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Peginterferon Lambda for COVID-19: real-time meta analysis of 4 studies

@CovidAnalysis, June 2024, Version 7V7
 
0 0.5 1 1.5+ All studies 7% 4 2,143 Improvement, Studies, Patients Relative Risk Mortality 27% 1 1,949 ICU admission -200% 1 14 Hospitalization 25% 4 2,143 Viral clearance 44% 3 193 RCTs 7% 4 2,143 Early 17% 3 2,129 Late -200% 1 14 Peginterferon Lambda for COVID-19 c19early.org June 2024 Favorspeg.. lambda Favorscontrol
Abstract
Meta analysis using the most serious outcome reported shows 7% [-138‑63%] lower risk, without reaching statistical significance. Early treatment is more effective than late treatment. Currently all studies are RCTs.
2 studies from 2 independent teams in 2 countries show significant improvements.
Currently there is limited data, with only 9 control events for the most serious outcome in trials to date.
The primary positive trial1 has major anomolies2. Results from NCT04967430 have not been reported and contact information was deleted in the registry.
No treatment or intervention is 100% effective. All practical, effective, and safe means should be used based on risk/benefit analysis. Multiple treatments are typically used in combination, and other treatments are significantly more effective.
All data to reproduce this paper and sources are in the appendix.
Evolution of COVID-19 clinical evidence Peginterferon Lambda p=0.89 Acetaminophen p=0.00000029 2020 2021 2022 2023 Effective Harmful c19early.org June 2024 meta analysis results (pooled effects) 100% 50% 0% -50%
Peginterferon Lambda for COVID-19 — Highlights
Meta analysis of studies to date shows no significant improvements with peginterferon lambda.
Outcome specific analyses and combined evidence from all studies, incorporating treatment delay, a primary confounding factor.
Real-time updates and corrections, transparent analysis with all results in the same format, consistent protocol for 75 treatments.
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Feld (DB RCT) 0% 1.00 [0.07-15.3] hosp. 1/30 1/30 Improvement, RR [CI] Treatment Control Jagannat.. (SB RCT) 0% 1.00 [0.15-6.87] hosp. 2/60 2/60 TOGETHER Reis (DB RCT) 27% 0.73 [0.21-2.58] death 4/931 6/1,018 Tau​2 = 0.00, I​2 = 0.0%, p = 0.71 Early treatment 17% 0.83 [0.31-2.21] 7/1,021 9/1,108 17% lower risk Kim (SB RCT) -200% 3.00 [0.14-63.2] ICU 1/7 0/7 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.49 Late treatment -200% 3.00 [0.14-63.2] 1/7 0/7 200% higher risk All studies 7% 0.93 [0.37-2.38] 8/1,028 9/1,115 7% lower risk 4 peginterferon lambda COVID-19 studies c19early.org June 2024 Tau​2 = 0.00, I​2 = 0.0%, p = 0.89 Effect extraction pre-specified(most serious outcome, see appendix) Favors peg.. lambda Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Feld (DB RCT) 0% hospitalization Improvement Relative Risk [CI] Jaganna.. (SB RCT) 0% hospitalization TOGETHER Reis (DB RCT) 27% death Tau​2 = 0.00, I​2 = 0.0%, p = 0.71 Early treatment 17% 17% lower risk Kim (SB RCT) -200% ICU admission Tau​2 = 0.00, I​2 = 0.0%, p = 0.49 Late treatment -200% 200% higher risk All studies 7% 7% lower risk 4 peginterferon lambda C19 studies c19early.org June 2024 Tau​2 = 0.00, I​2 = 0.0%, p = 0.89 Effect extraction pre-specifiedRotate device for details Favors peg.. lambda Favors control
B
-100% -50% 0% 50% 100% Timeline of COVID-19 peginterferon lambda studies (pooled effects) 2020 2021 2022 2023 Favorspeg.. lambda Favorscontrol c19early.org June 2024
Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. For details see the appendix. B. Timeline of results in peginterferon lambda studies.
Introduction
SARS-CoV-2 infection primarily begins in the upper respiratory tract and may progress to the lower respiratory tract, other tissues, and the nervous and cardiovascular systems, which may lead to cytokine storm, pneumonia, ARDS, neurological injury3-10 and cognitive deficits5,10, cardiovascular complications11, organ failure, and death. Minimizing replication as early as possible is recommended.
SARS-CoV-2 infection and replication involves the complex interplay of 50+ host and viral proteins and other factorsA,12-16, providing many therapeutic targets for which many existing compounds have known activity. Scientists have predicted that over 7,000 compounds may reduce COVID-19 risk17, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications.
We analyze all significant controlled studies of peginterferon lambda 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, and Randomized Controlled Trials (RCTs).
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.
Results
Table 1 summarizes the results for all stages combined, for Randomized Controlled Trials, and for specific outcomes. Table 2 shows results by treatment stage. Figure 3 plots individual results by treatment stage. Figure 4, 5, 6, 7, 8, 9, and 10 show forest plots for random effects meta-analysis of all studies with pooled effects, mortality results, ICU admission, hospitalization, progression, recovery, and viral clearance.
Table 1. Random effects meta-analysis for all stages combined, for Randomized Controlled Trials, and for specific outcomes. Results show the percentage improvement with treatment and the 95% confidence interval.
Improvement Studies Patients Authors
All studies7% [-138‑63%]4 2,143 112
Randomized Controlled TrialsRCTs7% [-138‑63%]4 2,143 112
HospitalizationHosp.25% [-14‑51%]4 2,143 112
Viral44% [-17‑73%]3 193 71
RCT hospitalizationRCT hosp.25% [-14‑51%]4 2,143 112
Table 2. Random effects meta-analysis results by treatment stage. Results show the percentage improvement with treatment, the 95% confidence interval, and the number of studies for the stage.treatment and the 95% confidence interval.
Early treatment Late treatment
All studies17% [-121‑69%]-200% [-6215‑86%]
Randomized Controlled TrialsRCTs17% [-121‑69%]-200% [-6215‑86%]
HospitalizationHosp.39% [-0‑63%]-25% [-173‑43%]
Viral58% [-6‑83%]12% [-144‑69%]
RCT hospitalizationRCT hosp.39% [-0‑63%]-25% [-173‑43%]
0 0.25 0.5 0.75 1 1.25 1.5+ All studies Late treatment Early treatment Efficacy in COVID-19 peginterferon lambda studies (pooled effects) Favors peg.. lambda Favors control c19early.org June 2024
Figure 3. Scatter plot showing the most serious outcome in all studies, and for studies within each stage. Diamonds shows the results of random effects meta-analysis.
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Figure 4. Random effects meta-analysis for all studies. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. For details see the appendix.
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Figure 5. Random effects meta-analysis for mortality results.
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Figure 6. Random effects meta-analysis for ICU admission.
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Figure 7. Random effects meta-analysis for hospitalization.
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Figure 8. Random effects meta-analysis for progression.
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Figure 9. Random effects meta-analysis for recovery.
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Figure 10. Random effects meta-analysis for viral clearance.
Randomized Controlled Trials (RCTs)
Currently all studies are RCTs.
Heterogeneity
Heterogeneity in COVID-19 studies arises from many factors including:
The time between infection or the onset of symptoms and treatment may critically affect how well a treatment works. For example an antiviral may be very effective when used early but may not be effective in late stage disease, and may even be harmful. Oseltamivir, for example, is generally only considered effective for influenza when used within 0-36 or 0-48 hours18,19. Baloxavir studies for influenza also show that treatment delay is critical — Ikematsu et al. report an 86% reduction in cases for post-exposure prophylaxis, Hayden et al. show a 33 hour reduction in the time to alleviation of symptoms for treatment within 24 hours and a reduction of 13 hours for treatment within 24-48 hours, and Kumar et al. report only 2.5 hours improvement for inpatient treatment.
Table 3. Studies of baloxavir for influenza show that early treatment is more effective.
Treatment delayResult
Post-exposure prophylaxis86% fewer cases20
<24 hours-33 hours symptoms21
24-48 hours-13 hours symptoms21
Inpatients-2.5 hours to improvement22
Figure 11 shows a mixed-effects meta-regression for efficacy as a function of treatment delay in COVID-19 studies from 75 treatments, showing that efficacy declines rapidly with treatment delay. Early treatment is critical for COVID-19.
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Figure 11. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 75 treatments.
Details of the patient population including age and comorbidities may critically affect how well a treatment works. For example, many COVID-19 studies with relatively young low-comorbidity patients show all patients recovering quickly with or without treatment. In such cases, there is little room for an effective treatment to improve results, for example as in López-Medina et al.
Efficacy may depend critically on the distribution of SARS-CoV-2 variants encountered by patients. Risk varies significantly across variants24, for example the Gamma variant shows significantly different characteristics25-28. 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 variants29,30.
Effectiveness may depend strongly on the dosage and treatment regimen.
The use of other treatments may significantly affect outcomes, including supplements, other medications, or other interventions such as prone positioning. Treatments may be synergistic31-41, therefore efficacy may depend strongly on combined treatments.
The quality of medications may vary significantly between manufacturers and production batches, which may significantly affect efficacy and safety. Williams et al. analyze ivermectin from 11 different sources, showing highly variable antiparasitic efficacy across different manufacturers. Xu et al. analyze a treatment from two different manufacturers, showing 9 different impurities, with significantly different concentrations for each manufacturer.
Across all studies there is a strong association between different outcomes, for example improved recovery is strongly associated with lower mortality. However, efficacy may differ depending on the effect measured, for example a treatment may be more effective against secondary complications and have minimal effect on viral clearance.
The distribution of studies will alter the outcome of a meta analysis. Consider a simplified example where everything is equal except for the treatment delay, and effectiveness decreases to zero or below with increasing delay. If there are many studies using very late treatment, the outcome may be negative, even though early treatment is very effective. All meta analyses combine heterogeneous studies, varying in population, variants, and potentially all factors above, and therefore may obscure efficacy by including studies where treatment is less effective. Generally, we expect the estimated effect size from meta analysis to be less than that for the optimal case. Looking at all studies is valuable for providing an overview of all research, important to avoid cherry-picking, and informative when a positive result is found despite combining less-optimal situations. However, the resulting estimate does not apply to specific cases such as early treatment in high-risk populations. While we present results for all studies, we also present treatment time and individual outcome analyses, which may be more informative for specific use cases.
Pooled Effects
For COVID-19, delay in clinical results translates into additional death and morbidity, as well as additional economic and societal damage. Combining the results of studies reporting different outcomes is required. There may be no mortality in a trial with low-risk patients, however a reduction in severity or improved viral clearance may translate into lower mortality in a high-risk population. Different studies may report lower severity, improved recovery, and lower mortality, and the significance may be very high when combining the results. "The studies reported different outcomes" is not a good reason for disregarding results.
We present both specific outcome and pooled analyses. In order to combine the results of studies reporting different outcomes we use the most serious outcome reported in each study, based on the thesis that improvement in the most serious outcome provides comparable measures of efficacy for a treatment. A critical advantage of this approach is simplicity and transparency. There are many other ways to combine evidence for different outcomes, along with additional evidence such as dose-response relationships, however these increase complexity.
Another way to view pooled analysis is that we are using more of the available information. Logically we should, and do, use additional information. For example dose-response and treatment delay-response relationships provide significant additional evidence of efficacy that is considered when reviewing the evidence for a treatment.
Trials with high-risk patients may be restricted due to ethics for treatments that are known or expected to be effective, and they increase difficulty for recruiting. Using less severe outcomes as a proxy for more serious outcomes allows faster collection of evidence.
For many COVID-19 treatments, a reduction in mortality logically follows from a reduction in hospitalization, which follows from a reduction in symptomatic cases, which follows from a reduction in PCR positivity. We can directly test this for COVID-19.
Analysis of the the association between different outcomes across studies from all 75 treatments we cover confirms the validity of pooled outcome analysis for COVID-19. Figure 12 shows that lower hospitalization is very strongly associated with lower mortality (p < 0.000000000001). Similarly, Figure 13 shows that improved recovery is very strongly associated with lower mortality (p < 0.000000000001). Considering the extremes, Singh et al. show an association between viral clearance and hospitalization or death, with p = 0.003 after excluding one large outlier from a mutagenic treatment, and based on 44 RCTs including 52,384 patients. Figure 14 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 = 0.0000014 to p = 0.000000005.
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Figure 12. Lower hospitalization is associated with lower mortality, supporting pooled outcome analysis.
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Figure 13. Improved recovery is associated with lower mortality, supporting pooled outcome analysis.
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Figure 12. Improved viral clearance is associated with fewer serious outcomes, supporting pooled outcome analysis.
Currently, 46 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 91% of these have been confirmed with one or more specific outcomes, with a mean delay of 5.0 months. When restricting to RCTs only, 54% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 6.4 months. Figure 15 shows when treatments were found effective during the pandemic. Pooled outcomes often resulted in earlier detection of efficacy.
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Figure 15. The time when studies showed that treatments were effective, defined as statistically significant improvement of ≥10% from ≥3 studies. Pooled results typically show efficacy earlier than specific outcome results. Results from all studies often shows efficacy much earlier than when restricting to RCTs. Results reflect conditions as used in trials to date, these depend on the population treated, treatment delay, and treatment regimen.
Pooled analysis could hide efficacy, for example a treatment that is beneficial for late stage patients but has no effect on viral clearance may show no efficacy if most studies only examine viral clearance. In practice, it is rare for a non-antiviral treatment to report viral clearance and to not report clinical outcomes; and in practice other sources of heterogeneity such as difference in treatment delay is more likely to hide efficacy.
Analysis validates the use of pooled effects and shows significantly faster detection of efficacy on average. However, as with all meta analyses, it is important to review the different studies included. We also present individual outcome analyses, which may be more informative for specific use cases.
Publishing is often biased towards positive results. 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 peginterferon lambda, there is currently not enough data to evaluate publication bias with high confidence.
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 alone31-41. 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.
Kelleni et al. present a review covering peginterferon lambda for COVID-19.
SARS-CoV-2 infection and replication involves a complex interplay of 50+ host and viral proteins and other factors12-16, providing many therapeutic targets. Over 7,000 compounds have been predicted to reduce COVID-19 risk17, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications. Figure 16 shows an overview of the results for peginterferon lambda in the context of multiple COVID-19 treatments, and Figure 17 shows a plot of efficacy vs. cost for COVID-19 treatments.
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Figure 16. Scatter plot showing results within the context of multiple COVID-19 treatments. Diamonds shows the results of random effects meta-analysis. 0.6% of 7,000+ proposed treatments show efficacy45.
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Figure 17. Efficacy vs. cost for COVID-19 treatments.
Meta analysis using the most serious outcome reported shows 7% [-138‑63%] lower risk, without reaching statistical significance. Early treatment is more effective than late treatment. Currently all studies are RCTs. 2 studies from 2 independent teams in 2 countries show significant improvements.
Currently there is limited data, with only 9 control events for the most serious outcome in trials to date.
The primary positive trial1 has major anomolies2. Results from NCT04967430 have not been reported and contact information was deleted in the registry.
0 0.5 1 1.5 2+ Hospitalization 0% Improvement Relative Risk ER visit 75% Viral clearance 66% Peg.. Lambda  Feld et al.  EARLY TREATMENT  DB RCT Is early treatment with peginterferon lambda beneficial for COVID-19? Double-blind RCT 60 patients in Canada (May - September 2020) Improved viral clearance with peginterferon lambda (p=0.029) c19early.org Feld et al., The Lancet Respiratory Me.., Nov 2020 Favors peg.. lambda Favors control
Feld: Small outpatient RCT with 30 peginterferon lambda and 30 control patients, showing improved viral clearance with treatment. Single subcutaneous injection of peginterferon lambda 180μg. NCT04354259.
0 0.5 1 1.5 2+ Hospitalization 0% Improvement Relative Risk Duration of symptoms -6% Change in viral load -14% Peg.. Lambda  Jagannathan et al.  EARLY TREATMENT  RCT Is early treatment with peginterferon lambda beneficial for COVID-19? RCT 120 patients in the USA (April - July 2020) Trial underpowered for serious outcomes c19early.org Jagannathan et al., Nature Communicati.., Mar 2021 Favors peg.. lambda Favors control
Jagannathan: RCT 120 outpatients with mild/moderate COVID-19, showing no significant differences with peginterferon lambda-1a treatment. 180μg subcutaneous peginterferon lambda-1a. NCT04331899.
0 0.5 1 1.5 2+ ICU admission -200% Improvement Relative Risk Hospitalization time -25% Viral clearance, day 14 12% Viral clearance, day 7 -67% Peg.. Lambda  Kim et al.  LATE TREATMENT  RCT Is late treatment with peginterferon lambda beneficial for COVID-19? RCT 14 patients in the USA (July 2020 - July 2021) Longer hospitalization with peginterferon lambda (not stat. sig., p=0.59) c19early.org Kim et al., Frontiers in Medicine, Feb 2023 Favors peg.. lambda Favors control
Kim: Very small RCT with 14 hospitalized patients in the USA showing no significant differences with peginterferon lambda. Viral load was improved, however 86% of treatment versus 14% of control patients received remdesivir, and the median baseline viral load for treatment patients was 3.6 log10 copies/ml versus 0 for control.
0 0.5 1 1.5 2+ Mortality 27% Improvement Relative Risk Mortality, day 28 61% Hospitalization 42% Hospitalization or ER >6hr.. 51% primary Peg.. Lambda  TOGETHER  EARLY TREATMENT  DB RCT Is early treatment with peginterferon lambda beneficial for COVID-19? Double-blind RCT 1,949 patients in Brazil (June 2021 - February 2022) Lower hospitalization (p=0.039) and fewer hosp./ER visits (p=0.0027) Multiple critical issues, see discussion c19early.org Reis et al., New England J. Medicine, Feb 2023 Favors peg.. lambda Favors control
Reis: High-risk outpatient RCT with 931 peginterferon lambda patients and 1,018 control patients, showing significantly lower hospitalization/ER visits with treatment. Single subcutaneous injection.

There were 85/931 and 286/1018 patients for which baseline SARS-CoV-2 status was unknown, p = 1.4e-27 (about 1 in 704 septillion).

The most frequent risk factors were more common in the placebo group, for example obesity 39.1% control vs. 34.5% treatment, p = 0.04.

Authors claim patients were unaware or the randomization assignments, however some patients received oral placebo in a trial of a treatment requiring subcutaneous injection.

The numbers in Table 1 and Table S1 do not match, e.g., the text and Table 1 indicate 931 ITT interferon patients, while Table S1 shows 916.

All deaths in the placebo arm were attributed to COVID-19, while only 50% were in the interferon arm. One placebo death is listed as both due to COVID-19 and due to acute myeloid leukemia (Table S6).

See also2.

The TOGETHER trial has extreme COI, impossible data, blinding failure, randomization failure, uncorrected errors, and many protocol violations. Authors do not respond to these issues and they have refused to release the data as promised. Some issues may apply only to specific arms. For more details see49-53.
We perform ongoing searches of PubMed, medRxiv, Europe PMC, ClinicalTrials.gov, The Cochrane Library, Google Scholar, Research Square, ScienceDirect, Oxford University Press, the reference lists of other studies and meta-analyses, and submissions to the site c19early.org. Search terms are peginterferon lambda 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 peginterferon lambda for COVID-19 that report a comparison with a control group are included in the main analysis. This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies. If studies report multiple kinds of effects then the most serious outcome is used in pooled analysis, while other outcomes are included in the outcome specific analyses. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days have preference. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms are not used, the next most serious outcome with one or more events is used. For example, in low-risk populations with no mortality, a reduction in mortality with treatment is not possible, however a reduction in hospitalization, for example, is still valuable. Clinical outcomes are considered more important than viral test status. When basically all patients recover in both treatment and control groups, preference for viral clearance and recovery is given to results mid-recovery where available. After most or all patients have recovered there is little or no room for an effective treatment to do better, however faster recovery is valuable. If only individual symptom data is available, the most serious symptom has priority, for example difficulty breathing or low SpO2 is more important than cough. When results provide an odds ratio, we compute the relative risk when possible, or convert to a relative risk according to54. Reported confidence intervals and p-values were used when available, using adjusted values when provided. If multiple types of adjustments are reported propensity score matching and multivariable regression has preference over propensity score matching or weighting, which has preference over multivariable regression. Adjusted results have preference over unadjusted results for a more serious outcome when the adjustments significantly alter results. When needed, conversion between reported p-values and confidence intervals followed Altman, Altman (B), and Fisher's exact test was used to calculate p-values for event data. If continuity correction for zero values is required, we use the reciprocal of the opposite arm with the sum of the correction factors equal to 157. Results are expressed with RR < 1.0 favoring treatment, and using the risk of a negative outcome when applicable (for example, the risk of death rather than the risk of survival). If studies only report relative continuous values such as relative times, the ratio of the time for the treatment group versus the time for the control group is used. Calculations are done in Python (3.12.3) with scipy (1.13.1), pythonmeta (1.26), numpy (1.26.4), statsmodels (0.14.2), and plotly (5.22.0).
Forest plots are computed using PythonMeta58 with the DerSimonian and Laird random effects model (the fixed effect assumption is not plausible in this case) and inverse variance weighting. Results are presented with 95% confidence intervals. Heterogeneity among studies was assessed using the I2 statistic. Mixed-effects meta-regression results are computed with R (4.4.0) using the metafor (4.6-0) and rms (6.8-0) packages, and using the most serious sufficiently powered outcome. For all statistical tests, a p-value less than 0.05 was considered statistically significant. Grobid 0.8.0 is used to parse PDF documents.
We have classified studies as early treatment if most patients are not already at a severe stage at the time of treatment (for example based on oxygen status or lung involvement), and treatment started within 5 days of the onset of symptoms. If studies contain a mix of early treatment and late treatment patients, we consider the treatment time of patients contributing most to the events (for example, consider a study where most patients are treated early but late treatment patients are included, and all mortality events were observed with late treatment patients). We note that a shorter time may be preferable. Antivirals are typically only considered effective when used within a shorter timeframe, for example 0-36 or 0-48 hours for oseltamivir, with longer delays not being effective18,19.
We received no funding, this research is done in our spare time. We have no affiliations with any pharmaceutical companies or political parties.
A summary of study results is below. Please submit updates and corrections at the bottom of this page.
A summary of study results is below. Please submit updates and corrections at https://c19early.org/ilmeta.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.
Feld, 11/12/2020, Double Blind Randomized Controlled Trial, placebo-controlled, Canada, peer-reviewed, 35 authors, study period 18 May, 2020 - 4 September, 2020, average treatment delay 4.3 days, trial NCT04354259 (history). risk of hospitalization, no change, RR 1.00, p = 1.00, treatment 1 of 30 (3.3%), control 1 of 30 (3.3%).
risk of ER visit, 75.0% lower, RR 0.25, p = 0.35, treatment 1 of 30 (3.3%), control 4 of 30 (13.3%), NNT 10.0.
risk of no viral clearance, 66.4% lower, RR 0.34, p = 0.03, treatment 6 of 30 (20.0%), control 11 of 30 (36.7%), NNT 6.0, inverted to make RR<1 favor treatment, odds ratio converted to relative risk, adjusted for baseline viral load, day 7.
Jagannathan, 3/30/2021, Single Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, 27 authors, study period 25 April, 2020 - 17 July, 2020, average treatment delay 5.0 days, trial NCT04331899 (history). risk of hospitalization, no change, RR 1.00, p = 1.00, treatment 2 of 60 (3.3%), control 2 of 60 (3.3%), day 28.
duration of symptoms, 6.4% higher, HR 1.06, p = 0.76, treatment 60, control 60, inverted to make HR<1 favor treatment.
relative change in viral load, 14.0% worse, RR 1.14, p = 0.91, treatment 60, control 60, day 14.
Reis, 2/9/2023, Double Blind Randomized Controlled Trial, placebo-controlled, Brazil, peer-reviewed, 41 authors, study period 24 June, 2021 - 7 February, 2022, trial NCT04727424 (history) (TOGETHER). risk of death, 27.1% lower, RR 0.73, p = 0.76, treatment 4 of 931 (0.4%), control 6 of 1,018 (0.6%), NNT 626, all-cause, Table S6.
risk of death, 61.0% lower, RR 0.39, p = 0.32, treatment 1 of 931 (0.1%), control 4 of 1,018 (0.4%), adjusted per study, attributed to COVID, day 28.
risk of hospitalization, 42.0% lower, RR 0.58, p = 0.04, treatment 21 of 931 (2.3%), control 40 of 1,018 (3.9%), NNT 60, adjusted per study, day 28.
hospitalization or ER >6hrs, 51.0% lower, RR 0.49, p = 0.003, treatment 25 of 931 (2.7%), control 57 of 1,018 (5.6%), NNT 34, adjusted per study, day 28, primary outcome.
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.
Kim, 2/24/2023, Single Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, median age 54.0, 9 authors, study period 14 July, 2020 - 16 July, 2021, trial NCT04343976 (history). risk of ICU admission, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 7 (14.3%), control 0 of 7 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
hospitalization time, 25.0% higher, relative time 1.25, p = 0.59, treatment median 5.0 IQR 4.0 n=7, control median 4.0 IQR 5.0 n=7.
risk of no viral clearance, 12.5% lower, RR 0.88, p = 1.00, treatment 3 of 6 (50.0%), control 4 of 7 (57.1%), NNT 14, day 14.
risk of no viral clearance, 66.7% higher, RR 1.67, p = 0.59, treatment 5 of 7 (71.4%), control 3 of 7 (42.9%), day 7.
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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