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Povidone-Iodine for COVID-19: real-time meta analysis of 20 studies

@CovidAnalysis, February 2024, Version 35V35
 
0 0.5 1 1.5+ All studies 50% 20 3,226 Improvement, Studies, Patients Relative Risk Mortality 72% 2 872 Hospitalization 76% 3 885 Recovery 25% 3 286 Cases 45% 1 1,354 Viral clearance 65% 17 1,517 RCTs 53% 17 2,865 RCT mortality 88% 1 606 Peer-reviewed 48% 17 3,132 Prophylaxis 45% 1 1,354 Early 64% 14 1,536 Late 42% 5 336 Povidone-Iodine for COVID-19 c19early.org February 2024 after exclusions Favorspovidone-iodine Favorscontrol
Abstract
Statistically significant lower risk is seen for mortality, cases, and viral clearance. 11 studies from 11 independent teams in 9 countries show statistically significant improvements.
Meta analysis using the most serious outcome reported shows 50% [37‑61%] lower risk. Results are similar for Randomized Controlled Trials, higher quality studies, and peer-reviewed studies. Early treatment is more effective than late treatment.
Results are robust — in exclusion sensitivity analysis 15 of 20 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
3 RCTs with 424 patients have not reported results (up to 2 years late).
Excessive use of PVP-I could affect thyroid function.
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 may be more effective. Povidone-Iodine may be detrimental to the natural microbiome, raising concern for side effects, especially with prolonged or excessive use.
All data to reproduce this paper and sources are in the appendix. Other meta analyses show significant improvements with povidone-iodine for viral load Hasan, Idrees and viral clearance Hasan.
Evolution of COVID-19 clinical evidence Povidone-Iodine p=0.000000037 early treatment Acetaminophen p=0.00000029 2020 2021 2022 2023 Effective Harmful c19early.org February 2024 meta analysis results (pooled effects) 100% 50% 0% -50%
Highlights
PVP-I reduces risk for COVID-19 with very high confidence for viral clearance and in pooled analysis, low confidence for mortality, hospitalization, and cases, and very low confidence for recovery.
PVP-I was the 13th treatment shown effective with ≥3 clinical studies in February 2021, now known with p = 0.000000037 from 20 studies.
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 66 treatments.
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mohamed (RCT) 86% 0.14 [0.01-2.21] viral+ 0/5 3/5 Improvement, RR [CI] Treatment Control Choudhury (RCT) 88% 0.12 [0.03-0.50] death 2/303 17/303 Guenezan (RCT) 63% 0.37 [0.06-1.63] viral load 12 (n) 12 (n) Elzein (DB RCT) 89% 0.11 [0.01-1.00] viral load 25 (n) 9 (n) Short term viral Arefin (RCT) 79% 0.21 [0.08-0.54] viral+ 4/27 19/27 Short term viral Pablo-Marcos 29% 0.71 [0.32-1.56] viral load 31 (n) 40 (n) Sulistyani (SB RCT) 6% 0.94 [0.45-1.96] viral load 15 (n) 15 (n) Elsersy (DB RCT) 91% 0.09 [0.01-1.62] hosp. 0/100 5/100 CT​2 Sevinç Gül (RCT) 99% 0.01 [0.00-439] viral load 21 (n) 20 (n) Short term viral OT​1 Natto (RCT) 74% 0.26 [0.03-2.76] viral load 12 (n) 12 (n) Short term viral OT​1 Sirijatuphat 33% 0.67 [0.17-2.67] viral load 12 (n) 12 (n) Short term viral Baxter (RCT) -214% 3.14 [0.13-74.7] hosp. 1/37 0/42 OT​1 Karaaltin (RCT) 83% 0.17 [0.05-0.62] viral load 30 (n) 30 (n) Matsuyama (RCT) 69% 0.31 [0.10-0.93] viral+ 4/139 13/140 Tau​2 = 0.23, I​2 = 32.3%, p < 0.0001 Early treatment 64% 0.36 [0.22-0.57] 11/769 57/767 64% lower risk Seneviratne (RCT) 33% 0.67 [0.50-0.91] viral load 4 (n) 2 (n) Short term viral Improvement, RR [CI] Treatment Control Zarabanda (RCT) -27% 1.27 [0.26-6.28] no recov. 3/13 2/11 OT​1 Jamir (ICU) 57% 0.43 [0.27-0.69] death 39/163 62/103 ICU patients Ferrer (RCT) 34% 0.66 [0.02-19.0] viral load 9 (n) 12 (n) Short term viral Fantozzi (RCT) 31% 0.69 [0.39-1.21] viral+ 5/8 10/11 Short term viral OT​1 Tau​2 = 0.03, I​2 = 28.0%, p = 0.00014 Late treatment 42% 0.58 [0.44-0.76] 47/197 74/139 42% lower risk Seet (CLUS. RCT) 45% 0.55 [0.38-0.80] symp. case 42/735 64/619 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.002 Prophylaxis 45% 0.55 [0.38-0.80] 42/735 64/619 45% lower risk All studies 50% 0.50 [0.39-0.63] 100/1,701 195/1,525 50% lower risk 20 povidone-iodine COVID-19 studies c19early.org February 2024 Tau​2 = 0.07, I​2 = 30.4%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 OT: comparison with other treatment2 CT: study uses combined treatment Favors povidone-iodine Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mohamed (RCT) 86% viral- Improvement Relative Risk [CI] Choudhury (RCT) 88% death Guenezan (RCT) 63% viral load Elzein (DB RCT) 89% viral- Short term viral Arefin (RCT) 79% viral- Short term viral Pablo-Marcos 29% viral- Sulisty.. (SB RCT) 6% viral- Elsersy (DB RCT) 91% hospitalization CT​2 Sevinç Gül (RCT) 99% viral load Short term viral OT​1 Natto (RCT) 74% viral load Short term viral OT​1 Sirijatuphat 33% viral load Short term viral Baxter (RCT) -214% hospitalization OT​1 Karaaltin (RCT) 83% viral load Matsuyama (RCT) 69% viral- Tau​2 = 0.23, I​2 = 32.3%, p < 0.0001 Early treatment 64% 64% lower risk Seneviratne (RCT) 33% viral load Short term viral Zarabanda (RCT) -27% recovery OT​1 Jamir (ICU) 57% death ICU patients Ferrer (RCT) 34% viral load Short term viral Fantozzi (RCT) 31% viral- Short term viral OT​1 Tau​2 = 0.03, I​2 = 28.0%, p = 0.00014 Late treatment 42% 42% lower risk Seet (CLUS. RCT) 45% symp. case OT​1 Tau​2 = 0.00, I​2 = 0.0%, p = 0.002 Prophylaxis 45% 45% lower risk All studies 50% 50% lower risk 20 povidone-iodine C19 studies c19early.org February 2024 Tau​2 = 0.07, I​2 = 30.4%, p < 0.0001 Effect extraction pre-specifiedRotate device for footnotes/details Favors povidone-iodine Favors control
B
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C
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D
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Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, see the specific outcome analyses for individual outcomes, and the heterogeneity section for discussion. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix. B. 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. C. Results within the context of multiple COVID-19 treatments. 0.6% of 6,687 proposed treatments show efficacy c19early.org. D. Timeline of results in povidone-iodine studies. The marked dates indicate the time when efficacy was known with a statistically significant improvement of ≥10% from ≥3 studies for pooled outcomes, one or more specific outcome, and pooled outcomes in RCTs. Efficacy based on specific outcomes was delayed by 1.3 months, compared to using pooled outcomes.
SARS-CoV-2 infection typically starts in the upper respiratory tract, and specifically the nasal respiratory epithelium. Entry via the eyes and gastrointestinal tract is possible, but less common, and entry via other routes is rare. Infection may progress to the lower respiratory tract, other tissues, and the nervous and cardiovascular systems. The primary initial route for entry into the central nervous system is thought to be the olfactory nerve in the nasal cavity Dai. Progression may lead to cytokine storm, pneumonia, ARDS, neurological issues Scardua-Silva, Yang, cardiovascular complications Eberhardt, organ failure, and death. Minimizing replication as early as possible is recommended. Logically, stopping replication in the upper respiratory tract should be simpler and more effective. Early or prophylactic nasopharyngeal/oropharyngeal treatment can avoid the consequences of viral replication in other tissues, and avoid the requirement for systemic treatments with greater potential for side effects.
SARS-CoV-2 infection and replication involves the complex interplay of 50+ host and viral proteins and other factors Note A, Malone, Murigneux, Lv, Lui, providing many therapeutic targets for which many existing compounds have known activity. Scientists have predicted that over 6,000 compounds may reduce COVID-19 risk c19early.org (B), either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications.
We analyze all significant controlled studies of povidone-iodine for COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random effects meta-analysis results for all studies, studies within each treatment stage, individual outcomes, peer-reviewed studies, Randomized Controlled Trials (RCTs), and higher quality studies.
Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
Several in vitro studies show that PVP-I is effective for SARS-CoV-2 at clinically relevant concentrations Anderson, Bidra, Frank, Hassandarvish, Pelletier, Tucker, Xu.
Preclinical research is an important part of the development of treatments, however results may be very different in clinical trials. Preclinical results are not used in this paper.
Table 1 summarizes the results for all stages combined, for Randomized Controlled Trials, for peer-reviewed studies, after exclusions, and for specific outcomes. Table 2 shows results by treatment stage. Figure 3, 4, 5, 6, 7, 8, and 9 show forest plots for random effects meta-analysis of all studies with pooled effects, mortality results, hospitalization, recovery, cases, viral clearance, and peer reviewed studies.
Table 1. Random effects meta-analysis for all stages combined, for Randomized Controlled Trials, for peer-reviewed studies, after exclusions, and for specific outcomes. Results show the percentage improvement with treatment and the 95% confidence interval. ** p<0.01  *** p<0.001  **** p<0.0001.
Improvement Studies Patients Authors
All studies50% [37‑61%]
****
20 3,226 194
After exclusions55% [35‑69%]
****
11 2,932 112
Peer-reviewed studiesPeer-reviewed48% [34‑60%]
****
17 3,132 158
Randomized Controlled TrialsRCTs53% [35‑66%]
****
17 2,865 178
Mortality72% [8‑92%]
*
2 872 12
HospitalizationHosp.76% [-14‑95%]3 885 26
Recovery25% [-18‑53%]3 286 33
Viral65% [42‑79%]
****
17 1,517 161
RCT hospitalizationRCT hosp.76% [-14‑95%]3 885 26
Table 2. Random effects meta-analysis results by treatment stage. Results show the percentage improvement with treatment, the 95% confidence interval, and the number of studies for the stage.treatment and the 95% confidence interval. ** p<0.01  *** p<0.001  **** p<0.0001.
Early treatment Late treatment Prophylaxis
All studies64% [43‑78%]
****
42% [24‑56%]
***
45% [20‑62%]
**
After exclusions68% [32‑85%]
**
45% [-34‑77%]45% [20‑62%]
**
Peer-reviewed studiesPeer-reviewed63% [36‑79%]
***
42% [24‑56%]
***
45% [20‑62%]
**
Randomized Controlled TrialsRCTs71% [50‑83%]
****
31% [11‑47%]
**
45% [20‑62%]
**
Mortality88% [50‑97%]
**
57% [31‑73%]
***
HospitalizationHosp.76% [-14‑95%]
Recovery32% [-28‑64%]-27% [-528‑74%]
Viral73% [49‑86%]
****
32% [11‑48%]
**
RCT hospitalizationRCT hosp.76% [-14‑95%]
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Figure 3. Random effects meta-analysis for all studies with pooled effects. This plot shows pooled effects, see the specific outcome analyses for individual outcomes, and the heterogeneity section for discussion. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
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Figure 4. Random effects meta-analysis for mortality results.
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Figure 5. Random effects meta-analysis for hospitalization.
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Figure 6. Random effects meta-analysis for recovery.
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Figure 7. Random effects meta-analysis for cases.
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Figure 8. Random effects meta-analysis for viral clearance.
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Figure 9. Random effects meta-analysis for peer reviewed studies. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details. Zeraatkar et al. analyze 356 COVID-19 trials, finding no significant evidence that preprint results are inconsistent with peer-reviewed studies. They also show extremely long peer-review delays, with a median of 6 months to journal publication. A six month delay was equivalent to around 1.5 million deaths during the first two years of the pandemic. Authors recommend using preprint evidence, with appropriate checks for potential falsified data, which provides higher certainty much earlier. Davidson et al. also showed no important difference between meta analysis results of preprints and peer-reviewed publications for COVID-19, based on 37 meta analyses including 114 trials.
Figure 10 shows a comparison of results for RCTs and non-RCT studies. The median effect size for RCTs is 69% improvement, compared to 33% for other studies. Figure 11, 12, and 13 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.
Bias in clinical research may be defined as something that tends to make conclusions differ systematically from the truth. RCTs help to make study groups more similar and can provide a higher level of evidence, however they are subject to many biases Jadad, and analysis of double-blind RCTs has identified extreme levels of bias Gøtzsche. For COVID-19, the overhead may delay treatment, dramatically compromising efficacy; they may encourage monotherapy for simplicity at the cost of efficacy which may rely on combined or synergistic effects; the participants that sign up may not reflect real world usage or the population that benefits most in terms of age, comorbidities, severity of illness, or other factors; standard of care may be compromised and unable to evolve quickly based on emerging research for new diseases; errors may be made in randomization and medication delivery; and investigators may have hidden agendas or vested interests influencing design, operation, analysis, and the potential for fraud. All of these biases have been observed with COVID-19 RCTs. There is no guarantee that a specific RCT provides a higher level of evidence.
RCTs are expensive and many RCTs are funded by pharmaceutical companies or interests closely aligned with pharmaceutical companies. For COVID-19, this creates an incentive to show efficacy for patented commercial products, and an incentive to show a lack of efficacy for inexpensive treatments. The bias is expected to be significant, for example Als-Nielsen et al. analyzed 370 RCTs from Cochrane reviews, showing that trials funded by for-profit organizations were 5 times more likely to recommend the experimental drug compared with those funded by nonprofit organizations. For COVID-19, some major philanthropic organizations are largely funded by investments with extreme conflicts of interest for and against specific COVID-19 interventions.
High quality RCTs for novel acute diseases are more challenging, with increased ethical issues due to the urgency of treatment, increased risk due to enrollment delays, and more difficult design with a rapidly evolving evidence base. For COVID-19, the most common site of initial infection is the upper respiratory tract. Immediate treatment is likely to be most successful and may prevent or slow progression to other parts of the body. For a non-prophylaxis RCT, it makes sense to provide treatment in advance and instruct patients to use it immediately on symptoms, just as some governments have done by providing medication kits in advance. Unfortunately, no RCTs have been done in this way. Every treatment RCT to date involves delayed treatment. Among the 66 treatments we have analyzed, 63% of RCTs involve very late treatment 5+ days after onset. No non-prophylaxis COVID-19 RCTs match the potential real-world use of early treatments (they may more accurately represent results for treatments that require visiting a medical facility, e.g., those requiring intravenous administration).
Evidence shows that non-RCT trials can also provide reliable results. Concato et al. found that well-designed observational studies do not systematically overestimate the magnitude of the effects of treatment compared to RCTs. Anglemyer et al. summarized reviews comparing RCTs to observational studies and found little evidence for significant differences in effect estimates. Lee et al. showed that only 14% of the guidelines of the Infectious Diseases Society of America were based on RCTs. Evaluation of studies relies on an understanding of the study and potential biases. Limitations in an RCT can outweigh the benefits, for example excessive dosages, excessive treatment delays, or Internet survey bias could have a greater effect on results. Ethical issues may also prevent running RCTs for known effective treatments. For more on issues with RCTs see Deaton, Nichol.
Currently, 44 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. Of the 44 treatments with statistically significant efficacy/harm, 28 have been confirmed in RCTs, with a mean delay of 5.7 months. When considering only low cost treatments, 23 have been confirmed with a delay of 6.9 months. For the 16 unconfirmed treatments, 3 have zero RCTs to date. The point estimates for the remaining 13 are all consistent with the overall results (benefit or harm), with 10 showing >20%. The only treatments showing >10% efficacy for all studies, but <10% for RCTs are sotrovimab and aspirin.
We need to evaluate each trial on its own merits. RCTs for a given medication and disease may be more reliable, however they may also be less reliable. For off-patent medications, very high conflict of interest trials may be more likely to be RCTs, and more likely to be large trials that dominate meta analyses.
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Figure 10. Results for RCTs and non-RCT studies.
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Figure 11. Random effects meta-analysis for all Randomized Controlled Trials. This plot shows pooled effects, see the specific outcome analyses for individual outcomes, and the heterogeneity section for discussion. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
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Figure 12. Random effects meta-analysis for RCT mortality results.
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Figure 13. Random effects meta-analysis for RCT hospitalization results.
3 povidone-iodine RCTs have not reported results Jacox, Keating, Khan. The trials report a total of 424 patients, with 2 trials having actual enrollment of 374, and the other estimated. The results are delayed from 1.5 years to over 2 years.
To avoid bias in the selection of studies, we analyze all non-retracted studies. Here we show the results after excluding studies with major issues likely to alter results, non-standard studies, and studies where very minimal detail is currently available. Our bias evaluation is based on analysis of each study and identifying when there is a significant chance that limitations will substantially change the outcome of the study. We believe this can be more valuable than checklist-based approaches such as Cochrane GRADE, which 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), and can be easily influenced by potential bias.
The studies excluded are as below. Figure 14 shows a forest plot for random effects meta-analysis of all studies after exclusions.
Arefin, study only provides short-term viral load results.
Elzein, study only provides short-term viral load results.
Fantozzi, study only provides short-term viral load results.
Ferrer, study only provides short-term viral load results.
Natto, study only provides short-term viral load results.
Pablo-Marcos, unadjusted results with no group details.
Seneviratne, study only provides short-term viral load results.
Sevinç Gül, study only provides short-term viral load results.
Sirijatuphat, study only provides short-term viral load results.
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Figure 14. Random effects meta-analysis for all studies after exclusions. This plot shows pooled effects, see the specific outcome analyses for individual outcomes, and the heterogeneity section for discussion. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
Heterogeneity in COVID-19 studies arises from many factors including:
The time between infection or the onset of symptoms and treatment may critically affect how well a treatment works. For example an antiviral may be very effective when used early but may not be effective in late stage disease, and may even be harmful. Oseltamivir, for example, is generally only considered effective for influenza when used within 0-36 or 0-48 hours McLean, Treanor. Baloxavir studies for influenza also show that treatment delay is critical — Ikematsu report an 86% reduction in cases for post-exposure prophylaxis, Hayden 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 report only 2.5 hours improvement for inpatient treatment.
Table 3. Studies of baloxavir for influenza show that early treatment is more effective.
Treatment delayResult
Post exposure prophylaxis86% fewer cases Ikematsu
<24 hours-33 hours symptoms Hayden
24-48 hours-13 hours symptoms Hayden
Inpatients-2.5 hours to improvement Kumar
Figure 15 shows a mixed-effects meta-regression for efficacy as a function of treatment delay in COVID-19 studies from 66 treatments, showing that efficacy declines rapidly with treatment delay. Early treatment is critical for COVID-19.
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Figure 15. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 66 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 (as in López-Medina).
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.
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.
Effectiveness may depend strongly on the dosage and treatment regimen.
The use of other treatments may significantly affect outcomes, including anything from supplements, other medications, or other kinds of treatment such as prone positioning.
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 (B) analyze a treatment from two different manufacturers, showing 9 different impurities, with significantly different concentrations for each manufacturer.
We present both pooled analyses and specific outcome analyses. Notably, pooled analysis often results in earlier detection of efficacy as shown in Figure 16. For many COVID-19 treatments, a reduction in mortality logically follows from a reduction in hospitalization, which follows from a reduction in symptomatic cases, etc. An antiviral tested with a low-risk population may report zero mortality in both arms, however a reduction in severity and improved viral clearance may translate into lower mortality among a high-risk population, and including these results in pooled analysis allows faster detection of efficacy. Trials with high-risk patients may also be restricted due to ethical concerns for treatments that are known or expected to be effective.
Pooled analysis enables using more of the available information. While there is much more information available, for example dose-response relationships, the advantage of the method used here is simplicity and transparency. Note that pooled analysis could hide efficacy, for example a treatment that is beneficial for late stage patients but has no effect on viral replication or early stage disease could show no efficacy in pooled analysis if most studies only examine viral clearance. While we present pooled results, we also present individual outcome analyses, which may be more informative for specific use cases.
Currently, 44 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 88% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 3.6 months. When restricting to RCTs only, 50% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 6.1 months.
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Figure 16. 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.
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. This may have a greater effect than pooling different outcomes such as mortality and hospitalization. For example a treatment may have 50% efficacy for mortality but only 40% for hospitalization when used within 48 hours. However efficacy could be 0% when used late.
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.
Safety analysis can be found in Frank (B), Frank (C), Khan (B). Frank (B) conclude that PVP-I can safely be used in the nose at concentrations up to 1.25% and in the mouth at concentrations up to 2.5% for up to 5 months.
Analysis of short-term changes in viral load using PCR may not detect effective treatments because PCR is unable to differentiate between intact infectious virus and non-infectious or destroyed virus particles. For example Alemany, Tarragó‐Gil perform RCTs with cetylpyridinium chloride (CPC) mouthwash that show no difference in PCR viral load, however there was significantly increased detection of SARS-CoV-2 nucleocapsid protein, indicating viral lysis. CPC inactivates SARS-CoV-2 by degrading its membrane, exposing the nucleocapsid of the virus. To better estimate changes in viral load and infectivity, methods like viral culture or antigen detection that can differentiate intact vs. degraded virus are preferred.
Studies to date use a variety of administration methods to the respiratory tract, including nasal and oral sprays, nasal irrigation, oral rinses, and inhalation. Table 4 shows the relative efficacy for nasal, oral, and combined administration. Combined administration shows the best results, and nasal administration is more effective than oral. Precise efficacy depends on the details of administration, e.g., mucoadhesion and sprayability for sprays.
Table 4. Respiratory tract administration efficacy. Relative efficacy of nasal, oral, and combined nasal/oral administration for treatments administered directly to the respiratory tract, based on studies for povidone-iodine, iota-carrageenan, alkalinization, hydrogen peroxide, nitric oxide, chlorhexidine, cetylpyridinium chloride, and phthalocyanine. Results show random effects meta analysis for the most serious outcome reported for all prophylaxis and early treatment studies.
Nasal/oral administration to the respiratory tract ImprovementStudies
Oral spray/rinse38% [25‑49%]8
Nasal spray/rinse54% [42‑63%]11
Nasal & oral94% [74‑99%]6
Nasopharyngeal/oropharyngeal treatments may not be highly selective. In addition to inhibiting or disabling SARS-CoV-2, they may also be harmful to beneficial microbes, disrupting the natural microbiome in the oral cavity and nasal passages that have important protective and metabolic roles. This may be especially important for prolonged use or overuse. Table 5 summarizes the potential for common nasopharyngeal/oropharyngeal treatments to affect the natural microbiome.
Table 5. Potential effect of treatments on the nasophyrngeal/oropharyngeal microbiome.
TreatmentMicrobiome disruption potentialNotes
Iota-carrageenanLowPrimarily antiviral, however extended use may mildly affect the microbiome
Nitric OxideLow to moderateMore selective towards pathogens, however excessive concentrations or prolonged use may disrupt the balance of bacteria
AlkalinizationModerateIncreases pH, negatively impacting beneficial microbes that thrive in a slightly acidic environment
Cetylpyridinium ChlorideModerateQuaternary ammonium broad-spectrum antiseptic that can disrupt beneficial and harmful bacteria
PhthalocyanineModerate to highPhotodynamic compound with antimicrobial activity, likely to affect the microbiome
ChlorhexidineHighPotent antiseptic with broad activity, significantly disrupts the microbiome
Hydrogen PeroxideHighStrong oxidizer, harming both beneficial and harmful microbes
Povidone-IodineHighPotent broad-spectrum antiseptic harmful to beneficial microbes
Publishing is often biased towards positive results, however evidence suggests that there may be a negative bias for inexpensive treatments for COVID-19. Both negative and positive results are very important for COVID-19, media in many countries prioritizes negative results for inexpensive treatments (inverting the typical incentive for scientists that value media recognition), and there are many reports of difficulty publishing positive results Boulware, Meeus, Meneguesso. For povidone-iodine, 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.
Figure 17 shows a scatter plot of results for prospective and retrospective studies. Prospective studies show 49% [33‑62%] improvement in meta analysis, compared to 57% [31‑73%] for retrospective studies, showing no significant difference. However, there has only been one retrospective study to date.
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Figure 17. Prospective vs. retrospective studies. The diamonds show the results of random effects meta-analysis.
Funnel plots have traditionally been used for analyzing publication bias. This is invalid for COVID-19 acute treatment trials — the underlying assumptions are invalid, which we can demonstrate with a simple example. Consider a set of hypothetical perfect trials with no bias. Figure 18 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 18. Example funnel plot analysis for simulated perfect trials.
Pharmaceutical drug trials often have conflicts of interest whereby sponsors or trial staff have a financial interest in the outcome being positive. PVP-I for COVID-19 lacks this because it is off-patent, has multiple manufacturers, and is very low cost. In contrast, most COVID-19 povidone-iodine trials have been run by physicians on the front lines with the primary goal of finding the best methods to save human lives and minimize the collateral damage caused by COVID-19. While pharmaceutical companies are careful to run trials under optimal conditions (for example, restricting patients to those most likely to benefit, only including patients that can be treated soon after onset when necessary, and ensuring accurate dosing), not all povidone-iodine trials represent the optimal conditions for efficacy.
Summary statistics from meta analysis necessarily lose information. As with all meta analyses, studies are heterogeneous, with differences in treatment delay, treatment regimen, patient demographics, variants, conflicts of interest, standard of care, and other factors. We provide analyses by 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 affiliated with special interests may use designs better suited to the preferred outcome.
In some cases, the most serious outcome has very few events, resulting in lower confidence results being used in pooled analysis, however the method is simpler and more transparent. This is less critical as the number of studies increases. Restriction to outcomes with sufficient power may be beneficial in pooled analysis and improve accuracy when there are few studies, however we maintain our pre-specified method to avoid any retrospective changes.
Studies show that combinations of treatments can be highly synergistic and may result in many times greater efficacy than individual treatments alone Alsaidi, Andreani, De Forni, Fiaschi, Jeffreys, Jitobaom, Jitobaom (B), Ostrov, Said, Thairu, Wan. Therefore standard of care may be critical and benefits may diminish or disappear if standard of care does not include certain treatments.
This real-time analysis is constantly updated based on submissions. Accuracy benefits from widespread review and submission of updates and corrections from reviewers. Less popular treatments may receive fewer reviews.
No treatment, vaccine, 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.
6 of the 20 studies compare against other treatments, which may reduce the effect seen. 1 of 20 studies combine treatments. The results of povidone-iodine alone may differ. 1 of 17 RCTs use combined treatment. Other meta analyses show significant improvements with povidone-iodine for viral load Hasan, Idrees and viral clearance Hasan.
Multiple reviews cover povidone-iodine for COVID-19, presenting additional background on mechanisms and related results, including Chavda, Chopra, Lim, O’Donnell, Ting.
SARS-CoV-2 infection typically starts in the upper respiratory tract. Progression may lead to cytokine storm, pneumonia, ARDS, neurological issues, organ failure, and death. Stopping replication in the upper respiratory tract, via early or prophylactic nasopharyngeal/oropharyngeal treatment, can avoid the consequences of progression to other tissues, and avoid the requirement for systemic treatments with greater potential for side effects.
PVP-I is an effective treatment for COVID-19. Statistically significant lower risk is seen for mortality, cases, and viral clearance. 11 studies from 11 independent teams in 9 countries show statistically significant improvements. Meta analysis using the most serious outcome reported shows 50% [37‑61%] lower risk. Results are similar for Randomized Controlled Trials, higher quality studies, and peer-reviewed studies. Early treatment is more effective than late treatment. Results are robust — in exclusion sensitivity analysis 15 of 20 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
Excessive use of PVP-I could affect thyroid function.
Other meta analyses show significant improvements with povidone-iodine for viral load Hasan, Idrees and viral clearance Hasan.
Povidone-Iodine may be detrimental to the natural microbiome, raising concern for side effects, especially with prolonged or excessive use.
0 0.5 1 1.5 2+ Viral clearance 79% Improvement Relative Risk Viral clearance (b) 89% Viral clearance (c) 53% Viral clearance (d) 80% Viral clearance (e) 64% Viral clearance (f) 74% Povidone-Iodine  Arefin et al.  EARLY TREATMENT  RCT Does povidone-iodine reduce short-term viral load for COVID-19? RCT 189 patients in Bangladesh (July - October 2020) Improved viral clearance with povidone-iodine (p=0.018) c19early.org Arefin et al., Indian J. Otolaryngolog.., May 2021 Favors povidone-iodine Favors control
Arefin: RCT with 189 patients showing significantly greater viral clearance with a single application of PVP-I. Authors recommend using PVP-I prophylactically in the nasopharynx and oropharynx. NCT04549376 trialsjournal.biomedcentral.com.
0 0.5 1 1.5 2+ Hospitalization -214% Improvement Relative Risk Recovery 57% Transmission 14% Hospitalization, vs. CDC 94% Povidone-Iodine  Baxter et al.  EARLY TREATMENT  RCT Is early treatment with povidone-iodine beneficial for COVID-19? RCT 79 patients in the USA (September - December 2020) Trial compares with sodium bicarbonate nasal irrigation Improved recovery with povidone-iodine (p=0.034) c19early.org Baxter et al., Ear, Nose & Throat J., Aug 2022 Favors povidone-iodine Favors sodium bicar..
Baxter: Small RCT 79 PCR+ patients 55+ comparing pressure-based nasal irrigation with povidone-iodine and sodium bicarbonate, showing improved recovery with povidone-iodine. Not all results comparing povidone-iodine and sodium bicarbonate are in the journal version, as authors focus on the comparison with CDC data. Earlier versions can be found at medrxiv.org. The reported hospitalization switched groups between the preprint and the journal version.
0 0.5 1 1.5 2+ Mortality 88% Improvement Relative Risk Hospitalization 84% Viral clearance 96% Povidone-Iodine  Choudhury et al.  EARLY TREATMENT  RCT Is early treatment with povidone-iodine beneficial for COVID-19? RCT 606 patients in Bangladesh (February - August 2020) Lower mortality (p=0.00061) and hospitalization (p<0.0001) c19early.org Choudhury et al., Bioresearch Communic.., Dec 2020 Favors povidone-iodine Favors control
Choudhury: RCT 606 patients in Bangladesh for povidone iodine mouthwash/gargle, nasal drops and eye drops showing significantly lower death, hospitalization, and PCR+ at day 7.
0 0.5 1 1.5 2+ Hospitalization 91% Improvement Relative Risk Recovery time 15% Recovery time, smell 49% Recovery time, taste 48% Viral clearance, day 7 68% Viral clearance, day 10 90% Viral clearance, day 4 29% Transmission 92% Transmission (b) 94% Povidone-Iodine  Elsersy et al.  EARLY TREATMENT  DB RCT Is early treatment with povidone-iodine + glycyrrhizic acid beneficial for COVID-19? Double-blind RCT 421 patients in Egypt (March - July 2021) Faster recovery (p=0.008) and improved viral clearance (p<0.0001) c19early.org Elsersy et al., Frontiers in Medicine, Apr 2022 Favors povidone-iodine Favors control
Elsersy: RCT with 200 patients and 421 contacts in Egypt, with 100 patients and their contacts treated with nasal and oropharyngeal sprays containing povidone-iodine and glycyrrhizic acid, showing significantly faster viral clearance and recovery, and significantly lower transmission.

SOC included vitamin C and zinc. The spray active ingredients included a compound of glycyrrhizic acid in the form of ammonium glycyrrhizate 2.5 mg/ml plus PVI 0.5% for oropharyngeal and dipotassium glycyrrhizinate 2.5 mg/ml plus PVI 0.5% for nasal spray. Patients were advised to concomitantly use oropharyngeal and nasal sprays 6 times per day. They were instructed to abstain from food, drink, and smoke for 20min, particularly after oropharyngeal spray. The oropharyngeal spray bottle contains an atomizer that ends with a long arm applicator to insert inside the mouth cavity and can be directed up, down, right, or left to cover the entire pharyngeal area.
0 0.5 1 1.5 2+ Improvement in Ct value 89% Improvement Relative Risk Povidone-Iodine  Elzein et al.  EARLY TREATMENT  DB RCT Does povidone-iodine reduce short-term viral load for COVID-19? Double-blind RCT 34 patients in Lebanon (June - September 2020) Improved viral clearance with povidone-iodine (not stat. sig., p=0.05) c19early.org Elzein et al., J. Evidence Based Denta.., Mar 2021 Favors povidone-iodine Favors control
Elzein: Small RCT comparing mouthwashing with PVP-I, chlorhexidine, and water, showing significant efficacy for both PVP-I and chlorhexidine, with PVP-I increasing Ct by a mean of 4.45 (p < 0.0001) and chlorhexidine by a mean of 5.69 (p < 0.0001), compared to no significant difference for water.
0 0.5 1 1.5 2+ Viral load 57% no CI Improvement Relative Risk Viral load (b) 100% no CI Viral clearance 31% Viral clearance (b) 59% Povidone-Iodine  Fantozzi et al.  LATE TREATMENT  RCT Does late treatment with povidone-iodine reduce short-term viral load? RCT 38 patients in Italy (December 2020 - May 2021) Trial compares with saline, results vs. placebo may differ Improved viral clearance with povidone-iodine (not stat. sig., p=0.26) c19early.org Fantozzi et al., American J. Otolaryng.., Jul 2022 Favors povidone-iodine Favors saline
Fantozzi: Mouthrinse RCT in Italy comparing short-term viral load after a single 60 second treatment with povidone-iodine, hydrogen peroxide, chlorhexidine, and saline. The greatest efficacy was seen with povidone-iodine, especially for patients with low viral load at baseline.
0 0.5 1 1.5 2+ Viral load reduction 34% Improvement Relative Risk Viral load T4 vs. T1 93% Povidone-Iodine  Ferrer et al.  LATE TREATMENT  RCT Does late treatment with povidone-iodine reduce short-term viral load? RCT 21 patients in Spain No significant difference in viral load c19early.org Ferrer et al., Scientific Reports, Dec 2021 Favors povidone-iodine Favors control
Ferrer: Small very late (>50% 7+ days from symptom onset, 9 PVP-I patients) RCT testing mouthwashing with cetylpyridinium chloride, chlorhexidine, povidone-iodine, hydrogen peroxide, and distilled water, showing no significant differences. Over 30% of patients show >90% decrease in viral load @2 hrs with all 5. Authors note that a trend was observed for viral load decrease with PVP-I @2h for patients <6 days from onset (p=0.06, Wilcox test).
0 0.5 1 1.5 2+ Improvement in viral titer r.. 63% Improvement Relative Risk Povidone-Iodine  Guenezan et al.  EARLY TREATMENT  RCT Is early treatment with povidone-iodine beneficial for COVID-19? RCT 24 patients in France (September - October 2020) Improved viral load with povidone-iodine (not stat. sig., p=0.25) c19early.org Guenezan et al., JAMA Otolaryngol Head.., Feb 2021 Favors povidone-iodine Favors control
Guenezan: RCT of PCR+ patients with Ct<=20 with 12 treatment and 12 control patients, concluding that nasopharyngeal decolonization may reduce the carriage of infectious SARS-CoV-2 in adults with mild to moderate COVID-19. All patients but 1 had negative viral titer by day 3 (group not specified). There was no significant difference in viral RNA quantification over time. The mean relative difference in viral titers between baseline and day 1 was 75% [43%-95%] in the intervention group and 32% [10%-65%] in the control group. Thyroid dysfunction occurred in 42% of treated patients, with spontaneous resolution after the end of treatment. Patients in the treatment group were younger.
Jacox: 129 patient povidone-iodine early treatment RCT with results not reported over 2 years after completion.
0 0.5 1 1.5 2+ Mortality 57% Improvement Relative Risk Povidone-Iodine  Jamir et al.  ICU PATIENTS Is very late treatment with povidone-iodine beneficial for COVID-19? Retrospective 266 patients in India (June - October 2020) Lower mortality with povidone-iodine (p=0.0004) c19early.org Jamir et al., Cureus, December 2021 Favors povidone-iodine Favors control
Jamir: Retrospective 266 COVID-19 ICU patients in India, showing significantly lower mortality with PVP-I oral gargling and topical nasal use, and non-statistically significant higher mortality with ivermectin and lower mortality with remdesivir.
0 0.5 1 1.5 2+ Viral load, day 5 83% Improvement Relative Risk Viral load, day 5 (b) 86% Viral load, day 3 82% Viral load, day 3 (b) 91% Povidone-Iodine  Karaaltin et al.  EARLY TREATMENT  RCT Is early treatment with povidone-iodine beneficial for COVID-19? RCT 60 patients in Turkey (September - October 2021) Improved viral load with povidone-iodine (p=0.007) c19early.org Karaaltin et al., Authorea, Inc., October 2022 Favors povidone-iodine Favors control
Karaaltin: RCT 120 outpatients in Turkey, showing improved reduction in viral load with PVP-I nasal irrigation.

PVP-I prepared with hypertonic alkaline solution had better results. Kreutzberger show that SARS-CoV-2 requires acidic pH to infect cells, therefore alkalinization may add additional benefits.

All patients received favipiravir. PVP-I 1% 4 times per day.
Keating: 245 participant povidone-iodine + chlorhexidine prophylaxis RCT with results not reported over 1.5 years after completion.
Khan: Estimated 50 patient povidone-iodine early treatment RCT with results not reported over 1.5 years after estimated completion.
0 0.5 1 1.5 2+ Viral infectivity, culture 69% Improvement Relative Risk Viral clearance, PCR 38% primary Povidone-Iodine  Matsuyama et al.  EARLY TREATMENT  RCT Is early treatment with povidone-iodine beneficial for COVID-19? RCT 279 patients in Japan (November 2020 - March 2021) Improved viral clearance with povidone-iodine (p=0.025) c19early.org Matsuyama et al., Scientific Reports, Nov 2022 Favors povidone-iodine Favors control
Matsuyama: RCT 430 COVID+ patients in Japan, showing significantly lower viral infectivity from culture, and significantly faster PCR viral clearance with PVP-I.

For days 2-4 the study compares treatment with PVP-I vs. water (on day 5 both groups received PVP-I). Most patients were asymptomatic. 4 times per day mouthwashing and gargling with 20mL of 15-fold diluted PVP–I 7% or water.
0 0.5 1 1.5 2+ Viral clearance 86% Improvement Relative Risk Povidone-Iodine  Mohamed et al.  EARLY TREATMENT  RCT Is early treatment with povidone-iodine beneficial for COVID-19? RCT 10 patients in Malaysia (June - June 2020) Improved viral clearance with povidone-iodine (not stat. sig., p=0.17) c19early.org Mohamed et al., medRxiv, September 2020 Favors povidone-iodine Favors control
Mohamed: Tiny RCT with 5 PVP-I patients, gargling 30 seconds, 3x per day, and 5 control patients (essential oils and tap water were also tested), showing improved viral clearance with PVP-I.
0 0.5 1 1.5 2+ Viral load, combined 74% Improvement Relative Risk Viral load, E 96% Viral load, S 44% Povidone-Iodine  Natto et al.  EARLY TREATMENT  RCT Does povidone-iodine reduce short-term viral load for COVID-19? RCT 24 patients in Saudi Arabia (June - July 2021) Trial compares with saline, results vs. placebo may differ Improved viral load with povidone-iodine (not stat. sig., p=0.27) c19early.org Natto et al., Medicine, July 2022 Favors povidone-iodine Favors saline
Natto: 60 patient RCT comparing chlorhexidine, PVP-I, and saline in Saudi Arabia with a single mouth rinse treatment and PCR testing 5 minutes later, showing statistically significant improvement in Ct value for PVP-I. PVP-I showed greater improvement than saline, without statistical significance.
0 0.5 1 1.5 2+ Viral load, mid-recovery 29% Improvement Relative Risk Viral load, 4th PCR 9% Povidone-Iodine  Pablo-Marcos et al.  EARLY TREATMENT Is early treatment with povidone-iodine beneficial for COVID-19? Prospective study of 71 patients in Spain (May - November 2020) Improved viral clearance with povidone-iodine (not stat. sig., p=0.4) c19early.org Pablo-Marcos et al., Enfermedades Infe.., Oct 2021 Favors povidone-iodine Favors control
Pablo-Marcos: Small prospective study with 31 patients gargling povidone-iodine, 17 hydrogen peroxide, and 40 control patients, showing lower viral load mid-recovery with povidone-iodine, without reaching statistical significance. Oropharyngeal only, and only every 8 hours for two days. Results may be better with the addition of nasopharyngeal use, more frequent use, and without the two day limit.

Authors report only one of the 7 previous trials for PVP-I and COVID-19. Non-randomized study with no adjustments or group details. Some results in Figure 1 appear to be switched compared to the text and the labels in the figure. The viral clearance figures do not match the group sizes - for example authors report 62% PCR- for PVP-I at the 3rd test, however there is no number of 31 patients that rounds to 62%.
0 0.5 1 1.5 2+ Symp. case 45% Improvement Relative Risk Case 31% Povidone-Iodine  Seet et al.  Prophylaxis  RCT Is prophylaxis with povidone-iodine beneficial for COVID-19? RCT 1,354 patients in Singapore (May - August 2020) Trial compares with vitamin C, results vs. placebo may differ Fewer symptomatic cases (p=0.0022) and cases (p=0.012) c19early.org Seet et al., Int. J. Infectious Diseases, Apr 2021 Favors povidone-iodine Favors vitamin C
Seet: Prophylaxis RCT in Singapore with 3,037 low risk patients, showing lower serious cases, lower symptomatic cases, and lower confirmed cases of COVID-19 with all treatments (ivermectin, HCQ, PVP-I, and Zinc + vitamin C) compared to vitamin C.

Meta-analysis of vitamin C in 6 previous trials shows a benefit of 16%, so the actual benefit of ivermectin, HCQ, and PVP-I may be higher. Cluster RCT with 40 clusters.

There were no hospitalizations and no deaths. NCT04446104.
0 0.5 1 1.5 2+ Fold change 33% Improvement Relative Risk Povidone-Iodine  Seneviratne et al.  LATE TREATMENT  RCT Does late treatment with povidone-iodine reduce short-term viral load? RCT 6 patients in Singapore (June - August 2020) Improved viral load with povidone-iodine (p=0.01) c19early.org Seneviratne et al., Infection, December 2020 Favors povidone-iodine Favors control
Seneviratne: Small mouthwash RCT with 4 PVP-I patients and 2 water patients concluding that PVP-I may have a sustained effect on reducing the salivary SARS-CoV-2 level in COVID-19 patients. ISRCTN95933274.
0 0.5 1 1.5 2+ Viral load 99% Improvement Relative Risk Povidone-Iodine  Sevinç Gül et al.  EARLY TREATMENT  RCT Does povidone-iodine reduce short-term viral load for COVID-19? RCT 41 patients in Turkey (September - December 2021) Trial compares with saline, results vs. placebo may differ Improved viral load with povidone-iodine (not stat. sig., p=0.37) c19early.org Sevinç Gül et al., Dental and Medical .., Jul 2022 Favors povidone-iodine Favors saline
Sevinç Gül: RCT with 21 PVP-I and 20 saline patients gargling for 30 seconds and testing PCR Ct after 30 minutes, showing greater improvement with PVP-I, without statistical significance.

Ct values differ across testing platforms, however the reported Ct value difference can represent a large difference in viral load. For example, using the calibration included with the ct2vl converter, the reported difference in mean Ct values corresponds to a reduction in viral load of over 3x for PVP-I.
0 0.5 1 1.5 2+ Viral load, 3m left 33% Improvement Relative Risk Viral load, 3m right 88% Viral load, 4h right 83% Povidone-Iodine  Sirijatuphat et al.  EARLY TREATMENT Does povidone-iodine reduce short-term viral load for COVID-19? Prospective study of 12 patients in Thailand (Feb - Mar 2021) Improved viral load with povidone-iodine (not stat. sig., p=0.58) c19early.org Sirijatuphat et al., medRxiv, August 2022 Favors povidone-iodine Favors control
Sirijatuphat: Small single-arm trial testing short-term viral load change after a single administration of three puffs of 0.4% PVP-I, showing lower viral titer at 3 minutes and 4 hours, not reaching statistical significance. Authors note that one reason for the lower change compared to in vitro results is that the spray administration may be less effective.
0 0.5 1 1.5 2+ Improvement in Ct value 6% Improvement Relative Risk Improvement in Ct value (b) 11% Povidone-Iodine  Sulistyani et al.  EARLY TREATMENT  RCT Is early treatment with povidone-iodine beneficial for COVID-19? RCT 30 patients in Indonesia (July - September 2021) No significant difference in viral clearance c19early.org Sulistyani et al., F1000Research, March 2022 Favors povidone-iodine Favors control
Sulistyani: Small mouth rinsing and gargling RCT with 15 1% PVP-I, 12 0.5% PVP-I, 15 3% hydrogen peroxide, 12 1.5% hydrogen peroxide, and 15 water patients, showing rapid improvement in Ct value in all groups, and no significant differences between groups.
0 0.5 1 1.5 2+ Recovery -27% Improvement Relative Risk Recovery (b) -50% Viral clearance 0% Povidone-Iodine  Zarabanda et al.  LATE TREATMENT  RCT Is late treatment with povidone-iodine beneficial for COVID-19? RCT 24 patients in the USA Trial compares with saline spray, results vs. placebo may differ Trial underpowered to detect differences c19early.org Zarabanda et al., Laryngoscope, November 2021 Favors povidone-iodine Favors saline spray
Zarabanda: Very late treatment (7 days from onset) RCT comparing 11 & 13 PVP-I (0.5% and 2%), and 11 saline spray patients in the USA, showing no significant differences. There was no control group (saline is likely not a placebo, showing efficacy in other trials). There are large unadjusted differences between groups, e.g. 7.1 days from onset for PVP-I versus 4.8 for saline. Baseline Ct was higher for PVP-I, providing less room for improvement. Authors note that they cannot determine if earlier use is more beneficial.
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 povidone-iodine 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 povidone-iodine for COVID-19 that report a comparison with a control group are included in the main analysis. Sensitivity analysis is performed, excluding studies with major issues, epidemiological studies, and studies with minimal available information. This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies. If studies report multiple kinds of effects then the most serious outcome is used in pooled analysis, while other outcomes are included in the outcome specific analyses. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days have preference. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms are not used, the next most serious outcome with one or more events is used. For example, in low-risk populations with no mortality, a reduction in mortality with treatment is not possible, however a reduction in hospitalization, for example, is still valuable. Clinical outcomes are considered more important than viral test status. When basically all patients recover in both treatment and control groups, preference for viral clearance and recovery is given to results mid-recovery where available. After most or all patients have recovered there is little or no room for an effective treatment to do better, however faster recovery is valuable. If only individual symptom data is available, the most serious symptom has priority, for example difficulty breathing or low SpO2 is more important than cough. When results provide an odds ratio, we compute the relative risk when possible, or convert to a relative risk according to Zhang. Reported confidence intervals and p-values were used when available, using adjusted values when provided. If multiple types of adjustments are reported propensity score matching and multivariable regression has preference over propensity score matching or weighting, which has preference over multivariable regression. Adjusted results have preference over unadjusted results for a more serious outcome when the adjustments significantly alter results. When needed, conversion between reported p-values and confidence intervals followed Altman, Altman (B), and Fisher's exact test was used to calculate p-values for event data. If continuity correction for zero values is required, we use the reciprocal of the opposite arm with the sum of the correction factors equal to 1 Sweeting. Results are expressed with RR < 1.0 favoring treatment, and using the risk of a negative outcome when applicable (for example, the risk of death rather than the risk of survival). If studies only report relative continuous values such as relative times, the ratio of the time for the treatment group versus the time for the control group is used. Calculations are done in Python (3.12.2) with scipy (1.12.0), pythonmeta (1.26), numpy (1.26.4), statsmodels (0.14.1), and plotly (5.19.0).
Forest plots are computed using PythonMeta Deng with the DerSimonian and Laird random effects model (the fixed effect assumption is not plausible in this case) and inverse variance weighting. Results are presented with 95% confidence intervals. Heterogeneity among studies was assessed using the I2 statistic. Mixed-effects meta-regression results are computed with R (4.1.2) using the metafor (3.0-2) and rms (6.2-0) packages, and using the most serious sufficiently powered outcome. For all statistical tests, a p-value less than 0.05 was considered statistically significant. Grobid 0.8.0 is used to parse PDF documents.
We have classified studies as early treatment if most patients are not already at a severe stage at the time of treatment (for example based on oxygen status or lung involvement), and treatment started within 5 days of the onset of symptoms. If studies contain a mix of early treatment and late treatment patients, we consider the treatment time of patients contributing most to the events (for example, consider a study where most patients are treated early but late treatment patients are included, and all mortality events were observed with late treatment patients). We note that a shorter time may be preferable. Antivirals are typically only considered effective when used within a shorter timeframe, for example 0-36 or 0-48 hours for oseltamivir, with longer delays not being effective McLean, Treanor.
We received no funding, this research is done in our spare time. We have no affiliations with any pharmaceutical companies or political parties.
A summary of study results is below. Please submit updates and corrections at the bottom of this page.
A summary of study results is below. Please submit updates and corrections at https://c19early.org/pmeta.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.
Arefin, 5/18/2021, Randomized Controlled Trial, Bangladesh, peer-reviewed, 9 authors, study period 1 July, 2020 - 30 October, 2020, trial NCT04549376 (history), excluded in exclusion analyses: study only provides short-term viral load results. risk of no viral clearance, 78.9% lower, RR 0.21, p = 0.02, treatment 4 of 27 (14.8%), control 19 of 27 (70.4%), NNT 1.8, 0.6% nasal irrigation.
risk of no viral clearance, 89.5% lower, RR 0.11, p < 0.001, treatment 2 of 27 (7.4%), control 19 of 27 (70.4%), NNT 1.6, 0.5% nasal irrigation.
risk of no viral clearance, 52.6% lower, RR 0.47, p = 0.006, treatment 9 of 27 (33.3%), control 19 of 27 (70.4%), NNT 2.7, 0.4% nasal irrigation.
risk of no viral clearance, 80.0% lower, RR 0.20, p < 0.001, treatment 5 of 27 (18.5%), control 25 of 27 (92.6%), NNT 1.4, 0.6% nasal spray.
risk of no viral clearance, 64.0% lower, RR 0.36, p < 0.001, treatment 9 of 27 (33.3%), control 25 of 27 (92.6%), NNT 1.7, 0.5% nasal spray.
risk of no viral clearance, 73.6% lower, RR 0.26, p < 0.001, treatment 29 of 135 (21.5%), control 44 of 54 (81.5%), NNT 1.7, all treatment vs. all control.
Baxter, 8/25/2022, Randomized Controlled Trial, USA, peer-reviewed, 12 authors, study period 24 September, 2020 - 21 December, 2020, average treatment delay 4.0 days, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04559035 (history). risk of hospitalization, 213.5% higher, RR 3.14, p = 0.47, treatment 1 of 37 (2.7%), control 0 of 42 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), preprint result reversed.
risk of no recovery, 56.8% lower, RR 0.43, p = 0.03, treatment 6 of 27 (22.2%), control 18 of 35 (51.4%), NNT 3.4, preprint V2.
risk of transmission, 13.6% lower, RR 0.86, p = 1.00, treatment 4 of 27 (14.8%), control 6 of 35 (17.1%), NNT 43, preprint V2.
Choudhury, 12/3/2020, Randomized Controlled Trial, Bangladesh, peer-reviewed, 6 authors, study period 1 February, 2020 - 30 August, 2020. risk of death, 88.2% lower, RR 0.12, p < 0.001, treatment 2 of 303 (0.7%), control 17 of 303 (5.6%), NNT 20.
risk of hospitalization, 84.4% lower, RR 0.16, p < 0.001, treatment 12 of 303 (4.0%), control 77 of 303 (25.4%), NNT 4.7.
risk of no viral clearance, 96.2% lower, RR 0.04, p < 0.001, treatment 8 of 303 (2.6%), control 213 of 303 (70.3%), NNT 1.5, day 7.
Elsersy, 4/19/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Egypt, peer-reviewed, 8 authors, study period March 2021 - July 2021, this trial uses multiple treatments in the treatment arm (combined with glycyrrhizic acid) - results of individual treatments may vary, trial PACTR202101875903773. risk of hospitalization, 90.9% lower, RR 0.09, p = 0.06, treatment 0 of 100 (0.0%), control 5 of 100 (5.0%), NNT 20, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
recovery time, 14.6% lower, relative time 0.85, p = 0.008, treatment mean 7.6 (±2.0) n=100, control mean 8.9 (±2.0) n=100.
recovery time, 49.1% lower, relative time 0.51, p < 0.001, treatment mean 5.6 (±1.3) n=100, control mean 11.0 (±3.4) n=100, smell.
recovery time, 48.2% lower, relative time 0.52, p < 0.001, treatment mean 5.7 (±1.0) n=100, control mean 11.0 (±4.0) n=100, taste.
risk of no viral clearance, 67.7% lower, RR 0.32, p < 0.001, treatment 21 of 100 (21.0%), control 65 of 100 (65.0%), NNT 2.3, mid-recovery, day 7.
risk of no viral clearance, 90.0% lower, RR 0.10, p = 0.010, treatment 1 of 100 (1.0%), control 10 of 100 (10.0%), NNT 11, day 10.
risk of no viral clearance, 29.3% lower, RR 0.71, p < 0.001, treatment 70 of 100 (70.0%), control 99 of 100 (99.0%), NNT 3.4, day 4.
risk of transmission, 91.9% lower, RR 0.08, p < 0.001, treatment 12 of 194 (6.2%), control 173 of 227 (76.2%), NNT 1.4, symptomatic.
risk of transmission, 94.0% lower, RR 0.06, p < 0.001, treatment 8 of 194 (4.1%), control 157 of 227 (69.2%), NNT 1.5, PCR+.
Elzein, 3/17/2021, Double Blind Randomized Controlled Trial, Lebanon, peer-reviewed, 7 authors, study period June 2020 - September 2020, excluded in exclusion analyses: study only provides short-term viral load results. relative improvement in Ct value, 88.8% better, RR 0.11, p < 0.05, treatment 25, control 9.
Guenezan, 2/4/2021, Randomized Controlled Trial, France, peer-reviewed, 7 authors, study period 1 September, 2020 - 23 October, 2020, trial NCT04371965 (history). relative improvement in viral titer reduction between baseline and day 1, 63.2% better, RR 0.37, p = 0.25, treatment 12, control 12.
Jacox, 10/20/2021, Double Blind Randomized Controlled Trial, USA, trial NCT04584684 (history) (MOR). 129 patient RCT with results unknown and over 2 years late.
Karaaltin, 10/26/2022, Randomized Controlled Trial, Turkey, preprint, 16 authors, study period September 2021 - October 2021. viral load, 83.1% lower, relative load 0.17, p = 0.007, treatment 30, control 30, relative change in viral load, PVP-I vs. control, day 5.
viral load, 85.5% lower, relative load 0.14, p = 0.001, treatment 30, control 30, relative change in viral load, PVP-I + HANI vs. control, day 5.
viral load, 82.1% lower, relative load 0.18, p = 0.14, treatment 30, control 30, relative change in viral load, PVP-I vs. control, day 3.
viral load, 90.8% lower, relative load 0.09, p < 0.001, treatment 30, control 30, relative change in viral load, PVP-I + HANI vs. control, day 3.
Khan, 7/31/2022, Double Blind Randomized Controlled Trial, Pakistan, trial NCT04341688 (history) (GARGLES). Estimated 50 patient RCT with results unknown and over 1.5 years late.
Matsuyama, 11/28/2022, Randomized Controlled Trial, Japan, peer-reviewed, mean age 45.1, 4 authors, study period 30 November, 2020 - 17 March, 2021, trial jRCT1051200078. viral infectivity, 69.0% lower, RR 0.31, p = 0.03, treatment 4 of 139 (2.9%), control 13 of 140 (9.3%), NNT 16, viral infectivity from culture, day 5.
risk of no viral clearance, 38.0% lower, HR 0.62, p = 0.01, treatment 139, control 140, inverted to make HR<1 favor treatment, day 5, primary outcome.
Mohamed, 9/9/2020, Randomized Controlled Trial, Malaysia, preprint, 16 authors, study period 22 June, 2020 - 29 June, 2020, trial NCT04410159 (history). risk of no viral clearance, 85.7% lower, RR 0.14, p = 0.17, treatment 0 of 5 (0.0%), control 3 of 5 (60.0%), NNT 1.7, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 12.
Natto, 7/29/2022, Randomized Controlled Trial, Saudi Arabia, peer-reviewed, 7 authors, study period June 2021 - July 2021, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04941131 (history), excluded in exclusion analyses: study only provides short-term viral load results. risk of viral load, 73.6% lower, RR 0.26, p = 0.27, treatment 12, control 12, relative improvement in Ct value, both genes combined.
risk of viral load, 96.2% lower, RR 0.04, p = 0.12, treatment mean 4.43 (±4.78) n=12, control mean 0.17 (±7.67) n=12, relative improvement in Ct value, E gene.
risk of viral load, 44.4% lower, RR 0.56, p = 0.60, treatment mean 3.33 (±5.6) n=12, control mean 1.85 (±7.68) n=12, relative improvement in Ct value, S gene.
Pablo-Marcos, 10/25/2021, prospective, Spain, peer-reviewed, mean age 43.0, 6 authors, study period May 2020 - November 2020, excluded in exclusion analyses: unadjusted results with no group details. relative viral load, 29.2% better, RR 0.71, p = 0.40, treatment 31, control 40, 3rd PCR (mid-recovery).
relative viral load, 9.1% better, RR 0.91, p = 0.91, treatment 31, control 40, 4th PCR (most patients recovered).
Sevinç Gül, 7/29/2022, Randomized Controlled Trial, Turkey, peer-reviewed, 4 authors, study period 1 September, 2021 - 1 December, 2021, this trial compares with another treatment - results may be better when compared to placebo, trial NCT05214196 (history), excluded in exclusion analyses: study only provides short-term viral load results. risk of viral load, 99.5% lower, RR 0.005, p = 0.37, treatment mean 1.85 (±7.06) n=21, control mean 0.01 (±5.89) n=20, relative improvement in Ct value.
Sirijatuphat, 8/22/2022, prospective, Thailand, preprint, median age 34.0, 4 authors, study period 15 February, 2021 - 15 March, 2021, trial TCTR20210125002, excluded in exclusion analyses: study only provides short-term viral load results. viral load, 33.3% lower, relative load 0.67, p = 0.58, after median 2560.0 IQR 17790.0 n=12, before median 3840.0 IQR 9600.0 n=12, before values 640.0 640.0 40960.0 2560.0 10240.0 10240.0 640.0 2560.0 10240.0 5120.0 40960.0 640.0, after values 10.0 40.0 2560.0 40960.0 5120.0 1280.0 160.0 2560.0 40960.0 40960.0 10240.0 40.0, relative median viral titer, 3 min, left vs. baseline, Mann-Whitney, Table 3.
viral load, 87.5% lower, relative load 0.12, p = 0.04, after median 480.0 IQR 4340.0 n=12, before median 3840.0 IQR 9600.0 n=12, before values 640.0 640.0 40960.0 2560.0 10240.0 10240.0 640.0 2560.0 10240.0 5120.0 40960.0 640.0, after values 80.0 160.0 10240.0 320.0 320.0 10240.0 40.0 640.0 640.0 40960.0 2560.0 0.0, relative median viral titer, 3 min, right vs. baseline, Mann-Whitney, Table 3.
viral load, 83.3% lower, relative load 0.17, p = 0.11, after median 640.0 IQR 6240.0 n=12, before median 3840.0 IQR 9600.0 n=12, before values 640.0 640.0 40960.0 2560.0 10240.0 10240.0 640.0 2560.0 10240.0 5120.0 40960.0 640.0, after values 160.0 10.0 10240.0 640.0 160.0 1280.0 320.0 640.0 5120.0 40960.0 20480.0 0.0, relative median viral titer, 4 hours, right vs. baseline, Mann-Whitney, Table 3.
Sulistyani, 3/15/2022, Single Blind Randomized Controlled Trial, Indonesia, peer-reviewed, 9 authors, study period July 2021 - September 2021. relative improvement in Ct value, 6.3% better, RR 0.94, p = 0.74, treatment mean 12.905 (±5.96) n=15, control mean 12.088 (±7.38) n=15, 1% PVP-I vs. water, day 5.
relative improvement in Ct value, 11.3% better, RR 0.89, p = 0.54, treatment mean 13.628 (±6.28) n=15, control mean 12.088 (±7.38) n=15, 0.5% PVP-I vs. water, day 5.
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.
Fantozzi, 7/28/2022, Randomized Controlled Trial, Italy, peer-reviewed, 14 authors, study period December 2020 - May 2021, this trial compares with another treatment - results may be better when compared to placebo, excluded in exclusion analyses: study only provides short-term viral load results. risk of no viral clearance, 31.2% lower, RR 0.69, p = 0.26, treatment 5 of 8 (62.5%), control 10 of 11 (90.9%), NNT 3.5, T2.
risk of no viral clearance, 58.7% lower, RR 0.41, p = 0.04, treatment 3 of 8 (37.5%), control 10 of 11 (90.9%), NNT 1.9, T1.
Ferrer, 12/22/2021, Randomized Controlled Trial, Spain, peer-reviewed, 19 authors, excluded in exclusion analyses: study only provides short-term viral load results. relative viral load reduction, 34.0% better, RR 0.66, p = 0.82, treatment 9, control 12, PVP-I vs. water, data from Table S1.
relative viral load T4 vs. T1, 93.0% better, RR 0.07, p = 0.35, treatment 9, control 9, data from Table S1.
Jamir, 12/13/2021, retrospective, India, peer-reviewed, 6 authors, study period June 2020 - October 2020. risk of death, 57.0% lower, HR 0.43, p < 0.001, treatment 39 of 163 (23.9%), control 62 of 103 (60.2%), NNT 2.8, adjusted per study, multivariable, Cox proportional hazards.
Seneviratne, 12/14/2020, Randomized Controlled Trial, Singapore, peer-reviewed, 12 authors, study period June 2020 - August 2020, excluded in exclusion analyses: study only provides short-term viral load results. relative fold change, 32.9% better, RR 0.67, p < 0.01, treatment 4, control 2, PVP-I vs. water, 6 hours.
Zarabanda, 11/1/2021, Randomized Controlled Trial, USA, peer-reviewed, 13 authors, average treatment delay 7.0 days, this trial compares with another treatment - results may be better when compared to placebo. risk of no recovery, 26.9% higher, RR 1.27, p = 1.00, treatment 3 of 13 (23.1%), control 2 of 11 (18.2%), 2%.
risk of no recovery, 50.0% higher, RR 1.50, p = 1.00, treatment 3 of 11 (27.3%), control 2 of 11 (18.2%), 0.5%.
risk of no viral clearance, no change, RR 1.00, p = 1.00, treatment 2 of 7 (28.6%), control 2 of 7 (28.6%), day 5, minus strand PCR.
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.
Keating, 6/30/2022, Randomized Controlled Trial, USA, this trial uses multiple treatments in the treatment arm (combined with chlorhexidine) - results of individual treatments may vary, trial NCT04478019 (history) (SHIELD). 245 patient RCT with results unknown and over 1.5 years late.
Seet, 4/14/2021, Cluster Randomized Controlled Trial, Singapore, peer-reviewed, 15 authors, study period 13 May, 2020 - 31 August, 2020, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04446104 (history). risk of symptomatic case, 44.7% lower, RR 0.55, p = 0.002, treatment 42 of 735 (5.7%), control 64 of 619 (10.3%), NNT 22.
risk of case, 31.1% lower, RR 0.69, p = 0.01, treatment 338 of 735 (46.0%), control 433 of 619 (70.0%), NNT 4.2, adjusted per study, odds ratio converted to relative risk, model 6.
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. Vaccines and treatments are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment, vaccine, 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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