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    Summary
    EudraCT Number:2020-002106-68
    Sponsor's Protocol Code Number:CTU/2020/354
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-07-07
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2020-002106-68
    A.3Full title of the trial
    Favipiravir, lopinavir/ritonavir or combination therapy: a randomised, double blind, 2x2 factorial placebo-controlled trial of early antiviral therapy in COVID-19
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    FLARE: Favipiravir +/- Lopinavir: A RCT of Early antivirals
    A.3.2Name or abbreviated title of the trial where available
    FLARE
    A.4.1Sponsor's protocol code numberCTU/2020/354
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity College London Comprehensive Clinical Trial Unit
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportLifeArc
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity College London Comprehensive Clinical Trial Unit
    B.5.2Functional name of contact pointFelicia Ikeji
    B.5.3 Address:
    B.5.3.1Street Address2nd Floor, 90 High Holborn
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeWC1V 6LJ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02076799506
    B.5.6E-mailcctu.flare@ucl.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameFavipiravir
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFavipiravir
    D.3.9.1CAS number 259793-96-9
    D.3.9.3Other descriptive nameAvigan
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200 to 200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Lopinavir/ritonavir
    D.2.1.1.2Name of the Marketing Authorisation holderAbbVie
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLopinavir/ritonavir
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLopinavir/ritonavir
    D.3.9.3Other descriptive nameKaletra
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200/50 to 200/50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    SARS-CoV-2 (Corona virus) infection
    E.1.1.1Medical condition in easily understood language
    COVID-19
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level LLT
    E.1.2Classification code 10053983
    E.1.2Term Corona virus infection
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The objective of this trial is to assess whether early antiviral therapy with either favipiravir + LPV/r, LPV/r or favipiravir is associated with a decrease in viral load in the upper respiratory tract after 5 days of therapy, compared with placebo.
    E.2.2Secondary objectives of the trial
    • Percentage of participants with undetectable upper respiratory tract viral load after 5 days of therapy
    • Proportion of participants with undetectable stool viral load after 7 days of therapy and 14 days post-randomisation
    • Rate of decrease in upper respiratory tract viral load during 7 days of therapy
    • Duration of fever following commencement of trial medications
    • Proportion of participants with hepatotoxicity after 7 days of therapy and 14 days post-randomisation
    • Proportion of participants with other medication-related toxicity after 7 days of therapy and 14 days post-randomisation
    • Proportion of participants admitted to hospital with COVID-19 related illness
    • Proportion of participants admitted to ICU with COVID-19 related illness
    • Proportion of participants who have died with COVID-19 related illness
    • Pharmacokinetic and pharmacodynamic analysis of favipiravir
    • Exploratory: Proportion of participants with deleterious or resistance-conferring mutations in SARS-CoV-2
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Key workers (see definition in Appendix 2) and their household members with the following:
    o 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 (date/time of enrolment must be within the first 5 days of symptom onset)
    o 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 (date/time of enrolment must be within the first 7 days of symptom onset)
    o 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
    E.4Principal 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 (See Appendix 3)
    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 (See Appendix 4)
    7. 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).

    * 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.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome is the upper respiratory tract viral load at Day 5.

    Method of measurement: Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy

    [Time Frame: Day 5 from randomisation]
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time Frame: Day 5 from randomisation
    E.5.2Secondary end point(s)
    1) Percentage of participants with undetectable upper respiratory tract viral load after 5 days of therapy
    Method of measurement: Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy [Time Frame: 5 days from randomisation]

    2) Proportion of participants with undetectable stool viral load after 7 days of therapy and 14 days post-randomisation
    Method of measurement: Quantitative polymerase chain reaction (PCR) performed on stool samples at Day 7 and Day 14 post-randomisation [Time Frame: Day 7 and Day 14 from randomisation]

    3) Rate of decrease in upper respiratory tract viral load during 7 days of therapy
    Method of measurement: PCR performed on daily saliva samples collected between Day 1 and Day 7 post-randomisation [Time Frame: 7 days]

    4) Duration of fever following commencement of medication
    Method of measurement: Daily body temperature records between Day 1 and Day 7 post-randomisation [Time Frame: 7 days]

    5) Proportion of participants with hepatotoxicity after 7 days of therapy and 14 days post-randomisation
    Method of measurement: Standard diagnostic laboratory assays for liver transaminases, alkaline phosphatase and bilirubin [Time Frame: Day 7 and Day 14 from randomisation]

    6) Proportion of participants with other medication-related toxicity after 7 days of therapy and 14 days post-randomisation
    Method of measurement: Determination of medication-related adverse events by investigators at Day 7 and Day 14 post-randomisation [Time Frame: Day 7 and Day 14 from randomisation]

    7) Proportion of participants admitted to hospital with COVID-19 related illness
    Method of measurement: Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation [Time Frame: 28 days]

    8) Proportion of participants admitted to ICU with COVID-19 related illness
    Method of measurement: Participant self-report, review of hospital records and discharge summaries within 28 days of randomisation [Time Frame: 28 days]

    9) Proportion of participants who have died with COVID-19 related illness
    Method of measurement: Next of kin report, review of hospital records and discharge summaries within 28 days of randomisation [Time Frame: 28 days]

    10) Pharmacokinetic and pharmacodynamic analysis of favipiravir
    Method of measurement: assay of favipiravir levels in plasma at Day 7 of therapy. All participants from each arm will provide a pre-dose trough sample and a post-dose (30 to 60 min) sample on Day 7 of therapy. A nonlinear mixed effects model will be fitted jointly to favipiravir pharmacokinetic and viral load (pharmacodynamic) data. The model will estimate the following primary PK parameters:
    PK: Clearance (CL), Volume of distribution (V), Absorption rate constant (Ka)
    From which the following secondary parameters will be derived:
    Maximum concentration (Cmax), Time to maximum concentration (Tmax), Elimination rate constant (Ke), Area Under the Curve extrapolated to infinity (AUC (0-inf)).
    The model will also estimate the following pharmacodynamic parameters:
    Rate of viral load decline (delta), Maximum increase in viral load under drug treatment (Emax), Concentration to achieve half the maximum possible effect (EC50)

    11) Exploratory: proportion of participants with deleterious or resistance-conferring mutations in SARS-CoV-2
    Method of measurement: deep sequencing of virus and bioinformatic analysis [Time Frame: 28 days]
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Time Frame: 5 days from randomisation

    2) Time Frame: Day 7 and Day 14 from randomisation

    3) Time Frame: 7 days

    4) Time Frame: 7 days

    5) Time Frame: Day 7 and Day 14 from randomisation

    6) Time Frame: Day 7 and Day 14 from randomisation

    7) Time Frame: 28 days

    8) Time Frame: 28 days

    9) Time Frame: 28 days

    10) Time Frame: 7 days

    11) Time Frame: 28 days
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Randomised, double-blind, 2x2 factorial placebo-controlled
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    When the whole target sample is recruited, the last participant has completed the last follow-up and the database is locked for analysis.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 240
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 240
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state240
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 240
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Trial treatment will not be available to any participants in this trial after its completion. A decision to stop taking part at any time will not affect the standard of care they may receive for COVID-19.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-07-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-16
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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