<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04499677</url>
  </required_header>
  <id_info>
    <org_study_id>132084</org_study_id>
    <nct_id>NCT04499677</nct_id>
  </id_info>
  <brief_title>FLARE: Favipiravir +/- Lopinavir: A RCT of Early Antivirals</brief_title>
  <acronym>FLARE</acronym>
  <official_title>Favipiravir, Lopinavir/Ritonavir or Combination Therapy: a Randomised, Double Blind, 2x2 Factorial Placebo-controlled Trial of Early Antiviral Therapy in COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University College, London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>LifeArc</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University College, London</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The current pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global&#xD;
      emergency. COVID-19 appears to be a disease with an early phase where the virus replicates,&#xD;
      coinciding with first presentation of symptoms, followed by a later 'inflammatory' phase&#xD;
      which results in severe disease in some individuals. It is known from other rapidly&#xD;
      progressive infections such as sepsis and influenza that early treatment with antimicrobials&#xD;
      is associated with better outcome. Antiviral medications are most likely to be effective when&#xD;
      administered soon after infection. There is therefore an urgent need to study subjects who&#xD;
      have recently developed symptoms, or have recently been tested positive with or without&#xD;
      symptoms, and who can be sampled frequently to understand changes in viral load. This cohort&#xD;
      will allow us to collect detailed trajectory data on early disease and understand how&#xD;
      pharmacological interventions may affect this. The objective of the FLARE trial is to assess&#xD;
      whether early antiviral therapy with either favipiravir + Lopinavir/ritonavir (LPV/r), LPV/r&#xD;
      or favipiravir is associated with a decrease in viral load compared with placebo. The&#xD;
      hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent&#xD;
      progression to the later phase of the disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      FLARE is a phase IIA randomised, double-blind, 2x2 factorial placebo-controlled,&#xD;
      interventional trial in which 240 participants, aged 18 years (≥ 18 years) to 70 years old&#xD;
      inclusive will be recruited. Participants will be adults who have developed the early&#xD;
      symptoms of COVID-19 within the first 5 days, or tested positive for SARS-CoV-2 within the&#xD;
      first 7 days of symptom onset, or not presenting symptoms but tested positive within the last&#xD;
      48 hours (date/time of test must be within 48 hours of enrolment).&#xD;
&#xD;
      Eligible participants will be randomised 1:1:1:1 to receive one of the following&#xD;
      combinations:&#xD;
&#xD;
      Favipiravir + Lopinavir/ritonavir (LPV/r) (both active); Favipiravir active +&#xD;
      Lopinavir/ritonavir (LPV/r) placebo; Favipiravir placebo + Lopinavir/ritonavir (LPV/r)&#xD;
      active; Favipiravir placebo + Lopinavir/ritonavir (LPV/r) placebo;&#xD;
&#xD;
      All participants will be enrolled and followed up for 28 days. A saliva sample for&#xD;
      virological analysis and safety blood samples will be collected at baseline, as well as a&#xD;
      diagnostic nose and throat swab, if the participant hasn't been tested for COVID-19 yet.&#xD;
      Following randomisation, participants will take trial medication for 7 days and during this&#xD;
      period will take a daily saliva sample and complete a symptoms diary including four daily&#xD;
      temperature measurements.&#xD;
&#xD;
      Participants will have two follow-up visits at Day 7 and Day 14 where they will be assessed&#xD;
      and undergo blood tests for toxicity and pharmacokinetic assessment (on Day 7 only) and&#xD;
      provide stool samples. Participants will have a telephone follow up three (3) weeks after&#xD;
      their last day of treatment (Day 7) and further information will be collected through a&#xD;
      questionnaire.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 24, 2020</start_date>
  <completion_date type="Actual">January 17, 2022</completion_date>
  <primary_completion_date type="Actual">December 1, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <intervention_model_description>Randomised, double-blind, 2x2 factorial placebo-controlled</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Double-blind</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Upper respiratory tract viral load at Day 5</measure>
    <time_frame>Day 5 from randomisation</time_frame>
    <description>Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percentage of participants with undetectable upper respiratory tract viral load after 5 days of therapy</measure>
    <time_frame>5 days from randomisation</time_frame>
    <description>Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of participants with undetectable stool viral load after 7 days of therapy.</measure>
    <time_frame>7 days from randomisation</time_frame>
    <description>Quantitative polymerase chain reaction (PCR) performed on stool samples at Day 7</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of decrease in upper respiratory tract viral load during 7 days of therapy</measure>
    <time_frame>7 days</time_frame>
    <description>PCR performed on daily saliva samples collected between Day 1 and Day 7 post-randomisation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of fever following commencement of medication</measure>
    <time_frame>7 days</time_frame>
    <description>Daily body temperature records between Day 1 and Day 7 post-randomisation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of participants with hepatotoxicity after 7 days of therapy</measure>
    <time_frame>7 days from randomisation</time_frame>
    <description>Standard diagnostic laboratory assays for liver transaminases, alkaline phosphatase and bilirubin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of participants with other medication-related toxicity after 7 days of therapy and 14 days post-randomisation</measure>
    <time_frame>Day 7 and Day 14 from randomisation</time_frame>
    <description>Determination of medication-related adverse events by investigators at Day 7 and Day 14 post-randomisation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of participants admitted to hospital with COVID-19 related illness</measure>
    <time_frame>28 days</time_frame>
    <description>Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of participants admitted to ICU with COVID-19 related illness</measure>
    <time_frame>28 days</time_frame>
    <description>Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of participants who have died with COVID-19 related illness</measure>
    <time_frame>28 days</time_frame>
    <description>Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of favipiravir as measured by Clearance (CL)</measure>
    <time_frame>Day 7 from randomisation</time_frame>
    <description>Assess pharmacokinetics of favipiravir as measured by Clearance (CL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of favipiravir as measured by Volume of distribution (V)</measure>
    <time_frame>Day 7 from randomisation</time_frame>
    <description>Assess pharmacokinetics of favipiravir as measured by Volume of distribution (V)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of favipiravir as measured by Absorption rate constant (Ka)</measure>
    <time_frame>Day 7 from randomisation</time_frame>
    <description>Assess pharmacokinetics of favipiravir as measured by Absorption rate constant (Ka)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of favipiravir as measured by Maximum concentration (Cmax)</measure>
    <time_frame>Day 7 from randomisation</time_frame>
    <description>Assess pharmacokinetics of favipiravir as measured by Maximum concentration (Cmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of favipiravir as measured by Time to maximum concentration (Tmax)</measure>
    <time_frame>Day 7 from randomisation</time_frame>
    <description>Assess pharmacokinetics of favipiravir as measured by Time to maximum concentration (Tmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of favipiravir as measured by Elimination rate constant (Ke)</measure>
    <time_frame>Day 7 from randomisation</time_frame>
    <description>Assess pharmacokinetics of favipiravir as measured by Elimination rate constant (Ke)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of favipiravir as measured by Area Under the Curve extrapolated to infinity (AUC (0-inf)</measure>
    <time_frame>Day 7 from randomisation</time_frame>
    <description>Assess pharmacokinetics of favipiravir as measured by Area Under the Curve extrapolated to infinity (AUC (0-inf)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamics of favipiravir as measured by Rate of viral load decline (delta)</measure>
    <time_frame>Day 7 from randomisation</time_frame>
    <description>Assess pharmacodynamics of favipiravir as measured by Rate of viral load decline (delta)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamics of favipiravir as measured by Maximum increase in viral load under drug treatment (Emax)</measure>
    <time_frame>Day 7 from randomisation</time_frame>
    <description>Assess pharmacodynamics of favipiravir as measured by Maximum increase in viral load under drug treatment (Emax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamics of favipiravir as measured by Concentration to achieve half the maximum possible effect (EC50)</measure>
    <time_frame>Day 7 from randomisation</time_frame>
    <description>Assess pharmacodynamics of favipiravir as measured by Concentration to achieve half the maximum possible effect (EC50)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of participants with deleterious or resistance-conferring mutations in SARS-CoV-2 by Day 7 of treatment</measure>
    <time_frame>Day 7 from randomisation</time_frame>
    <description>Deep sequencing of virus and bioinformatic analysis</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">240</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>Favipiravir + Lopinavir/ritonavir (LPV/r)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral favipiravir at 1800 mg twice daily on Day 1, followed by 400 mg four (4) times daily from Day 2 to Day 7 PLUS Lopinavir/ritonavir (LPV/r) at 400mg/100 mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Favipiravir + Lopinavir/ritonavir (LPV/r) placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral favipiravir at 1800 mg twice daily on Day 1, followed by 400 mg four (4) times daily from Day 2 to Day 7 PLUS Lopinavir/ritonavir (LPV/r) matched placebo at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Favipiravir placebo + Lopinavir/ritonavir (LPV/r)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral favipiravir matched placebo at 1800 mg twice daily on Day 1, by 400 mg four (4) times daily from Day 2 to Day 7 PLUS Lopinavir/ritonavir (LPV/r) at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Favipiravir placebo + Lopinavir/ritonavir (LPV/r) placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Oral favipiravir matched placebo at 1800 mg twice daily on Day 1, by 400 mg four (4) times daily from Day 2 to Day 7 PLUS Lopinavir/ritonavir (LPV/r) matched placebo at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Favipiravir</intervention_name>
    <description>Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.</description>
    <arm_group_label>Favipiravir + Lopinavir/ritonavir (LPV/r)</arm_group_label>
    <arm_group_label>Favipiravir + Lopinavir/ritonavir (LPV/r) placebo</arm_group_label>
    <other_name>Avigan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lopinavir/ Ritonavir</intervention_name>
    <description>Dosage and method of administration: Day 1: 400mg/100 mg twice daily; Day 2 to Day 7: 200mg/50mg four (4) times daily</description>
    <arm_group_label>Favipiravir + Lopinavir/ritonavir (LPV/r)</arm_group_label>
    <arm_group_label>Favipiravir placebo + Lopinavir/ritonavir (LPV/r)</arm_group_label>
    <other_name>Kaletra</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Favipiravir Placebo</intervention_name>
    <description>Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.</description>
    <arm_group_label>Favipiravir placebo + Lopinavir/ritonavir (LPV/r)</arm_group_label>
    <arm_group_label>Favipiravir placebo + Lopinavir/ritonavir (LPV/r) placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Lopinavir/ Ritonavir Placebo</intervention_name>
    <description>Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.</description>
    <arm_group_label>Favipiravir + Lopinavir/ritonavir (LPV/r) placebo</arm_group_label>
    <arm_group_label>Favipiravir placebo + Lopinavir/ritonavir (LPV/r) placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Any adult with the following:&#xD;
&#xD;
               -  Symptoms compatible with COVID-19 disease (Fever &gt;37.8oC on at least one occasion&#xD;
                  AND either cough and/ or anosmia) within the first 5 days of symptom onset&#xD;
&#xD;
               -  OR ANY symptoms compatible with COVID-19 disease (may include, but are not&#xD;
                  limited to fever, cough, shortness of breath, malaise, myalgia, headache, coryza)&#xD;
                  and tested positive for SARS-CoV-2 within the first 7 days of symptom onset&#xD;
&#xD;
               -  OR no symptoms but tested positive for SARS-CoV-2 within the last 48 hours&#xD;
                  (date/time of test must be within 48 hours of enrolment)&#xD;
&#xD;
          2. Male or female aged 18 years to 70 years old inclusive at screening&#xD;
&#xD;
          3. Willing and able to take daily saliva samples&#xD;
&#xD;
          4. Able to provide full informed consent and willing to comply with trial-related&#xD;
             procedures&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Known hypersensitivity to any of the active ingredients or excipients in favipiravir&#xD;
             and matched placebo, and in lopinavir/ritonavir and matched placebo&#xD;
&#xD;
          2. Chronic liver disease at screening (known cirrhosis of any aetiology, chronic&#xD;
             hepatitis (e.g. autoimmune, viral, steatohepatitis), cholangitis or any known&#xD;
             elevation of liver aminotransferases with AST or ALT &gt; 3 X ULN)*&#xD;
&#xD;
          3. Chronic kidney disease (stage 3 or beyond) at screening: eGFR &lt; 60 ml/min/1.73m2*&#xD;
&#xD;
          4. HIV infection, if untreated, detectable viral load or on protease inhibitor therapy&#xD;
&#xD;
          5. Any clinical condition which the investigator considers would make the participant&#xD;
             unsuitable for the trial&#xD;
&#xD;
          6. Concomitant medications known to interact with favipiravir and matched placebo, and&#xD;
             with lopinavir/ritonavir and matched placebo, and carry risk of toxicity for the&#xD;
             participant&#xD;
&#xD;
          7. Current severe illness requiring hospitalisation&#xD;
&#xD;
          8. Pregnancy and/ or breastfeeding&#xD;
&#xD;
          9. Eligible female participants of childbearing potential and male participants with a&#xD;
             partner of childbearing potential not willing to use highly effective contraceptive&#xD;
             measures during the trial and within the time point specified following last trial&#xD;
             treatment dose.&#xD;
&#xD;
         10. Participants enrolled in any other interventional drug or vaccine trial (co-enrolment&#xD;
             in observational studies is acceptable).&#xD;
&#xD;
               -  Considering the importance of early treatment of COVID-19 to impact viral load,&#xD;
                  the absence of chronic liver/ kidney disease will be confirmed verbally by the&#xD;
                  participant during pre-screening and Screening/Baseline visit. Safety blood&#xD;
                  samples will be collected at Screening/Baseline visit (Day 1) and test results&#xD;
                  will be examined as soon as they become available within 24 hours.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Lowe</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institute of Immunity and Transplantation, University College London</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Royal Free Hospital</name>
      <address>
        <city>London</city>
        <zip>NW3 2QG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University College London Hospital (UCLH)</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004120</url>
    <description>trial results</description>
  </link>
  <link>
    <url>https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-021-05139-2</url>
    <description>Initial trial Protocol</description>
  </link>
  <verification_date>December 2021</verification_date>
  <study_first_submitted>June 16, 2020</study_first_submitted>
  <study_first_submitted_qc>August 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 5, 2020</study_first_posted>
  <last_update_submitted>December 12, 2022</last_update_submitted>
  <last_update_submitted_qc>December 12, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 15, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ritonavir</mesh_term>
    <mesh_term>Lopinavir</mesh_term>
    <mesh_term>Favipiravir</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>No plan to share IPD has been made at this time.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04499677
org study id: 132084
nct id: NCT04499677
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The current pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global
      emergency. COVID-19 appears to be a disease with an early phase where the virus replicates,
      coinciding with first presentation of symptoms, followed by a later 'inflammatory' phase
      which results in severe disease in some individuals. It is known from other rapidly
      progressive infections such as sepsis and influenza that early treatment with antimicrobials
      is associated with better outcome. Antiviral medications are most likely to be effective when
      administered soon after infection. There is therefore an urgent need to study subjects who
      have recently developed symptoms, or have recently been tested positive with or without
      symptoms, and who can be sampled frequently to understand changes in viral load. This cohort
      will allow us to collect detailed trajectory data on early disease and understand how
      pharmacological interventions may affect this. The objective of the FLARE trial is to assess
      whether early antiviral therapy with either favipiravir + Lopinavir/ritonavir (LPV/r), LPV/r
      or favipiravir is associated with a decrease in viral load compared with placebo. The
      hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent
      progression to the later phase of the disease.
FLARE is a phase IIA randomised, double-blind, 2x2 factorial placebo-controlled,
      interventional trial in which 240 participants, aged 18 years (≥ 18 years) to 70 years old
      inclusive will be recruited. Participants will be adults who have developed the early
      symptoms of COVID-19 within the first 5 days, or tested positive for SARS-CoV-2 within the
      first 7 days of symptom onset, or not presenting symptoms but tested positive within the last
      48 hours (date/time of test must be within 48 hours of enrolment).

      Eligible participants will be randomised 1:1:1:1 to receive one of the following
      combinations:

      Favipiravir + Lopinavir/ritonavir (LPV/r) (both active); Favipiravir active +
      Lopinavir/ritonavir (LPV/r) placebo; Favipiravir placebo + Lopinavir/ritonavir (LPV/r)
      active; Favipiravir placebo + Lopinavir/ritonavir (LPV/r) placebo;

      All participants will be enrolled and followed up for 28 days. A saliva sample for
      virological analysis and safety blood samples will be collected at baseline, as well as a
      diagnostic nose and throat swab, if the participant hasn't been tested for COVID-19 yet.
      Following randomisation, participants will take trial medication for 7 days and during this
      period will take a daily saliva sample and complete a symptoms diary including four daily
      temperature measurements.

      Participants will have two follow-up visits at Day 7 and Day 14 where they will be assessed
      and undergo blood tests for toxicity and pharmacokinetic assessment (on Day 7 only) and
      provide stool samples. Participants will have a telephone follow up three (3) weeks after
      their last day of treatment (Day 7) and further information will be collected through a
      questionnaire.
allocation: Randomized
intervention model: Factorial Assignment
intervention model description: Randomised, double-blind, 2x2 factorial placebo-controlled
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: Double-blind
measure: Upper respiratory tract viral load at Day 5
time frame: Day 5 from randomisation
description: Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy
measure: Percentage of participants with undetectable upper respiratory tract viral load after 5 days of therapy
time frame: 5 days from randomisation
description: Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy
measure: Proportion of participants with undetectable stool viral load after 7 days of therapy.
time frame: 7 days from randomisation
description: Quantitative polymerase chain reaction (PCR) performed on stool samples at Day 7
measure: Rate of decrease in upper respiratory tract viral load during 7 days of therapy
time frame: 7 days
description: PCR performed on daily saliva samples collected between Day 1 and Day 7 post-randomisation
measure: Duration of fever following commencement of medication
time frame: 7 days
description: Daily body temperature records between Day 1 and Day 7 post-randomisation
measure: Proportion of participants with hepatotoxicity after 7 days of therapy
time frame: 7 days from randomisation
description: Standard diagnostic laboratory assays for liver transaminases, alkaline phosphatase and bilirubin
measure: Proportion of participants with other medication-related toxicity after 7 days of therapy and 14 days post-randomisation
time frame: Day 7 and Day 14 from randomisation
description: Determination of medication-related adverse events by investigators at Day 7 and Day 14 post-randomisation
measure: Proportion of participants admitted to hospital with COVID-19 related illness
time frame: 28 days
description: Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation
measure: Proportion of participants admitted to ICU with COVID-19 related illness
time frame: 28 days
description: Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation
measure: Proportion of participants who have died with COVID-19 related illness
time frame: 28 days
description: Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation
measure: Pharmacokinetics of favipiravir as measured by Clearance (CL)
time frame: Day 7 from randomisation
description: Assess pharmacokinetics of favipiravir as measured by Clearance (CL)
measure: Pharmacokinetics of favipiravir as measured by Volume of distribution (V)
time frame: Day 7 from randomisation
description: Assess pharmacokinetics of favipiravir as measured by Volume of distribution (V)
measure: Pharmacokinetics of favipiravir as measured by Absorption rate constant (Ka)
time frame: Day 7 from randomisation
description: Assess pharmacokinetics of favipiravir as measured by Absorption rate constant (Ka)
measure: Pharmacokinetics of favipiravir as measured by Maximum concentration (Cmax)
time frame: Day 7 from randomisation
description: Assess pharmacokinetics of favipiravir as measured by Maximum concentration (Cmax)
measure: Pharmacokinetics of favipiravir as measured by Time to maximum concentration (Tmax)
time frame: Day 7 from randomisation
description: Assess pharmacokinetics of favipiravir as measured by Time to maximum concentration (Tmax)
measure: Pharmacokinetics of favipiravir as measured by Elimination rate constant (Ke)
time frame: Day 7 from randomisation
description: Assess pharmacokinetics of favipiravir as measured by Elimination rate constant (Ke)
measure: Pharmacokinetics of favipiravir as measured by Area Under the Curve extrapolated to infinity (AUC (0-inf)
time frame: Day 7 from randomisation
description: Assess pharmacokinetics of favipiravir as measured by Area Under the Curve extrapolated to infinity (AUC (0-inf)
measure: Pharmacodynamics of favipiravir as measured by Rate of viral load decline (delta)
time frame: Day 7 from randomisation
description: Assess pharmacodynamics of favipiravir as measured by Rate of viral load decline (delta)
measure: Pharmacodynamics of favipiravir as measured by Maximum increase in viral load under drug treatment (Emax)
time frame: Day 7 from randomisation
description: Assess pharmacodynamics of favipiravir as measured by Maximum increase in viral load under drug treatment (Emax)
measure: Pharmacodynamics of favipiravir as measured by Concentration to achieve half the maximum possible effect (EC50)
time frame: Day 7 from randomisation
description: Assess pharmacodynamics of favipiravir as measured by Concentration to achieve half the maximum possible effect (EC50)
measure: Proportion of participants with deleterious or resistance-conferring mutations in SARS-CoV-2 by Day 7 of treatment
time frame: Day 7 from randomisation
description: Deep sequencing of virus and bioinformatic analysis
arm group label: Favipiravir + Lopinavir/ritonavir (LPV/r)
arm group type: Experimental
description: Oral favipiravir at 1800 mg twice daily on Day 1, followed by 400 mg four (4) times daily from Day 2 to Day 7 PLUS Lopinavir/ritonavir (LPV/r) at 400mg/100 mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7
arm group label: Favipiravir + Lopinavir/ritonavir (LPV/r) placebo
arm group type: Experimental
description: Oral favipiravir at 1800 mg twice daily on Day 1, followed by 400 mg four (4) times daily from Day 2 to Day 7 PLUS Lopinavir/ritonavir (LPV/r) matched placebo at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7.
arm group label: Favipiravir placebo + Lopinavir/ritonavir (LPV/r)
arm group type: Experimental
description: Oral favipiravir matched placebo at 1800 mg twice daily on Day 1, by 400 mg four (4) times daily from Day 2 to Day 7 PLUS Lopinavir/ritonavir (LPV/r) at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7.
arm group label: Favipiravir placebo + Lopinavir/ritonavir (LPV/r) placebo
arm group type: Placebo Comparator
description: Oral favipiravir matched placebo at 1800 mg twice daily on Day 1, by 400 mg four (4) times daily from Day 2 to Day 7 PLUS Lopinavir/ritonavir (LPV/r) matched placebo at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7.
intervention type: Drug
intervention name: Favipiravir
description: Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.
arm group label: Favipiravir + Lopinavir/ritonavir (LPV/r)
arm group label: Favipiravir + Lopinavir/ritonavir (LPV/r) placebo
other name: Avigan
intervention type: Drug
intervention name: Lopinavir/ Ritonavir
description: Dosage and method of administration: Day 1: 400mg/100 mg twice daily; Day 2 to Day 7: 200mg/50mg four (4) times daily
arm group label: Favipiravir + Lopinavir/ritonavir (LPV/r)
arm group label: Favipiravir placebo + Lopinavir/ritonavir (LPV/r)
other name: Kaletra
intervention type: Other
intervention name: Favipiravir Placebo
description: Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.
arm group label: Favipiravir placebo + Lopinavir/ritonavir (LPV/r)
arm group label: Favipiravir placebo + Lopinavir/ritonavir (LPV/r) placebo
intervention type: Other
intervention name: Lopinavir/ Ritonavir Placebo
description: Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.
arm group label: Favipiravir + Lopinavir/ritonavir (LPV/r) placebo
arm group label: Favipiravir placebo + Lopinavir/ritonavir (LPV/r) placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: David Lowe
role: Principal Investigator
affiliation: Institute of Immunity and Transplantation, University College London
facility: 
facility: 
country: United Kingdom
url: https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004120
description: trial results
url: https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-021-05139-2
description: Initial trial Protocol
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Ritonavir
mesh term: Lopinavir
mesh term: Favipiravir
sharing ipd: No
ipd description: No plan to share IPD has been made at this time.