Favipiravir +/- Lopinavir: A RCT of Early antivirals
1 February 2021
Recruitment for this trial has now ended, thank you for support!
Favipiravir, lopinavir/ritonavir or combination therapy: A Randomised, Double Blind, 2x2 Factorial Placebo-controlled Trial of Early Antiviral Therapy in COVID-19
RECRUITMENT TARGET = 240 participants
Recruitment has now ended
Study protocol: click here
- Trial Information
Background and Design
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 a stool sample.
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.
Who is organising and funding the research?
This research is being funded by LifeArc (grant reference COVID0005).
The trial is being co-ordinated by University College London Comprehensive Clinical Trials Unit.
- Eligibility criteria
Please find the eligibility criteria for FLARE below:
Participant Inclusion Criteria
- Any adult with the following:
- Symptoms compatible with COVID-19 disease (Fever >37.8°C 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
Participant 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.
**Hospitalisation for isolation or infection control reasons will not be considered an exclusion for this trial for international sites.
***Participants that have received the COVID-19 vaccine can be included in this trial.
- Upper respiratory tract viral load at Day 5
- 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
- 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
- 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
- Participating Sites / Research contacts
Please contact the local trial teams for more information.
- Royal Free Hospital London
Principal Investigator: Dr David Lowe
Email: email@example.com; firstname.lastname@example.org
- University College London Hospital (UCLH)
Tel: 07341 776 401
Principal Investigator: Dr Nicky Longley
Stravoula Maria Paraskevapoulou
Trial coordinator: Michelle Berkeley
- Royal Free Hospital London
- Meet the Team
Dr David Lowe
FLARE Chief Investigator
Prof Joe Standing
Prof Judy Breuer
Dr Li-An Brown
FLARE Clinical Project Manager
FLARE Trial Manager
FLARE Data Manager
- Trial Additional Information
Additional information about our trial on clinicaltrials.gov/ct2/show/NCT0449967 - a service of the U.S. National Institutes of Health
- UCL CCTU
The Comprehensive Clinical Trials Unit (CCTU) at UCL will design, conduct, analyse and report high quality clinical trials and other well designed studies that fit with the research strategies of UCL and UCL Partners.
In pursuit of this Mission, the UCL Comprehensive Clinical Trials Unit will:
- Develop partnerships with clinical investigators at all relevant institutions
- Promote a trial governance structure that supports a compliant, risk-based, proportional approach to the application of regulations
- Provide clinical trials leadership and expertise across the whole range of activities required to deliver trials from concept to dissemination and implementation of research findings
- Employ highly experienced staff with diverse research interests and expertise in clinical trial methodology to enhance the effectiveness of the research pathway
The UCL CCTU will accomplish its mission through CCTU staff and collaborators supporting adoption of its policies and procedures.
You can find more information about the CCTU in our website.