Favipiravir for COVID-19: real-time meta analysis of 70 studies
Abstract
Statistically significant lower risk is seen for recovery and viral clearance. 31 studies from 31 independent teams in 16 countries show 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 include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity3-7. Favipiravir may impair clotting8. Variants may be less susceptible to favipiravir9.
No treatment 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.
Favipiravir for COVID-19 — Highlights
Favipiravir reduces
risk with very high confidence for recovery, viral clearance, and in pooled analysis, and very low confidence for mortality and progression, however increased risk is seen with very high confidence for ICU admission.
Potential risks include the creation of dangerous variants, carcinogenicity, and genotoxicity.
Outcome specific analyses and combined evidence from all
studies, incorporating treatment delay, a primary confounding factor.
Real-time updates and corrections,
transparent analysis with all results in the same format, consistent protocol
for 109
treatments.
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 injury10-20 and
cognitive deficits12,17, cardiovascular
complications21-23, organ failure, and death.
Minimizing replication as early as possible is recommended.
SARS-CoV-2 infection and replication involves the complex interplay of 50+
host and viral proteins and other factorsA,24-29, providing many
therapeutic targets for which many existing compounds have known activity.
Scientists have predicted that over 8,000 compounds may
reduce COVID-19 risk30, 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 favipiravir31.
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.
| Improvement | Studies | Patients | Authors | |
|---|---|---|---|---|
| All studies | 15% [5‑24%] ** | 70 | 34,275 | 1,142 |
| After exclusions | 18% [6‑28%] ** | 54 | 28,020 | 940 |
| Peer-reviewed studiesPeer-reviewed | 16% [5‑25%] ** | 67 | 33,554 | 1,102 |
| Randomized Controlled TrialsRCTs | 15% [-2‑28%] | 34 | 9,630 | 716 |
| Mortality | 11% [-5‑25%] | 40 | 27,628 | 635 |
| VentilationVent. | -10% [-56‑23%] | 12 | 11,464 | 379 |
| ICU admissionICU | -31% [-56‑-10%] ** | 21 | 9,522 | 393 |
| HospitalizationHosp. | -4% [-23‑13%] | 19 | 6,502 | 329 |
| Recovery | 15% [4‑24%] ** | 27 | 8,826 | 548 |
| Viral | 18% [8‑27%] *** | 27 | 5,022 | 436 |
| RCT mortality | 3% [-26‑25%] | 16 | 7,335 | 378 |
| RCT hospitalizationRCT hosp. | 15% [-12‑36%] | 9 | 1,145 | 184 |
| Early treatment | Late treatment | |
|---|---|---|
| All studies | 17% [-12‑39%] | 14% [3‑25%] * |
| After exclusions | 19% [-17‑43%] | 18% [4‑30%] * |
| Peer-reviewed studiesPeer-reviewed | 18% [-12‑39%] | 16% [3‑27%] * |
| Randomized Controlled TrialsRCTs | 8% [-33‑37%] | 18% [-2‑34%] |
| Mortality | 42% [-22‑72%] | 9% [-9‑23%] |
| VentilationVent. | -2% [-60‑35%] | -10% [-66‑27%] |
| ICU admissionICU | -381% [-4086‑45%] | -30% [-55‑-9%] ** |
| HospitalizationHosp. | -4% [-137‑54%] | -7% [-27‑11%] |
| Recovery | 9% [-16‑28%] | 17% [5‑27%] ** |
| Viral | 8% [-9‑21%] | 40% [22‑53%] *** |
| RCT mortality | 67% [-219‑97%] | 0% [-33‑26%] |
| RCT hospitalizationRCT hosp. | -55% [-177‑14%] | 26% [9‑40%] ** |
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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.
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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.
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Figure 5. Random effects meta-analysis for mortality results.
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Figure 6. Random effects meta-analysis for ventilation.
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Figure 7. Random effects meta-analysis for ICU admission.
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Figure 8. Random effects meta-analysis for hospitalization.
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Figure 9. Random effects meta-analysis for progression.
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Figure 10. Random effects meta-analysis for recovery.
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Figure 11. Random effects meta-analysis for viral clearance.
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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.
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Figure 13. Results for RCTs and non-RCT studies.
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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.
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Figure 15. Random effects meta-analysis for RCT mortality results.
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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 biases36, and
analysis of double-blind RCTs has identified extreme levels of bias37.
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 109 treatments we have analyzed,
65% of RCTs involve very late treatment 5+ days after
onset. No non-prophylaxis COVID-19 RCTs match the potential real-world use of
early treatments. They may more accurately represent results for treatments
that require visiting a medical facility, e.g., those requiring intravenous
administration.
RCTs have a bias against finding an
effect for interventions that are widely available — patients that
believe they need the intervention are more likely to decline participation
and take the intervention. RCTs for favipiravir are more likely to
enroll low-risk participants that do not need treatment to recover, making the
results less applicable to clinical practice. This bias is likely to be
greater for widely known treatments, and may be greater when the risk of a
serious outcome is overstated. This bias does not apply to the typical
pharmaceutical trial of a new drug that is otherwise unavailable.
For COVID-19, observational study results do not systematically
differ from RCTs, RR 1.00 [0.92‑1.08]
across 109 treatments39.
Evidence shows that observational studies
can also provide reliable results. Concato et al. found that well-designed
observational studies do not systematically overestimate the magnitude of the
effects of treatment compared to RCTs. Anglemyer et al. analyzed reviews
comparing RCTs to observational studies and found little evidence for
significant differences in effect estimates.
We performed a similar analysis across the 109 treatments
we cover, showing no significant difference in the results of RCTs compared to
observational studies, RR 1.00 [0.92‑1.08]. Similar results are found for all low-cost treatments, RR
1.02 [0.92‑1.12]. High-cost treatments
show a non-significant trend towards RCTs showing greater efficacy,
RR 0.92 [0.82‑1.03].
Details can be found in the
supplementary data.
Lee et al. showed that only 14% of the guidelines of the Infectious
Diseases Society of America were based on RCTs. Evaluation of studies relies
on an understanding of the study and potential biases. Limitations in an RCT
can outweigh the benefits, for example excessive dosages, excessive treatment
delays, or remote survey bias may have a greater effect on results. Ethical
issues may also prevent running RCTs for known effective treatments. For more
on issues with RCTs see43,44.
Currently, 48 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. Of these, 60% have been confirmed in RCTs, with a mean delay of 7.1 months (68% with 8.2 months delay for low-cost treatments). The remaining treatments either have no RCTs, or the point estimate is consistent.
We need to
evaluate each trial on its own merits. RCTs for a given medication and disease
may be more reliable, however they may also be less reliable. For off-patent
medications, very high conflict of interest trials may be more likely to be
RCTs, and more likely to be large trials that dominate meta analyses.
To avoid bias in the selection of studies, we analyze all
non-retracted studies. Here we show the results after excluding
studies with major issues likely to alter results, non-standard studies, and
studies where very minimal detail is currently available. Our bias evaluation
is based on analysis of each study and identifying when there is a significant
chance that limitations will substantially change the outcome of the study. We
believe this can be more valuable than checklist-based approaches such as
Cochrane GRADE, which can be easily influenced by potential bias, may ignore
or underemphasize serious issues not captured in the checklists, and may
overemphasize issues unlikely to alter outcomes in specific cases (for example
certain specifics of randomization with a very large effect size and
well-matched baseline characteristics).
The studies excluded are as below.
Figure 17 shows a forest plot for random
effects meta-analysis of all studies after exclusions.
Abdulrahman, very late stage, ICU patients.
Acar Sevinc, very late stage, ICU patients.
Al Mutair, very late stage, ICU patients.
Alsaraj, potential data issue.
Arfijanto, unadjusted results with no group details.
Assiri, unadjusted results with no group details; very late stage, ICU patients.
Babayigit, substantial unadjusted confounding by indication possible.
Cilli, unadjusted results with no group details.
Damayanti, minimal details provided.
Khamis, study compares against another treatment showing significant efficacy.
Kurniyanto, unadjusted results with no group details.
Lokanuwatsatien, unadjusted results with no group details.
Saito, unadjusted results with no group details.
Shamsi, unadjusted results with no group details.
Sulaiman, very late stage, ICU patients.
Tawfik, unadjusted results with minimal group details.
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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 hours61,62.
Baloxavir marboxil studies for influenza also show that treatment delay is critical
— Ikematsu et al. report an 86% reduction in cases for post-exposure
prophylaxis, Hayden et al. show a 33 hour reduction in the time to
alleviation of symptoms for treatment within 24 hours and a reduction of 13
hours for treatment within 24-48 hours, and Kumar et al. report only 2.5
hours improvement for inpatient treatment.
| Treatment delay | Result |
| Post-exposure prophylaxis | 86% fewer cases63 |
| <24 hours | -33 hours symptoms64 |
| 24-48 hours | -13 hours symptoms64 |
| Inpatients | -2.5 hours to improvement65 |
Figure 18 shows a mixed-effects meta-regression for efficacy
as a function of treatment delay in COVID-19 studies from 109 treatments, showing
that efficacy declines rapidly with treatment delay. Early treatment is
critical for COVID-19.
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Figure 18. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 109 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 variants67, for
example the Gamma variant shows significantly different characteristics68-71. 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 variants72,73.
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 synergistic74-85, 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 109
treatments we cover confirms the validity of pooled outcome analysis for COVID-19.
Figure 19 shows that lower hospitalization is very strongly associated
with lower mortality (p < 0.000000000001).
Similarly, Figure 20 shows that improved recovery is very strongly associated
with lower mortality (p < 0.000000000001).
Considering the extremes, Singh et al. show an association between viral clearance and
hospitalization or death, with p = 0.003 after excluding one large
outlier from a mutagenic treatment, and based on 44 RCTs including 52,384
patients.
Figure 21 shows that improved viral clearance is strongly associated
with fewer serious outcomes. The association is very similar to
Singh et al., with higher confidence due to the larger number of
studies. As with Singh et al., the confidence increases
when excluding the outlier treatment, from p = 0.00000042 to p = 0.00000002.
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Figure 19. Lower hospitalization is associated with lower mortality, supporting pooled outcome analysis.
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Figure 20. Improved recovery is associated with lower mortality, supporting pooled outcome analysis.
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Figure 19. Improved viral clearance is associated with fewer serious outcomes, supporting pooled outcome analysis.
Currently, 48 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 89% of these have been confirmed with one or more specific outcomes, with a mean delay of 5.1 months. When restricting to RCTs only, 56% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 6.4 months.
Figure 22 shows when treatments were found effective during the
pandemic. Pooled outcomes often resulted in earlier detection of efficacy.
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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 results89-92.
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.
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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 < 0.0593-100.
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 alone74-85.
Therefore standard of care may be critical and benefits may diminish or
disappear if standard of care does not include certain treatments.
This real-time analysis is constantly updated based on
submissions. Accuracy benefits from widespread review and submission of
updates and corrections from reviewers. Less popular treatments may receive
fewer reviews.
No treatment or intervention is 100% available and
effective for all current and future variants. Efficacy may vary significantly
with different variants and within different populations. All treatments have
potential side effects. Propensity to experience side effects may be predicted
in advance by qualified physicians. We do not provide medical advice. Before
taking any medication, consult a qualified physician who can compare all
options, provide personalized advice, and provide details of risks and
benefits based on individual medical history and situations.
11 of the 70
studies compare against other treatments, which may reduce the effect
seen.
4 of 70 studies
combine treatments. The results of
favipiravir
alone may differ.
3 of 34 RCTs use combined treatment.
SARS-CoV-2 infection and replication involves a complex interplay of 50+ host
and viral proteins and other factors24-29,
providing many therapeutic targets.
Over 8,000 compounds have been predicted to reduce COVID-19
risk30, 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.
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Figure 25.
Scatter plot showing results within the context of multiple COVID-19 treatments.
Diamonds shows the results of random effects meta-analysis.
0.6% of 8,000+ proposed treatments show efficacy103.
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Figure 26. Efficacy vs. cost for COVID-19 treatments.
Statistically significant lower risk is seen for recovery and viral clearance. 31 studies from 31 independent teams in 16 countries show 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.
Abdulrahman:
Retrospective 1,699 ICU patients in Saudi Arabia, 193 treated with favipiravir, showing no significant difference in mortality.
Acar Sevinc:
Retrospective 100 ICU patients in Turkey, showing improved survival with favipiravir vs. lopinavir/ritonavir.
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.
Al Mutair:
Retrospective 269 favipiravir ICU patients in Saudi Arabia and 269 matched controls receiving different treatments, showing no significant difference.
Al-Muhsen:
Prospective observational study of 598 hospitalized patients in Saudi Arabia, showing higher risk of mortality and longer hospitalization time with favipiravir.
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.
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.
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.
Alosaimi:
Retrospective 200 hospitalized COVID-19 patients in Saudi Arabia, showing no significant difference in outcomes between HCQ and favipiravir.
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.
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.
Alsaraj:
RCT 156 COVID-19 patients showing higher mortality with favipiravir and remdesivir overall. Favipiravir and remdesivir were more effective when started earlier, however note that Table 10 compares earlier favipiravir/remdesivir+standard care with standard care at any time, which will exaggerate the benefits/harms of earlier/later treatment. The confidence intervals for the Cox results are unusually narrow suggesting a possible error in calculation.
Alshamrani:
PSM retrospective 29 hospitals in Saudi Arabia, showing higher mortality with favipiravir treatment, without statistical significance.
Arfijanto:
Retrospective 162 hospitalized COVID-19 patients in Indonesia, showing lower incidence of delayed viral clearance with favipiravir treatment in unadjusted results.
Assiri:
Retrospective 118 ICU patients in Saudi Arabia showing no significant differences in unadjusted results with zinc, vitamin D, and favipiravir treatment.
Atipornwanich:
RCT 200 moderate/severe patients in Thailand, showing significantly lower progression with favipiravir vs. oseltamivir. NCT04303299.
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.
Behboodikhah:
Retrospective 2,174 hospitalized patients showing significantly shorter length of stay with favipiravir treatment.
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.
Bruminhent:
Retrospective 514 patients in Thailand, showing higher risk of progression with favipiravir treatment.
Cai:
Comparison of 35 FPV patients and 35 LPV/RTV patients, showing significant improvements in chest CT and faster viral clearance with FPV.
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.
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.
Chuah:
RCT 500 hospitalized patients in Malaysia, showing no significant differences with favipiravir treatment.
Cilli:
Retrospective 46 idiopathic pulmonary fibrosis patients with COVID-19 in Turkey, showing lower mortality with favipiravir in unadjusted results, without statistical significance.
Damayanti:
Retrospective 192 hospitalized patients in Indonesia, 96 patients treated with favipiravir, showing improved recovery with treatment. Only the abstract is currently available.
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.
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.
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:124. 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 publication125. 1800mg bid day 1, 800mg bid days 2-10.
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.
Haji Aghajani:
Retrospective 991 hospitalized patients in Iran focusing on aspirin use but also showing results for HCQ, remdesivir, and favipiravir.
Hartantri:
Retrospective 689 hospitalized patients in Indonesia, showing lower mortality with favipiravir treatment.
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.
Hobbs:
RCT 3,622 (concurrent and eligible) COVID-19 outpatients in the UK showing significantly faster recovery with favipiravir, and significantly greater full recovery at 3, 6, and 12 months.
Authors note: "From 16 Dec 2021, a minority of extremely clinically vulnerable patients could also access antiviral treatment or a monoclonal antibody infusion". However, there is no information on treatments provided or procedures for determining eligibility. This change invalidates hospitalization/death data after 16 Dec 2021. Hospitalization/death events occured in a small minority of patients and are expected to be strongly biased towards the extremely clinically vulnerable patients. Patients randomized to usual care are more likely to obtain alternative treatment. During the trial extension period sotrovimab was the most common treatment, with paxlovid and molnupiravir also being used131. Sotrovimab showed very high efficacy during this period132,133. It is normal to provide details of other treatments used in cases like this, the lack of disclosure suggests that the data confirms alternative treatment use significantly biased the results.
Table 1 shows a median of 4 days delay from onset of symptoms, while Table S1 shows a mean of 5.1/5.0 days for the long-term followup patients (97% of patients) indicating a distribution skewed towards very late treatment.
Authors note: "From 16 Dec 2021, a minority of extremely clinically vulnerable patients could also access antiviral treatment or a monoclonal antibody infusion". However, there is no information on treatments provided or procedures for determining eligibility. This change invalidates hospitalization/death data after 16 Dec 2021. Hospitalization/death events occured in a small minority of patients and are expected to be strongly biased towards the extremely clinically vulnerable patients. Patients randomized to usual care are more likely to obtain alternative treatment. During the trial extension period sotrovimab was the most common treatment, with paxlovid and molnupiravir also being used131. Sotrovimab showed very high efficacy during this period132,133. It is normal to provide details of other treatments used in cases like this, the lack of disclosure suggests that the data confirms alternative treatment use significantly biased the results.
Table 1 shows a median of 4 days delay from onset of symptoms, while Table S1 shows a mean of 5.1/5.0 days for the long-term followup patients (97% of patients) indicating a distribution skewed towards very late treatment.
Holubar:
Small RCT 116 mITT patients in the USA, 59 treated with favipiravir, showing no significant differences with treatment.
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.
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.
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 3 years after completion.
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.
Kulzhanova:
Retrospective 40 favipiravir patients in Kazakhstan and 40 controls, showing faster recovery and viral clearance with treatment.
Kurniyanto:
Retrospective 477 hospitalized patients in Indonesia, showing lower mortality with favipiravir in unadjusted results, not reaching statistical significance.
Lokanuwatsatien:
Prospective analysis of 802 COVID-19 pediatric patients in Thailand, showing no significant difference in long COVID with favipiravir treatment in unadjusted results.
Lou:
Small late stage RCT with 10 favipiravir, 10 baloxavir marboxil, and 10 control patients in China, showing no significant differences.
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.
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 in32, 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 see142.
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 in32, 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 see142.
McMahon:
RCT with 99 favipiravir and 100 placebo patients in Australia, all except one being outpatients, showing no significant differences with treatment.
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.
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.
Rahman:
RCT hospitalized patients in Bangladesh, showing faster recovery and viral clearance with favipiravir treatment.
Ruzhentsova:
RCT 168 patients, 112 receiving favipiravir and 56 SOC, showing shorter time to clinical improvement and faster viral clearance with favipiravir.
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.
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.
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.
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.
Shamsi:
Retrospective 183 hospitalized pediatric COVID-19 patients in Iran, showing no significant difference in mortality with favipiravir in unadjusted results.
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.
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.
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-.
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-.
Smith:
120 patient favipiravir early treatment RCT with results not reported over 1.5 years after completion.
The protocol has been published154.
The protocol has been published154.
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.
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.
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.
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.
Tehrani:
RCT 78 patients in Iran, showing improved recovery with favipiravir treatment.
Tsuzuki:
Retrospective database analysis of 7,654 hospitalized patients in Japan, showing no significant differences with favipiravir treatment. NCGM-G-003494-0.
Udwadia:
RCT with 75 favipiravir patients and 75 control patients showing improved recovery with treatment.
Usanma Koban:
Retrospective 126 patients in Turkey, showing lower risk of PCR+ at day 14 with favipiravir treatment.
Uyaroğlu:
PSM retrospective 260 late stage hospitalized COVID-19 pneumonia patients in Turkey, showing no significant difference between favipiravir and HCQ.
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.
Yulia:
Retrospective hospitalized patients in Indonesia, showing lower mortality and shorter hospitalization with favipiravir.
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 to165.
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 1168.
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
(3.13.0) with
scipy (1.14.1), pythonmeta (1.26), numpy (1.26.4), statsmodels (0.14.4), and plotly (5.24.1).
Forest plots are computed using PythonMeta169
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 (4.4.0) using the metafor
(4.6-0) and rms (6.8-0) 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 effective61,62.
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 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 3 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. | Smith, 3/21/2023, Double Blind Randomized Controlled Trial, Mexico, trial NCT04918927 (history) (FANTAZE). | 120 patient RCT with results unknown and over 1.5 years late. |
| 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. | |
| 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. | |
| Alsaraj, 1/8/2024, Randomized Controlled Trial, Iraq, peer-reviewed, 6 authors, study period September 2021 - February 2022, excluded in exclusion analyses: potential data issue. | risk of death, 87.1% higher, HR 1.87, p = 0.26, treatment 9 of 51 (17.6%), control 5 of 53 (9.4%), adjusted per study, multivariable, Cox proportional hazards, day 30. |
| 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. | |
| Haji 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. |
| 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. | |
| Hobbs, 8/31/2024, Randomized Controlled Trial, United Kingdom, peer-reviewed, median age 54.1, 26 authors, study period 8 April, 2021 - 1 July, 2022, average treatment delay 5.1 days, trial ISRCTN86534580 (PRINCIPLE). | risk of death, 86.3% lower, RR 0.14, p = 0.11, treatment 0 of 1,829 (0.0%), control 3 of 1,668 (0.2%), NNT 556, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 28. |
| risk of ICU admission, 191.1% higher, RR 2.91, p = 1.00, treatment 1 of 1,825 (0.1%), control 0 of 1,663 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm). | |
| risk of death/hospitalization, 1.0% lower, HR 0.99, p = 0.51, treatment 1,829, control 3,256, adjusted per study. | |
| not fully recovered, 17.4% lower, RR 0.83, p = 0.003, treatment 350 of 1,582 (22.1%), control 378 of 1,412 (26.8%), NNT 22, day 365, Table 3. | |
| not fully recovered, 12.2% lower, RR 0.88, p = 0.04, treatment 378 of 1,503 (25.1%), control 384 of 1,340 (28.7%), NNT 29, day 180, Table 3. | |
| not fully recovered, 17.2% lower, RR 0.83, p < 0.001, treatment 418 of 1,507 (27.7%), control 459 of 1,370 (33.5%), NNT 17, day 90, Table 3. | |
| ongoing persistent symptoms at 3, 6, 12 months, 29.0% lower, RR 0.71, p = 0.02, treatment 1,829, control 1,668, Table 3. | |
| time to first reported recovery, 18.7% lower, HR 0.81, p < 0.001, treatment 1,829, control 3,256, adjusted per study, inverted to make HR<1 favor treatment, primary outcome. | |
| early sustained recovery, 34.2% lower, RR 0.66, p < 0.001, treatment 1,828, control 1,666, adjusted per study, inverted to make RR<1 favor treatment. | |
| sustained recovery, 24.8% lower, RR 0.75, p < 0.001, treatment 1,829, control 1,668, adjusted per study, inverted to make RR<1 favor treatment. | |
| alleviation of all symptoms, 12.3% lower, RR 0.88, p < 0.001, treatment 1,562, control 1,407, adjusted per study, inverted to make RR<1 favor treatment. | |
| sustained alleviation of all symptoms, 20.6% lower, RR 0.79, p < 0.001, treatment 1,562, control 1,407, adjusted per study, inverted to make RR<1 favor treatment. | |
| initial reduction of severity, 23.1% lower, RR 0.77, p < 0.001, treatment 1,828, control 1,667, adjusted per study, inverted to make RR<1 favor treatment. | |
| 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. |
Smith et al., Favipiravir and/or Nitazoxanide: a Randomized, Double-blind, Placebo-controlled Trial of Early Antiviral Therapy in COVID-19 (FANTAZE), NCT04918927, clinicaltrials.gov/study/NCT04918927.
Kara et al., Efficacy and Safety of Hydroxychloroquine and Favipiravir in the Treatment of Mild to Moderate COVID-19, NCT04411433, clinicaltrials.gov/study/NCT04411433.
Zhirnov et al., Favipiravir: the hidden threat of mutagenic action, Journal of microbiology, epidemiology and immunobiology, doi:10.36233/0372-9311-114.
Waters et al., Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir, Environmental and Molecular Mutagenesis, doi:10.1002/em.22471.
Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.
Shum, C., An investigational study into the drug-associated mutational signature in SARS-CoV-2 viruses, The University of Hong Kong, PhD Thesis, hub.hku.hk/handle/10722/344396.
Shiraki et al., Convenient screening of the reproductive toxicity of favipiravir and antiviral drugs in Caenorhabditis elegans, Heliyon, doi:10.1016/j.heliyon.2024.e35331.
Gül et al., Effect of favipiravir use on INR, PT, aPTT tests of COVID-19 patients, Sabuncuoglu Serefeddin Health Sciences, doi:10.55895/sshs.1213382.
Lopez et al., SARS-CoV-2 Resistance to Small Molecule Inhibitors, Current Clinical Microbiology Reports, doi:10.1007/s40588-024-00229-6.
Yang et al., SARS-CoV-2 infection causes dopaminergic neuron senescence, Cell Stem Cell, doi:10.1016/j.stem.2023.12.012.
Scardua-Silva et al., Microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19, Scientific Reports, doi:10.1038/s41598-024-52005-7.
Hampshire et al., Cognition and Memory after Covid-19 in a Large Community Sample, New England Journal of Medicine, doi:10.1056/NEJMoa2311330.
Duloquin et al., Is COVID-19 Infection a Multiorganic Disease? Focus on Extrapulmonary Involvement of SARS-CoV-2, Journal of Clinical Medicine, doi:10.3390/jcm13051397.
Sodagar et al., Pathological Features and Neuroinflammatory Mechanisms of SARS-CoV-2 in the Brain and Potential Therapeutic Approaches, Biomolecules, doi:10.3390/biom12070971.
Sagar et al., COVID-19-associated cerebral microbleeds in the general population, Brain Communications, doi:10.1093/braincomms/fcae127.
Verma et al., Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations, bioRxiv, doi:10.1101/2024.06.02.596989.
Panagea et al., Neurocognitive Impairment in Long COVID: A Systematic Review, Archives of Clinical Neuropsychology, doi:10.1093/arclin/acae042.
Ariza et al., COVID-19: Unveiling the Neuropsychiatric Maze—From Acute to Long-Term Manifestations, Biomedicines, doi:10.3390/biomedicines12061147.
Vashisht et al., Neurological Complications of COVID-19: Unraveling the Pathophysiological Underpinnings and Therapeutic Implications, Viruses, doi:10.3390/v16081183.
Ahmad et al., Neurological Complications and Outcomes in Critically Ill Patients With COVID-19: Results From International Neurological Study Group From the COVID-19 Critical Care Consortium, The Neurohospitalist, doi:10.1177/19418744241292487.
Eberhardt et al., SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels, Nature Cardiovascular Research, doi:10.1038/s44161-023-00336-5.
Van Tin et al., Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis through NLRP3 Inflammasomes and NF-κB Signaling, Cells, doi:10.3390/cells13161331.
Borka Balas et al., COVID-19 and Cardiac Implications—Still a Mystery in Clinical Practice, Reviews in Cardiovascular Medicine, doi:10.31083/j.rcm2405125.
Malone et al., Structures and functions of coronavirus replication–transcription complexes and their relevance for SARS-CoV-2 drug design, Nature Reviews Molecular Cell Biology, doi:10.1038/s41580-021-00432-z.
Murigneux et al., Proteomic analysis of SARS-CoV-2 particles unveils a key role of G3BP proteins in viral assembly, Nature Communications, doi:10.1038/s41467-024-44958-0.
Lv et al., Host proviral and antiviral factors for SARS-CoV-2, Virus Genes, doi:10.1007/s11262-021-01869-2.
Lui et al., Nsp1 facilitates SARS-CoV-2 replication through calcineurin-NFAT signaling, Virology, doi:10.1128/mbio.00392-24.
Niarakis et al., Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches, Frontiers in Immunology, doi:10.3389/fimmu.2023.1282859.
Katiyar et al., SARS-CoV-2 Assembly: Gaining Infectivity and Beyond, Viruses, doi:10.3390/v16111648.
Unal et al., Favipiravir, umifenovir and camostat mesylate: a comparative study against SARS-CoV-2, bioRxiv, doi:10.1101/2022.01.11.475889.
Yildiz Pekoz et al., Pulmonary delivery of favipiravir inhalation solution for COVID-19 treatment: in vitro characterization, stability, in vitro cytotoxicity, and antiviral activity using real time cell analysis, Drug Delivery, doi:10.1080/10717544.2022.2118398.
Purwati et al., An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and/or hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, Indonesia, PLOS One, doi:10.1371/journal.pone.0252302.
Zeraatkar et al., Consistency of covid-19 trial preprints with published reports and impact for decision making: retrospective review, BMJ Medicine, doi:10.1136/bmjmed-2022-0003091.
Davidson et al., No evidence of important difference in summary treatment effects between COVID-19 preprints and peer-reviewed publications: a meta-epidemiological study, Journal of Clinical Epidemiology, doi:10.1016/j.jclinepi.2023.08.011.
Jadad et al., Randomized Controlled Trials: Questions, Answers, and Musings, Second Edition, doi:10.1002/9780470691922.
Gøtzsche, P., Bias in double-blind trials, Doctoral Thesis, University of Copenhagen, www.scientificfreedom.dk/2023/05/16/bias-in-double-blind-trials-doctoral-thesis/.
Als-Nielsen et al., Association of Funding and Conclusions in Randomized Drug Trials, JAMA, doi:10.1001/jama.290.7.921.
Anglemyer et al., Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials, Cochrane Database of Systematic Reviews 2014, Issue 4, doi:10.1002/14651858.MR000034.pub2.
Lee et al., Analysis of Overall Level of Evidence Behind Infectious Diseases Society of America Practice Guidelines, Arch Intern Med., 2011, 171:1, 18-22, doi:10.1001/archinternmed.2010.482.
Deaton et al., Understanding and misunderstanding randomized controlled trials, Social Science & Medicine, 210, doi:10.1016/j.socscimed.2017.12.005.
Nichol et al., Challenging issues in randomised controlled trials, Injury, 2010, doi: 10.1016/j.injury.2010.03.033, www.injuryjournal.com/article/S0020-1383(10)00233-0/fulltext.
Abdulrahman et al., Favipiravir efficacy and safety for the treatment of severe coronavirus 2019: a retrospective study, Journal of Ayub Medical College Abbottabad, doi:10.55519/JAMC-03-10305.
Acar Sevinc, S., Favipiravir Experience in COVID-19 Patients at a Tertiary Center Intensive Care Unit, SiSli Etfal Hastanesi Tip Bulteni / The Medical Bulletin of Sisli Hospital, doi:10.14744/SEMB.2021.35902.
Al Mutair et al., Overview of Clinical Outcome and Therapeutic Effectiveness of Favipiravir in Patients with COVID-19 Admitted to Intensive Care Unit, Riyadh, Saudi Arabia, Journal of Infection and Public Health, doi:10.1016/j.jiph.2022.01.013.
Alsaraj et al., Consequence of Antivirals Versus Standard Care on Clinical Situation in Patients With COVID-19, Infectious Diseases in Clinical Practice, doi:10.1097/IPC.0000000000001336.
Arfijanto et al., Duration of SARS-CoV-2 RNA Shedding Is Significantly Influenced by Disease Severity, Bilateral Pulmonary Infiltrates, Antibiotic Treatment, and Diabetic Status: Consideration for Isolation Period, Pathophysiology, doi:10.3390/pathophysiology30020016.
Assiri et al., COVID-19 related treatment and outcomes among COVID-19 ICU patients: A retrospective cohort study, Journal of Infection and Public Health, doi:10.1016/j.jiph.2021.08.030.
Babayigit et al., The association of antiviral drugs with COVID-19 morbidity: The retrospective analysis of a nationwide COVID-19 cohort, Frontiers in Medicine, doi:10.3389/fmed.2022.894126.
Cilli et al., Characteristics and outcomes of COVID-19 patients with IPF: A multi-center retrospective study, Respiratory Medicine and Research, doi:10.1016/j.resmer.2022.100900.
Damayanti et al., The Effectiveness and Safety of Favipiravir in COVID-19 Hospitalized Patients in Bali, Indonesia, Kesmas: National Public Health Journal, doi:10.21109/kesmas.v16i4.5433.
Khamis et al., Randomized Controlled Open Label Trial on the Use of Favipiravir Combined with Inhaled Interferon beta-1b in Hospitalized Patients with Moderate to Severe COVID-19 Pneumonia, International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.11.008.
Kurniyanto et al., Factors Associated with Death and ICU Referral among COVID-19 Patients Hospitalized in the Secondary Referral Academic Hospital in East Jakarta, Indonesia, Journal of Clinical Virology Plus, doi:10.1016/j.jcvp.2022.100068.
Lokanuwatsatien et al., Prevalence and associating factors of long COVID in pediatric patients during the Delta and the Omicron variants, Frontiers in Pediatrics, doi:10.3389/fped.2023.1127582.
Saito et al., Predictors of in-hospital mortality in elderly unvaccinated patients during SARS-CoV-2 Alpha variants epidemic, Infection Prevention in Practice, doi:10.1016/j.infpip.2024.100341.
Shamsi et al., Survival and Mortality in Hospitalized Children with COVID-19: A Referral Center Experience in Yazd, Iran, Canadian Journal of Infectious Diseases and Medical Microbiology, doi:10.1155/2023/5205188.
Sulaiman et al., When Antivirals Backfire: An Evaluation of Favipiravir’s Clinical Outcomes in Critically Ill Patients with COVID-19: A Multicenter Cohort Study, Journal of Infection and Public Health, doi:10.1016/j.jiph.2023.06.011.
Tawfik et al., Effectiveness of Early Favipiravir Therapy in Hospitalised COVID-19 Patients, Advances in Virology, doi:10.1155/2022/9240941.
Treanor et al., Efficacy and Safety of the Oral Neuraminidase Inhibitor Oseltamivir in Treating Acute Influenza: A Randomized Controlled Trial, JAMA, 2000, 283:8, 1016-1024, doi:10.1001/jama.283.8.1016.
McLean et al., Impact of Late Oseltamivir Treatment on Influenza Symptoms in the Outpatient Setting: Results of a Randomized Trial, Open Forum Infect. Dis. September 2015, 2:3, doi:10.1093/ofid/ofv100.
Ikematsu et al., Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts, New England Journal of Medicine, doi:10.1056/NEJMoa1915341.
Hayden et al., Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents, New England Journal of Medicine, doi:10.1056/NEJMoa1716197.
Kumar et al., Combining baloxavir marboxil with standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a randomised, parallel-group, double-blind, placebo-controlled, superiority trial, The Lancet Infectious Diseases, doi:10.1016/S1473-3099(21)00469-2.
López-Medina et al., Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial, JAMA, doi:10.1001/jama.2021.3071.
Korves et al., SARS-CoV-2 Genetic Variants and Patient Factors Associated with Hospitalization Risk, medRxiv, doi:10.1101/2024.03.08.24303818.
Faria et al., Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil, Science, doi:10.1126/science.abh2644.
Nonaka et al., SARS-CoV-2 variant of concern P.1 (Gamma) infection in young and middle-aged patients admitted to the intensive care units of a single hospital in Salvador, Northeast Brazil, February 2021, International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.08.003.
Karita et al., Trajectory of viral load in a prospective population-based cohort with incident SARS-CoV-2 G614 infection, medRxiv, doi:10.1101/2021.08.27.21262754.
Zavascki et al., Advanced ventilatory support and mortality in hospitalized patients with COVID-19 caused by Gamma (P.1) variant of concern compared to other lineages: cohort study at a reference center in Brazil, Research Square, doi:10.21203/rs.3.rs-910467/v1.
Willett et al., The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism, medRxiv, doi:10.1101/2022.01.03.21268111.
Peacock et al., The SARS-CoV-2 variant, Omicron, shows rapid replication in human primary nasal epithelial cultures and efficiently uses the endosomal route of entry, bioRxiv, doi:10.1101/2021.12.31.474653.
Jitobaom et al., Favipiravir and Ivermectin Showed in Vitro Synergistic Antiviral Activity against SARS-CoV-2, Research Square, doi:10.21203/rs.3.rs-941811/v1.
Jitobaom (B) et al., Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations, BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00580-8.
Jeffreys et al., Remdesivir-ivermectin combination displays synergistic interaction with improved in vitro activity against SARS-CoV-2, International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2022.106542.
Ostrov et al., Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells, Pathogens, doi:10.3390/pathogens10111514.
Alsaidi et al., Griffithsin and Carrageenan Combination Results in Antiviral Synergy against SARS-CoV-1 and 2 in a Pseudoviral Model, Marine Drugs, doi:10.3390/md19080418.
Andreani et al., In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect, Microbial Pathogenesis, doi:10.1016/j.micpath.2020.104228.
De Forni et al., Synergistic drug combinations designed to fully suppress SARS-CoV-2 in the lung of COVID-19 patients, PLoS ONE, doi:10.1371/journal.pone.0276751.
Wan et al., Synergistic inhibition effects of andrographolide and baicalin on coronavirus mechanisms by downregulation of ACE2 protein level, Scientific Reports, doi:10.1038/s41598-024-54722-5.
Said et al., The effect of Nigella sativa and vitamin D3 supplementation on the clinical outcome in COVID-19 patients: A randomized controlled clinical trial, Frontiers in Pharmacology, doi:10.3389/fphar.2022.1011522.
Fiaschi et al., In Vitro Combinatorial Activity of Direct Acting Antivirals and Monoclonal Antibodies against the Ancestral B.1 and BQ.1.1 SARS-CoV-2 Viral Variants, Viruses, doi:10.3390/v16020168.
Xing et al., Published anti-SARS-CoV-2 in vitro hits share common mechanisms of action that synergize with antivirals, Briefings in Bioinformatics, doi:10.1093/bib/bbab249.
Thairu et al., A Comparison of Ivermectin and Non Ivermectin Based Regimen for COVID-19 in Abuja: Effects on Virus Clearance, Days-to-discharge and Mortality, Journal of Pharmaceutical Research International, doi:10.9734/jpri/2022/v34i44A36328.
Williams, T., Not All Ivermectin Is Created Equal: Comparing The Quality of 11 Different Ivermectin Sources, Do Your Own Research, doyourownresearch.substack.com/p/not-all-ivermectin-is-created-equal.
Xu et al., A study of impurities in the repurposed COVID-19 drug hydroxychloroquine sulfate by UHPLC-Q/TOF-MS and LC-SPE-NMR, Rapid Communications in Mass Spectrometry, doi:10.1002/rcm.9358.
Singh et al., The relationship between viral clearance rates and disease progression in early symptomatic COVID-19: a systematic review and meta-regression analysis, Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkae045.
Boulware, D., Comments regarding paper rejection, twitter.com/boulware_dr/status/1311331372884205570.
Rothstein, H., Publication Bias in Meta-Analysis: Prevention, Assessment and Adjustments, www.wiley.com/en-ae/Publication+Bias+in+Meta+Analysis:+Prevention,+Assessment+and+Adjustments-p-9780470870143.
Stanley et al., Meta-regression approximations to reduce publication selection bias, Research Synthesis Methods, doi:10.1002/jrsm.1095.
Rücker et al., Arcsine test for publication bias in meta-analyses with binary outcomes, Statistics in Medicine, doi:10.1002/sim.2971.
Peters, J., Comparison of Two Methods to Detect Publication Bias in Meta-analysis, JAMA, doi:10.1001/jama.295.6.676.
Moreno et al., Assessment of regression-based methods to adjust for publication bias through a comprehensive simulation study, BMC Medical Research Methodology, doi:10.1186/1471-2288-9-2.
Macaskill et al., A comparison of methods to detect publication bias in meta-analysis, Statistics in Medicine, doi:10.1002/sim.698.
Egger et al., Bias in meta-analysis detected by a simple, graphical test, BMJ, doi:10.1136/bmj.315.7109.629.
Harbord et al., A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints, Statistics in Medicine, doi:10.1002/sim.2380.
Lopez (B) et al., SARS-CoV-2 Resistance to Small Molecule Inhibitors, Current Clinical Microbiology Reports, doi:10.1007/s40588-024-00229-6.
Bacigalupo et al., Unveiling patenting strategies of therapeutics and vaccines: evergreening in the context of COVID-19 pandemic, Frontiers in Medicine, doi:10.3389/fmed.2023.1287542.
Adhikari et al., Efficacy of Favipiravir in treatment of mild & moderate COVID-19 infection in Nepal: a multi-center, randomized, open-labelled, phase III clinical trial, International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.12.109.
Al-Muhsen et al., Favipiravir Effectiveness and Safety in Hospitalized Moderate-Severe COVID-19 Patients: Observational Prospective Multicenter Investigation in Saudi Arabia, Frontiers in Medicine, doi:10.3389/fmed.2022.826247.
Alamer et al., Effectiveness and safety of favipiravir compared to supportive care in moderately to critically ill COVID-19 patients: a retrospective study with propensity score matching sensitivity analysis, Current Medical Research and Opinion, doi:10.1080/03007995.2021.1920900.
Alattar et al., Favipiravir for the Treatment of Coronavirus Disease 2019 Pneumonia; a Propensity Score-matched Cohort Study, Journal of Infection and Public Health, doi:10.1016/j.jiph.2022.08.011.
Almoosa et al., Favipiravir versus Standard of Care in Patients with Severe COVID-19 Infections: A Retrospective Comparative Study, Journal of Infection and Public Health, doi:10.1016/j.jiph.2021.08.022.
Alosaimi et al., Analyzing the Difference in the Length of Stay (LOS) in Moderate to Severe COVID-19 Patients Receiving Hydroxychloroquine or Favipiravir, Pharmaceuticals, doi:10.3390/ph15121456.
Alotaibi et al., Effectiveness and Safety of Favipiravir Compared to Hydroxychloroquine for Management of Covid-19: A Retrospective Study, International Journal of General Medicine, 2021:14, www.dovepress.com/getfile.php?fileID=73585.
AlQahtani et al., Randomized controlled trial of favipiravir, hydroxychloroquine, and standard care in patients with mild/moderate COVID-19 disease, Scientific Reports, doi:10.1038/s41598-022-08794-w.
Alshamrani et al., Comprehensive evaluation of six interventions for hospitalized patients with COVID-19: A propensity score matching study, Saudi Pharmaceutical Journal, doi:10.1016/j.jsps.2023.02.004.
Atipornwanich et al., Various Combinations of Favipiravir, Lopinavir-Ritonavir, Darunavir-Ritonavir, High-Dose Oseltamivir, and Hydroxychloroquine for the Treatment of COVID-19: A Randomized Controlled Trial (FIGHT-COVID-19 Study), SSRN Electronic Journal, doi:10.2139/ssrn.3936499.
Behboodikhah et al., Evaluation of the Costs and Outcomes of COVID-19 Therapeutic Regimens in Hospitalized Patients in Shiraz, Iranian Journal of Science and Technology, Transactions A: Science, doi:10.1007/s40995-022-01351-0.
Bosaeed et al., Efficacy of favipiravir in adults with mild COVID-19: a randomized, double-blind, multicenter, placebo-controlled trial clinical trial, Clinical Microbiology and Infection, doi:10.1016/j.cmi.2021.12.026.
Bruminhent et al., Clinical Course and Outcomes among COVID-19 Patients at the Hospitel in Bangkok: A Retrospective Study, Tropical Medicine and Infectious Disease, doi:10.3390/tropicalmed7090238.
Cai et al., Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study, Engineering, doi:10.1016/j.eng.2020.03.007.
Chandiwana et al., Safety and efficacy of four drug regimens versus standard-of-care for the treatment of symptomatic outpatients with COVID-19: A randomised, open-label, multi-arm, phase 2 clinical trial, eBioMedicine, doi:10.1016/j.ebiom.2022.104322.
Chen et al., Favipiravir Versus Arbidol for Clinical Recovery Rate in Moderate and Severe Adult COVID-19 Patients: A Prospective, Multicenter, Open-Label, Randomized Controlled Clinical Trial, Frontiers in Pharmacology, doi:10.3389/fphar.2021.683296.
Chuah et al., Efficacy of Early Treatment with Favipiravir on Disease Progression among High Risk COVID-19 Patients: A Randomized, Open-Label Clinical Trial, Clinical Infectious Diseases, doi:10.1093/cid/ciab962.
Delen et al., Effects of Hydroxychloroquine Plus Favipiravir Treatment on the Clinical Course and Biomarkers in Hospitalized COVID-19 Patients with Pneumonia, Acta Clinica Croatica, doi:10.20471/acc.2022.61.03.05.
Finberg et al., US201 Study: A Phase 2, Randomized Proof-of-Concept Trial of Favipiravir for the Treatment of COVID-19, Open Forum Infectious Diseases, doi:10.1093/ofid/ofab56310.
Golan et al., Favipiravir in patients with early mild-to-moderate COVID-19: a randomized controlled trial, Clinical Infectious Diseases, doi:10.1093/cid/ciac712.
Hafez et al., Antiviral Used among Non-Severe COVID-19 Cases in Relation to Time till Viral Clearance: A Retrospective Cohort Study, Antibiotics, doi:10.3390/antibiotics11040498.
Haji Aghajani et al., Decreased In-Hospital Mortality Associated with Aspirin Administration in Hospitalized Patients Due to Severe COVID-19, Journal of Medical Virology, doi:10.1002/jmv.27053.
Hartantri et al., Clinical and treatment factors associated with the mortality of COVID-19 patients admitted to a referral hospital in Indonesia, The Lancet Regional Health - Southeast Asia, doi:10.1016/j.lansea.2023.100167.
Hassaniazad et al., Efficacy and safety of favipiravir plus interferon-beta versus lopinavir/ritonavir plus interferon-beta in moderately ill patients with COVID-19: A randomized clinical trial, Journal of Medical Virology, doi:10.1002/jmv.27724.
Hobbs et al., Favipiravir for COVID-19 in adults in the community in PRINCIPLE, an open-label, randomised, controlled, adaptive platform trial of short- and longer-term outcomes, Journal of Infection, doi:10.1016/j.jinf.2024.106248.
england.nhs.uk, www.england.nhs.uk/statistics/wp-content/uploads/sites/2/2023/07/COVID-THERAPEUTICS-WEEKLY-PUBLICATION-week-ending-020723-V2.0-OCT-22-Onwards.xlsx.
Behzad et al., Real world Effectiveness of Sotrovimab in Preventing COVID-19–related Hospitalisation or Death in Patients Infected with Omicron BA.2, Journal of Infection and Public Health, doi:10.1016/j.jiph.2023.11.029.
De Vito et al., What Is the Efficacy of Sotrovimab in Reducing Disease Progression and Death in People with COVID-19 during the Omicron Era? Answers from a Real-Life Study, Viruses, doi:10.3390/v15081757.
Holubar et al., Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial, Clinical Infectious Diseases, doi:10.1093/cid/ciac312.
Horcajada et al., Safety and efficacy of favipiravir in COVID-19 patients with pneumonia. A randomized, double-blind, placebo-controlled study (FAVID), Pneumonia, doi:10.1186/s41479-023-00124-6.
Ivashchenko et al., AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial, Clinical Infectious Diseases, doi:10.1093/cid/ciaa1176.
Iwata et al., Findings from a discontinued clinical trial of favipiravir in high-risk patients with early-onset COVID-19, Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2023.10.010.
Kulzhanova et al., Clinical efficacy of the antiviral drug favipiravir in the complex treatment of patients with COVID-19 coronavirus infection, , newjournal.ssmu.kz/upload/iblock/026/6_15_4_23_2021.pdf.
Lou et al., Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: An Exploratory Randomized, Controlled Trial, European Journal of Pharmaceutical Sciences, doi:10.1016/j.ejps.2020.105631.
Lowe et al., Favipiravir, lopinavir-ritonavir, or combination therapy (FLARE): A randomised, double-blind, 2 × 2 factorial placebo-controlled trial of early antiviral therapy in COVID-19, PLOS Medicine, doi:10.1371/journal.pmed.1004120.
Luvira et al., Clinical antiviral efficacy of favipiravir in early COVID-19 (PLATCOV): an open-label, randomised, controlled, adaptive platform trial, BMC Infectious Diseases, doi:10.1186/s12879-023-08835-3.
Schilling et al., Pharmacometrics of high dose ivermectin in early COVID-19: an open label, randomized, controlled adaptive platform trial (PLATCOV), eLife, doi:10.7554/eLife.83201.
McMahon et al., Favipiravir in early symptomatic COVID-19, a randomised placebo-controlled trial, eClinicalMedicine, doi:10.1016/j.eclinm.2022.101703.
Pushkar et al., Study of Favipiravir Compared to Standard of Care in Hospitalized Patients With COVID-19, NCT04542694, clinicaltrials.gov/ct2/show/results/NCT04542694?view=results.
Qadir et al., Efficacy of Favipiravir in the Treatment of Mild to Moderate COVID-19 Patients in Erbil: A Controlled Clinical Trial, International Journal of Applied Sciences: Current and Future Research Trends, 13:1, ijascfrtjournal.isrra.org/index.php/Applied_Sciences_Journal/article/view/1235.
Rahman et al., Safety and Efficacy of Favipiravir for the management of COVID-19 Patients: A Randomized Control Trial, Clinical Infection in Practice, doi:10.1016/j.clinpr.2022.100145.
Ruzhentsova et al., Phase 3 Trial of Coronavir (Favipiravir) in Patients with Mild to Moderate COVID-19, SSRN, doi:10.2139/ssrn.3696907.
Sawanpanyalert et al., Assessment of outcomes following implementation of antiviral treatment guidelines for COVID-19 during the first wave in Thailand, Southeast Asian Journal of Tropical Medicine and Public Health, 52:4, journal.seameotropmednetwork.org/index.php/jtropmed/article/view/490.
Shah et al., Favipiravir in patients hospitalised with COVID-19 (PIONEER trial): a multicentre, open-label, phase 3, randomised controlled trial of early intervention versus standard care, The Lancet Respiratory Medicine, doi:10.1016/S2213-2600(22)00412-X.
Shenoy et al., Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial, medRxiv, doi:10.1101/2021.11.08.21265884.
Shinada et al., Longitudinal Analysis of Neutralizing Potency against SARS-CoV-2 in the Recovered Patients after Treatment with or without Favipiravir, Viruses, doi:10.3390/v14040670.
Shinkai et al., Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial, Infectious Diseases and Therapy, doi:10.1007/s40121-021-00517-4.
Sirijatuphat et al., Early Treatment of Favipiravir in COVID-19 Patients Without Pneumonia: A Multicentre, Open-Labelled, Randomized Control Study, medRxiv, doi:10.1101/2022.06.06.22275902.
trialsjournal.biomedcentral.com, trialsjournal.biomedcentral.com/articles/10.1186/s13063-022-06533-0.
Solaymani-Dodaran et al., Safety and efficacy of Favipiravir in moderate to severe SARS-CoV-2 pneumonia, International Immunopharmacology, doi:10.1016/j.intimp.2021.107522.
Tabarsi et al., Favipiravir Effects on the Control of Clinical Symptoms of Hospitalized COVID-19 Cases: An Experience with Iranian Formulated Dosage Form, Iranian Journal of Pharmaceutical Research, doi:10.22037/ijpr.2021.115510.15401.
Tehrani et al., Efficacy of Favipiravir in the Treatment of Moderate COVID-19 Patients: A Randomized, Open-label, Controlled Clinical Trial, Mediterranean Journal of Infection Microbes and Antimicrobials, doi:10.4274/mjima.galenos.2022.2022.30.
Tsuzuki et al., Effectiveness of Favipiravir on Nonsevere, Early-Stage COVID-19 in Japan: A Large Observational Study Using the COVID-19 Registry Japan, Infectious Diseases and Therapy, doi:10.1007/s40121-022-00617-9.
Udwadia et al., Efficacy and Safety of Favipiravir, an Oral RNA-Dependent RNA Polymerase Inhibitor, in Mild-to-Moderate COVID-19: A Randomized, Comparative, Open-Label, Multicenter, Phase 3 Clinical Trial, International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.11.142.
Usanma Koban et al., The factors affecting the prolonged PCR positivity in COVID-19 patients, Bratislava Medical Journal, doi:10.4149/BLL_2022_082.
Uyaroğlu et al., Comparison of Favipiravir to Hydroxychloroquine Plus Azithromycin in the Treatment of Patients with Non-critical COVID-19: A Single-center, Retrospective, Propensity Score-matched Study, Acta Medica, doi:10.32552/2022.ActaMedica.719.
Vaezi et al., Favipiravir in the Treatment of Outpatient COVID-19: A Multicenter, Randomized, Triple-Blind, Placebo-Controlled Clinical Trial, Advances in Respiratory Medicine, doi:10.3390/arm91010004.
Yulia et al., Evaluation of Antibacterial and Antiviral Drug Effectiveness in COVID-19 Therapy: A Data-Driven Retrospective Approach, Pathophysiology, doi:10.3390/pathophysiology29010009.
Zhao et al., Favipiravir in the treatment of patients with SARS-CoV-2 RNA recurrent positive after discharge: a multicenter, open-label, randomized trial, International Immunopharmacology, doi:10.1016/j.intimp.2021.107702.
Zhang et al., What's the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes, JAMA, 80:19, 1690, doi:10.1001/jama.280.19.1690.
Altman (B) et al., How to obtain the confidence interval from a P value, BMJ, doi:10.1136/bmj.d2090.
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