Favipiravir for COVID-19: real-time analysis of all 58 studies

Favipiravir for COVID-19: real-time meta analysis of 45 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for progression, recovery, and viral clearance. 24 studies from 24 independent teams in 16 different countries show statistically significant improvements in isolation (14 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 29% [17‑39%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Early treatment is more effective than late treatment.

• Results are robust — in exclusion sensitivity analysis 14 of 45 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.

• Studies to date do not show a significant benefit for mortality. Potential risks of the mechanism of action include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity [Hadj Hassine, Waters, Zhirnov].

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 7% of favipiravir studies show zero events in the treatment arm. Multiple treatments are typically used in combination, and other treatments are more effective.

• No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.

• All data to reproduce this paper and sources are in the appendix. Other meta analyses for favipiravir can be found in [Hung, Lan], showing significant improvements for viral clearance, improvement, and hospital discharge.

Covid Analysis et al., 8/18/2022, preprint, 1 author.

Effectiveness of Early Favipiravir Therapy in Hospitalised COVID-19 Patients

Tawfik et al., Advances in Virology, doi:10.1155/2022/9240941

Retrospective 103 hospitalized patients in Saudi Arabia, showing lower mortality with favipiravir in unadjusted results, and greater efficacy for treatment within 3 days of admission.

risk of death, 96.5% lower, RR 0.04, p < 0.001, treatment 1 of 103 (1.0%), control 17 of 62 (27.4%), NNT 3.8.

risk of ICU admission, 21.0% lower, RR 0.79, p = 0.45, treatment 21 of 103 (20.4%), control 16 of 62 (25.8%), NNT 18.

hospitalization time, 15.8% lower, relative time 0.84, p < 0.001, treatment mean 9.6 (±1.2) n=102, control mean 11.4 (±1.7) n=58.

Excluded in after exclusion results of meta analysis: unadjusted results with minimal group details.

Tawfik et al., 6/29/2022, retrospective, Saudi Arabia, peer-reviewed, mean age 60.1, 8 authors, study period 3 June, 2020 - 3 November, 2020.

Favipiravir in Early Symptomatic COVID-19, A Randomised Placebo-Controlled Trial

McMahon et al., SSRN Electronic Journal, doi:10.2139/ssrn.4135325

RCT with 99 favipiravir and 100 placebo patients in Australia, all except one being outpatients, showing no significant differences with treatment.

risk of oxygen therapy, 1.0% higher, RR 1.01, p = 1.00, treatment 6 of 99 (6.1%), control 6 of 100 (6.0%).

risk of hospitalization, 55.6% higher, RR 1.56, p = 0.38, treatment 14 of 99 (14.1%), control 9 of 99 (9.1%).

McMahon et al., 6/14/2022, Randomized Controlled Trial, placebo-controlled, Australia, peer-reviewed, median age 36.0, 33 authors, study period 31 July, 2020 - 19 September, 2021, trial NCT04445467 (history).

Early Treatment of Favipiravir in COVID-19 Patients Without Pneumonia: A Multicentre, Open-Labelled, Randomized Control Study

Sirijatuphat et al., medRxiv, doi:10.1101/2022.06.06.22275902

RCT 93 patients in Thailand showing significantly faster clinical improvement with favipiravir treatment. 1800mg favipiravir bid day 1, 800mg bid 5-14 days until PCR-.

time to clinical improvement, 63.9% lower, HR 0.36, p < 0.001, treatment 62, control 31, inverted to make RR<1 favor treatment, primary outcome.

clinical improvement, 89.9% lower, OR 0.10, p < 0.001, treatment 62, control 31, inverted to make RR<1 favor treatment, logistic regression, day 14, RR approximated with OR.

risk of mild pneumonia, 42.9% lower, RR 0.57, p = 0.25, treatment 8 of 62 (12.9%), control 7 of 31 (22.6%), NNT 10.

risk of no viral clearance, 4.2% higher, HR 1.04, p = 0.87, treatment 62, control 31, adjusted, inverted to make RR<1 favor treatment.

Sirijatuphat et al., 6/8/2022, Randomized Controlled Trial, Thailand, peer-reviewed, 9 authors, trial TCTR20200514001.

The factors affecting the prolonged PCR positivity in COVID-19 patients

Usanma Koban et al., Bratislava Medical Journal, doi:10.4149/BLL_2022_082

Retrospective 126 patients in Turkey, showing lower risk of PCR+ at day 14 with favipiravir treatment.

risk of no viral clearance, 86.0% lower, OR 0.14, p = 0.03, treatment 47, control 79, adjusted, multivariable, day 14, RR approximated with OR.

Usanma Koban et al., 6/7/2022, retrospective, Turkey, peer-reviewed, 3 authors, study period 1 March, 2020 - 30 September, 2020.

Efficacy of Favipiravir in the Treatment of Mild to Moderate COVID-19 Patients in Erbil: A Controlled Clinical Trial

Qadir et al., International Journal of Applied Sciences: Current and Future Research Trends, 13:1

Prospective study with 125 favipiravir patients and 125 patients declining favipiravir treatment, showing lower mortality and improved recovery with treatment. All patients received vitamin C, D, and zinc. Favipiravir 3200mg day 1, followed by 600mg bid days 2-10.

risk of death, 97.1% lower, RR 0.03, p < 0.001, treatment 0 of 125 (0.0%), control 17 of 125 (13.6%), NNT 7.4, relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization, 60.0% lower, RR 0.40, p = 0.001, treatment 14 of 125 (11.2%), control 35 of 125 (28.0%), NNT 6.0.

risk of no recovery, 97.1% lower, RR 0.03, p < 0.001, treatment 0 of 125 (0.0%), control 17 of 125 (13.6%), NNT 7.4, relative risk is not 0 because of continuity correction due to zero events, day 30, primary outcome.

risk of no recovery, 70.8% lower, RR 0.29, p < 0.001, treatment 14 of 125 (11.2%), control 48 of 125 (38.4%), NNT 3.7, day 15.

risk of no recovery, 78.8% lower, RR 0.21, p < 0.001, treatment 14 of 125 (11.2%), control 66 of 125 (52.8%), NNT 2.4, day 10.

risk of no recovery, 70.6% lower, RR 0.29, p < 0.001, treatment 32 of 125 (25.6%), control 109 of 125 (87.2%), NNT 1.6, day 5.

recovery time, 58.1% lower, relative time 0.42, p < 0.001, treatment 125, control 125.

Qadir et al., 5/23/2022, prospective, Iraq, peer-reviewed, 3 authors, study period 22 June, 2020 - 25 October, 2021.

Favipiravir-based treatment for outcomes of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials

Lan et al., Expert Review of Clinical Pharmacology, doi:10.1080/17512433.2022.2078701 (meta analysis)

Systematic review and meta analysis of favipiravir RCTs, showing improved viral clearance and recovery, but no significant difference for mortality, ICU admission, or ventilation.

Lan et al., 5/17/2022, peer-reviewed, 6 authors.

Safety and Efficacy of Favipiravir for the management of COVID-19 Patients: A Randomized Control Trial

Rahman et al., Clinical Infection in Practice, doi:10.1016/j.clinpr.2022.100145

RCT hospitalized patients in Bangladesh, showing faster recovery and viral clearance with favipiravir treatment.

risk of no chest x-ray improvement, 89.5% lower, RR 0.11, p = 0.005, treatment 1 of 19 (5.3%), control 8 of 16 (50.0%), NNT 2.2, day 10.

risk of no chest x-ray improvement, 64.9% lower, RR 0.35, p = 0.007, treatment 5 of 19 (26.3%), control 12 of 16 (75.0%), NNT 2.1, day 7.

risk of no chest x-ray improvement, 47.4% lower, RR 0.53, p = 0.001, treatment 10 of 19 (52.6%), control 16 of 16 (100.0%), NNT 2.1, day 4.

risk of no viral clearance, 91.7% lower, RR 0.08, p < 0.001, treatment 1 of 25 (4.0%), control 12 of 25 (48.0%), NNT 2.3, day 10.

risk of no viral clearance, 62.5% lower, RR 0.38, p = 0.010, treatment 6 of 25 (24.0%), control 16 of 25 (64.0%), NNT 2.5, day 7.

risk of no viral clearance, 48.0% lower, RR 0.52, p < 0.001, treatment 13 of 25 (52.0%), control 25 of 25 (100.0%), NNT 2.1, day 4.

Rahman et al., 5/13/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Bangladesh, peer-reviewed, mean age 37.8, 10 authors, study period May 2020 - July 2020, trial NCT04402203 (history).

Evaluation of the Safety and Efficacy of Favipiravir in Adult Indian Patients with Mild-to-Moderate COVID-19 in a Real-World Setting

Reddy et al., International Journal of General Medicine, doi:10.2147/IJGM.S349241

Prospective single-arm study of 1,083 patients receiving favipiravir in India, showing one death and no new safety issues.

Reddy et al., 5/3/2022, prospective, India, peer-reviewed, 19 authors, study period December 2020 - June 2021, trial CTRI/2020/11/029263.

The efficacy and adverse effects of favipiravir on COVID-19 patients: a systematic review and meta-analysis of published clinical trials and observational studies

Hung et al., SSRN, doi:10.2139/ssrn.3889346 (meta analysis)

Systematic review and meta analysis of 17 favipiravir trials, showing improved viral clearance and recovery.

Hung et al., 4/22/2022, peer-reviewed, 23 authors.

Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity

Hadj Hassine et al., Viruses, doi:10.3390/v14040841 (Review)

Review of lethal mutagenesis for RNA viruses, as used by molnupiravir, favipiravir, and ribavirin. Authors note the potential for permanently modifying the genomes of patients while causing teratogenicity or embryotoxicity, and the potential of creating novel virus variants with increased pathogenicity and transmissibility.

Authors recommend a registry of patients for long-term monitoring of potential adverse effects, including genetic, carcinogenic, teratogenic, and embryotoxic damage.

Hadj Hassine et al., 4/18/2022, peer-reviewed, 3 authors.

Antiviral Used among Non-Severe COVID-19 Cases in Relation to Time till Viral Clearance: A Retrospective Cohort Study

Hafez et al., Antibiotics, doi:10.3390/antibiotics11040498

Retrospective hospitalized patients in the United Arab Emirates, showing no significant difference in viral clearance with different combinations of HCQ, AZ, favipiravir, and lopinavir/ritonavir.

viral clearance time, 3.1% higher, HR 1.03, p = 0.09, treatment 59, control 1,446, inverted to make RR<1 favor treatment, HCQ + favipiravir, Cox proportional hazards.

viral clearance time, 58.7% lower, HR 0.41, p = 0.09, treatment 4, control 1,446, inverted to make RR<1 favor treatment, HCQ + favipiravir + lopinavir/ritonavir, Cox proportional hazards.

Hafez et al., 4/8/2022, retrospective, United Arab Emirates, peer-reviewed, 6 authors, this trial uses multiple treatments in the treatment arm (combined with HCQ) - results of individual treatments may vary.

Longitudinal Analysis of Neutralizing Potency against SARS-CoV-2 in the Recovered Patients after Treatment with or without Favipiravir

Shinada et al., Viruses, doi:10.3390/v14040670

Retrospective 17 COVID+ patients treated with favipiravir and 17 matched controls in Japan, showing faster viral clearance with treatment. Favipiravir 3600mg day one, 1600mg per day for up to 14 days.

hospitalization time, 7.5% lower, HR 0.93, p = 0.84, treatment 17, control 17.

viral clearance time, 55.2% lower, HR 0.45, p = 0.04, treatment 17, control 17.

Shinada et al., 3/24/2022, retrospective, Japan, peer-reviewed, 11 authors, study period 28 May, 2020 - 26 September, 2020, average treatment delay 8.9 days.

Randomized controlled trial of favipiravir, hydroxychloroquine, and standard care in patients with mild/moderate COVID-19 disease

AlQahtani et al., Scientific Reports, doi:10.1038/s41598-022-08794-w

RCT with 54 favipiravir, 51 HCQ, and 52 SOC hospitalized patients in Bahrain, showing no significant differences. Viral clearance improved with both treatments, but did not reach statistical significance with the small sample size.

risk of death, 196.3% higher, RR 2.96, p = 1.00, treatment 1 of 54 (1.9%), control 0 of 52 (0.0%), continuity correction due to zero event.

risk of ICU admission, 75.9% lower, RR 0.24, p = 0.20, treatment 1 of 54 (1.9%), control 4 of 52 (7.7%), NNT 17.

risk of no recovery, 41.9% higher, RR 1.42, p = 0.51, treatment 8 of 53 (15.1%), control 5 of 47 (10.6%).

risk of no viral clearance, 42.9% lower, RR 0.57, p = 0.21, treatment 8 of 40 (20.0%), control 14 of 40 (35.0%), NNT 6.7.

AlQahtani et al., 3/23/2022, Randomized Controlled Trial, Bahrain, peer-reviewed, 13 authors, study period August 2020 - March 2021, trial NCT04387760 (history).

Effectiveness of Favipiravir on Nonsevere, Early-Stage COVID-19 in Japan: A Large Observational Study Using the COVID-19 Registry Japan

Tsuzuki et al., Infectious Diseases and Therapy, doi:10.1007/s40121-022-00617-9

Retrospective database analysis of 7,654 hospitalized patients in Japan, showing no significant differences with favipiravir treatment. NCGM-G-003494-0.

risk of death, 13.1% lower, HR 0.87, p = 0.59, treatment 2,532, control 5,122, adjusted, day 30.

risk of mechanical ventilation, 2.0% higher, HR 1.02, p = 0.93, treatment 2,532, control 5,122, adjusted, IMV/ECMO.

risk of progression, 17.5% lower, HR 0.82, p = 0.10, treatment 2,532, control 5,122, adjusted, oxygen requirement.

Tsuzuki et al., 3/21/2022, retrospective, Japan, peer-reviewed, 21 authors, average treatment delay 4.0 days.

Comparison of Favipiravir to Hydroxychloroquine Plus Azithromycin in the Treatment of Patients with Non-critical COVID-19: A Single-center, Retrospective, Propensity Score-matched Study

Uyaroğlu et al., Acta Medica, doi:10.32552/2022.ActaMedica.719

PSM retrospective 260 late stage hospitalized COVID-19 pneumonia patients in Turkey, showing no significant difference between favipiravir and HCQ.

risk of death, 66.7% lower, RR 0.33, p = 1.00, treatment 0 of 42 (0.0%), control 1 of 42 (2.4%), NNT 42, relative risk is not 0 because of continuity correction due to zero events.

risk of ICU admission, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 42 (2.4%), control 0 of 42 (0.0%), continuity correction due to zero event.

hospitalization time, 10.8% higher, relative time 1.11, p = 0.90, treatment 42, control 42.

Uyaroğlu et al., 3/17/2022, retrospective, propensity score matching, Turkey, peer-reviewed, 6 authors, study period 20 March, 2020 - 30 September, 2020, this trial compares with another treatment - results may be better when compared to placebo.

Efficacy and safety of favipiravir plus interferon-beta versus lopinavir/ritonavir plus interferon-beta in moderately ill patients with COVID-19: A randomized clinical trial

Hassaniazad et al., Journal of Medical Virology, doi:10.1002/jmv.27724

RCT comparing favipiravir and lopinavir/ritonavir, showing no significant differences. All patients received interferon-beta. Favipiravir 1600mg bid for the first day and 600mg bid for the following 4 days.

risk of death, 67.7% lower, RR 0.32, p = 0.15, treatment 2 of 32 (6.2%), control 6 of 31 (19.4%), NNT 7.6, day 14.

risk of ICU admission, 35.4% lower, RR 0.65, p = 0.51, treatment 4 of 32 (12.5%), control 6 of 31 (19.4%), NNT 15, day 14.

hospitalization time, 25.0% lower, relative time 0.75, p = 0.14, treatment 32, control 31.

risk of no viral clearance, 18.0% lower, RR 0.82, p = 0.24, treatment 22 of 32 (68.8%), control 26 of 31 (83.9%), NNT 6.6, day 7.

Hassaniazad et al., 3/24/2022, Randomized Controlled Trial, Iran, peer-reviewed, mean age 53.8, 7 authors, this trial compares with another treatment - results may be better when compared to placebo, trial IRCT20200506047323N3.

Evaluation of Antibacterial and Antiviral Drug Effectiveness in COVID-19 Therapy: A Data-Driven Retrospective Approach

Yulia et al., Pathophysiology, doi:10.3390/pathophysiology29010009

Retrospective hospitalized patients in Indonesia, showing lower mortality and shorter hospitalization with favipiravir.

risk of death, 85.3% lower, OR 0.15, p = 0.05, inverted to make RR<1 favor treatment, RR approximated with OR.

Yulia et al., 3/7/2022, retrospective, Indonesia, peer-reviewed, median age 46.0, 10 authors, study period July 2020 - December 2020.

Characteristics and outcomes of COVID-19 patients with IPF: A multi-center retrospective study

Cilli et al., Respiratory Medicine and Research, doi:10.1016/j.resmer.2022.100900

Retrospective 46 idiopathic pulmonary fibrosis patients with COVID-19 in Turkey, showing lower mortality with favipiravir in unadjusted results, without statistical significance.

risk of death, 37.5% lower, RR 0.62, p = 0.51, treatment 5 of 23 (21.7%), control 8 of 23 (34.8%), NNT 7.7.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Cilli et al., 3/3/2022, retrospective, Turkey, peer-reviewed, 10 authors.

Efficacy of Favipiravir in treatment of mild & moderate COVID-19 infection in Nepal: a multi-center, randomized, open-labelled, phase III clinical trial

Adhikari et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.12.109

Preliminary report for an RCT in Nepal with 38 favipiravir patients and 32 control patients, showing no significant differences. There were no serious side effects.

risk of no improvement, 40.4% higher, RR 1.40, p = 0.57, treatment 10 of 38 (26.3%), control 6 of 32 (18.8%), all.

risk of no improvement, 36.3% higher, RR 1.36, p = 0.75, treatment 8 of 27 (29.6%), control 5 of 23 (21.7%), mild cases.

risk of no improvement, 63.6% higher, RR 1.64, p = 1.00, treatment 2 of 11 (18.2%), control 1 of 9 (11.1%), moderate cases.

Adhikari et al., 3/1/2022, Randomized Controlled Trial, Nepal, peer-reviewed, 12 authors.

Factors Associated with Death and ICU Referral among COVID-19 Patients Hospitalized in the Secondary Referral Academic Hospital in East Jakarta, Indonesia

Kurniyanto et al., Journal of Clinical Virology Plus, doi:10.1016/j.jcvp.2022.100068

Retrospective 477 hospitalized patients in Indonesia, showing lower mortality with favipiravir in unadjusted results, not reaching statistical significance.

risk of death, 48.0% lower, RR 0.52, p = 0.21, treatment 10 of 325 (3.1%), control 9 of 152 (5.9%), NNT 35.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Kurniyanto et al., 2/28/2022, retrospective, Indonesia, peer-reviewed, 11 authors.

Overview of Clinical Outcome and Therapeutic Effectiveness of Favipiravir in Patients with COVID-19 Admitted to Intensive Care Unit, Riyadh, Saudi Arabia

Al Mutair et al., Journal of Infection and Public Health, doi:10.1016/j.jiph.2022.01.013

Retrospective 269 favipiravir ICU patients in Saudi Arabia and 269 matched controls receiving different treatments, showing no significant difference.

risk of death, 7.0% lower, RR 0.93, p = 0.49, treatment 119 of 269 (44.2%), control 128 of 269 (47.6%), NNT 30.

risk of ARDS, 8.6% higher, RR 1.09, p = 0.63, treatment 76 of 269 (28.3%), control 70 of 269 (26.0%), severe ARDS.

ICU time, 33.7% higher, relative time 1.34, p = 0.001, treatment 269, control 269.

hospitalization time, 36.6% higher, relative time 1.37, p = 0.001, treatment 269, control 269.

Al Mutair et al., 2/15/2022, retrospective, Saudi Arabia, peer-reviewed, 14 authors, study period April 2020 - March 2021, this trial compares with another treatment - results may be better when compared to placebo.

Favipiravir, lopinavir-ritonavir or combination therapy (FLARE): a randomised, double blind, 2x2 factorial placebo-controlled trial of early antiviral therapy in COVID-19

Lowe et al., medRxiv, doi:10.1101/2022.02.11.22270775 (Preprint)

240 patient RCT comparing favipiravir, favipiravir + LPV/r, LPV/r, and placebo, showing improved viral clearance with favipiravir. Efficacy was lower in the combined favipiravir + LPV/r arm, where plasma levels of favipiravir were lower.

Favipiravir 1800mg twice daily on day 1 followed by 400mg four times daily on days 2-7.

risk of ICU admission, 196.3% higher, RR 2.96, p = 1.00, treatment 1 of 54 (1.9%), control 0 of 52 (0.0%), continuity correction due to zero event.

risk of hospitalization, 196.3% higher, RR 2.96, p = 1.00, treatment 1 of 54 (1.9%), control 0 of 52 (0.0%), continuity correction due to zero event.

risk of no viral clearance, 28.4% lower, RR 0.72, p = 0.03, treatment 29 of 54 (53.7%), control 38 of 52 (73.1%), NNT 5.2, inverted to make RR<1 favor treatment, OR converted to RR, day 5, primary outcome.

Lowe et al., 2/15/2022, Double Blind Randomized Controlled Trial, placebo-controlled, United Kingdom, preprint, 18 authors, study period 6 October, 2020 - 4 November, 2021, trial NCT04499677 (history) (FLARE).

The effect of favipiravir versus hydroxychloroquine on clinical and laboratory findings in COVID-19 in healthcare workers

Turan et al., The Brazilian Journal of Infectious Diseases, doi:10.1016/j.bjid.2022.102328

Retrospective 237 low-risk healthcare workers in Turkey, 123 treated with favipiravir and 114 treated with HCQ, showing lower hospitalization and faster viral clearance with favipiravir, and similar improvement. This study is subject to substantial confounding by time because the patients in each group are from different time periods with an overall period of 10 months including the beginning of the pandemic, resulting in significant differences in variants encountered and SOC. Propensity for hospital admission may also have changed significantly.

risk of hospitalization, 79.4% lower, RR 0.21, p = 0.001, treatment 4 of 123 (3.3%), control 18 of 114 (15.8%), NNT 8.0.

recovery time, 11.0% higher, relative time 1.11, p = 0.51, treatment 123, control 114.

time to viral-, 21.6% lower, relative time 0.78, p < 0.001, treatment 123, control 114.

Excluded in meta analysis: substantial confounding by time likely due to separation of groups in different time periods over an extended period of time.

Turan et al., 2/1/2022, retrospective, Turkey, peer-reviewed, mean age 33.4, 10 authors, study period 11 March, 2020 - 1 January, 2021, this trial compares with another treatment - results may be better when compared to placebo.

Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir

Waters et al., Environmental and Molecular Mutagenesis, doi:10.1002/em.22471 (Review)

Review of antiviral nucleoside analog drugs that induce lethal mutagenesis, including molnupiravir and favipiravir, and the potential mutagenic risks to human DNA and human mitochondrial DNA. Author recommends monitoring for mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity.

Waters et al., 1/28/2022, USA, peer-reviewed, 5 authors.

Favipiravir, umifenovir and camostat mesylate: a comparative study against SARS-CoV-2

Unal et al., bioRxiv, doi:10.1101/2022.01.11.475889 (Preprint) (In Vitro)

In Vitro and In Silico study showing that the combination of favipiravir and umifenovir or camostat mesylate has greater antiviral efficacy than single drug treatment.

Unal et al., 1/12/2022, preprint, 10 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Efficacy of favipiravir in adults with mild COVID-19: a randomized, double-blind, multicenter, placebo-controlled trial clinical trial

Bosaeed et al., Clinical Microbiology and Infection, doi:10.1016/j.cmi.2021.12.026

RCT with 112 favipiravir and 119 control patients showing no significant differences in outcomes. Viral clearance and clinical recovery for patients treated within 48 hours was better than those treated later. NCT04464408.

risk of ICU admission, 618.8% higher, RR 7.19, p = 0.11, treatment 3 of 112 (2.7%), control 0 of 119 (0.0%), continuity correction due to zero event.

risk of hospitalization, 218.8% higher, RR 3.19, p = 0.16, treatment 6 of 112 (5.4%), control 2 of 119 (1.7%).

time to clinical improvement, 11.9% higher, HR 1.12, p = 0.51, treatment 112, control 119, adjusted, inverted to make RR<1 favor treatment.

time to viral clearance, 14.9% higher, HR 1.15, p = 0.51, treatment 112, control 119, adjusted, inverted to make RR<1 favor treatment, primary outcome.

Bosaeed et al., 1/11/2022, Double Blind Randomized Controlled Trial, Saudi Arabia, peer-reviewed, 31 authors, study period 23 July, 2020 - 4 August, 2021, average treatment delay 3.0 days, trial NCT04464408 (history).

US201 Study: A Phase 2, Randomized Proof-of-Concept Trial of Favipiravir for the Treatment of COVID-19

Finberg et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofab56310

Small very late treatment RCT in the USA, with 25 favipiravir and 25 control patients, showing faster viral clearance with treatment. The benefit was only seen in patients <8 days from symptom onset. There were no significant differences in clinical outcomes. The death in the favipiravir group occurred after discharge and was believed to be unrelated to COVID-19 or favipiravir.

risk of death, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 25 (4.0%), control 0 of 25 (0.0%), continuity correction due to zero event.

risk of mechanical ventilation, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 25 (4.0%), control 0 of 25 (0.0%), continuity correction due to zero event.

hospitalization time, 19.8% higher, relative time 1.20, treatment 25, control 25.

risk of no recovery, 58.1% lower, OR 0.42, p = 0.08, treatment 25, control 25, inverted to make RR<1 favor treatment, day 8 mid-recovery, 6-point ordinal scale, RR approximated with OR.

risk of no recovery, 46.2% higher, OR 1.46, p = 0.54, treatment 25, control 25, inverted to make RR<1 favor treatment, day 15, 6-point ordinal scale, RR approximated with OR.

recovery time, 42.9% lower, relative time 0.57, treatment 25, control 25, median time to aggregate NEWS2 score ≤2 or discharge.

recovery time, 15.4% higher, relative time 1.15, treatment 25, control 25.

time to viral-, 46.7% lower, relative time 0.53, p = 0.04, treatment 25, control 25, primary outcome.

Finberg et al., 12/7/2021, Randomized Controlled Trial, USA, peer-reviewed, 10 authors, average treatment delay 8.4 days.

Favipiravir for the Treatment of Coronavirus Disease 2019; a propensity score-matched cohort study

Alattar et al., medRxiv, doi:10.1101/2021.11.29.21267042 (Preprint)

PSM retrospective with 1,493 patients, showing significantly improved viral clearance with favipiravir. There were no significant differences in clinical improvement or mortality. Mortality was lower (2.1% vs 3.1%), without statistical significance with the small number of events.

risk of death, 33.3% lower, RR 0.67, p = 0.50, treatment 8 of 387 (2.1%), control 12 of 387 (3.1%), NNT 97, propensity score matching.

risk of no clinical improvement, 2.2% higher, RR 1.02, p = 0.73, treatment 26 of 387 (6.7%), control 28 of 387 (7.2%), NNT 194, adjusted, inverted to make RR<1 favor treatment, day 28, Cox proportional hazards, propensity score matching, primary outcome.

days to clinical improvement, 6.2% higher, relative time 1.06, p = 0.07, treatment 387, control 387, propensity score matching.

risk of no viral clearance, 43.9% lower, RR 0.56, p < 0.001, treatment 78 of 387 (20.2%), control 139 of 387 (35.9%), NNT 6.3, propensity score matching.

Alattar et al., 11/30/2021, retrospective, Qatar, preprint, 25 authors, study period 23 May, 2020 - 18 July, 2020, average treatment delay 5.0 days.

Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial

Holubar et al., Clinical Infectious Diseases, doi:10.1093/cid/ciac312 (preprint 11/24/2021)

Small RCT 116 mITT patients in the USA, 59 treated with favipiravir, showing no significant differences with treatment.

risk of hospitalization, 89.0% lower, RR 0.11, p = 0.06, treatment 0 of 75 (0.0%), control 4 of 74 (5.4%), NNT 18, relative risk is not 0 because of continuity correction due to zero events.

risk of ER visit, 29.5% lower, RR 0.70, p = 0.56, treatment 5 of 75 (6.7%), control 7 of 74 (9.5%), NNT 36.

risk of no recovery, 19.0% higher, RR 1.19, p = 0.43, treatment 65, control 70, inverted to make RR<1 favor treatment, initial resolution of symptoms.

viral shedding, 31.6% higher, RR 1.32, p = 0.24, treatment 59, control 57, inverted to make RR<1 favor treatment, primary outcome.

Holubar et al., 11/24/2021, Double Blind Randomized Controlled Trial, USA, peer-reviewed, 26 authors, average treatment delay 5.0 days, conflicts of interest: Pfizer, Gates Foundation, Gilead, Regeneron, Janssen.

Efficacy of Early Treatment with Favipiravir on Disease Progression among High Risk COVID-19 Patients: A Randomized, Open-Label Clinical Trial

Chuah et al., Clinical Infectious Diseases, doi:10.1093/cid/ciab962

RCT 500 hospitalized patients in Malaysia, showing no significant differences with favipiravir treatment.

risk of death, 1154.0% higher, RR 12.54, p = 0.08, treatment 5 of 250 (2.0%), control 0 of 250 (0.0%), OR converted to RR, continuity correction due to zero event.

risk of mechanical ventilation, 19.5% higher, RR 1.20, p = 0.76, treatment 6 of 250 (2.4%), control 5 of 250 (2.0%), OR converted to RR.

risk of ICU admission, 8.5% higher, RR 1.09, p = 0.84, treatment 13 of 250 (5.2%), control 12 of 250 (4.8%), OR converted to RR.

Chuah et al., 11/19/2021, Randomized Controlled Trial, Malaysia, peer-reviewed, 18 authors.

Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial

Shenoy et al., medRxiv, doi:10.1101/2021.11.08.21265884 (Preprint)

Late stage RCT with 353 hospitalized patients, showing no significant differences with favipiravir treatment overall, however a trend towards benefit was seen within patients treated relatively early, including a statistically significant shorter time to discharge with treatment.

risk of death, 29.5% higher, RR 1.29, p = 0.54, treatment 14 of 175 (8.0%), control 11 of 178 (6.2%).

risk of mechanical ventilation, 33.0% higher, RR 1.33, p = 0.54, treatment 17 of 175 (9.7%), control 13 of 178 (7.3%).

risk of ICU admission, 1.7% higher, RR 1.02, p = 0.54, treatment 20 of 175 (11.4%), control 20 of 178 (11.2%).

time to resolution of hypoxia, 1.0% higher, HR 1.01, p = 0.94, treatment 157, control 158, inverted to make RR<1 favor treatment, primary outcome.

time to hospital discharge, 5.7% lower, HR 0.94, p = 0.60, treatment 175, control 178, inverted to make RR<1 favor treatment.

time to resolution of hypoxia, 17.4% lower, HR 0.83, p = 0.29, treatment 157, control 158, inverted to make RR<1 favor treatment, earlier treatment subgroup, primary outcome.

time to hospital discharge, 32.0% lower, HR 0.68, p = 0.01, treatment 175, control 178, inverted to make RR<1 favor treatment, earlier treatment subgroup.

Shenoy et al., 11/9/2021, Double Blind Randomized Controlled Trial, Kuwait, preprint, 8 authors, average treatment delay 6.3 days.

The Effectiveness and Safety of Favipiravir in COVID-19 Hospitalized Patients in Bali, Indonesia

Damayanti et al., Kesmas: National Public Health Journal, doi:10.21109/kesmas.v16i4.5433

Retrospective 192 hospitalized patients in Indonesia, 96 patients treated with favipiravir, showing improved recovery with treatment. Only the abstract is currently available.

risk of no recovery, 54.5% lower, RR 0.46, p = 0.03, treatment 96, control 96, adjusted, inverted to make RR<1 favor treatment.

Excluded in after exclusion results of meta analysis: minimal details provided.

Damayanti et al., 11/1/2021, retrospective, Indonesia, peer-reviewed, 3 authors.

Various Combinations of Favipiravir, Lopinavir-Ritonavir, Darunavir-Ritonavir, High-Dose Oseltamivir, and Hydroxychloroquine for the Treatment of COVID-19: A Randomized Controlled Trial (FIGHT-COVID-19 Study)

Atipornwanich et al., SSRN Electronic Journal, doi:10.2139/ssrn.3936499

RCT 200 moderate/severe patients in Thailand, showing significantly lower progression with favipiravir vs. oseltamivir. NCT04303299.

risk of death, 23.1% lower, RR 0.77, p = 0.66, treatment 10 of 100 (10.0%), control 13 of 100 (13.0%), NNT 33, favipiravir arms vs. oseltamivir arms.

risk of progression, 60.0% lower, RR 0.40, p = 0.009, treatment 10 of 100 (10.0%), control 25 of 100 (25.0%), NNT 6.7, favipiravir arms vs. oseltamivir arms.

time to viral-, 8.7% lower, relative time 0.91, p = 0.43, treatment mean 9.5 (±5.0) n=50, control mean 10.4 (±6.3) n=50, HCQ arms, primary outcome.

time to viral-, 8.9% lower, relative time 0.91, p = 0.34, treatment mean 10.2 (±4.6) n=50, control mean 11.2 (±5.7) n=50, non-HCQ arms, primary outcome.

Atipornwanich et al., 10/5/2021, Randomized Controlled Trial, Thailand, peer-reviewed, 16 authors, this trial compares with another treatment - results may be better when compared to placebo, this trial uses multiple treatments in the treatment arm (combined with lopinavir/ritonavir or duranivir/ritonavir/HCQ) - results of individual treatments may vary, trial NCT04303299 (history).

Favipiravir Effects on the Control of Clinical Symptoms of Hospitalized COVID-19 Cases: An Experience with Iranian Formulated Dosage Form

Tabarsi et al., Iranian Journal of Pharmaceutical Research, doi:10.22037/ijpr.2021.115510.15401

Small 62 patient late stage RCT in Iran comparing favipiravir and lopinavir/ritonavir, showing significant improvement in fever, cough, and dyspnea with favipiravir on day 5. There was no significant difference in mortality, ICU admission, or chest CT improvement. IRCT20151227025726N14.

risk of death, 29.7% lower, RR 0.70, p = 0.70, treatment 3 of 32 (9.4%), control 4 of 30 (13.3%), NNT 25.

risk of ICU admission, 41.4% lower, RR 0.59, p = 0.36, treatment 5 of 32 (15.6%), control 8 of 30 (26.7%), NNT 9.1.

risk of <50% improvement in chest CT, 6.2% lower, RR 0.94, p = 0.76, treatment 24 of 32 (75.0%), control 24 of 30 (80.0%), NNT 20.

hospitalization time, 25.0% lower, relative time 0.75, p = 0.03, treatment 32, control 30.

Tabarsi et al., 9/30/2021, Randomized Controlled Trial, Iran, peer-reviewed, 27 authors, study period 4 April, 2020 - 7 May, 2020, average treatment delay 7.0 days, this trial compares with another treatment - results may be better when compared to placebo.

Effectiveness and Safety of Favipiravir Compared to Hydroxychloroquine for Management of Covid-19: A Retrospective Study

Alotaibi et al., International Journal of General Medicine, 2021:14

Retrospective hospitalized patients in Saudi Arabia, showing lower mortality with favipiravir compared to HCQ, not quite reaching statistical significance. Authors do not indicate the factors behind which therapy was chosen. May be subject to significant confounding by indication and confounding by time.

risk of death, 57.2% lower, RR 0.43, p = 0.05, treatment 244, control 193, inverted to make RR<1 favor treatment, multivariate.

Alotaibi et al., 9/14/2021, retrospective, Saudi Arabia, peer-reviewed, 11 authors, this trial compares with another treatment - results may be better when compared to placebo.

Assessment of outcomes following implementation of antiviral treatment guidelines for COVID-19 during the first wave in Thailand

Sawanpanyalert et al., Southeast Asian Journal of Tropical Medicine and Public Health, 52:4

Retrospective 744 hospitalized patients in Thailand, showing lower risk of a poor outcome for favipiravir treatment within 4 days of symptom onset. Early treatment with CQ/HCQ and lopinavir/ritonavir or darunavir/ritonavir also showed lower risk, but without statistical significance. Sample sizes for the number of patients treated within 4 days of symptom onset are not provided.

risk of death, ICU, intubation, or high-flow oxygen, 68.0% lower, OR 0.32, p = 0.003, within 4 days of symptom onset, RR approximated with OR.

Sawanpanyalert et al., 9/9/2021, retrospective, Thailand, peer-reviewed, 11 authors.

Favipiravir Versus Arbidol for Clinical Recovery Rate in Moderate and Severe Adult COVID-19 Patients: A Prospective, Multicenter, Open-Label, Randomized Controlled Clinical Trial

Chen et al., Frontiers in Pharmacology, doi:10.3389/fphar.2021.683296

Very late stage (9 days from symptom onset) RCT with 116 favipiravir patients and 120 arbidol patients in China, showing no significant difference in clinical recovery (relief of fever and cough, respiratory frequency ≤24 times/min, and oxygen saturation ≥98%), however the time to resolution of fever and cough was significantly lower with favipiravir. ChiCTR2000030254.

risk of ICU admission, 3.4% higher, RR 1.03, p = 1.00, treatment 2 of 116 (1.7%), control 2 of 120 (1.7%).

risk of respiratory failure, 74.1% lower, RR 0.26, p = 0.37, treatment 1 of 116 (0.9%), control 4 of 120 (3.3%), NNT 40.

risk of oxygen therapy, 19.5% lower, RR 0.80, p = 0.42, treatment 21 of 116 (18.1%), control 27 of 120 (22.5%), NNT 23.

risk of progression to dyspnea, 70.4% lower, RR 0.30, p = 0.03, treatment 4 of 116 (3.4%), control 14 of 120 (11.7%), NNT 12.

risk of dyspnea, 10.3% lower, RR 0.90, p = 0.84, treatment 13 of 116 (11.2%), control 15 of 120 (12.5%), NNT 77.

risk of no recovery, 19.7% lower, RR 0.80, p = 0.15, treatment 45 of 116 (38.8%), control 58 of 120 (48.3%), NNT 10, day 7, primary outcome.

Chen et al., 9/2/2021, Randomized Controlled Trial, China, peer-reviewed, 14 authors, average treatment delay 9.0 days, this trial compares with another treatment - results may be better when compared to placebo.

Clinical efficacy of the antiviral drug favipiravir in the complex treatment of patients with COVID-19 coronavirus infection

Kulzhanova et al.,

Retrospective 40 favipiravir patients in Kazakhstan and 40 controls, showing faster recovery and viral clearance with treatment.

risk of no improvement, 88.0% lower, RR 0.12, p < 0.001, treatment 3 of 40 (7.5%), control 25 of 40 (62.5%), NNT 1.8, mid-recovery day 7.

risk of no improvement, 88.9% lower, RR 0.11, p = 0.12, treatment 0 of 40 (0.0%), control 4 of 40 (10.0%), NNT 10.0, relative risk is not 0 because of continuity correction due to zero events, day 14.

risk of no viral clearance, 50.0% lower, RR 0.50, p = 0.18, treatment 6 of 40 (15.0%), control 12 of 40 (30.0%), NNT 6.7.

Kulzhanova et al., 8/31/2021, retrospective, Kazakhstan, peer-reviewed, 10 authors, average treatment delay 6.45 days.

COVID-19 related treatment and outcomes among COVID-19 ICU patients: A retrospective cohort study

Assiri et al., Journal of Infection and Public Health, doi:10.1016/j.jiph.2021.08.030

Retrospective 118 ICU patients in Saudi Arabia showing no significant differences in unadjusted results with zinc, vitamin D, and favipiravir treatment.

risk of death, 79.3% higher, RR 1.79, p = 0.50, treatment 11 of 67 (16.4%), control 3 of 51 (5.9%), inverted to make RR<1 favor treatment, OR converted to RR.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Assiri et al., 8/28/2021, retrospective, Saudi Arabia, peer-reviewed, 8 authors.

Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial

Shinkai et al., Infectious Diseases and Therapy, doi:10.1007/s40121-021-00517-4

RCT 156 patients in Japan, 107 treated with favipiravir, showing significant improvement in a composite outcome defined as the time to improvement in temperature, SpO₂, CT findings, and recovery to PCR-.

time to improvement, 37.1% lower, HR 0.63, p = 0.01, treatment 107, control 49, adjusted, inverted to make RR<1 favor treatment, Cox proportional hazards, composite time to improvement in temperature, SpO2, CT findings, and recovery to PCR-.

time to improvement, 58.5% lower, HR 0.41, p = 0.01, treatment 47, control 13, adjusted, inverted to make RR<1 favor treatment, <5 days from onset of fever, Cox proportional hazards, composite time to improvement in temperature, SpO2, CT findings, and recovery to PCR-.

Shinkai et al., 8/27/2021, Single Blind Randomized Controlled Trial, Japan, peer-reviewed, 39 authors, average treatment delay 4.8 days.

Favipiravir versus Standard of Care in Patients with Severe COVID-19 Infections: A Retrospective Comparative Study

Almoosa et al., Journal of Infection and Public Health, doi:10.1016/j.jiph.2021.08.022

Retrospective 226 COVID-19 pneumonia patients, 110 treated with favipiravir, showing higher mortality (p=0.1) and ICU admission (p=0.02) with treatment in multivariate analysis.

risk of death, 42.3% higher, RR 1.42, p = 0.10, treatment 33 of 110 (30.0%), control 24 of 116 (20.7%), adjusted, OR converted to RR, overall mortality, multivariate binary logistic regression.

risk of ICU admission, 90.0% higher, OR 1.90, p = 0.02, treatment 110, control 116, adjusted, multivariate binary logistic regression, RR approximated with OR.

recovery time, 10.9% higher, relative time 1.11, p = 0.17, treatment 110, control 116.

Almoosa et al., 8/24/2021, retrospective, Saudi Arabia, peer-reviewed, 14 authors.

Effectiveness and safety of favipiravir compared to supportive care in moderately to critically ill COVID-19 patients: a retrospective study with propensity score matching sensitivity analysis

Alamer et al., Current Medical Research and Opinion, doi:10.1080/03007995.2021.1920900

Retrospective 234 favipiravir and 223 control patients in Saudi Arabia, showing shorter time to discharge and lower progression to ventilation, but no significant difference in mortality.

risk of death, 56.0% higher, HR 1.56, p = 0.26, treatment 12 of 233 (5.2%), control 21 of 223 (9.4%), adjusted.

risk of mechanical ventilation, 90.0% lower, HR 0.10, p < 0.001, treatment 4 of 218 (1.8%), control 27 of 165 (16.4%), NNT 6.9, adjusted.

adjusted discharge ratio, 49.0% lower, RR 0.51, p < 0.001, treatment 221, control 201, adjusted, inverted to make RR<1 favor treatment.

Alamer et al., 5/19/2021, retrospective, Saudi Arabia, peer-reviewed, 18 authors.

Favipiravir: the hidden threat of mutagenic action

Zhirnov et al., Journal of microbiology, epidemiology and immunobiology, doi:10.36233/0372-9311-114 (Review)

Review of the mutagenic effect of favipiravir and associated concerns.

Zhirnov et al., 5/5/2021, Russia, peer-reviewed, 2 authors.

Decreased In-Hospital Mortality Associated with Aspirin Administration in Hospitalized Patients Due to Severe COVID-19

Aghajani et al., Journal of Medical Virology, doi:10.1002/jmv.27053

Retrospective 991 hospitalized patients in Iran focusing on aspirin use but also showing results for HCQ, remdesivir, and favipiravir.

risk of death, 26.1% lower, HR 0.74, p = 0.28, treatment 40, control 951, univariate Cox proportional regression.

Aghajani et al., 4/29/2021, retrospective, Iran, peer-reviewed, 7 authors.

Favipiravir in the treatment of patients with SARS-CoV-2 RNA recurrent positive after discharge: a multicenter, open-label, randomized trial

Zhao et al., International Immunopharmacology, doi:10.1016/j.intimp.2021.107702

RCT with 55 patients (36 favipiravir, 19 control) who were PCR+ after recovery, showing improved viral clearance with treatment.

risk of no viral clearance, 59.0% lower, RR 0.41, p = 0.06, treatment 7 of 36 (19.4%), control 9 of 19 (47.4%), NNT 3.6.

time to viral-, 52.4% lower, relative time 0.48, p = 0.04, treatment 36, control 19, inverted to make RR<1 favor treatment.

Zhao et al., 4/21/2021, Randomized Controlled Trial, China, peer-reviewed, 25 authors.

Favipiravir Observational Study Interim Report 3

Favipiravir Observational Study Group, Fujita Health University (Preprint)

Retrospective analysis of favipiravir use in 10,986 hospitalized patients, including analysis of changes in clinical status and side effects. Common adverse events were uric acid level increase and liver function enzyme increase. Authors note that early embryonic lethality and teratogenicity due to favipiravir have been observed in animal models, that pregnant women must be excluded, and that all patients and partners should practice effective contraception.

Favipiravir Observational Study Group et al., 4/19/2021, preprint, 1 author.

Early favipiravir treatment was associated with early defervescence in non-severe COVID-19 patients

Fujii et al., Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2021.04.013

Retrospective 41 favipiravir patients finding that early treatment was more successful.

Fujii et al., 4/17/2021, peer-reviewed, 10 authors.

Safety and efficacy of Favipiravir in moderate to severe SARS-CoV-2 pneumonia

Solaymani-Dodaran et al., International Immunopharmacology, doi:10.1016/j.intimp.2021.107522

RCT late stage patients (median SpO₂ 89), 193 treated with favipiravir, 187 with lopinavir/ritonavir, showing no significant differences in mortality, intubation, or ICU admission.

risk of death, 19.2% higher, RR 1.19, p = 0.54, treatment 26 of 190 (13.7%), control 21 of 183 (11.5%).

risk of mechanical ventilation, 53.0% higher, RR 1.53, p = 0.15, treatment 27 of 190 (14.2%), control 17 of 183 (9.3%).

risk of ICU admission, 19.4% higher, RR 1.19, p = 0.56, treatment 31 of 190 (16.3%), control 25 of 183 (13.7%).

Solaymani-Dodaran et al., 3/11/2021, Randomized Controlled Trial, Iran, peer-reviewed, 44 authors, this trial compares with another treatment - results may be better when compared to placebo.

A single-center retrospective cohort study of Covid-19 medications: Remdesivir, Favipiravir, Methylprednisolone, Dexamethasone, and Interferon β1a and their combinations

Fateh et al., medRxiv, doi:10.1101/2021.03.05.21251351 (Preprint)

Retrospective 324 hospitalized patients in Iran reporting on the use Remdesivir, Favipiravir, Methylprednisolone, Dexamethasone, and Interferon β1a and their combinations. There is no control group in this study.

Fateh et al., 3/8/2021, retrospective, Iran, preprint, 7 authors.

Benefits of Treatment With Favipiravir in Hospitalized Patients for COVID-19: a Retrospective Observational Case-control Study

Uçan et al., Research Square, doi:10.21203/rs.3.rs-175340/v1 (Preprint)

Retrospective 144 COVID-19 patients in Turkey, one group receiving FPV after a mean of 4.7 days, a second group after a mean of 8.6 days, and all groups receiving HCQ. No improvement in clinical outcomes was seen with the addition of FPV, however the groups are not comparable and no adjustments were made. FPV was first used in patients whose clinical condition worsened or whose pneumonia findings progressed, while later patients started FPV treatment early.

Uçan et al., 2/4/2021, retrospective, Turkey, preprint, 8 authors, average treatment delay 4.73 days.

Efficacy of favipiravir in COVID-19 treatment: a multi-center randomized study

Dabbous et al., Archives of Virology, doi:10.1007/s00705-021-04956-9

This study was retracted.

Dabbous et al., 1/25/2021, peer-reviewed, 10 authors.

Early Onset Favipiravir Saves Lives

Karatas et al., Research Square, doi:10.21203/rs.3.rs-142868/v1 (Preprint)

Retrospective 180 hospitalized patients showing lower mortality when Favipiravir is given earlier. 17% of patients given Favipiravir within 3 days died, compared to 38% when given after 3 days.

Karatas et al., 1/14/2021, preprint, 5 authors.

A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19

Doi et al., Antimicrobial Agents and Chemotherapy, doi:10.1128/AAC.01897-20

Small RCT comparing late and very late (7 and 14 days from fever onset) favipiravir. Viral clearance was non-statistically significantly improved with relatively early treatment. There was a reduction in time to defervescence, and a significant improvement in fever was observed the day after starting therapy. There was no progression or mortality. While limited by the small sample size, authors conclude that the results suggest antiviral activity of favipiravir in this patient population. There was no control group.

Doi et al., 11/17/2020, Randomized Controlled Trial, peer-reviewed, 45 authors.

Efficacy and Safety of Favipiravir, an Oral RNA-Dependent RNA Polymerase Inhibitor, in Mild-to-Moderate COVID-19: A Randomized, Comparative, Open-Label, Multicenter, Phase 3 Clinical Trial

Udwadia et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.11.142

RCT with 75 favipiravir patients and 75 control patients showing reduced time to clinical cure and reduced time of viral shedding.

recovery time, 40.0% lower, relative time 0.60, p = 0.03, treatment 75, control 75.

time to viral-, 29.0% lower, relative time 0.71, p = 0.13, treatment 75, control 75.

Udwadia et al., 11/16/2020, Randomized Controlled Trial, India, peer-reviewed, 11 authors.

Randomized Controlled Open Label Trial on the Use of Favipiravir Combined with Inhaled Interferon beta-1b in Hospitalized Patients with Moderate to Severe COVID-19 Pneumonia

Khamis et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.11.008

Small 89 patient RCT comparing favipiravir and inhaled interferon with HCQ for moderate to severe COVID-19 pneumonia, not finding significant differences. There was no control group.

risk of death, 14.8% lower, RR 0.85, p = 1.00, treatment 5 of 44 (11.4%), control 6 of 45 (13.3%), NNT 51.

risk of ICU admission, 2.3% higher, RR 1.02, p = 1.00, treatment 8 of 44 (18.2%), control 8 of 45 (17.8%).

risk of no recovery, 9.6% higher, RR 1.10, p = 0.82, treatment 15 of 44 (34.1%), control 14 of 45 (31.1%).

Excluded in after exclusion results of meta analysis: trials compares against another treatment showing significant efficacy in trials.

Khamis et al., 11/9/2020, Randomized Controlled Trial, Oman, peer-reviewed, 11 authors, study period 22 June, 2020 - 13 August, 2020, this trial compares with another treatment - results may be better when compared to placebo, this trial uses multiple treatments in the treatment arm (combined with interferon beta-1b) - results of individual treatments may vary.

Study of Favipiravir Compared to Standard of Care in Hospitalized Patients With COVID-19

Pushkar et al., NCT04542694 (Preprint)

RCT 200 patients showing improvements in clinical recovery and viral clearance with favipiravir. There is no paper available but results are posted in clinicaltrials.gov.

risk of no clinical status improvement of 2+ WHO-OSCI at ~10 days, 14.1% lower, RR 0.86, p = 0.06, treatment 73 of 100 (73.0%), control 85 of 100 (85.0%), NNT 8.3.

relative time to clinical improvement, 33.3% lower, relative time 0.67, p < 0.001, treatment 100, control 100.

risk of no fever reduction by day 3, 45.2% lower, RR 0.55, p < 0.001, treatment 40 of 100 (40.0%), control 73 of 100 (73.0%), NNT 3.0.

relative time to resolution of fever, 20.0% lower, relative time 0.80, p = 0.05, treatment 100, control 100.

risk of no discharge at day 10, 69.7% lower, RR 0.30, p < 0.001, treatment 10 of 100 (10.0%), control 33 of 100 (33.0%), NNT 4.3.

risk of no full recovery at day 10, 26.7% lower, RR 0.73, p < 0.001, treatment 66 of 100 (66.0%), control 90 of 100 (90.0%), NNT 4.2.

risk of no improvement in lung CT, 33.3% lower, RR 0.67, p = 0.007, treatment 40 of 100 (40.0%), control 60 of 100 (60.0%), NNT 5.0.

risk of no viral clearance, 90.5% lower, RR 0.10, p < 0.001, treatment 2 of 100 (2.0%), control 21 of 100 (21.0%), NNT 5.3.

Pushkar et al., 11/5/2020, Randomized Controlled Trial, Russia, preprint, mean age 50.0, 1 author.

Phase 3 Trial of Coronavir (Favipiravir) in Patients with Mild to Moderate COVID-19

Ruzhentsova et al., SSRN, doi:10.2139/ssrn.3696907 (Preprint)

RCT 168 patients, 112 receiving favipiravir and 56 SOC, showing shorter time to clinical improvement and faster viral clearance with favipiravir.

risk of hospitalization, 6.0% lower, RR 0.94, p = 0.49, treatment 3 of 112 (2.7%), control 2 of 56 (3.6%), adjusted.

risk of mechanical ventilation, 150.0% higher, RR 2.50, p = 1.00, treatment 1 of 112 (0.9%), control 0 of 56 (0.0%), continuity correction due to zero event.

risk of ICU admission, 51.0% higher, RR 1.51, p = 0.63, treatment 3 of 112 (2.7%), control 1 of 56 (1.8%), adjusted.

hazard ratio for time to clinical improvement, 38.7% lower, HR 0.61, p = 0.007, treatment 112, control 56, inverted to make RR<1 favor treatment.

risk of no viral clearance, 21.9% lower, RR 0.78, p = 0.16, treatment 112, control 56, inverted to make RR<1 favor treatment, day 5 mid-recovery.

Ruzhentsova et al., 10/26/2020, Randomized Controlled Trial, Russia, preprint, 31 authors, average treatment delay 3.55 days.

Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: An Exploratory Randomized, Controlled Trial

Lou et al., European Journal of Pharmaceutical Sciences, doi:10.1016/j.ejps.2020.105631

Small late stage RCT with 10 favipiravir, 10 baloxavir marboxil, and 10 control patients in China, showing no significant differences. ChiCTR 2000029544.

risk of ICU admission, 422.2% higher, RR 5.22, p = 0.21, treatment 2 of 9 (22.2%), control 0 of 10 (0.0%), continuity correction due to zero event.

risk of no viral clearance, 422.2% higher, RR 5.22, p = 0.21, treatment 2 of 9 (22.2%), control 0 of 10 (0.0%), continuity correction due to zero event, day 14.

risk of no viral clearance, 11.1% higher, RR 1.11, p = 1.00, treatment 5 of 9 (55.6%), control 5 of 10 (50.0%), day 7.

Lou et al., 10/25/2020, Randomized Controlled Trial, China, peer-reviewed, 13 authors, average treatment delay 8.5 days.

Tocilizumab combined with favipiravir in the treatment of COVID-19: A multicenter trial in a small sample size

Zhaao et al., Biomedicine & Pharmacotherapy, doi:10.1016/j.biopha.2020.110825

Small study with 14 combined favipiravir/tocilizumab, 7 favipiravir, and 5 tocilizumab patients suggesting that tocilizumab combined with or without favipiravir can improve pulmonary inflammation and inhibit progression.

Zhaao et al., 9/30/2020, peer-reviewed, 12 authors.

AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial

Ivashchenko et al., Clin. Infect. Dis., doi:10.1093/cid/ciaa1176

Intermin results for a small RCT with 40 favipiravir and 20 control patients showing faster viral clearance with favipiravir. There is limited data in this report to evaluate the results. The report indicates that 75% of the control group received HCQ/CQ.

risk of no viral clearance, 46.4% lower, RR 0.54, p = 0.03, treatment 15 of 40 (37.5%), control 14 of 20 (70.0%), NNT 3.1, mid-recovery day 5.

risk of no viral clearance, 62.5% lower, RR 0.37, p = 0.21, treatment 3 of 40 (7.5%), control 4 of 20 (20.0%), NNT 8.0, day 10.

risk of no discharge and WHO-OSC>2, 66.7% higher, RR 1.67, p = 0.51, treatment 10 of 40 (25.0%), control 3 of 20 (15.0%).

risk of hospitalization, 300.0% higher, RR 4.00, p = 0.55, treatment 2 of 40 (5.0%), control 0 of 20 (0.0%), continuity correction due to zero event, 1600/600mg.

Ivashchenko et al., 8/9/2020, Randomized Controlled Trial, Russia, peer-reviewed, 21 authors, average treatment delay 6.7 days.

Favipiravir at high doses has potent antiviral activity in SARS-CoV-2−infected hamsters, whereas hydroxychloroquine lacks activity

Kaptein et al., bioRxiv, doi:10.1101/2020.06.19.159053

Animal study with Syrian hamsters, showing antiviral activity with favipiravir.

Kaptein et al., 6/19/2020, peer-reviewed, 35 authors.

Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study

Cai et al., Engineering, doi:10.1016/j.eng.2020.03.007

Comparison of 35 FPV patients and 35 LPV/RTV patients, showing significant improvements in chest CT and faster viral clearance with FPV.

risk of no improvement in CT, 68.7% lower, OR 0.31, p = 0.04, treatment 35, control 45, inverted to make RR<1 favor treatment, multivariate, RR approximated with OR.

risk of no viral clearance, 70.9% lower, HR 0.29, p = 0.03, treatment 35, control 45, inverted to make RR<1 favor treatment, multivariate.

Cai et al., 3/18/2020, retrospective, China, peer-reviewed, 26 authors.

Antiandrogens	(meta)	Melatonin	(meta)
Aspirin	(meta)	Metformin	(meta)
Bamlaniv../e..	(meta)	Molnupiravir	(meta)
Bebtelovimab	(meta)	N-acetylcys..	(meta)
Bromhexine	(meta)	Nigella Sativa	(meta)
Budesonide	(meta)	Nitazoxanide	(meta)
Cannabidiol	(meta)	Nitric Oxide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Peg.. Lambda	(meta)
Conv. Plasma	(meta)	Povidone-Iod..	(meta)
Curcumin	(meta)	Probiotics	(meta)
Diet	(meta)	Proxalutamide	(meta)
Ensitrelvir	(meta)	Quercetin	(meta)
Ensovibep	(meta)	Remdesivir	(meta)
Exercise	(meta)	Sleep	(meta)
Famotidine	(meta)	Sotrovimab	(meta)
Favipiravir	(meta)	Tixagev../c..	(meta)
Fluvoxamine	(meta)	Vitamin A	(meta)
Hydroxychlor..	(meta)	Vitamin C	(meta)
Iota-carragee..	(meta)	Vitamin D	(meta)
Ivermectin	(meta)	Zinc	(meta)
Lactoferrin	(meta)

Other Treatments		Global Adoption