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Casirivimab/imdevimab for COVID-19: real-time meta analysis of 24 studies
Covid Analysis, October 6, 2022, DRAFT
https://c19early.com/rmeta.html
 
0 0.5 1 1.5+ All studies 56% 24 48,169 Improvement, Studies, Patients Relative Risk Mortality 40% 8 32,929 Ventilation -1% 3 10,248 ICU admission 53% 3 9,896 Hospitalization 48% 11 39,822 Progression 56% 3 680 Recovery 33% 5 8,277 Cases 80% 4 3,265 Viral clearance 55% 2 1,709 RCTs 61% 9 21,306 RCT mortality 20% 3 15,162 Peer-reviewed 42% 14 33,029 Prophylaxis 93% 3 3,061 Early 51% 18 32,170 Late 33% 3 12,938 Casirivimab/imdevimab for COVID-19 c19early.com/r Oct 2022 Favorscasirivimab/im.. Favorscontrol after exclusions
Statistically significant improvements are seen for mortality, hospitalization, progression, recovery, cases, and viral clearance. 17 studies from 12 independent teams in 4 different countries show statistically significant improvements in isolation (7 for the most serious outcome).
Meta analysis using the most serious outcome reported shows 56% [37‑69%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and slightly worse for peer-reviewed studies. Results are consistent with early treatment being more effective than late treatment.
Results are robust — in exclusion sensitivity analysis 13 of 24 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
0 0.5 1 1.5+ All studies 56% 24 48,169 Improvement, Studies, Patients Relative Risk Mortality 40% 8 32,929 Ventilation -1% 3 10,248 ICU admission 53% 3 9,896 Hospitalization 48% 11 39,822 Progression 56% 3 680 Recovery 33% 5 8,277 Cases 80% 4 3,265 Viral clearance 55% 2 1,709 RCTs 61% 9 21,306 RCT mortality 20% 3 15,162 Peer-reviewed 42% 14 33,029 Prophylaxis 93% 3 3,061 Early 51% 18 32,170 Late 33% 3 12,938 Casirivimab/imdevimab for COVID-19 c19early.com/r Oct 2022 Favorscasirivimab/im.. Favorscontrol after exclusions
Efficacy is variant dependent. In Vitro studies suggest a lack of efficacy for omicron [Liu, Sheward, Tatham, VanBlargan]. Monoclonal antibody use with variants can be associated with prolonged viral loads, clinical deterioration, and immune escape [Choudhary].
No treatment, vaccine, or intervention is 100% effective and available. All practical, effective, and safe means should be used based on risk/benefit analysis. Multiple treatments are typically used in combination, and other treatments may be more effective. Only 29% of casirivimab/imdevimab studies show zero events with treatment.
All data to reproduce this paper and sources are in the appendix.
Highlights
Casirivimab/imdevimab reduces risk for COVID-19 with very high confidence for hospitalization, progression, recovery, and in pooled analysis, high confidence for mortality and ICU admission, and low confidence for cases and viral clearance. Efficacy is variant dependent. In Vitro research suggests a lack of efficacy for omicron.
We show traditional outcome specific analyses and combined evidence from all studies, incorporating treatment delay, a primary confounding factor in COVID-19 studies.
Real-time updates and corrections, transparent analysis with all results in the same format, consistent protocol for 47 treatments.
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Regeneron (RCT) 38% 0.62 [0.29-1.33] recov. time 92 (n) 91 (n) Improvement, RR [CI] Treatment Control Regeneron (RCT) 71% 0.29 [0.17-0.48] death/hosp. 18/1,355 62/1,341 Weinreich (RCT) 50% 0.50 [0.09-2.72] death 2/2,091 4/2,089 Webb 98% 0.0 [0.00-2e+04] death 0/115 57/5,536 Cooper 77% 0.23 [0.03-1.65] death 1/1,148 33/8,534 Kakinoki 58% 0.42 [0.17-0.92] progression 13/55 22/53 Komagamine 77% 0.23 [0.01-4.63] ventilation 0/53 2/75 Suzuki (PSM) -200% 3.00 [0.12-73.3] death 1/222 0/222 O'Brien (DB RCT) 85% 0.15 [0.01-2.78] hosp. 0/100 3/104 Shopen -46% 1.46 [0.73-2.67] severe case 24/116 26/243 Osugi 24% 0.76 [0.23-2.49] hosp. 4/30 15/74 Wei 61% 0.39 [0.26-0.60] death/hosp. 23/1,116 27/5,291 Wilden 82% 0.18 [0.05-0.50] hosp. n/a n/a Faraone 92% 0.08 [0.00-1.24] death 0/11 8/23 Miyashita 33% 0.67 [0.11-3.97] ventilation 2/461 3/461 Levey 31% 0.69 [0.07-7.37] ICU 1/36 2/50 Kneidinger 97% 0.0 [0.00-1e+04] severe case 0/3 34/215 Williams -21% 1.21 [0.14-9.86] oxygen 1/88 6/676 Tau​2 = 0.24, I​2 = 47.0%, p = 0.00039 Early treatment 51% 0.49 [0.33-0.72] 90/7,092 304/25,078 51% improvement Horby (RCT) 6% 0.94 [0.86-1.02] death 943/4,839 1,029/4,946 Improvement, RR [CI] Treatment Control Somersa.. (DB RCT) 36% 0.64 [0.44-0.93] death 59/804 45/393 McCreary (PSM) 93% 0.07 [0.01-0.51] death 1/652 29/1,304 Tau​2 = 0.15, I​2 = 80.8%, p = 0.16 Late treatment 33% 0.67 [0.39-1.17] 1,003/6,295 1,103/6,643 33% improvement Regeneron (RCT) 94% 0.06 [0.00-1.10] symp. case 0/186 8/223 Improvement, RR [CI] Treatment Control Regeneron (DB RCT) 92% 0.08 [0.00-1.36] hosp. 0/841 6/842 Isa (DB RCT) 93% 0.07 [0.01-0.28] symp. case 3/729 13/240 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Prophylaxis 93% 0.07 [0.03-0.21] 3/1,756 27/1,305 93% improvement All studies 56% 0.44 [0.31-0.63] 1,096/15,143 1,434/33,026 56% improvement 24 casirivimab/imdevimab COVID-19 studies c19early.com/r Oct 2022 Tau​2 = 0.32, I​2 = 73.1%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) Favors casirivimab/im.. Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Regeneron (RCT) 38% recovery Improvement Relative Risk [CI] Regeneron (RCT) 71% death/hosp. Weinreich (RCT) 50% death Webb 98% death Cooper 77% death Kakinoki 58% progression Komagamine 77% ventilation Suzuki (PSM) -200% death O'Brien (DB RCT) 85% hospitalization Shopen -46% severe case Osugi 24% hospitalization Wei 61% death/hosp. Wilden 82% hospitalization Faraone 92% death Miyashita 33% ventilation Levey 31% ICU admission Kneidinger 97% severe case Williams -21% oxygen therapy Tau​2 = 0.24, I​2 = 47.0%, p = 0.00039 Early treatment 51% 51% improvement Horby (RCT) 6% death Somersa.. (DB RCT) 36% death McCreary (PSM) 93% death Tau​2 = 0.15, I​2 = 80.8%, p = 0.16 Late treatment 33% 33% improvement Regeneron (RCT) 94% symp. case Regeneron (DB RCT) 92% hospitalization Isa (DB RCT) 93% symp. case Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Prophylaxis 93% 93% improvement All studies 56% 56% improvement 24 casirivimab/imdevimab COVID-19 studies c19early.com/r Oct 2022 Tau​2 = 0.32, I​2 = 73.1%, p < 0.0001 Effect extraction pre-specifiedRotate device for details Favors casirivimab/im.. Favors control
Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix. B. Scatter plot showing the distribution of effects reported in studies. C. History of all reported effects (chronological within treatment stages).
Introduction
We analyze all significant studies concerning the use of casirivimab/imdevimab 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, for studies within each treatment stage, for individual outcomes, for peer-reviewed studies, for Randomized Controlled Trials (RCTs), and after exclusions.
Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
Variant Dependence
Efficacy is variant dependent, for example in vitro studies suggest that casirivimab/imdevimab is not effective for the omicron variant [Liu, Sheward, Tatham, VanBlargan, Zhou].
Results
Figure 3 shows a visual overview of the results, with details in Table 1 and Table 2. Figure 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13 show forest plots for a random effects meta-analysis of all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, progression, recovery, cases, viral clearance, and peer reviewed studies.
0 0.5 1 1.5+ ALL STUDIES MORTALITY VENTILATION ICU ADMISSION HOSPITALIZATION PROGRESSION RECOVERY CASES VIRAL CLEARANCE RANDOMIZED CONTROLLED TRIALS RCT MORTALITY PEER-REVIEWED After Exclusions ALL STUDIES All Prophylaxis Early Late Casirivimab/imdevimab for COVID-19 C19EARLY.COM/R OCT 2022
Figure 3. Overview of results.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Early treatment 15 18 83.3% 51% improvement
RR 0.49 [0.33‑0.72]
p = 0.00039
Late treatment 3 3 100% 33% improvement
RR 0.67 [0.39‑1.17]
p = 0.16
Prophylaxis 3 3 100% 93% improvement
RR 0.07 [0.03‑0.21]
p < 0.0001
All studies 21 24 87.5% 56% improvement
RR 0.44 [0.31‑0.63]
p < 0.0001
Table 1. Results by treatment stage.
Studies Early treatment Late treatment Prophylaxis PatientsAuthors
All studies 2451% [28‑67%]33% [-17‑61%]93% [79‑97%] 48,169 371
With exclusions 2350% [25‑67%]33% [-17‑61%]93% [79‑97%] 38,487 362
Peer-reviewed 1457% [36‑71%]19% [-17‑44%] 33,029 229
Randomized Controlled TrialsRCTs 963% [42‑76%]19% [-17‑44%]93% [79‑97%] 21,306 178
Table 2. Results by treatment stage for all studies and with different exclusions.
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Figure 4. Random effects meta-analysis for all studies with pooled effects. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
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Figure 5. Random effects meta-analysis for mortality results.
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Figure 6. Random effects meta-analysis for ventilation.
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Figure 7. Random effects meta-analysis for ICU admission.
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Figure 8. Random effects meta-analysis for hospitalization.
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Figure 9. Random effects meta-analysis for progression.
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Figure 10. Random effects meta-analysis for recovery.
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Figure 11. Random effects meta-analysis for cases.
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Figure 12. Random effects meta-analysis for viral clearance.
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Figure 13. Random effects meta-analysis for peer reviewed studies. [Zeraatkar] analyze 356 COVID-19 trials, finding no significant evidence that peer-reviewed studies are more trustworthy. They also show extremely slow review times during a pandemic. Authors recommend using preprint evidence, with appropriate checks for potential falsified data, which provides higher certainty much earlier. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details.
Exclusions
To avoid bias in the selection of studies, we analyze all non-retracted studies. Here we show the results after excluding studies with major issues likely to alter results, non-standard studies, and studies where very minimal detail is currently available. Our bias evaluation is based on analysis of each study and identifying when there is a significant chance that limitations will substantially change the outcome of the study. We believe this can be more valuable than checklist-based approaches such as Cochrane GRADE, which may underemphasize serious issues not captured in the checklists, overemphasize issues unlikely to alter outcomes in specific cases (for example, lack of blinding for an objective mortality outcome, or certain specifics of randomization with a very large effect size), or be easily influenced by potential bias. However, they can also be very high quality.
The studies excluded are as below. Figure 14 shows a forest plot for random effects meta-analysis of all studies after exclusions.
[Cooper], unadjusted results with no group details.
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Figure 14. Random effects meta-analysis for all studies after exclusions. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
Randomized Controlled Trials (RCTs)
Figure 15 shows the distribution of results for Randomized Controlled Trials and other studies, and a chronological history of results. The median effect size for RCTs is 71% improvement, compared to 61% for other studies. Figure 16 and 17 show forest plots for a random effects meta-analysis of all Randomized Controlled Trials and RCT mortality results. Table 3 summarizes the results.
Figure 15. The distribution of results for Randomized Controlled Trials and other studies, and a chronological history of results.
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Figure 16. Random effects meta-analysis for all Randomized Controlled Trials. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
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Figure 17. Random effects meta-analysis for RCT mortality results.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Randomized Controlled Trials 9 9 100% 61% improvement
RR 0.39 [0.22‑0.68]
p = 0.00099
RCT mortality results 3 3 100% 20% improvement
RR 0.80 [0.58‑1.11]
p = 0.19
Table 3. Randomized Controlled Trial results.
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 hours [McLean, Treanor]. Figure 18 shows a mixed-effects meta-regression of efficacy as a function of treatment delay in COVID-19 casirivimab/imdevimab studies, with group estimates for early, late, and ICU studies that do not provide specific values. For comparison, Figure 19 shows a meta-regression for all studies providing specific values across 47 treatments. Efficacy declines rapidly with treatment delay. Early treatment is critical for COVID-19.
Figure 19. Meta-regression showing efficacy as a function of treatment delay in COVID-19 casirivimab/imdevimab studies. Early treatment is critical.
Figure 19. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 47 treatments. Early treatment is critical.
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 (as in [López-Medina]).
Effect measured.
Efficacy may differ significantly depending on the effect measured, for example a treatment may be very effective at reducing mortality, but less effective at minimizing cases or hospitalization. Or a treatment may have no effect on viral clearance while still being effective at reducing mortality.
Variants.
There are many different variants of SARS-CoV-2 and efficacy may depend critically on the distribution of variants encountered by the patients in a study. For example, the Gamma variant shows significantly different characteristics [Faria, Karita, Nonaka, Zavascki]. Different mechanisms of action may be more or less effective depending on variants, for example the viral entry process for the omicron variant has moved towards TMPRSS2-independent fusion, suggesting that TMPRSS2 inhibitors may be less effective [Peacock, Willett].
Regimen.
Effectiveness may depend strongly on the dosage and treatment regimen.
Other treatments.
The use of other treatments may significantly affect outcomes, including anything from supplements, other medications, or other kinds of treatment such as prone positioning.
Medication quality.
The quality of medications may vary significantly between manufacturers and production batches, which may significantly affect efficacy and safety. [Williams] analyze ivermectin from 11 different sources, showing highly variable antiparasitic efficacy across different manufacturers. [Xu] analyze a treatment from two different manufacturers, showing 9 different impurities, with significantly different concentrations for each manufacturer.
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 the treatment may be very effective when used earlier.
In general, by combining heterogeneous studies, as all meta analyses do, we run the risk of obscuring an effect by including studies where the treatment is less effective, not effective, or harmful.
When including studies where a treatment is less effective we expect the estimated effect size to be lower than that for the optimal case. We do not a priori expect that pooling all studies will create a positive result for an effective treatment. 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 pooled results for all studies, we also present individual outcome and treatment time analyses, which are more relevant for specific use cases.
Discussion
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).
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.
64% of retrospective studies report a statistically significant positive effect for one or more outcomes, compared to 80% of prospective studies, consistent with a bias toward publishing negative results. The median effect size for retrospective studies is 59% improvement, compared to 78% for prospective studies, suggesting a potential bias towards publishing results showing lower efficacy. Figure 20 shows a scatter plot of results for prospective and retrospective studies.
Figure 20. Prospective vs. retrospective studies.
Funnel plot analysis.
Funnel plots have traditionally been used for analyzing publication bias. This is invalid for COVID-19 acute treatment trials — the underlying assumptions are invalid, which we can demonstrate with a simple example. Consider a set of hypothetical perfect trials with no bias. Figure 21 plot A shows a funnel plot for a simulation of 80 perfect trials, with random group sizes, and each patient's outcome randomly sampled (10% control event probability, and a 30% effect size for treatment). Analysis shows no asymmetry (p > 0.05). In plot B, we add a single typical variation in COVID-19 treatment trials — treatment delay. Consider that efficacy varies from 90% for treatment within 24 hours, reducing to 10% when treatment is delayed 3 days. In plot B, each trial's treatment delay is randomly selected. Analysis now shows highly significant asymmetry, p < 0.0001, with six variants of Egger's test all showing p < 0.05 [Egger, Harbord, Macaskill, Moreno, Peters, Rothstein, Rücker, Stanley]. Note that these tests fail even though treatment delay is uniformly distributed. In reality treatment delay is more complex — each trial has a different distribution of delays across patients, and the distribution across trials may be biased (e.g., late treatment trials may be more common). Similarly, many other variations in trials may produce asymmetry, including dose, administration, duration of treatment, differences in SOC, comorbidities, age, variants, and bias in design, implementation, analysis, and reporting.
Figure 21. Example funnel plot analysis for simulated perfect trials.
Early/late vs. mild/moderate/severe.
Some analyses classify treatment based on early/late administration (as we do here), while others distinguish between mild/moderate/severe cases. We note that 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.
Conclusion
Casirivimab/imdevimab is an effective treatment for COVID-19. Statistically significant improvements are seen for mortality, hospitalization, progression, recovery, cases, and viral clearance. 17 studies from 12 independent teams in 4 different countries show statistically significant improvements in isolation (7 for the most serious outcome). Meta analysis using the most serious outcome reported shows 56% [37‑69%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and slightly worse for peer-reviewed studies. Results are consistent with early treatment being more effective than late treatment. Results are robust — in exclusion sensitivity analysis 13 of 24 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
Efficacy is variant dependent. In Vitro studies suggest a lack of efficacy for omicron [Liu, Sheward, Tatham, VanBlargan]. Monoclonal antibody use with variants can be associated with prolonged viral loads, clinical deterioration, and immune escape [Choudhary].
Study Notes
0 0.5 1 1.5 2+ Mortality 77% unadjusted Improvement Relative Risk ICU admission 48% unadjusted Hospitalization 52% unadjusted c19early.com/r Cooper et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Cooper] Retrospective 2,879 patients and matched controls in the USA, showing significantly lower mortality and hospitalization with bamlanivimab, bamlanivimab/etesevimab, and casirivimab/imdevimab. There was significantly lower hospitalization with casirivimab/imdevimab compared to bamlanivimab or bamlanivimab/etesevimab. PSM and multivariate analysis is only provided for all treatments combined.
0 0.5 1 1.5 2+ Mortality 92% Improvement Relative Risk Oxygen therapy 94% c19early.com/r Faraone et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Faraone] Retrospective 34 patients with hospital-acquired COVID-19, showing lower mortality and oxygen requirements with early casirivimab/imdevimab treatment.
0 0.5 1 1.5 2+ Mortality 6% Improvement Relative Risk Ventilation -1% Mortality (b) 21% Ventilation (b) 13% c19early.com/r Horby et al. Casirivimab/i.. for COVID-19 RCT LATE Favors casirivimab/im.. Favors control
[Horby] RCT 9,785 hospitalized patients in the UK showing lower mortality with casirivimab/imdevimab, with statistical significance reached for baseline seronegative patients.
0 0.5 1 1.5 2+ Symptomatic case 93% Improvement Relative Risk Case 93% c19early.com/r Isa et al. NCT04519437 Casirivimab/i.. for COVID-19 RCT Prophylaxis Favors casirivimab/im.. Favors control
[Isa] RCT 969 patients, 729 treated with monthly subcutaneous casirivimab/imdevimab, showing significantly lower risk of COVID-19 with treatment. There were no grade 3 injection site reactions or hypersensitivity reactions. Slightly more TEAEs were reported with treatment (54.9% vs. 48.3%), due to grade 1-2 ISRs. Serious adverse events were rare and occurred with similar percentages for treatment and control groups. There were no deaths. NCT04519437.
0 0.5 1 1.5 2+ Further treatment inclu.. 58% Improvement Relative Risk c19early.com/r Kakinoki et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Kakinoki] Retrospective 55 patients in Japan treated a median of 3 days from symptom onset with casirivimab/imdevimab, and 53 control patients, showing lower risk of further treatment including oxygen or antivirals.
0 0.5 1 1.5 2+ Severe case 97% Improvement Relative Risk c19early.com/r Kneidinger et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Kneidinger] Retrospective 218 COVID+ lung transplant patients in Germany, showing no significant difference in severe cases with early casirivimab/imdevimab use.
0 0.5 1 1.5 2+ Ventilation 77% Improvement Relative Risk ICU admission 92% Progression 68% primary Hospitalization time 29% c19early.com/r Komagamine et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Komagamine] Combined retrospective/prospective study in Japan with 53 casirivimab/imdevimab patients and 75 control patients, showing significantly lower progression with treatment.
0 0.5 1 1.5 2+ ICU admission 31% Improvement Relative Risk Oxygen therapy 7% Hospitalization -108% c19early.com/r Levey et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Levey] Retrospective 86 pregnant COVID-19 patients, 36 treated with casirivimab/imdevimab, showing no significant difference in COVID-19 outcomes with treatment.
0 0.5 1 1.5 2+ Mortality 93% Improvement Relative Risk Death/hospitalization 56% primary Hospitalization 48% Hospitalization/ER 40% SQ vs. IV death 53% SQ vs. IV death/hosp. -71% SQ vs. IV hospitalization -79% SQ vs. IV ER/hosp. 15% c19early.com/r McCreary et al. Casirivimab/i.. for COVID-19 LATE Favors casirivimab/im.. Favors control
[McCreary] Prospective study comparing subcutaneous and intravenous casirivimab/imdevimab, and comparing to a PSM matched control set, showing significantly lower mortality and hospitalization with treatment. Controls were matched with EUA-eligible risk factors only, authors were unable to determine symptom severity.
0 0.5 1 1.5 2+ Ventilation 33% Improvement Relative Risk Oxygen therapy 46% c19early.com/r Miyashita et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Miyashita] Retrospective 461 patients treated with casirivimab/imdevimab in Japan, and 461 matched controls, showing lower oxygen requirements with treatment.
0 0.5 1 1.5 2+ Hospitalization 85% Improvement Relative Risk Hospitalization/ER 92% Symptomatic case 33% primary Weeks with high viral load 40% c19early.com/r O'Brien et al. Casirivimab/i.. for COVID-19 RCT EARLY Favors casirivimab/im.. Favors control
[O'Brien] RCT 204 asymptomatic COVID+ patients, 100 treated with subcutaneous casirivimab/imdevimab, showing lower development of symptoms, lower hospitalization, and faster viral clearance with treatment. Study conducted prior to widespread circulation of delta and omicron in the study locations.
0 0.5 1 1.5 2+ Hospitalization 24% Improvement Relative Risk c19early.com/r Osugi et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Osugi] Retrospective 104 outpatients in Japan, 30 treated with casirivimab/imdevimab, showing no significant difference in hospitalization.
0 0.5 1 1.5 2+ Hospitalization 92% Improvement Relative Risk Case 81% Case (b) 82% Hospitalization/ER 89% Symptomatic case 81% Recovery time 62% Time to viral- 69% c19early.com/r Regeneron et al. NCT04452318 Casirivimab/i.. RCT Prophylaxis Favors casirivimab/im.. Favors control
[Regeneron (C)] Long-term results for PEP RCT NCT04452318, with 841 baseline seronegative casirivimab/imdevimab patients and 842 placebo patients, showing significantly lower cases with treatment.
0 0.5 1 1.5 2+ Symptomatic case 94% Improvement Relative Risk Case 48% c19early.com/r Regeneron et al. Casirivimab/i.. for COVID-19 RCT Prophylaxis Favors casirivimab/im.. Favors control
[Regeneron (D)] Interim results of REGEN-COV prophylaxis showing 100% prevention of symptomatic infection (8/223 placebo vs. 0/186 REGEN-COV), and approximately 50% lower overall rates of infection (symptomatic and asymptomatic) (23/223 placebo vs. 10/186 REGEN-COV).
0 0.5 1 1.5 2+ Death/hospitalization 71% Improvement Relative Risk Death/hospitalization (b) 70% Recovery time 29% Recovery time (b) 29% c19early.com/r Regeneron et al. Casirivimab/i.. for COVID-19 RCT EARLY Favors casirivimab/im.. Favors control
[Regeneron] Press release for new phase III data showing lower hospitalization/mortality, and faster symptom resolution among the subset of patients with at least one risk factor.

Some variants may escape antibodies [cell.com].
0 0.5 1 1.5 2+ Recovery time 38% Improvement Relative Risk Recovery time (b) 54% c19early.com/r Regeneron et al. Casirivimab/i.. for COVID-19 RCT EARLY Favors casirivimab/im.. Favors control
[Regeneron (B)] Analysis of the first 275 patients in a trial of the REGN-COV2 antibody cocktail showing reductions in viral load and the time to alleviate symptoms in non-hospitalized patients with COVID-19. Greatest improvements were seen with patients that had not mounted their own effective immune response prior to treatment.

The mean time-weighted-average change from baseline nasopharyngeal viral load through Day 7 in the seronegative (no measurable antiviral antibodies) group was a 0.60 log10 copies/mL greater reduction (p=0.03) in patients treated with high dose, and a 0.51 log10 copies/mL greater reduction (p=0.06) in patients treated with low dose, compared to placebo. In the overall population, there was a 0.51 log10 copies/mL greater reduction (p=0.0049) in patients treated with high dose, and a 0.23 log10 copies/mL greater reduction (p=0.20) in patients treated with low dose, compared to placebo.

Among seronegative patients, median time to symptom alleviation (defined as symptoms becoming mild or absent) was 13 days in placebo, 8 days in high dose (p=0.22), and 6 days in low dose (p=0.09).

Adverse reactions were similar with treatment and placebo. There were no deaths.
0 0.5 1 1.5 2+ Severe case -46% Improvement Relative Risk c19early.com/r Shopen et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Shopen] Retrospective 359 COVID+ patients in Israel, 116 treated with casirivimab/imdevimab, showing no significant difference with treatment in multivariable analysis.
0 0.5 1 1.5 2+ Mortality 36% Improvement Relative Risk Mortality (b) 56% Mortality (c) 21% Death/intubation 31% Discharge 30% c19early.com/r Somersan-Karakaya et al. NCT04426695 Casirivimab/i.. RCT LATE Favors casirivimab/im.. Favors control
[Somersan-Karakaya] RCT 1,336 hospitalized patients with symptom onset <=10 days on low-flow or no supplemental oxygen, showing lower mortality with treatment. Cohorts 2&3 were paused mid-trial due to increased deaths in the treatment arm and these results were not included. NCT04426695.
0 0.5 1 1.5 2+ Mortality -200% Improvement Relative Risk Mortality (b) 60% Progression 45% Progression (b) 50% c19early.com/r Suzuki et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Suzuki] Retrospective 949 patients in Japan, 314 treated with casirivimab/imdevimab showing significantly lower risk of deterioration with treatment.
0 0.5 1 1.5 2+ Mortality 98% Improvement Relative Risk Hospitalization 91% c19early.com/r Webb et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Webb] Retrospective 115 patients treated with casirivimab/imdevimab showing lower mortality, hospital admission, and emergency department visits with treatment. Authors falsely state that "no other COVID-19 therapies for ambulatory patients have proven effective".
0 0.5 1 1.5 2+ Death/hospitalization 61% Improvement Relative Risk Hospitalization 61% c19early.com/r Wei et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Wei] Retrospective 4,396 casirivimab/imdevimab patients in the USA, showing lower combined mortality/hospitalization (CDM database) and lower hospitalization (PMTX+ database) with treatment.
0 0.5 1 1.5 2+ Mortality 50% Improvement Relative Risk Mortality (b) 67% Mortality (c) -2% Death/hospitalization 71% Death/hospitalization (b) 70% Recovery time 29% Recovery time (b) 29% c19early.com/r Weinreich et al. NCT04425629 Casirivimab/i.. RCT EARLY Favors casirivimab/im.. Favors control
[Weinreich] RCT 4,057 outpatients with >=1 risk factor for severe disease, showing significantly lower combined hospitalization/death, and significantly faster recovery with treatment. Median time from onset of symptoms 3 days. NCT04425629.
0 0.5 1 1.5 2+ Hospitalization 82% Improvement Relative Risk c19early.com/r Wilden et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Wilden] Retrospective 395 patients in the USA receiving casirivimab/imdevimab or bamlanivimab, showing lower risk of hospitalization with treatment, statistically significant for casirivimab/imdevimab.
0 0.5 1 1.5 2+ Oxygen therapy -21% Improvement Relative Risk Severe case -1% Hospitalization 14% c19early.com/r Williams et al. Casirivimab/i.. for COVID-19 EARLY Favors casirivimab/im.. Favors control
[Williams (B)] Retrospective 764 pregnant patients with COVID-19 in the USA, 88 treated with casirivimab/imdevimab, showing no significant difference in outcomes.
We performed ongoing searches of PubMed, medRxiv, ClinicalTrials.gov, The Cochrane Library, Google Scholar, Collabovid, Research Square, ScienceDirect, Oxford University Press, the reference lists of other studies and meta-analyses, and submissions to the site c19early.com. Search terms were casirivimab, imdevimab, REGEN-COV, filtered for papers containing the terms COVID-19 or SARS-CoV-2. Automated searches are performed every few hours with notification of new matches. All studies regarding the use of casirivimab/imdevimab for COVID-19 that report a comparison with a control group are included in the main analysis. Sensitivity analysis is performed, excluding studies with major issues, epidemiological studies, and studies with minimal available information. This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies. If studies report multiple kinds of effects then the most serious outcome is used in pooled analysis, while other outcomes are included in the outcome specific analyses. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days are used. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms were not used (the next most serious outcome is used — no studies were excluded). 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 outcome is considered more important than PCR testing status. When basically all patients recover in both treatment and control groups, preference for viral clearance and recovery is given to results mid-recovery where available (after most or all patients have recovered there is no room for an effective treatment to do better). If only individual symptom data is available, the most serious symptom has priority, for example difficulty breathing or low SpO2 is more important than cough. When results provide an odds ratio, we computed the relative risk when possible, or converted to a relative risk according to [Zhang]. Reported confidence intervals and p-values were used when available, using adjusted values when provided. If multiple types of adjustments are reported including propensity score matching (PSM), the PSM results are used. Adjusted primary outcome results have preference over unadjusted results for a more serious outcome when the adjustments significantly alter results. When needed, conversion between reported p-values and confidence intervals followed [Altman, Altman (B)], and Fisher's exact test was used to calculate p-values for event data. If continuity correction for zero values is required, we use the reciprocal of the opposite arm with the sum of the correction factors equal to 1 [Sweeting]. Results are expressed with RR < 1.0 favoring treatment, and using the risk of a negative outcome when applicable (for example, the risk of death rather than the risk of survival). If studies only report relative continuous values such as relative times, the ratio of the time for the treatment group versus the time for the control group is used. Calculations are done in Python (3.10.7) with scipy (1.9.1), pythonmeta (1.26), numpy (1.23.3), statsmodels (0.13.2), and plotly (5.10.0).
Forest plots are computed using PythonMeta [Deng] with the DerSimonian and Laird random effects model (the fixed effect assumption is not plausible in this case) and inverse variance weighting. Mixed-effects meta-regression results are computed with R (4.1.2) using the metafor (3.0-2) and rms (6.2-0) packages, and using the most serious sufficiently powered outcome.
We received no funding, this research is done in our spare time. We have no affiliations with any pharmaceutical companies or political parties.
We have classified studies as early treatment if most patients are not already at a severe stage at the time of treatment (for example based on oxygen status or lung involvement), and treatment started within 5 days of the onset of symptoms. If studies contain a mix of early treatment and late treatment patients, we consider the treatment time of patients contributing most to the events (for example, consider a study where most patients are treated early but late treatment patients are included, and all mortality events were observed with late treatment patients). We note that a shorter time may be preferable. Antivirals are typically only considered effective when used within a shorter timeframe, for example 0-36 or 0-48 hours for oseltamivir, with longer delays not being effective [McLean, Treanor].
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.com/rmeta.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.
[Cooper], 10/8/2021, retrospective, USA, peer-reviewed, 9 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 77.5% lower, RR 0.23, p = 0.18, treatment 1 of 1,148 (0.1%), control 33 of 8,534 (0.4%), NNT 334, unadjusted.
risk of ICU admission, 47.5% lower, RR 0.52, p = 0.14, treatment 6 of 1,148 (0.5%), control 85 of 8,534 (1.0%), NNT 211, unadjusted.
risk of hospitalization, 52.4% lower, RR 0.48, p < 0.001, treatment 45 of 1,148 (3.9%), control 703 of 8,534 (8.2%), NNT 23, unadjusted.
[Faraone], 5/5/2022, retrospective, Italy, preprint, 12 authors, study period 25 October, 2020 - 30 April, 2021, average treatment delay 2.3 days. risk of death, 92.2% lower, RR 0.08, p = 0.03, treatment 0 of 11 (0.0%), control 8 of 23 (34.8%), NNT 2.9, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of oxygen therapy, 94.5% lower, RR 0.06, p = 0.02, treatment 0 of 11 (0.0%), control 15 of 23 (65.2%), NNT 1.5, odds ratio converted to relative risk, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
[Kakinoki], 11/4/2021, retrospective, Japan, peer-reviewed, 16 authors, average treatment delay 3.0 days. risk of further treatment including oxygen or antivirals, 57.6% lower, RR 0.42, p = 0.049, treatment 13 of 55 (23.6%), control 22 of 53 (41.5%), NNT 5.6, adjusted per study, odds ratio converted to relative risk, multivariable.
[Kneidinger], 9/9/2022, retrospective, Germany, peer-reviewed, 11 authors, study period 1 January, 2022 - 20 March, 2022, lung transplant patients. risk of severe case, 97.2% lower, RR 0.03, p = 0.45, treatment 0 of 3 (0.0%), control 34 of 215 (15.8%), NNT 6.3, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
[Komagamine], 12/19/2021, retrospective, Japan, peer-reviewed, 4 authors, average treatment delay 5.0 days. risk of mechanical ventilation, 77.3% lower, RR 0.23, p = 0.51, treatment 0 of 53 (0.0%), control 2 of 75 (2.7%), NNT 38, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of ICU admission, 92.3% lower, RR 0.08, p = 0.04, treatment 0 of 53 (0.0%), control 7 of 75 (9.3%), NNT 11, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of progression, 67.8% lower, RR 0.32, p = 0.006, treatment 8 of 53 (15.1%), control 33 of 75 (44.0%), NNT 3.5, adjusted per study, odds ratio converted to relative risk, multivariable, primary outcome.
hospitalization time, 28.9% lower, relative time 0.71, p < 0.001, treatment 53, control 75.
[Levey], 6/4/2022, retrospective, USA, peer-reviewed, 6 authors, study period March 2021 - October 2021. risk of ICU admission, 30.6% lower, RR 0.69, p = 1.00, treatment 1 of 36 (2.8%), control 2 of 50 (4.0%), NNT 82.
risk of oxygen therapy, 7.4% lower, RR 0.93, p = 1.00, treatment 2 of 36 (5.6%), control 3 of 50 (6.0%), NNT 225.
risk of hospitalization, 108.3% higher, RR 2.08, p = 0.15, treatment 9 of 36 (25.0%), control 6 of 50 (12.0%).
[Miyashita], 5/26/2022, retrospective, Japan, peer-reviewed, 6 authors, average treatment delay 4.0 days. risk of mechanical ventilation, 33.3% lower, RR 0.67, p = 1.00, treatment 2 of 461 (0.4%), control 3 of 461 (0.7%), NNT 461.
risk of oxygen therapy, 46.4% lower, RR 0.54, p = 0.004, treatment 30 of 461 (6.5%), control 56 of 461 (12.1%), NNT 18.
[O'Brien], 1/14/2022, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, 38 authors, study period 13 July, 2020 - 28 January, 2021. risk of hospitalization, 85.5% lower, RR 0.15, p = 0.25, treatment 0 of 100 (0.0%), control 3 of 104 (2.9%), NNT 35, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of hospitalization/ER, 92.2% lower, RR 0.08, p = 0.03, treatment 0 of 100 (0.0%), control 6 of 104 (5.8%), NNT 17, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of symptomatic case, 33.0% lower, RR 0.67, p = 0.04, treatment 29 of 100 (29.0%), control 44 of 104 (42.3%), NNT 7.5, odds ratio converted to relative risk, day 14, primary outcome.
relative weeks with high viral load, 39.7% better, RR 0.60, p = 0.001, treatment 100, control 104.
[Osugi], 2/3/2022, retrospective, Japan, peer-reviewed, mean age 47.8, 5 authors, study period 31 August, 2021 - 27 September, 2021. risk of hospitalization, 24.0% lower, HR 0.76, p = 0.65, treatment 4 of 30 (13.3%), control 15 of 74 (20.3%), adjusted per study, multivariable, Cox proportional hazards.
[Regeneron], 3/23/2021, Randomized Controlled Trial, USA, preprint, 1 author. risk of death/hospitalization, 71.3% lower, RR 0.29, p < 0.001, treatment 18 of 1,355 (1.3%), control 62 of 1,341 (4.6%), NNT 30, 2,400mg IV, >=1 risk factor.
risk of death/hospitalization, 70.4% lower, RR 0.30, p = 0.003, treatment 7 of 736 (1.0%), control 24 of 748 (3.2%), NNT 44, 1,200mg IV, >=1 risk factor.
recovery time, 28.6% lower, relative time 0.71, p < 0.001, treatment 1,355, control 1,341, 2,400mg IV, >=1 risk factor.
recovery time, 28.6% lower, relative time 0.71, p < 0.001, treatment 736, control 748, 1,200mg IV, >=1 risk factor.
[Regeneron (B)], 9/29/2020, Randomized Controlled Trial, USA, preprint, 1 author. recovery time, 38.0% lower, relative time 0.62, p = 0.22, treatment 92, control 91, high dose median time to recovery, group sizes estimated because they were not supplied.
recovery time, 54.0% lower, relative time 0.46, p = 0.09, treatment 92, control 91, low dose median time to recovery, group sizes estimated because they were not supplied.
[Shopen], 1/31/2022, retrospective, Israel, preprint, 11 authors, study period June 2021 - September 2021. risk of severe case, 45.6% higher, RR 1.46, p = 0.26, treatment 24 of 116 (20.7%), control 26 of 243 (10.7%), adjusted per study, odds ratio converted to relative risk.
[Suzuki], 12/21/2021, retrospective, Japan, preprint, 49 authors, study period 24 July, 2021 - 30 September, 2021. risk of death, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 222 (0.5%), control 0 of 222 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), propensity score matching.
risk of death, 59.6% lower, RR 0.40, p = 0.67, treatment 1 of 314 (0.3%), control 5 of 635 (0.8%), NNT 213, unadjusted.
risk of progression, 45.2% lower, RR 0.55, p = 0.02, treatment 17 of 222 (7.7%), control 31 of 222 (14.0%), NNT 16, propensity score matching.
risk of progression, 49.9% lower, RR 0.50, p = 0.002, treatment 34 of 314 (10.8%), control 70 of 365 (19.2%), NNT 12, odds ratio converted to relative risk, multivariate.
[Webb], 6/23/2021, retrospective, USA, peer-reviewed, 14 authors. risk of death, 98.3% lower, RR 0.02, p = 0.63, treatment 0 of 115 (0.0%), control 57 of 5,536 (1.0%), NNT 97, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of hospitalization, 91.1% lower, RR 0.09, p < 0.001, treatment 1 of 115 (0.9%), control 538 of 5,536 (9.7%), NNT 11.
[Wei], 2/28/2022, retrospective, database analysis, USA, preprint, 8 authors, study period December 2020 - June 2021. risk of death/hospitalization, 61.0% lower, HR 0.39, p < 0.001, treatment 23 of 1,116 (2.1%), control 27 of 5,291 (0.5%), Optum CDM, Cox proportional hazards.
risk of hospitalization, 61.0% lower, HR 0.39, p < 0.001, treatment 59 of 3,280 (1.8%), control 75 of 16,284 (0.5%), IQVIA PMTX+, Cox proportional hazards.
[Weinreich], 5/21/2021, Randomized Controlled Trial, USA, peer-reviewed, 39 authors, average treatment delay 3.0 days, trial NCT04425629 (history). risk of death, 50.0% lower, RR 0.50, p = 0.45, treatment 2 of 2,091 (0.1%), control 4 of 2,089 (0.2%), NNT 1044, Table S9.
risk of death, 67.0% lower, RR 0.33, p = 0.37, treatment 1 of 1,355 (0.1%), control 3 of 1,341 (0.2%), NNT 667, 2400mg,Table S9.
risk of death, 1.6% higher, RR 1.02, p = 1.00, treatment 1 of 736 (0.1%), control 1 of 748 (0.1%), 1200mg,Table S9.
risk of death/hospitalization, 71.3% lower, RR 0.29, p < 0.001, treatment 18 of 1,355 (1.3%), control 62 of 1,341 (4.6%), NNT 30, 2400mg.
risk of death/hospitalization, 70.4% lower, RR 0.30, p = 0.002, treatment 7 of 736 (1.0%), control 24 of 748 (3.2%), NNT 44, 1200mg.
recovery time, 28.6% lower, relative time 0.71, p < 0.001, treatment 1,355, control 1,341, 2400mg.
recovery time, 28.6% lower, relative time 0.71, p < 0.001, treatment 736, control 748, 1200mg.
[Wilden], 3/31/2022, retrospective, USA, peer-reviewed, 9 authors, study period December 2020 - July 2021. risk of hospitalization, 82.0% lower, OR 0.18, p = 0.004, adjusted per study, multivariable, RR approximated with OR.
[Williams (B)], 9/12/2022, retrospective, USA, peer-reviewed, 6 authors. risk of oxygen therapy, 20.8% higher, RR 1.21, p = 0.87, treatment 1 of 88 (1.1%), control 6 of 676 (0.9%), odds ratio converted to relative risk.
risk of severe case, 1.0% higher, RR 1.01, p = 0.99, treatment 1 of 88 (1.1%), control 7 of 676 (1.0%), odds ratio converted to relative risk.
risk of hospitalization, 13.9% lower, RR 0.86, p = 0.90, treatment 1 of 88 (1.1%), control 8 of 676 (1.2%), NNT 2125, odds ratio converted to relative risk.
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.
[Horby], 6/16/2021, Randomized Controlled Trial, United Kingdom, peer-reviewed, 32 authors, study period 18 September, 2020 - 22 May, 2021, average treatment delay 9.0 days. risk of death, 6.0% lower, RR 0.94, p = 0.16, treatment 943 of 4,839 (19.5%), control 1,029 of 4,946 (20.8%), NNT 76, all patients.
risk of mechanical ventilation, 1.0% higher, RR 1.01, p = 0.88, treatment 484 of 4,556 (10.6%), control 488 of 4,642 (10.5%), all patients.
risk of death, 21.0% lower, RR 0.79, p = 0.001, treatment 396 of 1,633 (24.2%), control 452 of 1,520 (29.7%), NNT 18, seronegative patients.
risk of mechanical ventilation, 13.0% lower, RR 0.87, p = 0.13, treatment 190 of 1,599 (11.9%), control 202 of 1,484 (13.6%), NNT 58, seronegative patients.
[McCreary], 12/1/2021, prospective, USA, preprint, 27 authors, study period 14 July, 2021 - 26 October, 2021, average treatment delay 6.0 days. risk of death, 93.0% lower, RR 0.07, p = 0.009, treatment 1 of 652 (0.2%), control 29 of 1,304 (2.2%), NNT 48, propensity score matching.
risk of death/hospitalization, 56.0% lower, RR 0.44, p < 0.001, treatment 22 of 652 (3.4%), control 101 of 1,304 (7.7%), NNT 23, propensity score matching, primary outcome.
risk of hospitalization, 48.0% lower, RR 0.52, p = 0.005, treatment 22 of 652 (3.4%), control 85 of 1,304 (6.5%), NNT 32, propensity score matching.
risk of hospitalization/ER, 40.0% lower, RR 0.60, p = 0.003, treatment 40 of 652 (6.1%), control 133 of 1,304 (10.2%), NNT 25, propensity score matching.
[Somersan-Karakaya], 11/8/2021, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, median age 62.0, 34 authors, study period 10 June, 2020 - 9 April, 2021, average treatment delay 6.0 days, trial NCT04426695 (history), conflicts of interest: research funding from the drug patent holder, employee of the drug patent holder. risk of death, 35.9% lower, RR 0.64, p = 0.02, treatment 59 of 804 (7.3%), control 45 of 393 (11.5%), NNT 24, day 28, mFAS.
risk of death, 55.6% lower, RR 0.44, p = 0.005, treatment 24 of 360 (6.7%), control 24 of 160 (15.0%), NNT 12, seronegative, day 28, mFAS.
risk of death, 21.3% lower, RR 0.79, p = 0.42, treatment 26 of 369 (7.0%), control 18 of 201 (9.0%), NNT 52, seropositive, day 28, mFAS.
risk of death/intubation, 30.9% lower, RR 0.69, p = 0.03, treatment 82 of 804 (10.2%), control 58 of 393 (14.8%), NNT 22, day 1-29, mFAS.
risk of no hospital discharge, 30.2% lower, RR 0.70, p = 0.02, treatment 90 of 804 (11.2%), control 63 of 393 (16.0%), NNT 21, day 1-29, mFAS.
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.
[Isa], 11/16/2021, Double Blind Randomized Controlled Trial, USA, preprint, 31 authors, trial NCT04519437 (history), conflicts of interest: employee of the drug patent holder. risk of symptomatic case, 92.6% lower, RR 0.07, p = 0.002, treatment 3 of 729 (0.4%), control 13 of 240 (5.4%), NNT 20, odds ratio converted to relative risk.
risk of case, 92.7% lower, RR 0.07, p = 0.002, treatment 0 of 729 (0.0%), control 10 of 240 (4.2%), NNT 24, odds ratio converted to relative risk, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), seroconversion.
[Regeneron (C)], 11/8/2021, Double Blind Randomized Controlled Trial, multiple countries, preprint, 1 author, trial NCT04452318 (history). risk of hospitalization, 92.3% lower, RR 0.08, p = 0.03, treatment 0 of 841 (0.0%), control 6 of 842 (0.7%), NNT 140, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), 8 months.
risk of case, 81.5% lower, RR 0.19, p < 0.001, treatment 20 of 841 (2.4%), control 108 of 842 (12.8%), NNT 9.6, months 1-8.
risk of case, 81.6% lower, RR 0.18, p < 0.001, treatment 7 of 841 (0.8%), control 38 of 842 (4.5%), NNT 27, months 2-8.
risk of hospitalization/ER, 88.9% lower, RR 0.11, p = 0.06, treatment 0 of 753 (0.0%), control 4 of 752 (0.5%), NNT 188, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 29.
risk of symptomatic case, 81.4% lower, RR 0.19, p < 0.001, treatment 11 of 753 (1.5%), control 59 of 752 (7.8%), NNT 16, day 29.
recovery time, 62.5% lower, relative time 0.37, p < 0.001, treatment 753, control 752, short-term followup, relative time with symptoms.
time to viral-, 69.2% lower, relative time 0.31, p < 0.001, treatment 753, control 752, short-term followup, relative time with high viral load.
[Regeneron (D)], 1/26/2021, Randomized Controlled Trial, USA, preprint, 1 author. risk of symptomatic case, 93.6% lower, RR 0.06, p = 0.009, treatment 0 of 186 (0.0%), control 8 of 223 (3.6%), NNT 28, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of case, 47.9% lower, RR 0.52, p = 0.07, treatment 10 of 186 (5.4%), control 23 of 223 (10.3%), NNT 20.
Supplementary Data
References
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