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Vitamin C for COVID-19: real-time meta analysis of 73 studies (71 treatment studies and 2 sufficiency studies)

@CovidAnalysis, June 2024, Version 78V78
 
0 0.5 1 1.5+ All studies 21% 71 88,767 Improvement, Studies, Patients Relative Risk Mortality 19% 42 48,527 Ventilation 9% 10 12,076 ICU admission 14% 7 10,322 Hospitalization 19% 15 18,949 Recovery 29% 10 2,182 Cases 3% 7 32,285 Viral clearance -5% 2 236 RCTs 20% 21 4,605 RCT mortality 14% 14 4,038 Peer-reviewed 22% 64 85,216 High dose IV 20% 22 4,758 Symptomatic 24% 67 62,955 Prophylaxis 19% 17 62,441 Early 39% 7 1,843 Late 20% 47 24,483 Vitamin C for COVID-19 c19early.org June 2024 after exclusions Favorsvitamin C Favorscontrol
Abstract
Statistically significant lower risk is seen for mortality, ICU admission, hospitalization, and recovery. 24 studies from 24 independent teams in 12 countries show significant improvements.
Meta analysis using the most serious outcome reported shows 21% [14‑27%] lower risk. Results are similar for Randomized Controlled Trials, higher quality studies, and peer-reviewed studies. Clinical outcomes suggest benefit while viral and case outcomes do not, consistent with an intervention that aids the immune system or recovery but may have limited antiviral effects. Early treatment is more effective than late treatment.
Results are robust — in exclusion sensitivity analysis 29 of 71 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
6 RCTs with 1,420 patients have not reported results (up to 3 years late).
The European Food Safety Authority has found evidence for a causal relationship between the intake of vitamin C and optimal immune system function1,2.
Early cessation of high dose IV treatment may result in a detrimental rebound effect3. Ongoing treatment is more effective than early cessation: 33% [22‑42%] vs. 16% [-31‑46%].
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 more effective. The quality of non-prescription supplements can vary widely and the quantity of the active ingredient may be significantly lower than stated4-6.
All data to reproduce this paper and sources are in the appendix. 6 other meta analyses show significant improvements with vitamin C for mortality7-10, progression11, severity7, and cases12.
Evolution of COVID-19 clinical evidence Vitamin C p=0.000000038 Acetaminophen p=0.00000029 2020 2021 2022 2023 2024 Effective Harmful c19early.org June 2024 meta analysis results (pooled effects) 100% 50% 0% -50%
Vitamin C for COVID-19 — Highlights
Vitamin C reduces risk with very high confidence for mortality, hospitalization, recovery, and in pooled analysis, high confidence for ICU admission, and low confidence for progression.
6th treatment shown effective with ≥3 clinical studies in September 2020, now with p = 0.000000038 from 71 studies, and recognized in 12 countries.
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+ Su -135% 2.35 [0.67-8.27] progression n/a n/a Improvement, RR [CI] Treatment Control COVIDAtoZ Thomas (RCT) -204% 3.04 [0.13-72.9] death 1/48 0/50 Zhao (PSM) 72% 0.28 [0.08-0.93] progression 4/55 12/55 Ried (RCT) 31% 0.69 [0.54-0.89] no recov. 69/162 46/75 Usanma Koban 33% 0.67 [0.07-5.38] viral+ 31 (n) 95 (n) Madamombe 53% 0.47 [0.31-0.71] death 672 (all patients) Rahman 40% 0.60 [0.47-0.76] hosp. 128/476 56/124 Tau​2 = 0.04, I​2 = 40.2%, p = 0.00035 Early treatment 39% 0.61 [0.47-0.80] 202/772 114/399 39% lower risk Krishnan 31% 0.69 [0.47-0.92] death 40/79 52/73 Improvement, RR [CI] Treatment Control Zhang (RCT) 50% 0.50 [0.20-1.50] death 6/27 11/29 ICU patients Yüksel (ICU) 19% 0.81 [0.66-0.99] death 31/42 40/44 ICU patients Patel 29% 0.71 [0.43-1.14] death 22/96 26/80 Kumari (RCT) 36% 0.64 [0.26-1.55] death 7/75 11/75 Darban (RCT) 33% 0.67 [0.14-3.17] progression 2/10 3/10 ICU patients CT​2 Jang 51% 0.49 [0.23-1.01] no recov. 5/12 6/7 ECMO patients JamaliMo.. (RCT) 0% 1.00 [0.22-4.56] death 3/30 3/30 Gao 86% 0.14 [0.03-0.72] death 1/46 5/30 Hamidi-A.. (RCT) 44% 0.56 [0.20-1.51] death 5/40 9/40 CT​2 Al Sulaiman (PSM) 15% 0.85 [0.61-1.12] death 46/142 59/142 Mulhem -32% 1.32 [1.07-1.62] death 157/794 359/2,425 Gadhiya -1% 1.01 [0.48-1.91] death 19/55 36/226 Hakamifard (RCT) 46% 0.54 [0.14-2.08] ICU 3/38 5/34 CT​2 Elhadi (ICU) -12% 1.12 [0.96-1.31] death 175/277 106/188 ICU patients Suna 21% 0.79 [0.44-1.41] death 17/153 24/170 Pourhoseingholi 13% 0.87 [0.63-1.19] death 54/199 285/2,269 Li (ICU) -11% 1.11 [0.79-1.54] death 7/8 19/24 ICU patients Vishnuram 54% 0.46 [0.24-0.86] death 164/8,634 10/241 Özgünay (ICU) 9% 0.91 [0.63-1.30] death 17/32 75/128 ICU patients Tan 25% 0.75 [0.10-2.98] death/int. 1/46 14/115 CT​2 Zheng (PSM) -157% 2.57 [0.39-16.8] death 12/70 7/327 Simsek 44% 0.56 [0.23-1.35] death 6/58 15/81 Tehrani (RCT) 87% 0.13 [0.01-2.25] death 0/18 4/26 Majidi (DB RCT) 14% 0.86 [0.76-0.98] death 26/31 67/69 ICU patients Baguma -48% 1.48 [0.41-4.70] death 385 (n) 96 (n) Tu 83% 0.17 [0.08-0.35] death 8/116 26/64 Yang (RCT) 33% 0.67 [0.55-0.81] recov. time 10 (n) 10 (n) CT​2 Gavrielatou (ICU) 58% 0.42 [0.12-1.48] death 2/10 49/103 ICU patients Salehi (ICU) 10% 0.90 [0.65-1.25] death 22/40 52/85 ICU patients Coppock (RCT) 5% 0.95 [0.16-7.84] progression 4/44 2/22 Hess (PSW) 20% 0.80 [0.40-1.60] death 10/25 37/75 Zangeneh (ICU) 4% 0.96 [0.64-1.45] death n/a n/a ICU patients LINCOLN Izzo 41% 0.59 [0.50-0.69] recovery 869 (n) 521 (n) LONG COVID OT​1 CT​2 Fogleman (DB RCT) 4% 0.96 [0.65-1.40] recovery 32 (n) 34 (n) Kumar (DB RCT) 23% 0.77 [0.40-1.47] death 10/30 13/30 ICU patients Özgülteki̇n (ICU) -5% 1.05 [0.81-1.36] death 18/21 18/22 ICU patients Doocy 63% 0.37 [0.08-1.82] death 2/64 22/80 Labbani-.. (DB RCT) 33% 0.67 [0.20-2.17] death 4/37 6/37 Coskun (ICU) 25% 0.75 [0.48-1.15] death 17/38 24/40 ICU patients Kyagambiddwa 50% 0.50 [0.24-1.04] death 246 (all patients) Rana (DB RCT) 55% 0.45 [0.16-1.27] death 5/139 11/139 ICU patients Mousaviasl (DB RCT) 20% 0.80 [0.32-1.98] death 8/201 10/200 Seely (DB RCT) 48% 0.52 [0.10-2.71] progression 2/42 4/44 CT​2 REMAP-CAP Adhikari (RCT) -19% 1.19 [0.98-1.46] death 1,303 (n) 903 (n) LOVIT-COVID Adhikari (DB RCT) 28% 0.72 [0.45-1.17] death 190 (n) 194 (n) SAFE EVICT CORONA-ALI Fowler (DB RCT) 19% 0.81 [0.30-2.19] death 5/22 7/25 ICU patients Tau​2 = 0.06, I​2 = 65.4%, p < 0.0001 Late treatment 20% 0.80 [0.72-0.89] 943/14,630 1,532/9,607 20% lower risk Behera 18% 0.82 [0.45-1.57] cases case control Improvement, RR [CI] Treatment Control Louca 0% 1.00 [0.97-1.04] cases population-based cohort Mahto -26% 1.26 [0.63-2.28] IgG+ 34/140 59/549 Bejan 34% 0.66 [0.29-1.53] death 569 (n) 8,637 (n) COVIDENCE UK Holt -3% 1.03 [0.77-1.39] cases 49/1,580 397/13,647 Abdulateef 19% 0.81 [0.37-1.78] hosp. 8/132 22/295 Aldwihi 36% 0.64 [0.45-0.86] hosp. 142/505 95/233 Mohseni -44% 1.44 [1.22-1.71] cases 34/43 307/560 Nimer 25% 0.75 [0.54-1.04] hosp. 52/651 167/1,497 Shehab 4% 0.96 [0.46-1.99] severe case 14/139 12/114 Loucera 28% 0.72 [0.58-0.88] death 840 (n) 15,128 (n) Guldemir 31% 0.69 [0.48-0.99] hosp. 33/173 84/304 Sharif 46% 0.54 [0.01-0.92] severe case n/a n/a Asoudeh 69% 0.31 [0.14-0.65] severe case 250 (all patients) Vaisi 38% 0.62 [0.31-1.23] hosp. 2,818 (n) 1,137 (n) Akbar 14% 0.86 [0.65-1.14] cases 665 (n) 9,335 (n) Guan 31% 0.69 [0.50-0.86] symp. case 28/46 2,017/2,454 Tau​2 = 0.06, I​2 = 81.5%, p = 0.0058 Prophylaxis 19% 0.81 [0.70-0.94] 394/8,301 3,160/53,890 19% lower risk All studies 21% 0.79 [0.73-0.86] 1,539/23,703 4,806/63,896 21% lower risk 71 vitamin C COVID-19 studies c19early.org June 2024 Tau​2 = 0.06, I​2 = 74.2%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 OT: comparison with other treatment2 CT: study uses combined treatment Favors vitamin C Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Su -135% progression Improvement Relative Risk [CI] COVIDAtoZ Thomas (RCT) -204% death Zhao (PSM) 72% progression Ried (RCT) 31% recovery Usanma Koban 33% viral- Madamombe 53% death Rahman 40% hospitalization Tau​2 = 0.04, I​2 = 40.2%, p = 0.00035 Early treatment 39% 39% lower risk Krishnan 31% death Zhang (RCT) 50% death ICU patients Yüksel (ICU) 19% death ICU patients Patel 29% death Kumari (RCT) 36% death Darban (RCT) 33% progression ICU patients CT​2 Jang 51% recovery ECMO patients JamaliM.. (RCT) 0% death Gao 86% death Hamidi-.. (RCT) 44% death CT​2 Al Sulai.. (PSM) 15% death Mulhem -32% death Gadhiya -1% death Hakamifard (RCT) 46% ICU admission CT​2 Elhadi (ICU) -12% death ICU patients Suna 21% death Pourhoseingholi 13% death Li (ICU) -11% death ICU patients Vishnuram 54% death Özgünay (ICU) 9% death ICU patients Tan 25% death/intubation CT​2 Zheng (PSM) -157% death Simsek 44% death Tehrani (RCT) 87% death Majidi (DB RCT) 14% death ICU patients Baguma -48% death Tu 83% death Yang (RCT) 33% recovery CT​2 Gavrielatou (ICU) 58% death ICU patients Salehi (ICU) 10% death ICU patients Coppock (RCT) 5% progression Hess (PSW) 20% death Zangeneh (ICU) 4% death ICU patients LINCOLN Izzo 41% recovery LONG COVID OT​1 CT​2 Fogleman (DB RCT) 4% recovery Kumar (DB RCT) 23% death ICU patients Özgülteki̇n (ICU) -5% death ICU patients Doocy 63% death Labbani.. (DB RCT) 33% death Coskun (ICU) 25% death ICU patients Kyagambiddwa 50% death Rana (DB RCT) 55% death ICU patients Mousavi.. (DB RCT) 20% death Seely (DB RCT) 48% progression CT​2 REMAP-CAP Adhikari (RCT) -19% death LOVIT-COVID Adhikari (DB RCT) 28% death SAFE EVICT CORONA-ALI Fowler (DB RCT) 19% death ICU patients Tau​2 = 0.06, I​2 = 65.4%, p < 0.0001 Late treatment 20% 20% lower risk Behera 18% case Louca 0% case Mahto -26% IgG positive Bejan 34% death COVIDENCE UK Holt -3% case Abdulateef 19% hospitalization Aldwihi 36% hospitalization Mohseni -44% case Nimer 25% hospitalization Shehab 4% severe case Loucera 28% death Guldemir 31% hospitalization Sharif 46% severe case Asoudeh 69% severe case Vaisi 38% hospitalization Akbar 14% case Guan 31% symp. case Tau​2 = 0.06, I​2 = 81.5%, p = 0.0058 Prophylaxis 19% 19% lower risk All studies 21% 21% lower risk 71 vitamin C C19 studies c19early.org June 2024 Tau​2 = 0.06, I​2 = 74.2%, p < 0.0001 Effect extraction pre-specifiedRotate device for footnotes/details Favors vitamin C Favors control
B
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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 vitamin C 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 RCTs only was delayed by 5.6 months, compared to using all 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 injury13-20 and cognitive deficits15,20, cardiovascular complications21, 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,22-26, providing many therapeutic targets for which many existing compounds have known activity. Scientists have predicted that over 7,000 compounds may reduce COVID-19 risk27, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications.
Vitamin C has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function1,2,28. Vitamin C plays a key role in the immune system, supporting the production and function of leukocytes, or white blood cells, which defend against infection and disease, including the production of lymphocytes, which make antibodies, and enhancing phagocytosis, the process by which immune system cells ingest and destroy viruses and infected cells. Vitamin C is an antioxidant, protecting cells from damage caused by free radicals. Vitamin C inhibits SARS-CoV-2 3CLpro29,30 and inhibits SARS-CoV-2 infection by reducing ACE2 levels in a dose-dependent manner31. Intracellular levels of vitamin C decline during COVID-19 hospitalization suggesting ongoing utilization and depletion of vitamin C32. Threonic acid, a metabolite of vitamin C, is lower in mild and severe cases, consistent with increased need for and metabolization of vitamin C with moderate infection, but more limited ability to produce threonic acid in severe infection due to depletion or existing lower levels of vitamin C33. Symptomatic COVID-19 is associated with a lower frequency of natural killer (NK) cells, and vitamin C has been shown to improve NK cell numbers and functioning34,35.
Studies have shown efficacy with vitamin C for the common cold36 and acute respiratory tract infections37.
We analyze all significant controlled studies of vitamin C 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.
Preclinical Research
Vitamin C inhibits SARS-CoV-2 3CLpro29,30 and inhibits SARS-CoV-2 infection by reducing ACE2 levels in a dose-dependent manner31.
6 In Silico studies support the efficacy of vitamin C30,38-42.
6 In Vitro studies support the efficacy of vitamin C29-31,43-45.
An In Vivo animal study supports the efficacy of vitamin C31.
Preclinical research is an important part of the development of treatments, however results may be very different in clinical trials. Preclinical results are not used in this paper.
Results
Table 1 summarizes the results for all stages combined, for Randomized Controlled Trials, for peer-reviewed studies, after exclusions, and for specific outcomes. Table 2 shows results by treatment stage. Figure 3 plots individual results by treatment stage. Figure 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, and 17 show forest plots for random effects meta-analysis of all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, progression, recovery, cases, viral clearance, high dose IV studies, high-dose IV RCTs with early cessation vs. ongoing treatment, sufficiency studies, peer reviewed studies, and non-symptomatic vs. symptomatic results.
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<0.05  ** p<0.01  *** p<0.001  **** p<0.0001.
Improvement Studies Patients Authors
All studies21% [14‑27%]
****
71 88,767 770
After exclusions26% [16‑34%]
****
40 55,941 490
Peer-reviewed studiesPeer-reviewed22% [15‑29%]
****
64 85,216 689
Randomized Controlled TrialsRCTs20% [9‑30%]
**
21 4,605 288
Mortality19% [9‑27%]
***
42 48,527 484
VentilationVent.9% [-12‑27%]10 12,076 166
ICU admissionICU14% [3‑24%]
*
7 10,322 65
HospitalizationHosp.19% [6‑30%]
**
15 18,949 139
Recovery29% [22‑35%]
****
10 2,182 98
Cases3% [-16‑19%]7 32,285 96
Viral-5% [-73‑36%]2 236 18
RCT mortality14% [-2‑28%]14 4,038 227
RCT hospitalizationRCT hosp.9% [-9‑24%]8 856 101
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<0.05  ** p<0.01  *** p<0.001  **** p<0.0001.
Early treatment Late treatment Prophylaxis
All studies39% [20‑53%]
***
20% [11‑28%]
****
19% [6‑30%]
**
After exclusions30% [-9‑55%]24% [10‑36%]
**
26% [11‑38%]
**
Peer-reviewed studiesPeer-reviewed39% [20‑53%]
***
22% [12‑32%]
***
19% [6‑30%]
**
Randomized Controlled TrialsRCTs30% [10‑46%]
**
19% [6‑30%]
**
Mortality40% [-105‑82%]16% [6‑25%]
**
29% [13‑42%]
**
VentilationVent.8% [-15‑27%]25% [-62‑65%]
ICU admissionICU14% [0‑26%]
*
15% [-69‑57%]
HospitalizationHosp.40% [24‑53%]
****
9% [-10‑24%]29% [18‑38%]
****
Recovery25% [10‑37%]
**
29% [21‑36%]
****
Cases3% [-16‑19%]
Viral-5% [-73‑36%]
RCT mortality-204% [-7189‑87%]15% [-2‑29%]
RCT hospitalizationRCT hosp.31% [-298‑88%]9% [-10‑24%]
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Figure 3. Scatter plot showing the most serious outcome in all studies, and for studies within each stage. Diamonds shows the results of random effects meta-analysis.
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Figure 4. Random effects meta-analysis for all studies. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. For details see the appendix.
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Figure 5. Random effects meta-analysis for mortality results.
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Figure 6. Random effects meta-analysis for ventilation.
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Figure 7. Random effects meta-analysis for ICU admission.
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Figure 8. Random effects meta-analysis for hospitalization.
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Figure 9. Random effects meta-analysis for progression.
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Figure 10. Random effects meta-analysis for recovery.
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Figure 11. Random effects meta-analysis for cases.
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Figure 12. Random effects meta-analysis for viral clearance.
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Figure 13. Random effects meta-analysis for high dose IV studies. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details. Analysis validating pooled outcomes for COVID-19 can be found below.
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Figure 14. Random effects meta-analysis for high-dose IV RCTs with early cessation vs. ongoing treatment. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details. Analysis validating pooled outcomes for COVID-19 can be found below.
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Figure 15. Random effects meta-analysis for sufficiency studies. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details. Analysis validating pooled outcomes for COVID-19 can be found below.
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Figure 16. Random effects meta-analysis for peer reviewed studies. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details. Analysis validating pooled outcomes for COVID-19 can be found below. Zeraatkar et al. analyze 356 COVID-19 trials, finding no significant evidence that preprint results are inconsistent with peer-reviewed studies. They also show extremely long peer-review delays, with a median of 6 months to journal publication. A six month delay was equivalent to around 1.5 million deaths during the first two years of the pandemic. Authors recommend using preprint evidence, with appropriate checks for potential falsified data, which provides higher certainty much earlier. Davidson et al. also showed no important difference between meta analysis results of preprints and peer-reviewed publications for COVID-19, based on 37 meta analyses including 114 trials.
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Figure 17. Random effects meta-analysis for non-symptomatic vs. symptomatic results. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details. Analysis validating pooled outcomes for COVID-19 can be found below.
Randomized Controlled Trials (RCTs)
Figure 18 shows a comparison of results for RCTs and non-RCT studies. Figure 19, 20, and 21 show forest plots for random effects meta-analysis of all Randomized Controlled Trials, RCT mortality results, and RCT hospitalization results. RCT results are included in Table 1 and Table 2.
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Figure 18. Results for RCTs and non-RCT studies.
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Figure 19. Random effects meta-analysis for all Randomized Controlled Trials. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. For details see the appendix.
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Figure 20. Random effects meta-analysis for RCT mortality results.
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Figure 21. Random effects meta-analysis for RCT hospitalization results.
RCTs help to make study groups more similar and can provide a higher level of evidence, however they are subject to many biases48, and analysis of double-blind RCTs has identified extreme levels of bias49. For COVID-19, the overhead may delay treatment, dramatically compromising efficacy; they may encourage monotherapy for simplicity at the cost of efficacy which may rely on combined or synergistic effects; the participants that sign up may not reflect real world usage or the population that benefits most in terms of age, comorbidities, severity of illness, or other factors; standard of care may be compromised and unable to evolve quickly based on emerging research for new diseases; errors may be made in randomization and medication delivery; and investigators may have hidden agendas or vested interests influencing design, operation, analysis, reporting, and the potential for fraud. All of these biases have been observed with COVID-19 RCTs. There is no guarantee that a specific RCT provides a higher level of evidence.
RCTs are expensive and many RCTs are funded by pharmaceutical companies or interests closely aligned with pharmaceutical companies. For COVID-19, this creates an incentive to show efficacy for patented commercial products, and an incentive to show a lack of efficacy for inexpensive treatments. The bias is expected to be significant, for example Als-Nielsen et al. analyzed 370 RCTs from Cochrane reviews, showing that trials funded by for-profit organizations were 5 times more likely to recommend the experimental drug compared with those funded by nonprofit organizations. For COVID-19, some major philanthropic organizations are largely funded by investments with extreme conflicts of interest for and against specific COVID-19 interventions.
High quality RCTs for novel acute diseases are more challenging, with increased ethical issues due to the urgency of treatment, increased risk due to enrollment delays, and more difficult design with a rapidly evolving evidence base. For COVID-19, the most common site of initial infection is the upper respiratory tract. Immediate treatment is likely to be most successful and may prevent or slow progression to other parts of the body. For a non-prophylaxis RCT, it makes sense to provide treatment in advance and instruct patients to use it immediately on symptoms, just as some governments have done by providing medication kits in advance. Unfortunately, no RCTs have been done in this way. Every treatment RCT to date involves delayed treatment. Among the 75 treatments we have analyzed, 64% of RCTs involve very late treatment 5+ days after onset. No non-prophylaxis COVID-19 RCTs match the potential real-world use of early treatments. They may more accurately represent results for treatments that require visiting a medical facility, e.g., those requiring intravenous administration.
RCTs have a bias against finding an effect for interventions that are widely available — patients that believe they need the intervention are more likely to decline participation and take the intervention. RCTs for vitamin C are more likely to enroll low-risk participants that do not need treatment to recover, making the results less applicable to clinical practice. This bias is likely to be greater for widely known treatments, and may be greater when the risk of a serious outcome is overstated. This bias does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable.
Evidence shows that non-RCT studies can also provide reliable results. Concato et al. found that well-designed observational studies do not systematically overestimate the magnitude of the effects of treatment compared to RCTs. Anglemyer et al. 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 may have a greater effect on results. Ethical issues may also prevent running RCTs for known effective treatments. For more on issues with RCTs see54,55.
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. Of these, 30 have been confirmed in RCTs, with a mean delay of 7.0 months. When considering only low cost treatments, 25 have been confirmed with a delay of 8.4 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.
Unreported RCTs
6 vitamin C RCTs have not reported results56-61. The trials report a total of 1,420 patients, with 3 trials having actual enrollment of 602, and the remainder estimated. The results are delayed from 1 year to over 3 years.
Exclusions
To avoid bias in the selection of studies, we analyze all non-retracted studies. Here we show the results after excluding studies with major issues likely to alter results, non-standard studies, and studies where very minimal detail is currently available. Our bias evaluation is based on analysis of each study and identifying when there is a significant chance that limitations will substantially change the outcome of the study. We believe this can be more valuable than checklist-based approaches such as Cochrane GRADE, which can be easily influenced by potential bias, may ignore or underemphasize serious issues not captured in the checklists, and may overemphasize issues unlikely to alter outcomes in specific cases (for example certain specifics of randomization with a very large effect size and well-matched baseline characteristics).
The studies excluded are as below. Figure 22 shows a forest plot for random effects meta-analysis of all studies after exclusions.
Abdulateef, unadjusted results with no group details.
Coskun, very late stage, ICU patients.
Darban, very late stage, ICU patients.
Elhadi, unadjusted results with no group details; very late stage, ICU patients.
Fowler, very late stage, ICU patients.
Gadhiya, substantial unadjusted confounding by indication likely.
Gavrielatou, very late stage, ICU patients.
Guldemir, unadjusted results with no group details.
Holt, significant unadjusted confounding possible.
Jang, very late stage, ECMO patients.
Krishnan, unadjusted results with no group details.
Kumar (B), very late stage, ICU patients.
Li, very late stage, ICU patients.
Majidi, very late stage, ICU patients.
Mohseni, unadjusted results with no group details.
Mulhem, substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
Rahman, unadjusted results with no group details; significant unadjusted confounding possible.
Rana, very late stage, ICU patients.
Salehi, unadjusted results with no group details; very late stage, ICU patients.
Shehab, unadjusted results with no group details.
Suna, substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
Tu, unadjusted results with no group details.
Vishnuram, unadjusted results with no group details; minimal details of groups provided.
Yang (B), combined treatments may contribute significantly to the effect seen.
Yüksel, very late stage, ICU patients.
Zangeneh, very late stage, ICU patients.
Zhang, very late stage, ICU patients.
Zhao, substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
Zheng, substantial unadjusted confounding by indication likely; immortal time bias may significantly affect results; treatment start times unknown, treatment may not have started at baseline.
Özgülteki̇n, very late stage, ICU patients.
Özgünay, substantial unadjusted confounding by indication likely; very late stage, ICU patients.
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Figure 22. Random effects meta-analysis for all studies after exclusions. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. For details see the appendix.
Heterogeneity
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 hours93,94. 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 (C) 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 cases95
<24 hours-33 hours symptoms96
24-48 hours-13 hours symptoms96
Inpatients-2.5 hours to improvement97
Figure 23 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 23. 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 variants99, for example the Gamma variant shows significantly different characteristics100-103. 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 variants104,105.
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 synergistic106-116, 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 (B) et al. analyze a treatment from two different manufacturers, showing 9 different impurities, with significantly different concentrations for each manufacturer. Non-prescription supplements may show very wide variations in quality4,5.
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 24 shows that lower hospitalization is very strongly associated with lower mortality (p < 0.000000000001). Similarly, Figure 25 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 26 shows that improved viral clearance is strongly associated with fewer serious outcomes. The association is very similar to Singh et al., with higher confidence due to the larger number of studies. As with Singh et al., the confidence increases when excluding the outlier treatment, from p = 0.0000014 to p = 0.000000005.
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Figure 24. Lower hospitalization is associated with lower mortality, supporting pooled outcome analysis.
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Figure 25. Improved recovery is associated with lower mortality, supporting pooled outcome analysis.
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Figure 24. 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 27 shows when treatments were found effective during the pandemic. Pooled outcomes often resulted in earlier detection of efficacy.
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Figure 27. The time when studies showed that treatments were effective, defined as statistically significant improvement of ≥10% from ≥3 studies. Pooled results typically show efficacy earlier than specific outcome results. Results from all studies often shows efficacy much earlier than when restricting to RCTs. Results reflect conditions as used in trials to date, these depend on the population treated, treatment delay, and treatment regimen.
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.
Studies have also shown efficacy with vitamin C for the common cold36 and acute respiratory tract infections37.
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 results120-123.
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 28 shows a scatter plot of results for prospective and retrospective treatment studies. Prospective studies show 20% [8‑30%] improvement in meta analysis, compared to 22% [13‑29%] for retrospective studies, showing no significant difference.
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Figure 28. Prospective vs. retrospective studies. The diamonds show the results of random effects meta-analysis.
Studies for vitamin C were primarily late treatment studies, in contrast with typical patented treatments that were tested with early treatment as recommended.
Figure 29. Patented treatments received mostly early treatment studies, while low cost treatments were typically tested for late treatment.
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 30 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 < 0.05124-131. 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 30. 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. Vitamin C for COVID-19 lacks this because it is an inexpensive and widely available supplement. In contrast, most COVID-19 vitamin C 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 vitamin C trials represent the optimal conditions for efficacy.
Summary statistics from meta analysis necessarily lose information. As with all meta analyses, studies are heterogeneous, with differences in treatment delay, treatment regimen, patient demographics, variants, conflicts of interest, standard of care, and other factors. We provide analyses for specific outcomes and by treatment delay, and we aim to identify key characteristics in the forest plots and summaries. Results should be viewed in the context of study characteristics.
Some analyses classify treatment based on early or late administration, as done here, while others distinguish between mild, moderate, and severe cases. Viral load does not indicate degree of symptoms — for example patients may have a high viral load while being asymptomatic. With regard to treatments that have antiviral properties, timing of treatment is critical — late administration may be less helpful regardless of severity.
Details of treatment delay per patient is often not available. For example, a study may treat 90% of patients relatively early, but the events driving the outcome may come from 10% of patients treated very late. Our 5 day cutoff for early treatment may be too conservative, 5 days may be too late in many cases.
Comparison across treatments is confounded by differences in the studies performed, for example dose, variants, and conflicts of interest. Trials with conflicts of interest may use designs better suited to the preferred outcome.
In some cases, the most serious outcome has very few events, resulting in lower confidence results being used in pooled analysis, however the method is simpler and more transparent. This is less critical as the number of studies increases. Restriction to outcomes with sufficient power may be beneficial in pooled analysis and improve accuracy when there are few studies, however we maintain our pre-specified method to avoid any retrospective changes.
Studies show that combinations of treatments can be highly synergistic and may result in many times greater efficacy than individual treatments alone106-116. 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.
1 of the 71 studies compare against other treatments, which may reduce the effect seen. 7 of 71 studies combine treatments. The results of vitamin C alone may differ. 5 of 21 RCTs use combined treatment. 6 other meta analyses show significant improvements with vitamin C for mortality7-10, progression11, severity7, and cases12.
Many reviews cover vitamin C for COVID-19, presenting additional background on mechanisms and related results, including3,132-141.
NIH provides an analysis of vitamin C for COVID-19142, concluding that there is insufficient evidence to recommend for or against use. However, they appear not to have looked at the majority of the evidence. For example, considering RCTs providing clinical results for COVID-19 and vitamin C, they reference only88,143-145, and appear not to know about 17 other RCTs64,66,73,75,79,85,146-156 as shown in Figure 31. Notably, the NIH selection does not correspond to the most relevant and highest quality studies, for example including Zhang et al., with very late treatment of ICU patients.
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Figure 31. Analysis by NIH is missing 17 RCTs.
SARS-CoV-2 infection and replication involves a complex interplay of 50+ host and viral proteins and other factors22-26, providing many therapeutic targets. Over 7,000 compounds have been predicted to reduce COVID-19 risk27, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications. Figure 32 shows an overview of the results for vitamin C in the context of multiple COVID-19 treatments, and Figure 33 shows a plot of efficacy vs. cost for COVID-19 treatments.
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Figure 32. 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 efficacy157.
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Figure 33. Efficacy vs. cost for COVID-19 treatments.
Vitamin C is an effective treatment for COVID-19. Statistically significant lower risk is seen for mortality, ICU admission, hospitalization, and recovery. 24 studies from 24 independent teams in 12 countries show significant improvements. Meta analysis using the most serious outcome reported shows 21% [14‑27%] lower risk. Results are similar for Randomized Controlled Trials, higher quality studies, and peer-reviewed studies. Clinical outcomes suggest benefit while viral and case outcomes do not, consistent with an intervention that aids the immune system or recovery but may have limited antiviral effects. Early treatment is more effective than late treatment. 2 sufficiency studies analyze outcomes based on serum levels, showing 55% [-10‑81%] lower risk for patients with higher vitamin C levels. Results are robust — in exclusion sensitivity analysis 29 of 71 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
The European Food Safety Authority has found evidence for a causal relationship between the intake of vitamin C and optimal immune system function1,2.
Early cessation of high dose IV treatment may result in a detrimental rebound effect3. Ongoing treatment is more effective than early cessation: 33% [22‑42%] vs. 16% [-31‑46%].
6 other meta analyses show significant improvements with vitamin C for mortality7-10, progression11, severity7, and cases12.
Hospitalization 19% Improvement Relative Risk Vitamin C for COVID-19  Abdulateef et al.  Prophylaxis Is prophylaxis with vitamin C beneficial for COVID-19? Retrospective 427 patients in Iraq (July - August 2020) Study underpowered to detect differences c19early.org Abdulateef et al., Open Medicine, April 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Abdulateef: Survey of 428 recovered COVID-19 patients in Iraq, showing fewer hospital visits for patients on prophylactic vitamin C or D. Hospitalization was lower for those on vitamin C, D, or zinc, without statistical significance.
Mortality, combined 28% Improvement Relative Risk Mortality, LOVIT-COVID cri.. 28% Mortality, LOVIT-COVID.. 28% Mortality, REMAP-CAP crit.. -16% Mortality, REMAP-CAP n.. -27% Mortality, combined trials.. -6% Mortality, combined tria.. (b) -8% Mortality, combined tria.. (c) -6% Mortality, combined tria.. (d) -6% Ventilation, combined trials.. -35% Ventilation, combined tr.. (b) -69% Vitamin C  LOVIT-COVID  LATE TREATMENT  DB RCT Is late treatment with vitamin C beneficial for COVID-19? Double-blind RCT 1,560 patients in multiple countries Higher ventilation with vitamin C (p=0.038) c19early.org Adhikari et al., JAMA, October 2023 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Adhikari (B): Very late stage (APACHE II 8 and 12 for non-critical and critical) RCT with publication delayed over a year showing higher ventilation and no significant difference in mortality with vitamin C.

Authors have combined what was to be two separate trials into one trial, however there are very large differences between the trials. The results for each source trial are shown separately here146,147.

eTable 15 shows that results in LOVIT-COVID were substantially better than those in REMAP-CAP. eTable 13 shows improved survival for LOVIT-COVID and worse survival for REMAP-CAP (authors provide mortality breakdown only for hospital survival):

LOVIT-COVID shows 85% and 82% probability of superiority of vitamin C (critical and non-critical).
REMAP-CAP shows 12% and 7% probability of superiority of vitamin C.

Notably, LOVIT-COVID patients were blinded, while REMAP-CAP was open-label, introducing additional opportunity for bias on this highly politicized treatment. REMAP-CAP had more patients and dominates the combined results.

eFigure 8b also shows that the REMAP-CAP results were initially positive, switching to negative around September 2021. Authors note that they were unable to explain this reversal. The overall negative result is only due to the larger number of patients in the REMAP-CAP later time period.

Results for intubation are much worse than mortality, with statistically significant higher intubation for the treatment group. Hypothetically, if the actual risk matched other trials (~20% lower risk in meta analysis of 18 RCTs at the time), and there was something causing biased intubation of treatment patients in this mostly open-label trial, we may get the observed results whereby intubation is significantly worse due to the bias, but this has a muted effect on mortality which may reflect the change in risk due to intubation combined with that due to treatment.

Results varied dramatically over time. For example, during 22 Jan ‐ 21 Apr 2021, the probability of superiority for vitamin C was 1.0 for critical and 0.97 for non-critical (eTable 17).

There were dramatic changes in randomization proportions and in overall clinical outcomes over time, leading to potential issues and inaccuracies in the attempted adjustment for confounding by time.

The very long delay between the end of the trial and publication also raises questions.

See also Hemilä et al. which shows that the poor results may be explained by a rebound effect due to the abrupt termination of treatment after 4 days.

NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP). 50mg/kg vitamin C administered intravenously over 30-60 minutes every 6 hours for 4 days.
Mortality, combined -19% Improvement Relative Risk Mortality, REMAP-CAP crit.. -16% Mortality, REMAP-CAP n.. -27% Mortality, LOVIT-COVID cri.. 28% Mortality, LOVIT-COVID.. 28% Mortality, combined trials.. -6% Mortality, combined tria.. (b) -8% Mortality, combined tria.. (c) -6% Mortality, combined tria.. (d) -6% Ventilation, combined trials.. -35% Ventilation, combined tr.. (b) -69% Vitamin C  REMAP-CAP  LATE TREATMENT  RCT Is late treatment with vitamin C beneficial for COVID-19? RCT 2,206 patients in multiple countries Higher ventilation with vitamin C (p=0.038) c19early.org Adhikari et al., JAMA, October 2023 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Adhikari: Very late stage (APACHE II 8 and 12 for non-critical and critical) RCT with publication delayed over a year showing higher ventilation and no significant difference in mortality with vitamin C.

Authors have combined what was to be two separate trials into one trial, however there are very large differences between the trials. The results for each source trial are shown separately here146,147.

eTable 15 shows that results in LOVIT-COVID were substantially better than those in REMAP-CAP. eTable 13 shows improved survival for LOVIT-COVID and worse survival for REMAP-CAP (authors provide mortality breakdown only for hospital survival):

LOVIT-COVID shows 85% and 82% probability of superiority of vitamin C (critical and non-critical).
REMAP-CAP shows 12% and 7% probability of superiority of vitamin C.

Notably, LOVIT-COVID patients were blinded, while REMAP-CAP was open-label, introducing additional opportunity for bias on this highly politicized treatment. REMAP-CAP had more patients and dominates the combined results.

eFigure 8b also shows that the REMAP-CAP results were initially positive, switching to negative around September 2021. Authors note that they were unable to explain this reversal. The overall negative result is only due to the larger number of patients in the REMAP-CAP later time period.

Results for intubation are much worse than mortality, with statistically significant higher intubation for the treatment group. Hypothetically, if the actual risk matched other trials (~20% lower risk in meta analysis of 18 RCTs at the time), and there was something causing biased intubation of treatment patients in this mostly open-label trial, we may get the observed results whereby intubation is significantly worse due to the bias, but this has a muted effect on mortality which may reflect the change in risk due to intubation combined with that due to treatment.

Results varied dramatically over time. For example, during 22 Jan ‐ 21 Apr 2021, the probability of superiority for vitamin C was 1.0 for critical and 0.97 for non-critical (eTable 17).

There were dramatic changes in randomization proportions and in overall clinical outcomes over time, leading to potential issues and inaccuracies in the attempted adjustment for confounding by time.

The very long delay between the end of the trial and publication also raises questions.

See also Hemilä et al. which shows that the poor results may be explained by a rebound effect due to the abrupt termination of treatment after 4 days.

NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP). 50mg/kg vitamin C administered intravenously over 30-60 minutes every 6 hours for 4 days.
Case 14% Improvement Relative Risk Vitamin C for COVID-19  Akbar et al.  Prophylaxis Does vitamin C reduce COVID-19 infections? Retrospective 10,000 patients in Qatar (March - September 2020) Fewer cases with vitamin C (not stat. sig., p=0.29) c19early.org Akbar et al., Nutrients, November 2023 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Akbar: Retrospective 10,000 adults in Qatar, showing lower risk of COVID-19 cases with vitamin C supplementation, without statistical significance. Authors do not analyze COVID-19 severity.
Mortality 15% Improvement Relative Risk Vitamin C  Al Sulaiman et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? PSM retrospective 284 patients in Saudi Arabia Lower mortality with vitamin C (not stat. sig., p=0.27) c19early.org Al Sulaiman et al., Research Square, Apr 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Al Sulaiman: Retrospective 158 critically ill patients receiving vitamin C and propensity matched controls, showing mortality OR 0.77 [0.48-1.23], and statistically significantly lower thrombosis, OR 0.42 [0.18-0.94]. 1000mg of vitamin C was given daily.
Hospitalization 36% Improvement Relative Risk Vitamin C for COVID-19  Aldwihi et al.  Prophylaxis Is prophylaxis with vitamin C beneficial for COVID-19? Retrospective 738 patients in Saudi Arabia (August - October 2020) Lower hospitalization with vitamin C (p=0.0061) c19early.org Aldwihi et al., Int. J. Environmental .., May 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Aldwihi: Retrospective survey-based analysis of 738 COVID-19 patients in Saudi Arabia, showing lower hospitalization with vitamin C, turmeric, zinc, and nigella sativa, and higher hospitalization with vitamin D. For vitamin D, most patients continued prophylactic use. For vitamin C, the majority of patients continued prophylactic use. For nigella sativa, the majority of patients started use during infection. Authors do not specify the fraction of prophylactic use for turmeric and zinc.
Severe case 69% Improvement Relative Risk Vitamin C for COVID-19  Asoudeh et al.  Prophylaxis Is prophylaxis with vitamin C beneficial for COVID-19? Retrospective 250 patients in Iran (June - September 2021) Lower severe cases with vitamin C (p=0.0028) c19early.org Asoudeh et al., Clinical Nutrition ESPEN, Mar 2023 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Asoudeh: Retrospective 250 recovered COVID-19 patients, showing lower risk of severe cases with higher vitamin C intake.
Mortality -48% Improvement Relative Risk Vitamin C for COVID-19  Baguma et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Retrospective 481 patients in Uganda (March 2020 - October 2021) Higher mortality with vitamin C (not stat. sig., p=0.54) c19early.org Baguma et al., Research Square, December 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Baguma: Retrospective COVID+ hospitalized patients in Uganda, 385 patients receiving vitamin C treatment, showing higher mortality with treatment, without statistical significance.
Case 18% Improvement Relative Risk Case (b) 29% Vitamin C for COVID-19  Behera et al.  Prophylaxis Does vitamin C reduce COVID-19 infections? Retrospective 215 patients in India Fewer cases with vitamin C (not stat. sig., p=0.58) c19early.org Behera et al., PLoS ONE, November 2020 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Behera: Retrospective matched case-control prophylaxis study for HCQ, ivermectin, and vitamin C with 372 healthcare workers, showing lower COVID-19 incidence for all treatments, with statistical significance reached for ivermectin.

HCQ OR 0.56, p = 0.29
Ivermectin OR 0.27, p < 0.001
Vitamin C OR 0.82, p = 0.58
Mortality 34% Improvement Relative Risk Ventilation 25% ICU admission 15% Hospitalization 0% Vitamin C for COVID-19  Bejan et al.  Prophylaxis Is prophylaxis with vitamin C beneficial for COVID-19? Retrospective 9,748 patients in the USA Lower mortality (p=0.33) and ventilation (p=0.47), not sig. c19early.org Bejan et al., Clinical Pharmacology & .., Feb 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Bejan: Retrospective 9,748 COVID-19 patients in the USA showing lower risk of mortality, ventilation, and ICU admission with vitamin C prophylaxis, without statistical significance.
Critical case 56% Improvement Relative Risk Vitamin C for COVID-19  Boerenkamp et al.  Sufficiency Are vitamin C levels associated with COVID-19 outcomes? Prospective study of 70 patients in Netherlands (Dec 2020 - Mar 2021) Lower severe cases with higher vitamin C levels (not stat. sig., p=0.096) c19early.org Boerenkamp et al., Nutrients, August 2023 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Boerenkamp: Analysis of serum and intracellular vitamin C levels in hospitalized COVID-19 patients. Low vitamin C levels were common with 36% having serum levels <26 μmol/L and 15% <11 μmol/L.

Intracellular vitamin C levels in peripheral blood mononuclear cells (PBMCs) were low at admission and declined during hospitalization, suggesting ongoing utilization and depletion of vitamin C stores.

Critical patients had higher odds of low serum vitamin C levels. There was a weak negative correlation between serum vitamin C levels and severity, without statistical significance.
Boukef: 150 patient vitamin C early treatment RCT with results not reported over 1 year after completion.
Progression 5% Improvement Relative Risk Improvement 50% Discharge 22% Vitamin C  Coppock et al.  LATE TREATMENT  RCT Is late treatment with vitamin C beneficial for COVID-19? RCT 66 patients in the USA Greater improvement (p=0.16) and higher discharge (p=0.071), not sig. c19early.org Coppock et al., Life, March 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Coppock: RCT with 66 very late stage (8 days from symptom onset) hospitalized patients, 44 treated with vitamin C and 22 control patients, showing no significant differences with treatment.
Mortality 25% Improvement Relative Risk Ventilation 2% ICU time 0% no CI SOFA score, @96 hours 28% Vitamin C for COVID-19  Coskun et al.  ICU PATIENTS Is very late treatment with vitamin C beneficial for COVID-19? Retrospective 78 patients in Turkey (March - June 2020) Improved recovery with vitamin C (p=0.005) c19early.org Coskun et al., SiSli Etfal Hastanesi T.., Mar 2023 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Coskun: Retrospective 78 ICU patients in Turkey, showing lower mortality with high-dose vitamin C treatment, without statistical significance. The SOFA score was significantly better with treatment at day 4.

Authors incorrectly state that "HDVC treatment did not reduce the short-term mortality...". Mortality was lower with treatment, although not statistically significant given the sample size.

6g of vitamin C daily in 4 equal doses every 6h, for a total of 96h.
Progression 33% Improvement Relative Risk ICU time 6% Vitamin C  Darban et al.  ICU PATIENTS  RCT Is very late treatment with vitamin C + melatonin and zinc beneficial for COVID-19? RCT 20 patients in Iran (April - June 2020) Trial underpowered to detect differences c19early.org Darban et al., J. Cellular & Molecular.., Dec 2020 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Darban: Small RCT in Iran with 20 ICU patients, 10 treated with high-dose vitamin C, melatonin, and zinc, not showing significant differences.
Mortality 63% Improvement Relative Risk Vitamin C for COVID-19  Doocy et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Prospective study of 144 patients in multiple countries (Dec 2020 - Jun 2021) Lower mortality with vitamin C (not stat. sig., p=0.22) c19early.org Doocy et al., PLOS Global Public Health, Oct 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Doocy: Prospective study of 144 hospitalized COVID-19 patients in the DRC and South Sudan, showing lower mortality with vitamin C treatment.
Mortality -12% Improvement Relative Risk Vitamin C for COVID-19  Elhadi et al.  ICU PATIENTS Is very late treatment with vitamin C beneficial for COVID-19? Prospective study of 465 patients in Libya (May - December 2020) No significant difference in mortality c19early.org Elhadi et al., PLOS ONE, April 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Elhadi: Prospective study of 465 COVID-19 ICU patients in Libya showing no significant differences with treatment.
Recovery 4% Improvement Relative Risk Vitamin C  Fogleman et al.  LATE TREATMENT  DB RCT Is late treatment with vitamin C beneficial for COVID-19? Double-blind RCT 66 patients in the USA (October 2020 - June 2021) No significant difference in recovery c19early.org Fogleman et al., The J. the American B.., Jul 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Fogleman: Early terminated low-risk patient RCT with 32 low-dose vitamin C, 32 melatonin, and 34 placebo patients, showing faster resolution of symptoms with melatonin in spline regression analysis, and no significant difference for vitamin C. All patients recovered with no serious outcomes reported. Baseline symptoms scores were higher in the melatonin and vitamin C arms (median 27 and 24 vs. 18 for placebo).
Mortality 19% Improvement Relative Risk WHO status -2% Vitamin C  SAFE EVICT CORONA-ALI  ICU PATIENTS  DB RCT Is very late treatment with vitamin C beneficial for COVID-19? Double-blind RCT 47 patients in the USA Trial underpowered to detect differences c19early.org Fowler et al., NCT04344184, April 2024 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Fowler: RCT 47 ICU patients showing no significant differences with vitamin C treatment.
Mortality -1% Improvement Relative Risk Vitamin C for COVID-19  Gadhiya et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Retrospective 281 patients in the USA Study underpowered to detect differences c19early.org Gadhiya et al., BMJ Open, April 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Gadhiya: Retrospective 283 patients in the USA showing higher mortality with all treatments (not statistically significant). Confounding by indication is likely. In the supplementary appendix, authors note that the treatments were usually given for patients that required oxygen therapy. Oxygen therapy and ICU admission (possibly, the paper includes ICU admission for model 2 in some places but not others) were the only variables indicating severity used in adjustments.
Galindo: Estimated 160 patient vitamin C late treatment RCT with results not reported over 2 years after estimated completion.
Mortality 86% Improvement Relative Risk Vitamin C for COVID-19  Gao et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Retrospective 76 patients in China Lower mortality with vitamin C (p=0.037) c19early.org Gao et al., Aging, February 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Gao: Retrospective 76 COVID-19 patients, 46 treated with intravenous high-dose vitamin C, showing lower mortality and improved oxygen requirements with treatment. Dosage was 6g intravenous infusion per 12hr on the first day, and 6g once for the following 4 days.
Mortality 58% Improvement Relative Risk Vitamin C  Gavrielatou et al.  ICU PATIENTS Is very late treatment with vitamin C beneficial for COVID-19? Retrospective 113 patients in Greece (October 2020 - March 2021) Lower mortality with vitamin C (not stat. sig., p=0.11) c19early.org Gavrielatou et al., Frontiers in Medic.., Feb 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Gavrielatou: Retrospective 113 consecutive mechanically ventilated COVID+ ICU patients in Greece, 10 receiving high dose IV vitamin C, showing lower mortality with treatment, without statistical significance (p=0.11).

The associated meta analysis includes only 11 studies, while there are currently 71 studies, 42 with mortality results. Authors only include critical patients, however not all studies with critical patients are included, for example75,86,92,150. The meta analysis also uses unadjusted results, while PSM, Cox proportional hazards, or KM results are reported by88,90,159,166. For88 authors use 28 day mortality, while the study reports longer term in-hospital mortality.
Symp. case, high dose 31% Improvement Relative Risk Symp. case, medium dose 18% Symp. case, low dose 7% Vitamin C for COVID-19  Guan et al.  Prophylaxis Is prophylaxis with vitamin C beneficial for COVID-19? Retrospective 2,621 patients in China (December 2022 - January 2023) Fewer symptomatic cases with vitamin C (p=0.0073) c19early.org Guan et al., The American J. the Medic.., May 2024 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Guan: Retrospective 2,746 individuals in China showing significantly lower incidence of COVID-19 symptoms and fever with higher vitamin C intake, with a dose response relationship.
Hospitalization 31% Improvement Relative Risk Vitamin C for COVID-19  Guldemir et al.  Prophylaxis Is prophylaxis with vitamin C beneficial for COVID-19? Retrospective 477 patients in Turkey (March - September 2020) Lower hospitalization with vitamin C (p=0.046) c19early.org Guldemir et al., Work, November 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Guldemir: Retrospective 477 COVID+ public transportation workers in Turkey, showing lower risk of hospitalization with vitamin C use in unadjusted results.
ICU admission 46% Improvement Relative Risk Hospitalization time 1% Vitamin C  Hakamifard et al.  LATE TREATMENT  RCT Is late treatment with vitamin C + vitamin E beneficial for COVID-19? RCT 72 patients in Iran (March - April 2020) Lower ICU admission with vitamin C + vitamin E (not stat. sig., p=0.46) c19early.org Hakamifard et al., Immunopathologia Pe.., Apr 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Hakamifard: RCT with 38 patients treated with vitamin C and vitamin E, and 34 control patients, showing lower ICU admission with treatment, but not statistically significant.
Mortality 44% Improvement Relative Risk Hospitalization time 38% Vitamin C  Hamidi-Alamdari et al.  LATE TREATMENT  RCT Is late treatment with vitamin C + combined treatments beneficial for COVID-19? RCT 80 patients in Iran (April - September 2020) Shorter hospitalization with vitamin C + combined treatments (p=0.004) c19early.org Hamidi-Alamdari et al., Clinical and T.., Mar 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Hamidi-Alamdari: RCT 80 hospitalized patients with severe COVID-19, 40 treated with methylene blue + vitamin C + N-acetylcysteine, showing lower mortality, shorter hospitalization, and significantly improved SpO2 and respiratory distress with treatment.
He: 60 patient vitamin C late treatment RCT with results not reported over 3 years after completion.
Mortality 20% Improvement Relative Risk Ventilation 40% Ventilation (b) 50% ICU admission 27% ICU admission (b) 30% Vitamin C for COVID-19  Hess et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Retrospective 100 patients in the USA (March - July 2020) Lower mortality (p=0.54) and ICU admission (p=0.11), not sig. c19early.org Hess et al., Internal and Emergency Me.., Mar 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Hess: Retrospective 100 severe condition hospitalized patients in the USA, 25 treated with high dose IV vitamin C, showing lower mechanical ventilation and cardiac arrest, and increased length of survival with treatment. 3g IV vitamin C every 6h for 7 days.
Case -3% Improvement Relative Risk Vitamin C for COVID-19  COVIDENCE UK  Prophylaxis Does vitamin C reduce COVID-19 infections? Prospective study of 15,227 patients in the United Kingdom (May 2020 - Feb 2021) No significant difference in cases c19early.org Holt et al., Thorax, March 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Holt: Prospective survey-based study with 15,227 people in the UK, showing lower risk of COVID-19 cases with vitamin A, vitamin D, zinc, selenium, probiotics, and inhaled corticosteroids; and higher risk with metformin and vitamin C. Statistical significance was not reached for any of these. Except for vitamin D, the results for treatments we follow were only adjusted for age, sex, duration of participation, and test frequency. NCT04330599. COVIDENCE UK.
Recovery 41% Improvement Relative Risk Recovery (b) 68% Vitamin C  LINCOLN  LATE TREATMENT  LONG COVID Does vitamin C + L-arginine reduce the risk of long COVID (PASC)? Prospective study of 1,390 patients in Italy Study compares with another combination of treatments Improved recovery with vitamin C + L-arginine (p<0.000001) c19early.org Izzo et al., Pharmacological Research, Jul 2022 Favorsvitamin C FavorsVitamin B1, .. 0 0.5 1 1.5 2+
Izzo: Long COVID trial comparing L-arginine + vitamin C with multivitamin treatment (vitamin B1, B2, B6, B12, nicotinamide, folic acid, pantothenic acid), showing significant improvement in symptoms with L-arginine + vitamin C treatment.
Mortality 0% Improvement Relative Risk Ventilation -25% Hospitalization time -31% Vitamin C  JamaliMoghadamSiahkali et al.  LATE TREATMENT  RCT Is late treatment with vitamin C beneficial for COVID-19? RCT 60 patients in Iran (April - May 2020) Longer hospitalization with vitamin C (p=0.028) c19early.org JamaliMoghadamSiahkali et al., Researc.., Jan 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
JamaliMoghadamSiahkali: Small late stage RCT for the addition of vitamin C to HCQ and lopinavir/ritonavir, with 30 treatment and 30 control patients, finding a significant reduction in temperature and a significant improvement in oxygenation after 3 days in the vitamin C group. However, hospitalization time was longer and there was no significant difference in mortality.
Recovery 51% Improvement Relative Risk Vitamin C for COVID-19  Jang et al.  ECMO PATIENTS Is late treatment with vitamin C beneficial for COVID-19? Retrospective 19 patients in South Korea (February - April 2020) Improved recovery with vitamin C (not stat. sig., p=0.15) c19early.org Jang et al., Heart & Lung, December 2020 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Jang: Retrospective 19 COVID-19 ECMO patients in South Korea, showing a higher rate of weaning from ECMO with vitamin C treatment, without statistical significance. Authors perform multivariate analysis but do not provide full results, only reporting p > 0.05.
Mortality 31% Improvement Relative Risk Vitamin C  Krishnan et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Retrospective 152 patients in the USA Lower mortality with vitamin C (p=0.036) c19early.org Krishnan et al., J Clin Anesth., July 2020 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Krishnan: Retrospective 152 mechanically ventilated patients in the USA showing unadjusted lower mortality with vitamin C, vitamin D, HCQ, and zinc treatment, statistically significant only for vitamin C.
Mortality 23% Improvement Relative Risk Ventilation 21% Vitamin C  Kumar et al.  ICU PATIENTS  DB RCT Is very late treatment with vitamin C beneficial for COVID-19? Double-blind RCT 60 patients in India Lower mortality with vitamin C (not stat. sig., p=0.6) c19early.org Kumar et al., J. Family Medicine and P.., Aug 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Kumar (B): RCT 60 ICU patients in India, showing no significant difference in outcomes with vitamin C. Mortality was lower in the vitamin C arm despite having more severe cases at baseline (87% vs. 67%). 1 gram intravenous vitamin C 8 hourly for four days.
Mortality 36% Improvement Relative Risk Ventilation 20% Recovery time 26% Hospitalization time 24% Vitamin C  Kumari et al.  LATE TREATMENT  RCT Is late treatment with vitamin C beneficial for COVID-19? RCT 150 patients in Pakistan (March - July 2020) Faster recovery (p=0.0001) and shorter hospitalization (p=0.0001) c19early.org Kumari et al., Cureus 12(11): e11779, Nov 2020 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Kumari: RCT 150 hospitalized patients in Pakistan showing 26% faster recovery, p < 0.0001. 36% lower mortality, not statistically significant due to the small number of events. Dosage was 50 mg/kg/day of intravenous vitamin C.
Mortality 50% Improvement Relative Risk Vitamin C  Kyagambiddwa et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Retrospective 246 patients in Uganda (May 2020 - August 2022) Lower mortality with vitamin C (not stat. sig., p=0.062) c19early.org Kyagambiddwa et al., Infection and Dru.., May 2023 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Kyagambiddwa: Retrospective 246 severe COVID-19 patients in Uganda, showing lower mortality with vitamin C treatment, without statistical significance (p = 0.06).
Mortality 33% Improvement Relative Risk Hospitalization time -13% Progression, SOFA 16% Progression, NEWS -9% Progression, WHO -6% Progression, AKI 60% Vitamin C  Labbani-Motlagh et al.  LATE TREATMENT  DB RCT Is late treatment with vitamin C beneficial for COVID-19? Double-blind RCT 74 patients in Iran (April - November 2020) Lower progression with vitamin C (not stat. sig., p=0.12) c19early.org Labbani-Motlagh et al., J. Research in.., Dec 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Labbani-Motlagh: RCT 74 patients in Iran, showing no significant differences in outcomes with high dose vitamin C treatment. Tables 1b and 2a show conflicting baseline SOFA scores. The percentages of patients receiving antiviral treatments and corticosteroids are switched between the text and Table 1b. Authors indicate ICU admission was an outcome, but the result is not provided. AKI was lower with treatment, though not reaching statistical significance.
Lamontagne: 392 patient vitamin C late treatment RCT with results not reported over 1.5 years after completion. The companion non-COVID trial NCT03680274 has reported results.
Mortality -11% Improvement Relative Risk Vitamin C for COVID-19  Li et al.  ICU PATIENTS Is very late treatment with vitamin C beneficial for COVID-19? PSM retrospective 32 patients in the USA No significant difference in mortality c19early.org Li et al., J. Pharmacy Practice, June 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Li: PSM retrospective 8 ICU patients treated with vitamin C and 24 matched controls, showing no significant difference. Authors note that "it is possible for the delayed timing of IV vitamin C to have blunted the beneficial effects as these patients may have already progressed to the late fibroproliferative phase or ARDS". IV vitamin C 1.5 grams every 6 hours.
Liu: Estimated 608 patient vitamin C late treatment RCT with results not reported over 1 year after estimated completion.
Case 0% Improvement Relative Risk Vitamin C for COVID-19  Louca et al.  Prophylaxis Does vitamin C reduce COVID-19 infections? Retrospective 372,720 patients in the United Kingdom No significant difference in cases c19early.org Louca et al., BMJ Nutrition, Preventio.., Nov 2020 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Louca: Survey analysis of dietary supplements showing no significant difference in PCR+ cases with vitamin C usage in the UK, however significant reductions were found in the US and Sweden. These results are for PCR+ cases only, they do not reflect potential benefits for reducing the severity of cases. A number of biases could affect the results, for example users of the app may not be representative of the general population, and people experiencing symptoms may be more likely to install and use the app.
Mortality 28% Improvement Relative Risk Vitamin C for COVID-19  Loucera et al.  Prophylaxis Is prophylaxis with vitamin C beneficial for COVID-19? Retrospective 15,968 patients in Spain (January - November 2020) Lower mortality with vitamin C (p=0.0018) c19early.org Loucera et al., Virology J., August 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Loucera: Retrospective 15,968 COVID-19 hospitalized patients in Spain, showing lower mortality with existing use of several medications including metformin, HCQ, azithromycin, aspirin, vitamin D, vitamin C, and budesonide. Since only hospitalized patients are included, results do not reflect different probabilities of hospitalization across treatments.
Mortality 53% Improvement Relative Risk Vitamin C  Madamombe et al.  EARLY TREATMENT Is early treatment with vitamin C beneficial for COVID-19? Retrospective 672 patients in Zimbabwe (April 2020 - April 2022) Lower mortality with vitamin C (p=0.00038) c19early.org Madamombe et al., Pan African Medical J., Mar 2023 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Madamombe: Retrospective 672 COVID-19 patients in Zimbabwe, showing lower mortality with vitamin C treatment.
IgG positive -26% Improvement Relative Risk Vitamin C for COVID-19  Mahto et al.  Prophylaxis Is prophylaxis with vitamin C beneficial for COVID-19? Retrospective 689 patients in India Higher IgG positivity with vitamin C (not stat. sig., p=0.49) c19early.org Mahto et al., American J. Blood Research, Feb 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Mahto: Retrospective 689 healthcare workers in India, showing no significant difference in IgG positivity with vitamin C prophylaxis.
Mortality 14% Improvement Relative Risk Vitamin C  Majidi et al.  ICU PATIENTS  DB RCT Is very late treatment with vitamin C beneficial for COVID-19? Double-blind RCT 100 patients in Iran (May - July 2020) Lower mortality with vitamin C (p=0.028) c19early.org Majidi et al., Frontiers in Immunology, Dec 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Majidi: RCT 100 ICU patients in Iran, 31 treated with vitamin C, showing lower mortality with treatment.
Case -44% Improvement Relative Risk Vitamin C for COVID-19  Mohseni et al.  Prophylaxis Does vitamin C reduce COVID-19 infections? Retrospective 603 patients in Iran More cases with vitamin C (p=0.0021) c19early.org Mohseni et al., Nutrition & Food Science, Aug 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Mohseni: Retrospective 603 patients in Iran, 34 taking vitamin C supplements, showing increased risk of COVID-19 cases in unadjusted results. IR.SHOUSHTAR.REC.1399.015.
Mortality 20% Improvement Relative Risk Mortality, ICU -99% Ventilation -200% ICU admission -33% Vitamin C  Mousaviasl et al.  LATE TREATMENT  DB RCT Is late treatment with vitamin C beneficial for COVID-19? Double-blind RCT 401 patients in Iran (November 2020 - May 2021) Trial underpowered to detect differences c19early.org Mousaviasl et al., Disease and Diagnosis, Jul 2023 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Mousaviasl: RCT 401 hospitalized COVID-19 patients showing no significant differences with low-dose oral vitamin C (1000mg daily for 5 days).
Mortality -32% Improvement Relative Risk Vitamin C for COVID-19  Mulhem et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Retrospective 3,219 patients in the USA Higher mortality with vitamin C (p=0.011) c19early.org Mulhem et al., BMJ Open, April 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Mulhem: Retrospective database analysis of 3,219 hospitalized patients in the USA. Very different results in the time period analysis (Table S2), and results significantly different to other studies for the same medications (e.g., heparin OR 3.06 [2.44-3.83]) suggest significant confounding by indication and confounding by time.
Hospitalization 25% Improvement Relative Risk Severe case 17% Vitamin C for COVID-19  Nimer et al.  Prophylaxis Is prophylaxis with vitamin C beneficial for COVID-19? Retrospective 2,148 patients in Jordan (March - July 2021) Lower hospitalization (p=0.08) and severe cases (p=0.18), not sig. c19early.org Nimer et al., Bosnian J. Basic Medical.., Feb 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Nimer: Retrospective 2,148 COVID-19 recovered patients in Jordan, showing lower risk of severity and hospitalization with vitamin C prophylaxis, without statistical significance.
Mortality 29% Improvement Relative Risk Mortality (b) 16% Vitamin C for COVID-19  Patel et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Retrospective 176 patients in the USA Lower mortality with vitamin C (not stat. sig., p=0.18) c19early.org Patel et al., Chest Infections, October 2020 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Patel: Retrospective 176 hospitalized patients, 96 treated with oral vitamin C (from 500mg to 1500mg daily), showing lower mortality with treatment.
Mortality 13% Improvement Relative Risk Vitamin C  Pourhoseingholi et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Prospective study of 2,468 patients in Iran (Feb - Jul 2020) Lower mortality with vitamin C (not stat. sig., p=0.38) c19early.org Pourhoseingholi et al., Research Square, May 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Pourhoseingholi: Prospective study of 2,468 hospitalized COVID-19 patients in Iran, showing no significant difference with vitamin C treatment. IR.MUQ.REC.1399.013.
Hospitalization 40% Improvement Relative Risk Vitamin C for COVID-19  Rahman et al.  EARLY TREATMENT Is early treatment with vitamin C beneficial for COVID-19? Retrospective 600 patients in Bangladesh Lower hospitalization with vitamin C (p=0.00012) c19early.org Rahman et al., Molecular Mechanism Res.., Nov 2023 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Rahman: Retrospective 416 non-hospitalized and 184 hospitalized COVID-19 patients in Bangladesh, showing higher acetaminophen and lower vitamin C usage for hospitalized patients. Confounding may be significant and baseline details per treatment group are not provided, however fever and symptomatic patients were more common in the non-hospitalized group. Note there is an alignment mismatch in Table 1.
Mortality 55% Improvement Relative Risk Ventilation 44% Hospitalization time 37% Vitamin C  Rana et al.  ICU PATIENTS  DB RCT Is very late treatment with vitamin C beneficial for COVID-19? Double-blind RCT 278 patients in Pakistan (December 2020 - April 2022) Lower mortality (p=0.2) and ventilation (p=0.41), not sig. c19early.org Rana et al., Biological and Clinical S.., Jun 2023 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Rana: RCT 278 COVID-19 ICU patients in Pakistan, showing lower mortality and ventilation, and shorter length of stay with high dose vitamin C treatment, without statistical significance. 30 grams IV vitamin C for four days.
Recovery 31% Improvement Relative Risk Vitamin C  Ried et al.  EARLY TREATMENT  RCT Is early treatment with vitamin C beneficial for COVID-19? RCT 237 patients in Turkey (January - June 2021) Improved recovery with vitamin C (p=0.0081) c19early.org Ried et al., Cureus, November 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Ried: RCT 237 patients in Turkey, 162 treated with IV vitamin C in addition to HCQ/AZ/zinc/vitamin D used for all patients, showing significantly faster recovery with the addition of IV vitamin C.

97% of patients were vitamin D deficient, and lower vitamin D levels were associated with ICU admission and longer hospital stay.

Only 1 of 237 hospitalized patients died (average age 63, range 22-99) - a 70-year-old patient with heart and lung disease and severely deficient vitamin D levels (6 nmol/L). IV vitamin C (sodium ascorbate) was given as 50 mg/kg every six hours on day 1, followed by 100 mg/kg every six hours (four times daily, 400 mg/kg/day) for seven days. NCT04395768.
Mortality 10% Improvement Relative Risk Vitamin C for COVID-19  Salehi et al.  ICU PATIENTS Is very late treatment with vitamin C beneficial for COVID-19? Retrospective 125 patients in Iran (April - September 2021) Lower mortality with vitamin C (not stat. sig., p=0.56) c19early.org Salehi et al., Research Square, March 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Salehi: Retrospective 125 mechanically ventilated ICU patients in Iran, showing no significant difference with vitamin C treatment in unadjusted results.
ER visit 48% Improvement Relative Risk Mean cumulative sympt.. 14% EQ-VAS average score <80 29% EQ5D improvement, Wk 1 29% EQ5D improvement, Wk 2 14% EQ5D improvement, Wk 3 50% EQ5D improvement, Wk 4 -12% Recovery time -4% PASC, 12 weeks 12% PASC, 8 weeks 36% PASC, 4 weeks 1% Vitamin C  Seely et al.  LATE TREATMENT  DB RCT Is late treatment with vitamin C + combined treatments beneficial for COVID-19? Double-blind RCT 90 patients in Canada (September 2021 - April 2022) Patients likely mostly recovered before treatment received c19early.org Seely et al., BMJ Open, September 2023 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Seely: Early terminated low-risk population (no hospitalization) very late treatment (mean 8 days) RCT with 44 patients treated with vitamin C, D, K, and zinc, and 46 control patients, showing no significant differences.

Authors acknowledge that the very late treatment is a major limitation, noting that in an ideal setting, "patients would begin taking therapeutic interventions immediately after noticing symptoms". Authors note that patients already had a low symptom burden at baseline and that "it is likely that the majority of the participants had almost fully recovered before starting treatment."

Authors note that most participants were young, had few comorbidities and had excellent self-rated health at baseline, leaving less room for improvement.

There was low compliance with completing surveys. Data from only 64% of patients was in the main analysis.

Authors claim "high internal validity", but the loss of data was statistically significantly different between arms, without analysis or mention. Since the study involves widely available treatments, one possibility is that patients in the control arm who feel sick may be more likely to independently take the treatments (via supplementation or food/sun exposure), believing that they are in the control arm or that additional dosing is safe, and they may then feel it's inappropriate to continue submitting the surveys.

Discussion is biased, stating that "evidence for the use of these products in people with COVID-19 is limited", however there were 219 controlled studies at the time, including 8, 27, and 16 RCTs for vitamin C, D, and zinc. Authors claim high similarity between arms however there was 60% vs. 41% male patients, and 88% vs. 68% of patients that received a third dose.

Authors claim that treatment "showed no beneficial effects for overall health or symptom burden". However 48% lower ER visits is beneficial, and most outcomes show a benefit. The only statistically significant effect was the loss of data, however significant clinical effects are not expected based on the small sample, very late treatment, event rates, and outcomes.
Severe case, C 46% Improvement Relative Risk Severe case, C+D+zinc 97% Vitamin C for COVID-19  Sharif et al.  Prophylaxis Is prophylaxis with vitamin C beneficial for COVID-19? Retrospective study in Bangladesh (December 2020 - February 2021) Lower severe cases with vitamin C (p=0.001) c19early.org Sharif et al., Nutrients, November 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Sharif: Retrospective 962 COVID-19 patients in Bangladesh, showing significantly lower severity with vitamin C, vitamin D, and zinc supplementation, and improved results from the combination of all three.
Sharmin: Estimated 50 patient vitamin C late treatment RCT with results not reported over 2 years after estimated completion.
Severe case 4% unadjusted Improvement Relative Risk Vitamin C for COVID-19  Shehab et al.  Prophylaxis Is prophylaxis with vitamin C beneficial for COVID-19? Retrospective 253 patients in multiple countries (Sep 2020 - Mar 2021) Study underpowered to detect differences c19early.org Shehab et al., Tropical J. Pharmaceuti.., Feb 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Shehab: Retrospective survey-based analysis of 349 COVID-19 patients, showing no significant difference with vitamin C prophylaxis in unadjusted analysis. REC/UG/2020/03.
Mortality 44% Improvement Relative Risk ICU admission 10% Vitamin C for COVID-19  Simsek et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Retrospective 139 patients in Turkey Lower mortality with vitamin C (not stat. sig., p=0.19) c19early.org Simsek et al., Annals of Medical Resea.., Sep 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Simsek: Retrospective 139 hospitalized patients in Turkey, 58 treated with high dose vitamin C, showing improved kidney functioning with treatment. Mortality was lower with treatment, but not reaching statistical significance with the small sample size.
Mortality 42% Improvement Relative Risk Ventilation 41% Hospitalization 61% Vitamin C for COVID-19  Sinnberg et al.  Sufficiency Are vitamin C levels associated with COVID-19 outcomes? Retrospective 74 patients in Germany (February - November 2020) Lower hospitalization with higher vitamin C levels (p=0.05) c19early.org Sinnberg et al., Antioxidants, August 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Sinnberg: Analysis of 74 COVID-19 patients and 8 controls in Germany, showing low vitamin C levels associated with mortality. There was no significant difference for vitamin A, D, or E levels. Very few group details are provided, for example the age of patients in the control group and each severity group is not provided.
Progression -135% Improvement Relative Risk Improvement time -34% Vitamin C for COVID-19  Su et al.  EARLY TREATMENT Is early treatment with vitamin C beneficial for COVID-19? Retrospective study in China (January - April 2020) Slower improvement with vitamin C (p=0.036) c19early.org Su et al., BioScience Trends, December 2020 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Su: Retrospective 616 patients in China showing increased risk of disease progression with vitamin C treatment.
Mortality 21% Improvement Relative Risk ICU admission -2% Vitamin C for COVID-19  Suna et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Retrospective 323 patients in Turkey Lower mortality with vitamin C (not stat. sig., p=0.52) c19early.org Suna et al., Med. Clin., May 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Suna: Retrospective 323 hospitalized patients, 153 treated with vitamin C, showing no significant differences. Patients in each group were in different time periods, with the vitamin C group first. Time based confounding is possible due to improvements in SOC.
Death/intubation 25% primary Improvement Relative Risk ARDS 73% Vitamin C for COVID-19  Tan et al.  LATE TREATMENT Is late treatment with vitamin C + combined treatments beneficial for COVID-19? Retrospective 161 patients in China Lower progression with vitamin C + combined treatments (p=0.002) c19early.org Tan et al., QJM, July 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Tan: PSM retrospective 207 hospitalized patients in China, 46 treated with diammonium glycyrrhizinate and vitamin C, showing lower risk of ARDS with treatment.
Mortality 87% Improvement Relative Risk Hospitalization time 18% Vitamin C  Tehrani et al.  LATE TREATMENT  RCT Is late treatment with vitamin C beneficial for COVID-19? RCT 44 patients in Iran (March - May 2020) Lower mortality (p=0.13) and shorter hospitalization (p=0.23), not sig. c19early.org Tehrani et al., Urology J., November 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Tehrani: RCT 54 late stage patients, 18 treated with IV vitamin C (2g every 6h for 5 days), showing significant relative improvements in oxygen saturation and respiratory rate.
Mortality -204% Improvement Relative Risk Hospitalization 31% Recovery time 18% primary Vitamin C  COVIDAtoZ  EARLY TREATMENT  RCT Is early treatment with vitamin C beneficial for COVID-19? RCT 98 patients in the USA (April 2020 - February 2021) Faster recovery with vitamin C (not stat. sig., p=0.15) c19early.org Thomas et al., JAMA Network Open, February 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Thomas: Small 214 low-risk outpatient RCT showing non-statistically significant faster recovery with zinc and with vitamin C. A secondary analysis concludes that vitamin C increases recovery rate by 71% (p = 0.036)183. See also184.
Mortality 83% Improvement Relative Risk Vitamin C for COVID-19  Tu et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Retrospective 180 patients in Sierra Leone (March - August 2020) Lower mortality with vitamin C (p<0.000001) c19early.org Tu et al., Infectious Diseases & Immun.., Jan 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Tu: Retrospective 180 hospitalized COVID-19 patients in Sierra Leone, showing lower mortality with vitamin C treatment in unadjusted results.
Viral clearance 33% Improvement Relative Risk Vitamin C  Usanma Koban et al.  EARLY TREATMENT Is early treatment with vitamin C beneficial for COVID-19? Retrospective 126 patients in Turkey (March - September 2020) No significant difference in viral clearance c19early.org Usanma Koban et al., Bratislava Medica.., Jun 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Usanma Koban: Retrospective 126 patients in Turkey, showing no significant difference in PCR+ at day 14 with vitamin C treatment.
Hospitalization 38% Improvement Relative Risk Symp. case 10% Vitamin C for COVID-19  Vaisi et al.  Prophylaxis Is prophylaxis with vitamin C beneficial for COVID-19? Retrospective 3,955 patients in Iran Lower hospitalization with vitamin C (not stat. sig., p=0.17) c19early.org Vaisi et al., The Clinical Respiratory.., May 2023 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Vaisi: Analysis of nutrient intake and COVID-19 outcomes for 3,996 people in Iran, showing lower risk of COVID-19 hospitalization with sufficient vitamin A, vitamin C, and selenium intake, with statistical significance for vitamin A and selenium.
Mortality 54% Improvement Relative Risk Vitamin C  Vishnuram et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Retrospective 8,875 patients in India Lower mortality with vitamin C (p=0.028) c19early.org Vishnuram et al., Indian J. Basic and .., Jun 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Vishnuram: Retrospective 8,634 hospitalized patients in India, showing lower mortality with high-dose vitamin C in unadjusted results. No group details are provided, the text and table appear to show different results, and some numbers do not match.
Recovery time, SD, S 33% Improvement Relative Risk Recovery time, SD, NS 45% Recovery time, SD, S, vs... 24% Recovery time, SD, NS, vs... 28% Recovery time, DR, S 27% Recovery time, DR, NS 23% Recovery time, DR, S, vs... 15% Recovery time, DR, NS, vs.. 15% Time to viral-, S 36% Time to viral-, NS 32% Time to viral-, S, vs. low d.. 14% Time to viral-, NS, vs. low.. 19% Vitamin C  Yang et al.  LATE TREATMENT  RCT Is late treatment with vitamin C + TCM beneficial for COVID-19? RCT 20 patients in China (February - February 2020) Faster recovery (p<0.0001) and viral clearance (p<0.0001) c19early.org Yang et al., Am. J. Transl. Res., January 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Yang (B): Prospective study of 60 patients in China with three arms: SOC, SOC+TCM, and SOC+TCM+high dose vitamin C, showing successively faster recovery with the addition of TCM and the addition of high dose vitamin C. TCM included inhaled vitamin C 10g, 3-7 times per day. IV vitamin C 10g/60kg twice a day, and oral vitamin C 3g three times a day. Group C vs. group A includes combined treatment with TCM, while group C vs. group B both include vitamin C (high vs. low dose).
Mortality 19% Improvement Relative Risk Vitamin C for COVID-19  Yüksel et al.  ICU PATIENTS Is very late treatment with vitamin C beneficial for COVID-19? PSM retrospective 86 patients in Turkey Lower mortality with vitamin C (p=0.037) c19early.org Yüksel et al., Intensive Care Medicine.., Sep 2020 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Yüksel: PSM retrospective 86 ICU patients on mechanical ventilation in Turkey, showing lower mortality with high dose vitamin C treatment (≥200mg/kg for 4 days).
Mortality 4% Improvement Relative Risk Vitamin C for COVID-19  Zangeneh et al.  ICU PATIENTS Is very late treatment with vitamin C beneficial for COVID-19? Retrospective study in Iran No significant difference in mortality c19early.org Zangeneh et al., Obesity Medicine, May 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Zangeneh: Retrospective 193 ICU patients in Iran, showing no significant difference with vitamin C treatment.
Mortality 50% Improvement Relative Risk Mortality (b) 80% Mortality (c) 50% Mortality (d) 70% Vitamin C  Zhang et al.  ICU PATIENTS  RCT Is very late treatment with vitamin C beneficial for COVID-19? RCT 56 patients in China (February - March 2020) Lower mortality with vitamin C (not stat. sig., p=0.2) c19early.org Zhang et al., Annals of Intensive Care, Aug 2020 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Zhang: Small RCT for high dose vitamin C for ICU patients showing reduced (but not statistically significant) mortality. Dosage was 12g of vitamin C/50ml every 12 hours for 7 days at a rate of 12ml/hour.
Progression 72% Improvement Relative Risk Time to viral- -8% Vitamin C for COVID-19  Zhao et al.  EARLY TREATMENT Is early treatment with vitamin C beneficial for COVID-19? PSM retrospective 110 patients in China Lower progression with vitamin C (p=0.03) c19early.org Zhao et al., Frontiers in Pharmacology, Apr 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Zhao: PSM retrospective 110 patients, 55 treated with high-dose IV vitamin C, showing lower progression to severe disease with treatment. Patients in each group were in different time periods, time based confounding is likely due to SOC improving over time. ChiCTR2000033050.
Mortality -157% Improvement Relative Risk Mortality (b) -169% Clinical improvement ≥ 2.. -35% Clinical improvement.. (b) -32% Vitamin C for COVID-19  Zheng et al.  LATE TREATMENT Is late treatment with vitamin C beneficial for COVID-19? Retrospective 397 patients in China (February - February 2020) Higher mortality (p=0.33) and worse improvement (p=0.17), not sig. c19early.org Zheng et al., Open Medicine, September 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Zheng: Retrospective 397 severe COVID-19 patients in China, showing worse outcomes with vitamin C treatment, without statistical significance. IV vitamin C 2-4g/day. Subject to confounding by indication and immortal time bias. Exclusion criteria were (a) the duration of hospitalization was less than 3 days; (b) vitamin C treatment started before admission; and (c) the length of vitamin C use was less than 3 days. Includes vitamin C use started at any time during hospitalization, for many patients this was >15 days later (Figure A2). Duration of treatment varied widely (Figure A1). Treatment was determined by clinicians according to the condition of each patient.
Mortality -5% Improvement Relative Risk Vitamin C  Özgülteki̇n et al.  ICU PATIENTS Is very late treatment with vitamin C beneficial for COVID-19? Retrospective 43 patients in Turkey (March - June 2020) No significant difference in mortality c19early.org Özgülteki̇n et al., Kastamonu Medical J., Sep 2022 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Özgülteki̇n: Retrospective 43 ICU patients in Turkey, 21 treated with vitamin C, showing no significant difference in mortality and increased renal failure. Treatment included stage 1 AKI patients. Vitamin C 45-50 g/day for 5 days.
Mortality 9% Improvement Relative Risk Ventilation -1% Vitamin C for COVID-19  Özgünay et al.  ICU PATIENTS Is very late treatment with vitamin C beneficial for COVID-19? Retrospective 160 patients in Turkey No significant difference in outcomes seen c19early.org Özgünay et al., The European Research J., Jul 2021 Favorsvitamin C Favorscontrol 0 0.5 1 1.5 2+
Özgünay: Retrospective 160 ICU patients, 32 with raised neutrophil/lymphocyte ratio treated with vitamin C, showing no significant differences.
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 "vitamin C", "ascorbic acid" 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 vitamin C 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 to187. 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 1190. 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 PythonMeta191 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 effective93,94.
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/cmeta.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.
Boukef, 2/28/2023, Double Blind Randomized Controlled Trial, placebo-controlled, Tunisia, trial NCT05670444 (history). 150 patient RCT with results unknown and over 1 year late.
Madamombe, 3/21/2023, retrospective, Zimbabwe, peer-reviewed, 9 authors, study period April 2020 - April 2022, dosage not specified. risk of death, 53.0% lower, OR 0.47, p < 0.001, adjusted per study, multivariable, RR approximated with OR.
Rahman, 11/8/2023, retrospective, Bangladesh, peer-reviewed, 5 authors, dosage not specified, excluded in exclusion analyses: unadjusted results with no group details; significant unadjusted confounding possible. risk of hospitalization, 40.5% lower, RR 0.60, p < 0.001, treatment 128 of 476 (26.9%), control 56 of 124 (45.2%), NNT 5.5.
Ried, 11/25/2021, Randomized Controlled Trial, Turkey, peer-reviewed, 3 authors, study period January 2021 - June 2021, average treatment delay 4.0 days, dosage 50mg/kg qid day 1, 100mg/kg qid days 2-7, trial ACTRN12620000557932. risk of no recovery, 30.6% lower, RR 0.69, p = 0.008, treatment 69 of 162 (42.6%), control 46 of 75 (61.3%), NNT 5.3, mid-recovery, day 15.
Su, 12/23/2020, retrospective, China, peer-reviewed, 9 authors, study period 20 January, 2020 - 30 April, 2020, dosage 10000mg days 1-3, 5-15g per day for at least 3 days. risk of progression, 135.3% higher, HR 2.35, p = 0.18, adjusted per study, binary logistic regression.
improvement time, 34.2% worse, relative time 1.34, p = 0.04, adjusted per study, inverted to make RR<1 favor treatment, Cox proportional hazards.
Thomas, 2/12/2021, Randomized Controlled Trial, USA, peer-reviewed, 11 authors, study period 8 April, 2020 - 11 February, 2021, dosage 8000mg days 1-10, trial NCT04342728 (history) (COVIDAtoZ). risk of death, 204.2% higher, RR 3.04, p = 0.49, treatment 1 of 48 (2.1%), control 0 of 50 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of hospitalization, 30.6% lower, RR 0.69, p = 1.00, treatment 2 of 48 (4.2%), control 3 of 50 (6.0%), NNT 55.
recovery time, 17.9% lower, relative time 0.82, p = 0.15, treatment mean 5.5 (±3.7) n=48, control mean 6.7 (±4.4) n=50, mean time to a 50% reduction in symptoms, primary outcome.
Usanma Koban, 6/7/2022, retrospective, Turkey, peer-reviewed, 3 authors, study period 1 March, 2020 - 30 September, 2020, dosage not specified. risk of no viral clearance, 33.0% lower, OR 0.67, p = 0.73, treatment 31, control 95, adjusted per study, multivariable, day 14, RR approximated with OR.
Zhao, 4/22/2021, retrospective, propensity score matching, China, peer-reviewed, 15 authors, average treatment delay 4.0 days, dosage 100mg/kg days 1-7, excluded in exclusion analyses: substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically. risk of progression, 72.0% lower, RR 0.28, p = 0.03, treatment 4 of 55 (7.3%), control 12 of 55 (21.8%), NNT 6.9, adjusted per study, PSM.
time to viral-, 7.7% higher, relative time 1.08, p = 0.79, treatment 55, control 55, PSM.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. For pooled analyses, the first (most serious) outcome is used, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.
Adhikari (B), 10/25/2023, Double Blind Randomized Controlled Trial, multiple countries, peer-reviewed, 82 authors, dosage 50mg/kg qid days 1-4, trial NCT04401150 (history) (LOVIT-COVID). risk of death, 27.8% lower, HR 0.72, p = 0.19, treatment 190, control 194, combined.
risk of death, 27.5% lower, HR 0.72, p = 0.34, treatment 84, control 97, inverted to make HR<1 favor treatment, LOVIT-COVID critical.
risk of death, 28.1% lower, HR 0.72, p = 0.37, treatment 106, control 97, inverted to make HR<1 favor treatment, LOVIT-COVID non-critical.
Adhikari, 10/25/2023, Randomized Controlled Trial, multiple countries, peer-reviewed, 82 authors, dosage 50mg/kg qid days 1-4, trial NCT04401150 (history) (REMAP-CAP). risk of death, 19.5% higher, HR 1.19, p = 0.08, treatment 1,303, control 903, combined.
risk of death, 16.3% higher, HR 1.16, p = 0.22, treatment 953, control 434, inverted to make HR<1 favor treatment, REMAP-CAP critical.
risk of death, 26.6% higher, HR 1.27, p = 0.19, treatment 350, control 469, inverted to make HR<1 favor treatment, REMAP-CAP non-critical.
risk of mechanical ventilation, 35.1% higher, HR 1.35, p = 0.04, treatment 1,032, control 528, inverted to make HR<1 favor treatment, combined trials, critical.
risk of mechanical ventilation, 69.5% higher, HR 1.69, p = 0.008, treatment 454, control 563, inverted to make HR<1 favor treatment, combined trials, non-critical.
Al Sulaiman, 4/2/2021, retrospective, propensity score matching, Saudi Arabia, preprint, 12 authors, dosage 1000mg days 1-11. risk of death, 14.9% lower, RR 0.85, p = 0.27, treatment 46 of 142 (32.4%), control 59 of 142 (41.5%), NNT 11, odds ratio converted to relative risk, PSM.
Baguma, 12/28/2021, retrospective, Uganda, preprint, 16 authors, study period March 2020 - October 2021, dosage not specified. risk of death, 48.5% higher, RR 1.48, p = 0.54, treatment 385, control 96, adjusted per study, inverted to make RR<1 favor treatment, odds ratio converted to relative risk, multivariable, control prevalance approximated with overall prevalence.
Coppock, 3/19/2022, Randomized Controlled Trial, USA, peer-reviewed, 14 authors, dosage 300mg/kg day 1, 600mg/kg day 2, 900mg/kg days 3-6. risk of progression, 5.0% lower, HR 0.95, p = 0.64, treatment 4 of 44 (9.1%), control 2 of 22 (9.1%), adjusted per study, within 36 hours.
risk of no improvement, 49.7% better, RR 0.50, p = 0.16, treatment 6 of 44 (13.6%), control 6 of 22 (27.3%), NNT 7.3, adjusted per study, inverted to make RR<1 favor treatment, odds ratio converted to relative risk, within 36 hours.
risk of no hospital discharge, 22.5% lower, RR 0.78, p = 0.07, treatment 31 of 44 (70.5%), control 20 of 22 (90.9%), NNT 4.9, within 36 hours.
Coskun, 3/21/2023, retrospective, Turkey, peer-reviewed, 1 author, study period March 2020 - June 2020, trial NCT04710329 (history), excluded in exclusion analyses: very late stage, ICU patients. risk of death, 25.4% lower, RR 0.75, p = 0.26, treatment 17 of 38 (44.7%), control 24 of 40 (60.0%), NNT 6.6.
risk of mechanical ventilation, 1.8% lower, RR 0.98, p = 1.00, treatment 28 of 38 (73.7%), control 30 of 40 (75.0%), NNT 76.
relative SOFA score, 28.4% better, RR 0.72, p = 0.005, treatment 38, control 40, mean SOFA score, day 4.
Darban, 12/15/2020, Randomized Controlled Trial, Iran, peer-reviewed, 8 authors, study period 7 April, 2020 - 8 June, 2020, dosage 2000mg qid days 1-10, this trial uses multiple treatments in the treatment arm (combined with melatonin and zinc) - results of individual treatments may vary, trial IRCT20151228025732N52, excluded in exclusion analyses: very late stage, ICU patients. risk of progression, 33.3% lower, RR 0.67, p = 1.00, treatment 2 of 10 (20.0%), control 3 of 10 (30.0%), NNT 10.
ICU time, 6.0% lower, relative time 0.94, p = 0.30, treatment 10, control 10.
Doocy, 10/19/2022, prospective, multiple countries, peer-reviewed, 6 authors, study period December 2020 - June 2021, dosage not specified, trial NCT04568499 (history). risk of death, 62.8% lower, RR 0.37, p = 0.22, treatment 2 of 64 (3.1%), control 22 of 80 (27.5%), NNT 4.1, adjusted per study, inverted to make RR<1 favor treatment, multivariable.
Elhadi, 4/30/2021, prospective, Libya, peer-reviewed, 21 authors, study period 29 May, 2020 - 30 December, 2020, dosage not specified, excluded in exclusion analyses: unadjusted results with no group details; very late stage, ICU patients. risk of death, 12.0% higher, RR 1.12, p = 0.15, treatment 175 of 277 (63.2%), control 106 of 188 (56.4%).
Fogleman, 7/27/2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, mean age 52.0, 7 authors, study period 5 October, 2020 - 21 June, 2021, average treatment delay 6.0 days, dosage 1000mg days 1-14, trial NCT04530539 (history). relative recovery, 4.4% better, RR 0.96, p = 0.83, treatment mean 17.59 (±13.1) n=32, control mean 16.82 (±15.7) n=34, mid-recovery, relative symptom improvement, day 9.
Fowler, 4/4/2024, Double Blind Randomized Controlled Trial, placebo-controlled, USA, preprint, 1 author, trial NCT04344184 (history) (SAFE EVICT CORONA-ALI), excluded in exclusion analyses: very late stage, ICU patients. risk of death, 18.8% lower, RR 0.81, p = 0.75, treatment 5 of 22 (22.7%), control 7 of 25 (28.0%), NNT 19.
relative WHO status, 1.7% worse, RR 1.02, p = 0.28, treatment mean 3.05 (±0.218) n=21, control mean 3.0 (±0.0) n=23, day 27.
Gadhiya, 4/8/2021, retrospective, USA, peer-reviewed, 4 authors, dosage not specified, excluded in exclusion analyses: substantial unadjusted confounding by indication likely. risk of death, 0.7% higher, RR 1.01, p = 0.98, treatment 19 of 55 (34.5%), control 36 of 226 (15.9%), adjusted per study, odds ratio converted to relative risk, multivariate logistic regression.
Galindo, 5/15/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Colombia, trial NCT05029037 (history). Estimated 160 patient RCT with results unknown and over 2 years late.
Gao, 2/26/2021, retrospective, China, peer-reviewed, 14 authors, dosage 12000mg day 1, 6,000mg days 2-5. risk of death, 86.0% lower, HR 0.14, p = 0.04, treatment 1 of 46 (2.2%), control 5 of 30 (16.7%), NNT 6.9, adjusted per study, KM.
Gavrielatou, 2/11/2022, retrospective, Greece, peer-reviewed, 10 authors, study period 21 October, 2020 - 8 March, 2021, average treatment delay 5.5 days, excluded in exclusion analyses: very late stage, ICU patients. risk of death, 58.0% lower, RR 0.42, p = 0.11, treatment 2 of 10 (20.0%), control 49 of 103 (47.6%), NNT 3.6.
Hakamifard, 4/14/2021, Randomized Controlled Trial, Iran, peer-reviewed, 8 authors, study period March 2020 - April 2020, dosage 1000mg daily, this trial uses multiple treatments in the treatment arm (combined with vitamin E) - results of individual treatments may vary. risk of ICU admission, 46.3% lower, RR 0.54, p = 0.46, treatment 3 of 38 (7.9%), control 5 of 34 (14.7%), NNT 15.
hospitalization time, 1.0% lower, relative time 0.99, p = 0.82, treatment 38, control 34.
Hamidi-Alamdari, 3/8/2021, Randomized Controlled Trial, Iran, peer-reviewed, 23 authors, study period 19 April, 2020 - 21 September, 2020, this trial uses multiple treatments in the treatment arm (combined with methylene blue and N-acetyl cysteine) - results of individual treatments may vary, trial NCT04370288 (history). risk of death, 44.4% lower, RR 0.56, p = 0.38, treatment 5 of 40 (12.5%), control 9 of 40 (22.5%), NNT 10.0.
hospitalization time, 37.6% lower, relative time 0.62, p = 0.004, treatment 40, control 40.
He, 1/31/2021, Single Blind Randomized Controlled Trial, China, trial NCT04664010 (history). 60 patient RCT with results unknown and over 3 years late.
Hess, 3/29/2022, retrospective, USA, peer-reviewed, 9 authors, study period March 2020 - July 2020. risk of death, 20.0% lower, HR 0.80, p = 0.54, treatment 10 of 25 (40.0%), control 37 of 75 (49.3%), NNT 11, time to event analysis, propensity score weighting.
risk of mechanical ventilation, 39.5% lower, RR 0.60, p = 0.05, treatment 18 of 25 (72.0%), control 54 of 75 (72.0%), odds ratio converted to relative risk, propensity score weighting.
risk of mechanical ventilation, 50.0% lower, HR 0.50, p = 0.03, treatment 18 of 25 (72.0%), control 54 of 75 (72.0%), time to event analysis, propensity score weighting.
risk of ICU admission, 27.2% lower, RR 0.73, p = 0.10, treatment 22 of 25 (88.0%), control 63 of 75 (84.0%), odds ratio converted to relative risk, propensity score weighting.
risk of ICU admission, 30.0% lower, HR 0.70, p = 0.19, treatment 22 of 25 (88.0%), control 63 of 75 (84.0%), time to event analysis, propensity score weighting.
Izzo, 7/19/2022, prospective, Italy, peer-reviewed, 21 authors, this trial compares with another treatment - results may be better when compared to placebo, this trial uses multiple treatments in the treatment arm (combined with L-arginine) - results of individual treatments may vary, LINCOLN trial. relative recovery, 41.4% better, RR 0.59, p < 0.001, treatment mean 8.15 (±1.3) n=869, control mean 13.9 (±2.3) n=521, relative symptom score.
relative recovery, 67.5% better, RR 0.33, p < 0.001, treatment 869, control 521, relative Borg score.
JamaliMoghadamSiahkali, 1/9/2021, Randomized Controlled Trial, Iran, preprint, 17 authors, study period April 2020 - May 2020, dosage 1500mg qid days 1-5. risk of death, no change, RR 1.00, p = 1.00, treatment 3 of 30 (10.0%), control 3 of 30 (10.0%).
risk of mechanical ventilation, 25.0% higher, RR 1.25, p = 1.00, treatment 5 of 30 (16.7%), control 4 of 30 (13.3%).
hospitalization time, 30.8% higher, relative time 1.31, p = 0.03, treatment 30, control 30.
Jang, 12/16/2020, retrospective, South Korea, peer-reviewed, median age 63.0, 10 authors, study period February 2020 - April 2020, dosage not specified, excluded in exclusion analyses: very late stage, ECMO patients. risk of no recovery, 51.4% lower, RR 0.49, p = 0.15, treatment 5 of 12 (41.7%), control 6 of 7 (85.7%), NNT 2.3, weaning from ECMO.
Krishnan, 7/20/2020, retrospective, USA, peer-reviewed, 13 authors, dosage not specified, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 30.7% lower, RR 0.69, p = 0.04, treatment 40 of 79 (50.6%), control 52 of 73 (71.2%), NNT 4.9, odds ratio converted to relative risk.
Kumar (B), 8/30/2022, Double Blind Randomized Controlled Trial, placebo-controlled, India, peer-reviewed, mean age 57.0, 11 authors, average treatment delay 7.5 days, dosage 1000mg tid days 1-4, trial CTRI/2020/11/029230, excluded in exclusion analyses: very late stage, ICU patients. risk of death, 23.1% lower, RR 0.77, p = 0.60, treatment 10 of 30 (33.3%), control 13 of 30 (43.3%), NNT 10.0.
risk of mechanical ventilation, 21.4% lower, RR 0.79, p = 0.60, treatment 11 of 30 (36.7%), control 14 of 30 (46.7%), NNT 10.0.
Kumari, 11/30/2020, Randomized Controlled Trial, Pakistan, peer-reviewed, 10 authors, study period March 2020 - July 2020, dosage 50mg/kg daily. risk of death, 36.4% lower, RR 0.64, p = 0.45, treatment 7 of 75 (9.3%), control 11 of 75 (14.7%), NNT 19.
risk of mechanical ventilation, 20.0% lower, RR 0.80, p = 0.67, treatment 12 of 75 (16.0%), control 15 of 75 (20.0%), NNT 25.
recovery time, 26.0% lower, relative time 0.74, p < 0.001, treatment 75, control 75, days to symptom-free.
hospitalization time, 24.3% lower, relative time 0.76, p < 0.001, treatment 75, control 75, days spent in hospital.
Kyagambiddwa, 5/11/2023, retrospective, Uganda, peer-reviewed, mean age 39.0, 15 authors, study period May 2020 - August 2022, dosage not specified. risk of death, 50.0% lower, HR 0.50, p = 0.06, adjusted per study, multivariable, Cox proportional hazards.
Labbani-Motlagh, 12/14/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Iran, peer-reviewed, 12 authors, study period 5 April, 2020 - 19 November, 2020, dosage 12000mg days 1-4, trial IRCT20190917044805N2. risk of death, 33.3% lower, RR 0.67, p = 0.74, treatment 4 of 37 (10.8%), control 6 of 37 (16.2%), NNT 18, day 28.
hospitalization time, 12.8% higher, relative time 1.13, p = 0.49, treatment mean 9.24 (±7.5) n=37, control mean 8.19 (±5.34) n=37.
risk of progression, 15.9% lower, RR 0.84, p = 0.12, treatment 37, control 37, SOFA, day 5.
risk of progression, 9.3% higher, RR 1.09, p = 0.47, treatment 37, control 37, NEWS, day 5.
risk of progression, 5.8% higher, RR 1.06, p = 0.38, treatment 37, control 37, WHO, day 5.
risk of progression, 60.0% lower, RR 0.40, p = 0.14, treatment 4 of 37 (10.8%), control 10 of 37 (27.0%), NNT 6.2, AKI.
Lamontagne, 12/6/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Canada, trial NCT04401150 (history) (LOVIT-COVID). 392 patient RCT with results unknown and over 1.5 years late.
Li, 6/8/2021, retrospective, propensity score matching, USA, peer-reviewed, 6 authors, excluded in exclusion analyses: very late stage, ICU patients; very late stage, ICU patients. risk of death, 10.5% higher, RR 1.11, p = 1.00, treatment 7 of 8 (87.5%), control 19 of 24 (79.2%), PSM.
Liu, 6/1/2023, Single Blind Randomized Controlled Trial, China, trial NCT05694975 (history) (CEMVISCC). Estimated 608 patient RCT with results unknown and over 1 year late.
Majidi, 12/15/2021, Double Blind Randomized Controlled Trial, Iran, peer-reviewed, 16 authors, study period May 2020 - July 2020, dosage 500mg days 1-14, trial IRCT20151226025699N5, excluded in exclusion analyses: very late stage, ICU patients. risk of death, 13.6% lower, RR 0.86, p = 0.03, treatment 26 of 31 (83.9%), control 67 of 69 (97.1%), NNT 7.6, day 28.
Mousaviasl, 7/22/2023, Double Blind Randomized Controlled Trial, placebo-controlled, Iran, peer-reviewed, 13 authors, study period November 2020 - May 2021, dosage 500mg bid days 1-5. risk of death, 20.4% lower, RR 0.80, p = 0.64, treatment 8 of 201 (4.0%), control 10 of 200 (5.0%), NNT 98, day 28.
risk of death, 99.0% higher, RR 1.99, p = 1.00, treatment 2 of 201 (1.0%), control 1 of 200 (0.5%), ICU mortality.
risk of mechanical ventilation, 199.5% higher, RR 3.00, p = 1.00, treatment 1 of 201 (0.5%), control 0 of 200 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of ICU admission, 32.7% higher, RR 1.33, p = 0.79, treatment 8 of 201 (4.0%), control 6 of 200 (3.0%).
Mulhem, 4/7/2021, retrospective, database analysis, USA, peer-reviewed, 3 authors, dosage not specified, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically. risk of death, 32.2% higher, RR 1.32, p = 0.01, treatment 157 of 794 (19.8%), control 359 of 2,425 (14.8%), adjusted per study, odds ratio converted to relative risk, logistic regression.
Patel, 10/1/2020, retrospective, USA, peer-reviewed, 8 authors, dosage 1000mg days 1-4, 500mg to 1500mg daily. risk of death, 29.5% lower, RR 0.71, p = 0.18, treatment 22 of 96 (22.9%), control 26 of 80 (32.5%), NNT 10.
risk of death, 15.6% lower, RR 0.84, p = 0.60, treatment 15 of 30 (50.0%), control 16 of 27 (59.3%), NNT 11, ICU patients.
Pourhoseingholi, 5/26/2021, prospective, Iran, preprint, mean age 57.9, 11 authors, study period 2 February, 2020 - 20 July, 2020, average treatment delay 7.4 days, dosage not specified. risk of death, 13.0% lower, HR 0.87, p = 0.38, treatment 54 of 199 (27.1%), control 285 of 2,269 (12.6%), adjusted per study, multivariable, Cox proportional hazards.
Rana, 6/28/2023, Double Blind Randomized Controlled Trial, placebo-controlled, Pakistan, peer-reviewed, 10 authors, study period 28 December, 2020 - 10 April, 2022, dosage 30000mg days 1-4, trial NCT04682574 (history), excluded in exclusion analyses: very late stage, ICU patients. risk of death, 54.5% lower, RR 0.45, p = 0.20, treatment 5 of 139 (3.6%), control 11 of 139 (7.9%), NNT 23.
risk of mechanical ventilation, 44.4% lower, RR 0.56, p = 0.41, treatment 5 of 139 (3.6%), control 9 of 139 (6.5%), NNT 35.
hospitalization time, 36.8% lower, relative time 0.63, p = 0.91, treatment 139, control 139.
Salehi, 3/11/2022, retrospective, Iran, preprint, mean age 62.0, 11 authors, study period April 2021 - September 2021, excluded in exclusion analyses: unadjusted results with no group details; very late stage, ICU patients. risk of death, 10.1% lower, RR 0.90, p = 0.56, treatment 22 of 40 (55.0%), control 52 of 85 (61.2%), NNT 16.
Seely, 9/22/2023, Double Blind Randomized Controlled Trial, placebo-controlled, Canada, peer-reviewed, mean age 39.9, 10 authors, study period September 2021 - April 2022, this trial uses multiple treatments in the treatment arm (combined with vitamin C, D, K2, and zinc) - results of individual treatments may vary, trial NCT04780061 (history). ER visit, 47.6% lower, RR 0.52, p = 0.68, treatment 2 of 42 (4.8%), control 4 of 44 (9.1%), NNT 23.
relative mean cumulative symptom score, 13.8% better, RR 0.86, p = 0.41, treatment mean 166.3 (±92.3) n=34, control mean 192.9 (±153.6) n=24.
EQ-VAS average score <80, 29.4% lower, RR 0.71, p = 0.54, treatment 7 of 34 (20.6%), control 7 of 24 (29.2%), NNT 12, average daily EQ-VAS score <80.
relative EQ5D improvement, 28.6% better, RR 0.71, p = 0.44, treatment 32, control 31, relative improvement in EQ5D, week 1.
relative EQ5D improvement, 14.3% better, RR 0.86, p = 0.73, treatment 33, control 30, relative improvement in EQ5D, week 2.
relative EQ5D improvement, 50.0% better, RR 0.50, p = 0.17, treatment 32, control 33, relative improvement in EQ5D, week 3.
relative EQ5D improvement, 12.5% worse, RR 1.12, p = 0.47, treatment 30, control 25, relative improvement in EQ5D, week 4.
recovery time, 4.0% higher, relative time 1.04, p = 0.81, treatment 34, control 24.
risk of PASC, 12.1% lower, RR 0.88, p = 1.00, treatment 3 of 33 (9.1%), control 3 of 29 (10.3%), NNT 80, 12 weeks.
risk of PASC, 35.7% lower, RR 0.64, p = 0.69, treatment 3 of 35 (8.6%), control 4 of 30 (13.3%), NNT 21, 8 weeks.
risk of PASC, 0.6% lower, RR 0.99, p = 1.00, treatment 6 of 35 (17.1%), control 5 of 29 (17.2%), NNT 1015, 4 weeks.
Sharmin, 9/1/2021, Double Blind Randomized Controlled Trial, placebo-controlled, Bangladesh, trial NCT04558424 (history). Estimated 50 patient RCT with results unknown and over 2 years late.
Simsek, 9/27/2021, retrospective, Turkey, peer-reviewed, 16 authors, dosage 25000mg days 1-7. risk of death, 44.1% lower, RR 0.56, p = 0.18, treatment 6 of 58 (10.3%), control 15 of 81 (18.5%), NNT 12.
risk of ICU admission, 10.2% lower, RR 0.90, p = 0.66, treatment 18 of 58 (31.0%), control 28 of 81 (34.6%), NNT 28.
Suna, 5/11/2021, retrospective, Turkey, peer-reviewed, 5 authors, dosage 2000mg daily, excluded in exclusion analyses: substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically. risk of death, 21.3% lower, RR 0.79, p = 0.52, treatment 17 of 153 (11.1%), control 24 of 170 (14.1%), NNT 33.
risk of ICU admission, 1.9% higher, RR 1.02, p = 1.00, treatment 11 of 153 (7.2%), control 12 of 170 (7.1%).
Tan, 7/26/2021, retrospective, China, peer-reviewed, 7 authors, dosage 500mg tid days 1-7, this trial uses multiple treatments in the treatment arm (combined with diammonium glycyrrhizinate) - results of individual treatments may vary. risk of death/intubation, 24.5% lower, RR 0.75, p = 0.74, treatment 1 of 46 (2.2%), control 14 of 115 (12.2%), NNT 10.0, odds ratio converted to relative risk, primary outcome.
risk of ARDS, 73.3% lower, RR 0.27, p = 0.002, treatment 7 of 46 (15.2%), control 41 of 115 (35.7%), NNT 4.9, odds ratio converted to relative risk.
Tehrani, 11/8/2021, Randomized Controlled Trial, Iran, peer-reviewed, 10 authors, study period March 2020 - May 2020, average treatment delay 9.0 days, dosage 2000mg qid days 1-5. risk of death, 87.1% lower, RR 0.13, p = 0.13, treatment 0 of 18 (0.0%), control 4 of 26 (15.4%), NNT 6.5, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
hospitalization time, 17.6% lower, relative time 0.82, p = 0.23, treatment 18, control 26.
Tu, 1/13/2022, retrospective, Sierra Leone, peer-reviewed, 11 authors, study period 31 March, 2020 - 11 August, 2020, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 83.0% lower, RR 0.17, p < 0.001, treatment 8 of 116 (6.9%), control 26 of 64 (40.6%), NNT 3.0.
Vishnuram, 6/30/2021, retrospective, India, peer-reviewed, 5 authors, dosage 4000mg days 1-10, excluded in exclusion analyses: unadjusted results with no group details; minimal details of groups provided. risk of death, 54.2% lower, RR 0.46, p = 0.03, treatment 164 of 8,634 (1.9%), control 10 of 241 (4.1%), NNT 44.
Yang (B), 1/15/2022, Randomized Controlled Trial, China, peer-reviewed, 11 authors, study period 1 February, 2020 - 29 February, 2020, this trial uses multiple treatments in the treatment arm (combined with TCM) - results of individual treatments may vary, trial ChiCTR2000032717, excluded in exclusion analyses: combined treatments may contribute significantly to the effect seen. recovery time, 32.9% lower, relative time 0.67, p < 0.001, treatment mean 10.2 (±1.75) n=10, control mean 15.2 (±2.49) n=10, symptom disappearance, severe patients, group C vs. group A.
recovery time, 44.6% lower, relative time 0.55, p < 0.001, treatment mean 4.1 (±0.88) n=10, control mean 7.4 (±1.26) n=10, symptom disappearance, non-severe patients, group C vs. group A.
recovery time, 23.9% lower, relative time 0.76, p = 0.006, treatment mean 10.2 (±1.75) n=10, control mean 13.4 (±2.76) n=10, symptom disappearance, severe patients, group C vs. group B (high vs. low dose).
recovery time, 28.1% lower, relative time 0.72, p = 0.003, treatment mean 4.1 (±0.88) n=10, control mean 5.7 (±1.16) n=10, symptom disappearance, non-severe patients, group C vs. group B (high vs. low dose).
recovery time, 27.1% lower, relative time 0.73, p = 0.002, treatment mean 13.45 (±3.11) n=10, control mean 18.45 (±3.12) n=10, disease recovery, severe patients, group C vs. group A.
recovery time, 23.2% lower, relative time 0.77, p < 0.001, treatment mean 7.0 (±0.94) n=10, control mean 9.11 (±1.25) n=10, disease recovery, non-severe patients, group C vs. group A.
recovery time, 15.4% lower, relative time 0.85, p = 0.15, treatment mean 13.45 (±3.11) n=10, control mean 15.89 (±4.06) n=10, disease recovery, severe patients, group C vs. group B (high vs. low dose).
recovery time, 14.6% lower, relative time 0.85, p = 0.02, treatment mean 7.0 (±0.94) n=10, control mean 8.2 (±1.14) n=10, disease recovery, non-severe patients, group C vs. group B (high vs. low dose).
Yüksel, 9/20/2020, retrospective, Turkey, preprint, 13 authors, dosage 200mg/kg days 1-4, excluded in exclusion analyses: very late stage, ICU patients. risk of death, 18.8% lower, RR 0.81, p = 0.04, treatment 31 of 42 (73.8%), control 40 of 44 (90.9%), NNT 5.8, propensity score matching.
Zangeneh, 5/13/2022, retrospective, Iran, peer-reviewed, 3 authors, dosage not specified, excluded in exclusion analyses: very late stage, ICU patients. risk of death, 4.0% lower, HR 0.96, p = 0.86, Cox proportional hazards.