Requests for COVID-19 Related Drugs and Biological Products (May 2020).9 
75 
 
76 
This guidance focuses on the development of drugs with direct antiviral activity or 
77 
immunomodulatory activity. However, the recommendations in this guidance may be applicable 
78 
to development plans for drugs for COVID-19 with other mechanisms of action. The mechanism 
79 
of action of the drug may impact key study design elements (e.g., population, endpoints, safety 
80 
assessments, duration of follow-up). Additionally, for some biological products (e.g., cellular 
81 
and gene therapies and blood products) there may be additional considerations and we encourage 
82 
you to reach out to the applicable review division as appropriate. 
83 
 
84 
 
85 
III. 
DISCUSSION 
86 
 
87 
A. 
Population 
88 
 
89 
Sponsors of drugs to treat or prevent COVID-19 should consider the following: 
90 
 
91 
• A range of populations is appropriate for evaluation and may include outpatient, 
92 
inpatient, or inpatient on mechanical ventilation populations. 
93 
 
94 
• For treatment trials, sponsors should document diagnosis of COVID-19. Laboratory-
95 
confirmed disease is preferred. 
96 
 
97 
• For treatment trials, FDA recommends that sponsors categorize the baseline severity of 
98 
the enrolled population. The criteria used to describe baseline severity should incorporate 
99 
objective measures. Examples of severity criteria are provided in the Appendix. 
100 
 
101 
• For prevention trials, sponsors should conduct trials in communities with documentation 
102 
of circulating SARS-CoV-2 infection.10 Populations including the following may be 
103 
considered: 
104 
                                                 
8 Phase 2 and phase 3 trials need to be registered at www.ClinicalTrials.gov as required by 42 CFR part 11. 
 
9 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
 
10 Subjects in prophylaxis trials may be either SARS-CoV-2 negative or have an unknown SARS-CoV-2 status. 
 
DocuSign Envelope ID: 1AFB0EAA-9EB5-497C-BA92-EC85CE6F0C9B


Contains Nonbinding Recommendations 
4 
 
105 
– Pre-exposure prophylaxis trials in persons at high risk for SARS-CoV-2 exposure 
106 
with no symptoms (e.g., health care workers and first responders) 
107 
 
108 
– Post-exposure prophylaxis trials in health care workers or household contacts with no 
109 
symptoms and with a documented exposure to a definite or clinically presumed case 
110 
 
111 
• Given the expected fluctuation in regions in the frequency of SARS-CoV-2 infection, 
112 
sponsors should address the need to open new sites and potentially suspend existing sites. 
113 
 
114 
• Clinical trials should include persons at high risk of complications such as the elderly, 
115 
persons with underlying cardiovascular or respiratory disease, diabetes, chronic kidney 
116 
disease, or other comorbidities, and immunocompromised persons (e.g., HIV-infected 
117 
patients, organ transplant recipients, or patients receiving cancer chemotherapy).11 
118 
 
119 
• COVID-19 disproportionately affects adults, including older individuals. The geriatric 
120 
population should be appropriately represented in clinical trials.12 Sponsors should 
121 
consider conducting trials in nursing homes or other elder care facilities. 
122 
 
123 
• Racial and ethnic minority persons should be represented in clinical trials. Sponsors 
124 
should ensure that clinical trial sites include geographic locations with a higher 
125 
concentration of racial and ethnic minorities to recruit a diverse study population.13 
126 
 
127 
• Patients with renal or hepatic impairment should be enrolled in clinical trials provided the 
128 
pharmacokinetics of the drug have been evaluated in these patients and appropriate 
129 
dosing regimens have been identified. 
130 
 
131 
• The principles outlined in this document can be used to guide drug development for 
132 
children and pregnant and lactating individuals. There is a need to generate clinical trial 
133 
data to inform the use of drugs in these populations. 
134 
 
135 
                                                 
11 See the Centers for Disease Control and Prevention Interim Clinical Guidance for Management of Patients with 
Confirmed Coronavirus Disease (COVID-19), available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-
guidance-management-patients.html, and the web page Information for People who are at Higher Risk for Severe 
Illness, available at https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/groups-at-higher-risk.html. 
 
12 See the draft guidance for industry Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, 
Enrollment Practices, and Trial Design (June 2019). When final, this guidance will represent the FDA’s current 
thinking on this topic. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
13 Ibid. 
 
 
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– FDA encourages the enrollment of pregnant and lactating individuals in the phase 3 
136 
(efficacy) clinical trials if appropriate.14 
137 
 
138 
– Children should not be categorically excluded from clinical trials of investigational 
139 
COVID-19 products in which there is a prospect for direct benefit.15 
140 
 
141 
 Sponsors are encouraged to discuss pediatric drug development with FDA early in 
142 
the course of clinical development, including the potential for extrapolation of 
143 
adult efficacy data, appropriate pharmacokinetic trials in pediatric subjects to 
144 
support dose selection, and the recommended size of the preapproval safety 
145 
database in children. In addition, disease severity classification should reflect age-
146 
appropriate norms, as applicable. Decisions on the timing of initiating pediatric 
147 
studies depend on several factors, including but not limited to the amount of 
148 
available clinical and/or nonclinical safety data for the drug. For example, if 
149 
dosing recommendations for a drug are the same for adults and adolescents16 and 
150 
there is sufficient prospect of benefit to justify the risks, then it may be 
151 
appropriate to include adolescents in the initial phase 3 clinical trials. 
152 
 
153 
 Sponsors are encouraged to submit an initial pediatric study plan as soon as 
154 
practicable.17 
155 
 
156 
 Under the Pediatric Research Equity Act, all applications for new active 
157 
ingredients (which includes new salts and new fixed combinations), new 
158 
indications, new dosage forms, new dosing regimens, or new routes of 
159 
administration are required to contain an assessment of the safety and 
160 
effectiveness of the product for the claimed indication or indications in pediatric 
161 
populations unless this requirement is waived, deferred, or inapplicable.18 FDA 
162 
intends to work with sponsors to reach agreement on the initial pediatric study 
163 
plan and any pediatric trial protocols as quickly as possible to avoid any 
164 
unnecessary delays in the initiation of trials or submission of any marketing 
165 
application. 
166 
 
167 
                                                 
14 FDA has proposed relevant recommendations in the draft guidance to industry Pregnant Women: Scientific and 
Ethical Considerations for Inclusion in Clinical Trials (April 2018). When final, this guidance will represent the 
FDA’s current thinking on this topic. 
 
15 See 21 CFR part 50, subpart D. 
 
16 For the purposes of this guidance, adolescents are defined as age 12 to younger than 18 years of age. 
 
17 See 505B(e) of the FD&C Act. Additionally, FDA has proposed relevant recommendations in the draft guidance 
for industry Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and 
Amended Pediatric Study Plans (March 2016). When final, this guidance will represent the FDA’s current thinking 
on this topic. 
 
18 See 21 U.S.C 355c. 
 
 
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B. 
Trial Design 
168 
 
169 
Sponsors of drugs to treat or prevent COVID-19 should consider the following: 
170 
 
171 
• FDA strongly recommends that drugs to treat or prevent COVID-19 be evaluated in 
172 
randomized, placebo-controlled, double-blind clinical trials using a superiority design.19 
173 
 
174 
– Background standard of care should be maintained in all treatment arms. Sponsors 
175 
should address anticipated off-label use of any other drugs, devices, or interventions 
176 
that might be used to manage COVID-19. 
177 
 
178 
– The standard of care is expected to change as additional information, such as from 
179 
randomized controlled trials, emerges. Where treatments become standard of care for 
180 
specific COVID-19 populations (e.g., severely ill hospitalized patients), trials in these 
181 
populations should generally be designed as placebo-controlled superiority studies 
182 
with an add-on design (i.e., the investigational agent or placebo added on to the 
183 
standard of care agent). For agents with a similar mechanism of action as the standard 
184 
of care (e.g., direct antiviral agent as the investigational agent when the new standard 
185 
of care is also a direct antiviral agent), an active-comparator controlled study design 
186 
may be considered if there is sufficient preclinical and initial clinical evidence of 
187 
activity of the investigational agent. Sponsors should plan early discussion with the 
188 
appropriate clinical division. 
189 
 
190 
• Under certain circumstances it may be appropriate to conduct decentralized and/or 
191 
platform clinical trials. Sponsors considering these approaches should discuss their plans 
192 
with the Agency. FDA recognizes the potential of, and significant interest in, such 
193 
approaches, and may provide additional recommendations as we gain more experience 
194 
regarding their use in this context. 
195 
 
196 
• Given the infection control concerns associated with COVID-19, sponsors should limit 
197 
in-person data collection to those measurements intended to ensure safety and establish 
198 
effectiveness or influence the benefit-risk assessment. 
199 
 
200 
• The trial should be of sufficient duration to evaluate safety and effectiveness reliably (i.e., 
201 
the duration should be adequate to capture the vast majority of COVID-19-related 
202 
outcomes that are relevant for the population under study). For example, a 4-week 
203 
duration would likely be sufficient to capture most important outcomes (e.g., mortality) 
204 
in a trial of mechanically ventilated patients. Longer durations would potentially be 
205 
appropriate for trials of patients who are less ill at baseline and for trials of preventive 
206 
treatments. In some cases, longer follow-up should be considered to assess safety. 
207 
 
208 
                                                 
19 FDA has proposed relevant recommendations in the draft guidance for industry Demonstrating Substantial 
Evidence of Effectiveness for Human Drug and Biological Products (December 2019). When final, this guidance 
will represent the FDA’s current thinking on this topic. 
 
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• When there is compelling preclinical or preliminary clinical evidence, it may be 
209 
appropriate to move directly to conduct a trial of sufficient size and appropriate design to 
210 
provide substantial evidence of effectiveness and adequate characterization of safety. 
211 
 
212 
• In instances where there is some but limited information supporting the potential for 
213 
efficacy,20 approaches where an initial assessment of potential benefit can be made before 
214 
enrolling a large number of subjects are appropriate. These approaches may include the 
215 
following: 
216 
 
217 
– Conducting an initial small, controlled trial to assess for drug activity (proof-of-
218 
concept) that suggests the potential for clinical benefit. 
219 
 
220 
– Conducting a trial that incorporates prospectively planned criteria to stop the trial for 
221 
futility (i.e., with the prospect of expanding from a proof-of-concept phase to a larger 
222 
confirmatory trial). Such a trial might also incorporate additional prospectively 
223 
planned adaptations (see additional comments on adaptive design proposals below). 
224 
 
225 
• FDA encourages sponsors to use an independent data monitoring committee (DMC) to 
226 
ensure subject safety and trial integrity. 
227 
 
228 
– Sponsors should submit the DMC charter as early as possible. 
229 
 
230 
– Sponsors should ensure there will be appropriate DMC monitoring to safeguard the 
231 
welfare of subjects, accounting for important factors such as the expected enrollment 
232 
rate, the expected lag time to analyze interim data for DMC meetings, and the 
233 
frequency of DMC meetings.21 
234 
 
235 
– If enrollment is anticipated to be rapid, but additional safety data are needed before 
236 
dosing a large number of subjects, an enrollment pause could be built into the trial. In 
237 
this case, enrollment would be temporarily halted, and the DMC would assess the 
238 
data and then recommend that the trial or dosing group either terminate or resume 
239 
enrollment. 
240 
 
241 
• FDA encourages sponsors to incorporate prospectively planned criteria to stop the trial 
242 
for futility (lack of efficacy) or harm in any confirmatory trial. The stopping criteria 
243 
should aim to ensure a high probability of halting the trial if the drug is harmful (e.g., 
244 
associated with a higher risk of death), a reasonable probability of halting the trial if the 
245 
                                                 
20 See the guidance for industry and investigators COVID-19 Public Health Emergency: General Considerations for 
Pre-IND Meeting Requests for COVID-19 Related Drugs and Biological Products, which describes the information 
and data recommended to support FDA’s review for the initiation of clinical trials during the COVID-19 public 
health emergency. 
 
21 FDA has proposed relevant recommendations in the draft guidances for industry Establishment and Operation of 
Clinical Trial Data Monitoring Committees (March 2006) and Safety Assessment for IND Safety Reporting 
(December 2015). When final, these guidances will represent the FDA’s current thinking on these topics. 
 
 
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drug is ineffective, and a high probability of continuing the trial if the drug is effective. If 
246 
accrual in such a trial is expected to be rapid, an enrollment pause may be considered to 
247 
support stopping for futility. 
248 
 
249 
• If a trial incorporates the possibility of early stopping for evidence of benefit or any 
250 
adaptations to the sample size, dosing arms, or other design features, sponsors should 
251 
prospectively plan the design in a manner to ensure control of the type I error rate and 
252 
reliable treatment effect estimation.22 An independent committee, such as a DMC, should 
253 
be tasked with providing any recommendations for early termination or design 
254 
adaptations based on unblinded interim data. 
255 
 
256 
• FDA anticipates events that occur outside of an ongoing trial may provide important new 
257 
information relevant to the ongoing trial (e.g., changes to the standard of care) and may 
258 
motivate revisions to the trial design.  Well-motivated changes based on information 
259 
external to the trial can be acceptable and sponsors are encouraged to discuss these 
260 
changes with the FDA. 
261 
 
262 
C. 
Efficacy Endpoints 
263 
 
264 
Sponsors of drugs to treat or prevent COVID-19 should consider the following: 
265 
 
266 
• The drug development program should evaluate the effect of the investigational drug 
267 
relative to placebo on clinically meaningful aspects of the disease. The relevance and 
268 
appropriateness of measures may depend on the population studied, the clinical setting, 
269 
and/or baseline disease severity (see Appendix). 
270 
 
271 
• Examples of important clinical outcome measures in treatment trials include the 
272 
following: 
273 
 
274 
– All-cause mortality 
275 
 
276 
– Respiratory failure (i.e., need for mechanical ventilation, ECMO, noninvasive 
277 
ventilation, or high-flow nasal cannula oxygen delivery) 
278 
 
279 
– Need for invasive mechanical ventilation 
280 
 
281 
– Need for intensive care unit (ICU) level care based on clear definitions and specific 
282 
clinical criteria 
283 
 
284 
– Need for hospitalization based on clear definitions and specific clinical criteria 
285 
 
286 
– Objective measures of sustained improvement (e.g., return to room air or baseline 
287 
oxygen requirement) 
288 
 
289 
                                                 
22 See the guidance for industry Adaptive Design Clinical Trials for Drugs and Biologics (November 2019). 
 
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– Sustained clinical recovery (e.g., resolution of symptoms) 
290 
 
291 
• The choice, time frame, and interpretation of endpoints may differ depending on the 
292 
population evaluated in the trial. For example, 
293 
 
294 
– In a trial in severe and/or critical patients, examples of appropriate endpoints could be 
295 
 
296 
 All-cause mortality at an appropriate time point (e.g., at least 28 days) 
297 
 
298 
 Proportion of patients alive and free of respiratory failure at an appropriate time 
299 
point (e.g., at least 28 days) 
300 
 
301 
 Clinical status at an appropriate time point assessed using an ordinal scale23 that 
302 
incorporates multiple clinical outcomes of interest (e.g., death, mechanical 
303 
ventilation) ordered by their clinical importance24 
304 
 
305 
 Time to sustained recovery assessed over an appropriate duration 
306 
 
307 
– In an outpatient treatment trial, examples of appropriate endpoints could be 
308 
 
309 
 Proportion of patients hospitalized by an appropriate time point (e.g., at least 28 
310 
days) 
311 
 
312 
 Time to sustained clinical recovery assessed over an appropriate duration 
313 
 
314 
• Sponsors should address potential relapses in their endpoint definitions to ensure 
315 
adequate assessment of the durability of response. 
316 
 
317 
• In phase 2 treatment trials, a virologic measure may be acceptable as a primary endpoint 
318 
to support a phase 3 clinical endpoint study. However, virologic endpoints are not 
319 
appropriate as primary endpoints in a phase 3 trial because there is no established 
320 
predictive relationship between magnitude and timing of viral reductions and the extent 
321 
of clinical benefit of how a patient feels, functions, or survives. Additionally, the optimal 
322 
sample size, timing, methods for collection procedures, and assays for clinically relevant 
323 
virologic measurements have not been established. In phase 3 treatment trials, virologic 
324 
endpoints may be assessed as secondary endpoints. Collection of virologic data and 
325 
evaluation of antiviral resistance are important components of drug development for 
326 
COVID-19. 
327 
 
328 
• For endpoints defined by events through or at a prespecified time point, the time point 
329 
should be defined as number of days after randomization. The time window should be 
330 
                                                 
23 An example can be found at WHO R&D Blueprint novel Coronavirus, available at 
https://apps.who.int/iris/handle/10665/330695. 
 
24 Ordinal data should be collected daily to inform analyses. 
 
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sufficiently long to ensure capture of important events related to patient status, treatment, 
331 
and COVID-19 progression. 
332 
 
333 
• In prevention trials, the primary endpoint should be the occurrence of laboratory-
334 
confirmed SARS-CoV-2 infection (with or without symptoms) or SARS-CoV-2 infection 
335 
with symptoms (i.e., COVID-19) through a prespecified time point. 
336 
 
337 
– Sponsors are encouraged to evaluate both laboratory-confirmed SARS-CoV-2 
338 
infections (with or without symptoms) and SARS-CoV-2 with symptoms (i.e., 
339 
COVID-19) when possible. 
340 
 
341 
– Ascertaining whether COVID-19 is milder in persons receiving prophylaxis 
342 
compared with persons not receiving prophylaxis is of interest. Sponsors should 
343 
collect clinical outcome data (e.g., hospitalization) and data on symptoms to support 
344 
such analyses. 
345 
 
346 
D. 
Safety Considerations 
347 
 
348 
Sponsors of drugs to treat or prevent COVID-19 should consider the following:  
349 
 
350 
• It is important to include a broad population of subjects in adequate and well-controlled 
351 
clinical trials to generate a safety database that will best inform the safe use of the drug. 
352 
 
353 
• The size and composition of the safety database needed to support an indication for 
354 
COVID-19 depends on factors such as the proposed population, the treatment effect, the 
355 
drug’s toxicity, and the extent of the prior clinical experience with the drug (and possibly 
356 
with related drugs). 
357 
 
358 
• Sponsors may provide a standardized toxicity grading scale for clinical trials in patients 
359 
with severe COVID-19 or patients with serious comorbidities. Examples of toxicity 
360 
grading scales include those published by the National Institutes of Health’s Division of 
361 
AIDS25 and the National Cancer Institute (NCI).26 
362 
 
363 
• Sponsors should address the potential for drug-drug interactions that could increase the 
364 
risk for toxicities (caused by increased exposures of the drug or the drug that it interacts 
365 
with) and propose mitigation strategies. 
366 
 
367 
                                                 
25 See the National Institutes of Health’s Division of AIDS Adverse Event Grading Tables, available at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables. 
 
26 See the National Cancer Institute’s Common Terminology Criteria for Adverse Events, available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 
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• Safety assessments (e.g., vital signs, laboratory studies, electrocardiograms) should be 
368 
performed on a schedule commensurate with severity of illness and the identified 
369 
potential risk of the study drug. 
370 
 
371 
• Sponsors should conduct safety reporting as outlined in FDA regulations27 and relevant 
372 
guidance.28 
373 
 
374 
E. 
Statistical Considerations 
375 
 
376 
Sponsors of drugs to treat or prevent COVID-19 should consider the following statistical 
377 
considerations: 
378 
 
379 
• The primary efficacy analysis should be conducted in an intention-to-treat population, 
380 
defined as all randomized subjects. 
381 
 
382 
• The primary efficacy analysis should be prespecified in the protocol. 
383 
 
384 
• To the extent possible, sponsors should justify their assumptions in sample size 
385 
calculations. The sample size should be large enough to provide a reliable answer to the 
386 
safety and efficacy questions the trial is meant to address. 
387 
 
388 
• Examples of analytic approaches for the primary efficacy analysis include: 
389 
 
390 
– Binary outcome analysis: each person is classified as having a successful or an 
391 
unsuccessful outcome, with a difference in proportions used to compare treatment 
392 
arms. 
393 
 
394 
– Ordinal outcome analysis: options include a proportional odds approach, a rank-based 
395 
approach, and an approach to compare means with a score or weight assigned to each 
396 
category. Any of these approaches should be supplemented by analyses 
397 
communicating how treatment impacts different categories of the scale. 
398 
 
399 
– Time-to-event analysis: use of a proportional hazards model or log-rank test should 
400 
be supplemented by a display of Kaplan-Meier curves in each treatment group. 
401 
 
402 
• To improve the precision of treatment effect estimation and inference, sponsors should 
403 
consider adjusting for prespecified prognostic baseline covariates (e.g., age, baseline 
404 
severity, comorbidities) in the primary efficacy analysis and should propose methods of 
405 
                                                 
27 See 21 CFR 312.32. 
 
28 See the guidance for industry Safety Reporting Requirements for INDs and BA/BE Studies (December 2012). In 
addition, FDA has proposed relevant recommendations in the draft guidance for industry Safety Assessment for IND 
Safety Reporting. When final, this guidance will represent the FDA’s current thinking on this topic. 
 
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covariate adjustment. For example, for a binary endpoint, methods can be used to gain 
406 
precision in the evaluation of the difference in proportions.29 
407 
 
408 
• If a treatment trial enrolls a mixture of patients with different baseline severity levels, 
409 
sponsors should conduct subgroup or interaction analyses by baseline severity to assess 
410 
for differential treatment effects. 
411 
 
412 
• The trial should aim to minimize missing data. The protocol should distinguish between 
413 
discontinuation from the study drug and withdrawal from study assessments. Sponsors 
414 
should encourage subjects who discontinue therapy to remain in the study and to continue 
415 
follow-up for key outcomes. Virtual follow-up is acceptable if appropriate, and the aim 
416 
should be to record vital status for all subjects. 
417 
 
418 
• For the primary analyses, death should not be considered a form of missing data or 
419 
censoring. Death should be incorporated into the endpoint as a highly unfavorable 
420 
possible outcome. For primary endpoints other than all-cause mortality, a treatment effect 
421 
could be driven by non-mortality components (e.g., hospitalization) despite increased 
422 
mortality on drug. Therefore, analyses of all-cause mortality will be important regardless 
423 
of the selected primary endpoint. 
424 
 
 
425 
                                                 
29 Ge M, Durham LK, Meyer RD, Xie W, and Thomas N, 2011, Covariate-Adjusted Difference in Proportions from 
Clinical Trials Using Logistic Regression and Weighted Risk Differences, Drug Inf J, 45:481–493. 
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APPENDIX 
426 
 
427 
EXAMPLES OF BASELINE SEVERITY CATEGORIZATION 
428 
 
429 
SARS-CoV-2 infection without symptoms 
430 
 
431 
• Positive testing by standard reverse transcription polymerase chain reaction (RT-PCR) 
432 
assay or equivalent test 
433 
 
434 
• No symptoms 
435 
 
436 
Mild COVID-19 
437 
 
438 
• Positive testing by standard RT-PCR assay or equivalent test 
439 
 
440 
• Symptoms of mild illness with COVID-19 that could include fever, cough, sore throat, 
441 
malaise, headache, muscle pain, gastrointestinal symptoms, without shortness of breath or 
442 
dyspnea 
443 
 
444 
• No clinical signs indicative of Moderate, Severe, or Critical Severity 
445 
 
446 
Moderate COVID-19 
447 
 
448 
• Positive testing by standard RT-PCR assay or equivalent testing 
449 
 
450 
• Symptoms of moderate illness with COVID-19, which could include any symptom of 
451 
mild illness or shortness of breath with exertion 
452 
 
453 
• Clinical signs suggestive of moderate illness with COVID-19, such as respiratory rate ≥ 
454 
20 breaths per minute, saturation of oxygen (SpO2) > 93% on room air at sea level, heart 
455 
rate ≥ 90 beats per minute  
456 
 
457 
• No clinical signs indicative of Severe or Critical Illness Severity 
458 
 
459 
Severe COVID-19 
460 
 
461 
• Positive testing by standard RT-PCR assay or an equivalent test 
462 
 
463 
• Symptoms suggestive of severe systemic illness with COVID-19, which could include 
464 
any symptom of moderate illness or shortness of breath at rest, or respiratory distress 
465 
 
466 
• Clinical signs indicative of severe systemic illness with COVID-19, such as respiratory 
467 
rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air at sea level or 
468 
PaO2/FiO2 < 300 
469 
 
470 
• No criteria for Critical Severity 
471 
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472 
Critical COVID-19 
473 
 
474 
• Positive testing by standard RT-PCR assay or equivalent test  
475 
 
476 
• Evidence of critical illness, defined by at least one of the following: 
477 
 
478 
– Respiratory failure defined based on resource utilization requiring at least one of the 
479 
following:  
480 
 
481 
 Endotracheal intubation and mechanical ventilation, oxygen delivered by high-
482 
flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal 
483 
cannula at flow rates > 20 L/min with fraction of delivered oxygen ≥ 0.5), 
484 
noninvasive positive pressure ventilation, ECMO, or clinical diagnosis of 
485 
respiratory failure (i.e., clinical need for one of the preceding therapies, but 
486 
preceding therapies not able to be administered in setting of resource limitation) 
487 
 
488 
– Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood pressure < 
489 
60 mm Hg or requiring vasopressors) 
490 
 
491 
– Multi-organ dysfunction/failure 
492 
 
493 
NOTE: A clinical diagnosis of respiratory failure (in the setting of resource limitation) in which 
494 
the management deviates from standard of care should be recorded as part of formal data 
495 
collection. 
496 
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Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
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Appendix II: Ethical Principles for Medical Research Involving Human Subjects 
World Medical Association Declaration of Helsinki: Recommendation guiding Medical 
Doctors in Biomedical Research Involving Human Subjects. 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington, DC, USA, October 2002 
(Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 
(Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
 
A. INTRODUCTION 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research 
on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. 
The WMA encourages others who are involved in medical research involving human subjects to 
adopt these principles.  
 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
subject will be my first consideration,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the subject's best interest when providing medical care.” 
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Study code: NV-05-983-2020 
  
Protocol No.: CVD-04-CD-001  
 
 
 
    Good Health Can't Wait. 
Sponsor name: Dr. Reddy’s Laboratories, Limited 
Clinical Study Protocol  
 
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CONFIDENTIAL 
Page 140 of 146 
 
Confidential 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality.  
7. Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights.  
8. While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information 
of research subjects. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professionals and never with the research subjects, even 
though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access 
to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic 
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Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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value and if the physician has good reason to believe that participation in the research study will 
not adversely affect the health of the patients who serve as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits  
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects.  
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. Measures to minimize the risks must be implemented. The risks must be 
continuously monitored, assessed and documented by the researcher.  
 
18. Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood 
of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-vulnerable 
group. In addition, this group should stand to benefit from the knowledge, practices or 
interventions that result from the research. 
Scientific Requirements and Research Protocols  
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
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information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected.  
22. The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, Sponsor, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and approval 
to the concerned research ethics committee before the study begins. This committee must be 
transparent in its functioning, must be independent of the researcher, the Sponsor and any other 
undue influence and must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.  
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any SAE. No amendment 
to the protocol may be made without consideration and approval by the committee. After the end 
of the study, the researchers must submit a final report to the committee containing a summary of 
the study’s findings and conclusions.  
Privacy and Confidentiality  
24.Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent  
25. Participation by individuals capable of giving informed consent as subjects in medical research 
must be voluntary. Although it may be appropriate to consult family members or community 
leaders, no individual capable of giving informed consent may be enrolled in a research study 
unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
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possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and 
potential risks of the study and the discomfort it may entail, post-study provisions and any other 
relevant aspects of the study. The potential subject must be informed of the right to refuse to 
participate in the study or to withdraw consent to participate at any time without reprisal. Special 
attention should be given to the specific information needs of individual potential subjects as well 
as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed.  
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or 
may consent under duress. In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorised representative. These individuals must not 
be included in a research study that has no likelihood of benefit for them unless it is intended to 
promote the health of the group represented by the potential subject, the research cannot instead 
be performed with persons capable of providing informed consent, and the research entails only 
minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able 
to give assent to decisions about participation in research, the physician must seek that assent in 
addition to the consent of the legally authorised representative. The potential subject’s dissent 
should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research group. In such circumstances 
the physician must seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the research must 
be obtained as soon as possible from the subject or a legally authorised representative.  
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CONFIDENTIAL 
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31. The physician must fully inform the subject which aspects of their care are related to the 
research. The refusal of a subject to participate in a study or the subject’s decision to withdraw 
from the study must never adversely affect the subject-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material 
or data contained in biobanks or similar repositories, physicians must seek informed consent for 
its collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research. In such situations the research may be 
done only after consideration and approval of a research ethics committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to 
determine the efficacy or safety of an intervention and the patients who receive any intervention 
less effective than the best proven one, placebo, or no intervention will not be subject to additional 
risks of serious or irreversible harm as a result of not receiving the best proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, Sponsor, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as 
beneficial in the trial. This information must also be disclosed to participants during the informed 
consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. Researchers, authors, Sponsor, editors and publishers all have ethical obligations with regard 
to the publication and dissemination of the results of research. Researchers have a duty to make 
publicly available the results of their research on human subjects and are accountable for the 
completeness and accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
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Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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interest must be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual subject, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the subject or a legally authorized representative, may use an unproven 
intervention if in the physician's judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available.  
 
 
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Clinical Study Protocol  
 
Final Version 5.0, dated 06 Jan 2021  
CONFIDENTIAL 
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Confidential 
Appendix III: INVESTIGATOR’S DECLARATION 
I, the undersigned declare that I have read and understood this protocol and hereby agree to conduct 
this study in accordance with the design and specific provision of this protocol. I will provide 
copies of this protocol and access to all information furnished by Sponsor/CRO to study personnel 
under my supervision. I will discuss this material with them to ensure they are fully informed about 
the study products and study procedures. I will let them know that this information is confidential 
and proprietary to the Sponsor and that it may not be further disclosed to third parties. I will 
maintain all information supplied by Sponsor/CRO in confidence and, when this information is 
submitted to an Independent/Institutional Ethics Committee (IEC) or another group, it will be 
submitted with a designation that the material is confidential. 
I further agree to conduct the study in accordance with all applicable requirements of local 
regulatory authority including national drug and data protection laws, Institutional Review Board 
/Ethic Committee regulations, International Council for Harmonization Guidelines for Good 
Clinical Practices, Declaration of Helsinki by World Medical Association and applicable standard 
operating procedures. I understand that the study may be terminated or enrolment suspended at 
any time by Sponsor, with or without cause, or by me if it becomes necessary to protect the best 
interests of the study patients. 
 
 
_____________________________  
 
 
__________________ 
 Investigator’s Signature  
 
 
 
 
Date  
 
 
_____________________________  
Investigator’s Name 
 
 
Address: __________________________ 
 
  __________________________ 
 
  __________________________ 
 
  __________________________ 
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SAP_001.pdf: 
 
Statistical Analysis Plan 
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Version: 2.0   Date: 06JAN2021 
 
 
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Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan 
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1 
Table of Contents 
1 
Table of Contents ...................................................................................................................... 2 
2 
Signatures ................................................................................................................................. 5 
3 
Document History ..................................................................................................................... 6 
4 
Abbreviations ............................................................................................................................ 7 
5 
Documents ................................................................................................................................ 8 
6 
Introduction ............................................................................................................................... 8 
7 
Study Objectives ....................................................................................................................... 8 
8 
Study Design ............................................................................................................................. 8 
8.1 
Overview .......................................................................................................................... 8 
8.1.1 
Study Design .................................................................................................................. 8 
8.1.2 
Treatment Groups ........................................................................................................ 17 
8.2 
Efficacy endpoints .......................................................................................................... 17 
8.3 
Safety Endpoints ............................................................................................................ 21 
9 
General Statistical Considerations .......................................................................................... 21 
9.1 
Descriptive Statistics ...................................................................................................... 21 
9.2 
Analysis Population ........................................................................................................ 22 
9.3 
Definitions ....................................................................................................................... 22 
9.4 
Protocol Violation/Deviation ........................................................................................... 23 
9.5 
Data Handling................................................................................................................. 24 
9.5.1 
Imputation of Missing data ............................................................................................ 24 
9.6 
Sample Size Calculation ................................................................................................ 25 
9.7 
Interim Analysis .............................................................................................................. 25 
9.8 
Statistical Software ......................................................................................................... 25 
10 
Statistical Analyses ............................................................................................................ 25 
10.1 
Subject Disposition ......................................................................................................... 25 
10.2 
Demographic Data and Baseline Characteristics .......................................................... 26 
10.3 
Medical History ............................................................................................................... 26 
10.4 
Prior, concomitant and rescue medication ..................................................................... 26 
10.5 
Treatment Exposure and Compliance ........................................................................... 27 
10.6 
Efficacy Analysis ............................................................................................................ 27 
10.6.1 
Primary Efficacy endpoint ......................................................................................... 27 
10.6.2 
Secondary Analysis: .................................................................................................. 29 
10.7 
Safety Analysis ............................................................................................................... 38 
10.7.1 
Adverse Events ......................................................................................................... 38 
10.7.2 
Laboratory assessments ............................................................................................. 39 
10.7.3 
Vital Signs ............................................................................................................... 40 
10.7.4 
ECG ........................................................................................................................ 40 
10.7.5 
Physical Examination ................................................................................................ 41 
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10.7.6 
Chest X ray .............................................................................................................. 41 
10.7.7 
Pregnancy Test ......................................................................................................... 41 
10.7.8 
IMP Administration .................................................................................................. 41 
10.7.9 
COVID-19 associated symptom severity assessment .................................................... 41 
10.7.10 
Hospitalization ......................................................................................................... 42 
10.7.11 
Subgroup Analysis: ................................................................................................... 42 
11 
Deviation from the Study Protocol...................................................................................... 42 
12 
Database Lock and Unblinding .......................................................................................... 42 
13 
References ......................................................................................................................... 42 
14 
Appendices......................................................................................................................... 43 
 
 
 
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STATISTICAL ANALYSIS PLAN 
Study Title: 
A Multi-center, Randomized, Double Blind, Placebo Controlled 
Clinical Trial Evaluating the Efficacy and Safety of Favipiravir in 
Moderate to Severe COVID-19 Patients 
Sponsor Identification: 
Dr. Reddy’s Laboratories Limited 
Phase: 
Phase III 
Sponsor Study Number: 
CVD-04-CD-001 
NLS Study Number: 
NV-05-983-2020 
Date of SAP: 
06JAN2021 
Version: 
2.0 
Scope: 
Final 
 
 
 
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2 
Signatures 
Sponsor: 
Dr. Reddy’s Laboratories Limited 
Protocol No/NLS Study No.: 
CVD-04-CD-001/NV-05-983-2020 
Protocol Version No./Date 
Final 5.0/ 06JAN2021 
Study Title 
Multi-center, Randomized, Double Blind, Placebo Controlled Clinical Trial 
Evaluating the Efficacy and Safety of Favipiravir in Moderate to Severe COVID-19 
Patients 
CRF Version No./Date 
Version 3.0/26NOV2020 
SAP Version No./Date: 
2.0 / 06JAN2021 
 
 
 
 
Prepared By 
 
(Navitas Life Sciences) 
 
 
Rajesh kumar Gajendran 
Principal Biostatistician  
Date (DD-MMM-YYYY) 
 
 
 
Reviewed By 
 
(Navitas Life Sciences) 
 
Venkatesan Balu 
Senior Principal Biostatistician 
Date (DD-MMM-YYYY) 
 
Approved By  
 
(Dr Reddy’s Laboratories) 
Srinivas Shenoy B., MD 
Director – Clinical Development 
Date (DD-MMM-YYYY) 
 
 
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06JAN2021
06JAN2021
06JAN2021


 
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3 
Document History 
Version 
Date 
Change to previous version 
1.0 
09NOV2020 
NA 
2.0 
06JAN2021 
Updated SAP as per FDA inputs 
 
 
 
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4 
Abbreviations 
ABBREVIATION 
DEFINITION 
AE 
Adverse Event 
BP  
Blood Pressure  
COVID-19  
Novel Corona Virus Disease 2019  
DMP  
Data Management Plan  
ECG  
Electrocardiogram  
eCRF  
Electronic Case Report Form  
ENT  
Ear Nose Throat  
FDA 
Food and Drug Administration 
ICU  
Intensive Care Unit  
IMP  
Investigational Medicinal Product  
ITT 
Intention-to-treat 
mITT 
Modified Intention-to-treat 
MedDRA  
Medical Dictionary for Regulatory Activities  
NEWS  
National Early Warning Score  
PPS  
Per Protocol Set  
RNA  
Ribonucleic Acid  
RT-PCR  
Reverse Transcriptase – Polymerase Chain Reaction  
SAE  
Serious Adverse Event  
SAF  
Safety Population  
SAP  
Statistical Analysis Plan  
TEAE  
Treatment Emergent Adverse Event  
WHO  
World Health Organization  
WHO-DG  
World Health Organization Drug Global  
 
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5 
Documents 
This statistical analysis plan is based on the study protocol, version Final 5.0 dated 06 JAN 2021 
 
6 
Introduction 
This statistical analysis plan (SAP) provides explicit guidance and describes the planned statistical and data 
handling methods to be followed during the final analyses and reporting of data collected in clinical trial 
CVD-04-CD-001. The intention of this document is to provide detailed information of the planned analysis 
of trial data related to safety and efficacy, and to describe applicable statistical procedures explicitly. 
Relevant statements are quoted directly from the protocol, within the applicable sections in this document 
(SAP). This SAP should read in conjunction with the study protocol version Final 5.0 dated 06 JAN 2021 
and electronic case report form (eCRF) (version Final 3.0 dated 26-NOV-2020). 
7 
Study Objectives 
Primary Objective: 
 
To evaluate the efficacy of oral favipiravir in improving the time to resolution of hypoxia in 
moderate to severe COVID-19 patients  
Secondary Objectives: 
 
To evaluate the efficacy of oral favipiravir in improving the clinical and virological outcomes in 
moderate to severe COVID-19 patients  
 
To assess the tolerability and safety of favipiravir in the targeted study population  
8 
Study Design 
8.1 Overview 
8.1.1 Study Design 
This is a prospective, interventional, multi-centre, phase III, randomized, double blind, placebo-controlled, 
parallel design trial to evaluate the efficacy, safety and tolerability of favipiravir as adjunct (‘add on’) to 
supportive care, in comparison to placebo with supportive care, in the acute treatment of patients who have 
tested positive for SARS-CoV-2 presenting with moderate to severe COVID-19 and require hospitalization. 
This study will be conducted in two parts; Stage I – Main study and Stage II – Extended Follow up. 
 
Stage I – Main Study: 
All the eligible patients will be randomized to receive either favipiravir + supportive care or placebo + 
supportive care. The treatment duration with the IMP will be for a period of 10 consecutive days. If the 
patient is discharged before Day 10, the patient will be required to continue the remainder of the treatment 
course of the assigned IMP at home. Patients in both the groups will receive supportive care, as appropriate. 
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The duration of supportive care will be based Investigator’s judgement and as per individual patient’s 
requirement. The study data collection period will be up to 28 (+2) days.  
Day 10 will be considered as the End of treatment (EOT) assessment. 
  
1. If the patient remains in the hospital until Day 10, the EOT will be performed at the site and all the 
scheduled assessments for Day 10 will be performed.  
2. If the patient is discharged before Day 10, the EOT can be performed either as an onsite visit or will 
be performed at the patient’s home. 
a. 
On-site visit: If the patient is able to visit the hospital on Day 10, procedures for an unscheduled 
visit will be performed. 
OR 
b. At home: If the patient is unable to visit the hospital for the EOT, study nurse or phlebotomist 
will visit the patient at his/her residence to collect blood sample for safety assessments. A 
nasopharyngeal swab or oropharyngeal swab will be collected from the patient and sent for 
detection (qualitative) of SARS-CoV-2 RNA by RT-PCR assay based on Investigator’s 
discretion for individual patients. A telephonic follow up will be performed to enquire on 
treatment emergent AEs experienced, concomitant medication and COVID-19 associated 
symptom for assessment of clinical relapse. 
 
Day 28 will be considered the end of study visit.  
 
If patient is discharged from the hospital before Day 28, the assessments mentioned in the end of study visit 
(Day 28) will be performed before the patient is discharged. After discharge, telephonic follow up will be 
performed on Day 10 (applicable only for patients who are discharged earlier than Day 10 and if patients are 
unable to visit the site for EOT on Day 10), Day 14, Day 21 and Day 28. The telephonic follow up will be as 
applicable for the individual patient, depending upon the actual day when (s)he is discharged. A 2-day 
window period is allowed for telephonic follow up. 
 
In case the patient remains admitted in the hospital beyond Study Day 28, the end of study assessments will 
be performed for the patient on Day 28 (+2) days. 
 
Stage I of the study will be completed when the ‘Day 28’ assessment is completed either as an in-patient 
assessment if the patient is still hospitalized, or as a telephonic follow up assessment if the patients are 
discharged earlier to Day 28. 
 
Once all the patients complete the Stage I of the study, the database would be locked, and analysis will be 
performed. 
Stage II – Extended Follow Up: 
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All the patients will be followed up for AEs or for ‘clinical relapse’ of COVID 19. Two telephonic follow 
up assessments will be performed on Day 42 and Day 60. An additional visit to the hospital (for further 
assessment) may be scheduled for such patients, if required. A 2-day window period is allowed for telephonic 
follow up. 
 
The below flowchart will describe about the study design. 
 
 
V1 
V2 
V3 
Treatment period (until Day 10) 
(Supportive care may be continued 
beyond Day 10) 
Screening  
(Day -3 to 
Day -1) 
Up to 72 
hours 
Favipiravir  
+ Supportive Care  
Placebo  
+ Supportive Care 
Day 10 
Randomization 
End of Study  
(Stage I) 
Day 1 
Day 60 
V
1
V
1
Stage I – Main Study*  
(until Day 28) 
V
1
V
1
Stage II – Extended Follow Up period for 
relapse 
(from Day 29 to 60 days after start of study 
treatment) 
Day 28 
Day 42 
Telephonic FU 1 
Telephonic FU 2 
V4 
V5 
Database 
lock 
* If patient is discharged from the hospital before Day 28, a telephonic follow up will be performed on 
Day 10 (applicable only for patients who are discharged earlier than Day 10 and if patients are unable 
to visit the site for EOT on Day 10), Day 14, Day 21 and Day 28 as applicable for the individual 
patient. 
End of Treatment 
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The schedule of assessments will be as follows: 
 
Table 1: Study Assessment Schedule 
Assessments 
STAGE I – Main Study1 
Datab
ase 
Lock 
Stage II – 
Extended 
Follow Up2 
Unsched
uled 
Visit 
 
Screen
ing3 
Randomization 
(Baseline)4 
 
EOT5 
 
End of 
Study 
Day 
-3 
to -1 
(72 
hrs) 
1  
(Pre-
dose) 
1 (Post-
dose) 
On all 
days 
until 
discha
rge 
On all 
days 
until 
Day 
10 
4 
5 
7 
10 
14 
21 
28 or 
discharg
e 
42 
60  
Window Period 
N/A 
0 
0 
N/A 
N/A 
0 
0 
0 
0/+2 
0/+2 
0/+2 
0/+2 
 
+2 
+2 
 
                                                     
1 Stage I of the study includes a treatment period of 10 consecutive days and a study data collection period until Day 28. The treatment period may be shortened if it is 
necessary to discontinue administration of the study drug due to AEs or other circumstances. Principal Investigator or a medically qualified Sub Investigator may discharge a 
patient, if (s)he considers the patient to be clinically fit and eligible (per applicable National Regulations/ Hospital practice) for discharge. After discharge, telephonic follow 
up will be performed on Days 10, 14, 21 and 28 (as applicable for the individual patient, depending on actual day of discharge). For patients who remain admitted in the 
hospital until Study Day 28, the End of Study assessments will be performed on Day 28. A window period of 2 days will be allowed for the telephonic follow ups. 
2 During the Stage II of the study, the patients will be followed up for AEs or for ‘clinical relapse’ of COVID 19, on Day 42 and Day 60. An additional visit to the hospital 
(for further assessment) may be scheduled for such patients, if required. A window period of 2 days will be allowed for the telephonic follow ups. 
3 Screening investigations, including clinical laboratory evaluations (hematology, serum biochemistry, urinalysis, serum pregnancy test), chest X ray, ECG and RT-PCR assay 
for detection of SARS-CoV-2 RNA, performed within 72 hours prior to Randomization Day (Day 1) can be considered for eligibility assessments. Refer to Section Error! R
eference source not found. for further details. 
4 The investigations (chest X ray and 12 lead ECG) mentioned in Visit 2 - Randomization/Baseline Visit can be waived off if Randomization/Baseline Visit (Visit 2) is being 
performed on the same day of screening or if the investigations were performed within 72 hours before Randomization/Baseline Visit. Refer to Section Error! Reference s
ource not found. for further details 
5 The EOT assessment will be performed on Day 10 (+2 days). If the patient remains in the hospital until Day 10, the EOT will be performed at the site and all the scheduled 
assessments for Day 10 will be performed.  If the patient is discharged before Day 10, the EOT can be performed either as an onsite visit or will be performed at the patient’s 
home (refer to Section Error! Reference source not found.). 
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Assessments 
STAGE I – Main Study1 
Datab
ase 
Lock 
Stage II – 
Extended 
Follow Up2 
Unsched
uled 
Visit 
 
Screen
ing3 
Randomization 
(Baseline)4 
 
EOT5 
 
End of 
Study 
Day 
-3 
to -1 
(72 
hrs) 
1  
(Pre-
dose) 
1 (Post-
dose) 
On all 
days 
until 
discha
rge 
On all 
days 
until 
Day 
10 
4 
5 
7 
10 
14 
21 
28 or 
discharg
e 
42 
60  
(Days)6 
Obtaining informed 
consent  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline patient 
characteristics7 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test8  
●  
 
 
 
 
 
 
 
 
 
 
● 
 
 
 
 
Assessment 
of 
inclusion/exclusion 
criteria 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Measurement of Blood 
Oxygen Saturation at 
rest on room air 
(without oxygen 
supplementation) or 
SpO2/ FiO2 estimated 
on supplemental 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                     
6 If patient is discharged before Day 28, a telephonic follow up assessment will be performed on Days 10 (applicable only for patients who are discharged earlier than Day 10 
and if patients are unable to visit the site for EOT on Day 10), 14, 21 and 28 (as applicable for the individual patient). A window period for telephonic follow up will be +2 
days from scheduled day of follow up.  
7 Includes age, gender, nationality, race, height and weight. 
8 Pregnancy test only for female subjects of childbearing potential. Serum pregnancy will be performed at Screening and End of Study (Day 28 or discharge, whichever is 
earlier).  
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Assessments 
STAGE I – Main Study1 
Datab
ase 
Lock 
Stage II – 
Extended 
Follow Up2 
Unsched
uled 
Visit 
 
Screen
ing3 
Randomization 
(Baseline)4 
 
EOT5 
 
End of 
Study 
Day 
-3 
to -1 
(72 
hrs) 
1  
(Pre-
dose) 
1 (Post-
dose) 
On all 
days 
until 
discha
rge 
On all 
days 
until 
Day 
10 
4 
5 
7 
10 
14 
21 
28 or 
discharg
e 
42 
60  
oxygen for 
confirmation of 
eligibility 
Randomization 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing 
and 
complianc
e status9 
Morning 
 
 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
Evening 
 
 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 associated 
symptom 
severity 
assessment 10 
● 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
●11 
RT-PCR (qualitative)12 
● 
 
 
 
 
 
● 
 
● 
 
 
● 
 
 
 
● 
                                                     
9 IMPs will be administered twice daily (in the morning and evening) from Day 1 to Day 10. If the patient is discharged before Day 10, the patient will be required to continue 
the remainder of the IMP treatment course at home. Dosing compliance status will be checked for 10 days. Compliance will be assessed daily assessment if the patient is the 
hospital or based on the details in the patient diary and the empty blister packs and / unused IMP in case of patients discharged before study Day 10. 
10 COVID-19 associated symptom severity assessment will be done on all days (Day 1 up to Day 28 or until discharge, whichever is earlier).  
11 COVID-19 associated symptom severity assessment will be done and recorded in case of patients in whom the follow up (unscheduled) visit was necessitated for reporting 
of clinical relapse 
12 Qualitative RT-PCR assay for detection of SARS-CoV-2 RNA in a respiratory tract sample will be performed at Screening, on Day 5, Day 10 and Day 28, or discharge 
(i.e., if the patient happens to be discharged before one or more of the mentioned time points, then the sample will be collected at discharge). No sample will be collected 
from patients at any time point after discharge, EXCEPT if individual patients are scheduled for an additional (unscheduled) visit, either to follow up on an AE or to report a 
possible ‘clinical relapse’ of COVID-19 or based on Investigator’s discretion during the Day 10 - home visit. A sample for RT-PCR will be collected during the unscheduled 
visit in such cases. 
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Assessments 
STAGE I – Main Study1 
Datab
ase 
Lock 
Stage II – 
Extended 
Follow Up2 
Unsched
uled 
Visit 
 
Screen
ing3 
Randomization 
(Baseline)4 
 
EOT5 
 
End of 
Study 
Day 
-3 
to -1 
(72 
hrs) 
1  
(Pre-
dose) 
1 (Post-
dose) 
On all 
days 
until 
discha
rge 
On all 
days 
until 
Day 
10 
4 
5 
7 
10 
14 
21 
28 or 
discharg
e 
42 
60  
Clinical Status by 10-
point 
ordinal 
scale 
(SOLIDARITY 
SCALE)13 
● 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Status by 8-
point ordinal scale 14 
● 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
NEWS-2 score15 
● 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Laboratory 
Evaluations 
(Hematology, 
Serum 
Biochemistry, 
Urinalysis) 
● 
 
 
 
 
● 
 
● 
● 
● 
● 
● 
 
 
 
● 
Chest X-ray 
● 
● 
 
 
 
● 
 
● 
● 
● 
 
● 
 
 
 
● 
12-lead ECG 
● 
● 
 
 
 
● 
 
● 
● 
● 
● 
● 
 
 
 
● 
Vital signs16 
● 
● 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
● 
Complete Physical 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                     
13 Clinical Status by 10-point ordinal scale (SOLIDARITY SCALE) will be assessed once daily at screening, on all days (Day 1 up to Day 28 or until discharge, whichever 
is earlier). 
14 Clinical Status by 8-point ordinal scale will be assessed once daily at screening, on all days (Day 1 up to Day 28 or until discharge, whichever is earlier). 
15 NEWS-2 score will be assessed once daily on all days (Day 1 up to Day 28 or until discharge, whichever is earlier). 
16 Vital signs will be assessed on all days (Day 1 to Day 28 or until discharge, whichever is earlier). Includes SpO2, body temperature (axillary), systolic BP, diastolic BP, 
pulse rate, and respiratory rate. Vital signs will be measured at pre-dose only on Day 1 and at least twice, morning and afternoon, daily from Day 2 to Day 28 or until discharge, 
whichever is earlier. 
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Assessments 
STAGE I – Main Study1 
Datab
ase 
Lock 
Stage II – 
Extended 
Follow Up2 
Unsched
uled 
Visit 
 
Screen
ing3 
Randomization 
(Baseline)4 
 
EOT5 
 
End of 
Study 
Day 
-3 
to -1 
(72 
hrs) 
1  
(Pre-
dose) 
1 (Post-
dose) 
On all 
days 
until 
discha
rge 
On all 
days 
until 
Day 
10 
4 
5 
7 
10 
14 
21 
28 or 
discharg
e 
42 
60  
Examination17  
Partial 
Physical 
Examination18  
 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
Hospitalization 
period19 
● 
● 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Medications 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
 
● 
● 
● 
 
 
 
 
 
● 
● 
● 
 
● 
● 
● 
Pre-treatment Adverse 
Events 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Emergent 
Adverse events 
 
 
● 
● 
 
 
 
 
 
● 
● 
● 
 
● 
● 
●20 
ICU admission status, 
supplemental oxygen 
and 
mechanical 
ventilation details 21 
 
 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
                                                     
17 Includes general appearance, skin, head, neck, ENT, heart, lungs, abdomen, extremities, neurological, musculoskeletal, and lymph nodes 
18 Includes general appearance, ENT, heart, lungs and lymph nodes. 
19 The patients will be discharged when the Principal Investigator or a medically qualified Sub Investigator judges that the patient is fit for discharge. If the patient is discharged 
before Day 10, the remaining treatment course will be continued at home. 
20 Treatment Emergent Adverse Events will be assessed and recorded in case of patients in whom the follow up (unscheduled) visit was necessitated for follow up of an 
adverse event/reporting of a new Treatment Emergent Adverse Event after discharge. 
21 Will be evaluated on all days during the study period (until Day 28 or discharge, whichever is earlier) and also may be evaluated when patient retiurns for additional visit  
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Assessments 
STAGE I – Main Study1 
Datab
ase 
Lock 
Stage II – 
Extended 
Follow Up2 
Unsched
uled 
Visit 
 
Screen
ing3 
Randomization 
(Baseline)4 
 
EOT5 
 
End of 
Study 
Day 
-3 
to -1 
(72 
hrs) 
1  
(Pre-
dose) 
1 (Post-
dose) 
On all 
days 
until 
discha
rge 
On all 
days 
until 
Day 
10 
4 
5 
7 
10 
14 
21 
28 or 
discharg
e 
42 
60  
Clinical relapse22 
 
 
 
 
 
 
 
 
● 
● 
● 
● 
 
● 
● 
 
 
 
                                                     
22 Patients will be asked if they experience any COVID-19 symptoms after discharge. 
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8.1.2 Treatment Groups 
The study population will consist of patients of either sex, aged between 21 and 80 years (both inclusive) 
that have tested positive for SARS-CoV-2 by Reverse Transcriptase -Polymerase Chain Reaction (RT-PCR) 
assay using a respiratory tract sample (nasopharyngeal swab or oropharyngeal swab or nasal aspirate or 
tracheobronchial aspirate) and clinically assessed to have moderate to severe COVID-19. The study will be 
conducted in the Arabian Gulf region. An adequate number of patients will be screened in order to randomize 
780 patients into two treatment groups at a 1:1 ratio, so as to have approximately 390 patients in favipiravir 
+ supportive care group and 390 patients in placebo + supportive care group. 
8.2 Efficacy endpoints 
Stage I 
 
Primary Efficacy Endpoint: 
 
Time to resolution of hypoxia (Time frame: Up to 28 days) 
This endpoint will be considered to have been met when the patient has attained a score of 4 or lower on 
the 10-point ordinal scale of clinical status and either of a) or b), and c) is met: 
a) Score is ≤ 4 on consecutive assessments over the next 5 days, if patient continues to remain in 
hospital (i.e., has not been discharged). 
OR 
b) Patient was discharged before five consecutive assessments (after reaching a score of 4). 
AND 
c) The patient has survived and has not been re-admitted to hospital for COVID-19 management 
through Day 28. 
Note: Part c) is applicable to patients in both a) and b)  
i.e. Time to resolution of Hypoxia = either “a and c” OR “b and c” is met. 
 
Secondary Efficacy Endpoints: 
1. Time to discharge from hospital. 
 
2. Time (no. of days) from randomization to the earliest time when ALL COVID-19 associated 
symptoms (fever, chills, cough, sore throat, malaise, headache, muscle pain, gastrointestinal 
symptoms – specifically diarrhoea and vomiting, shortness of breath or dyspnoea) are scored by the 
Investigator/trained study personnel as either ‘0=absent’ or ‘mild =1’ in assessments over a period 
of 24 hours, when assessed from baseline to Day 28 or discharge from hospital (if discharge happens 
earlier than Day 28).   
 
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3. Percentage of patients with  score of  either ‘0=absent’ or ‘mild =1’ over a period of 24 hours, for 
ALL COVID-19 associated symptoms, by Days 4, 7, 10 14, 21 and 28 or discharge (if discharge 
happens earlier than one or more of the above-mentioned time points)  
Note: Symptoms evaluated are fever, chills, cough, sore throat, malaise, headache, muscle pain, 
gastrointestinal symptoms- specifically, diarrhoea and vomiting, shortness of breath or dyspnoea. 
The Investigator/trained study personnel will assess (including by enquiry with the patient, as 
necessary) and score the severity of each COVID-19 associated symptom on a 5 point Likert-type 
scale (0= absent, 1= mild, 2=moderate, 3= severe, 4= very severe/critical). 
 
4. Time to improvement in EACH of the symptoms of fever, chills, cough, sore throat, malaise, 
headache, muscle pain, gastrointestinal symptoms- specifically diarrhoea and vomiting, shortness 
of breath or dyspnoea by at least 1 grade over baseline.  
Note: Severity of symptoms will be evaluated once daily (preferably at or around the same clock 
time) on each day that the patient is admitted in the hospital. The Investigator/trained study 
personnel will assess (including by enquiry with the patient, as necessary) and score the severity of 
each COVID-19 associated symptom on a 5-point Likert-type scale (0= absent, 1= mild, 
2=moderate, 3= severe, 4= very severe/critical). The improvement observed must be sustained at 
evaluations over a period of 24 hours, in order for this secondary efficacy endpoint to be reached. 
 
5. Percentage of patients reporting a clinical relapse of COVID-19 when assessed from day of 
discharge to 27 days after randomization (Day 28). 
Note: ‘Clinical relapse’ is defined as either the reappearance or worsening of severity (over the 
assessment on the day of discharge) of one or more of the above-mentioned COVID-19 associated 
symptoms, or the appearance of any of these symptoms (due to COVID-19 infection) for the first 
time after discharge. This endpoint will be assessed only for those patients that were discharged 
before Day 28.   
 
6. Time (no. of days) to negative conversion of detectable SARS-CoV-2 viral RNA in the RT-PCR 
assays of respiratory sample, from randomization.  
 
7. Percentage of patients showing negative conversion of detectable SARS-CoV-2 viral RNA in the 
RT-PCR assays of respiratory samples on Days 5, 10 and 28 or discharge (if discharge happens 
earlier than one or more of the above-mentioned time points)  
 
8. Changes over time in patient’s clinical status on the 10-point ordinal scale used in the SOLIDARITY 
trial by WHO 
 
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a. 
Changes in the 10-point ordinal scale score from baseline until discharge   
b. Proportion of patients in whom clinical status score of 4 (‘hospitalized, no oxygen 
required’) or lower has been attained by Days 4, 7, 10, 14, 21 and 28 or discharge (if 
discharge happens earlier than one or more of the above-mentioned time points) 
c. 
Time (no. of days) from randomization to clinical status score improvement by 1 and by 2 
points (from baseline)  
d. Proportion of patients for whom clinical status score improvement by 1 and by 2 points 
has been attained by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier 
than one or more of the above-mentioned time points) 
 
9. Changes over time in patient’s clinical status on the 8-point ordinal scale  
a. Time (no. of days) from randomization to attain clinical status score of 4 or lower  
b. Proportion of patients in whom clinical status score of 4 or lower has been attained by 
Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier than one or 
more of the above-mentioned time points) 
c. Time (no. of days) from randomization to attain clinical status score of 3 or lower  
d. Proportion of patients in whom clinical status score of 3 or lower has been attained by 
Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier than one or 
more of the above-mentioned time points) 
e. Time (no. of days) from randomization to clinical status score improvement by 1 and 
by 2 points (from baseline)  
f. Proportion of patients for whom clinical status score improvement by 1 and by 2 
points has been attained by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge 
happens earlier than one or more of the above-mentioned time points) 
 
10. Changes over time in findings on chest X-ray 
11. Changes over time in the National Early Warning Score-2 (NEWS) 
12. Percentage of patients requiring, until Day 28 or discharge from hospital (if discharge happens 
earlier) 
a. Management in intensive care unit 
b. High Flow Nasal Oxygen or Non-invasive mechanical ventilation 
c. Invasive mechanical ventilation 
 
 
 
13. Time (no. of days) from randomization to: 
a. 
Management in intensive care unit 
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b. High Flow Nasal Oxygen or  Non-invasive mechanical ventilation 
c. 
Invasive mechanical ventilation 
over an assessment period from randomization until Day 28 or discharge from hospital (if discharge happens 
earlier) 
 
14. Duration (no. of days) the patient requires: 
a. 
Management in intensive care unit 
b. Oxygen supplementation 
c. 
High Flow Nasal Oxygen 
d. Non-invasive mechanical ventilation 
e. 
Invasive mechanical ventilation 
over an assessment period from randomization until Day 28 or discharge from hospital (if discharge happens 
earlier) 
 
15. Percentage of patients: 
a. 
dying from any cause 
b. dying from a COVID-19 associated complication 
Over an assessment period from randomization until Day 28 or discharge from hospital (if discharge happens 
earlier). 
 
Stage II 
 
1. Percentage of patients reporting a clinical relapse of COVID-19 when assessed from day of 
discharge to 59 days after randomization (Day 60). 
Note: ‘Clinical relapse’ is defined as either the reappearance or worsening of severity (over the 
assessment on the day of discharge) of one or more of the above-mentioned COVID-19 associated 
symptoms, or the appearance of any of these symptoms (due to COVID 19 infection) for the first 
time after discharge. 
 
2. Proportion of patients  
a. 
with disease worsening and requires: 
i. 
Admission to ICU 
ii. 
High flow nasal oxygen 
iii. 
Non-invasive mechanical ventilation 
iv. 
Invasive mechanical ventilation 
(AND) 
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b. Dying  
until day 60 (regardless of whether patients are discharged from hospital before Day 28 
or not) 
8.3 Safety Endpoints 
Safety endpoint will be as follows: 
Stage I 
1. Number (and percentage) of patients reporting treatment emergent adverse events (TEAEs) (by 
MedDRA system organ class and preferred term) 
2. Changes of parameters at each assessment during the study/follow-up period, compared to 
baseline for: 
 
Vital signs: body temperature, heart rate, respiratory rate, systolic/diastolic blood 
pressure (BP) and oxygen saturation.  
 
Clinical laboratory assessments: hematology, serum chemistry, urinalysis. 
 
12-lead ECG: Changes in heart rate, PR, QRS, QT and QTcB intervals. 
Stage II 
 
1. Number (and percentage) of patients reporting treatment emergent adverse events (TEAEs) (by 
MedDRA system organ class and preferred term) 
9 
General Statistical Considerations  
9.1 Descriptive Statistics  
The following descriptive statistics will be calculated for continuous data and for ordered categorical data 
(ordinal data): 
Summary statistics are displayed with the following digits:  
Description 
Characteristic 
Number of 
decimal places 
Count 
n 
0 
Count corresponding to the number of patients for a group 
N 
0 
Mean 
Mean 
As in source + 1 
Standard Deviation 
SD 
Mean+1 
Minimum 
Min  
As in source 
Median 
Median 
As in source + 1 
Maximum 
Max 
As in source 
Quartile 1 
Q1 
As in source+1 
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Description 
Characteristic 
Number of 
decimal places 
Quartile 3 
Q3 
As in source+1 
Inter Quartile Range 
IQR 
As in source+1 
Percentage relative to N # 
% 
1 
 
# Number of decimal places can be more than one, if necessary. All table percentages should be rounded to 
one decimal place if not stated otherwise.  
All data will be presented in the subject data listings.  
If either table or listing does not include any observation, then the following placeholder will be used: “NO 
DATA CONTRIBUTED TO THIS TABLE / LISTING”. 
9.2 Analysis Population 
Four analysis populations will be considered as defined below: 
Analysis Population 
Definition 
Screened Population  
All participants who signed the informed consent form 
Safety Population (SAF) 
All randomized patients who received at least one dose of the study medication 
Intention-to-treat (ITT) 
All randomized patients who received at least one dose of the study medication 
Modified Intention to treat 
(mITT) 
All randomized patients who received at least one dose of the study medication and has 
at least one post dose primary efficacy endpoint assessment available. 
(Note: if there is a greater than 5% difference in the number of patients in the ITT and 
mITT populations, then analysis for mITT population will be provided additionally.) 
Per protocol set (PPS) 
All patients included in the ITT who complete the study without major protocol 
deviation which would affect the primary endpoint of the study. 
 
9.3 Definitions 
In the following table, the definitions and calculation of derived variables are summarized 
Variable / Term 
Definition / Way of calculation 
Age 
Int ((informed consent date – Birth date +1)/365.25) 
Baseline 
The last valid value prior to the first dose of study treatment 
Treatment Start Date 
Date of dose administration on Day 1  
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Variable / Term 
Definition / Way of calculation 
Treatment End Date 
Date of Last Study Medication Taken  
Duration of exposure 
Treatment end date- Date of randomization + 1 
Treatment Emergent AE (TEAE) 
An AE will be considered as treatment-emergent if the time of onset is on or 
after the time of the first study drug administration or any AE that exist prior 
to first dose and its severity increased during the study. 
Time to Resolution of Hypoxia 
Date of first time the status trial score to become 4 or lower following 
baseline assessment when evaluated over a period of 24 hours – Date of 
randomization +1  
Time to discharge 
Date of discharge – date of randomization + 1 
Time to ALL COVID-19 associated 
symptoms to become ‘0=absent’ or 
‘mild =1’ from Randomization 
Earliest Date of ALL COVID-19 associated symptoms to become either 
‘0=absent’ or ‘mild =1’ in assessments over a period of 24 hours – date of 
randomization + 1 
                                    
Time to achieve symptom 
improvement 
Date of Change from baseline value for the particular symptom score  to 
become less than or equal to ‘-1’and sustained at evaluations over a period 
of 24 hours – Date of randomization  +1   
Time to Negative 
Date of first time to negative conversion in RT-PCR – Date of randomization 
+ 1 
 
9.4 Protocol Violation/Deviation 
The relevant protocol violations/deviations have to be defined by a systematic data review prior to database 
closure. For this purpose, protocol violations that occurred during the study such as violations of 
inclusion/exclusion criteria or forbidden concomitant medications or subject non-compliance will be 
assessed as ‘major’ or ‘minor’ by depending on their potential to interfere with the objectives of the study. 
Listings will be prepared to show the eligibility of all patients. Comprehensive justification for the 
classification of a protocol violation/deviation as “major” will be given in the integrated clinical study report. 
The list of protocol violations/deviations will be reviewed by the Sponsor and finalized before locking the 
database.  
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9.5 Data Handling  
9.5.1 
Imputation of Missing data 
 
Efficacy: As the patients were in the hospital until discharge, missing data in the daily WHO clinical status 
scores were few.  To facilitate the definition of the durable response as part of the primary efficacy endpoint 
which now requires five consecutive days of clinical status score at 4 or lower, a very limited and 
conservative imputation will be implemented to impute a missing clinical status score if adjacent to a valid 
score on both sides, the imputed score will be the higher (worse) of the two.  For example, if Day 10 score 
is missing with Day 9 score of 5 and Day 11 score of 4, then the imputed Day 10 score will be 5.   
 
Safety: To handle missing or partial AE and concomitant medication date, the following rules will be applied. 
 
For partial start dates: 
1. If the year is unknown, then do not impute the date but assign a missing value. 
2. If the month is unknown, then: 
a. If the year matches the year of the dose date, then impute the month and day of the dose date. 
3. If the day is unknown, then: 
a. If the month and year match the month and year of the first dose date, then impute the day of the  
                  dose date. 
b. otherwise, assign “01” 
 
For partial end dates: 
1. If the year is unknown, then do not impute the date but assign a missing value. 
2. If the month is unknown, then do not impute the date and mark as ongoing for AE and Concomitant 
medication. 
3. If month is known but the day is unknown, then assign the last day of the month. 
 
After implementing the rules above, to determine whether AEs (or medications) with missing start or stop 
dates are pretreatment or on/after treatment, the following strategy will be used: 
 
1. If the start date and stop date are both missing, then the most conservative approach is taken and the AE 
(or medication) is considered to be treatment emergent (or concomitant medication). 
 
2. If the start date is missing but the stop date is not missing and is on or after the day of study dose 
administration, then the most conservative approach is taken and the AE (or medication) is considered to be 
treatment emergent (or concomitant medication). 
 
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3. If the start date is missing but the stop date is not missing and is before the day of first study dose and after 
the date of signed informed consent, then the AE (or medication) is considered to be before treatment (or 
prior medication). 
 
4. If the start date is not missing but the stop date is missing, then the most conservative approach is taken 
and medication is considered to be concomitant while the AE is defined by start date. 
If the Adverse Event Relationship flag is missing, the relationship for adverse event will be imputed and will 
be considered as possibly related. If the Adverse Event Severity flag is missing, the severity will be imputed 
with the maximum severity will be considered as severity. 
9.6 Sample Size Calculation 
Based on review of published literature, a hazard ratio of 1.25 is reported (adjusted for the stratification in 
randomization) for time to clinical improvement in COVID-19 patients receiving anti-viral intervention. The 
hazard ratio of 1.25 is also assumed to be constant throughout the study as per the assumptions of the Cox 
proportional hazards regression model with the expected average probability of the event over the course of 
the study to be 0.9 and 0.8 in test and control group respectively. Inequality testing of the hazard ratio using 
the Cox proportional hazards regression model with 371 subjects in Favipiravir group and 371 subjects in 
Placebo group achieves 80% power at the 0.05 significance level for an actual hazard ratio of 1.25 assuming 
the hazard ratio is 1 under the null hypothesis and that the total number of events achieved is 631. Based on 
the above assumption and considering the dropout rate to be 5%, overall, 390 patients will be randomized in 
each treatment group. i.e. 780 patients in total to be randomized in the study. The sample size is estimated 
using nQuery version 8.5.0.0 using Cox proportional hazard regression. Sample size will be re-estimated 
based on the analysis of results for the primary endpoint observed during interim analyses. 
9.7 Interim Analysis 
Details of the interim analysis are provided in the appendix I “Interim Analysis”. 
9.8 Statistical Software 
All statistical analyses will be performed with SAS®, Version 9.4 or later.  
10 Statistical Analyses 
10.1  Subject Disposition 
Subject disposition will be tabulated with number and percentages of patient’s screen failed, randomized, 
received one or more doses of study treatment, completed the study according to the protocol or discontinued 
the study prematurely. The patients who prematurely discontinued the study and the reasons for their 
discontinuation will be presented. The disposition table will be summarized using “Screened population” by 
treatment group. 
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10.2  Demographic Data and Baseline Characteristics 
The demographic data and baseline characteristics will be summarized using descriptive statistics or by 
frequency and percentage for the applicable parameters using SAF Population by treatment group. 
 
Gender 
 
Age 
 
Race 
 
Height 
 
Weight 
 
Nationality 
 
BMI 
 
No. of days since first onset of symptoms associated with COVID-19 (at baseline) 
 
Clinical Status by 10-point ordinal scale 
 
Clinical Status by 8-point ordinal scale 
 
National Early Warning Score (NEWS Score) 
 
COVID-19 associated symptoms 
 
RT-PCR (Was RT-PCR test performed for SARS-CoV 2 ?) 
 
RT-PCR result 
 
Chest X-ray total RALE score 
 
10.3 Medical History  
All general medical history conditions and concomitant diseases will be coded using MedDRA version 23.0. 
General medical history conditions and concomitant diseases will be summarized by system organ class, 
preferred term and by treatment group using SAF population. The version of the utilized dictionary will be 
presented as part of the provided tables and listings. Listing of medical history will be provided. 
10.4 Prior, concomitant and rescue medication 
Prior, concomitant and rescue medications will be assessed at screening and at each subsequent study visit. 
Medications will be coded using WHODG B3 Mar 1, 2020. 
Medication will be classified as prior, if the end date is known and is prior to the first use of the study 
medication. Medications that are ongoing or ended after the first use of the study medication will be classified 
as concomitant. All concomitant medication which are classified as rescue medication in eCRF will be 
considered as rescue medication. If the end date of the medication is unknown, it will also be considered as 
concomitant. Handling of missing date explained in section (Imputation of missing data section 9.5).  
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Prior, concomitant and rescue medications will be separately summarized by ATC class (the highest available 
level), preferred name, treatment group and by Stage I (both Prior and concomitant) and Stage II (Only for 
Concomitant medication) for the SAF population. Listings will be presented for prior and concomitant 
medications. 
10.5 Treatment Exposure and Compliance 
 
Treatment start date will be defined as date of first dose administration on Day 1. Treatment end date will be 
defined as date of Last Study Medication. 
 
Treatment duration:  
Duration of treatment exposure is derived as treatment end date – treatment start date + 1. 
The duration of treatment exposure will be summarized descriptively using SAF population by treatment 
group. Also, number of tablets administered, missed, additional tablets administered will be summarized; 
Data listing will be presented for dose administration. 
 
Overall Treatment compliance: [{(A/B) * 100} + {(C/D)*100}]/2 
Where,  
A= Total actual number of tablets taken in the morning 
B= Total Planned number of tablets to be taken in the morning  
C= Total actual number of tablets taken in the evening 
D= Total Planned number of tablets to be taken in the evening  
The treatment compliance will be summarized descriptively using SAF population.  
 
10.6 Efficacy Analysis 
10.6.1 Primary Efficacy endpoint 
Primary Efficacy endpoint will be as follows: 
1. Time to resolution of hypoxia  
 
The primary efficacy endpoint is “Time to resolution of hypoxia (Time frame: Up to 28 days)” 
 This endpoint will be considered to have been met when the patient has attained a score of 4 or lower    
 on the 10-point ordinal scale of clinical status and either of a) or b), (as applicable) and c) is met: 
a) Score is ≤ 4 on consecutive assessments over the next 5 days, if patient continues to remain in 
hospital (i.e., has not been discharged). 
OR 
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b) Patient was discharged before five consecutive assessments (after reaching a score of 4)  
AND 
c) The patient has survived and has not been re-admitted to hospital for COVID-19 management 
through Day 28. 
 
Note: Part c) is applicable to patients in both a) and b).   
      i.e. Time to resolution of Hypoxia = either “a and c” OR “b and c” is met. 
 
Time to resolution of hypoxia will be compared between the treatment groups using the Cox 
proportional hazard model with age, gender, and baseline score on the 10-point ordinal scale of clinical 
status as covariates. The hazard ratio and its corresponding two-sided 95% confidence interval (CI) and 
two-sided p-value at 5% level of significance will be obtained from the above Cox proportional hazard 
model. 
As the patients were in the hospital until discharge, missing data in the daily WHO clinical status score 
were few.  To facilitate the definition of the durable response, a very limited and conservative 
imputation will be implemented to impute a missing clinical status score if adjacent to a valid score on 
both sides, the imputed score will be the higher (worse) of the two, as discussed in Section 9.5.1.     
Necessary steps will be taken to properly manage the situation of informative censoring for patients 
who did not reach the resolution of hypoxia endpoint.  For censored patients who died of any cause, 
discontinued or were lost to follow-up due to treatment-related adverse events or lack of efficacy, they 
will be censored at Day 28.  However, censored patients who discontinued or were lost to follow-up for 
reasons that were independent of the study medication will be censored at the day of discontinuation of 
lost to follow-up.  Censored patients who were still in the study follow-up at the time of the analysis 
will be censored at the last day of available follow-up data. 
The above primary endpoint analysis will be done using ITT population  
Also, the primary efficacy analysis will be repeated using PP population.  
 Sensitivity analysis for primary endpoint 1 2:  
Three sensitivity analyses are planned.  
1. The first is a more relaxed definition of time to resolution of hypoxia.  In this analysis, the 
resolution of hypoxia is defined if subject’s clinical status score ≤ 4 is maintained for two 
consecutive days.  The timing of the resolution event will still be the first day when the score falls 
to 4 or lower. This sensitivity analysis will be done using ITT as described in the primary endpoint.   
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2. The second sensitivity analysis will be based on Kaplan-Meier estimates and log-rank test.   Median 
time to event, along with standard error, percentage of patients achieved resolution of hypoxia, 
percentage of patients censored, and two-sided p-value obtained using log-rank test at 5% level of 
significance will be presented for observed case using ITT population. 
3. The third sensitivity analysis will be a worst-rank analysis proposed by Lachin (1999).  The two 
treatment groups will be compared by a Wilcoxon-Mann-Whitney test as implemented in SAS 
PROC NPAR1WAY.  Tied ranks will be assigned the midrank. The ranks will be determined as 
follows: 
1) The lowest (best) ranks will be given to patients who meet the primary endpoint definition of 
treatment success, beginning with the earliest treatment success after beginning of treatment, and 
survive to Day 28. 
2) The next lowest ranks will be given to patients who do not meet the definition of success but are 
lost to follow-up or are missing endpoint data for Day 28, but survive to Day 28, beginning with the 
earliest day for which data are lost for the rest of the study. 
3) The next lowest ranks will be given to patients who are informative withdrawals – i.e., they 
withdraw for a reason related to probable treatment failure – but survive to Day 28, beginning with 
the withdrawals closest to Day 28 (i.e., the latest withdrawals). 
4) The next lowest ranks will be given to patients who are followed to Day 28 but do not meet the 
primary endpoint definition, beginning with patients with the lowest clinical status score on Day 
28. 
5) The highest (worst) ranks will be given to patients who die, beginning with the deaths closest to 
Day 28. Thus, the highest rank will be assigned to the first death. 
This sensitivity analysis will be done using ITT population.  
Listing will be provided for the 10-point ordinal scale of clinical status and oxygen saturation level. 
10.6.2 Secondary Analysis: 
 
All secondary analysis will be done using ITT population. 
 
1. Time to discharge from hospital 
 
Time to discharge from hospital = Date of discharge – Date of randomization +1   
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Time to discharge in days will be summarized descriptively. Time to discharge will be compared 
between the treatment groups using the Cox proportional hazard model. The hazard ratio and its 
corresponding two-sided 95% confidence interval (CI) and two sided p-value at 5% level of significance 
will be obtained from the above Cox proportional hazard model; Also Median time, quartile, inter 
quartile range estimate will be presented. 
Patients whose does not discharged up to Day 28 will be right censored as of day 28. Patients who 
discontinue the study for any reason – withdrawal because of an adverse event or worsening of 
symptoms, switch to rescue therapy, loss to follow-up, etc. – will be right censored at Day 28. 
  
2. Time (no. of days) from randomization to the earliest time when ALL COVID-19 associated symptoms 
(fever, chills, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms – 
specifically diarrhoea and vomiting, shortness of breath or dyspnoea) are scored by the 
Investigator/trained study personnel as either ‘0=absent’ or ‘mild =1’ in assessments over a period of 
24 hours, when assessed from baseline to Day 28 or discharge from hospital (if discharge happens 
earlier than Day 28).  
 
Time to ALL COVID-19 associated symptoms to become ‘0=absent’ or ‘mild =1’ from Randomization 
= Earliest Date of ALL COVID-19 associated symptoms became either ‘0=absent’ or ‘mild =1’ in 
assessments over a period of 24 hours – Date of randomization + 1 
 
Time to ALL COVID-19 associated symptoms to become ‘0=absent’ or ‘mild =1’ from Randomization  
will be summarized descriptively. Time to ALL COVID-19 associated symptoms to become ‘0=absent’ 
or ‘mild =1’ from Randomization will be compared between the treatment groups using the Cox 
proportional hazard model. The hazard ratio and its corresponding two-sided 95% confidence interval 
(CI) and two sided p-value at 5% level of significance will be obtained from the above Cox proportional 
hazard model; Also Median time, quartile, inter quartile range estimate will be presented.  
Patients whose symptom score not improved to either ‘0=absent’ or ‘mild =1 by Day 28 will be right 
censored as of day 28. Patients who discontinue the study for any reason – withdrawal because of an 
adverse event or worsening of symptoms, switch to rescue therapy, loss to follow-up, etc. – will be right 
censored at Day 28. 
Listing will be provided for COVID-19 associated symptoms. 
3. Percentage of patients with  score of  either ‘0=absent’ or ‘mild =1’ over a period of 24 hours, for ALL 
COVID-19 associated symptoms by Days 4, 7, 10 14, 21 and 28 or discharge (if discharge happens 
earlier than one or more of the above-mentioned time points)  
 
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Patients will be considered as improvement in ALL COVID-19 associated symptoms if ALL COVID-
19 associated symptoms as either ‘0=absent’ or ‘mild =1’ 
Patients will be considered as improvement in ALL COVID-19 associated symptoms by Days 4, 7, 10 
14, 21 and 28 will be summarized by number and percentage. Two sided Chi-square test/ Fisher-Exact 
(Fisher Exact test will be performed when the expected count for any cell is less than 5) test at 5% level 
of significance will be performed to test the difference of proportion between two treatments.  
4. 
Time to improvement in EACH of the symptoms of fever, chills, cough, sore throat, malaise, headache, 
muscle pain, gastrointestinal symptoms- specifically diarrhoea and vomiting, shortness of breath or 
dyspnoea by at least 1 grade over baseline.  
 
Note: Severity of symptoms will be evaluated once daily (preferably at or around the same clock time) 
on each day that the patient is admitted in the hospital. The Investigator/trained study personnel will 
assess (including by enquiry with the patient, as necessary) and score the severity of each COVID-19 
associated symptom on a 5 point Likert-type scale (0= absent, 1= mild, 2=moderate, 3= severe, 4= 
very severe/critical). The improvement observed must be sustained at evaluations over a period of 24 
hours, in order for this secondary efficacy endpoint to be reached. 
Time to achieve symptom improvement will be considered to have been met at the earliest timepoint 
when the particular symptoms score has decreased by at least 1 grade over baseline. 
Time to achieve symptom improvement = Date of Change from baseline value for the particular 
symptom score to become less than or equal to ‘-1’ and sustained at evaluations over a period of 24 
hours – Date of randomization +1   
Time to achieve symptom improvement will be as follows: 
Time to achieve symptom improvement will be summarized for each of the listed COVID-19 associated 
symptoms descriptively. Time to achieve symptom improvement of the listed COVID-19 associated 
symptom will be compared between the treatment groups using the Cox proportional hazard model with 
the baseline symptom score of each symptom as covariate and median time to achieve change from 
baseline as dependent variable. The hazard ratio and its corresponding two-sided 95% confidence 
interval (CI) and two sided p-value at 5% level of significance will be obtained from the above Cox 
proportional hazard model; Also Median time, quartile, inter quartile range estimate will be presented. 
Patients whose each symptom score does not improved by at least 1 grade over baseline up to Day 28 
will be right censored as of day 28. Patients who discontinue the study for any reason – withdrawal 
because of an adverse event or worsening of symptoms, switch to rescue therapy, loss to follow-up, etc. 
– will be right censored at Day 28. 
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5. 
Percentage of patients reporting a clinical relapse of COVID-19 when assessed from day of discharge 
to 27 days after randomization (Day 28). 
 
Note: ‘Clinical relapse’ is defined as either the reappearance or worsening of severity (over the 
assessment on the day of discharge) of one or more of the above-mentioned COVID-19 associated 
symptoms, or the appearance of any of the symptoms (due to COVID 19 infection) for the first time 
after discharge. This endpoint will be assessed only for those patients that were discharged before Day 
28. 
Patients reporting a clinical relapse of COVID-19 will be summarized by number and percentage. Two-
sided Chi-square test/ Fisher-Exact test at 5% level of significance will be performed to test the 
difference of proportion between two treatments with two-sided 95% level of significance. 
6. 
Time (no. of days) to negative conversion of detectable SARS-CoV 2 viral RNA in the RT-PCR assays 
of respiratory sample, from randomization. 
 
Time to negative conversion will be compared between the treatment groups using the Cox proportional 
hazard model with cycle threshold value (RdRp Target) at baseline as covariate. The hazard ratio and 
its corresponding two-sided 95% confidence interval (CI) and two sided p-value at 5% level of 
significance will be obtained from the above Cox proportional hazard model; Also Median time, 
Quartile, Inter quartile range estimate will be presented and Kaplan-Meier plot will be plotted. Patients 
who don’t turn to be SARS-CoV-2 negative by Day 28 will be right-censored as of day 28. Patients 
who discontinue the study for any reason – withdrawal because of an adverse event or worsening of 
symptoms, switch to rescue therapy, loss to follow-up, etc. – will be right censored at Day 28. 
Listing will be provided for RT-PCR. 
7. 
Percentage of patients showing negative conversion of detectable SARS-CoV-2 viral RNA in the RT-
PCR assays of respiratory samples on Days 5, 10 and 28 or discharge (if discharge happens earlier than 
one or more of the above-mentioned timepoints). 
  
Patients showing negative conversion (of detectable SARS-CoV-2 viral RNA) in the RT-PCR assays 
of respiratory samples on Days 5, 10 and 28 or discharge will be summarized by number and percentage. 
Two-sided Chi-square test/ Fisher-Exact (Fisher Exact test will be performed when the expected count 
for any cell is less than 5) test at 5% level of significance will be performed to test the difference of 
proportion between two treatments.  
8. 
Changes over time in patient’s clinical status on the 10-point ordinal scale used in the SOLIDARITY 
trial by WHO 
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a. 
Changes in the 10-point ordinal scale score from baseline until discharge   
b. 
Proportion of patients in whom clinical status score of 4 (‘hospitalized, no oxygen required’) 
or lower has been attained by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens 
earlier than one or more of the above-mentioned timepoints) 
c. 
Time (no. of days) from randomization to clinical status score improvement by 1 and by 2 
points (from baseline)  
d. 
Proportion of patients for whom clinical status score improvement by 1 and by 2 points has 
been attained by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier than 
one or more of the above-mentioned time points) 
Time to Clinical status score improvement by 1 = Date of first time the status trial score improved by 1 
following baseline assessment – Date of randomization +1  
Time to Clinical status score improvement by 2 = Date of first time the status trial score improved by 2 
following baseline assessment – Date of randomization +1  
Changes in 10-point ordinal scale score from baseline until discharge will be summarized descriptively 
by visit and treatment group. The LSM, its 95% CI, and SE will be calculated by treatment group for 
each measurement point using the Mixed Model Repeated Measures (MMRM) with changes from 
baseline as an objective variable. Furthermore, differences in LSM between the treatment groups and 
its 95% CI will be calculated and compared between the treatment groups. Corresponding two-sided p-
value at 5% level of significance will be presented. 
Time to clinical status score improvement by 1 and by 2 points will be compared between the treatment 
groups using the Cox proportional hazard model with 10 point ordinal clinical status score at baseline 
as covariate. The hazard ratio and its corresponding two-sided 95% confidence interval (CI) and two 
sided p-value at 5% level of significance will be obtained from the above Cox proportional hazard 
model; Also, Median time, Inter quartile range estimate will be presented. Patients who doesn’t have 
any Clinical status score of 4 or lower up to day 28 and patients who doesn’t have improvement by 1 
and 2 point in clinical status score from baseline up to day 28 will be right-censored as of day 28. 
Patients who discontinue the study for any reason – withdrawal because of an adverse event or 
worsening of symptoms, switch to rescue therapy, loss to follow-up, etc. – will be right censored at Day 
28. 
Proportion of patients showing clinical status score of 4 (‘hospitalized, no oxygen required’) or lower 
which has been attained by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier than 
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one or more of the above-mentioned time points) will be summarized by number and percentage. Two-
sided Chi-square test/ Fisher-Exact (Fisher Exact test will be performed when the expected count for 
any cell is less than 5) test at 5% level of significance will be performed to test the difference of 
proportion between two treatments. 
Proportion of patients showing clinical status score improvement by 1 and by 2 points attained by Days 
4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier than one or more of the above-
mentioned time points) will be summarized by number and percentage. Two-sided Chi-square test/ 
Fisher-Exact (Fisher Exact test will be performed when the expected count for any cell is less than 5) 
test at 5% level of significance will be performed to test the difference of proportion between two 
treatments. 
9. 
Changes over time in patient’s clinical status on the 8-point ordinal scale  
a. 
Time (no. of days) from randomization to attain clinical status score of 4 or lower  
b. Proportion of patients in whom clinical status score of 4 or lower has been attained by 
Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier than one or more 
of the above-mentioned time points) 
c. 
Time (no. of days) from randomization to attain clinical status score of 3 or lower  
d. Proportion of patients in whom clinical status score of 3 or lower has been attained by 
Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier than one or more 
of the above-mentioned time points) 
e. 
Time (no. of days) from randomization to clinical status score improvement by 1 and by 
2 points (from baseline)  
f. 
Proportion of patients for whom clinical status score improvement by 1 and by 2 points 
has been attained by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens 
earlier than one or more of the above-mentioned time points) 
 
Time (no. of days) from randomization to attain clinical status score of 4 or lower, Time (no. of days) 
from randomization to attain clinical status score of 3 or lower and Time (no. of days) from 
randomization to clinical status score improvement by 1 and by 2 points (from baseline) will be analysed 
descriptively by treatment group. 
 
Proportion of patients in whom clinical status score of 4 or lower has been attained by Days 4, 7, 10, 
14, 21 and 28 or discharge (if discharge happens earlier than one or more of the above-mentioned 
timepoints), Proportion of patients in whom clinical status score of 3 or lower has been attained by Days 
4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier than one or more of the above-
mentioned time points) and Proportion of patients for whom clinical status score improvement by 1 and 
by 2 points has been attained by Days 4, 7, 10, 14, 21 and 28 or discharge (if discharge happens earlier 
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than one or more of the above-mentioned time points) will be summarized by number and percentage 
using treatment group.  
 
Listing will be provided for 8-point ordinal scale. 
10. Changes over time in findings on chest X-ray  
 
Change from baseline will be calculated for Total RALE Score based on average score of both the 
examiners.  
Change from baseline will be summarized descriptively by visit and treatment group. The LSM, its 
95% CI, and SE will be calculated by treatment group for each measurement point using the Mixed 
Model Repeated Measures (MMRM) with changes from baseline as an objective variable. Furthermore, 
differences in LSM between the treatment groups and its 95% CI will be calculated and compared 
between the treatment groups. Corresponding two-sided p-value at 5% level of significance will be 
presented. 
Also, proportion analysis of patients that ‘improved’ ‘no change’ and ‘worsened’ from baseline by Days 
4, 7, 10, 14, 28 or discharge (if discharge happens earlier than one or more of the above-mentioned 
timepoints) will be presented. 
Listing will be provided for chest X-ray. 
11. Changes over time in the National Early Warning Score-2 (NEWS)  
 
Changes over time in the National Early Warning Score-2 will be summarized descriptively.  
The LSM, its 95% CI, and SE will be calculated by treatment group for each measurement point using 
the MMRM with changes from baseline as an objective variable. Furthermore, differences in LSM 
between the treatment groups and its 95% CI will be calculated and compared between the treatment 
groups. Corresponding two-sided p-value at 5% level of significance will be presented. 
Listing will be provided for National Early Warning Score-2. 
12. Percentage of patients requiring, until Day 28 or discharge from hospital (if discharge happens earlier) 
a) Management in intensive care unit (ICU) 
b) High Flow Nasal Oxygen or Non-invasive mechanical ventilation 
c) Invasive mechanical ventilation  
 
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Percentage of patients requiring, until Day 28 of treatment of Management in intensive care unit (ICU), 
High Flow Nasal Oxygen supplementation or Non-invasive mechanical ventilation and Invasive 
mechanical ventilation will be summarized by number and percentage.  
Listing will be provided for Hospitalization. 
13. Time (no. of days) from randomization to 
a) Management in intensive care unit 
b) High Flow Nasal Oxygen  or Non-invasive mechanical ventilation 
c) Invasive mechanical ventilation 
Definition of time to Management in intensive care unit, High Flow Nasal Oxygen supplementation 
and Non-Invasive Mechanical Ventilation and Invasive mechanical ventilation will be as follows: 
Time to Management in intensive care unit = Start date of first admission to ICU of the COVID 
management hospital facility – Date of randomization +1 
Time to High Flow Nasal Oxygen supplementation or Non-invasive Mechanical Ventilation = Start 
date of first administration of high flow nasal oxygen or non-invasive mechanical ventilation (earlier 
of the two, in case both have been administered) – Date of randomization +1 
Time to Invasive mechanical ventilation= Start date of first time Invasive mechanical ventilation– Date 
of randomization +1 
Time (no. of days) for Management in intensive care unit (ICU), High Flow Nasal Oxygen 
supplementation or non-invasive mechanical ventilation and Invasive mechanical ventilation will be 
analyzed descriptively. Log-rank test will be used to compare the median time for patients to start 
“Management in intensive care unit (ICU)”, “High Flow Nasal Oxygen supplementation”, “Non-
invasive mechanical ventilation” and “Invasive mechanical ventilation” between the two treatment 
groups. 
14. Duration (no. of days) the patient requires: 
a) Management in intensive care unit  
b) Oxygen supplementation 
c) High Flow Nasal Oxygen 
d) Non-invasive mechanical ventilation 
e) Invasive mechanical ventilation 
 
Over an assessment period from randomization until Day 28 or discharge from hospital (if discharge 
happens earlier) 
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Definition of time to Managed in intensive care unit, On Oxygen supplementation, On High Flow Nasal 
Oxygen Supplementation, On Non-invasive Mechanical Ventilation and On Invasive mechanical 
ventilation will be as follows: 
Number of days Managed in intensive care unit = Stop date of ICU management – start date of ICU 
management + 1 
Number of days On Oxygen supplementation= Stop date of Oxygen supplementation – start date of 
Oxygen supplementation + 1 
Number of days On High Flow Nasal Oxygen = Stop date of High Flow Nasal Oxygen – start date of 
High Flow Nasal Oxygen + 1 
Number of days On Non-Invasive mechanical ventilation= Stop date of Non-Invasive mechanical 
ventilation – Start date of Non-Invasive mechanical ventilation + 1 
Number of days On Invasive mechanical ventilation= Stop date of Invasive mechanical ventilation – Start 
date of Invasive mechanical ventilation + 1 
Duration (no. of days) for Managed in intensive care unit (ICU), on Oxygen supplementation On High 
Flow Nasal Oxygen Supplementation, On Non-invasive Mechanical Ventilation and on Invasive 
mechanical ventilation will be summarized descriptively. ANOVA will be used to compare the mean 
time(days): “Managed in intensive care unit (ICU), On Oxygen supplementation, On High Flow Nasal 
Oxygen Supplementation, On Non-invasive Mechanical Ventilation and On Invasive mechanical 
ventilation” between the two treatment groups.  
Note: patients with multiple episodes of Managed in intensive care unit (ICU), On Oxygen 
supplementation, On High Flow Nasal Oxygen Supplementation, On Non-invasive Mechanical will be 
summed together and total duration (number of days) will be used for analysis. 
15. Percentage of patients  
a. dying from any cause 
b. dying from a COVID-19 associated complication 
Over an assessment period from randomization until Day 28 or discharge from hospital (if discharge 
happens earlier). 
Patients dying due to any cause and COVID-19 associated complication will be summarized by number 
and percentage. Two-sided Chi-square test/ Fisher-Exact test at 5% level of significance will be 
performed to test the difference of proportion between two treatments with two-sided 95% level of 
significance. 
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Stage II 
 
1. Percentage of patients reporting a clinical relapse of COVID-19 when assessed from day of 
discharge to 59 days after randomization (Day 60). 
 
Note: ‘Clinical relapse’ is defined as either the reappearance or worsening of severity (over the 
assessment on the day of discharge) of one or more of the above-mentioned COVID-19 associated 
symptoms, or the appearance of any of these symptoms (due to COVID 19 infection) for the first 
time after discharge.  
Percentage of patients reporting a clinical relapse of COVID-19 when assessed from day of discharge to 
59 days after the start of study treatment (Day 60) will be summarized by number and percentage. Two-
sided Chi-square test/ Fisher-Exact test at 5% level of significance will be performed to test the difference 
of proportion between two treatments with two-sided 95% level of significance. 
 
2. Proportion of patients  
a. 
with disease worsening and requires: 
v. 
Admission to ICU 
vi. 
High flow nasal oxygen 
vii. 
Non-invasive mechanical ventilation 
viii. 
Invasive mechanical ventilation 
(AND) 
b. dying  
until day 60 (regardless of whether patients are discharged from hospital before Day 28 
or not) 
Proportion of patients with disease worsening will be summarized by number and percentage. Two-sided 
Chi-square test/ Fisher-Exact test at 5% level of significance will be performed to test the difference of 
proportion between two treatments with two-sided 95% level of significance. 
10.7 Safety Analysis 
10.7.1 Adverse Events 
Adverse Events will be coded using the Medical Dictionary of Regulatory Activities (MedDRA version 
23.0), the coded terms will be used for summarizing the AE(s). Only treatment emergent adverse events 
(TEAE) will be summarized in tables, while all events will be listed. Adverse events will be analyzed using 
SAF population. 
 
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An AE will be considered as treatment-emergent if the time of onset is on or after the time of the first study 
drug administration or any AE that exist prior to first dose and if it increased in severity during the study 
period. All AEs reported in stage II period- “Day of discharge to 59 days after date of first dose of study 
treatment’ will be considered as TEAE.  Handling of missing data and date are explained in section 9.5.1 
(Imputation of missing data). 
 
An overall summary table, which summarizes, the number and percentages of patients with treatment 
emergent adverse events at stage I & stage II , serious adverse events, adverse events leading to death, adverse 
events related to study drug, Study Drug Discontinued Permanently due to adverse event and adverse events 
by severity categories will be provided by treatment groups. 
 
A separate treatment emergent adverse event table for stage II will be summarized for number and percentage 
of patients with treatment emergent adverse event (TEAE), serious TEAE, TEAE related to study drug and 
TEAE by severity categories will be provided by treatment groups.  
 
Patients experiencing any treatment emerging adverse events will be summarized by Preferred Term (PT), 
SOC and treatment group. The number and percentage of patients with at least one TEAE, SAE, permanently 
discontinued study treatment (IP) due to AE, AE leading to Death, AE by relationship and TEAEs of severe 
intensity will be summarized by system organ class, preferred term and treatment group.  
 
Furthermore, listings of SAEs and AEs that lead to study withdrawal will be provided.   
 
AEs Tables by primary system organ class, preferred term and treatment group will be sorted in descending 
order of counts. 
 
A patient experiencing the same AE multiple times will be counted only once for that preferred term. 
Similarly, if a patient experiences multiple AEs within the same system organ class that patient will be 
counted only once in that system organ class. Maximum severity will be considered if a patient has multiple 
severity reported for same AE. In summaries by relationship, if a subject has the same AE on multiple 
occasions, the closest relationship to study drug, will be used for summary. 
10.7.2 Laboratory assessments 
Laboratory assessments will be measured at screening, Day 4, Day 7, Day 10, Day 14, Day 21 and Day 28 
or discharge (if discharge happens earlier than one or more of the above-mentioned timepoints). Laboratory 
assessments will be summarized by treatment group and time point using SAF population. 
The actual and change from baseline laboratory assessments parameters will be summarized descriptively 
by time point and treatment group.  
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The results falling out of normal ranges will be classified as High and Low and will be summarized by time 
point and treatment group. In addition, number and percentage of patients having ‘Normal’, ‘Abnormal CS’ 
and ‘Abnormal NCS’ results for laboratory parameters will be summarized by visits and treatment group.  
Data listings will be presented for laboratory parameters. 
10.7.3 Vital Signs 
Vital signs will be measured at Screening, Day 1, Day 2 to Day 28 or discharge (if discharge happens earlier)  
Vital signs will be analyzed using SAF population. 
The vital signs parameters include: 
 
Systolic Blood Pressure (mmHg) 
 
Diastolic Blood Pressure (mmHg) 
 
Heart Rate (bpm) 
 
Respiratory Rate (brpm) 
 
Body Temperature (°F) 
 
Blood Oxygen Saturation (SpO2) (%) 
The actual and change from baseline vital signs parameters will be summarized descriptively by visits and 
treatment group.  
Data listings will be presented for vital signs parameters. 
10.7.4 ECG 
ECG will be assessed at Screening, Day 1, Day 4, Day 7, Day 10, Day 14, Day 21 and Day 28 or discharge 
( if discharge happens earlier then one or more of the above-mentioned timepoints). The ECG parameters are 
as follows: 
• PR Interval 
• RR Interval 
• QRS Duration 
• QT Interval 
• QTcB Interval 
• Heart Rate 
The actual and change from baseline of quantitative ECG parameters will be summarized descriptively by 
visits and treatment group. 
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Quantitative ECG parameters will be analyzed descriptively and the proportion of patients in each class based 
on ECG interpretation (Normal, Abnormal CS, Abnormal NCS) will be summarized by frequencies and 
percentages using the SAF population by time point and treatment group. 
Listing will be provided for the ECG. 
10.7.5 Physical Examination 
Complete Physical Examination will be assessed at screening. Partial Physical Examination will be assessed 
at Day 1, Day 2 to Day 28 or discharge (if discharge happens earlier). Complete Physical examination will 
include general appearance, skin, head, neck, ENT, heart, lungs, abdomen, extremities, neurological, 
musculoskeletal, and lymph nodes. Partial Physical examination will include general appearance, ENT, heart 
and lungs nodes. 
Physical Examination findings will be summarized by frequencies and percentages using the SAF population 
and treatment group. 
Listing will be provided by subject for the Physical Examination. 
10.7.6 Chest X ray 
Chest X ray will be assessed at screening, Baseline, Day 4, Day 7, Day 10, Day 14 and Day 28/EOS.  
The chest-X ray analysis has been described in the secondary endpoint section point number 9;  
Listing will be provided by subject for the Chest-X ray. 
10.7.7 Pregnancy Test 
Listing will be provided for female subjects for the serum Pregnancy Test at each time point 
10.7.8 IMP Administration 
Listing will be provided for the IMP administration along with treatment compliance for each patient. 
10.7.9 COVID-19 associated symptom severity assessment  
COVID-19 associated symptom severity will be assessed at screening. Day 1, Day 2 to Day 28 or 
discharge (if discharge happens earlier). 
 
COVID-19 associated symptom severity assessment parameters will be summarized by frequencies and 
percentages using the SAF population by study day and treatment group. 
 
Listing will be provided for the COVID-19 associated symptom severity assessment. 
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10.7.10 Hospitalization 
Listing of patients who require oxygen supplementation, ICU admission, Oxygen by HFNC or NIV and 
Invasive Mechanical Ventilation will be listed. 
 
10.7.11 Subgroup Analysis: 
Subgroup analysis will be performed for the “Time to resolution of hypoxia” by considering the severity 
category (moderate vs severe categories) as a subgroup using ITT population as an observed case analysis. 
Subgroup analysis will be performed for the “Time to resolution of hypoxia” by considering the race category 
(White/ Caucasian vs Non-White / Non-Caucasian) as a subgroup using ITT population as an observed case 
analysis. 
Subgroup analysis will be performed for the “Time to resolution of hypoxia” by considering the age category 
(Age group <50 years, Age group >=50 years) as a subgroup using ITT population as an observed case 
analysis. 
Subgroup analysis will be performed for the “Time to resolution of hypoxia” by considering the gender 
category as a subgroup using ITT population as an observed case analysis. 
11 Deviation from the Study Protocol 
Not applicable 
12 Database Lock and Unblinding 
There will be two database lock for this study. One for stage I (Primary) and another one for Stage II 
(Secondary) analysis. The SAP will be finalized prior to primary database lock. After the data cleaning 
process is finalized according to the data management plan (DMP) and the assignment of patients to the 
analysis populations is agreed and signed by the Sponsor, the study database will be locked for primary and 
secondary separately.  
 
13 References 
1. Lachin J. M. (1999). Worst-Rank Score Analysis with Informatively Missing Observations in 
Clinical Trials.  Controlled Clinical Trials. 20:408–422. 
 
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14 Appendices 
Appendix I: Interim Analysis Plan 
 
 
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Appendix I: Interim Analysis Plan 
 
A single unblinded interim analysis of the primary efficacy endpoint, that is, time to resolution of hypoxia, 
will be conducted.  Resolution of hypoxia is defined as described in Section 10.6.1.  This endpoint will be 
considered to have been met when the patient had attained a score of 4 or lower on the 10-point ordinal scale 
of clinical status used by the WHO in the SOLIDARITY trial, and either maintained the score of 4 or lower 
for five consecutive assessments over 5 days or was discharged after reaching the score of 4 or lower.  In 
addition, the patient must also survive and not be readmitted to hospital due to COVID-19 related 
complications through Day 28 to be considered meeting the endpoint. To be performed when data for time 
to resolution of hypoxia become available for either the first 390 randomized subjects (50% of the target 
enrollment) or subjects enrolled by the end of year 2020, whichever is earlier, interim analysis will be 
conducted for three purposes: 1) Possible early stopping for demonstrated efficacy of the study treatment, 2) 
Possible early stopping for futility (lack of efficacy), and 3) Sample size reassessment.  After reviewing the 
analysis, the DMC will make a recommendation concerning continuation of the study as planned, 
termination, or continuation with a larger sample size. 
 
The interim analysis for efficacy will be performed like the primary efficacy analysis detailed in Section 
10.6.1 of the Statistical Analysis Plan for the final analysis.  Time to resolution of hypoxia will be compared 
between the treatment groups using the Cox proportional hazard model with age, gender, and baseline score 
on the 10-point ordinal scale of clinical status as covariates.  A Lan-DeMets alpha spending function 
approach will be adopted in order to maintain the overall Type-I error or alpha at the desired two-sided 0.05 
level (Lan & DeMets, 1983).  The boundary for possible early stopping for demonstrated efficacy will be 
determined using a Type I error rate of 0.005 (one-sided); that is, the null hypothesis of zero treatment effect 
will be rejected if the observed effect is in the direction of treatment benefit and it is significant with one-
sided p < 0.005.  If the trial is not stopped after the interim analysis, the final primary efficacy analysis 
conducted upon study completion will be based on an adjusted Type I error rate of two-sided 0.04521 (i.e., 
the result will be considered statistically significant for a Z-statistic ≥ 2.0027).   
 
Assuming the Z-statistic does not reach the boundary for early stopping for demonstrated efficacy, an 
analysis will be conducted for possible early stopping for futility.  A DMC recommendation of early stopping 
for futility will be based on two factors.  The first factor is the conditional power, i.e., the probability of 
finding a significant beneficial treatment effect with adjusted Type I error rate of two-sided 0.04521 at the 
end of the study, given the current data and appropriate assumptions about the true treatment effect. The 
second factor is the estimated effect size from the interim analysis.  The DMC may recommend the study be 
stopped for reasons of futility if either 1) the conditional power is very low (for example, 20% or lower), 
assuming a hazard ratio equal to the estimated hazard ratio from the current data, or 2) the upper limit of a 
95% confidence interval for the difference in median time to resolution of hypoxia is < 1 day.  The conditional 
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power will be calculated as in Lachin (2005) and Chen, DeMets, & Lan (2004).  Median times to resolution 
of hypoxia will be estimated by the Kaplan-Meier method. 
 
If the interim analysis results do not suggest early stopping for efficacy or futility, the DMC will consider 
whether to recommend an increase in sample size, following the method given by Chen, DeMets, & Lan 
(2004).  Conditional power will be calculated under the assumption that the true underlying hazard ratio is 
the same as the estimate from the current data.  If this conditional power is less than 80%, the increase in 
sample size necessary to make the conditional power 70%, 75%, or 80% will be calculated.  If the conditional 
power with the currently planned sample size is ≥ 50% and the sample size increment required for the desired 
power is less than approximately 1.5 times the original sample size, increasing sample size by this method 
will not affect the Type I error rate.  In addition, simulations suggest the Type I error in this analysis will not 
be inflated for conditional power ≥ 20% and < 50%, as long as there is a stopping rule for very low conditional 
power (Lan & Trost, 1997).  If the increase in sample size required to achieve a desired power is not feasible, 
a smaller increase may be made.   
 
Two key secondary endpoints will also be analyzed in the interim analysis for considering by the DMC in 
their deliberations.  These two endpoints are time to discharge from hospital and time to improvement from 
baseline of at least 2 points on the 10-point clinical status scale.   Cox models and Kaplan-Meier analysis 
will be employed, as for the primary endpoint.  Missing values will not be imputed. 
 
Mortality and disease progression endpoints will be analyzed in the interim analysis.  These analyses will be 
exploratory and will be based on the observed data only.  The mortality endpoints will include patients dying 
from any cause and patients dying from a COVID-19 associated complication.  Between-treatment 
comparisons will be performed for these mortality endpoints, as both binary and as time to event outcomes.  
For disease progression, patients requiring, until the earlier of Day 28 or discharge from hospital, 
management in intensive care unit, high flow nasal oxygen / non-invasive mechanical ventilation, and 
invasive mechanical ventilation will be separately tabulated.  Time from randomization to each of these 
disease progression events will be compared between treatments.  In addition, the duration of requiring (as 
measured by the number of days) management in intensive care unit, non-invasive mechanical ventilation, 
and invasive mechanical ventilation will be compared separately.  Covariate-adjusted analyses will be 
performed if needed. 
 
References: 
Chen, Y. H., DeMets, D. L., & Lan, K. K. G. (2004). Increasing the sample size when the unblinded interim 
result is promising. Stat Med. 23(7): 1023-38. 
Lachin J. M. (2005). A review of methods for futility stopping based on conditional power. Stat Med. 24: 
2747-2764. 
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Lan K. K. G., DeMets D. L. (1983). Discrete sequential boundaries for clinical trials. Biometrika. 70: 659–
663. 
Lan, K. K. G., Trost D. C. (1997). Estimation of parameters and sample size re-estimation. Proceedings of 
the American Statistical Association, Biopharmaceutical Section: 48-51. 
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