Clinical Trial Evaluating the Efficacy and Safety of Favipiravir in Moderate to Severe COVID-19 Patients
Condition: Covid19
MeSH terms: COVID-19
Intervention: AVIGAN; Placebo Comparator
Intervention description: Patients will be randomized to the favipiravir + supportive care group in a 1:1 ratio; Patients will be randomized to the placebo + supportive care group in a 1:1 ratio
Intervention MeSH terms: Favipiravir
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 780 patients are randomized 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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: 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.
Enrollment: 353.0
Sex: All
Minimum age: 21 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: AVIGAN; Favipiravir; COVID-19; Phase 3

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.
    

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