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FLARE: Favipiravir +/- Lopinavir: A RCT of Early Antivirals (FLARE)

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ClinicalTrials.gov Identifier: NCT04499677
Recruitment Status : Recruiting
First Posted : August 5, 2020
Last Update Posted : April 30, 2021
Sponsor:
Collaborator:
LifeArc
Information provided by (Responsible Party):
University College, London

Tracking Information
First Submitted Date  ICMJE June 16, 2020
First Posted Date  ICMJE August 5, 2020
Last Update Posted Date April 30, 2021
Actual Study Start Date  ICMJE September 24, 2020
Estimated Primary Completion Date November 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 3, 2020)
Upper respiratory tract viral load at Day 5 [ Time Frame: Day 5 from randomisation ]
Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 27, 2021)
  • Percentage of participants with undetectable upper respiratory tract viral load after 5 days of therapy [ Time Frame: 5 days from randomisation ]
    Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy
  • Proportion of participants with undetectable stool viral load after 7 days of therapy. [ Time Frame: 7 days from randomisation ]
    Quantitative polymerase chain reaction (PCR) performed on stool samples at Day 7
  • Rate of decrease in upper respiratory tract viral load during 7 days of therapy [ Time Frame: 7 days ]
    PCR performed on daily saliva samples collected between Day 1 and Day 7 post-randomisation
  • Duration of fever following commencement of medication [ Time Frame: 7 days ]
    Daily body temperature records between Day 1 and Day 7 post-randomisation
  • Proportion of participants with hepatotoxicity after 7 days of therapy [ Time Frame: 7 days from randomisation ]
    Standard diagnostic laboratory assays for liver transaminases, alkaline phosphatase and bilirubin
  • 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 ]
    Determination of medication-related adverse events by investigators at Day 7 and Day 14 post-randomisation
  • Proportion of participants admitted to hospital with COVID-19 related illness [ Time Frame: 28 days ]
    Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation
  • Proportion of participants admitted to ICU with COVID-19 related illness [ Time Frame: 28 days ]
    Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation
  • Proportion of participants who have died with COVID-19 related illness [ Time Frame: 28 days ]
    Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation
  • Pharmacokinetics of favipiravir as measured by Clearance (CL) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Clearance (CL)
  • Pharmacokinetics of favipiravir as measured by Volume of distribution (V) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Volume of distribution (V)
  • Pharmacokinetics of favipiravir as measured by Absorption rate constant (Ka) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Absorption rate constant (Ka)
  • Pharmacokinetics of favipiravir as measured by Maximum concentration (Cmax) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Maximum concentration (Cmax)
  • Pharmacokinetics of favipiravir as measured by Time to maximum concentration (Tmax) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Time to maximum concentration (Tmax)
  • Pharmacokinetics of favipiravir as measured by Elimination rate constant (Ke) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Elimination rate constant (Ke)
  • Pharmacokinetics of favipiravir as measured by Area Under the Curve extrapolated to infinity (AUC (0-inf) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Area Under the Curve extrapolated to infinity (AUC (0-inf)
  • Pharmacodynamics of favipiravir as measured by Rate of viral load decline (delta) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacodynamics of favipiravir as measured by Rate of viral load decline (delta)
  • Pharmacodynamics of favipiravir as measured by Maximum increase in viral load under drug treatment (Emax) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacodynamics of favipiravir as measured by Maximum increase in viral load under drug treatment (Emax)
  • Pharmacodynamics of favipiravir as measured by Concentration to achieve half the maximum possible effect (EC50) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacodynamics of favipiravir as measured by Concentration to achieve half the maximum possible effect (EC50)
  • Proportion of participants with deleterious or resistance-conferring mutations in SARS-CoV-2 by Day 7 of treatment [ Time Frame: Day 7 from randomisation ]
    Deep sequencing of virus and bioinformatic analysis
Original Secondary Outcome Measures  ICMJE
 (submitted: August 3, 2020)
  • Percentage of participants with undetectable upper respiratory tract viral load after 5 days of therapy [ Time Frame: 5 days from randomisation ]
    Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy
  • Proportion of participants with undetectable stool viral load after 7 days of therapy and 14 days post-randomisation [ Time Frame: Day 7 and Day 14 from randomisation ]
    Quantitative polymerase chain reaction (PCR) performed on stool samples at Day 7 and Day 14 post-randomisation
  • Rate of decrease in upper respiratory tract viral load during 7 days of therapy [ Time Frame: 7 days ]
    PCR performed on daily saliva samples collected between Day 1 and Day 7 post-randomisation
  • Duration of fever following commencement of medication [ Time Frame: 7 days ]
    Daily body temperature records between Day 1 and Day 7 post-randomisation
  • Proportion of participants with hepatotoxicity after 7 days of therapy and 14 days post-randomisation [ Time Frame: Day 7 and Day 14 from randomisation ]
    Standard diagnostic laboratory assays for liver transaminases, alkaline phosphatase and bilirubin
  • 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 ]
    Determination of medication-related adverse events by investigators at Day 7 and Day 14 post-randomisation
  • Proportion of participants admitted to hospital with COVID-19 related illness [ Time Frame: 28 days ]
    Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation
  • Proportion of participants admitted to ICU with COVID-19 related illness [ Time Frame: 28 days ]
    Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation
  • Proportion of participants who have died with COVID-19 related illness [ Time Frame: 28 days ]
    Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation
  • Pharmacokinetics of favipiravir as measured by Clearance (CL) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Clearance (CL)
  • Pharmacokinetics of favipiravir as measured by Volume of distribution (V) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Volume of distribution (V)
  • Pharmacokinetics of favipiravir as measured by Absorption rate constant (Ka) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Absorption rate constant (Ka)
  • Pharmacokinetics of favipiravir as measured by Maximum concentration (Cmax) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Maximum concentration (Cmax)
  • Pharmacokinetics of favipiravir as measured by Time to maximum concentration (Tmax) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Time to maximum concentration (Tmax)
  • Pharmacokinetics of favipiravir as measured by Elimination rate constant (Ke) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Elimination rate constant (Ke)
  • Pharmacokinetics of favipiravir as measured by Area Under the Curve extrapolated to infinity (AUC (0-inf) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacokinetics of favipiravir as measured by Area Under the Curve extrapolated to infinity (AUC (0-inf)
  • Pharmacodynamics of favipiravir as measured by Rate of viral load decline (delta) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacodynamics of favipiravir as measured by Rate of viral load decline (delta)
  • Pharmacodynamics of favipiravir as measured by Maximum increase in viral load under drug treatment (Emax) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacodynamics of favipiravir as measured by Maximum increase in viral load under drug treatment (Emax)
  • Pharmacodynamics of favipiravir as measured by Concentration to achieve half the maximum possible effect (EC50) [ Time Frame: Day 7 from randomisation ]
    Assess pharmacodynamics of favipiravir as measured by Concentration to achieve half the maximum possible effect (EC50)
  • Proportion of participants with deleterious or resistance-conferring mutations in SARS-CoV-2 by Day 7 of treatment [ Time Frame: Day 7 from randomisation ]
    Deep sequencing of virus and bioinformatic analysis
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE FLARE: Favipiravir +/- Lopinavir: A RCT of Early Antivirals
Official Title  ICMJE Favipiravir, Lopinavir/Ritonavir or Combination Therapy: a Randomised, Double Blind, 2x2 Factorial Placebo-controlled Trial of Early Antiviral Therapy in COVID-19
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description:
Randomised, double-blind, 2x2 factorial placebo-controlled
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:
Double-blind
Primary Purpose: Treatment
Condition  ICMJE COVID-19
Intervention  ICMJE
  • Drug: Favipiravir
    Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.
    Other Name: Avigan
  • Drug: Lopinavir/ Ritonavir
    Dosage and method of administration: Day 1: 400mg/100 mg twice daily; Day 2 to Day 7: 200mg/50mg four (4) times daily
    Other Name: Kaletra
  • Other: Favipiravir Placebo
    Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.
  • Other: Lopinavir/ Ritonavir Placebo
    Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.
Study Arms  ICMJE
  • Experimental: Favipiravir + Lopinavir/ritonavir (LPV/r)
    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
    Interventions:
    • Drug: Favipiravir
    • Drug: Lopinavir/ Ritonavir
  • Experimental: Favipiravir + Lopinavir/ritonavir (LPV/r) placebo
    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.
    Interventions:
    • Drug: Favipiravir
    • Other: Lopinavir/ Ritonavir Placebo
  • Experimental: Favipiravir placebo + Lopinavir/ritonavir (LPV/r)
    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.
    Interventions:
    • Drug: Lopinavir/ Ritonavir
    • Other: Favipiravir Placebo
  • Placebo Comparator: Favipiravir placebo + Lopinavir/ritonavir (LPV/r) placebo
    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.
    Interventions:
    • Other: Favipiravir Placebo
    • Other: Lopinavir/ Ritonavir Placebo
Publications * Brown LK, Freemantle N, Breuer J, Dehbi HM, Chowdhury K, Jones G, Ikeji F, Ndoutoumou A, Santhirakumar K, Longley N, Checkley AM, Standing JF, Lowe DM. Early antiviral treatment in outpatients with COVID-19 (FLARE): a structured summary of a study protocol for a randomised controlled trial. Trials. 2021 Mar 8;22(1):193. doi: 10.1186/s13063-021-05139-2.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 3, 2020)
240
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date November 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Any adult with the following:

    • Symptoms compatible with COVID-19 disease (Fever >37.8oC on at least one occasion AND either cough and/ or anosmia) within the first 5 days of symptom onset
    • OR ANY symptoms compatible with COVID-19 disease (may include, but are not limited to fever, cough, shortness of breath, malaise, myalgia, headache, coryza) and tested positive for SARS-CoV-2 within the first 7 days of symptom onset
    • OR no symptoms but tested positive for SARS-CoV-2 within the last 48 hours (date/time of test must be within 48 hours of enrolment)
  2. Male or female aged 18 years to 70 years old inclusive at screening
  3. Willing and able to take daily saliva samples
  4. Able to provide full informed consent and willing to comply with trial-related procedures

Exclusion Criteria:

  1. Known hypersensitivity to any of the active ingredients or excipients in favipiravir and matched placebo, and in lopinavir/ritonavir and matched placebo
  2. Chronic liver disease at screening (known cirrhosis of any aetiology, chronic hepatitis (e.g. autoimmune, viral, steatohepatitis), cholangitis or any known elevation of liver aminotransferases with AST or ALT > 3 X ULN)*
  3. Chronic kidney disease (stage 3 or beyond) at screening: eGFR < 60 ml/min/1.73m2*
  4. HIV infection, if untreated, detectable viral load or on protease inhibitor therapy
  5. Any clinical condition which the investigator considers would make the participant unsuitable for the trial
  6. Concomitant medications known to interact with favipiravir and matched placebo, and with lopinavir/ritonavir and matched placebo, and carry risk of toxicity for the participant
  7. Current severe illness requiring hospitalisation
  8. Pregnancy and/ or breastfeeding
  9. Eligible female participants of childbearing potential and male participants with a partner of childbearing potential not willing to use highly effective contraceptive measures during the trial and within the time point specified following last trial treatment dose.
  10. Participants enrolled in any other interventional drug or vaccine trial (co-enrolment in observational studies is acceptable).
  11. Participants who have received the COVID-19 vaccine

    • Considering the importance of early treatment of COVID-19 to impact viral load, the absence of chronic liver/ kidney disease will be confirmed verbally by the participant during pre-screening and Screening/Baseline visit. Safety blood samples will be collected at Screening/Baseline visit (Day 1) and test results will be examined as soon as they become available within 24 hours.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: FLARE Trial Team UCL CCTU 020 3108 9840 cctu.flare@ucl.ac.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04499677
Other Study ID Numbers  ICMJE 132084
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Plan Description: No plan to share IPD has been made at this time.
Responsible Party University College, London
Study Sponsor  ICMJE University College, London
Collaborators  ICMJE LifeArc
Investigators  ICMJE
Principal Investigator: David Lowe Institute of Immunity and Transplantation, University College London
PRS Account University College, London
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP