Favipiravir for COVID-19: real-time analysis of all 35 studies

Favipiravir for COVID-19: real-time meta analysis of 26 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for progression, recovery, and viral clearance. 17 studies from 17 independent teams in 12 different countries show statistically significant improvements in isolation (9 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 28% [11‑42%] 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.

• Overall mortality results are negative, however this is dominated by late treatment studies. Early treatment shows positive results for mortality, but with very limited data.

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 4% of favipiravir studies show zero events in the treatment arm.

• Multiple treatments are typically used in combination, and other treatments are more effective.

• Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used, including treatments, as supported by Pfizer [Pfizer]. 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.

	Studies	Early treatment	Late treatment	Patients	Authors
All studies	26	45% [11‑66%]	24% [4‑40%]	6,386	466
With exclusions	23	45% [11‑66%]	24% [2‑41%]	5,987	444
Peer-reviewed	21	45% [-26‑76%]	28% [3‑46%]	4,742	375
RCTs	16	30% [-79‑72%]	21% [2‑36%]	3,032	333
Percentage improvement with favipiravir treatment

Covid Analysis et al., 1/16/2022, preprint, 1 author.

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 (Peer Reviewed)

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, RR 1.12, p = 0.51, treatment 112, control 119, adjusted.

time to viral clearance, 14.9% higher, RR 1.15, p = 0.51, treatment 112, control 119, adjusted.

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

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 (Peer Reviewed)

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, RR 0.42, p = 0.08, treatment 25, control 25, day 8 mid-recovery, 6-point ordinal scale, RR approximated with OR.

risk of no recovery, 46.2% higher, RR 1.46, p = 0.54, treatment 25, control 25, 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.

Finberg et al., 12/7/2021, Randomized Controlled Trial, USA, North America, 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 signficant 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, day 28, Cox proportional hazards, propensity score matching.

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

risk of no virological cure, 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, Middle East, preprint, 25 authors, study period 23 May, 2020 - 18 July, 2020.

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

Holubar et al., medRxiv, doi:10.1101/2021.11.22.21266690 (Preprint)

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. With the observed event rates, ~11 more patients per arm would result in statistical significance.

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, 16.0% lower, RR 0.84, p = 0.43, treatment 65, control 70, initial resolution of symptoms.

viral shedding, 31.6% higher, RR 1.32, p = 0.24, treatment 59, control 57.

Holubar et al., 11/24/2021, Double Blind Randomized Controlled Trial, USA, North America, preprint, 26 authors, average treatment delay 5.0 days.

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 (Peer Reviewed)

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, Europe, 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, RR 1.01, p = 0.94, treatment 157, control 158.

time to hospital discharge, 5.7% lower, RR 0.94, p = 0.60, treatment 175, control 178.

time to resolution of hypoxia, 17.4% lower, RR 0.83, p = 0.29, treatment 157, control 158, earlier treatment subgroup.

time to hospital discharge, 32.0% lower, RR 0.68, p = 0.01, treatment 175, control 178, earlier treatment subgroup.

Shenoy et al., 11/9/2021, Double Blind Randomized Controlled Trial, Kuwait, Middle East, 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 (Peer Reviewed)

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.

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

Damayanti et al., 11/1/2021, retrospective, Indonesia, South Asia, 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 (Peer Reviewed)

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.

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.

Atipornwanich et al., 10/5/2021, Randomized Controlled Trial, Thailand, South Asia, peer-reviewed, 16 authors, this trial uses multiple treatments in the treatment arm (combined with lopinavir/ritonavir or duranivir/ritonavir/HCQ) - results of individual treatments may vary.

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 (Peer Reviewed)

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, Middle East, 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 (Peer Reviewed)

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. Confounding by indication and time are possible.

risk of death, 57.2% lower, RR 0.43, p = 0.05, treatment 244, control 193, multivariate.

Alotaibi et al., 9/14/2021, retrospective, Saudi Arabia, Middle East, 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 (Peer Reviewed)

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, RR 0.32, p = 0.003, within 4 days of symptom onset, RR approximated with OR.

Sawanpanyalert et al., 9/9/2021, retrospective, Thailand, South Asia, 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 (Peer Reviewed)

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.

Chen et al., 9/2/2021, Randomized Controlled Trial, China, Asia, 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., (Peer Reviewed)

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 virological cure, 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, Asia, 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 (Peer Reviewed)

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%), 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, Middle East, 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 (Peer Reviewed)

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, RR 0.63, p = 0.01, treatment 107, control 49, adjusted, Cox proportional hazards, composite time to improvement in temperature, SpO2, CT findings, and recovery to PCR-.

time to improvement, 58.5% lower, RR 0.41, p = 0.01, treatment 47, control 13, adjusted, <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, Asia, peer-reviewed, 39 authors.

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 (Peer Reviewed)

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, RR 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, Middle East, peer-reviewed, 14 authors.

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 (Preprint) (meta analysis)

Systematic review and meta analysis of 15 favipiravir trials, showing improved viral clearance and recovery.

Hung et al., 7/20/2021, preprint, 23 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 (Peer Reviewed)

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, RR 1.56, p = 0.26, treatment 12 of 233 (5.2%), control 21 of 223 (9.4%), NNT 23, adjusted.

risk of mechanical ventilation, 90.0% lower, RR 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.

Alamer et al., 5/19/2021, retrospective, Saudi Arabia, Middle East, peer-reviewed, 18 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 (Peer Reviewed)

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, RR 0.74, p = 0.28, treatment 40, control 951, univariate Cox proportional regression.

Aghajani et al., 4/29/2021, retrospective, Iran, Middle East, 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 (Peer Reviewed)

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

risk of no virological cure, 59.0% lower, RR 0.41, p = 0.06, treatment 7 of 36 (19.4%), control 9 of 19 (47.4%), NNT 3.6. With the observed event rates, ~3 more patients per arm would result in statistical significance.

time to viral-, 52.4% lower, relative time 0.48, p = 0.04, treatment 36, control 19.

Zhao et al., 4/21/2021, Randomized Controlled Trial, China, Asia, 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 (Peer Reviewed)

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 (Peer Reviewed)

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, Middle East, 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, Middle East, 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, Europe, 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 (Peer Reviewed)

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 (Peer Reviewed)

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 (Peer Reviewed)

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, South Asia, 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 (Peer Reviewed)

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, Middle East, 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. With the observed event rates, ~3 more patients per arm would result in statistical significance.

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 virological cure, 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, Europe, 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%), NNT 112, 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, RR 0.61, p = 0.007, treatment 112, control 56.

risk of no virological cure, 21.9% lower, RR 0.78, p = 0.16, treatment 112, control 56, day 5 mid-recovery.

Ruzhentsova et al., 10/26/2020, Randomized Controlled Trial, Russia, Europe, preprint, 31 authors, average treatment delay 3.55 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 (Peer Reviewed)

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 (Peer Reviewed)

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 virological cure, 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 virological cure, 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, Europe, peer-reviewed, 21 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 (Peer Reviewed)

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, RR 0.31, p = 0.04, treatment 35, control 45, multivariate, RR approximated with OR.

risk of no virological cure, 70.9% lower, RR 0.29, p = 0.03, treatment 35, control 45, multivariate.

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

Antiandrogens	(meta)	Metformin	(meta)
Aspirin	(meta)	Molnupiravir	(meta)
Bamlanivimab	(meta)	N-acetylcys..	(meta)
Bromhexine	(meta)	Nigella Sativa	(meta)
Budesonide	(meta)	Nitazoxanide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Povidone-Iod..	(meta)
Conv. Plasma	(meta)	Probiotics	(meta)
Curcumin	(meta)	Proxalutamide	(meta)
Ensovibep	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychlor..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Melatonin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption