Clinical Trial Evaluating the Efficacy and Safety of Favipiravir in Moderate to Severe COVID-19 Patients

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.

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.

Eligibility Criteria:
Inclusion Criteria:

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 tracheobronchial aspirate) collected within 72 hours of 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
   1. 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
   2. blood oxygen saturation (SpO2) of 94% at rest on room air at sea level

   II. 'severe' COVID-19
   1. 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
   2. 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\*

   1. must have a negative serum pregnancy test at screening
   2. 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.
   3. 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:
   1. postmenopausal for at least 12 months prior to study product administration, or
   2. without a uterus and/or both ovaries or has been surgically sterilized (i.e, 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:

1. Critically ill patients, defined as those who are candidates for endotracheal intubation and mechanical ventilation, oxygen delivered by high- flow nasal cannula, (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5), non-invasive positive pressure 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 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-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 8 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 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