Favipiravir is a ribonucleic acid (RNA) dependent RNA polymerase (RdRp) anti-viral drug that is already used in Japan and China to treat patients with drug-resistant influenza. In vitro studies of favipiravir showed chain termination or accumulation of deleterious mutations in the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) genome, thus indicating that it might be a potent drug against SARS-CoV-2.
Although some early trials suggest that favipiravir can improve clinical or virologic outcomes in coronavirus disease 2019 (COVID-19) patients, data on this is limited and further research is needed on a large scale.
Study: Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial. Image Credit: visona29 / Shutterstock.com
About the study
In a recent preprint study published on the medRxiv* server, researchers conducted a Phase II randomized placebo-controlled, double-blinded trial between July 8, 2020, and March 23. 2021.
Patients who tested positive for SARS-CoV-2 infection by reverse-transcription polymerase chain reaction (RT-PCR) test and exhibited mild or no symptoms were enrolled in the study, as they were at an early stage of infection and were most likely to be benefited. The participants enrolled in the current study were randomized into either a control group with a placebo or were treated with favipiravir.
A total of 149 patients were enrolled and randomized in the intention-to-treat (ITT) cohort study. Of these, 116 patients whose RT-PCR test was positive within 72 hours of enrollment were included in the modified intention-to-treat (mITT) cohort, and 135 patients who reported at least one symptom other than a mild cough, mild fatigue, or reduced taste or smell during enrollment were included in the symptomatic modified intention-to-treat (smITT) cohorts. A total of 112 patients were included in all 3 analytic cohorts.
The participants were examined for 28 days and their clinical assessment included RT-PCR tests from oropharyngeal (OP) swabs and anti-SARS-CoV-2 serology tests from blood samples collected by study staff during each visit.
During primary analyses, a Cox proportional hazards model was used to compare the time to shedding cessation of SARS-CoV-2 between both arms. The results were in favor of the placebo group; however, no statistically significant difference was observed in shedding cessation between the placebo and treatment groups.
Secondary analyses were also carried out using a Cox proportional hazards model to compare symptom resolution in both groups. To this end, no statistically significant difference was observed between the two treatment groups.
However, the control group showed earlier symptom resolution by one day as compared to the treatment group. Fatigue, cough/dyspnea, myalgia, and headache were the most common symptoms observed and fewer and milder symptoms were reported over time.
Twelve participants (7 control and 5 treatment) from the ITT cohort reported at least one visit to the emergency room and four participants from the control group were hospitalized.
The pre-specified and post hoc analyses in gender, high-risk comorbid, age group, seropositivity, or duration of symptoms at enrollment subgroups showed no difference in time to shedding cessation. In the sensitivity analysis using the ITT cohort, the median time to shedding declined to nine days in both the control and treatment groups.
To determine the role of favipiravir in the mutagenesis of SARS-CoV-2, the researchers sequenced SARS-CoV-2 from nasal swab samples of participants on residual days 1, 5, and 10. No evidence of mutagenesis was observed in the treatment group after at least 5 days of favipiravir administration.
The findings were in contrast to in vitro studies that showed a three-fold increase in the total number of mutations and a 12-fold increase in C to T or G to A transitions in SARS-CoV-2-infected Vero cells treated with favipiravir compared to the controls.
Adverse events (AEs)
Participants in the treatment group reported more AEs as compared to the control group, although this difference was not statistically significant. The most common AE reported in the treatment group was dizziness. Furthermore, many participants receiving favipiravir developed hyperuricemia on day 10, while only three participants were symptomatic.
Limitations and conclusions
The current study has many limitations. Using the RT-PCR test to detect antiviral activity is not a fool-proof method, as individuals can have viral RNA for extended periods of time after illness and may therefore not reflect actively replicating virus.
The primary endpoint of the current study was based on the nasal swabs, which are less accurate as compared to nasopharyngeal swabs; however, similar results were obtained from oropharyngeal swabs collected by study staff. Additionally, this study was performed before the arrival of the now dominantDelta variant in the United States.
Overall, the findings of the current study do not favor the use of favipiravir at currently recommended doses in mild or asymptomatic COVID-19 patients. Further studies on dose optimization are required to determine the efficacy and safety of favipiravir at high doses or in combination with other therapeutic agents in COVID-19 patients.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.