c19early.org COVID-19 treatment researchFavipiravirFavipiravir (more..)
Melatonin Meta
Metformin Meta
Antihistamines Meta
Azvudine Meta Molnupiravir Meta
Bromhexine Meta
Budesonide Meta
Colchicine Meta Nigella Sativa Meta
Conv. Plasma Meta Nitazoxanide Meta
Curcumin Meta PPIs Meta
Famotidine Meta Paxlovid Meta
Favipiravir Meta Quercetin Meta
Fluvoxamine Meta Remdesivir Meta
Hydroxychlor.. Meta Thermotherapy Meta
Ivermectin Meta

Loading...
 
More

Favipiravir for COVID-19: real-time meta analysis of 70 studies

@CovidAnalysis, December 2024, Version 81V81
 
0 0.5 1 1.5+ All studies 15% 70 34,275 Improvement, Studies, Patients Relative Risk Mortality 11% 40 27,628 Ventilation -10% 12 11,464 ICU admission -31% 21 9,522 Hospitalization -4% 19 6,502 Progression 21% 10 12,134 Recovery 15% 27 8,826 Viral clearance 18% 27 5,022 RCTs 15% 34 9,630 Peer-reviewed 16% 67 33,554 Early 17% 20 12,457 Late 14% 50 21,818 Favipiravir for COVID-19 c19early.org December 2024 after exclusions Favorsfavipiravir Favorscontrol
Abstract
Significantly lower risk is seen for recovery and viral clearance. 31 studies from 31 independent teams in 16 countries show significant benefit.
Meta analysis using the most serious outcome reported shows 15% [5‑24%] lower risk. Results are similar for Randomized Controlled Trials, higher quality studies, and peer-reviewed studies.
Studies to date show no significant difference for mortality. A small mortality improvement is seen, without statistical significance, however meta regression with followup duration shows decreasing efficacy with longer followup. There is also no benefit seen for mechanical ventilation, ICU admission, or hospitalization. This may reflect antiviral efficacy being offset by side effects of treatment.
0 0.5 1 1.5+ All studies 15% 70 34,275 Improvement, Studies, Patients Relative Risk Mortality 11% 40 27,628 Ventilation -10% 12 11,464 ICU admission -31% 21 9,522 Hospitalization -4% 19 6,502 Progression 21% 10 12,134 Recovery 15% 27 8,826 Viral clearance 18% 27 5,022 RCTs 15% 34 9,630 Peer-reviewed 16% 67 33,554 Early 17% 20 12,457 Late 14% 50 21,818 Favipiravir for COVID-19 c19early.org December 2024 after exclusions Favorsfavipiravir Favorscontrol
2 RCTs with 1,128 patients have not reported results (up to 3 years late)1,2.
Potential risks include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity3-7. Favipiravir may impair clotting8. Variants may be less susceptible to favipiravir9.
No treatment is 100% effective. Protocols combine safe and effective options with individual risk/benefit analysis and monitoring. Other treatments are more effective. All data and sources to reproduce this analysis are in the appendix.
Followup duration (days) Efficacy Favipiravir mortality by followup duration 0 15 30 45 60 75 90 105 -25% 0% 25% 50% 75% 100% c19early.org December 2024 mixed-effects meta-regression
Favipiravir for COVID-19 — Highlights
Favipiravir reduces risk with very high confidence for recovery, viral clearance, and in pooled analysis, and very low confidence for mortality and progression, however increased risk is seen with very high confidence for ICU admission. Potential risks include the creation of dangerous variants, carcinogenicity, and genotoxicity.
Real-time updates and corrections with a consistent protocol for 111 treatments. Outcome specific analysis and combined evidence from all studies including treatment delay, a primary confounding factor.
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Ruzhentsova (RCT) 6% 0.94 [0.78-1.14] hosp. 3/112 2/56 Improvement, RR [CI] Treatment Control Udwadia (RCT) 66% 0.34 [0.01-8.12] death 0/73 1/75 Sawanpanyalert 68% 0.32 [0.15-0.66] progression n/a n/a Holubar (DB RCT) 89% 0.11 [0.01-2.02] hosp. 0/75 4/74 Alattar (PSM) 33% 0.67 [0.28-1.61] death 8/387 12/387 Bosaeed (DB RCT) -619% 7.19 [0.38-138] ICU 3/112 0/119 FLARE Lowe (DB RCT) -202% 3.02 [0.13-72.6] ICU 1/59 0/60 Adhikari (RCT) -40% 1.40 [0.57-3.44] no improv. 10/38 6/32 Tsuzuki 13% 0.87 [0.52-1.46] death 2,532 (n) 5,122 (n) Qadir 97% 0.03 [0.00-0.47] death 0/125 17/125 Usanma Koban 86% 0.14 [0.02-0.70] viral+ 47 (n) 79 (n) Sirijatuphat (RCT) 64% 0.36 [0.20-0.64] improv. 62 (n) 31 (n) McMahon (RCT) -1% 1.01 [0.34-3.03] oxygen 6/99 6/100 PRESECO Golan (DB RCT) 67% 0.33 [0.01-8.12] death 0/599 1/588 Bruminhent -227% 3.27 [1.43-7.50] progression n/a n/a Chandiwana (RCT) -13% 1.13 [0.23-5.46] progression 37 (n) 39 (n) CT​2 Vaezi (DB RCT) -105% 2.05 [0.40-10.6] hosp. 4/38 2/39 PLATCOV Luvira (RCT) -6% 1.06 [0.93-1.21] viral rate 116 (n) 132 (n) Lokanuwatsatien 14% 0.86 [0.64-1.17] PASC 400 (n) 402 (n) Iwata (DB RCT) -16% 1.16 [0.45-2.21] oxygen 12/43 12/43 Tau​2 = 0.17, I​2 = 61.3%, p = 0.22 Early treatment 17% 0.83 [0.61-1.12] 47/4,954 63/7,503 17% lower risk Cai 69% 0.31 [0.10-0.96] pneumonia 35 (n) 45 (n) Improvement, RR [CI] Treatment Control Ivashchenko (RCT) -300% 4.00 [0.20-79.6] death 2/40 0/20 Lou (RCT) -422% 5.22 [0.28-96.2] ICU 2/9 0/10 Pushkar (RCT) 14% 0.86 [0.73-1.00] no recov. 73/100 85/100 Khamis (RCT) 15% 0.85 [0.28-2.59] death 5/44 6/45 OT​1 CT​2 Solaymani.. (RCT) -19% 1.19 [0.70-2.04] death 26/190 21/183 OT​1 Zhao (RCT) 59% 0.41 [0.16-1.03] viral+ 7/36 9/19 Haji Aghajani 26% 0.74 [0.43-1.27] death 40 (n) 951 (n) Alamer -56% 1.56 [0.73-3.36] death 12/233 21/223 Almoosa -42% 1.42 [0.90-2.25] death 33/110 24/116 Shinkai (SB RCT) 37% 0.63 [0.40-0.98] imp. time 107 (n) 49 (n) Assiri (ICU) -79% 1.79 [0.33-8.02] death 11/67 3/51 ICU patients Kulzhanova 88% 0.12 [0.04-0.37] no improv. 3/40 25/40 Chen (RCT) -3% 1.03 [0.15-7.22] ICU 2/116 2/120 OT​1 Alotaibi 57% 0.43 [0.18-1.01] death 244 (n) 193 (n) OT​1 Tabarsi (RCT) 30% 0.70 [0.17-2.88] death 3/32 4/30 OT​1 FIGHT-COVID-19 Atipornwa.. (RCT) 23% 0.77 [0.35-1.67] death 10/100 13/100 OT​1 CT​2 Damayanti 54% 0.46 [0.22-0.92] no recov. 96 (n) 96 (n) Shenoy (DB RCT) -29% 1.29 [0.60-2.77] death 14/175 11/178 Chuah (RCT) -1154% 12.54 [0.76-208] death 5/250 0/250 Finberg (RCT) -200% 3.00 [0.13-70.3] death 1/25 0/25 Al Mutair (ICU) 7% 0.93 [0.77-1.12] death 119/269 128/269 ICU patients OT​1 Kurniyanto 48% 0.52 [0.22-1.25] death 10/325 9/152 Cilli 38% 0.62 [0.24-1.63] death 5/23 8/23 Al-Muhsen -263% 3.63 [1.06-12.4] death 156 (n) 442 (n) Yulia 85% 0.15 [0.02-1.02] death 432 (all patients) Uyaroğlu (PSM) 67% 0.33 [0.01-7.96] death 0/42 1/42 OT​1 AlQahtani (RCT) -196% 2.96 [0.12-71.1] death 1/54 0/52 Shinada 7% 0.93 [0.45-1.89] hosp. 17 (n) 17 (n) Hassaniazad (RCT) 68% 0.32 [0.07-1.48] death 2/32 6/31 OT​1 Hafez -3% 1.03 [0.68-1.56] viral+ 59 (n) 1,446 (n) CT​2 Rahman (DB RCT) 89% 0.11 [0.01-0.75] no improv. 1/19 8/16 Tehrani (RCT) 34% 0.66 [0.34-1.26] hosp. 10/38 16/40 Abdulrahman (ICU) 3% 0.97 [0.81-1.18] death 74/193 593/1,506 ICU patients Acar Sevinc (ICU) 16% 0.84 [0.62-1.12] death 57/85 12/15 ICU patients OT​1 Tawfik 96% 0.04 [0.00-0.26] death 1/103 17/62 Babayigit -184% 2.84 [1.27-6.14] ventilation 47/325 17/977 Behboodikhah 68% 0.32 [0.05-1.83] death 95 (n) 2,079 (n) PIONEER Shah (RCT) 26% 0.74 [0.44-1.23] death 26/251 34/248 Alosaimi (PSM) 80% 0.20 [0.01-4.03] death 0/37 2/37 OT​1 Delen 23% 0.77 [0.19-3.20] ICU 3/34 4/35 Hartantri 76% 0.24 [0.11-0.54] death n/a n/a Alshamrani (PSM) -14% 1.14 [0.96-1.35] death 326/1,159 316/1,380 Arfijanto 51% 0.49 [0.26-0.94] viral+ 8/37 55/125 Sulaiman (ICU) -17% 1.17 [0.73-1.87] death 73 (n) 73 (n) ICU patients Shamsi 96% 0.04 [0.00-3.01] death 0/19 24/164 FAVID Horcajada (DB RCT) -383% 4.83 [0.24-95.1] death 2/23 0/21 Alsaraj (RCT) -87% 1.87 [0.67-5.21] death 9/51 5/53 Saito -168% 2.68 [0.96-7.48] death 7/40 6/92 PRINCIPLE Hobbs (RCT) 86% 0.14 [0.01-2.65] death 0/1,829 3/1,668 Tau​2 = 0.06, I​2 = 66.0%, p = 0.017 Late treatment 14% 0.86 [0.75-0.97] 917/7,477 1,488/13,909 14% lower risk All studies 15% 0.85 [0.76-0.95] 964/12,431 1,551/21,412 15% lower risk 70 favipiravir COVID-19 studies c19early.org December 2024 Tau​2 = 0.06, I​2 = 64.4%, p = 0.0054 Effect extraction pre-specified(most serious outcome, see appendix) 1 OT: comparison with other treatment2 CT: study uses combined treatment Favors favipiravir Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Ruzhentsova (RCT) 6% hospitalization Improvement Relative Risk [CI] Udwadia (RCT) 66% death Sawanpanyalert 68% progression Holubar (DB RCT) 89% hospitalization Alattar (PSM) 33% death Bosaeed (DB RCT) -619% ICU admission FLARE Lowe (DB RCT) -202% ICU admission Adhikari (RCT) -40% improvement Tsuzuki 13% death Qadir 97% death Usanma Koban 86% viral- Sirijatup.. (RCT) 64% improv. McMahon (RCT) -1% oxygen therapy PRESECO Golan (DB RCT) 67% death Bruminhent -227% progression Chandiwana (RCT) -13% progression CT​2 Vaezi (DB RCT) -105% hospitalization PLATCOV Luvira (RCT) -6% viral rate Lokanuwatsatien 14% PASC Iwata (DB RCT) -16% oxygen therapy Tau​2 = 0.17, I​2 = 61.3%, p = 0.22 Early treatment 17% 17% lower risk Cai 69% pneumonia Ivashchenko (RCT) -300% death Lou (RCT) -422% ICU admission Pushkar (RCT) 14% recovery Khamis (RCT) 15% death OT​1 CT​2 Solayman.. (RCT) -19% death OT​1 Zhao (RCT) 59% viral- Haji Aghajani 26% death Alamer -56% death Almoosa -42% death Shinkai (SB RCT) 37% imp. time Assiri (ICU) -79% death ICU patients Kulzhanova 88% improvement Chen (RCT) -3% ICU admission OT​1 Alotaibi 57% death OT​1 Tabarsi (RCT) 30% death OT​1 FIGHT-COVID-19 Atipornw.. (RCT) 23% death OT​1 CT​2 Damayanti 54% recovery Shenoy (DB RCT) -29% death Chuah (RCT) -1154% death Finberg (RCT) -200% death Al Mutair (ICU) 7% death ICU patients OT​1 Kurniyanto 48% death Cilli 38% death Al-Muhsen -263% death Yulia 85% death Uyaroğlu (PSM) 67% death OT​1 AlQahtani (RCT) -196% death Shinada 7% hospitalization Hassaniazad (RCT) 68% death OT​1 Hafez -3% viral- CT​2 Rahman (DB RCT) 89% improvement Tehrani (RCT) 34% hospitalization Abdulrahman (ICU) 3% death ICU patients Acar Sevinc (ICU) 16% death ICU patients OT​1 Tawfik 96% death Babayigit -184% ventilation Behboodikhah 68% death PIONEER Shah (RCT) 26% death Alosaimi (PSM) 80% death OT​1 Delen 23% ICU admission Hartantri 76% death Alshamrani (PSM) -14% death Arfijanto 51% viral- Sulaiman (ICU) -17% death ICU patients Shamsi 96% death FAVID Horcajada (DB RCT) -383% death Alsaraj (RCT) -87% death Saito -168% death PRINCIPLE Hobbs (RCT) 86% death Tau​2 = 0.06, I​2 = 66.0%, p = 0.017 Late treatment 14% 14% lower risk All studies 15% 15% lower risk 70 favipiravir C19 studies c19early.org December 2024 Tau​2 = 0.06, I​2 = 64.4%, p = 0.0054 Effect extraction pre-specifiedRotate device for footnotes/details Favors favipiravir Favors control
B
Loading..
Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. For details see the appendix. B. Timeline of results in favipiravir studies.
Introduction
SARS-CoV-2 infection primarily begins in the upper respiratory tract and may progress to the lower respiratory tract, other tissues, and the nervous and cardiovascular systems, which may lead to cytokine storm, pneumonia, ARDS, neurological injury10-21 and cognitive deficits13,18, cardiovascular complications22-24, organ failure, and death. Minimizing replication as early as possible is recommended.
SARS-CoV-2 infection and replication involves the complex interplay of 50+ host and viral proteins and other factorsA,25-30, providing many therapeutic targets for which many existing compounds have known activity. Scientists have predicted that over 8,000 compounds may reduce COVID-19 risk31, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications.
We analyze all significant controlled studies of favipiravir for COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random effects meta-analysis results for all studies, studies within each treatment stage, individual outcomes, peer-reviewed studies, Randomized Controlled Trials (RCTs), and higher quality studies.
Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
regular treatment to prevent or minimize infectionstreat immediately on symptoms or shortly thereafterlate stage after disease progressionexposed to virusEarly TreatmentProphylaxisTreatment delayLate Treatment
Figure 2. Treatment stages.
Preclinical Research
An In Silico study supports the efficacy of favipiravir32.
3 In Vitro studies support the efficacy of favipiravir32-34.
Preclinical research is an important part of the development of treatments, however results may be very different in clinical trials. Preclinical results are not used in this paper.
Results
Table 1 summarizes the results for all stages combined, for Randomized Controlled Trials, for peer-reviewed studies, after exclusions, and for specific outcomes. Table 2 shows results by treatment stage. Figure 3 plots individual results by treatment stage. Figure 4, 5, 6, 7, 8, 9, 10, 11, and 12 show forest plots for random effects meta-analysis of all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, progression, recovery, viral clearance, and peer reviewed studies.
Table 1. Random effects meta-analysis for all stages combined, for Randomized Controlled Trials, for peer-reviewed studies, after exclusions, and for specific outcomes. Results show the percentage improvement with treatment and the 95% confidence interval. * p<0.05  ** p<0.01  *** p<0.001.
Improvement Studies Patients Authors
All studies15% [5‑24%]
**
70 34,275 1,142
After exclusions18% [6‑28%]
**
54 28,020 940
Peer-reviewed studiesPeer-reviewed16% [5‑25%]
**
67 33,554 1,102
Randomized Controlled TrialsRCTs15% [-2‑28%]34 9,630 716
Mortality11% [-5‑25%]40 27,628 635
VentilationVent.-10% [-56‑23%]12 11,464 379
ICU admissionICU-31% [-56‑-10%]
**
21 9,522 393
HospitalizationHosp.-4% [-23‑13%]19 6,502 329
Recovery15% [4‑24%]
**
27 8,826 548
Viral18% [8‑27%]
***
27 5,022 436
RCT mortality3% [-26‑25%]16 7,335 378
RCT hospitalizationRCT hosp.15% [-12‑36%]9 1,145 184
Table 2. Random effects meta-analysis results by treatment stage. Results show the percentage improvement with treatment, the 95% confidence interval, and the number of studies for the stage.treatment and the 95% confidence interval. * p<0.05  ** p<0.01  *** p<0.001.
Early treatment Late treatment
All studies17% [-12‑39%]14% [3‑25%]
*
After exclusions19% [-17‑43%]18% [4‑30%]
*
Peer-reviewed studiesPeer-reviewed18% [-12‑39%]16% [3‑27%]
*
Randomized Controlled TrialsRCTs8% [-33‑37%]18% [-2‑34%]
Mortality42% [-22‑72%]9% [-9‑23%]
VentilationVent.-2% [-60‑35%]-10% [-66‑27%]
ICU admissionICU-381% [-4086‑45%]-30% [-55‑-9%]
**
HospitalizationHosp.-4% [-137‑54%]-7% [-27‑11%]
Recovery9% [-16‑28%]17% [5‑27%]
**
Viral8% [-9‑21%]40% [22‑53%]
***
RCT mortality67% [-219‑97%]0% [-33‑26%]
RCT hospitalizationRCT hosp.-55% [-177‑14%]26% [9‑40%]
**
Loading..
Figure 3. Scatter plot showing the most serious outcome in all studies, and for studies within each stage. Diamonds shows the results of random effects meta-analysis.
Loading..
Loading..
Figure 4. Random effects meta-analysis for all studies. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. For details see the appendix.
Loading..
Loading..
Figure 5. Random effects meta-analysis for mortality results.
Loading..
Figure 6. Random effects meta-analysis for ventilation.
Loading..
Figure 7. Random effects meta-analysis for ICU admission.
Loading..
Figure 8. Random effects meta-analysis for hospitalization.
Loading..
Figure 9. Random effects meta-analysis for progression.
Loading..
Figure 10. Random effects meta-analysis for recovery.
Loading..
Figure 11. Random effects meta-analysis for viral clearance.
Loading..
Figure 12. Random effects meta-analysis for peer reviewed studies. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details. Analysis validating pooled outcomes for COVID-19 can be found below. Zeraatkar et al. analyze 356 COVID-19 trials, finding no significant evidence that preprint results are inconsistent with peer-reviewed studies. They also show extremely long peer-review delays, with a median of 6 months to journal publication. A six month delay was equivalent to around 1.5 million deaths during the first two years of the pandemic. Authors recommend using preprint evidence, with appropriate checks for potential falsified data, which provides higher certainty much earlier. Davidson et al. also showed no important difference between meta analysis results of preprints and peer-reviewed publications for COVID-19, based on 37 meta analyses including 114 trials.
Randomized Controlled Trials (RCTs)
Figure 13 shows a comparison of results for RCTs and non-RCT studies. Figure 14, 15, and 16 show forest plots for random effects meta-analysis of all Randomized Controlled Trials, RCT mortality results, and RCT hospitalization results. RCT results are included in Table 1 and Table 2.
Loading..
Figure 13. Results for RCTs and non-RCT studies.
Loading..
Figure 14. Random effects meta-analysis for all Randomized Controlled Trials. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. For details see the appendix.
Loading..
Figure 15. Random effects meta-analysis for RCT mortality results.
Loading..
Figure 16. Random effects meta-analysis for RCT hospitalization results.
RCTs help to make study groups more similar and can provide a higher level of evidence, however they are subject to many biases37, and analysis of double-blind RCTs has identified extreme levels of bias38. For COVID-19, the overhead may delay treatment, dramatically compromising efficacy; they may encourage monotherapy for simplicity at the cost of efficacy which may rely on combined or synergistic effects; the participants that sign up may not reflect real world usage or the population that benefits most in terms of age, comorbidities, severity of illness, or other factors; standard of care may be compromised and unable to evolve quickly based on emerging research for new diseases; errors may be made in randomization and medication delivery; and investigators may have hidden agendas or vested interests influencing design, operation, analysis, reporting, and the potential for fraud. All of these biases have been observed with COVID-19 RCTs. There is no guarantee that a specific RCT provides a higher level of evidence.
RCTs are expensive and many RCTs are funded by pharmaceutical companies or interests closely aligned with pharmaceutical companies. For COVID-19, this creates an incentive to show efficacy for patented commercial products, and an incentive to show a lack of efficacy for inexpensive treatments. The bias is expected to be significant, for example Als-Nielsen et al. analyzed 370 RCTs from Cochrane reviews, showing that trials funded by for-profit organizations were 5 times more likely to recommend the experimental drug compared with those funded by nonprofit organizations. For COVID-19, some major philanthropic organizations are largely funded by investments with extreme conflicts of interest for and against specific COVID-19 interventions.
High quality RCTs for novel acute diseases are more challenging, with increased ethical issues due to the urgency of treatment, increased risk due to enrollment delays, and more difficult design with a rapidly evolving evidence base. For COVID-19, the most common site of initial infection is the upper respiratory tract. Immediate treatment is likely to be most successful and may prevent or slow progression to other parts of the body. For a non-prophylaxis RCT, it makes sense to provide treatment in advance and instruct patients to use it immediately on symptoms, just as some governments have done by providing medication kits in advance. Unfortunately, no RCTs have been done in this way. Every treatment RCT to date involves delayed treatment. Among the 111 treatments we have analyzed, 65% of RCTs involve very late treatment 5+ days after onset. No non-prophylaxis COVID-19 RCTs match the potential real-world use of early treatments. They may more accurately represent results for treatments that require visiting a medical facility, e.g., those requiring intravenous administration.
RCTs have a bias against finding an effect for interventions that are widely available — patients that believe they need the intervention are more likely to decline participation and take the intervention. RCTs for favipiravir are more likely to enroll low-risk participants that do not need treatment to recover, making the results less applicable to clinical practice. This bias is likely to be greater for widely known treatments, and may be greater when the risk of a serious outcome is overstated. This bias does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable.
For COVID-19, observational study results do not systematically differ from RCTs, RR 1.00 [0.92‑1.08] across 111 treatments40.
Evidence shows that observational studies can also provide reliable results. Concato et al. found that well-designed observational studies do not systematically overestimate the magnitude of the effects of treatment compared to RCTs. Anglemyer et al. analyzed reviews comparing RCTs to observational studies and found little evidence for significant differences in effect estimates. We performed a similar analysis across the 111 treatments we cover, showing no significant difference in the results of RCTs compared to observational studies, RR 1.00 [0.92‑1.08]. Similar results are found for all low-cost treatments, RR 1.02 [0.92‑1.12]. High-cost treatments show a non-significant trend towards RCTs showing greater efficacy, RR 0.92 [0.82‑1.03]. Details can be found in the supplementary data. Lee et al. showed that only 14% of the guidelines of the Infectious Diseases Society of America were based on RCTs. Evaluation of studies relies on an understanding of the study and potential biases. Limitations in an RCT can outweigh the benefits, for example excessive dosages, excessive treatment delays, or remote survey bias may have a greater effect on results. Ethical issues may also prevent running RCTs for known effective treatments. For more on issues with RCTs see44,45.
Currently, 48 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. Of these, 60% have been confirmed in RCTs, with a mean delay of 7.1 months (68% with 8.2 months delay for low-cost treatments). The remaining treatments either have no RCTs, or the point estimate is consistent.
We need to evaluate each trial on its own merits. RCTs for a given medication and disease may be more reliable, however they may also be less reliable. For off-patent medications, very high conflict of interest trials may be more likely to be RCTs, and more likely to be large trials that dominate meta analyses.
Unreported RCTs
2 favipiravir RCTs have not reported results1,2. The trials report total actual enrollment of 1,128 patients. The results are delayed from 1.5 years to over 3 years.
Exclusions
To avoid bias in the selection of studies, we analyze all non-retracted studies. Here we show the results after excluding studies with major issues likely to alter results, non-standard studies, and studies where very minimal detail is currently available. Our bias evaluation is based on analysis of each study and identifying when there is a significant chance that limitations will substantially change the outcome of the study. We believe this can be more valuable than checklist-based approaches such as Cochrane GRADE, which can be easily influenced by potential bias, may ignore or underemphasize serious issues not captured in the checklists, and may overemphasize issues unlikely to alter outcomes in specific cases (for example certain specifics of randomization with a very large effect size and well-matched baseline characteristics).
The studies excluded are as below. Figure 17 shows a forest plot for random effects meta-analysis of all studies after exclusions.
Abdulrahman, very late stage, ICU patients.
Acar Sevinc, very late stage, ICU patients.
Al Mutair, very late stage, ICU patients.
Alsaraj, potential data issue.
Arfijanto, unadjusted results with no group details.
Assiri, unadjusted results with no group details; very late stage, ICU patients.
Babayigit, substantial unadjusted confounding by indication possible.
Cilli, unadjusted results with no group details.
Damayanti, minimal details provided.
Khamis, study compares against another treatment showing significant efficacy.
Kurniyanto, unadjusted results with no group details.
Lokanuwatsatien, unadjusted results with no group details.
Saito, unadjusted results with no group details.
Shamsi, unadjusted results with no group details.
Sulaiman, very late stage, ICU patients.
Tawfik, unadjusted results with minimal group details.
Loading..
Figure 17. Random effects meta-analysis for all studies after exclusions. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. For details see the appendix.
Heterogeneity
Heterogeneity in COVID-19 studies arises from many factors including:
The time between infection or the onset of symptoms and treatment may critically affect how well a treatment works. For example an antiviral may be very effective when used early but may not be effective in late stage disease, and may even be harmful. Oseltamivir, for example, is generally only considered effective for influenza when used within 0-36 or 0-48 hours62,63. Baloxavir marboxil studies for influenza also show that treatment delay is critical — Ikematsu et al. report an 86% reduction in cases for post-exposure prophylaxis, Hayden et al. show a 33 hour reduction in the time to alleviation of symptoms for treatment within 24 hours and a reduction of 13 hours for treatment within 24-48 hours, and Kumar et al. report only 2.5 hours improvement for inpatient treatment.
Table 3. Studies of baloxavir marboxil for influenza show that early treatment is more effective.
Treatment delayResult
Post-exposure prophylaxis86% fewer cases64
<24 hours-33 hours symptoms65
24-48 hours-13 hours symptoms65
Inpatients-2.5 hours to improvement66
Figure 18 shows a mixed-effects meta-regression for efficacy as a function of treatment delay in COVID-19 studies from 111 treatments, showing that efficacy declines rapidly with treatment delay. Early treatment is critical for COVID-19.
Loading..
Figure 18. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 111 treatments.
Details of the patient population including age and comorbidities may critically affect how well a treatment works. For example, many COVID-19 studies with relatively young low-comorbidity patients show all patients recovering quickly with or without treatment. In such cases, there is little room for an effective treatment to improve results, for example as in López-Medina et al.
Efficacy may depend critically on the distribution of SARS-CoV-2 variants encountered by patients. Risk varies significantly across variants68, for example the Gamma variant shows significantly different characteristics69-72. Different mechanisms of action may be more or less effective depending on variants, for example the degree to which TMPRSS2 contributes to viral entry can differ across variants73,74.
Effectiveness may depend strongly on the dosage and treatment regimen.
The quality of medications may vary significantly between manufacturers and production batches, which may significantly affect efficacy and safety. Williams et al. analyze ivermectin from 11 different sources, showing highly variable antiparasitic efficacy across different manufacturers. Xu et al. analyze a treatment from two different manufacturers, showing 9 different impurities, with significantly different concentrations for each manufacturer.
The use of other treatments may significantly affect outcomes, including supplements, other medications, or other interventions such as prone positioning. Treatments may be synergistic77-88, therefore efficacy may depend strongly on combined treatments.
Across all studies there is a strong association between different outcomes, for example improved recovery is strongly associated with lower mortality. However, efficacy may differ depending on the effect measured, for example a treatment may be more effective against secondary complications and have minimal effect on viral clearance.
The distribution of studies will alter the outcome of a meta analysis. Consider a simplified example where everything is equal except for the treatment delay, and effectiveness decreases to zero or below with increasing delay. If there are many studies using very late treatment, the outcome may be negative, even though early treatment is very effective. All meta analyses combine heterogeneous studies, varying in population, variants, and potentially all factors above, and therefore may obscure efficacy by including studies where treatment is less effective. Generally, we expect the estimated effect size from meta analysis to be less than that for the optimal case. Looking at all studies is valuable for providing an overview of all research, important to avoid cherry-picking, and informative when a positive result is found despite combining less-optimal situations. However, the resulting estimate does not apply to specific cases such as early treatment in high-risk populations. While we present results for all studies, we also present treatment time and individual outcome analyses, which may be more informative for specific use cases.
Pooled Effects
For COVID-19, delay in clinical results translates into additional death and morbidity, as well as additional economic and societal damage. Combining the results of studies reporting different outcomes is required. There may be no mortality in a trial with low-risk patients, however a reduction in severity or improved viral clearance may translate into lower mortality in a high-risk population. Different studies may report lower severity, improved recovery, and lower mortality, and the significance may be very high when combining the results. "The studies reported different outcomes" is not a good reason for disregarding results. Pooling the results of studies reporting different outcomes allows us to use more of the available information. Logically we should, and do, use additional information when evaluating treatments—for example dose-response and treatment delay-response relationships provide additional evidence of efficacy that is considered when reviewing the evidence for a treatment.
We present both specific outcome and pooled analyses. In order to combine the results of studies reporting different outcomes we use the most serious outcome reported in each study, based on the thesis that improvement in the most serious outcome provides comparable measures of efficacy for a treatment. A critical advantage of this approach is simplicity and transparency. There are many other ways to combine evidence for different outcomes, along with additional evidence such as dose-response relationships, however these increase complexity.
Trials with high-risk patients may be restricted due to ethics for treatments that are known or expected to be effective, and they increase difficulty for recruiting. Using less severe outcomes as a proxy for more serious outcomes allows faster and safer collection of evidence.
For many COVID-19 treatments, a reduction in mortality logically follows from a reduction in hospitalization, which follows from a reduction in symptomatic cases, which follows from a reduction in PCR positivity. We can directly test this for COVID-19.
Analysis of the the association between different outcomes across studies from all 111 treatments we cover confirms the validity of pooled outcome analysis for COVID-19. Figure 19 shows that lower hospitalization is very strongly associated with lower mortality (p < 0.000000000001). Similarly, Figure 20 shows that improved recovery is very strongly associated with lower mortality (p < 0.000000000001). Considering the extremes, Singh et al. show an association between viral clearance and hospitalization or death, with p = 0.003 after excluding one large outlier from a mutagenic treatment, and based on 44 RCTs including 52,384 patients. Figure 21 shows that improved viral clearance is strongly associated with fewer serious outcomes. The association is very similar to Singh et al., with higher confidence due to the larger number of studies. As with Singh et al., the confidence increases when excluding the outlier treatment, from p = 0.00000042 to p = 0.00000002.
Loading..
Figure 19. Lower hospitalization is associated with lower mortality, supporting pooled outcome analysis.
Loading..
Figure 20. Improved recovery is associated with lower mortality, supporting pooled outcome analysis.
Loading..
Figure 19. Improved viral clearance is associated with fewer serious outcomes, supporting pooled outcome analysis.
Currently, 48 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 89% of these have been confirmed with one or more specific outcomes, with a mean delay of 5.1 months. When restricting to RCTs only, 56% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 6.4 months. Figure 22 shows when treatments were found effective during the pandemic. Pooled outcomes often resulted in earlier detection of efficacy.
Loading..
Loading..
Figure 22. The time when studies showed that treatments were effective, defined as statistically significant improvement of ≥10% from ≥3 studies. Pooled results typically show efficacy earlier than specific outcome results. Results from all studies often shows efficacy much earlier than when restricting to RCTs. Results reflect conditions as used in trials to date, these depend on the population treated, treatment delay, and treatment regimen.
Pooled analysis could hide efficacy, for example a treatment that is beneficial for late stage patients but has no effect on viral clearance may show no efficacy if most studies only examine viral clearance. In practice, it is rare for a non-antiviral treatment to report viral clearance and to not report clinical outcomes; and in practice other sources of heterogeneity such as difference in treatment delay is more likely to hide efficacy.
Analysis validates the use of pooled effects and shows significantly faster detection of efficacy on average. However, as with all meta analyses, it is important to review the different studies included. We also present individual outcome analyses, which may be more informative for specific use cases.
Discussion
Publishing is often biased towards positive results, however evidence suggests that there may be a negative bias for inexpensive treatments for COVID-19. Both negative and positive results are very important for COVID-19, media in many countries prioritizes negative results for inexpensive treatments (inverting the typical incentive for scientists that value media recognition), and there are many reports of difficulty publishing positive results90-93.
One method to evaluate bias is to compare prospective vs. retrospective studies. Prospective studies are more likely to be published regardless of the result, while retrospective studies are more likely to exhibit bias. For example, researchers may perform preliminary analysis with minimal effort and the results may influence their decision to continue. Retrospective studies also provide more opportunities for the specifics of data extraction and adjustments to influence results.
Figure 23 shows a scatter plot of results for prospective and retrospective studies. 36% of retrospective studies report a statistically significant positive effect for one or more outcomes, compared to 51% of prospective studies, consistent with a bias toward publishing negative results.
Loading..
Figure 23. Prospective vs. retrospective studies. The diamonds show the results of random effects meta-analysis.
Funnel plots have traditionally been used for analyzing publication bias. This is invalid for COVID-19 acute treatment trials — the underlying assumptions are invalid, which we can demonstrate with a simple example. Consider a set of hypothetical perfect trials with no bias. Figure 24 plot A shows a funnel plot for a simulation of 80 perfect trials, with random group sizes, and each patient's outcome randomly sampled (10% control event probability, and a 30% effect size for treatment). Analysis shows no asymmetry (p > 0.05). In plot B, we add a single typical variation in COVID-19 treatment trials — treatment delay. Consider that efficacy varies from 90% for treatment within 24 hours, reducing to 10% when treatment is delayed 3 days. In plot B, each trial's treatment delay is randomly selected. Analysis now shows highly significant asymmetry, p < 0.0001, with six variants of Egger's test all showing p < 0.0594-101. Note that these tests fail even though treatment delay is uniformly distributed. In reality treatment delay is more complex — each trial has a different distribution of delays across patients, and the distribution across trials may be biased (e.g., late treatment trials may be more common). Similarly, many other variations in trials may produce asymmetry, including dose, administration, duration of treatment, differences in SOC, comorbidities, age, variants, and bias in design, implementation, analysis, and reporting.
Log Risk Ratio Standard Error 1.406 1.055 0.703 0.352 0 -3 -2 -1 0 1 2 A: Simulated perfect trials p > 0.05 Log Risk Ratio Standard Error 1.433 1.074 0.716 0.358 0 -4 -3 -2 -1 0 1 2 B: Simulated perfect trials with varying treatment delay p < 0.0001
Figure 24. Example funnel plot analysis for simulated perfect trials.
Pharmaceutical drug trials often have conflicts of interest whereby sponsors or trial staff have a financial interest in the outcome being positive. Favipiravir for COVID-19 lacks this because it is off-patent, has multiple manufacturers, and is very low cost. In contrast, most COVID-19 favipiravir trials have been run by physicians on the front lines with the primary goal of finding the best methods to save human lives and minimize the collateral damage caused by COVID-19. While pharmaceutical companies are careful to run trials under optimal conditions (for example, restricting patients to those most likely to benefit, only including patients that can be treated soon after onset when necessary, and ensuring accurate dosing), not all favipiravir trials represent the optimal conditions for efficacy.
Summary statistics from meta analysis necessarily lose information. As with all meta analyses, studies are heterogeneous, with differences in treatment delay, treatment regimen, patient demographics, variants, conflicts of interest, standard of care, and other factors. We provide analyses for specific outcomes and by treatment delay, and we aim to identify key characteristics in the forest plots and summaries. Results should be viewed in the context of study characteristics.
Some analyses classify treatment based on early or late administration, as done here, while others distinguish between mild, moderate, and severe cases. Viral load does not indicate degree of symptoms — for example patients may have a high viral load while being asymptomatic. With regard to treatments that have antiviral properties, timing of treatment is critical — late administration may be less helpful regardless of severity.
Details of treatment delay per patient is often not available. For example, a study may treat 90% of patients relatively early, but the events driving the outcome may come from 10% of patients treated very late. Our 5 day cutoff for early treatment may be too conservative, 5 days may be too late in many cases.
Comparison across treatments is confounded by differences in the studies performed, for example dose, variants, and conflicts of interest. Trials with conflicts of interest may use designs better suited to the preferred outcome.
In some cases, the most serious outcome has very few events, resulting in lower confidence results being used in pooled analysis, however the method is simpler and more transparent. This is less critical as the number of studies increases. Restriction to outcomes with sufficient power may be beneficial in pooled analysis and improve accuracy when there are few studies, however we maintain our pre-specified method to avoid any retrospective changes.
Studies show that combinations of treatments can be highly synergistic and may result in many times greater efficacy than individual treatments alone77-88. Therefore standard of care may be critical and benefits may diminish or disappear if standard of care does not include certain treatments.
This real-time analysis is constantly updated based on submissions. Accuracy benefits from widespread review and submission of updates and corrections from reviewers. Less popular treatments may receive fewer reviews.
No treatment or intervention is 100% available and effective for all current and future variants. Efficacy may vary significantly with different variants and within different populations. All treatments have potential side effects. Propensity to experience side effects may be predicted in advance by qualified physicians. We do not provide medical advice. Before taking any medication, consult a qualified physician who can compare all options, provide personalized advice, and provide details of risks and benefits based on individual medical history and situations.
11 of the 70 studies compare against other treatments, which may reduce the effect seen. 4 of 70 studies combine treatments. The results of favipiravir alone may differ. 3 of 34 RCTs use combined treatment.
Multiple reviews cover favipiravir for COVID-19, presenting additional background on mechanisms and related results, including3-5,102,103.
Perspective
SARS-CoV-2 infection and replication involves a complex interplay of 50+ host and viral proteins and other factors25-30, providing many therapeutic targets. Over 8,000 compounds have been predicted to reduce COVID-19 risk31, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications. Figure 25 shows an overview of the results for favipiravir in the context of multiple COVID-19 treatments, and Figure 26 shows a plot of efficacy vs. cost for COVID-19 treatments.
Loading..
Figure 25. Scatter plot showing results within the context of multiple COVID-19 treatments. Diamonds shows the results of random effects meta-analysis. 0.6% of 8,000+ proposed treatments show efficacy104.
Loading..
Loading..
Figure 26. Efficacy vs. cost for COVID-19 treatments.
Significantly lower risk is seen for recovery and viral clearance. 31 studies from 31 independent teams in 16 countries show significant benefit. Meta analysis using the most serious outcome reported shows 15% [5‑24%] lower risk. Results are similar for Randomized Controlled Trials, higher quality studies, and peer-reviewed studies. Studies to date show no significant difference for mortality. A small mortality improvement is seen, without statistical significance, however meta regression with followup duration shows decreasing efficacy with longer followup. There is also no benefit seen for mechanical ventilation, ICU admission, or hospitalization. This may reflect antiviral efficacy being offset by side effects of treatment.
Potential risks include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity3-7. Favipiravir may impair clotting8. Variants may be less susceptible to favipiravir9.
Mortality 3% Improvement Relative Risk Favipiravir  Abdulrahman et al.  ICU PATIENTS Is very late treatment with favipiravir beneficial for COVID-19? Retrospective 1,699 patients in Saudi Arabia (Jun - Aug 2020) No significant difference in mortality c19early.org Abdulrahman et al., J. Ayub Medical Co.., Jun 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 1,699 ICU patients in Saudi Arabia, 193 treated with favipiravir, showing no significant difference in mortality. Submit Corrections or Updates.
Mortality 16% Improvement Relative Risk Ventilation 10% Favipiravir  Acar Sevinc et al.  ICU PATIENTS Is very late treatment with favipiravir beneficial for COVID-19? Retrospective 100 patients in Turkey (March - May 2020) Study compares with lopinavir/ritonavir, results vs. placebo may differ Lower mortality with favipiravir (not stat. sig., p=0.38) c19early.org Acar Sevinc, S., SiSli Etfal Hastanesi.., Jun 2022 Favorsfavipiravir Favorslopinavir/ri.. 0 0.5 1 1.5 2+
Retrospective 100 ICU patients in Turkey, showing improved survival with favipiravir vs. lopinavir/ritonavir. Submit Corrections or Updates.
Improvement -40% Improvement Relative Risk Improvement (b) -36% Improvement (c) -64% Favipiravir  Adhikari et al.  EARLY TREATMENT  RCT Is early treatment with favipiravir beneficial for COVID-19? RCT 70 patients in Nepal (May - October 2020) Worse improvement with favipiravir (not stat. sig., p=0.57) c19early.org Adhikari et al., Int. J. Infectious Di.., Mar 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality 7% Improvement Relative Risk ARDS -9% ICU time -34% Hospitalization time -37% Favipiravir  Al Mutair et al.  ICU PATIENTS Is very late treatment with favipiravir beneficial for COVID-19? Retrospective 538 patients in Saudi Arabia (April 2020 - March 2021) Study compares with various, results vs. placebo may differ Longer ICU admission (p=0.001) and hospitalization (p=0.001) c19early.org Al Mutair et al., J. Infection and Pub.., Feb 2022 Favorsfavipiravir Favorsvarious 0 0.5 1 1.5 2+
Retrospective 269 favipiravir ICU patients in Saudi Arabia and 269 matched controls receiving different treatments, showing no significant difference. Submit Corrections or Updates.
Mortality -263% Improvement Relative Risk Oxygen therapy 41% Hospitalization time -40% Favipiravir  Al-Muhsen et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Prospective study of 598 patients in Saudi Arabia (Jun 2020 - Jan 2021) Higher mortality (p=0.04) and lower oxygen therapy (p<0.0001) c19early.org Al-Muhsen et al., Frontiers in Medicine, Mar 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Prospective observational study of 598 hospitalized patients in Saudi Arabia, showing higher risk of mortality and longer hospitalization time with favipiravir. Submit Corrections or Updates.
Mortality -56% Improvement Relative Risk Ventilation 90% Adjusted discharge ratio 49% Favipiravir  Alamer et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 456 patients in Saudi Arabia Lower ventilation (p<0.0001) and higher discharge (p<0.0001) c19early.org Alamer et al., Current Medical Researc.., May 2021 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality 33% Improvement Relative Risk Clinical improvement -2% primary Days to clinical improv.. -6% Viral clearance 44% Favipiravir  Alattar et al.  EARLY TREATMENT Is early treatment with favipiravir beneficial for COVID-19? PSM retrospective 774 patients in Qatar (May - July 2020) Improved viral clearance with favipiravir (p=0.0000014) c19early.org Alattar et al., J. Infection and Publi.., Nov 2021 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality -42% Improvement Relative Risk Mortality, day 28 -149% Mortality, day 14 62% ICU admission -90% Recovery time -11% Favipiravir  Almoosa et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 226 patients in Saudi Arabia Higher ICU admission with favipiravir (p=0.02) c19early.org Almoosa et al., J. Infection and Publi.., Aug 2021 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality 80% Improvement Relative Risk Hospitalization time -75% Time to discharge -40% Favipiravir  Alosaimi et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? PSM retrospective 74 patients in Saudi Arabia (Apr 2020 - Mar 2021) Study compares with HCQ, results vs. placebo may differ Lower mortality with favipiravir (not stat. sig., p=0.49) c19early.org Alosaimi et al., Pharmaceuticals, November 2022 Favorsfavipiravir FavorsHCQ 0 0.5 1 1.5 2+
Retrospective 200 hospitalized COVID-19 patients in Saudi Arabia, showing no significant difference in outcomes between HCQ and favipiravir. Submit Corrections or Updates.
Mortality 57% Improvement Relative Risk Favipiravir  Alotaibi et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 437 patients in Saudi Arabia Study compares with HCQ, results vs. placebo may differ Lower mortality with favipiravir (not stat. sig., p=0.051) c19early.org Alotaibi et al., Int. J. General Medic.., Sep 2021 Favorsfavipiravir FavorsHCQ 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality -196% Improvement Relative Risk ICU admission 76% Recovery -42% Viral clearance 43% Favipiravir  AlQahtani et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 106 patients in Bahrain (August 2020 - March 2021) Lower ICU admission (p=0.2) and worse recovery (p=0.51), not sig. c19early.org AlQahtani et al., Scientific Reports, Mar 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality -87% Improvement Relative Risk Favipiravir  Alsaraj et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 104 patients in Iraq (September 2021 - February 2022) Higher mortality with favipiravir (not stat. sig., p=0.26) c19early.org Alsaraj et al., Infectious Diseases in.., Jan 2024 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
RCT 156 COVID-19 patients showing higher mortality with favipiravir and remdesivir overall. Favipiravir and remdesivir were more effective when started earlier, however note that Table 10 compares earlier favipiravir/remdesivir+standard care with standard care at any time, which will exaggerate the benefits/harms of earlier/later treatment. The confidence intervals for the Cox results are unusually narrow suggesting a possible error in calculation. Submit Corrections or Updates.
Mortality -14% Improvement Relative Risk Progression -2% ICU time -19% Hospitalization time -29% Favipiravir  Alshamrani et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? PSM retrospective 2,539 patients in Saudi Arabia (Mar 2020 - Jan 2021) Longer ICU admission (p=0.005) and hospitalization (p=0.001) c19early.org Alshamrani et al., Saudi Pharmaceutica.., Feb 2023 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
PSM retrospective 29 hospitals in Saudi Arabia, showing higher mortality with favipiravir treatment, without statistical significance. Submit Corrections or Updates.
Delayed viral clearance 51% Improvement Relative Risk Favipiravir  Arfijanto et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 162 patients in Indonesia (June - December 2021) Improved viral clearance with favipiravir (p=0.02) c19early.org Arfijanto et al., Pathophysiology, May 2023 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 162 hospitalized COVID-19 patients in Indonesia, showing lower incidence of delayed viral clearance with favipiravir treatment in unadjusted results. Submit Corrections or Updates.
Mortality -79% Improvement Relative Risk Favipiravir for COVID-19  Assiri et al.  ICU PATIENTS Is very late treatment with favipiravir beneficial for COVID-19? Retrospective 118 patients in Saudi Arabia Higher mortality with favipiravir (not stat. sig., p=0.5) c19early.org Assiri et al., J. Infection and Public.., Aug 2021 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 118 ICU patients in Saudi Arabia showing no significant differences in unadjusted results with zinc, vitamin D, and favipiravir treatment. Submit Corrections or Updates.
Mortality 23% Improvement Relative Risk Progression 60% Time to viral- 9% primary Time to viral- (b) 9% primary Favipiravir  FIGHT-COVID-19  LATE TREATMENT  RCT Is late treatment with favipiravir + combined treatments beneficial for COVID-19? RCT 200 patients in Thailand (August 2020 - August 2021) Trial compares with oseltamivir, results vs. placebo may differ Lower progression with favipiravir + combined treatments (p=0.0085) c19early.org Atipornwanich et al., SSRN Electronic J., Oct 2021 Favorsfavipiravir Favorsoseltamivir 0 0.5 1 1.5 2+
RCT 200 moderate/severe patients in Thailand, showing significantly lower progression with favipiravir vs. oseltamivir. NCT04303299. Submit Corrections or Updates.
Ventilation -184% Improvement Relative Risk ICU admission -181% Hospitalization time -100% Favipiravir  Babayigit et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 1,302 patients in Turkey (March - July 2020) Higher ventilation (p=0.011) and ICU admission (p=0.001) c19early.org Babayigit et al., Frontiers in Medicine, Aug 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 1,472 hospitalized patients in Turkey, showing a higher ICU admission and ventilation with favipiravir. Results may be subject to confounding by indication. Submit Corrections or Updates.
Mortality 68% Improvement Relative Risk Favipiravir  Behboodikhah et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 2,174 patients in Iran Lower mortality with favipiravir (not stat. sig., p=0.2) c19early.org Behboodikhah et al., Iranian J. Scienc.., Sep 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 2,174 hospitalized patients showing significantly shorter length of stay with favipiravir treatment. Submit Corrections or Updates.
ICU admission -619% Improvement Relative Risk Hospitalization -219% Time to clinical improvem.. -12% Time to viral clearance -15% primary Favipiravir  Bosaeed et al.  EARLY TREATMENT  DB RCT Is early treatment with favipiravir beneficial for COVID-19? Double-blind RCT 231 patients in Saudi Arabia (Jul 2020 - Aug 2021) Higher ICU admission (p=0.11) and hospitalization (p=0.16), not sig. c19early.org Bosaeed et al., Clinical Microbiology .., Jan 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Progression -227% Improvement Relative Risk Favipiravir  Bruminhent et al.  EARLY TREATMENT Is early treatment with favipiravir beneficial for COVID-19? Retrospective study in Thailand (April - May 2021) Higher progression with favipiravir (p=0.005) c19early.org Bruminhent et al., Tropical Medicine a.., Sep 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 514 patients in Thailand, showing higher risk of progression with favipiravir treatment. Submit Corrections or Updates.
Improvement in CT 69% Improvement Relative Risk Viral clearance 71% Favipiravir for COVID-19  Cai et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 80 patients in China Lower pneumonia (p=0.042) and improved viral clearance (p=0.025) c19early.org Cai et al., Engineering, March 2020 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Comparison of 35 FPV patients and 35 LPV/RTV patients, showing significant improvements in chest CT and faster viral clearance with FPV. Submit Corrections or Updates.
Progression -13% Improvement Relative Risk Time to WHO zero score -23% Viral clearance -67% Favipiravir  Chandiwana et al.  EARLY TREATMENT  RCT Is early treatment with favipiravir + nitazoxanide beneficial for COVID-19? RCT 76 patients in South Africa (September 2020 - August 2021) Slower recovery (p=0.42) and worse viral clearance (p=0.13), not sig. c19early.org Chandiwana et al., eBioMedicine, November 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Very high COI low-risk patient RCT in South Africa, showing no significant differences with favipiravir plus nitazoxanide. There were no deaths and no COVID-19 hospitalizations for favipiravir plus nitazoxanide. More patients were seropositive at baseline in the treatment arm (28% vs 22%). Favipiravir 1600mg 12-hourly for 1 day, then 600mg 12-hourly for 6 days. Nitazoxanide 1000mg 12-hourly for 7 days. Submit Corrections or Updates.
ICU admission -3% Improvement Relative Risk Respiratory failure 74% Oxygen therapy 20% Progression to dyspnea 70% Dyspnea 10% Recovery 20% primary Favipiravir  Chen et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 236 patients in China Trial compares with arbidol, results vs. placebo may differ Lower progression (p=0.37) and lower oxygen therapy (p=0.42), not sig. c19early.org Chen et al., Frontiers in Pharmacology, Sep 2021 Favorsfavipiravir Favorsarbidol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality -1154% Improvement Relative Risk Ventilation -20% ICU admission -9% Favipiravir  Chuah et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 500 patients in Malaysia (February - July 2021) Higher mortality with favipiravir (not stat. sig., p=0.08) c19early.org Chuah et al., Clinical Infectious Dise.., Nov 2021 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
RCT 500 hospitalized patients in Malaysia, showing no significant differences with favipiravir treatment. Submit Corrections or Updates.
Mortality 38% Improvement Relative Risk Favipiravir for COVID-19  Cilli et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 46 patients in Turkey Lower mortality with favipiravir (not stat. sig., p=0.51) c19early.org Cilli et al., Respiratory Medicine and.., Mar 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 46 idiopathic pulmonary fibrosis patients with COVID-19 in Turkey, showing lower mortality with favipiravir in unadjusted results, without statistical significance. Submit Corrections or Updates.
Recovery 54% Improvement Relative Risk Favipiravir  Damayanti et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 192 patients in Indonesia Improved recovery with favipiravir (p=0.029) c19early.org Damayanti et al., Kesmas: National Pub.., Nov 2021 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 192 hospitalized patients in Indonesia, 96 patients treated with favipiravir, showing improved recovery with treatment. Only the abstract is currently available. Submit Corrections or Updates.
ICU admission 23% Improvement Relative Risk Recovery 88% Hospitalization time -2% Discharge -3% Favipiravir for COVID-19  Delen et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 69 patients in Turkey (March - July 2020) Improved recovery with favipiravir (p=0.02) c19early.org Delen et al., Acta Clinica Croatica, Dec 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 69 COVID-19 patients in Turkey, showing improved fever recovery with the addition of favipiravir to HCQ, but no significant difference in discharge, ICU admission, or hospitalization time. Submit Corrections or Updates.
Mortality -200% Improvement Relative Risk Ventilation -200% Hospitalization time -20% no CI Recovery 58% Recovery (b) -46% Recovery time 43% no CI Recovery time (b) -15% no CI Time to viral- 47% primary Favipiravir  Finberg et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 50 patients in the USA (April - October 2020) Faster viral clearance with favipiravir (p=0.042) c19early.org Finberg et al., Open Forum Infectious .., Dec 2021 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality 67% Improvement Relative Risk Progression 2% Progression (b) 7% Recovery 4% Time to viral- 14% Favipiravir  PRESECO  EARLY TREATMENT  DB RCT Is early treatment with favipiravir beneficial for COVID-19? Double-blind RCT 1,187 patients in the USA (November 2020 - October 2021) Faster viral clearance with favipiravir (p<0.000001) c19early.org Golan et al., Clinical Infectious Dise.., Sep 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
RCT low-risk (1 death in the control arm) patients in the USA, showing no significant differences with favipiravir. A majority of trial outcomes were modified after completion:105. 44% of patients had no detectable viral load at baseline in the viral shedding sub-study. The primary outcome required 4 days of sustained clinical recovery and occurred after a median of 7 days, suggesting there was limited room for improvement in the population studied. The percentages for viral clearance at day 10 do not match any number of the reported group sizes. Authors write "of the six RCTs conducted", however there has been at least 24 other RCTs at the time of publication106. 1800mg bid day 1, 800mg bid days 2-10. Submit Corrections or Updates.
Viral clearance time -3% Improvement Relative Risk Viral clearance time (b) 59% Favipiravir for COVID-19  Hafez et al.  LATE TREATMENT Is late treatment with favipiravir + HCQ beneficial for COVID-19? Retrospective 1,505 patients in United Arab Emirates No significant difference in viral clearance c19early.org Hafez et al., Antibiotics, April 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality 26% Improvement Relative Risk Favipiravir  Haji Aghajani et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 991 patients in Iran Lower mortality with favipiravir (not stat. sig., p=0.28) c19early.org Haji Aghajani et al., J. Medical Virol.., Apr 2021 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 991 hospitalized patients in Iran focusing on aspirin use but also showing results for HCQ, remdesivir, and favipiravir. Submit Corrections or Updates.
Mortality, mild/moderate 76% Improvement Relative Risk Mortality, severe 60% Favipiravir  Hartantri et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective study in Indonesia (March - December 2020) Lower mortality with favipiravir (p=0.00047) c19early.org Hartantri et al., The Lancet Regional .., Feb 2023 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 689 hospitalized patients in Indonesia, showing lower mortality with favipiravir treatment. Submit Corrections or Updates.
Mortality, day 14 68% Improvement Relative Risk Mortality, day 7 3% ICU admission 35% Hospitalization time 25% Viral clearance 18% Favipiravir  Hassaniazad et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 63 patients in Iran Trial compares with lopinavir/ritonavir, results vs. placebo may differ Lower mortality (p=0.15) and ICU admission (p=0.51), not sig. c19early.org Hassaniazad et al., J. Medical Virology, Mar 2022 Favorsfavipiravir Favorslopinavir/ri.. 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality 86% Improvement Relative Risk ICU admission -191% Death/hospitalization 1% Not fully recovered, day 365 17% Not fully recovered, day 180 12% Not fully recovered, day 90 17% Ongoing persistent symp.. 29% Time to first reported re.. 19% primary Early sustained recovery 34% Sustained recovery 25% Alleviation of all symptoms 12% Sustained alleviation of al.. 21% Initial reduction of severity 23% Favipiravir  PRINCIPLE  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 3,622 patients in the United Kingdom (April 2021 - July 2022) Improved recovery with favipiravir (p=0.0032) c19early.org Hobbs et al., J. Infection, August 2024 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
RCT 3,622 (concurrent and eligible) COVID-19 outpatients in the UK showing significantly faster recovery with favipiravir, and significantly greater full recovery at 3, 6, and 12 months.

Authors note: "From 16 Dec 2021, a minority of extremely clinically vulnerable patients could also access antiviral treatment or a monoclonal antibody infusion". However, there is no information on treatments provided or procedures for determining eligibility. This change invalidates hospitalization/death data after 16 Dec 2021. Hospitalization/death events occured in a small minority of patients and are expected to be strongly biased towards the extremely clinically vulnerable patients. Patients randomized to usual care are more likely to obtain alternative treatment. During the trial extension period sotrovimab was the most common treatment, with paxlovid and molnupiravir also being used107. Sotrovimab showed very high efficacy during this period108,109. It is normal to provide details of other treatments used in cases like this, the lack of disclosure suggests that the data confirms alternative treatment use significantly biased the results.

Table 1 shows a median of 4 days delay from onset of symptoms, while Table S1 shows a mean of 5.1/5.0 days for the long-term followup patients (97% of patients) indicating a distribution skewed towards very late treatment. Submit Corrections or Updates.
Hospitalization 89% Improvement Relative Risk ER visit 30% Recovery -19% Viral shedding -32% primary Favipiravir  Holubar et al.  EARLY TREATMENT  DB RCT Is early treatment with favipiravir beneficial for COVID-19? Double-blind RCT 149 patients in the USA (July 2020 - March 2021) Lower hospitalization (p=0.058) and progression (p=0.56), not sig. c19early.org Holubar et al., Clinical Infectious Di.., Nov 2021 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Small RCT 116 mITT patients in the USA, 59 treated with favipiravir, showing no significant differences with treatment. Submit Corrections or Updates.
Mortality -383% Improvement Relative Risk Ventilation -37% Time to improvement 0% no CI Dischage or NEWS <3 17% Time to viral- -125% Favipiravir  FAVID  LATE TREATMENT  DB RCT Is late treatment with favipiravir beneficial for COVID-19? Double-blind RCT 44 patients in Spain (November 2020 - October 2021) Higher mortality (p=0.49) and slower viral clearance (p=0.51), not sig. c19early.org Horcajada et al., Pneumonia, August 2023 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Underpowered RCT with 44 hospitalized patients in Spain, showing no significant difference with favipiravir treatment in the primary outcome of time to clinical improvement, or in the secondary efficacy outcomes. Adverse events were more frequent in the favipiravir group (68%) compared to placebo (32%), but most were mild. Submit Corrections or Updates.
Mortality -300% Improvement Relative Risk Ventilation -300% ICU admission -300% Viral clearance 46% Viral clearance (b) 62% Discharge and WHO-OSC>2 -67% Favipiravir  Ivashchenko et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 60 patients in Russia (April - May 2020) Improved viral clearance with favipiravir (p=0.028) c19early.org Ivashchenko et al., Clinical Infectiou.., Aug 2020 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Interim 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. 75% of the control group received HCQ/CQ. Submit Corrections or Updates.
Oxygen therapy -16% Improvement Relative Risk Oxygen therapy, ≤48 hours 19% Viral clearance, day 15 -16% Viral clearance, day 10 6% Viral clearance, day 7 1% Viral clearance, day 4 6% Favipiravir  Iwata et al.  EARLY TREATMENT  DB RCT Is early treatment with favipiravir beneficial for COVID-19? Double-blind RCT 86 patients in Japan Trial underpowered for serious outcomes c19early.org Iwata et al., J. Infection and Chemoth.., Oct 2023 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Early terminated RCT 84 patients in Japan, showing no significant difference in outcomes with favipiravir treatment. There was a trend for improved efficacy for patients enrolled within 48 hours of symptom onset. Submit Corrections or Updates.
1,008 patient favipiravir early treatment RCT with results not reported over 3 years after completion. Submit Corrections or Updates.
Mortality 15% Improvement Relative Risk ICU admission -2% Recovery -10% Favipiravir  Khamis et al.  LATE TREATMENT  RCT Is late treatment with favipiravir + interferon beta-1b beneficial for COVID-19? RCT 89 patients in Oman (June - August 2020) Trial compares with HCQ, results vs. placebo may differ Trial underpowered for serious outcomes c19early.org Khamis et al., Int. J. Infectious Dise.., Nov 2020 Favorsfavipiravir FavorsHCQ 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Improvement 88% Improvement Relative Risk Improvement (b) 89% Viral clearance 50% Favipiravir  Kulzhanova et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 80 patients in Kazakhstan Greater improvement with favipiravir (p<0.000001) c19early.org Kulzhanova et al., , August 2021 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 40 favipiravir patients in Kazakhstan and 40 controls, showing faster recovery and viral clearance with treatment. Submit Corrections or Updates.
Mortality 48% Improvement Relative Risk Favipiravir  Kurniyanto et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 477 patients in Indonesia Lower mortality with favipiravir (not stat. sig., p=0.21) c19early.org Kurniyanto et al., J. Clinical Virolog.., Feb 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 477 hospitalized patients in Indonesia, showing lower mortality with favipiravir in unadjusted results, not reaching statistical significance. Submit Corrections or Updates.
PASC 14% Improvement Relative Risk Favipiravir  Lokanuwatsatien et al.  EARLY TREATMENT Is early treatment with favipiravir beneficial for COVID-19? Prospective study of 802 patients in Thailand (Sep 2021 - Mar 2022) Lower PASC with favipiravir (not stat. sig., p=0.34) c19early.org Lokanuwatsatien et al., Frontiers in P.., May 2023 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Prospective analysis of 802 COVID-19 pediatric patients in Thailand, showing no significant difference in long COVID with favipiravir treatment in unadjusted results. Submit Corrections or Updates.
ICU admission -422% Improvement Relative Risk Recovery, day 14 11% Recovery, day 7 14% Viral clearance, day 14 -422% Viral clearance, day 7 -11% Favipiravir  Lou et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 19 patients in China Higher ICU admission (p=0.21) and worse viral clearance (p=0.21), not sig. c19early.org Lou et al., European J. Pharmaceutical.., Oct 2020 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Small late stage RCT with 10 favipiravir, 10 baloxavir marboxil, and 10 control patients in China, showing no significant differences. Submit Corrections or Updates.
ICU admission -202% Improvement Relative Risk Hospitalization -202% Viral clearance 28% primary Favipiravir  FLARE  EARLY TREATMENT  DB RCT Is early treatment with favipiravir beneficial for COVID-19? Double-blind RCT 119 patients in the United Kingdom (Oct 2020 - Nov 2021) Improved viral clearance with favipiravir (p=0.03) c19early.org Lowe et al., PLOS Medicine, February 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Clearance rate -6% primary Improvement Relative Risk Favipiravir  PLATCOV  EARLY TREATMENT  RCT Is early treatment with favipiravir beneficial for COVID-19? RCT 248 patients in multiple countries (September 2021 - October 2022) No significant difference in viral clearance c19early.org Luvira et al., BMC Infectious Diseases, Apr 2023 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
High conflict of interest RCT with very low risk patients, high existing immunity, and a post-hoc change to exclude patients more likely to benefit. There was no significant difference in viral clearance with favipiravir among patients with high viral load at baseline. Patients in both arms had very short viral clearance half-life times.

With rapid viral clearance and very low risk patients, infection is less likely to spread to other tissues. Systemic treatment is less applicable, and has less time to reach therapeutic concentrations before self-recovery.

Treatment administered directly to the respiratory tract, e.g. as in33, may be more effective for COVID-19 in general, and extend applicability to fast-resolving cases with infection primarily localized to the respiratory tract.

Authors note that "all-cause hospitalisation for clinical deterioration (until day 28) was a secondary endpoint", but do not provide the result.

For more discussion of the post-hoc change and other issues see110. Submit Corrections or Updates.
Oxygen therapy -1% Improvement Relative Risk Hospitalization -56% Favipiravir  McMahon et al.  EARLY TREATMENT  RCT Is early treatment with favipiravir beneficial for COVID-19? RCT 199 patients in Australia (July 2020 - September 2021) Higher hospitalization with favipiravir (not stat. sig., p=0.38) c19early.org McMahon et al., eClinicalMedicine, Jun 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
RCT with 99 favipiravir and 100 placebo patients in Australia, all except one being outpatients, showing no significant differences with treatment. Submit Corrections or Updates.
Clinical status improvem.. 14% Improvement Relative Risk Time to clinical improvem.. 33% Fever reduction by day 3 45% Time to resolution of fever 20% Discharge at day 10 70% Full recovery at day 10 27% Improvement in lung CT 33% Viral clearance 90% Favipiravir  Pushkar et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 200 patients in Russia Higher discharge (p=0.00012) and improved viral clearance (p<0.0001) c19early.org Pushkar et al., NCT04542694, November 2020 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality 97% Improvement Relative Risk Hospitalization 60% Recovery, day 30 97% primary Recovery, day 15 71% Recovery, day 10 79% Recovery, day 5 71% Recovery time 58% Favipiravir  Qadir et al.  EARLY TREATMENT Is early treatment with favipiravir beneficial for COVID-19? Prospective study of 250 patients in Iraq (June 2020 - October 2021) Lower mortality (p<0.0001) and hospitalization (p=0.0013) c19early.org Qadir et al., Int. J. Applied Sciences.., May 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Chest x-ray improvement.. 89% Improvement Relative Risk Chest x-ray improvem.. (b) 65% Chest x-ray improvem.. (c) 47% Viral clearance, day 10 92% Viral clearance, day 7 62% Viral clearance, day 4 48% Favipiravir  Rahman et al.  LATE TREATMENT  DB RCT Is late treatment with favipiravir beneficial for COVID-19? Double-blind RCT 50 patients in Bangladesh (May - July 2020) Greater improvement (p=0.0049) and improved viral clearance (p=0.00076) c19early.org Rahman et al., Clinical Infection in P.., May 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
RCT hospitalized patients in Bangladesh, showing faster recovery and viral clearance with favipiravir treatment. Submit Corrections or Updates.
Hospitalization 6% Improvement Relative Risk Ventilation -150% ICU admission -51% HR for time to clinical i.. 39% Viral clearance 22% Favipiravir  Ruzhentsova et al.  EARLY TREATMENT  RCT Is early treatment with favipiravir beneficial for COVID-19? RCT 168 patients in Russia (May - June 2020) Faster recovery with favipiravir (p=0.007) c19early.org Ruzhentsova et al., SSRN, October 2020 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
RCT 168 patients, 112 receiving favipiravir and 56 SOC, showing shorter time to clinical improvement and faster viral clearance with favipiravir. Submit Corrections or Updates.
Mortality -168% Improvement Relative Risk Favipiravir for COVID-19  Saito et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 132 patients in Japan (February 2020 - June 2021) Higher mortality with favipiravir (not stat. sig., p=0.063) c19early.org Saito et al., Infection Prevention in .., Jan 2024 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 132 hospitalized COVID-19 patients over age 65 in Japan during the Alpha variant surge, showing higher mortality with favipiravir in unadjusted results, without statistical significance. Submit Corrections or Updates.
Death, ICU, intubation, or h.. 68% Improvement Relative Risk Favipiravir  Sawanpanyalert et al.  EARLY TREATMENT Is early treatment with favipiravir beneficial for COVID-19? Retrospective study in Thailand Lower progression with favipiravir (p=0.003) c19early.org Sawanpanyalert et al., Southeast Asian.., Sep 2021 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality 26% Improvement Relative Risk Ventilation 24% Recovery 6% Favipiravir  PIONEER  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 499 patients in multiple countries (May 2020 - May 2021) Lower mortality (p=0.24) and ventilation (p=0.21), not sig. c19early.org Shah et al., The Lancet Respiratory Me.., Sep 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
PIONEER very late treatment RCT showing lower mortality and mechanical ventilation with favipiravir, without statistical significance.

The conclusion "favipiravir is not efficacious in treating hospitalised adult patients with COVID-19" is incorrect. Authors show 26% and 24% lower mortality and mechanical ventilation. While these results are not statistically significant, they predict efficacy, and cannot be used to rule out efficacy.

Favipiravir 1,800mg bid day 1, 800mg bid days 2-10. Submit Corrections or Updates.
Mortality 96% Improvement Relative Risk Favipiravir  Shamsi et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 183 patients in Iran (March 2020 - August 2021) Lower mortality with favipiravir (not stat. sig., p=0.14) c19early.org Shamsi et al., Canadian J. Infectious .., Jul 2023 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 183 hospitalized pediatric COVID-19 patients in Iran, showing no significant difference in mortality with favipiravir in unadjusted results. Submit Corrections or Updates.
Mortality -29% Improvement Relative Risk Ventilation -33% ICU admission -2% Time to resolution of hypo.. -1% primary Time to hospital discharge 6% Time to resolution of.. (b) 17% primary Time to hospital disc.. (b) 32% Favipiravir  Shenoy et al.  LATE TREATMENT  DB RCT Is late treatment with favipiravir beneficial for COVID-19? Double-blind RCT 353 patients in Kuwait (August 2020 - January 2021) Higher mortality (p=0.54) and ventilation (p=0.54), not sig. c19early.org Shenoy et al., medRxiv, November 2021 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Hospitalization time 7% Improvement Relative Risk Viral clearance time 55% Favipiravir  Shinada et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 34 patients in Japan (May - September 2020) Faster viral clearance with favipiravir (p=0.039) c19early.org Shinada et al., Viruses, March 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Time to improvement 37% Improvement Relative Risk Time to improvement (b) 59% Favipiravir  Shinkai et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 156 patients in Japan Faster recovery with favipiravir (p=0.014) c19early.org Shinkai et al., Infectious Diseases an.., Aug 2021 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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-. Submit Corrections or Updates.
Time to clinical improvem.. 64% primary Improvement Relative Risk Clinical improvement 90% Mild pneumonia 43% Viral clearance -4% Favipiravir  Sirijatuphat et al.  EARLY TREATMENT  RCT Is early treatment with favipiravir beneficial for COVID-19? RCT 93 patients in Thailand (December 2020 - July 2021) Faster improvement with favipiravir (p=0.00046) c19early.org Sirijatuphat et al., medRxiv, June 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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-. Submit Corrections or Updates.
120 patient favipiravir early treatment RCT with results not reported over 1.5 years after completion.

The protocol has been published111. Submit Corrections or Updates.
Mortality -19% Improvement Relative Risk Ventilation -53% ICU admission -19% Favipiravir  Solaymani-Dodaran et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 373 patients in Iran (February - March 2020) Trial compares with lopinavir/ritonavir, results vs. placebo may differ Higher mortality (p=0.54) and ventilation (p=0.15), not sig. c19early.org Solaymani-Dodaran et al., Int. Immunop.., Mar 2021 Favorsfavipiravir Favorslopinavir/ri.. 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality -17% Improvement Relative Risk Mortality, day 30 14% Ventilation time -47% ICU time -50% Favipiravir  Sulaiman et al.  ICU PATIENTS Is very late treatment with favipiravir beneficial for COVID-19? PSM retrospective 146 patients in Saudi Arabia (Mar 2020 - Jul 2021) Longer ventilation (p=0.008) and ICU admission (p=0.01) c19early.org Sulaiman et al., J. Infection and Publ.., Jun 2023 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
PSM retrospective 1,218 COVID-19 ICU patients in Saudi Arabia, showing no significant difference in mortality, and longer ICU/MV time with favipiravir treatment. Submit Corrections or Updates.
Mortality 30% Improvement Relative Risk ICU admission 41% <50% improvement in che.. 6% Hospitalization time 25% Favipiravir  Tabarsi et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 62 patients in Iran (April - May 2020) Trial compares with lopinavir/ritonavir, results vs. placebo may differ Shorter hospitalization with favipiravir (p=0.03) c19early.org Tabarsi et al., Iranian J. Pharmaceuti.., Sep 2021 Favorsfavipiravir Favorslopinavir/ri.. 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality 96% Improvement Relative Risk ICU admission 21% Hospitalization time 16% Favipiravir  Tawfik et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 165 patients in Saudi Arabia (June - November 2020) Lower mortality (p<0.0001) and shorter hospitalization (p<0.0001) c19early.org Tawfik et al., Advances in Virology, Jun 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Hospitalization 34% Improvement Relative Risk Recovery, day 7, dyspnea 80% Recovery, day 5, dyspnea 58% Recovery, day 7, fever 47% Recovery, day 5, fever 47% Recovery, day 7, sore throat 66% Recovery, day 5, sore throat 47% Recovery, day 7, cough 30% Recovery, day 5, cough 7% Recovery, day 7, myalgia 21% Recovery, day 5, myalgia 38% Favipiravir  Tehrani et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 78 patients in Iran (April - September 2021) Lower hospitalization (p=0.24) and improved recovery (p=0.49), not sig. c19early.org Tehrani et al., Mediterranean J. Infec.., Jun 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
RCT 78 patients in Iran, showing improved recovery with favipiravir treatment. Submit Corrections or Updates.
Mortality 13% Improvement Relative Risk Ventilation -2% Progression 18% Favipiravir  Tsuzuki et al.  EARLY TREATMENT Is early treatment with favipiravir beneficial for COVID-19? Retrospective 7,654 patients in Japan Lower mortality (p=0.59) and progression (p=0.098), not sig. c19early.org Tsuzuki et al., Infectious Diseases an.., Mar 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective database analysis of 7,654 hospitalized patients in Japan, showing no significant differences with favipiravir treatment. NCGM-G-003494-0. Submit Corrections or Updates.
Mortality 66% Improvement Relative Risk Time to discharge 29% Time to clinical cure 43% Time to viral clearance 27% Favipiravir  Udwadia et al.  EARLY TREATMENT  RCT Is early treatment with favipiravir beneficial for COVID-19? RCT 148 patients in India (May - July 2020) Faster recovery (p=0.069) and viral clearance (p=0.098), not sig. c19early.org Udwadia et al., Int. J. Infectious Dis.., Nov 2020 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
RCT with 75 favipiravir patients and 75 control patients showing improved recovery with treatment. Submit Corrections or Updates.
Viral clearance 86% Improvement Relative Risk Favipiravir  Usanma Koban et al.  EARLY TREATMENT Is early treatment with favipiravir beneficial for COVID-19? Retrospective 126 patients in Turkey (March - September 2020) Improved viral clearance with favipiravir (p=0.03) c19early.org Usanma Koban et al., Bratislava Medica.., Jun 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
Retrospective 126 patients in Turkey, showing lower risk of PCR+ at day 14 with favipiravir treatment. Submit Corrections or Updates.
Mortality 67% Improvement Relative Risk ICU admission -200% Hospitalization time -11% Favipiravir  Uyaroğlu et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? PSM retrospective 84 patients in Turkey (March - September 2020) Study compares with HCQ, results vs. placebo may differ Study underpowered for serious outcomes c19early.org Uyaroğlu et al., Acta Medica, March 2022 Favorsfavipiravir FavorsHCQ 0 0.5 1 1.5 2+
PSM retrospective 260 late stage hospitalized COVID-19 pneumonia patients in Turkey, showing no significant difference between favipiravir and HCQ. Submit Corrections or Updates.
Hospitalization -105% Improvement Relative Risk Favipiravir  Vaezi et al.  EARLY TREATMENT  DB RCT Is early treatment with favipiravir beneficial for COVID-19? Double-blind RCT 77 patients in Iran (December 2020 - March 2021) Higher hospitalization with favipiravir (not stat. sig., p=0.43) c19early.org Vaezi et al., Advances in Respiratory .., Jan 2023 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
RCT 77 outpatients in Iran, showing increased hospitalization with treatment, without statistical significance. Favipiravir 1600mg daily for five days. 21% of favipiravir patients did not complete treatment. Submit Corrections or Updates.
Mortality 85% Improvement Relative Risk Favipiravir for COVID-19  Yulia et al.  LATE TREATMENT Is late treatment with favipiravir beneficial for COVID-19? Retrospective 432 patients in Indonesia (July - December 2020) Lower mortality with favipiravir (not stat. sig., p=0.052) c19early.org Yulia et al., Pathophysiology, March 2022 Favors<