- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04499677
FLARE: Favipiravir +/- Lopinavir: A RCT of Early Antivirals (FLARE)
Favipiravir, Lopinavir/Ritonavir or Combination Therapy: a Randomised, Double Blind, 2x2 Factorial Placebo-controlled Trial of Early Antiviral Therapy in COVID-19
Study Overview
Status
Conditions
Intervention / Treatment
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
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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London, United Kingdom, NW3 2QG
- Royal Free Hospital
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London, United Kingdom
- University College London Hospital (UCLH)
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
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)
- Male or female aged 18 years to 70 years old inclusive at screening
- Willing and able to take daily saliva samples
- Able to provide full informed consent and willing to comply with trial-related procedures
Exclusion Criteria:
- Known hypersensitivity to any of the active ingredients or excipients in favipiravir and matched placebo, and in lopinavir/ritonavir and matched placebo
- 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)*
- Chronic kidney disease (stage 3 or beyond) at screening: eGFR < 60 ml/min/1.73m2*
- HIV infection, if untreated, detectable viral load or on protease inhibitor therapy
- Any clinical condition which the investigator considers would make the participant unsuitable for the trial
- 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
- Current severe illness requiring hospitalisation
- Pregnancy and/ or breastfeeding
- 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.
Participants enrolled in any other interventional drug or vaccine trial (co-enrolment in observational studies is acceptable).
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Factorial Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
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
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Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.
Other Names:
Dosage and method of administration: Day 1: 400mg/100 mg twice daily; Day 2 to Day 7: 200mg/50mg four (4) times daily
Other Names:
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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.
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Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.
Other Names:
Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.
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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.
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Dosage and method of administration: Day 1: 400mg/100 mg twice daily; Day 2 to Day 7: 200mg/50mg four (4) times daily
Other Names:
Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.
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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.
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Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.
Dosage and method of administration: Day 1: 1800 mg twice daily; Day 2 to Day 7: 400 mg four (4) times daily.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Upper respiratory tract viral load at Day 5
Time Frame: Day 5 from randomisation
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Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy
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Day 5 from randomisation
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percentage of participants with undetectable upper respiratory tract viral load after 5 days of therapy
Time Frame: 5 days from randomisation
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Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy
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5 days from randomisation
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Proportion of participants with undetectable stool viral load after 7 days of therapy.
Time Frame: 7 days from randomisation
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Quantitative polymerase chain reaction (PCR) performed on stool samples at Day 7
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7 days from randomisation
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Rate of decrease in upper respiratory tract viral load during 7 days of therapy
Time Frame: 7 days
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PCR performed on daily saliva samples collected between Day 1 and Day 7 post-randomisation
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7 days
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Duration of fever following commencement of medication
Time Frame: 7 days
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Daily body temperature records between Day 1 and Day 7 post-randomisation
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7 days
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Proportion of participants with hepatotoxicity after 7 days of therapy
Time Frame: 7 days from randomisation
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Standard diagnostic laboratory assays for liver transaminases, alkaline phosphatase and bilirubin
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7 days from randomisation
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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
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Determination of medication-related adverse events by investigators at Day 7 and Day 14 post-randomisation
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Day 7 and Day 14 from randomisation
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Proportion of participants admitted to hospital with COVID-19 related illness
Time Frame: 28 days
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Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation
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28 days
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Proportion of participants admitted to ICU with COVID-19 related illness
Time Frame: 28 days
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Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation
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28 days
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Proportion of participants who have died with COVID-19 related illness
Time Frame: 28 days
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Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation
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28 days
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Pharmacokinetics of favipiravir as measured by Clearance (CL)
Time Frame: Day 7 from randomisation
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Assess pharmacokinetics of favipiravir as measured by Clearance (CL)
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Day 7 from randomisation
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Pharmacokinetics of favipiravir as measured by Volume of distribution (V)
Time Frame: Day 7 from randomisation
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Assess pharmacokinetics of favipiravir as measured by Volume of distribution (V)
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Day 7 from randomisation
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Pharmacokinetics of favipiravir as measured by Absorption rate constant (Ka)
Time Frame: Day 7 from randomisation
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Assess pharmacokinetics of favipiravir as measured by Absorption rate constant (Ka)
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Day 7 from randomisation
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Pharmacokinetics of favipiravir as measured by Maximum concentration (Cmax)
Time Frame: Day 7 from randomisation
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Assess pharmacokinetics of favipiravir as measured by Maximum concentration (Cmax)
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Day 7 from randomisation
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Pharmacokinetics of favipiravir as measured by Time to maximum concentration (Tmax)
Time Frame: Day 7 from randomisation
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Assess pharmacokinetics of favipiravir as measured by Time to maximum concentration (Tmax)
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Day 7 from randomisation
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Pharmacokinetics of favipiravir as measured by Elimination rate constant (Ke)
Time Frame: Day 7 from randomisation
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Assess pharmacokinetics of favipiravir as measured by Elimination rate constant (Ke)
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Day 7 from randomisation
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Pharmacokinetics of favipiravir as measured by Area Under the Curve extrapolated to infinity (AUC (0-inf)
Time Frame: Day 7 from randomisation
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Assess pharmacokinetics of favipiravir as measured by Area Under the Curve extrapolated to infinity (AUC (0-inf)
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Day 7 from randomisation
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Pharmacodynamics of favipiravir as measured by Rate of viral load decline (delta)
Time Frame: Day 7 from randomisation
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Assess pharmacodynamics of favipiravir as measured by Rate of viral load decline (delta)
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Day 7 from randomisation
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Pharmacodynamics of favipiravir as measured by Maximum increase in viral load under drug treatment (Emax)
Time Frame: Day 7 from randomisation
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Assess pharmacodynamics of favipiravir as measured by Maximum increase in viral load under drug treatment (Emax)
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Day 7 from randomisation
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Pharmacodynamics of favipiravir as measured by Concentration to achieve half the maximum possible effect (EC50)
Time Frame: Day 7 from randomisation
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Assess pharmacodynamics of favipiravir as measured by Concentration to achieve half the maximum possible effect (EC50)
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Day 7 from randomisation
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Proportion of participants with deleterious or resistance-conferring mutations in SARS-CoV-2 by Day 7 of treatment
Time Frame: Day 7 from randomisation
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Deep sequencing of virus and bioinformatic analysis
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Day 7 from randomisation
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: David Lowe, Institute of Immunity and Transplantation, University College London
Publications and helpful links
General Publications
- Lowe DM, Brown LK, Chowdhury K, Davey S, Yee P, Ikeji F, Ndoutoumou A, Shah D, Lennon A, Rai A, Agyeman AA, Checkley A, Longley N, Dehbi HM, Freemantle N, Breuer J, Standing JF; FLARE Investigators. Favipiravir, lopinavir-ritonavir, or combination therapy (FLARE): A randomised, double-blind, 2 x 2 factorial placebo-controlled trial of early antiviral therapy in COVID-19. PLoS Med. 2022 Oct 19;19(10):e1004120. doi: 10.1371/journal.pmed.1004120. eCollection 2022 Oct.
- 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.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Coronavirus Infections
- Coronaviridae Infections
- Nidovirales Infections
- RNA Virus Infections
- Virus Diseases
- Infections
- Respiratory Tract Infections
- Respiratory Tract Diseases
- Pneumonia, Viral
- Pneumonia
- Lung Diseases
- COVID-19
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Enzyme Inhibitors
- Anti-HIV Agents
- Anti-Retroviral Agents
- Protease Inhibitors
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 Enzyme Inhibitors
- HIV Protease Inhibitors
- Viral Protease Inhibitors
- Favipiravir
- Ritonavir
- Lopinavir
Other Study ID Numbers
- 132084
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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