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Vitamin C for COVID-19: real-time meta analysis of 25 studies
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Covid Analysis, November 18, 2021
https://c19vitaminc.com/meta.html
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ All studies 11% 25 30,398 Improvement, Studies, Patients Relative Risk, 95% CI With exclusions 17% 15 1,416 Mortality 20% 17 14,205 Ventilation 1% 3 370 ICU admission 6% 4 554 Hospitalization 12% 6 504 Recovery 24% 2 248 Cases -8% 4 15,830 Viral clearance -8% 1 110 RCTs 41% 8 580 Peer-reviewed 13% 22 14,827 Prophylaxis -8% 4 15,830 Early 43% 2 208 Late 21% 19 14,360 Vitamin C for COVID-19 c19vitaminc.com Nov 18, 2021 Favors vitamin C Favors control
Meta analysis using the most serious outcome reported shows 11% [-2‑22%] improvement, without reaching statistical significance. Results are better for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Clinical outcomes suggest benefit while viral and case outcomes do not, consistent with an intervention that may help recovery but is not antiviral. Early treatment is more effective than late treatment.
Statistically significant improvements are seen for mortality and recovery. 8 studies show statistically significant improvements in isolation (4 for the most serious outcome).
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ All studies 11% 25 30,398 Improvement, Studies, Patients Relative Risk, 95% CI With exclusions 17% 15 1,416 Mortality 20% 17 14,205 Ventilation 1% 3 370 ICU admission 6% 4 554 Hospitalization 12% 6 504 Recovery 24% 2 248 Cases -8% 4 15,830 Viral clearance -8% 1 110 RCTs 41% 8 580 Peer-reviewed 13% 22 14,827 Prophylaxis -8% 4 15,830 Early 43% 2 208 Late 21% 19 14,360 Vitamin C for COVID-19 c19vitaminc.com Nov 18, 2021 Favors vitamin C Favors control
While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 4% of vitamin C studies show zero events in the treatment arm.
Multiple treatments are typically used in combination, and other treatments are significantly more effective. Treatment varies widely across studies and may be high-dose IV vitamin C.
Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used, including treatments, as supported by Pfizer [Pfizer]. Denying the efficacy of treatments increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage.
All data to reproduce this paper and sources are in the appendix.
Studies Early treatment Late treatment Prophylaxis PatientsAuthors
All studies 2543% [-378‑93%]21% [4‑35%]-8% [-35‑14%] 30,398 287
With exclusions 15-204% [-7189‑87%]29% [12‑42%]0% [-3‑3%] 1,416 194
Peer-reviewed 2243% [-378‑93%]23% [4‑38%]-9% [-45‑19%] 14,827 227
Randomized Controlled TrialsRCTs 8-204% [-7189‑87%]43% [11‑63%] 580 98
Percentage improvement with vitamin C treatment
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Thomas (RCT) -204% 3.04 [0.13-72.9] death 1/48 0/50 Improvement, RR [CI] Treatment Control Zhao (PSM) 72% 0.28 [0.08-0.93] progression 4/55 12/55 Tau​2 = 1.38; I​2 = 48.6% Early treatment 43% 0.57 [0.07-4.78] 5/103 12/105 43% improvement 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 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 CT​1 JamaliMog.. (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-Ala.. (RCT) 44% 0.56 [0.20-1.51] death 5/40 9/40 CT​1 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​1 Suna 21% 0.79 [0.44-1.41] death 17/153 24/170 Li (PSM) -11% 1.11 [0.79-1.54] death 7/8 19/24 Vishnuram 54% 0.46 [0.24-0.86] death 164/8,634 10/241 Özgünay 9% 0.91 [0.63-1.30] death 17/32 75/128 Tan 25% 0.75 [0.10-2.98] int./death 1/46 14/115 CT​1 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 Tau​2 = 0.07; I​2 = 55.1% Late treatment 21% 0.79 [0.65-0.96] 523/10,381 740/3,979 21% improvement 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 Holt -3% 1.03 [0.77-1.39] cases 49/1,580 397/13,647 Mohseni -44% 1.44 [1.22-1.71] cases 34/43 307/560 Tau​2 = 0.04; I​2 = 83.4% Prophylaxis -8% 1.08 [0.86-1.35] 83/1,623 704/14,207 -8% improvement All studies 11% 0.89 [0.78-1.02] 611/12,107 1,456/18,291 11% improvement 25 vitamin C COVID-19 studies c19vitaminc.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.04; I​2 = 63.5%; Z = 1.70 Effect extraction pre-specified, see appendix Favors vitamin C Favors control
Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix. B. Scatter plot showing the distribution of effects reported in studies. C. History of all reported effects (chronological within treatment stages).
Introduction
We analyze all significant studies concerning the use of 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, for studies within each treatment stage, for individual outcomes, for peer-reviewed studies, for Randomized Controlled Trials (RCTs), and after exclusions.
Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
Results
Figure 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 show forest plots for a random effects meta-analysis of all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, progression, recovery, cases, viral clearance, and peer reviewed studies. Table 1 summarizes the results by treatment stage.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Early treatment 1 2 50.0% 43% improvement
RR 0.57 [0.07‑4.78]
p = 0.61
Late treatment 15 19 78.9% 21% improvement
RR 0.79 [0.65‑0.96]
p = 0.02
Prophylaxis 1 4 25.0% -8% improvement
RR 1.08 [0.86‑1.35]
p = 0.52
All studies 17 25 68.0% 11% improvement
RR 0.89 [0.78‑1.02]
p = 0.09
Table 1. Results by treatment stage.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Thomas (RCT) -204% 3.04 [0.13-72.9] death 1/48 0/50 Improvement, RR [CI] Treatment Control Zhao (PSM) 72% 0.28 [0.08-0.93] progression 4/55 12/55 Tau​2 = 1.38; I​2 = 48.6% Early treatment 43% 0.57 [0.07-4.78] 5/103 12/105 43% improvement 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 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 CT​1 JamaliMog.. (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-Ala.. (RCT) 44% 0.56 [0.20-1.51] death 5/40 9/40 CT​1 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​1 Suna 21% 0.79 [0.44-1.41] death 17/153 24/170 Li (PSM) -11% 1.11 [0.79-1.54] death 7/8 19/24 Vishnuram 54% 0.46 [0.24-0.86] death 164/8,634 10/241 Özgünay 9% 0.91 [0.63-1.30] death 17/32 75/128 Tan 25% 0.75 [0.10-2.98] int./death 1/46 14/115 CT​1 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 Tau​2 = 0.07; I​2 = 55.1% Late treatment 21% 0.79 [0.65-0.96] 523/10,381 740/3,979 21% improvement 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 Holt -3% 1.03 [0.77-1.39] cases 49/1,580 397/13,647 Mohseni -44% 1.44 [1.22-1.71] cases 34/43 307/560 Tau​2 = 0.04; I​2 = 83.4% Prophylaxis -8% 1.08 [0.86-1.35] 83/1,623 704/14,207 -8% improvement All studies 11% 0.89 [0.78-1.02] 611/12,107 1,456/18,291 11% improvement 25 vitamin C COVID-19 studies c19vitaminc.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.04; I​2 = 63.5%; Z = 1.70 Effect extraction pre-specified, see appendix Favors vitamin C Favors control
Figure 3. Random effects meta-analysis for all studies with pooled effects. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Thomas (RCT) -204% 3.04 [0.13-72.9] 1/48 0/50 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Early treatment -204% 3.04 [0.13-72.9] 1/48 0/50 -204% improvement Krishnan 31% 0.69 [0.47-0.92] 40/79 52/73 Improvement, RR [CI] Treatment Control Zhang (RCT) 50% 0.50 [0.20-1.50] 6/27 11/29 Patel 29% 0.71 [0.43-1.14] 22/96 26/80 Kumari (RCT) 36% 0.64 [0.26-1.55] 7/75 11/75 JamaliMog.. (RCT) 0% 1.00 [0.22-4.56] 3/30 3/30 Gao 86% 0.14 [0.03-0.72] 1/46 5/30 Hamidi-Ala.. (RCT) 44% 0.56 [0.20-1.51] 5/40 9/40 CT​1 Al Sulaiman (PSM) 15% 0.85 [0.61-1.12] 46/142 59/142 Mulhem -32% 1.32 [1.07-1.62] 157/794 359/2,425 Gadhiya -1% 1.01 [0.48-1.91] 19/55 36/226 Suna 21% 0.79 [0.44-1.41] 17/153 24/170 Li (PSM) -11% 1.11 [0.79-1.54] 7/8 19/24 Vishnuram 54% 0.46 [0.24-0.86] 164/8,634 10/241 Özgünay 9% 0.91 [0.63-1.30] 17/32 75/128 Simsek 44% 0.56 [0.23-1.35] 6/58 15/81 Tehrani (RCT) 87% 0.13 [0.01-2.25] 0/18 4/26 Tau​2 = 0.08; I​2 = 61.7% Late treatment 20% 0.80 [0.65-0.98] 517/10,287 718/3,820 20% improvement All studies 20% 0.80 [0.66-0.98] 518/10,335 718/3,870 20% improvement 17 vitamin C COVID-19 mortality results c19vitaminc.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.08; I​2 = 59.7%; Z = 2.12 Favors vitamin C Favors control
Figure 4. Random effects meta-analysis for mortality results.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Kumari (RCT) 20% 0.80 [0.40-1.59] 12/75 15/75 Improvement, RR [CI] Treatment Control JamaliMog.. (RCT) -25% 1.25 [0.37-4.21] 5/30 4/30 Özgünay -1% 1.01 [0.79-1.29] 23/32 91/128 Tau​2 = 0.00; I​2 = 0.0% Late treatment 1% 0.99 [0.79-1.24] 40/137 110/233 1% improvement All studies 1% 0.99 [0.79-1.24] 40/137 110/233 1% improvement 3 vitamin C COVID-19 mechanical ventilation results c19vitaminc.com Nov 18, 2021 Tau​2 = 0.00; I​2 = 0.0%; Z = 0.06 Favors vitamin C Favors control
Figure 5. Random effects meta-analysis for ventilation.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Darban (RCT) 6% 0.94 [0.84-1.06] 10 (n) 10 (n) CT​1 Improvement, RR [CI] Treatment Control Hakamifard (RCT) 46% 0.54 [0.14-2.08] 3/38 5/34 CT​1 Suna -2% 1.02 [0.46-2.24] 11/153 12/170 Simsek 10% 0.90 [0.55-1.46] 18/58 28/81 Tau​2 = 0.00; I​2 = 0.0% Late treatment 6% 0.94 [0.84-1.05] 32/259 45/295 6% improvement All studies 6% 0.94 [0.84-1.05] 32/259 45/295 6% improvement 4 vitamin C COVID-19 ICU results c19vitaminc.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.00; I​2 = 0.0%; Z = 1.17 Favors vitamin C Favors control
Figure 6. Random effects meta-analysis for ICU admission.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Thomas (RCT) 31% 0.69 [0.12-3.98] hosp. 2/48 3/50 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Early treatment 31% 0.69 [0.12-3.98] 2/48 3/50 31% improvement Kumari (RCT) 24% 0.76 [0.66-0.87] hosp. time 75 (n) 75 (n) Improvement, RR [CI] Treatment Control JamaliMog.. (RCT) -31% 1.31 [1.03-1.66] hosp. time 30 (n) 30 (n) Hamidi-Ala.. (RCT) 38% 0.62 [0.45-0.86] hosp. time 40 (n) 40 (n) CT​1 Hakamifard (RCT) 1% 0.99 [0.91-1.07] hosp. time 38 (n) 34 (n) CT​1 Tehrani (RCT) 18% 0.82 [0.60-1.13] hosp. time 18 (n) 26 (n) Tau​2 = 0.04; I​2 = 84.0% Late treatment 12% 0.88 [0.72-1.09] 0/201 0/205 12% improvement All studies 12% 0.88 [0.72-1.08] 2/249 3/255 12% improvement 6 vitamin C COVID-19 hospitalization results c19vitaminc.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.04; I​2 = 80.0%; Z = 1.23 Favors vitamin C Favors control
Figure 7. Random effects meta-analysis for hospitalization.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Zhao (PSM) 72% 0.28 [0.08-0.93] 4/55 12/55 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Early treatment 72% 0.28 [0.08-0.93] 4/55 12/55 72% improvement Darban (RCT) 33% 0.67 [0.14-3.17] 2/10 3/10 CT​1 Improvement, RR [CI] Treatment Control Tan 73% 0.27 [0.09-0.61] 7/46 41/115 CT​1 Tau​2 = 0.03; I​2 = 7.9% Late treatment 68% 0.32 [0.16-0.66] 9/56 44/125 68% improvement All studies 70% 0.30 [0.17-0.53] 13/111 56/180 70% improvement 3 vitamin C COVID-19 progression results c19vitaminc.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.00; I​2 = 0.0%; Z = 4.16 Favors vitamin C Favors control
Figure 8. Random effects meta-analysis for progression.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Thomas (RCT) 18% 0.82 [0.63-1.07] recov. time 48 (n) 50 (n) Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Early treatment 18% 0.82 [0.63-1.07] 0/48 0/50 18% improvement Kumari (RCT) 26% 0.74 [0.64-0.86] recov. time 75 (n) 75 (n) Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Late treatment 26% 0.74 [0.64-0.86] 0/75 0/75 26% improvement All studies 24% 0.76 [0.67-0.86] 0/123 0/125 24% improvement 2 vitamin C COVID-19 recovery results c19vitaminc.com Nov 18, 2021 Tau​2 = 0.00; I​2 = 0.0%; Z = 4.13 Favors vitamin C Favors control
Figure 9. Random effects meta-analysis for recovery.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Behera 18% 0.82 [0.45-1.57] case control Improvement, RR [CI] Treatment Control Louca 0% 1.00 [0.97-1.04] Holt -3% 1.03 [0.77-1.39] 49/1,580 397/13,647 Mohseni -44% 1.44 [1.22-1.71] 34/43 307/560 Tau​2 = 0.04; I​2 = 83.4% Prophylaxis -8% 1.08 [0.86-1.35] 83/1,623 704/14,207 -8% improvement All studies -8% 1.08 [0.86-1.35] 83/1,623 704/14,207 -8% improvement 4 vitamin C COVID-19 case results c19vitaminc.com Nov 18, 2021 Tau​2 = 0.04; I​2 = 83.4%; Z = 0.66 Favors vitamin C Favors control
Figure 10. Random effects meta-analysis for cases.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Zhao (PSM) -8% 1.08 [0.64-1.80] viral time 55 (n) 55 (n) Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Early treatment -8% 1.08 [0.64-1.80] 0/55 0/55 -8% improvement All studies -8% 1.08 [0.64-1.80] 0/55 0/55 -8% improvement 1 vitamin C COVID-19 viral clearance result c19vitaminc.com Nov 18, 2021 Tau​2 = 0.00; I​2 = 0.0%; Z = 0.28 Favors vitamin C Favors control
Figure 11. Random effects meta-analysis for viral clearance.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Thomas (RCT) -204% 3.04 [0.13-72.9] death 1/48 0/50 Improvement, RR [CI] Treatment Control Zhao (PSM) 72% 0.28 [0.08-0.93] progression 4/55 12/55 Tau​2 = 1.38; I​2 = 48.6% Early treatment 43% 0.57 [0.07-4.78] 5/103 12/105 43% improvement 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 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 CT​1 Gao 86% 0.14 [0.03-0.72] death 1/46 5/30 Hamidi-Ala.. (RCT) 44% 0.56 [0.20-1.51] death 5/40 9/40 CT​1 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​1 Suna 21% 0.79 [0.44-1.41] death 17/153 24/170 Li (PSM) -11% 1.11 [0.79-1.54] death 7/8 19/24 Vishnuram 54% 0.46 [0.24-0.86] death 164/8,634 10/241 Özgünay 9% 0.91 [0.63-1.30] death 17/32 75/128 Tan 25% 0.75 [0.10-2.98] int./death 1/46 14/115 CT​1 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 Tau​2 = 0.09; I​2 = 59.6% Late treatment 23% 0.77 [0.62-0.96] 474/10,209 678/3,807 23% improvement 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 Mohseni -44% 1.44 [1.22-1.71] cases 34/43 307/560 Tau​2 = 0.05; I​2 = 89.0% Prophylaxis -9% 1.09 [0.81-1.45] 34/43 307/560 -9% improvement All studies 13% 0.87 [0.75-1.01] 513/10,355 997/4,472 13% improvement 22 vitamin C COVID-19 peer reviewed trials c19vitaminc.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.05; I​2 = 67.5%; Z = 1.79 Effect extraction pre-specified, see appendix Favors vitamin C Favors control
Figure 12. Random effects meta-analysis for peer reviewed studies. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details.
Exclusions
To avoid bias in the selection of studies, we analyze all non-retracted studies. Here we show the results after excluding studies with major issues likely to alter results, non-standard studies, and studies where very minimal detail is currently available. Our bias evaluation is based on analysis of each study and identifying when there is a significant chance that limitations will substantially change the outcome of the study. We believe this can be more valuable than checklist-based approaches such as Cochrane GRADE, which may underemphasize serious issues not captured in the checklists, overemphasize issues unlikely to alter outcomes in specific cases (for example, lack of blinding for an objective mortality outcome, or certain specifics of randomization with a very large effect size), or be easily influenced by potential bias. However, they can also be very high quality.
The studies excluded are as below. Figure 13 shows a forest plot for random effects meta-analysis of all studies after exclusions.
[Gadhiya], substantial unadjusted confounding by indication likely.
[Holt], significant unadjusted confounding possible.
[Krishnan], unadjusted results with no group details.
[Li], very late stage, ICU patients.
[Mohseni], unadjusted results with no group details.
[Mulhem], substantial unadjusted confounding by indication likely, substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
[Suna], substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
[Vishnuram], unadjusted results with no group details, minimal details of groups provided.
[Zhao], substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
[Özgünay], substantial unadjusted confounding by indication likely.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Thomas (RCT) -204% 3.04 [0.13-72.9] death 1/48 0/50 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Early treatment -204% 3.04 [0.13-72.9] 1/48 0/50 -204% improvement Zhang (RCT) 50% 0.50 [0.20-1.50] death 6/27 11/29 Improvement, RR [CI] Treatment Control 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 CT​1 JamaliMog.. (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-Ala.. (RCT) 44% 0.56 [0.20-1.51] death 5/40 9/40 CT​1 Al Sulaiman (PSM) 15% 0.85 [0.61-1.12] death 46/142 59/142 Hakamifard (RCT) 46% 0.54 [0.14-2.08] ICU 3/38 5/34 CT​1 Tan 25% 0.75 [0.10-2.98] int./death 1/46 14/115 CT​1 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 Tau​2 = 0.00; I​2 = 0.0% Late treatment 29% 0.71 [0.58-0.88] 102/626 165/692 29% improvement 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 Tau​2 = 0.00; I​2 = 0.0% Prophylaxis 0% 1.00 [0.97-1.03] 0/0 0/0 0% improvement All studies 17% 0.83 [0.71-0.98] 103/674 165/742 17% improvement 15 vitamin C COVID-19 studies after exclusions c19vitaminc.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.02; I​2 = 19.0%; Z = 2.22 Effect extraction pre-specified, see appendix Favors vitamin C Favors control
Figure 13. Random effects meta-analysis for all studies after exclusions. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
Randomized Controlled Trials (RCTs)
Figure 14 and 15 show forest plots for a random effects meta-analysis of all Randomized Controlled Trials and RCT mortality results. Table 2 summarizes the results.
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. This is illustrated with the extreme example of an RCT showing no significant differences for use of a parachute when jumping from a plane [Yeh]. 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. Note that this bias does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable.
Evidence shows that non-RCT trials can also provide reliable results. [Concato] find that well-designed observational studies do not systematically overestimate the magnitude of the effects of treatment compared to RCTs. [Anglemyer] summarized reviews comparing RCTs to observational studies and found little evidence for significant differences in effect estimates. [Lee] shows that only 14% of the guidelines of the Infectious Diseases Society of America were based on RCTs. Evaluation of studies relies on an understanding of the study and potential biases. Limitations in an RCT can outweigh the benefits, for example excessive dosages, excessive treatment delays, or Internet survey bias could have a greater effect on results. Ethical issues may also prevent running RCTs for known effective treatments. For more on issues with RCTs see [Deaton, Nichol].
Figure 16. Randomized Controlled Trials. The distribution of results for RCTs and other studies.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Thomas (RCT) -204% 3.04 [0.13-72.9] death 1/48 0/50 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Early treatment -204% 3.04 [0.13-72.9] 1/48 0/50 -204% improvement