Ensitrelvir for COVID-19: real-time meta-analysis of 10 studies

@CovidAnalysis, October 2026, Version 17V17 (V1 2022)
Abstract
Significantly lower risk is seen for recovery, cases, and viral clearance. 9 studies from 5 independent teams (all from the same country) show significant benefit.
Meta-analysis using the most serious outcome reported shows 12% [1‑22%] lower risk. Results are similar for Randomized Controlled Trials and worse for peer-reviewed studies. Early treatment is more effective than late treatment.
Currently there is limited data, with only 17 control events for the most serious outcome in trials to date.
Variants may be resistant to ensitrelvir1,2.
No treatment is 100% effective. Protocols combine safe and effective options with individual risk/benefit analysis and monitoring. Other treatments are more effective. All data and sources to reproduce this analysis are in the appendix.
Ul Haq et al. present another meta-analysis for ensitrelvir, showing significant improvement for viral load.
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Evolution of COVID-19 clinical evidence Meta-analysis results over time Ensitrelvir p=0.036 Acetaminophen p=0.00000021 2020 2021 2022 2023 2024 2025 2026 Lowerrisk Higherrisk c19early.org October 2026 50% 0% -50%
Ensitrelvir for COVID-19 — Highlights
Ensitrelvir reduces risk with very high confidence for recovery and viral clearance, high confidence for pooled analysis, and low confidence for hospitalization and cases, however increased risk is seen with very low confidence for mortality and ventilation.
Early treatment is more effective than late treatment.
50th treatment shown effective in July 2023, now with p = 0.036 from 10 studies, recognized in 2 countries.
Real-time updates and corrections with a consistent protocol for 226 treatments. Outcome specific analysis and combined evidence from all studies including treatment delay, a primary confounding factor.
c19early.org
October 2026

Ensitrelvir COVID-19 studies

StudyImprovementRR · 95% CIOutcomeTreatmentControlRelative Risk
Mukae (DB RCT)45%0.55 · 0.37–0.81viral load14 (n)14 (n) Mukae (DB RCT)9%0.91 · 0.76–1.08improv.116 (n)111 (n) Yotsuyan.. (DB RCT)−1%1.01 · 0.06–16.09hosp.1/5951/600SCORPIO-SR Takazono (PSW)−24%1.24 · 0.17–9.05deathpopulation-based cohort Luetkem.. (DB RCT)80%0.20 · 0.01–4.18death0/1,0372/1,048SCORPIO-HR Katsuta10%0.90 · 0.81–0.99recov. time60 (n)42 (n) Schilling (RCT)67%0.33 · 0.01–8.05hosp.0/1971/191PLATCOV Nakano (DB RCT)4%0.96 · 0.68–1.37recov. time77 (n)37 (n)
Early treatment13%0.87 · 0.79–0.971/2,0964/2,04313% lower risk
Tau² = 0.00, I² = 7.8%, p = 0.009
Baker (RCT)−40%1.40 · 0.70–2.80death18/29313/296STRIVE
Late treatment−40%1.40 · 0.70–2.8018/29313/29640% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.35
Hayden (DB RCT)−396%4.96 · 0.24–103hosp.2/1,0300/1,011SCORPIO-PEP
Prophylaxis−396%4.96 · 0.24–1032/1,0300/1,011396% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.31
All studies12%0.88 · 0.78–0.9921/3,41917/3,35012% lower risk
Tau² = 0.01, I² = 14.2%, p = 0.03600.511.52+
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← Ensitrelvir
reduces riskEnsitrelvir
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B
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Fig. 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 ensitrelvir studies. The marked dates indicate the time when efficacy was known with a statistically significant improvement of ≥10% from ≥3 studies for pooled outcomes and one or more specific outcome.
Introduction
Fig. 2. SARS-CoV-2 spike protein fibrin binding leads to thromboinflammation and neuropathology, from4.
Immediate treatment recommended
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 injury5-21 and cognitive deficits8,13, cardiovascular complications22-28, DNA damage29-32, organ failure, and death. Even mild untreated infections may result in persistent cognitive deficits33—the spike protein binds to fibrin leading to fibrinolysis-resistant blood clots, thromboinflammation, and neuropathology. Minimizing replication as early as possible is recommended.
Many treatments are expected to modulate infection
SARS-CoV-2 infection and replication involves the complex interplay of 500+ host and viral proteins and other factorsA,34-41, providing many therapeutic targets for which many existing compounds have known activity. Scientists have predicted that over 12,000 compounds may reduce COVID-19 risk42, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications.
Supporting research
In vitro studies demonstrate efficacy in VeroE6/TMPRSS2B,43, HEK293T/ACE2-TMPRSS2C,43, and MucilAirD,43 cells. Animal studies demonstrate efficacy in BALB/c miceE,43,44 and Syrian hamstersF,43. Preclinical studies demonstrate efficacy for the ancestralG,43, deltaH,43, and omicronI,43 variants.
3CLpro inhibitors
We currently cover 11 3CLpro inhibitors45-55 with clinical data. Paxlovid, xiannuoxin, and atilotrelvir require ritonavir-boosting. Ritonavir inhibits key enzymes and transporters, which disrupts endogenous physiological pathways (with incompletely characterized consequences) and creates serious drug-drug interaction risks. Lufotrelvir is formulated for IV use. Olgotrelvir, ensitrelvir, ibuzatrelvir, leritrelvir, pomotrelvir, and ratutrelvir are newer-generation drugs that do not require ritonavir. Olgotrelvir may be the most technologically advanced with dual-mechanism inhibition and activity against paxlovid-resistant variants, while potentially minimizing the lipid disruption seen with ensitrelvir and leritrelvir. Ratutrelvir may have increased safety supporting longer treatment duration while minimizing side effects.
Analysis
We analyze all significant controlled studies of ensitrelvir 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, and Randomized Controlled Trials (RCTs).
Treatment timing
Fig. 3 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early treatment refers to treatment immediately or soon after symptoms appear, while late treatment refers to more delayed treatment.
regular treatment to prevent or minimize infectionstreat immediately on symptoms or shortly thereafterlate stage after disease progressionexposed to virusEarly TreatmentProphylaxisTreatment delayLate Treatment
Fig. 3. Treatment stages.
Preclinical Research
In vitro studies demonstrate efficacy in VeroE6/TMPRSS2B,43, HEK293T/ACE2-TMPRSS2C,43, and MucilAirD,43 cells. Animal studies demonstrate efficacy in BALB/c miceE,43,44 and Syrian hamstersF,43. Preclinical studies demonstrate efficacy for the ancestralG,43, deltaH,43, and omicronI,43 variants.
3 in vitro studies support the efficacy of ensitrelvir43,56,57.
2 in vivo animal studies support the efficacy of ensitrelvir43,44.
Preclinical research is an important part of the development of treatments, however results may be very different in clinical trials. Preclinical results are not used in this paper.
Results
Table 1 summarizes the results for all stages combined, for Randomized Controlled Trials, for peer-reviewed studies, and for specific outcomes. Table 2 shows results by treatment stage. Fig. 4 plots individual results by treatment stage. Fig. 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 show forest plots for random-effects meta-analysis of all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, recovery, cases, viral clearance, peer reviewed studies, and long COVID.
Table 1. Random-effects meta-analysis for all stages combined, for Randomized Controlled Trials, for peer-reviewed studies, and for specific outcomes. Results show the relative risk with treatment and the 95% confidence interval. * p<0.05  ** p<0.01  **** p<0.0001.
Relative Risk Studies Patients
All studies0.88 [0.78‑0.99]*106,769
Peer-reviewedPeer-reviewed0.91 [0.84‑0.98]*96,741
RCTsRCTs0.86 [0.67‑1.10]86,667
Mortality1.27 [0.67‑2.40]32,674
HospitalizationHosp.0.68 [0.46‑1.00]55,709
Recovery0.93 [0.90‑0.97]***74,457
Viral0.64 [0.54‑0.75]****63,682
RCT mortality0.95 [0.21‑4.34]22,674
RCT hospitalizationRCT hosp.1.70 [0.43‑6.70]45,709
Table 2. Random-effects meta-analysis results by treatment stage. Results show the relative risk with treatment and the 95% confidence interval.treatment and the 95% confidence interval. * p<0.05  ** p<0.01  **** p<0.0001.
Early treatment Late treatment Prophylaxis
All studies0.87 [0.79‑0.97]**0.87**
[0.79‑0.97]		1.40 [0.70‑2.80]1.40
[0.70‑2.80]		4.96 [0.24‑103.26]4.96
[0.24‑103.26]
Peer-reviewedPeer-reviewed0.90 [0.83‑0.98]*0.90*
[0.83‑0.98]		1.40 [0.70‑2.80]1.40
[0.70‑2.80]		4.96 [0.24‑103.26]4.96
[0.24‑103.26]
RCTsRCTs0.81 [0.63‑1.03]0.81
[0.63‑1.03]		1.40 [0.70‑2.80]1.40
[0.70‑2.80]		4.96 [0.24‑103.26]4.96
[0.24‑103.26]
Mortality0.72 [0.14‑3.78]0.72
[0.14‑3.78]		1.40 [0.70‑2.80]1.40
[0.70‑2.80]
HospitalizationHosp.0.66 [0.45‑0.97]*0.66*
[0.45‑0.97]		4.96 [0.24‑103.26]4.96
[0.24‑103.26]
Recovery0.93 [0.89‑0.96]****0.93****
[0.89‑0.96]		1.22 [0.92‑1.61]1.22
[0.92‑1.61]
Viral0.64 [0.54‑0.75]****0.64****
[0.54‑0.75]
RCT mortality0.20 [0.01‑4.18]0.20
[0.01‑4.18]		1.40 [0.70‑2.80]1.40
[0.70‑2.80]
RCT hospitalizationRCT hosp.1.29 [0.28‑6.01]1.29
[0.28‑6.01]		4.96 [0.24‑103.26]4.96
[0.24‑103.26]
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Fig. 4. 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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October 2026

Ensitrelvir COVID-19 studies

StudyImprovementRR · 95% CIOutcomeTreatmentControlRelative Risk
Mukae (DB RCT)45%0.55 · 0.37–0.81viral load14 (n)14 (n) Mukae (DB RCT)9%0.91 · 0.76–1.08improv.116 (n)111 (n) Yotsuyan.. (DB RCT)−1%1.01 · 0.06–16.09hosp.1/5951/600SCORPIO-SR Takazono (PSW)−24%1.24 · 0.17–9.05deathpopulation-based cohort Luetkem.. (DB RCT)80%0.20 · 0.01–4.18death0/1,0372/1,048SCORPIO-HR Katsuta10%0.90 · 0.81–0.99recov. time60 (n)42 (n) Schilling (RCT)67%0.33 · 0.01–8.05hosp.0/1971/191PLATCOV Nakano (DB RCT)4%0.96 · 0.68–1.37recov. time77 (n)37 (n)
Early treatment13%0.87 · 0.79–0.971/2,0964/2,04313% lower risk
Tau² = 0.00, I² = 7.8%, p = 0.009
Baker (RCT)−40%1.40 · 0.70–2.80death18/29313/296STRIVE
Late treatment−40%1.40 · 0.70–2.8018/29313/29640% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.35
Hayden (DB RCT)−396%4.96 · 0.24–103hosp.2/1,0300/1,011SCORPIO-PEP
Prophylaxis−396%4.96 · 0.24–1032/1,0300/1,011396% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.31
All studies12%0.88 · 0.78–0.9921/3,41917/3,35012% lower risk
Tau² = 0.01, I² = 14.2%, p = 0.03600.511.52+
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← Ensitrelvir
reduces riskEnsitrelvir
increases risk →
Fig. 5. 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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October 2026

Ensitrelvir COVID-19 mortality results

StudyImprovementRR · 95% CITreatmentControlRelative Risk
Takazono (PSW)−24%1.24 · 0.17–9.05population-based cohort Luetkem.. (DB RCT)80%0.20 · 0.01–4.180/1,0372/1,048SCORPIO-HR
Early treatment28%0.72 · 0.14–3.780/1,0372/1,04828% lower risk
Tau² = 0.00, I² = 0.0%, p = 0.71
Baker (RCT)−40%1.40 · 0.70–2.8018/29313/296STRIVE
Late treatment−40%1.40 · 0.70–2.8018/29313/29640% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.35
All studies−27%1.27 · 0.67–2.4018/1,33015/1,34427% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.4800.511.52+
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Fig. 6. Random-effects meta-analysis for mortality results.
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October 2026

Ensitrelvir COVID-19 mechanical ventilation results

StudyImprovementRR · 95% CITreatmentControlRelative Risk
Takazono (PSW)−158%2.58 · 0.60–11.12population-based cohort
Early treatment−158%2.58 · 0.60–11.12158% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.2
All studies−158%2.58 · 0.60–11.12158% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.200.511.52+
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← Ensitrelvir
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Fig. 7. Random-effects meta-analysis for ventilation.
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October 2026

Ensitrelvir COVID-19 ICU results

StudyImprovementRR · 95% CITreatmentControlRelative Risk
Takazono97%0.03 · 0.00–0.44population-based cohort
Early treatment97%0.03 · 0.00–0.4497% lower risk
Tau² = 0.00, I² = 0.0%, p = 0.011
All studies97%0.03 · 0.00–0.4497% lower risk
Tau² = 0.00, I² = 0.0%, p = 0.01100.511.52+
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← Ensitrelvir
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Fig. 8. Random-effects meta-analysis for ICU admission.
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October 2026

Ensitrelvir COVID-19 hospitalization results

StudyImprovementRR · 95% CIOutcomeTreatmentControlRelative Risk
Yotsuyan.. (DB RCT)−1%1.01 · 0.06–16.09hosp.1/5951/600SCORPIO-SR Takazono (PSW)37%0.63 · 0.42–0.94hosp.population-based cohort Luetkem.. (DB RCT)−203%3.03 · 0.32–29.10hosp.3/1,0371/1,048SCORPIO-HR Schilling (RCT)67%0.33 · 0.01–8.05hosp.0/1971/191PLATCOV
Early treatment34%0.66 · 0.45–0.974/1,8293/1,83934% lower risk
Tau² = 0.00, I² = 0.0%, p = 0.036
Hayden (DB RCT)−396%4.96 · 0.24–103hosp.2/1,0300/1,011SCORPIO-PEP
Prophylaxis−396%4.96 · 0.24–1032/1,0300/1,011396% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.31
All studies32%0.68 · 0.46–1.006/2,8593/2,85032% lower risk
Tau² = 0.00, I² = 0.0%, p = 0.05200.511.52+
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← Ensitrelvir
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Fig. 9. Random-effects meta-analysis for hospitalization.
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October 2026

Ensitrelvir COVID-19 recovery results

StudyImprovementRR · 95% CIOutcomeTreatmentControlRelative Risk
Mukae (DB RCT)9%0.91 · 0.76–1.08improv.116 (n)111 (n) Yotsuyan.. (DB RCT)11%0.89 · 0.71–1.11recov. time577 (n)572 (n)SCORPIO-SR Luetkem.. (DB RCT)5%0.95 · 0.90–1.02recov. time945 (n)943 (n)SCORPIO-HR Katsuta10%0.90 · 0.81–0.99recov. time60 (n)42 (n) Schilling (RCT)8%0.92 · 0.86–0.97recov. time197 (n)191 (n)PLATCOV Nakano (DB RCT)4%0.96 · 0.68–1.37recov. time77 (n)37 (n)
Early treatment7%0.93 · 0.89–0.961,972 (n)1,896 (n)7% lower risk
Tau² = 0.00, I² = 0.0%, p < 0.0001
Baker (RCT)−22%1.22 · 0.92–1.61no recov.293 (n)296 (n)STRIVE
Late treatment−22%1.22 · 0.92–1.62293 (n)296 (n)22% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.17
All studies7%0.93 · 0.90–0.972,265 (n)2,192 (n)7% lower risk
Tau² = 0.00, I² = 0.0%, p = 0.0002200.511.52+
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increases risk →
Fig. 10. Random-effects meta-analysis for recovery.
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October 2026

Ensitrelvir COVID-19 case results

StudyImprovementRR · 95% CIOutcomeTreatmentControlRelative Risk
Hayden (DB RCT)68%0.32 · 0.22–0.48symp. case30/1,03091/1,011SCORPIO-PEP
Prophylaxis68%0.32 · 0.22–0.4830/1,03091/1,01168% lower risk
Tau² = 0.00, I² = 0.0%, p < 0.0001
All studies68%0.32 · 0.22–0.4830/1,03091/1,01168% lower risk
Tau² = 0.00, I² = 0.0%, p < 0.000100.511.52+
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Fig. 11. Random-effects meta-analysis for cases.
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October 2026

Ensitrelvir COVID-19 viral clearance results

StudyImprovementRR · 95% CIOutcomeTreatmentControlRelative Risk
Mukae (DB RCT)45%0.55 · 0.37–0.81viral load14 (n)14 (n) Mukae (DB RCT)32%0.68 · 0.56–0.82viral time113 (n)108 (n) Yotsuyan.. (DB RCT)49%0.51 · 0.34–0.76viral load579 (n)589 (n)SCORPIO-SR Luetkem.. (DB RCT)19%0.81 · 0.68–0.97viral+175/882215/881SCORPIO-HR Schilling (RCT)49%0.51 · 0.42–0.62viral rate201 (n)191 (n)PLATCOV Nakano (DB RCT)28%0.72 · 0.60–0.85viral load74 (n)36 (n)
Early treatment36%0.64 · 0.54–0.75175/1,863215/1,81936% lower risk
Tau² = 0.03, I² = 67.1%, p < 0.0001
All studies36%0.64 · 0.54–0.75175/1,863215/1,81936% lower risk
Tau² = 0.03, I² = 67.1%, p < 0.000100.511.52+
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Fig. 12. Random-effects meta-analysis for viral clearance.
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October 2026

Ensitrelvir COVID-19 peer reviewed studies

StudyImprovementRR · 95% CIOutcomeTreatmentControlRelative Risk
Mukae (DB RCT)9%0.91 · 0.76–1.08improv.116 (n)111 (n) Yotsuyan.. (DB RCT)−1%1.01 · 0.06–16.09hosp.1/5951/600SCORPIO-SR Takazono (PSW)−24%1.24 · 0.17–9.05deathpopulation-based cohort Luetkem.. (DB RCT)80%0.20 · 0.01–4.18death0/1,0372/1,048SCORPIO-HR Katsuta10%0.90 · 0.81–0.99recov. time60 (n)42 (n) Schilling (RCT)67%0.33 · 0.01–8.05hosp.0/1971/191PLATCOV Nakano (DB RCT)4%0.96 · 0.68–1.37recov. time77 (n)37 (n)
Early treatment10%0.90 · 0.83–0.981/2,0824/2,02910% lower risk
Tau² = 0.00, I² = 0.0%, p = 0.012
Baker (RCT)−40%1.40 · 0.70–2.80death18/29313/296STRIVE
Late treatment−40%1.40 · 0.70–2.8018/29313/29640% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.35
Hayden (DB RCT)−396%4.96 · 0.24–103hosp.2/1,0300/1,011SCORPIO-PEP
Prophylaxis−396%4.96 · 0.24–1032/1,0300/1,011396% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.31
All studies9%0.91 · 0.84–0.9821/3,40517/3,3369% lower risk
Tau² = 0.00, I² = 0.0%, p = 0.01800.511.52+
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Fig. 13. Random-effects meta-analysis for peer reviewed studies. 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. 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.
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October 2026

Ensitrelvir COVID-19 long COVID results

StudyImprovementRR · 95% CIOutcomeTreatmentControlRelative Risk
Luetkem.. (DB RCT)−2%1.02 · 0.88–1.19PASC256/1,037253/1,048SCORPIO-HR
Early treatment−2%1.02 · 0.88–1.19256/1,037253/1,0482% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.78
All studies−2%1.02 · 0.88–1.19256/1,037253/1,0482% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.7800.511.52+
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← Ensitrelvir
reduces riskEnsitrelvir
increases risk →
Fig. 14. Random-effects meta-analysis for long COVID. 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.
Randomized Controlled Trials (RCTs)
Fig. 15 shows a comparison of results for RCTs and observational studies. Random-effects meta-analysis of RCTs shows 14% improvement, compared to 10% for other studies. Fig. 16, 17, and 18 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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Fig. 15. Results for RCTs and observational studies.
RCTs have many potential biases
RCTs help to make study groups more similar and can provide a higher level of evidence, however they are subject to many biases60, and analysis of double-blind RCTs has identified extreme levels of bias61. 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.
Conflicts of interest for COVID-19 RCTs
RCTs are expensive and many RCTs are funded by pharmaceutical companies or other organizations with conflicts of interest, for example governments that previously denied treatment with the study drug. 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. Bekelman et al. and Lundh et al. show that industry-sponsored studies are more likely to be favorable. For COVID-19, some major philanthropic organizations are largely funded by investments with extreme conflicts of interest for and against specific COVID-19 interventions.
RCTs for novel acute diseases requiring rapid treatment
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 226 treatments we have analyzed, 67% 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.
0 0.5 1 1.5 2 Low-cost 0.98 [0.90-1.06] RR CI High-profit 0.93 [0.85-1.02] All treatments 0.97 [0.91-1.03] COVID-19 RCT vs. observationalresults from 6,000+ studies c19early.org October 2026 RCTs showhigher efficacy RCTs showlower efficacy
Fig. 19. For COVID-19, observational study results do not systematically differ from RCTs, RR 0.97 [0.91‑1.03] across 226 treatments65.
Observational studies have been shown to be reliable
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 226 treatments we cover, showing no significant difference in the results of RCTs compared to observational studies, RR 0.97 [0.91‑1.03]68. Similar results are found for all low-cost treatments, RR 0.98 [0.90‑1.06]. High-cost treatments show a non-significant trend towards RCTs showing greater efficacy, RR 0.93 [0.85‑1.02]. 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 see70,71.
RCTs may be less reliable
Concato et al. report a paradoxical finding—RCT results had higher variability, and only RCTs were found to sometimes report significant results the opposite of the overall result. The same trend is seen for the most popular (most politicized) COVID-19 treatments—considering all statistically significant results reported in studies, RCTs are slightly more likely to report a result in the opposite direction. In other words, for these COVID-19 treatments and for the topics covered by Concato et al., assuming causality from a single study is more likely to result in an incorrect conclusion for RCTs.
Increased risk of inconsistent results for RCTs suggests higher prevalence of bias, which may arise due to many issues including design bias, conflicts of interest, treatment differences by physicians aware of allocation, attrition bias, ascertainment bias, randomization failures, errors, or fraud.
Using all studies identifies efficacy 8+ months faster (9+ months for low-cost treatments)
Currently, 59 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, 54% have been confirmed in RCTs, with a mean delay of 7.8 months (62% with 8.7 months delay for low-cost treatments). The remaining treatments either have no RCTs, or the point estimate is consistent.
All studies must be carefully analyzed
Neither observational studies nor RCTs prove causation—any study can be flawed or fraudulent. We need much more, for example a combination of results from many independent teams, detailed understanding of each study, knowledge of conflicts/team reliability, dose-response relationships, delay-response relationships, logical results across outcomes, or details consistent with preclinical expectations.
All studies must be evaluated individually. 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.
c19early.org
October 2026

Ensitrelvir COVID-19 Randomized Controlled Trials

StudyImprovementRR · 95% CIOutcomeTreatmentControlRelative Risk
Mukae (DB RCT)45%0.55 · 0.37–0.81viral load14 (n)14 (n) Mukae (DB RCT)9%0.91 · 0.76–1.08improv.116 (n)111 (n) Yotsuyan.. (DB RCT)−1%1.01 · 0.06–16.09hosp.1/5951/600SCORPIO-SR Luetkem.. (DB RCT)80%0.20 · 0.01–4.18death0/1,0372/1,048SCORPIO-HR Schilling (RCT)67%0.33 · 0.01–8.05hosp.0/1971/191PLATCOV Nakano (DB RCT)4%0.96 · 0.68–1.37recov. time77 (n)37 (n)
Early treatment19%0.81 · 0.63–1.031/2,0364/2,00119% lower risk
Tau² = 0.02, I² = 29.8%, p = 0.078
Baker (RCT)−40%1.40 · 0.70–2.80death18/29313/296STRIVE
Late treatment−40%1.40 · 0.70–2.8018/29313/29640% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.35
Hayden (DB RCT)−396%4.96 · 0.24–103hosp.2/1,0300/1,011SCORPIO-PEP
Prophylaxis−396%4.96 · 0.24–1032/1,0300/1,011396% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.31
All studies14%0.86 · 0.67–1.1021/3,35917/3,30814% lower risk
Tau² = 0.03, I² = 31.9%, p = 0.2200.511.52+
Rotate screen for more detailsIncrease width for more details
← Ensitrelvir
reduces riskEnsitrelvir
increases risk →
Fig. 16. 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.
c19early.org
October 2026

Ensitrelvir COVID-19 RCT mortality results

StudyImprovementRR · 95% CITreatmentControlRelative Risk
Luetkem.. (DB RCT)80%0.20 · 0.01–4.180/1,0372/1,048SCORPIO-HR
Early treatment80%0.20 · 0.01–4.180/1,0372/1,04880% lower risk
Tau² = 0.00, I² = 0.0%, p = 0.3
Baker (RCT)−40%1.40 · 0.70–2.8018/29313/296STRIVE
Late treatment−40%1.40 · 0.70–2.8018/29313/29640% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.35
All studies5%0.95 · 0.21–4.3418/1,33015/1,3445% lower risk
Tau² = 0.62, I² = 33.0%, p = 0.9500.511.52+
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← Ensitrelvir
reduces riskEnsitrelvir
increases risk →
Fig. 17. Random-effects meta-analysis for RCT mortality results.
c19early.org
October 2026

Ensitrelvir COVID-19 RCT hospitalization results

StudyImprovementRR · 95% CIOutcomeTreatmentControlRelative Risk
Yotsuyan.. (DB RCT)−1%1.01 · 0.06–16.09hosp.1/5951/600SCORPIO-SR Luetkem.. (DB RCT)−203%3.03 · 0.32–29.10hosp.3/1,0371/1,048SCORPIO-HR Schilling (RCT)67%0.33 · 0.01–8.05hosp.0/1971/191PLATCOV
Early treatment−29%1.29 · 0.28–6.014/1,8293/1,83929% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.76
Hayden (DB RCT)−396%4.96 · 0.24–103hosp.2/1,0300/1,011SCORPIO-PEP
Prophylaxis−396%4.96 · 0.24–1032/1,0300/1,011396% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.31
All studies−70%1.70 · 0.43–6.706/2,8593/2,85070% higher risk
Tau² = 0.00, I² = 0.0%, p = 0.4600.511.52+
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← Ensitrelvir
reduces riskEnsitrelvir
increases risk →
Fig. 18. Random-effects meta-analysis for RCT hospitalization results.
Media Bias
Low-cost treatments were subject to bias and censorship during the pandemic. Scientific bias is seen in the design, analysis, presentation, and selective reporting of studies, which favored negative results. A similar bias is seen in the media coverage for low-cost treatments. However, the opposite is seen for high-profit treatments.
We analyze media coverage for the 226 treatments we cover using Altmetric72, which reports the number of ~12,000 tracked news outlets that covered each study73. Studies are considered to have received significant media coverage if they were covered by at least 0.5% of the tracked news outlets. Fig. 20, 21, and 22 show the bias toward positive results for high-profit treatments, in contrast to the opposite bias for low-cost treatments. This may result in widespread incorrect perceptions on the relative efficacy of high-profit and low-cost treatments. The impact is significant—increased cost limits the use of high-profit treatments and treatment equity, and high-profit treatments were also more difficult to access, especially for earlier treatment which improves efficacy and minimizes community transmission.
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Fig. 20. Media was more likely to cover negative or inconclusive results for low-cost treatments, and positive results for high-profit treatments.
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Fig. 21. Mainstream media was biased towards positive results for high-profit treatments.
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Fig. 22. In contrast to the results for high-profit treatments, mainstream media was biased against positive results for low-cost treatments.
A combination of factors may have led to the media's suppression of low-cost treatments:
•
Politicization
led to a media environment where coverage was often framed to support a political narrative rather than to provide objective scientific information. As Scott Alexander said:
"if you say anything in favor of ivermectin you will be cast out of civilization and thrown into the circle of social hell reserved for Klan members and 1/6 insurrectionists. All the health officials in the world will shout 'horse dewormer!' at you and compare you to Josef Mengele."
There was strong social pressure to discredit low-cost treatments.
•
Censorship
of information conflicting with selected authorities. For example, individuals and organizations presenting conflicting science were often banned on Twitter and YouTube.
•
FDA requires "no adequate, approved, and available alternatives"
in order to grant an EUA for novel high-profit interventions, creating a strong incentive for authorities to ignore or downplay existing low-cost treatments.
•
Regulatory capture
biases authorities towards high-profit interventions.
•
Authorities ignored most evidence for low-cost treatments
, for example the NIH references only 2% of studies in delayed, rarely-updated, biased commentaries with no quantitive analysis.
•
Media coverage of science is often not very accurate
, e.g., misunderstanding confounding issues. For example the media widely considered the RECOVERY HCQ RCT to be conclusive on efficacy, but very late treatment of late stage patients (mostly on oxygen already) with an excessive toxic dose (shown dangerous in a dose comparison RCT) provides no information on the recommended early/prophylactic treatment. With difficulting in understanding basic confounders like treatment delay and dose, the media may favor deferring to authorities. Many studies for low-cost treatments require greater expertise to analyze. Relatively few journalists have a strong ability to analyze clinical trials and are outnumbered by the rest.
•
Substantial funding from pharmaceutical advertising
biases editorial decisions towards high-profit interventions.
•
PR power
- companies/teams with strong PR presence are favored in the media, which correlates with high-profit and high conflict of interest studies.
•
The media was very negative in general
, inflating risk, fear, and anxieties. A negative bias may improve ratings and revenue, increasing motivation to continue watching coverage. A combination of low-cost treatments greatly reducing risk conflicts with the negative narrative.
Heterogeneity
Heterogeneity in COVID-19 studies arises from many factors including:
Treatment delay
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 hours74,75. Baloxavir marboxil studies for influenza also show that treatment delay is critical — Ikematsu et al. report an 86% reduction in cases for post-exposure prophylaxis, Hayden et al. show a 33 hour reduction in the time to alleviation of symptoms for treatment within 24 hours and a reduction of 13 hours for treatment within 24-48 hours, and Kumar et al. report only 2.5 hours improvement for inpatient treatment.
Table 3. Studies of baloxavir marboxil for influenza show that early treatment is more effective.
Treatment delayResult
Post-exposure prophylaxis86% fewer cases76
<24 hours-33 hours symptoms77
24-48 hours-13 hours symptoms77
Inpatients-2.5 hours to improvement78
Fig. 23 shows a mixed-effects meta-regression for efficacy as a function of treatment delay in COVID-19 studies from 226 treatments, showing that efficacy declines rapidly with treatment delay. Early treatment is critical for COVID-19.
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Fig. 23. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 226 treatments.
Patient demographics
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.
SARS-CoV-2 variants
Efficacy may depend critically on the distribution of SARS-CoV-2 variants encountered by patients. Risk varies significantly across variants80, for example the Gamma variant shows significantly different characteristics81-84. 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 variants85,86.
Treatment regimen
Effectiveness may depend strongly on the dosage and treatment regimen.
Medication quality
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.
Other treatments
The use of other treatments may significantly affect outcomes, including supplements, other medications, or other interventions such as prone positioning. Treatments may be synergistic89-113, therefore efficacy may depend strongly on combined treatments.
Effect measured
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.
Meta-analysis
The distribution of studies will alter the outcome of a meta-analysis. Consider a simplified example where everything is equal except for the treatment delay, and effectiveness decreases to zero or below with increasing delay. If there are many studies using very late treatment, the outcome may be negative, even though early treatment is very effective. All meta-analyses combine heterogeneous studies, varying in population, variants, and potentially all factors above, and therefore may obscure efficacy by including studies where treatment is less effective. Generally, we expect the estimated effect size from meta-analysis to be less than that for the optimal case. Looking at all studies is valuable for providing an overview of all research, important to avoid cherry-picking, and informative when a positive result is found despite combining less-optimal situations. However, the resulting estimate does not apply to specific cases such as early treatment in high-risk populations. While we present results for all studies, we also present treatment time and individual outcome analyses, which may be more informative for specific use cases.
Pooled Effects
Pooled effects are no longer required to show efficacy as of July 2023
This section validates the use of pooled effects for COVID-19, which enables earlier detection of efficacy, however pooled effects are no longer required for ensitrelvir as of July 2023. Efficacy is now known based on specific outcomes.
Combining studies is required
For COVID-19, delay in clinical results translates into additional death and morbidity, as well as additional economic and societal damage. Combining the results of studies reporting different outcomes is required. There may be no mortality in a trial with low-risk patients, however a reduction in severity or improved viral clearance may translate into lower mortality in a high-risk population. Different studies may report lower severity, improved recovery, and lower mortality, and the significance may be very high when combining the results. "The studies reported different outcomes" is not a good reason for disregarding results. Pooling the results of studies reporting different outcomes allows us to use more of the available information. Logically we should, and do, use additional information when evaluating treatments—for example dose-response and treatment delay-response relationships provide additional evidence of efficacy that is considered when reviewing the evidence for a treatment.
Specific outcome and pooled analyses
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.
Ethical and practical issues limit high-risk trials
Trials with high-risk patients may be restricted due to ethics for treatments that are known or expected to be effective, and they increase difficulty for recruiting. Using less severe outcomes as a proxy for more serious outcomes allows faster and safer collection of evidence.
Validating pooled outcome analysis for COVID-19
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 226 treatments we cover confirms the validity of pooled outcome analysis for COVID-19. Fig. 24 shows that lower hospitalization is very strongly associated with lower mortality (p < 0.0000000001). Similarly, Fig. 25 shows that improved recovery is very strongly associated with lower mortality (p < 0.0000000001). 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. Fig. 26 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 = 0.0000000074 to p = 0.00000000015.
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Fig. 24. Lower hospitalization is associated with lower mortality, supporting pooled outcome analysis.
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Fig. 25. Improved recovery is associated with lower mortality, supporting pooled outcome analysis.
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Fig. 24. Improved viral clearance is associated with fewer serious outcomes, supporting pooled outcome analysis.
Pooled outcomes identify efficacy 5 months faster (7 months for RCTs)
Currently, 59 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 85% of these have been confirmed with one or more specific outcomes, with a mean delay of 4.6 months. When restricting to RCTs only, 53% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 7.5 months. Fig. 27 shows when treatments were found effective during the pandemic. Pooled outcomes often resulted in earlier detection of efficacy.
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Fig. 27. 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.
Limitations
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 differences in treatment delay are more likely to hide efficacy.
Summary
Analysis validates the use of pooled effects and shows significantly faster detection of efficacy on average. However, as with all meta-analyses, it is important to review the different studies included. We also present individual outcome analyses, which may be more informative for specific use cases.
Discussion
3CLpro inhibitors
We currently cover 11 3CLpro inhibitors45-55 with clinical data. Paxlovid, xiannuoxin, and atilotrelvir require ritonavir-boosting. Ritonavir inhibits key enzymes and transporters, which disrupts endogenous physiological pathways (with incompletely characterized consequences) and creates serious drug-drug interaction risks. Lufotrelvir is formulated for IV use. Olgotrelvir, ensitrelvir, ibuzatrelvir, leritrelvir, pomotrelvir, and ratutrelvir are newer-generation drugs that do not require ritonavir. Olgotrelvir may be the most technologically advanced with dual-mechanism inhibition and activity against paxlovid-resistant variants, while potentially minimizing the lipid disruption seen with ensitrelvir and leritrelvir. Ratutrelvir may have increased safety supporting longer treatment duration while minimizing side effects.
Publication bias
Publishing is often biased towards positive results. Trials with patented drugs may have a financial conflict of interest that results in positive studies being more likely to be published, or bias towards more positive results. For example with molnupiravir, trials with negative results remain unpublished to date (CTRI/2021/05/033864 and CTRI/2021/08/0354242). For ensitrelvir, there is currently not enough data to evaluate publication bias with high confidence.
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.
Fig. 28 shows a scatter plot of results for prospective and retrospective studies. 100% of retrospective studies report a statistically significant positive effect for one or more outcomes, compared to 88% of prospective studies, consistent with a bias toward publishing positive results.
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Fig. 28. 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. Fig. 29 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 < 0.05115-122. Note that these tests fail even though treatment delay is uniformly distributed. In reality treatment delay is more complex — each trial has a different distribution of delays across patients, and the distribution across trials may be biased (e.g., late treatment trials may be more common). Similarly, many other variations in trials may produce asymmetry, including dose, administration, duration of treatment, differences in SOC, comorbidities, age, variants, and bias in design, implementation, analysis, and reporting.
Log Risk Ratio Standard Error 1.406 1.055 0.703 0.352 0 -3 -2 -1 0 1 2 A: Simulated perfect trials p > 0.05 Log Risk Ratio Standard Error 1.433 1.074 0.716 0.358 0 -4 -3 -2 -1 0 1 2 B: Simulated perfect trials with varying treatment delay p < 0.0001
Fig. 29. Example funnel plot analysis for simulated perfect trials.
Limitations
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 alone89-113. 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.
Notes
Ul Haq et al. present another meta-analysis for ensitrelvir, showing significant improvement for viral load.
Reviews
Multiple reviews cover ensitrelvir for COVID-19, presenting additional background on mechanisms and related results, including1,123.
Other studies
Additional preclinical or review papers suggesting potential benefits of ensitrelvir for COVID-19 include134-168. We have not reviewed these studies in detail.
Perspective
Results compared with other treatments
SARS-CoV-2 infection and replication involves a complex interplay of 500+ host and viral proteins and other factors34-41, providing many therapeutic targets. Over 12,000 compounds have been predicted to reduce COVID-19 risk42, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications. Fig. 30 shows an overview of the results for ensitrelvir in the context of multiple COVID-19 treatments, and Fig. 31 shows a plot of efficacy vs. cost for COVID-19 treatments.
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Fig. 30. Scatter plot showing results within the context of multiple COVID-19 treatments. Diamonds shows the results of random-effects meta-analysis. 0.5% of 12,000+ proposed treatments show efficacy169.
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Fig. 31. Efficacy vs. cost for COVID-19 treatments.
Conclusion
Significantly lower risk is seen for recovery, cases, and viral clearance. 9 studies from 5 independent teams (all from the same country) show significant benefit. Meta-analysis using the most serious outcome reported shows 12% [1‑22%] lower risk. Results are similar for Randomized Controlled Trials and worse for peer-reviewed studies. Early treatment is more effective than late treatment.
Currently there is limited data, with only 17 control events for the most serious outcome in trials to date.
Variants may be resistant to ensitrelvir1,2.
Ul Haq et al. present another meta-analysis for ensitrelvir, showing significant improvement for viral load.
We currently cover 11 3CLpro inhibitors45-55 with clinical data. Paxlovid, xiannuoxin, and atilotrelvir require ritonavir-boosting. Ritonavir inhibits key enzymes and transporters, which disrupts endogenous physiological pathways (with incompletely characterized consequences) and creates serious drug-drug interaction risks. Lufotrelvir is formulated for IV use. Olgotrelvir, ensitrelvir, ibuzatrelvir, leritrelvir, pomotrelvir, and ratutrelvir are newer-generation drugs that do not require ritonavir. Olgotrelvir may be the most technologically advanced with dual-mechanism inhibition and activity against paxlovid-resistant variants, while potentially minimizing the lipid disruption seen with ensitrelvir and leritrelvir. Ratutrelvir may have increased safety supporting longer treatment duration while minimizing side effects.
 
Contact.
Contact us on X at @CovidAnalysis.
Funding.
We have received no funding or compensation in any form, and do not accept donations. This is entirely volunteer work.
Conflicts of interest.
We have no conflicts of interest. We have no affiliation with any pharmaceutical companies, supplement companies, governments, political parties, or advocacy organizations.
AI.
We use AI models (Gemini, Grok, Claude, and ChatGPT) tasked with functioning as additional peer-reviewers to check for errors, suggest improvements, and review spelling and grammar. Any corrections are manually verified. Our preference for em dashes is independent of AI.
Updates.
Our COVID-19 meta-analyses involve the extraction of over 228,000 datapoints from thousands of papers for 226 treatments. We thank the thousands of scientists, physicians, and other contributors that have provided updates, suggestions, feedback, and corrections. These are all welcome and can be submitted at https://c19early.org/enmeta.html.
Dedication.
This work is dedicated to top evidence-based physicians that worked tirelessly to analyze evidence and greatly reduce mortality and morbidity during the pandemic. In alphabetical order: Dr. Thomas J. Borody, Dr. Mary Talley Bowden, Dr. Flavio Cadegiani, Dr. Shankara Chetty, Dr. Ryan Cole, Dr. George Fareed, Dr. Sabine Hazan, Dr. Pierre Kory, Dr. Tess Lawrie, Dr. Robert Malone, Dr. Paul Marik, Dr. Peter McCullough, Dr. Didier Raoult, Dr. Harvey Risch, Dr. Jackie Stone, Dr. Brian Tyson, Dr. Joseph Varon, and Dr. Vladimir Zelenko.
Public domain.
This is a public domain work distributed in accordance with the Creative Commons CC0 1.0 Universal license, which dedicates the work to the public domain by waiving all rights worldwide under copyright law. You can distribute, remix, adapt, and build upon this work in any medium or format, including for commercial purposes, without asking permission. Referenced material and third-party images retain any original copyrights or restrictions. See: https://creativecommons.org/publicdomain/zero/1.0/.
Study Notes
Late treatmentRCT · NCT05605093 · 589 patients · multinational
Ensitrelvir for COVID-19
STRIVE Baker et al. Clinical Infectious Diseases · April 2026
Outcome
Improvement
Relative Risk · 95% CI
Mortality
-40%1.40 · 0.70–2.80
Recovery
-22%1.22 · 0.92–1.61
00.511.52+
← Ensitrelvir
reduces riskEnsitrelvir
increases risk →
Higher mortality and worse recovery
Not statistically significant · p = 0.36 (mortality) and p = 0.17 (recovery)
RCT 589 hospitalized patients showing no significant benefit for clinical outcomes with ensitrelvir treatment. Submit Corrections or Updates.
ProphylaxisRCT · 2,041 patients · multinational · Jun 2023 – Sep 2024
Ensitrelvir for COVID-19
SCORPIO-PEP Hayden et al. New England J. Medicine · March 2025
Outcome
Improvement
Relative Risk · 95% CI
Hospitalization, all-cause
-396%4.96 · 0.24 to >9
Symp. case
68%0.32 · 0.22–0.48
Case
58%0.42 · 0.31–0.57
00.511.52+
← Ensitrelvir
reduces riskEnsitrelvir
increases risk →
Fewer symptomatic cases and cases
p < 0.0001 (Fewer symptomatic cases) and p < 0.0001 (cases)
3 critical issues, no response from authors
RCT 2,041 household contacts showing significantly lower symptomatic COVID-19 cases with ensitrelvir post-exposure prophylaxis. Some results are from the registry (posted September 16, 2026).
Concerns with this trial include:
CRITICAL
1. Potential imputation bias
CRITICAL
2. HHC/patient mismatch
CRITICAL
3. HDL adverse event ascertainment
MAJOR
4. Efficacy in Japan not shown in the US
MAJOR
5. Efficacy for <48 hours from onset
Responses: authors have not responded to any of these issues.
CRITICALPotential imputation bias. The protocol states that “missing data will not be imputed” but then specifies imputation in Table 9-1: “For participants with intercurrent events 'b or c', the participant will be assumed to have been infected with SARS-CoV-2” - withdrawals “before occurrence of the event for the primary endpoint” are treated as positive COVID-19 events. Imputing dropouts as positive may be reasonable in certain trials but does not make sense for a COVID-19 prophylaxis trial - e.g., consider if there were 5 events and 50 dropouts. Imputation could significantly alter the result. In this trial there were 22 treatment and 35 placebo dropouts. We do not know how many led to imputation, if any (the protocol reports both the imputation and that no missing data were imputed).
CRITICALHHC/patient mismatch. The distribution of Randomized Household Contacts per Index Patient appears inconsistent. Table S1 shows that out of 1,319 Index Patients, 546 had ≥4 randomized HHCs, 275 had 3, 273 had 2, and 225 had 1. This indicates a minimum of (546*4) + (275*3) + (273*2) + (225*1) = 3,780 randomized HHCs. However, the CONSORT diagram shows only 2,387 randomized HHCs.
CRITICALHDL adverse event ascertainment. Previous trials reported HDL decreases as the most common TEAE (>30% of patients). In this study, authors acknowledge a 27% median reduction in HDL on day 6 in the treatment group. The protocol specified that HDL-C results would be withheld from study sites/blinded personnel until unblinding because HDL-C decreases could reveal treatment assignment. Authors state that the changes are transient and are not a safety concern. We do not see evidence that HDL values were reported after unblinding and captured as adverse events. Therefore, the headline AE table may not fully account for treatment adverse effects.
MAJOREfficacy in Japan not shown in the US. Figure 3 shows efficacy in Japan but only a non-significant trend in the US.
MAJOREfficacy for <48 hours from onset. Figure 3 shows efficacy for <48 hours from onset, but no significant effect for ≥48 hours. In some countries, utility may be reduced by delays involved in accessing prescription treatment.
c19early.org
Ensitrelvir - breakthrough COVID-19 treatment?
May 2026 news portrays ensitrelvir as a new breakthrough COVID-19 treatment, despite the SCORPIO-PEP study having released results in 2024, and ensitrelvir being approved in Japan in 2022. Data and safety are favorable compared with paxlovid, and ensitrelvir should have been approved in the US. Here we compare the recovery and prophylaxis results for different treatments seen in key trials.
Paxlovid Ensitrelvir Ivermectin HCQ
Prophylaxis RR 0.73, p < 0.13170 RR 0.32, p < 0.001133 HR 0.28, p < 0.001171 HR 0.43, p < 0.001172
withheld 820 days
Recovery HR 0.83, p < 0.002173
best case use
 RR 0.95, p = 0.14127
best case use
 HR 0.83, p < 0.001174
worst case: delay, regimen, population
withheld 600 days
 HR 0.76, p = 0.03175
late treatment
withheld 5 years
Side effects Significant DDI risks, black-box warning Significant DDI risks Relatively low (not zero) Moderate DDI, off-target risks
Cost $1,390176 $500177 <$1178 <$1179
Revenue $28.5B ~$1.0B Many low-cost manufacturers Many low-cost manufacturers
Submit Corrections or Updates.
Retrospective 102 healthcare workers in Japan showing shorter time to return-to-work with ensitrelvir treatment for COVID-19. Submit Corrections or Updates.
Early treatmentDouble-blind RCT · 2,085 patients · multinational
Ensitrelvir for COVID-19
SCORPIO-HR Luetkemeyer et al. Clinical Infect. Dis. · February 2025
Improved viral clearance with ensitrelvir
p = 0.022
RCT 2,093 outpatients with mild-to-moderate COVID-19 showing improved viral clearance but no significant difference in time to symptom resolution with ensitrelvir. Participants were randomized to receive ensitrelvir or placebo within five days of symptom onset, with the primary analysis focusing on those treated within three days. A mid-trial protocol change excluded participants treated more than three days post-symptom onset from the primary analysis.

Revisions: added mortality and long COVID outcomes reported in the registy on 8/20/2026. Submit Corrections or Updates.
Early treatmentRCT · 227 patients · Japan · Jan – Feb 2022
Ensitrelvir for COVID-19
Mukae et al. Clinical Infectious Diseases · December 2022 · jRCT2031210350
Faster viral clearance with ensitrelvir
p = 0.0001
RCT 428 COVID-19 patients in Japan showing faster viral clearance and improved recovery with ensitrelvir. Submit Corrections or Updates.
Early treatmentRCT · 69 patients · Japan · Sep 2021 – Jan 2022
Ensitrelvir for COVID-19
Mukae et al. medRxiv · May 2022 · jRCT2031210350
Outcome
Improvement
Relative Risk · 95% CI
Change in viral titer, 250mg
45%0.55 · 0.37–0.81
Change in viral titer, 125mg
36%0.64 · 0.41–1.00
Time to viral clearance, 125mg
45%0.55 · 0.34–0.90
Time to viral clearance, 250mg
44%0.56 · 0.35–0.92
Viral clearance, 250mg, day 14
54%0.46 · 0.05–4.38
Viral clearance, 125mg, day 14
-10%1.10 · 0.22–5.51
Viral clearance, 250mg, day 9
80%0.20 · 0.01–3.80
Viral clearance, 125mg, day 9
54%0.46 · 0.05–4.53
Viral clearance, 250mg, day 6
54%0.46 · 0.10–2.12
Viral clearance, 125mg, day 6
90%0.10 · 0.01–0.85
Viral clearance, 250mg, day 4
80%0.20 · 0.05–0.75
Viral clearance, 125mg, day 4
63%0.37 · 0.15–0.92
Viral clearance, 250mg, day 2
9%0.91 · 0.59–1.40
Viral clearance, 125mg, day 2
-10%1.10 · 0.79–1.55
primary
primary
00.511.52+
← Ensitrelvir
reduces riskEnsitrelvir
increases risk →
Improved viral clearance with ensitrelvir
p = 0.0025
RCT 69 patients in in Japan, showing faster viral clearance with ensitrelvir. 5-day ensitrelvir (375mg on day 1 followed by 125 mg daily or 750mg on day 1 followed by 250mg daily). Submit Corrections or Updates.
Early treatmentDouble-blind RCT · jRCT2031230140 · 114 patients · Japan
Ensitrelvir for COVID-19
Nakano et al. J. Pediatric Infectious Diseases Society · Aug 2026
Outcome
Improvement
Relative Risk · 95% CI
Recovery time
4%0.96 · 0.68–1.37
Viral load
28%0.72 · 0.60–0.85
00.511.52+
← Ensitrelvir
reduces riskEnsitrelvir
increases risk →
Improved viral load with ensitrelvir
p = 0.0002
RCT 117 pediatric outpatients (6-11 years) with mild-to-moderate COVID-19 in Japan showing improved viral clearance, but no significant difference in time to symptom resolution with ensitrelvir vs. placebo. Submit Corrections or Updates.
Early treatmentRCT · 392 patients · multinational · Mar 2023 – Apr 2024
Ensitrelvir for COVID-19
PLATCOV Schilling et al. Lancet Infectious Diseases · May 2025
Faster recovery and improved viral clearance
p = 0.0058 (recovery) and p < 0.0001 (viral clearance)
RCT 604 low-risk adults with early COVID-19 symptoms showing significantly improved SARS-CoV-2 viral clearance with both ensitrelvir and paxlovid.

Inclusion criteria selected for low-risk patients with high viral loads which may not generalize to high-risk patients or patients treated prior to having high viral load.

Authors indicate that "between March 2023 and April 2024 the three study arms randomised 604 patients", however figure S7 shows paxlovid patients starting before July 2022.

120 day long COVID results in the protocol are not reported.

The protocol was modified mid-trial in October 2024: the number of patients was increased, the swabbing schedule was changed, and patient self-swabbing was added. Results appear to have improved in the post-change period.

The swabbing schedule in the paper conflicts with the October 2024 change reported in the protocol ("now swabbing day 0 to day 5 once or twice per day to characterise viral clearance"). Submit Corrections or Updates.
Early treatmentRetrospective · 167,310 patients · Nov 2022 – Jul 2023
Ensitrelvir for COVID-19
Takazono et al. Infectious Diseases and Therapy · June 2024
Lower hospitalization with ensitrelvir
p = 0.024
Retrospective 167,310 high-risk COVID-19 outpatients in Japan showing significantly lower hospitalization with ensitrelvir treatment. Submit Corrections or Updates.
Early treatmentRCT · 1,821 patients · multinational · Feb – Jul 2022
Ensitrelvir for COVID-19
SCORPIO-SR Yotsuyanagi et al. JAMA Network Open · July 2023
Improved viral clearance with ensitrelvir
p = 0.001
RCT 1,821 COVID-19 outpatients in Japan, Vietnam, and South Korea, showing improved viral clearance and improved recovery (significant for patients treated within 3 days of onset) with ensitrelvir. Only 2 hospitalizations were reported, with no deaths. Submit Corrections or Updates.
Appendix 1. Methods and Data
Search methods
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, which regularly receives notification of studies upon publication. Search terms are ensitrelvir 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 ensitrelvir for COVID-19 that report a comparison with a control group are included in the main analysis. Studies with major unexplained data issues, for example major outcome data that is impossible to be correct with no response from the authors, are excluded.
Fig. 32. Mid-recovery results can more accurately reflect efficacy when almost all patients recover. Mateja et al. confirm that intermediate viral load results more accurately reflect hospitalization/death.
Effect extraction
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 reported then they are both used in specific outcome analyses, while mortality is used for pooled analysis. If symptomatic results are reported at multiple times, we use 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 outcomes. 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. An IPD meta-analysis confirms that intermediate viral load reduction is more closely associated with hospitalization/death than later viral load reduction180. 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.
Statistical methods
Forest plots are computed using PythonMeta181 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. When results provide an odds ratio, we compute the relative risk when possible, or convert to a relative risk according to Zhang et al. Reported confidence intervals and p-values are used when available, and adjusted values are used 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 1185. 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 (3.14.7) with scipy (1.18.1), pythonmeta (1.26), numpy (2.5.3), statsmodels (0.15.0), and plotly (6.9.0). 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 0.8.2 is used to parse PDF documents.
When evaluating potential effect modification across groups, we use an interaction test as described by Altman (C) et al. We compared the log-transformed relative risks using a z-test, deriving the standard error of the difference from the 95% confidence intervals. A two-sided interaction p-value of < 0.05 was considered a statistically significant difference in treatment effect between the groups.
Quality evaluation
Cochrane RoB 2/ROBINS-I are often used to evaluate studies, and have the advantage of providing standardized rules that can be applied with minimal understanding of the domain and study. However, the rules do not account for many real-world issues, often overemphasize or underemphasize others, and studies show low inter-rater reliability193. Certain domains are more applicable for these tools, however the time-sensitive nature of a pandemic, with significant mortality for every day of delay in evidence assessment, and the characteristics of COVID-19 make them inappropriate for this domain. This can be demonstrated with examples where expert RoB 2/ROBINS-I ratings do not match reality for COVID-19. Popp et al. use RoB 2 to classify Reis et al. as low risk of bias, however this is the opposite of reality—the trial not only has very high risk of bias, but has very high actual known bias, refusing to release data despite pledging to, reporting multiple impossible numbers, having blinding and randomization failure, and many other issues195. Axfors et al. use RoB 2 to classify Horby et al. as low risk of bias, however this is the opposite of reality—the very late treatment and excessive dosage used produces results with no relevance to recommended usage. HCQ shows poor results with late treatment and excessive dosage, and the combination shows harmJ. Hempenius et al. use ROBINS-I to classify 33 studies for HCQ. The two rated as having the lowest risk of bias191,192 are far from the most informative. Both involve very late treatment, providing no information on recommended usage, and ROBINS-I does a very poor job of accounting for the impact of confounding factorsK.
Our quality evaluation focuses on known issues and bias, and the potential impact on outcomes, rather than just the risk of bias. The estimated potential impact of each confounding factor, and the direction of the impact is considered. For example, consider a study that shows significantly lower risk, the value of the study varies significantly if confounding points to an underestimate or an overestimate of efficacy. In one case, the real effect may be null, while the other case provides stronger evidence of efficacy (which may be greater than the study shows). Analysis focusing on the risk of bias, while simpler, may penalize studies for theoretical or technical issues that have no or minimal impact on outcomes. Analysis also depends on the outcome, for example certain issues are less relevant for objective outcomes such as mortality. Inaccurate penalization, and inaccurate high-quality evaluation in the face of known major issues affecting outcomes, increases in significance during a pandemic when immediate recognition of new evidence is critical, and when considering all global studies, as required during a pandemic. Investigators in other countries may have different customs for design, analysis, and reporting, and different English language skills, however they may not be less diligent or have greater bias. Investigators in lower-pharmaceutical-profit countries may have lower bias towards profitable interventions.
Treatment time
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 effective74,75.
Living analysis
This is a living analysis and is updated regularly. Submit updates or corrections with the form below. We received no funding, this research is done in our spare time. We have no affiliation with any pharmaceutical companies, supplement companies, governments, political parties, or advocacy organizations.
A summary of study results is below. Please submit updates and corrections at the bottom of this page.
A summary of study results is below. Please submit updates and corrections at https://c19early.org/enmeta.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.
Katsuta, 4/30/2025, retrospective, Japan, peer-reviewed, 8 authors, study period 1 June, 2023 - 30 September, 2023.
Submit Corrections or Updates.
 recovery time, 10.4% lower, relative time 0.90, p = 0.02, treatment mean 6.9 (±1.6) n=60, control mean 7.7 (±1.9) n=42.
Luetkemeyer, 2/17/2025, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, 22 authors, SCORPIO-HR trial.
Submit Corrections or Updates.
 risk of death, 79.9% lower, RR 0.20, p = 0.50, treatment 0 of 1,037 (0.0%), control 2 of 1,048 (0.2%), NNT 524, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 168.
risk of hospitalization, 203.2% higher, RR 3.03, p = 0.37, treatment 3 of 1,037 (0.3%), control 1 of 1,048 (0.1%).
recovery time, 4.6% lower, relative time 0.95, p = 0.14, treatment 945, control 943.
risk of long COVID, 2.3% higher, RR 1.02, p = 0.80, treatment 256 of 1,037 (24.7%), control 253 of 1,048 (24.1%), day 84.
risk of no viral clearance, 18.7% lower, RR 0.81, p = 0.02, treatment 175 of 882 (19.8%), control 215 of 881 (24.4%), NNT 22, day 8.
risk of no viral clearance, 16.1% lower, RR 0.84, p < 0.001, treatment 420 of 835 (50.3%), control 517 of 862 (60.0%), NNT 10, day 4.
Mukae, 12/7/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Japan, peer-reviewed, 11 authors, study period 2 January, 2022 - 9 February, 2022, trial jRCT2031210350.
Submit Corrections or Updates.
 relative improvement in symptom score, 9.2% better, RR 0.91, p = 0.28, treatment mean 5.42 (±3.7) n=116, control mean 4.92 (±3.25) n=111, 250mg, Table 2.
relative improvement in symptom score, 17.3% better, RR 0.83, p = 0.04, treatment mean 5.95 (±4.02) n=114, control mean 4.92 (±3.25) n=111, 125mg, Table 2.
time to viral-, 32.4% lower, relative time 0.68, p < 0.001, treatment 113, control 108, relative time to first negative viral titer, 250mg, Figure 3.
time to viral-, 44.2% lower, relative time 0.56, p < 0.001, treatment 113, control 108, relative time to first negative viral titer, 125mg, Figure 3.
Mukae (B), 5/17/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Japan, preprint, 13 authors, study period 28 September, 2021 - 1 January, 2022, trial jRCT2031210350.
Submit Corrections or Updates.
 relative change in viral titer, 45.2% better, RR 0.55, p = 0.002, treatment mean 2.81 (±1.21) n=14, control mean 1.54 (±0.74) n=14, day 4, 250mg, primary outcome.
relative change in viral titer, 36.4% better, RR 0.64, p = 0.048, treatment mean 2.42 (±1.42) n=15, control mean 1.54 (±0.74) n=14, day 4, 125mg, primary outcome.
time to viral-, 44.8% lower, relative time 0.55, p = 0.02, treatment 15, control 14, 125mg.
time to viral-, 43.6% lower, relative time 0.56, p = 0.02, treatment 13, control 14, 250mg.
risk of no viral clearance, 54.2% lower, RR 0.46, p = 0.59, treatment 1 of 12 (8.3%), control 2 of 11 (18.2%), NNT 10, day 14, 250mg, Figure S1.
risk of no viral clearance, 10.0% higher, RR 1.10, p = 1.00, treatment 3 of 15 (20.0%), control 2 of 11 (18.2%), day 14, 125mg, Figure S1.
risk of no viral clearance, 80.0% lower, RR 0.20, p = 0.48, treatment 0 of 13 (0.0%), control 2 of 13 (15.4%), NNT 6.5, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 9, 250mg, Figure S1.
risk of no viral clearance, 53.6% lower, RR 0.46, p = 0.60, treatment 1 of 14 (7.1%), control 2 of 13 (15.4%), NNT 12, day 9, 125mg, Figure S1.
risk of no viral clearance, 53.6% lower, RR 0.46, p = 0.38, treatment 2 of 14 (14.3%), control 4 of 13 (30.8%), NNT 6.1, day 6, 250mg, Figure S1.
risk of no viral clearance, 89.6% lower, RR 0.10, p = 0.03, treatment 0 of 15 (0.0%), control 4 of 13 (30.8%), NNT 3.2, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 6, 125mg, Figure S1.
risk of no viral clearance, 80.0% lower, RR 0.20, p = 0.006, treatment 2 of 14 (14.3%), control 10 of 14 (71.4%), NNT 1.8, day 4, 250mg, Figure S1.
risk of no viral clearance, 62.7% lower, RR 0.37, p = 0.03, treatment 4 of 15 (26.7%), control 10 of 14 (71.4%), NNT 2.2, day 4, 125mg, Figure S1.
risk of no viral clearance, 9.1% lower, RR 0.91, p = 1.00, treatment 10 of 14 (71.4%), control 11 of 14 (78.6%), NNT 14, day 2, 250mg, Figure S1.
risk of no viral clearance, 10.3% higher, RR 1.10, p = 0.65, treatment 13 of 15 (86.7%), control 11 of 14 (78.6%), day 2, 125mg, Figure S1.
Nakano, 8/19/2026, Double Blind Randomized Controlled Trial, placebo-controlled, Japan, peer-reviewed, median age 10.0, 7 authors, trial jRCT2031230140.
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 recovery time, 3.9% lower, relative time 0.96, p = 0.84, treatment 140.5 [109.4-168] n=77, control 146.2 [92.0-188.9] n=37, median time to resolution of key symptoms, Kaplan-Meier.
viral load, 28.4% lower, relative load 0.72, p < 0.001, treatment mean 3.34 (±1.23) n=74, control mean 2.39 (±1.26) n=36, adjusted per study, "SARS-CoV-2 viral RNA reduction from baseline, log10 copies/mL, day 4.
Schilling, 5/21/2025, Randomized Controlled Trial, multiple countries, peer-reviewed, median age 31.0, 37 authors, study period 17 March, 2023 - 21 April, 2024, average treatment delay 1.8 days, trial NCT05041907 (history) (PLATCOV).
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 risk of hospitalization, 67.0% lower, RR 0.33, p = 0.49, treatment 0 of 197 (0.0%), control 1 of 191 (0.5%), NNT 191, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), COVID-19 related.
risk of hospitalization, 3.0% lower, RR 0.97, p = 1.00, treatment 2 of 197 (1.0%), control 2 of 191 (1.0%), NNT 3136, all cause.
recovery time, 8.5% lower, relative time 0.92, p = 0.006, treatment 5.4 [5.2-5.7] n=197, control 5.9 [5.6-6.1] n=191, all.
recovery time, 14.3% lower, relative time 0.86, p = 0.37, treatment 1.2 [0.9-1.6] n=197, control 1.4 [1.2-1.7] n=191, fever.
relative clearance half-life, 49.1% better, RR 0.51, p < 0.001, treatment median 5.9 IQR 4.6 n=201, control median 11.6 IQR 6.4 n=191, primary outcome.
Takazono, 6/28/2024, retrospective, Japan, peer-reviewed, 13 authors, study period November 2022 - July 2023.
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 risk of death, 23.7% higher, RR 1.24, p = 0.84, treatment 5,177, control 162,133, propensity score weighting.
risk of mechanical ventilation, 158.5% higher, RR 2.58, p = 0.20, treatment 5,177, control 162,133, propensity score weighting.
risk of ICU admission, 97.3% lower, RR 0.03, p = 0.63, treatment 0 of 5,177 (0.0%), control 35 of 162,133 (0.0%), NNT 4632, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of oxygen therapy, 36.5% lower, RR 0.64, p = 0.33, treatment 5,177, control 162,133, propensity score weighting.
risk of hospitalization, 37.1% lower, RR 0.63, p = 0.02, treatment 5,177, control 162,133, propensity score weighting.
Yotsuyanagi, 7/13/2023, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, mean age 35.7, 13 authors, study period 10 February, 2022 - 10 July, 2022, trial jRCT2031210350 (SCORPIO-SR).
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 risk of hospitalization, 0.8% higher, RR 1.01, p = 1.00, treatment 1 of 595 (0.2%), control 1 of 600 (0.2%), 250mg.
risk of hospitalization, 66.7% lower, RR 0.33, p = 0.50, treatment 0 of 603 (0.0%), control 1 of 600 (0.2%), NNT 600, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), 125mg.
recovery time, 11.4% lower, relative time 0.89, p = 0.30, treatment 577, control 572, 14 symptoms, randomized within 120 hours, 250mg.
recovery time, 10.1% lower, relative time 0.90, p = 0.46, treatment 582, control 572, 14 symptoms, randomized within 120 hours, 125mg.
recovery time, 17.9% lower, relative time 0.82, p = 0.05, treatment 330, control 321, 14 symptoms, randomized within 72 hours, 250mg.
recovery time, 19.0% lower, relative time 0.81, p = 0.03, treatment 336, control 321, 14 symptoms, randomized within 72 hours, 125mg.
recovery time, 13.3% lower, relative time 0.87, p = 0.35, treatment 577, control 572, 12 symptoms, randomized within 120 hours, 250mg.
recovery time, 9.7% lower, relative time 0.90, p = 0.76, treatment 582, control 572, 12 symptoms, randomized within 120 hours, 125mg.
recovery time, 13.3% lower, relative time 0.87, p = 0.08, treatment 330, control 321, 12 symptoms, randomized within 72 hours, 250mg.
recovery time, 15.9% lower, relative time 0.84, p = 0.07, treatment 336, control 321, 12 symptoms, randomized within 72 hours, 125mg.
relative change in viral load, 48.8% better, RR 0.51, p < 0.001, treatment 579, control 589, randomized within 120 hours, 250mg.
relative change in viral load, 48.8% better, RR 0.51, p < 0.001, treatment 592, control 589, randomized within 120 hours, 125mg.
relative change in viral load, 59.4% better, RR 0.41, p < 0.001, treatment 330, control 321, randomized within 72 hours, 250mg.
relative change in viral load, 59.3% better, RR 0.41, p < 0.001, treatment 336, control 321, randomized within 72 hours, 125mg.
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.
Baker, 4/22/2026, Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, median age 69.0, 55 authors, trial NCT05605093 (history) (STRIVE).
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 risk of death, 39.9% higher, RR 1.40, p = 0.36, treatment 18 of 293 (6.1%), control 13 of 296 (4.4%).
risk of no recovery, 22.0% higher, OR 1.22, p = 0.17, treatment 293, control 296, inverted to make OR<1 favor treatment, RR approximated with OR.
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.
Hayden (B), 3/9/2025, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, 16 authors, study period June 2023 - September 2024, trial NCT05897541 (history) (SCORPIO-PEP).
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 risk of hospitalization, 396.3% higher, RR 4.96, p = 0.50, treatment 2 of 1,030 (0.2%), control 0 of 1,011 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), all-cause, registry.
risk of symptomatic case, 67.6% lower, RR 0.32, p < 0.001, treatment 30 of 1,030 (2.9%), control 91 of 1,011 (9.0%), NNT 16.
risk of case, 58.0% lower, RR 0.42, p < 0.001, treatment 56 of 1,030 (5.4%), control 131 of 1,011 (13.0%), NNT 13, registry.
Footnotes
a.
Viral infection and replication involves attachment, entry, uncoating and release, genome replication and transcription, translation and protein processing, assembly and budding, and release. Each step can be disrupted by therapeutics.
b.
VeroE6/TMPRSS2 is a Vero E6 cell line engineered to express the human serine protease TMPRSS2, enabling SARS-CoV-2 S protein priming and entry.
c.
HEK293T/ACE2-TMPRSS2 is a human embryonic kidney cell line engineered to express human ACE2 and TMPRSS2, making it highly susceptible to SARS-CoV-2 infection.
d.
MucilAir cells are primary human nasal epithelial cells that mimic the structure and physiology of the human airway epithelium.
e.
A mouse model commonly used in infectious disease and cancer research due to higher immune response and susceptibility to infection.
f.
A rodent model used in SARS-CoV-2 research that replicates key aspects of human infection including efficient replication in the upper and lower respiratory tract.
g.
The original SARS-CoV-2 strain that emerged in Wuhan, China in late 2019. Also referred to as wild-type.
h.
A variant of concern first identified in India in late 2020, delta (B.1.617.2) transmitted more efficiently than previous variants. It contains spike mutations including L452R which increases binding to the ACE2 receptor.
i.
A highly transmissible variant of concern first detected in South Africa in late 2021. Omicron possesses many spike mutations which confer partial immune evasion, including deletions near the furin cleavage site.
j.
When administered late in infection, HCQ may enhance viral egress by further increasing lysosomal pH beyond the effect of ORF3a's water channel activity, thereby promoting lysosomal exocytosis, inactivating degradative enzymes, and facilitating the release of SARS-CoV-2 particles into the extracellular environment187,188. Research also suggests potential cardioprotective effects at lower doses, but cardiotoxicity with excessive dosage189. Bobrowski et al. also indicate negative effects if HCQ and remdesivir are combined.
k.
Peters (B) et al. is subject to confounding by calendar-time (SOC evolved rapidly early in the pandemic, the linear covariate does not reflect non-linear SOC changes and hospital specific effects), hospital type (non-treatment hospitals were tertiary university centers), confounding by indication (4/7 hospitals initiated treatment on deterioration), immortal-time bias for as-treated (exposure assigned after baseline), significant differences for other experimental treatments, potential overadjustment from collider bias (steroid use and indication bias), limited baseline severity information, differences in hospice referral propensity across hospitals, unadjusted difference in time from onset to admission, difference in PCR positivity, and other factors. Mahévas et al. is subject to confounding by hospital (treatment highly dependent on the hospital, different SOC/ICU transfer practices, not included in PS), immortal time (only partly addressed in sensitivity analysis), co-treatment differences, calendar-time (SOC evolved rapidly early in the pandemic), binary coding for age (age ≥65 despite steep age-risk gradient), residual imbalance (variables dropped from PS), a composite outcome dependent on hospital triage/capacity, and other factors.
References