Top
Overview
Introduction
Preclinical
Results
RCTs
Unreported RCTs
Exclusions
Heterogeneity
Pooled Effects
Discussion
Perspective
Conclusion
 
Study Notes
Methods and Data
Supplementary
References
 
All studies
Mortality
Ventilation
ICU admission
Hospitalization
Progression
Recovery
Viral clearance
Peer reviewed
Exclusions
All RCTs
RCT mortality
RCT hospitalization
 
Feedback
Home
c19early.org COVID-19 treatment researchFavipiravirFavipiravir (more..)
Melatonin Meta
Metformin Meta
Azvudine Meta
Bromhexine Meta Molnupiravir Meta
Budesonide Meta
Colchicine Meta
Conv. Plasma Meta Nigella Sativa Meta
Curcumin Meta Nitazoxanide 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 68 studies

@CovidAnalysis, April 2024, Version 79V79
 
0 0.5 1 1.5+ All studies 15% 68 30,674 Improvement, Studies, Patients Relative Risk Mortality 12% 38 24,027 Ventilation -10% 12 11,464 ICU admission -31% 20 6,034 Hospitalization -4% 19 6,502 Progression 21% 10 12,134 Recovery 14% 26 5,832 Viral clearance 18% 27 5,022 RCTs 16% 32 6,029 Peer-reviewed 16% 65 29,953 Early 17% 20 12,457 Late 15% 48 18,217 Favipiravir for COVID-19 c19early.org April 2024 after exclusions Favorsfavipiravir Favorscontrol
Abstract
Statistically significant lower risk is seen for recovery and viral clearance. 30 studies from 30 independent teams in 16 countries show statistically significant improvements.
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.
1 RCT with 1,008 patients has not reported results (2 years late) Kara.
Potential risks of the mechanism of action include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity Hadj Hassine, Waters, Zhirnov. Favipiravir may impair clotting Gül.
No treatment or intervention is 100% effective. All practical, effective, and safe means should be used based on risk/benefit analysis. Multiple treatments are typically used in combination, and other treatments are significantly more effective.
All data to reproduce this paper and sources 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 April 2024 mixed-effects meta-regression
Highlights
Favipiravir reduces risk for COVID-19 with very high confidence for viral clearance and in pooled analysis, high confidence for recovery, 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.
We show outcome specific analyses and combined evidence from all studies, incorporating treatment delay, a primary confounding factor for COVID-19.
Real-time updates and corrections, transparent analysis with all results in the same format, consistent protocol for 69 treatments.
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 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 Saito -168% 2.68 [0.96-7.48] death 7/40 6/92 Tau​2 = 0.06, I​2 = 66.6%, p = 0.014 Late treatment 15% 0.85 [0.75-0.97] 908/5,597 1,480/12,188 15% lower risk All studies 15% 0.85 [0.76-0.95] 955/10,551 1,543/19,691 15% lower risk 68 favipiravir COVID-19 studies c19early.org April 2024 Tau​2 = 0.06, I​2 = 64.8%, p = 0.0043 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- 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 Saito -168% death Tau​2 = 0.06, I​2 = 66.6%, p = 0.014 Late treatment 15% 15% lower risk All studies 15% 15% lower risk 68 favipiravir C19 studies c19early.org April 2024 Tau​2 = 0.06, I​2 = 64.8%, p = 0.0043 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.
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 issues Duloquin, Hampshire, Scardua-Silva, Sodagar, Yang, cardiovascular complications Eberhardt, 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 factors Note A, Malone, Murigneux, Lv, Lui, Niarakis, providing many therapeutic targets for which many existing compounds have known activity. Scientists have predicted that over 7,000 compounds may reduce COVID-19 risk c19early.org, 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.
Figure 2. Treatment stages.
An In Silico study supports the efficacy of favipiravir Unal.
2 In Vitro studies support the efficacy of favipiravir Unal, Yildiz Pekoz.
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.
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%]
**
68 30,674 1,110
After exclusions17% [6‑28%]
**
53 24,523 914
Peer-reviewed studiesPeer-reviewed16% [6‑26%]
**
65 29,953 1,070
Randomized Controlled TrialsRCTs16% [-0‑29%]32 6,029 684
Mortality12% [-4‑26%]38 24,027 603
VentilationVent.-10% [-56‑23%]12 11,464 379
ICU admissionICU-31% [-56‑-9%]
**
20 6,034 367
HospitalizationHosp.-4% [-23‑13%]19 6,502 329
Recovery14% [3‑25%]
*
26 5,832 522
Viral18% [8‑27%]
***
27 5,022 436
RCT mortality6% [-23‑28%]14 3,734 346
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%]15% [3‑25%]
*
After exclusions19% [-17‑43%]18% [4‑30%]
*
Peer-reviewed studiesPeer-reviewed18% [-12‑39%]17% [4‑28%]
*
Randomized Controlled TrialsRCTs8% [-33‑37%]20% [1‑35%]
*
Mortality42% [-22‑72%]10% [-8‑24%]
VentilationVent.-2% [-60‑35%]-10% [-66‑27%]
ICU admissionICU-381% [-4086‑45%]-29% [-55‑-8%]
**
HospitalizationHosp.-4% [-137‑54%]-7% [-27‑11%]
Recovery9% [-16‑28%]17% [3‑29%]
*
Viral8% [-9‑21%]40% [22‑53%]
***
RCT mortality67% [-219‑97%]5% [-25‑27%]
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.
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 biases Jadad, and analysis of double-blind RCTs has identified extreme levels of bias Gøtzsche. 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 69 treatments we have analyzed, 63% 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.
Evidence shows that non-RCT 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. summarized reviews comparing RCTs to observational studies and found little evidence for significant differences in effect estimates. 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 Internet 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 see Deaton, Nichol.
Currently, 44 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, 28 have been confirmed in RCTs, with a mean delay of 7.0 months. When considering only low cost treatments, 23 have been confirmed with a delay of 8.4 months. For the 16 unconfirmed treatments, 3 have zero RCTs to date. The point estimates for the remaining 13 are all consistent with the overall results (benefit or harm), with 10 showing >20%. The only treatments showing >10% efficacy for all studies, but <10% for RCTs are sotrovimab and aspirin.
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.
1 favipiravir RCT has not reported results Kara. The trial reports total actual enrollment of 1,008 patients. The result is delayed over 2 years.
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.
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 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 hours McLean, Treanor. Baloxavir 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 for influenza show that early treatment is more effective.
Treatment delayResult
Post-exposure prophylaxis86% fewer cases Ikematsu
<24 hours-33 hours symptoms Hayden
24-48 hours-13 hours symptoms Hayden
Inpatients-2.5 hours to improvement Kumar
Figure 18 shows a mixed-effects meta-regression for efficacy as a function of treatment delay in COVID-19 studies from 69 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 69 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 variants Korves, for example the Gamma variant shows significantly different characteristics Faria, Karita, Nonaka, Zavascki. 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 variants Peacock, Willett.
Effectiveness may depend strongly on the dosage and treatment regimen.
The use of other treatments may significantly affect outcomes, including supplements, other medications, or other interventions such as prone positioning. Treatments may be synergistic Alsaidi, Andreani, De Forni, Fiaschi, Jeffreys, Jitobaom, Jitobaom (B), Ostrov, Said, Thairu, Wan, therefore efficacy may depend strongly on combined treatments.
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.
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.
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.
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.
Another way to view pooled analysis is that we are using more of the available information. Logically we should, and do, use additional information. For example dose-response and treatment delay-response relationships provide significant additional evidence of efficacy that is considered when reviewing the evidence for a treatment.
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 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 69 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 = 0.0000031 to p = 0.0000000067.
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, 44 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 88% of these have been confirmed with one or more specific outcomes, with a mean delay of 4.7 months. When restricting to RCTs only, 54% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 5.5 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.
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 results Boulware, Meeus, Meneguesso, twitter.com.
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 < 0.05 Egger, Harbord, Macaskill, Moreno, Peters, Rothstein, Rücker, Stanley. 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.
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 alone Alsaidi, Andreani, De Forni, Fiaschi, Jeffreys, Jitobaom, Jitobaom (B), Ostrov, Said, Thairu, Wan. 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 68 studies compare against other treatments, which may reduce the effect seen. 4 of 68 studies combine treatments. The results of favipiravir alone may differ. 3 of 32 RCTs use combined treatment.
Multiple reviews cover favipiravir for COVID-19, presenting additional background on mechanisms and related results, including Bacigalupo, Hadj Hassine, Waters, Zhirnov.
SARS-CoV-2 infection and replication involves a complex interplay of 50+ host and viral proteins and other factors Lui, Lv, Malone, Murigneux, Niarakis, providing many therapeutic targets. Over 7,000 compounds have been predicted to reduce COVID-19 risk c19early.org, 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 7,000+ proposed treatments show efficacy c19early.org (B).
Loading..
Loading..
Figure 26. Efficacy vs. cost for COVID-19 treatments.
Statistically significant lower risk is seen for recovery and viral clearance. 30 studies from 30 independent teams in 16 countries show statistically significant improvements. 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 of the mechanism of action include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity Hadj Hassine, Waters, Zhirnov. Favipiravir may impair clotting Gül.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Abdulrahman: Retrospective 1,699 ICU patients in Saudi Arabia, 193 treated with favipiravir, showing no significant difference in mortality.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors lopinavir/ri..
Acar Sevinc: Retrospective 100 ICU patients in Turkey, showing improved survival with favipiravir vs. lopinavir/ritonavir.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Adhikari: 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.
0 0.5 1 1.5 2+ Mortality 26% Improvement Relative Risk Favipiravir  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 Aghajani et al., J. Medical Virology, Apr 2021 Favors favipiravir Favors control
Aghajani: Retrospective 991 hospitalized patients in Iran focusing on aspirin use but also showing results for HCQ, remdesivir, and favipiravir.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors various
Al Mutair: Retrospective 269 favipiravir ICU patients in Saudi Arabia and 269 matched controls receiving different treatments, showing no significant difference.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Al-Muhsen: Prospective observational study of 598 hospitalized patients in Saudi Arabia, showing higher risk of mortality and longer hospitalization time with favipiravir.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Alamer: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Alattar: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Almoosa: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors HCQ
Alosaimi: Retrospective 200 hospitalized COVID-19 patients in Saudi Arabia, showing no significant difference in outcomes between HCQ and favipiravir.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors HCQ
Alotaibi: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
AlQahtani: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Alshamrani: PSM retrospective 29 hospitals in Saudi Arabia, showing higher mortality with favipiravir treatment, without statistical significance.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Arfijanto: Retrospective 162 hospitalized COVID-19 patients in Indonesia, showing lower incidence of delayed viral clearance with favipiravir treatment in unadjusted results.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Assiri: Retrospective 118 ICU patients in Saudi Arabia showing no significant differences in unadjusted results with zinc, vitamin D, and favipiravir treatment.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors oseltamivir
Atipornwanich: RCT 200 moderate/severe patients in Thailand, showing significantly lower progression with favipiravir vs. oseltamivir. NCT04303299.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Babayigit: Retrospective 1,472 hospitalized patients in Turkey, showing a higher ICU admission and ventilation with favipiravir. Results may be subject to confounding by indication.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Behboodikhah: Retrospective 2,174 hospitalized patients showing significantly shorter length of stay with favipiravir treatment.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Bosaeed: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Bruminhent: Retrospective 514 patients in Thailand, showing higher risk of progression with favipiravir treatment.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Cai: Comparison of 35 FPV patients and 35 LPV/RTV patients, showing significant improvements in chest CT and faster viral clearance with FPV.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Chandiwana: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors arbidol
Chen: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Chuah: RCT 500 hospitalized patients in Malaysia, showing no significant differences with favipiravir treatment.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Cilli: Retrospective 46 idiopathic pulmonary fibrosis patients with COVID-19 in Turkey, showing lower mortality with favipiravir in unadjusted results, without statistical significance.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Damayanti: Retrospective 192 hospitalized patients in Indonesia, 96 patients treated with favipiravir, showing improved recovery with treatment. Only the abstract is currently available.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Delen: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Finberg: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Golan: 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: clinicaltrials.gov. 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 publication c19favipiravir.com. 1800mg bid day 1, 800mg bid days 2-10.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Hafez: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Hartantri: Retrospective 689 hospitalized patients in Indonesia, showing lower mortality with favipiravir treatment.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors lopinavir/ri..
Hassaniazad: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Holubar: Small RCT 116 mITT patients in the USA, 59 treated with favipiravir, showing no significant differences with treatment.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Horcajada: 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.
0 0.5 1 1.5 2+ 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., Clin. Infect. Dis., Aug 2020 Favors favipiravir Favors control
Ivashchenko: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Iwata: 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.
Kara: 1,008 patient favipiravir early treatment RCT with results not reported over 2 years after completion.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors HCQ
Khamis: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Kulzhanova: Retrospective 40 favipiravir patients in Kazakhstan and 40 controls, showing faster recovery and viral clearance with treatment.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Kurniyanto: Retrospective 477 hospitalized patients in Indonesia, showing lower mortality with favipiravir in unadjusted results, not reaching statistical significance.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Lokanuwatsatien: Prospective analysis of 802 COVID-19 pediatric patients in Thailand, showing no significant difference in long COVID with favipiravir treatment in unadjusted results.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Lou: Small late stage RCT with 10 favipiravir, 10 baloxavir marboxil, and 10 control patients in China, showing no significant differences.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Lowe: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Luvira: 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 in Yildiz Pekoz, 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 see Schilling.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
McMahon: RCT with 99 favipiravir and 100 placebo patients in Australia, all except one being outpatients, showing no significant differences with treatment.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Pushkar: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Qadir: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Rahman: RCT hospitalized patients in Bangladesh, showing faster recovery and viral clearance with favipiravir treatment.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Ruzhentsova: RCT 168 patients, 112 receiving favipiravir and 56 SOC, showing shorter time to clinical improvement and faster viral clearance with favipiravir.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Saito: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Sawanpanyalert: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Shah: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Shamsi: Retrospective 183 hospitalized pediatric COVID-19 patients in Iran, showing no significant difference in mortality with favipiravir in unadjusted results.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Shenoy: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Shinada: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Shinkai: 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-.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Sirijatuphat: 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-.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors lopinavir/ri..
Solaymani-Dodaran: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Sulaiman: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors lopinavir/ri..
Tabarsi: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Tawfik: 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.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Tehrani: RCT 78 patients in Iran, showing improved recovery with favipiravir treatment.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Tsuzuki: Retrospective database analysis of 7,654 hospitalized patients in Japan, showing no significant differences with favipiravir treatment. NCGM-G-003494-0.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Udwadia: RCT with 75 favipiravir patients and 75 control patients showing improved recovery with treatment.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Usanma Koban: Retrospective 126 patients in Turkey, showing lower risk of PCR+ at day 14 with favipiravir treatment.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors HCQ
Uyaroğlu: PSM retrospective 260 late stage hospitalized COVID-19 pneumonia patients in Turkey, showing no significant difference between favipiravir and HCQ.
0 0.5 1 1.5 2+ 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 Favors favipiravir Favors control
Vaezi: 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.
0 0.5 1 1.5 2+ 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 favipiravir Favors control
Yulia: Retrospective hospitalized patients in Indonesia, showing lower mortality and shorter hospitalization with favipiravir.
0 0.5 1 1.5 2+ Viral clearance 59% Improvement Relative Risk Time to viral- 52% Favipiravir  Zhao et al.  LATE TREATMENT  RCT Is late treatment with favipiravir beneficial for COVID-19? RCT 55 patients in China (March - May 2020) Improved viral clearance with favipiravir (not stat. sig., p=0.059) c19early.org Zhao et al., Int. Immunopharmacology, Apr 2021 Favors favipiravir Favors control
Zhao: RCT with 55 patients (36 favipiravir, 19 control) who were PCR+ after recovery, showing improved viral clearance with treatment.
We perform ongoing searches of PubMed, medRxiv, Europe PMC, ClinicalTrials.gov, The Cochrane Library, Google Scholar, Research Square, ScienceDirect, Oxford University Press, the reference lists of other studies and meta-analyses, and submissions to the site c19early.org. Search terms are favipiravir and COVID-19 or SARS-CoV-2. Automated searches are performed twice daily, with all matches reviewed for inclusion. All studies regarding the use of favipiravir for COVID-19 that report a comparison with a control group are included in the main analysis. Sensitivity analysis is performed, excluding studies with major issues, epidemiological studies, and studies with minimal available information. This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies. If studies report multiple kinds of effects then the most serious outcome is used in pooled analysis, while other outcomes are included in the outcome specific analyses. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days have preference. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms are not used, the next most serious outcome with one or more events is used. For example, in low-risk populations with no mortality, a reduction in mortality with treatment is not possible, however a reduction in hospitalization, for example, is still valuable. Clinical outcomes are considered more important than viral test status. When basically all patients recover in both treatment and control groups, preference for viral clearance and recovery is given to results mid-recovery where available. After most or all patients have recovered there is little or no room for an effective treatment to do better, however faster recovery is valuable. If only individual symptom data is available, the most serious symptom has priority, for example difficulty breathing or low SpO2 is more important than cough. When results provide an odds ratio, we compute the relative risk when possible, or convert to a relative risk according to Zhang. Reported confidence intervals and p-values were used when available, using adjusted values when provided. If multiple types of adjustments are reported propensity score matching and multivariable regression has preference over propensity score matching or weighting, which has preference over multivariable regression. Adjusted results have preference over unadjusted results for a more serious outcome when the adjustments significantly alter results. When needed, conversion between reported p-values and confidence intervals followed Altman, Altman (B), and Fisher's exact test was used to calculate p-values for event data. If continuity correction for zero values is required, we use the reciprocal of the opposite arm with the sum of the correction factors equal to 1 Sweeting. Results are expressed with RR < 1.0 favoring treatment, and using the risk of a negative outcome when applicable (for example, the risk of death rather than the risk of survival). If studies only report relative continuous values such as relative times, the ratio of the time for the treatment group versus the time for the control group is used. Calculations are done in Python (3.12.3) with scipy (1.13.0), pythonmeta (1.26), numpy (1.26.4), statsmodels (0.14.2), and plotly (5.21.0).
Forest plots are computed using PythonMeta Deng with the DerSimonian and Laird random effects model (the fixed effect assumption is not plausible in this case) and inverse variance weighting. Results are presented with 95% confidence intervals. Heterogeneity among studies was assessed using the I2 statistic. Mixed-effects meta-regression results are computed with R (4.1.2) using the metafor (3.0-2) and rms (6.2-0) packages, and using the most serious sufficiently powered outcome. For all statistical tests, a p-value less than 0.05 was considered statistically significant. Grobid 0.8.0 is used to parse PDF documents.
We have classified studies as early treatment if most patients are not already at a severe stage at the time of treatment (for example based on oxygen status or lung involvement), and treatment started within 5 days of the onset of symptoms. If studies contain a mix of early treatment and late treatment patients, we consider the treatment time of patients contributing most to the events (for example, consider a study where most patients are treated early but late treatment patients are included, and all mortality events were observed with late treatment patients). We note that a shorter time may be preferable. Antivirals are typically only considered effective when used within a shorter timeframe, for example 0-36 or 0-48 hours for oseltamivir, with longer delays not being effective McLean, Treanor.
We received no funding, this research is done in our spare time. We have no affiliations with any pharmaceutical companies or political parties.
A summary of study results is below. Please submit updates and corrections at the bottom of this page.
A summary of study results is below. Please submit updates and corrections at https://c19early.org/ameta.html.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. For pooled analyses, the first (most serious) outcome is used, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.
Adhikari, 3/1/2022, Randomized Controlled Trial, Nepal, peer-reviewed, 12 authors, study period May 2020 - October 2020. risk of no improvement, 40.4% higher, RR 1.40, p = 0.57, treatment 10 of 38 (26.3%), control 6 of 32 (18.8%), all.
risk of no improvement, 36.3% higher, RR 1.36, p = 0.75, treatment 8 of 27 (29.6%), control 5 of 23 (21.7%), mild cases.
risk of no improvement, 63.6% higher, RR 1.64, p = 1.00, treatment 2 of 11 (18.2%), control 1 of 9 (11.1%), moderate cases.
Alattar, 11/30/2021, retrospective, Qatar, peer-reviewed, median age 46.0, 25 authors, study period 23 May, 2020 - 18 July, 2020, average treatment delay 5.0 days. risk of death, 33.3% lower, RR 0.67, p = 0.50, treatment 8 of 387 (2.1%), control 12 of 387 (3.1%), NNT 97, propensity score matching, day 28.
risk of no clinical improvement, 2.2% higher, RR 1.02, p = 0.73, treatment 26 of 387 (6.7%), control 28 of 387 (7.2%), NNT 194, adjusted per study, inverted to make RR<1 favor treatment, day 28, Cox proportional hazards, propensity score matching, primary outcome.
days to clinical improvement, 6.2% higher, relative time 1.06, p = 0.07, treatment 387, control 387, propensity score matching.
risk of no viral clearance, 43.9% lower, RR 0.56, p < 0.001, treatment 78 of 387 (20.2%), control 139 of 387 (35.9%), NNT 6.3, propensity score matching.
Bosaeed, 1/11/2022, Double Blind Randomized Controlled Trial, Saudi Arabia, peer-reviewed, 31 authors, study period 23 July, 2020 - 4 August, 2021, average treatment delay 3.0 days, trial NCT04464408 (history). risk of ICU admission, 618.8% higher, RR 7.19, p = 0.11, treatment 3 of 112 (2.7%), control 0 of 119 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of hospitalization, 218.8% higher, RR 3.19, p = 0.16, treatment 6 of 112 (5.4%), control 2 of 119 (1.7%).
time to clinical improvement, 11.9% higher, HR 1.12, p = 0.51, treatment 112, control 119, adjusted per study, inverted to make HR<1 favor treatment.
time to viral clearance, 14.9% higher, HR 1.15, p = 0.51, treatment 112, control 119, adjusted per study, inverted to make HR<1 favor treatment, primary outcome.
Bruminhent, 9/10/2022, retrospective, Thailand, peer-reviewed, 6 authors, study period 26 April, 2021 - 27 May, 2021. risk of progression, 227.0% higher, OR 3.27, p = 0.005, adjusted per study, multivariable, RR approximated with OR.
Chandiwana, 11/1/2022, Randomized Controlled Trial, South Africa, peer-reviewed, mean age 34.9, 16 authors, study period 3 September, 2020 - 23 August, 2021, this trial uses multiple treatments in the treatment arm (combined with nitazoxanide) - results of individual treatments may vary, trial NCT04532931 (history). risk of progression, 13.0% higher, OR 1.13, p = 0.89, treatment 37, control 39, adjusted per study, day 28, Table S9, RR approximated with OR.
time to WHO zero score, 23.5% higher, HR 1.23, p = 0.42, treatment 37, control 39, inverted to make HR<1 favor treatment, Cox proportional hazards, Table S10.
risk of no viral clearance, 66.7% higher, RR 1.67, p = 0.13, treatment 27 of 37 (73.0%), control 25 of 38 (65.8%), adjusted per study, inverted to make RR<1 favor treatment.
Golan, 9/6/2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, 9 authors, study period November 2020 - October 2021, trial NCT04600895 (history) (PRESECO). risk of death, 66.9% lower, RR 0.33, p = 0.50, treatment 0 of 599 (0.0%), control 1 of 588 (0.2%), NNT 588, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 28.
risk of progression, 1.8% lower, RR 0.98, p = 1.00, treatment 11 of 599 (1.8%), control 11 of 588 (1.9%), NNT 2911, narrow definition.
risk of progression, 7.1% lower, RR 0.93, p = 0.44, treatment 159 of 599 (26.5%), control 168 of 588 (28.6%), NNT 49, broad definition.
risk of no recovery, 4.5% lower, RR 0.96, p = 0.79, treatment 73 of 599 (12.2%), control 75 of 588 (12.8%), NNT 176.
time to viral-, 14.3% lower, relative time 0.86, p < 0.001, treatment median 6.0 IQR 2.0 n=140, control median 7.0 IQR 2.0 n=132, 50% conversion.
Holubar, 11/24/2021, Double Blind Randomized Controlled Trial, USA, peer-reviewed, 26 authors, study period 8 July, 2020 - 23 March, 2021, average treatment delay 5.0 days, conflicts of interest: Pfizer, Gates Foundation, Gilead, Regeneron, Janssen. risk of hospitalization, 89.0% lower, RR 0.11, p = 0.06, treatment 0 of 75 (0.0%), control 4 of 74 (5.4%), NNT 18, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of ER visit, 29.5% lower, RR 0.70, p = 0.56, treatment 5 of 75 (6.7%), control 7 of 74 (9.5%), NNT 36.
risk of no recovery, 19.0% higher, RR 1.19, p = 0.43, treatment 65, control 70, inverted to make RR<1 favor treatment, initial resolution of symptoms.
viral shedding, 31.6% higher, RR 1.32, p = 0.24, treatment 59, control 57, inverted to make RR<1 favor treatment, primary outcome.
Iwata, 10/12/2023, Double Blind Randomized Controlled Trial, placebo-controlled, Japan, peer-reviewed, 13 authors, trial jRCT2041210004. risk of oxygen therapy, 16.2% higher, RR 1.16, p = 0.73, treatment 12 of 43 (27.9%), control 12 of 43 (27.9%), adjusted per study, odds ratio converted to relative risk, multivariable, day 28.
risk of oxygen therapy, 18.5% lower, RR 0.81, p = 0.77, treatment 5 of 24 (20.8%), control 6 of 22 (27.3%), NNT 16, adjusted per study, odds ratio converted to relative risk, patients with onset ≤48 hours, multivariable, day 28.
risk of no viral clearance, 15.9% higher, RR 1.16, p = 0.66, treatment 21 of 41 (51.2%), control 19 of 43 (44.2%), day 15.
risk of no viral clearance, 6.0% lower, RR 0.94, p = 0.82, treatment 26 of 41 (63.4%), control 29 of 43 (67.4%), NNT 25, day 10.
risk of no viral clearance, 0.9% lower, RR 0.99, p = 1.00, treatment 34 of 41 (82.9%), control 36 of 43 (83.7%), NNT 126, day 7.
risk of no viral clearance, 5.6% lower, RR 0.94, p = 0.48, treatment 36 of 41 (87.8%), control 40 of 43 (93.0%), NNT 19, day 4.
Kara, 6/1/2021, Randomized Controlled Trial, Turkey, peer-reviewed, trial NCT04411433 (history). 1,008 patient RCT with results unknown and over 2 years late.
Lokanuwatsatien, 5/24/2023, prospective, Thailand, peer-reviewed, 8 authors, study period September 2021 - March 2022, excluded in exclusion analyses: unadjusted results with no group details. risk of PASC, 14.0% lower, OR 0.86, p = 0.34, treatment 400, control 402, RR approximated with OR.
Lowe, 2/15/2022, Double Blind Randomized Controlled Trial, placebo-controlled, United Kingdom, peer-reviewed, 18 authors, study period 6 October, 2020 - 4 November, 2021, trial NCT04499677 (history) (FLARE). risk of ICU admission, 201.7% higher, RR 3.02, p = 0.50, treatment 1 of 59 (1.7%), control 0 of 60 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of hospitalization, 201.7% higher, RR 3.02, p = 0.50, treatment 1 of 59 (1.7%), control 0 of 60 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of no viral clearance, 28.4% lower, RR 0.72, p = 0.03, treatment 29 of 54 (53.7%), control 38 of 52 (73.1%), NNT 5.2, inverted to make RR<1 favor treatment, odds ratio converted to relative risk, day 5, primary outcome.
Luvira, 4/5/2023, Randomized Controlled Trial, multiple countries, peer-reviewed, median age 30.1, 36 authors, study period 30 September, 2021 - 31 October, 2022, trial NCT05041907 (history) (PLATCOV). relative clearance rate, 5.7% worse, RR 1.06, p = 0.42, treatment median 16.6 IQR 10.0 n=116, control median 15.7 IQR 13.0 n=132, primary outcome.
McMahon, 6/14/2022, Randomized Controlled Trial, placebo-controlled, Australia, peer-reviewed, median age 36.0, 33 authors, study period 31 July, 2020 - 19 September, 2021, trial NCT04445467 (history). risk of oxygen therapy, 1.0% higher, RR 1.01, p = 1.00, treatment 6 of 99 (6.1%), control 6 of 100 (6.0%).
risk of hospitalization, 55.6% higher, RR 1.56, p = 0.38, treatment 14 of 99 (14.1%), control 9 of 99 (9.1%).
Qadir, 5/23/2022, prospective, Iraq, peer-reviewed, 3 authors, study period 22 June, 2020 - 25 October, 2021. risk of death, 97.1% lower, RR 0.03, p < 0.001, treatment 0 of 125 (0.0%), control 17 of 125 (13.6%), NNT 7.4, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 30.
risk of hospitalization, 60.0% lower, RR 0.40, p = 0.001, treatment 14 of 125 (11.2%), control 35 of 125 (28.0%), NNT 6.0.
risk of no recovery, 97.1% lower, RR 0.03, p < 0.001, treatment 0 of 125 (0.0%), control 17 of 125 (13.6%), NNT 7.4, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 30, primary outcome.
risk of no recovery, 70.8% lower, RR 0.29, p < 0.001, treatment 14 of 125 (11.2%), control 48 of 125 (38.4%), NNT 3.7, day 15.
risk of no recovery, 78.8% lower, RR 0.21, p < 0.001, treatment 14 of 125 (11.2%), control 66 of 125 (52.8%), NNT 2.4, day 10.
risk of no recovery, 70.6% lower, RR 0.29, p < 0.001, treatment 32 of 125 (25.6%), control 109 of 125 (87.2%), NNT 1.6, day 5.
recovery time, 58.1% lower, relative time 0.42, p < 0.001, treatment 125, control 125.
Ruzhentsova, 10/26/2020, Randomized Controlled Trial, Russia, preprint, 31 authors, study period 23 May, 2020 - 30 June, 2020, average treatment delay 3.55 days. risk of hospitalization, 6.0% lower, RR 0.94, p = 0.49, treatment 3 of 112 (2.7%), control 2 of 56 (3.6%), adjusted per study.
HR for time to clinical improvement, 38.7% lower, HR 0.61, p = 0.007, treatment 112, control 56, inverted to make HR<1 favor treatment.
risk of no viral clearance, 21.9% lower, RR 0.78, p = 0.16, treatment 112, control 56, inverted to make RR<1 favor treatment, day 5 mid-recovery.
Sawanpanyalert, 9/9/2021, retrospective, Thailand, peer-reviewed, 11 authors. risk of death, ICU, intubation, or high-flow oxygen, 68.0% lower, OR 0.32, p = 0.003, within 4 days of symptom onset, RR approximated with OR.
Sirijatuphat, 6/8/2022, Randomized Controlled Trial, Thailand, peer-reviewed, 9 authors, study period December 2020 - July 2021, trial TCTR20200514001. time to clinical improvement, 63.9% lower, HR 0.36, p < 0.001, treatment 62, control 31, inverted to make HR<1 favor treatment, primary outcome.
clinical improvement, 89.9% lower, OR 0.10, p < 0.001, treatment 62, control 31, inverted to make OR<1 favor treatment, logistic regression, day 14, RR approximated with OR.
risk of mild pneumonia, 42.9% lower, RR 0.57, p = 0.25, treatment 8 of 62 (12.9%), control 7 of 31 (22.6%), NNT 10.
risk of no viral clearance, 4.2% higher, HR 1.04, p = 0.87, treatment 62, control 31, adjusted per study, inverted to make HR<1 favor treatment.
Tsuzuki, 3/21/2022, retrospective, Japan, peer-reviewed, 21 authors, average treatment delay 4.0 days. risk of death, 13.1% lower, HR 0.87, p = 0.59, treatment 2,532, control 5,122, adjusted per study, day 30.
risk of mechanical ventilation, 2.0% higher, HR 1.02, p = 0.93, treatment 2,532, control 5,122, adjusted per study, IMV/ECMO.
risk of progression, 17.5% lower, HR 0.82, p = 0.10, treatment 2,532, control 5,122, adjusted per study, oxygen requirement.
Udwadia, 11/16/2020, Randomized Controlled Trial, India, peer-reviewed, 11 authors, study period 14 May, 2020 - 3 July, 2020, trial CTRI/2020/05/025114. risk of death, 66.4% lower, RR 0.34, p = 1.00, treatment 0 of 73 (0.0%), control 1 of 75 (1.3%), NNT 75, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
time to discharge, 28.9% lower, HR 0.71, p = 0.07, treatment 75, control 72, inverted to make HR<1 favor treatment.
time to clinical cure, 42.8% lower, HR 0.57, p = 0.02, treatment 75, control 72, inverted to make HR<1 favor treatment.
time to viral clearance, 26.8% lower, HR 0.73, p = 0.10, treatment 75, control 72, inverted to make HR<1 favor treatment.
Usanma Koban, 6/7/2022, retrospective, Turkey, peer-reviewed, 3 authors, study period 1 March, 2020 - 30 September, 2020. risk of no viral clearance, 86.0% lower, OR 0.14, p = 0.03, treatment 47, control 79, adjusted per study, multivariable, day 14, RR approximated with OR.
Vaezi, 1/28/2023, Double Blind Randomized Controlled Trial, placebo-controlled, Iran, peer-reviewed, 6 authors, study period 5 December, 2020 - 31 March, 2021, trial IRCT20171219037964N3. risk of hospitalization, 105.3% higher, RR 2.05, p = 0.43, treatment 4 of 38 (10.5%), control 2 of 39 (5.1%), day 28.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. For pooled analyses, the first (most serious) outcome is used, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.
Abdulrahman, 6/21/2022, retrospective, Saudi Arabia, peer-reviewed, 15 authors, study period June 2020 - August 2020, excluded in exclusion analyses: very late stage, ICU patients. risk of death, 2.6% lower, RR 0.97, p = 0.81, treatment 74 of 193 (38.3%), control 593 of 1,506 (39.4%), NNT 97.
Acar Sevinc, 6/28/2022, retrospective, Turkey, peer-reviewed, mean age 65.6, 1 author, study period 10 March, 2020 - 10 May, 2020, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04645433 (history), excluded in exclusion analyses: very late stage, ICU patients. risk of death, 16.2% lower, RR 0.84, p = 0.38, treatment 57 of 85 (67.1%), control 12 of 15 (80.0%), NNT 7.7.
risk of mechanical ventilation, 10.3% lower, RR 0.90, p = 0.75, treatment 61 of 85 (71.8%), control 12 of 15 (80.0%), NNT 12.
Aghajani, 4/29/2021, retrospective, Iran, peer-reviewed, 7 authors. risk of death, 26.1% lower, HR 0.74, p = 0.28, treatment 40, control 951, univariate Cox proportional regression.
Al Mutair, 2/15/2022, retrospective, Saudi Arabia, peer-reviewed, 14 authors, study period April 2020 - March 2021, this trial compares with another treatment - results may be better when compared to placebo, excluded in exclusion analyses: very late stage, ICU patients. risk of death, 7.0% lower, RR 0.93, p = 0.49, treatment 119 of 269 (44.2%), control 128 of 269 (47.6%), NNT 30.
risk of ARDS, 8.6% higher, RR 1.09, p = 0.63, treatment 76 of 269 (28.3%), control 70 of 269 (26.0%), severe ARDS.
ICU time, 33.7% higher, relative time 1.34, p = 0.001, treatment 269, control 269.
hospitalization time, 36.6% higher, relative time 1.37, p = 0.001, treatment 269, control 269.
Al-Muhsen, 3/4/2022, prospective, Saudi Arabia, peer-reviewed, 11 authors, study period June 2020 - January 2021. risk of death, 263.0% higher, HR 3.63, p = 0.04, treatment 156, control 442, Cox proportional hazards, day 65.
risk of oxygen therapy, 40.6% lower, RR 0.59, p < 0.001, treatment 52 of 156 (33.3%), control 248 of 442 (56.1%), NNT 4.4.
hospitalization time, 40.0% higher, relative time 1.40, p = 0.03, treatment 156, control 442.
Alamer, 5/19/2021, retrospective, Saudi Arabia, peer-reviewed, 18 authors. risk of death, 56.0% higher, HR 1.56, p = 0.26, treatment 12 of 233 (5.2%), control 21 of 223 (9.4%), adjusted per study, day 90.
risk of mechanical ventilation, 90.0% lower, HR 0.10, p < 0.001, treatment 4 of 218 (1.8%), control 27 of 165 (16.4%), NNT 6.9, adjusted per study.
adjusted discharge ratio, 49.0% lower, RR 0.51, p < 0.001, treatment 221, control 201, adjusted per study, inverted to make RR<1 favor treatment.
Almoosa, 8/24/2021, retrospective, Saudi Arabia, peer-reviewed, 14 authors. risk of death, 42.3% higher, RR 1.42, p = 0.10, treatment 33 of 110 (30.0%), control 24 of 116 (20.7%), adjusted per study, odds ratio converted to relative risk, overall mortality, multivariate binary logistic regression.
risk of death, 149.3% higher, RR 2.49, p = 0.006, treatment 26 of 110 (23.6%), control 11 of 116 (9.5%), day 28.
risk of death, 61.7% lower, RR 0.38, p = 0.11, treatment 4 of 110 (3.6%), control 11 of 116 (9.5%), NNT 17, day 14.
risk of ICU admission, 90.0% higher, OR 1.90, p = 0.02, treatment 110, control 116, adjusted per study, multivariate binary logistic regression, RR approximated with OR.
recovery time, 10.9% higher, relative time 1.11, p = 0.17, treatment 110, control 116.
Alosaimi, 11/24/2022, retrospective, Saudi Arabia, peer-reviewed, 13 authors, study period April 2020 - March 2021, this trial compares with another treatment - results may be better when compared to placebo. risk of death, 80.0% lower, RR 0.20, p = 0.49, treatment 0 of 37 (0.0%), control 2 of 37 (5.4%), NNT 18, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), propensity score matching.
hospitalization time, 75.0% higher, relative time 1.75, p = 0.63, treatment 37, control 37, propensity score matching.
time to discharge, 40.0% higher, relative time 1.40, p = 0.74, treatment 37, control 37, propensity score matching.
Alotaibi, 9/14/2021, retrospective, Saudi Arabia, peer-reviewed, 11 authors, this trial compares with another treatment - results may be better when compared to placebo. risk of death, 57.2% lower, RR 0.43, p = 0.05, treatment 244, control 193, inverted to make RR<1 favor treatment, multivariate, day 30.
AlQahtani, 3/23/2022, Randomized Controlled Trial, Bahrain, peer-reviewed, 14 authors, study period August 2020 - March 2021, trial NCT04387760 (history). risk of death, 196.3% higher, RR 2.96, p = 1.00, treatment 1 of 54 (1.9%), control 0 of 52 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), day 30.
risk of ICU admission, 75.9% lower, RR 0.24, p = 0.20, treatment 1 of 54 (1.9%), control 4 of 52 (7.7%), NNT 17.
risk of no recovery, 41.9% higher, RR 1.42, p = 0.51, treatment 8 of 53 (15.1%), control 5 of 47 (10.6%).
risk of no viral clearance, 42.9% lower, RR 0.57, p = 0.21, treatment 8 of 40 (20.0%), control 14 of 40 (35.0%), NNT 6.7.
Alshamrani, 2/15/2023, retrospective, Saudi Arabia, peer-reviewed, 3 authors, study period March 2020 - January 2021. risk of death, 14.0% higher, RR 1.14, p = 0.13, treatment 326 of 1,159 (28.1%), control 316 of 1,380 (22.9%), adjusted per study, odds ratio converted to relative risk, propensity score matching, multivariable.
risk of progression, 1.9% higher, RR 1.02, p = 0.83, treatment 475 of 1,159 (41.0%), control 499 of 1,380 (36.2%), adjusted per study, odds ratio converted to relative risk, AKI, ARDS, multi-organ failure, or mortality, propensity score matching, multivariable.
ICU time, 18.6% higher, relative time 1.19, p = 0.005, treatment 668, control 633, propensity score matching.
hospitalization time, 28.8% higher, relative time 1.29, p < 0.001, treatment 1,159, control 1,380, propensity score matching.
Arfijanto, 5/4/2023, retrospective, Indonesia, peer-reviewed, 8 authors, study period June 2021 - December 2021, excluded in exclusion analyses: unadjusted results with no group details. delayed viral clearance, 50.9% lower, RR 0.49, p = 0.02, treatment 8 of 37 (21.6%), control 55 of 125 (44.0%), NNT 4.5.
Assiri, 8/28/2021, retrospective, Saudi Arabia, peer-reviewed, 8 authors, excluded in exclusion analyses: unadjusted results with no group details; very late stage, ICU patients. risk of death, 79.3% higher, RR 1.79, p = 0.50, treatment 11 of 67 (16.4%), control 3 of 51 (5.9%), inverted to make RR<1 favor treatment, odds ratio converted to relative risk.
Atipornwanich, 10/5/2021, Randomized Controlled Trial, Thailand, peer-reviewed, 16 authors, study period 19 August, 2020 - 28 August, 2021, this trial compares with another treatment - results may be better when compared to placebo, this trial uses multiple treatments in the treatment arm (combined with lopinavir/ritonavir or duranivir/ritonavir/HCQ) - results of individual treatments may vary, trial NCT04303299 (history) (FIGHT-COVID-19). risk of death, 23.1% lower, RR 0.77, p = 0.66, treatment 10 of 100 (10.0%), control 13 of 100 (13.0%), NNT 33, favipiravir arms vs. oseltamivir arms.
risk of progression, 60.0% lower, RR 0.40, p = 0.009, treatment 10 of 100 (10.0%), control 25 of 100 (25.0%), NNT 6.7, favipiravir arms vs. oseltamivir arms.
time to viral-, 8.7% lower, relative time 0.91, p = 0.43, treatment mean 9.5 (±5.0) n=50, control mean 10.4 (±6.3) n=50, HCQ arms, primary outcome.
time to viral-, 8.9% lower, relative time 0.91, p = 0.34, treatment mean 10.2 (±4.6) n=50, control mean 11.2 (±5.7) n=50, non-HCQ arms, primary outcome.
Babayigit, 8/31/2022, retrospective, Turkey, peer-reviewed, mean age 51.9, 68 authors, study period 11 March, 2020 - 18 July, 2020, excluded in exclusion analyses: substantial unadjusted confounding by indication possible. risk of mechanical ventilation, 184.4% higher, RR 2.84, p = 0.01, treatment 47 of 325 (14.5%), control 17 of 977 (1.7%), adjusted per study, odds ratio converted to relative risk, multivariable.
risk of ICU admission, 181.5% higher, RR 2.81, p = 0.001, treatment 75 of 325 (23.1%), control 35 of 969 (3.6%), adjusted per study, odds ratio converted to relative risk, multivariable.
hospitalization time, 100% higher, relative time 2.00, p = 0.001, treatment 265, control 746.
Behboodikhah, 9/15/2022, retrospective, Iran, peer-reviewed, 8 authors. risk of death, 68.5% lower, OR 0.32, p = 0.20, treatment 95, control 2,079, adjusted per study, multivariable, RR approximated with OR.
Cai, 3/18/2020, retrospective, China, peer-reviewed, 26 authors. risk of no improvement in CT, 68.7% lower, OR 0.31, p = 0.04, treatment 35, control 45, inverted to make OR<1 favor treatment, multivariate, RR approximated with OR.
risk of no viral clearance, 70.9% lower, HR 0.29, p = 0.03, treatment 35, control 45, inverted to make HR<1 favor treatment, multivariate.
Chen, 9/2/2021, Randomized Controlled Trial, China, peer-reviewed, 14 authors, average treatment delay 9.0 days, this trial compares with another treatment - results may be better when compared to placebo. risk of ICU admission, 3.4% higher, RR 1.03, p = 1.00, treatment 2 of 116 (1.7%), control 2 of 120 (1.7%).
risk of respiratory failure, 74.1% lower, RR 0.26, p = 0.37, treatment 1 of 116 (0.9%), control 4 of 120 (3.3%), NNT 40.
risk of oxygen therapy, 19.5% lower, RR 0.80, p = 0.42, treatment 21 of 116 (18.1%), control 27 of 120 (22.5%), NNT 23.
risk of progression to dyspnea, 70.4% lower, RR 0.30, p = 0.03, treatment 4 of 116 (3.4%), control 14 of 120 (11.7%), NNT 12.
risk of dyspnea, 10.3% lower, RR 0.90, p = 0.84, treatment 13 of 116 (11.2%), control 15 of 120 (12.5%), NNT 77.
risk of no recovery, 19.7% lower, RR 0.80, p = 0.15, treatment 45 of 116 (38.8%), control 58 of 120 (48.3%), NNT 10, day 7, primary outcome.
Chuah, 11/19/2021, Randomized Controlled Trial, Malaysia, peer-reviewed, 18 authors, study period February 2021 - July 2021. risk of death, 1154.0% higher, RR 12.54, p = 0.08, treatment 5 of 250 (2.0%), control 0 of 250 (0.0%), odds ratio converted to relative risk, continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of mechanical ventilation, 19.5% higher, RR 1.20, p = 0.76, treatment 6 of 250 (2.4%), control 5 of 250 (2.0%), odds ratio converted to relative risk.
risk of ICU admission, 8.5% higher, RR 1.09, p = 0.84, treatment 13 of 250 (5.2%), control 12 of 250 (4.8%), odds ratio converted to relative risk.
Cilli, 3/3/2022, retrospective, Turkey, peer-reviewed, 10 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 37.5% lower, RR 0.62, p = 0.51, treatment 5 of 23 (21.7%), control 8 of 23 (34.8%), NNT 7.7, day 30.
Damayanti, 11/1/2021, retrospective, Indonesia, peer-reviewed, 4 authors, excluded in exclusion analyses: minimal details provided. risk of no recovery, 54.5% lower, RR 0.46, p = 0.03, treatment 96, control 96, adjusted per study, inverted to make RR<1 favor treatment.
Delen, 12/31/2022, retrospective, Turkey, peer-reviewed, mean age 60.1, 8 authors, study period March 2020 - July 2020. risk of ICU admission, 22.8% lower, RR 0.77, p = 1.00, treatment 3 of 34 (8.8%), control 4 of 35 (11.4%), NNT 38.
risk of no recovery, 87.5% lower, RR 0.12, p = 0.02, treatment 1 of 21 (4.8%), control 8 of 21 (38.1%), NNT 3.0, day 5, fever.
hospitalization time, 2.2% higher, relative time 1.02, p = 0.74, treatment 34, control 35.
risk of no hospital discharge, 2.9% higher, RR 1.03, p = 1.00, treatment 31 of 34 (91.2%), control 31 of 35 (88.6%).
Finberg, 12/7/2021, Randomized Controlled Trial, USA, peer-reviewed, 10 authors, study period 17 April, 2020 - 30 October, 2020, average treatment delay 8.4 days, trial NCT04358549 (history). risk of death, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 25 (4.0%), control 0 of 25 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), day 60.
risk of mechanical ventilation, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 25 (4.0%), control 0 of 25 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of no recovery, 58.1% lower, OR 0.42, p = 0.08, treatment 25, control 25, inverted to make OR<1 favor treatment, day 8 mid-recovery, 6-point ordinal scale, RR approximated with OR.
risk of no recovery, 46.2% higher, OR 1.46, p = 0.54, treatment 25, control 25, inverted to make OR<1 favor treatment, day 15, 6-point ordinal scale, RR approximated with OR.
time to viral-, 46.7% lower, relative time 0.53, p = 0.04, treatment 25, control 25, primary outcome.
Hafez, 4/8/2022, retrospective, United Arab Emirates, peer-reviewed, 6 authors, this trial uses multiple treatments in the treatment arm (combined with HCQ) - results of individual treatments may vary. viral clearance time, 3.1% higher, HR 1.03, p = 0.09, treatment 59, control 1,446, inverted to make HR<1 favor treatment, HCQ + favipiravir, Cox proportional hazards.
viral clearance time, 58.7% lower, HR 0.41, p = 0.09, treatment 4, control 1,446, inverted to make HR<1 favor treatment, HCQ + favipiravir + lopinavir/ritonavir, Cox proportional hazards.
Hartantri, 2/9/2023, retrospective, Indonesia, peer-reviewed, 10 authors, study period 1 March, 2020 - 31 December, 2020. risk of death, 76.0% lower, HR 0.24, p < 0.001, adjusted per study, mild/moderate, multivariable, Cox proportional hazards, day 28.
risk of death, 60.0% lower, HR 0.40, p = 0.04, adjusted per study, severe, multivariable, Cox proportional hazards, day 28.
Hassaniazad, 3/24/2022, Randomized Controlled Trial, Iran, peer-reviewed, mean age 53.8, 7 authors, this trial compares with another treatment - results may be better when compared to placebo, trial IRCT20200506047323N3. risk of death, 67.7% lower, RR 0.32, p = 0.15, treatment 2 of 32 (6.2%), control 6 of 31 (19.4%), NNT 7.6, day 14.
risk of death, 3.1% lower, RR 0.97, p = 1.00, treatment 1 of 32 (3.1%), control 1 of 31 (3.2%), NNT 992, day 7.
risk of ICU admission, 35.4% lower, RR 0.65, p = 0.51, treatment 4 of 32 (12.5%), control 6 of 31 (19.4%), NNT 15, day 14.
hospitalization time, 25.0% lower, relative time 0.75, p = 0.14, treatment 32, control 31.
risk of no viral clearance, 18.0% lower, RR 0.82, p = 0.24, treatment 22 of 32 (68.8%), control 26 of 31 (83.9%), NNT 6.6, day 7.
Horcajada, 8/24/2023, Double Blind Randomized Controlled Trial, placebo-controlled, Spain, peer-reviewed, 30 authors, study period November 2020 - October 2021, trial EudraCT2020-002753-22 (FAVID). risk of death, 382.6% higher, RR 4.83, p = 0.49, treatment 2 of 23 (8.7%), control 0 of 21 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), day 28.
risk of mechanical ventilation, 37.0% higher, RR 1.37, p = 1.00, treatment 3 of 23 (13.0%), control 2 of 21 (9.5%), day 28.
dischage or NEWS <3, 16.7% lower, relative time 0.83, p = 0.64, treatment 23, control 21.
time to viral-, 125.0% higher, relative time 2.25, p = 0.51, treatment 23, control 21.
Ivashchenko, 8/9/2020, Randomized Controlled Trial, Russia, peer-reviewed, 21 authors, study period April 2020 - May 2020, average treatment delay 6.7 days. risk of death, 300.0% higher, RR 4.00, p = 0.55, treatment 2 of 40 (5.0%), control 0 of 20 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), day 29.
risk of mechanical ventilation, 300.0% higher, RR 4.00, p = 0.55, treatment 2 of 40 (5.0%), control 0 of 20 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of ICU admission, 300.0% higher, RR 4.00, p = 0.55, treatment 2 of 40 (5.0%), control 0 of 20 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of no viral clearance, 46.4% lower, RR 0.54, p = 0.03, treatment 15 of 40 (37.5%), control 14 of 20 (70.0%), NNT 3.1, mid-recovery day 5.
risk of no viral clearance, 62.5% lower, RR 0.37, p = 0.21, treatment 3 of 40 (7.5%), control 4 of 20 (20.0%), NNT 8.0, day 10.
risk of no discharge and WHO-OSC>2, 66.7% higher, RR 1.67, p = 0.51, treatment 10 of 40 (25.0%), control 3 of 20 (15.0%).
Khamis, 11/9/2020, Randomized Controlled Trial, Oman, peer-reviewed, 11 authors, study period 22 June, 2020 - 13 August, 2020, this trial compares with another treatment - results may be better when compared to placebo, this trial uses multiple treatments in the treatment arm (combined with interferon beta-1b) - results of individual treatments may vary, excluded in exclusion analyses: study compares against another treatment showing significant efficacy. risk of death, 14.8% lower, RR 0.85, p = 1.00, treatment 5 of 44 (11.4%), control 6 of 45 (13.3%), NNT 51, day 14.
risk of ICU admission, 2.3% higher, RR 1.02, p = 1.00, treatment 8 of 44 (18.2%), control 8 of 45 (17.8%).
risk of no recovery, 9.6% higher, RR 1.10, p = 0.82, treatment 15 of 44 (34.1%), control 14 of 45 (31.1%).
Kulzhanova, 8/31/2021, retrospective, Kazakhstan, peer-reviewed, 10 authors, average treatment delay 6.45 days. risk of no improvement, 88.0% lower, RR 0.12, p < 0.001, treatment 3 of 40 (7.5%), control 25 of 40 (62.5%), NNT 1.8, mid-recovery day 7.
risk of no improvement, 88.9% lower, RR 0.11, p = 0.12, treatment 0 of 40 (0.0%), control 4 of 40 (10.0%), NNT 10.0, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 14.
risk of no viral clearance, 50.0% lower, RR 0.50, p = 0.18, treatment 6 of 40 (15.0%), control 12 of 40 (30.0%), NNT 6.7.
Kurniyanto, 2/28/2022, retrospective, Indonesia, peer-reviewed, 11 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 48.0% lower, RR 0.52, p = 0.21, treatment 10 of 325 (3.1%), control 9 of 152 (5.9%), NNT 35.
Lou, 10/25/2020, Randomized Controlled Trial, China, peer-reviewed, 13 authors, average treatment delay 8.5 days, trial ChiCTR2000029544. risk of ICU admission, 422.2% higher, RR 5.22, p = 0.21, treatment 2 of 9 (22.2%), control 0 of 10 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of no recovery, 11.1% lower, RR 0.89, p = 1.00, treatment 4 of 9 (44.4%), control 5 of 10 (50.0%), NNT 18, day 14.
risk of no recovery, 13.6% lower, RR 0.86, p = 0.58, treatment 7 of 9 (77.8%), control 9 of 10 (90.0%), NNT 8.2, day 7.
risk of no viral clearance, 422.2% higher, RR 5.22, p = 0.21, treatment 2 of 9 (22.2%), control 0 of 10 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), day 14.
risk of no viral clearance, 11.1% higher, RR 1.11, p = 1.00, treatment 5 of 9 (55.6%), control 5 of 10 (50.0%), day 7.
Pushkar, 11/5/2020, Randomized Controlled Trial, Russia, preprint, mean age 50.0, 1 author. risk of no clinical status improvement of 2+ WHO-OSCI at ~10 days, 14.1% lower, RR 0.86, p = 0.06, treatment 73 of 100 (73.0%), control 85 of 100 (85.0%), NNT 8.3.
relative time to clinical improvement, 33.3% lower, relative time 0.67, p < 0.001, treatment 100, control 100.
risk of no fever reduction by day 3, 45.2% lower, RR 0.55, p < 0.001, treatment 40 of 100 (40.0%), control 73 of 100 (73.0%), NNT 3.0.
relative time to resolution of fever, 20.0% lower, relative time 0.80, p = 0.05, treatment 100, control 100.
risk of no discharge at day 10, 69.7% lower, RR 0.30, p < 0.001, treatment 10 of 100 (10.0%), control 33 of 100 (33.0%), NNT 4.3.
risk of no full recovery at day 10, 26.7% lower, RR 0.73, p < 0.001, treatment 66 of 100 (66.0%), control 90 of 100 (90.0%), NNT 4.2.
risk of no improvement in lung CT, 33.3% lower, RR 0.67, p = 0.007, treatment 40 of 100 (40.0%), control 60 of 100 (60.0%), NNT 5.0.
risk of no viral clearance, 90.5% lower, RR 0.10, p < 0.001, treatment 2 of 100 (2.0%), control 21 of 100 (21.0%), NNT 5.3.
Rahman, 5/13/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Bangladesh, peer-reviewed, mean age 37.8, 10 authors, study period May 2020 - July 2020, trial NCT04402203 (history). risk of no chest x-ray improvement, 89.5% lower, RR 0.11, p = 0.005, treatment 1 of 19 (5.3%), control 8 of 16 (50.0%), NNT 2.2, day 10.
risk of no chest x-ray improvement, 64.9% lower, RR 0.35, p = 0.007, treatment 5 of 19 (26.3%), control 12 of 16 (75.0%), NNT 2.1, day 7.
risk of no chest x-ray improvement, 47.4% lower, RR 0.53, p = 0.001, treatment 10 of 19 (52.6%), control 16 of 16 (100.0%), NNT 2.1, day 4.
risk of no viral clearance, 91.7% lower, RR 0.08, p < 0.001, treatment 1 of 25 (4.0%), control 12 of 25 (48.0%), NNT 2.3, day 10.
risk of no viral clearance, 62.5% lower, RR 0.38, p = 0.010, treatment 6 of 25 (24.0%), control 16 of 25 (64.0%), NNT 2.5, day 7.
risk of no viral clearance, 48.0% lower, RR 0.52, p < 0.001, treatment 13 of 25 (52.0%), control 25 of 25 (100.0%), NNT 2.1, day 4.
Saito, 1/28/2024, retrospective, Japan, peer-reviewed, 6 authors, study period February 2020 - June 2021, average treatment delay 6.9 days, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 168.3% higher, RR 2.68, p = 0.06, treatment 7 of 40 (17.5%), control 6 of 92 (6.5%).
Shah, 9/22/2022, Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, median age 58.9, 120 authors, study period 5 May, 2020 - 26 May, 2021, average treatment delay 8.9 days, trial NCT04373733 (history) (PIONEER). risk of death, 26.0% lower, HR 0.74, p = 0.24, treatment 26 of 251 (10.4%), control 34 of 248 (13.7%), NNT 30, day 28.
risk of mechanical ventilation, 24.0% lower, HR 0.76, p = 0.21, treatment 251, control 248.
risk of no recovery, 5.7% lower, HR 0.94, p = 0.53, treatment 251, control 248, inverted to make HR<1 favor treatment.
Shamsi, 7/17/2023, retrospective, Iran, peer-reviewed, 4 authors, study period 1 March, 2020 - 1 August, 2021, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 96.4% lower, RR 0.04, p = 0.14, treatment 0 of 19 (0.0%), control 24 of 164 (14.6%), NNT 6.8, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
Shenoy, 11/9/2021, Double Blind Randomized Controlled Trial, Kuwait, preprint, 8 authors, study period 22 August, 2020 - 27 January, 2021, average treatment delay 6.3 days, trial NCT04529499 (history). risk of death, 29.5% higher, RR 1.29, p = 0.54, treatment 14 of 175 (8.0%), control 11 of 178 (6.2%), day 28.
risk of mechanical ventilation, 33.0% higher, RR 1.33, p = 0.54, treatment 17 of 175 (9.7%), control 13 of 178 (7.3%).
risk of ICU admission, 1.7% higher, RR 1.02, p = 0.54, treatment 20 of 175 (11.4%), control 20 of 178 (11.2%).
time to resolution of hypoxia, 1.0% higher, HR 1.01, p = 0.94, treatment 157, control 158, inverted to make HR<1 favor treatment, primary outcome.
time to hospital discharge, 5.7% lower, HR 0.94, p = 0.60, treatment 175, control 178, inverted to make HR<1 favor treatment.
time to resolution of hypoxia, 17.4% lower, HR 0.83, p = 0.29, treatment 157, control 158, inverted to make HR<1 favor treatment, earlier treatment subgroup, primary outcome.
time to hospital discharge, 32.0% lower, HR 0.68, p = 0.01, treatment 175, control 178, inverted to make HR<1 favor treatment, earlier treatment subgroup.
Shinada, 3/24/2022, retrospective, Japan, peer-reviewed, 11 authors, study period 28 May, 2020 - 26 September, 2020, average treatment delay 8.9 days. hospitalization time, 7.5% lower, HR 0.93, p = 0.84, treatment 17, control 17.
viral clearance time, 55.2% lower, HR 0.45, p = 0.04, treatment 17, control 17.
Shinkai, 8/27/2021, Single Blind Randomized Controlled Trial, Japan, peer-reviewed, 39 authors, average treatment delay 4.8 days. time to improvement, 37.1% lower, HR 0.63, p = 0.01, treatment 107, control 49, adjusted per study, inverted to make HR<1 favor treatment, Cox proportional hazards, composite time to improvement in temperature, SpO2, CT findings, and recovery to PCR-.
time to improvement, 58.5% lower, HR 0.41, p = 0.01, treatment 47, control 13, adjusted per study, inverted to make HR<1 favor treatment, <5 days from onset of fever, Cox proportional hazards, composite time to improvement in temperature, SpO2, CT findings, and recovery to PCR-.
Solaymani-Dodaran, 3/11/2021, Randomized Controlled Trial, Iran, peer-reviewed, 44 authors, study period 4 February, 2020 - 8 March, 2020, this trial compares with another treatment - results may be better when compared to placebo. risk of death, 19.2% higher, RR 1.19, p = 0.54, treatment 26 of 190 (13.7%), control 21 of 183 (11.5%).
risk of mechanical ventilation, 53.0% higher, RR 1.53, p = 0.15, treatment 27 of 190 (14.2%), control 17 of 183 (9.3%).
risk of ICU admission, 19.4% higher, RR 1.19, p = 0.56, treatment 31 of 190 (16.3%), control 25 of 183 (13.7%).
Sulaiman, 6/14/2023, retrospective, Saudi Arabia, peer-reviewed, mean age 60.1, 20 authors, study period 1 March, 2020 - 31 July, 2021, excluded in exclusion analyses: very late stage, ICU patients. risk of death, 17.0% higher, HR 1.17, p = 0.51, treatment 73, control 73, in-hospital, propensity score matching.
risk of death, 14.0% lower, HR 0.86, p = 0.53, treatment 73, control 73, propensity score matching, day 30.
ventilation time, 46.7% higher, relative time 1.47, p = 0.008, treatment 73, control 73, propensity score matching.
ICU time, 50.0% higher, relative time 1.50, p = 0.01, treatment 73, control 73, propensity score matching.
Tabarsi, 9/30/2021, Randomized Controlled Trial, Iran, peer-reviewed, 27 authors, study period 4 April, 2020 - 7 May, 2020, average treatment delay 7.0 days, this trial compares with another treatment - results may be better when compared to placebo. risk of death, 29.7% lower, RR 0.70, p = 0.70, treatment 3 of 32 (9.4%), control 4 of 30 (13.3%), NNT 25.
risk of ICU admission, 41.4% lower, RR 0.59, p = 0.36, treatment 5 of 32 (15.6%), control 8 of 30 (26.7%), NNT 9.1.
risk of <50% improvement in chest CT, 6.2% lower, RR 0.94, p = 0.76, treatment 24 of 32 (75.0%), control 24 of 30 (80.0%), NNT 20.
hospitalization time, 25.0% lower, relative time 0.75, p = 0.03, treatment 32, control 30.
Tawfik, 6/29/2022, retrospective, Saudi Arabia, peer-reviewed, mean age 60.1, 8 authors, study period 3 June, 2020 - 3 November, 2020, excluded in exclusion analyses: unadjusted results with minimal group details. risk of death, 96.5% lower, RR 0.04, p < 0.001, treatment 1 of 103 (1.0%), control 17 of 62 (27.4%), NNT 3.8.
risk of ICU admission, 21.0% lower, RR 0.79, p = 0.45, treatment 21 of 103 (20.4%), control 16 of 62 (25.8%), NNT 18.
hospitalization time, 15.8% lower, relative time 0.84, p < 0.001, treatment mean 9.6 (±1.2) n=102, control mean 11.4 (±1.7) n=58.
Tehrani, 6/15/2022, Randomized Controlled Trial, Iran, peer-reviewed, mean age 52.5, 5 authors, study period April 2021 - September 2021, average treatment delay 5.29 days, trial IRCT20211004052664N1. risk of hospitalization, 34.2% lower, RR 0.66, p = 0.24, treatment 10 of 38 (26.3%), control 16 of 40 (40.0%), NNT 7.3.
risk of no recovery, 79.6% lower, RR 0.20, p = 0.49, treatment 0 of 38 (0.0%), control 2 of 40 (5.0%), NNT 20, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 7, dyspnea.
risk of no recovery, 57.9% lower, RR 0.42, p = 0.010, treatment 8 of 38 (21.1%), control 20 of 40 (50.0%), NNT 3.5, day 5, dyspnea.
risk of no recovery, 47.4% lower, RR 0.53, p = 1.00, treatment 1 of 38 (2.6%), control 2 of 40 (5.0%), NNT 42, day 7, fever.
risk of no recovery, 47.4% lower, RR 0.53, p = 0.25, treatment 5 of 38 (13.2%), control 10 of 40 (25.0%), NNT 8.4, day 5, fever.
risk of no recovery, 66.1% lower, RR 0.34, p = 1.00, treatment 0 of 38 (0.0%), control 1 of 40 (2.5%), NNT 40, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 7, sore throat.
risk of no recovery, 47.4% lower, RR 0.53, p = 0.68, treatment 2 of 38 (5.3%), control 4 of 40 (10.0%), NNT 21, day 5, sore throat.
risk of no recovery, 29.8% lower, RR 0.70, p = 0.17, treatment 16 of 38 (42.1%), control 24 of 40 (60.0%), NNT 5.6, day 7, cough.
risk of no recovery, 7.1% lower, RR 0.93, p = 0.56, treatment 30 of 38 (78.9%), control 34 of 40 (85.0%), NNT 17, day 5, cough.
risk of no recovery, 21.1% lower, RR 0.79, p = 0.77, treatment 6 of 38 (15.8%), control 8 of 40 (20.0%), NNT 24, day 7, myalgia.
risk of no recovery, 38.1% lower, RR 0.62, p = 0.16, treatment 10 of 38 (26.3%), control 17 of 40 (42.5%), NNT 6.2, day 5, myalgia.
Uyaroğlu, 3/17/2022, retrospective, propensity score matching, Turkey, peer-reviewed, 6 authors, study period 20 March, 2020 - 30 September, 2020, this trial compares with another treatment - results may be better when compared to placebo. risk of death, 66.7% lower, RR 0.33, p = 1.00, treatment 0 of 42 (0.0%), control 1 of 42 (2.4%), NNT 42, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of ICU admission, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 42 (2.4%), control 0 of 42 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
hospitalization time, 10.8% higher, relative time 1.11, p = 0.90, treatment 42, control 42.
Yulia, 3/7/2022, retrospective, Indonesia, peer-reviewed, median age 46.0, 10 authors, study period July 2020 - December 2020. risk of death, 85.3% lower, OR 0.15, p = 0.05, inverted to make OR<1 favor treatment, RR approximated with OR.
Zhao, 4/21/2021, Randomized Controlled Trial, China, peer-reviewed, 25 authors, study period 27 March, 2020 - 9 May, 2020. risk of no viral clearance, 59.0% lower, RR 0.41, p = 0.06, treatment 7 of 36 (19.4%), control 9 of 19 (47.4%), NNT 3.6.
time to viral-, 52.4% lower, relative time 0.48, p = 0.04, treatment 36, control 19, inverted to make RR<1 favor treatment.