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Research Article
Harri Hemilä
University of Helsinki, Helsinki, Finland
Corresponding Author
ORCiD: https://orcid.org/0000-0002-4710-307X
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This work is licensed under a CC BY 4.0 License. Read Full License
Declarations:
Declarations
- This study involved human subjects.
- The author confirmed that all appropriate ethical guidelines for the use of human subjects have been followed, any necessary IRB and/or ethics committee review has been obtained, and information about the IRB/ethics committee is included in the manuscript.
- The author has confirmed that all necessary patient/participant consent or assent has been obtained and the appropriate institutional forms have been archived. If the IRB/ethics committee waived the requirement for patient/participant consent or assent, an explanation for the waiver is included in the text.
- This study reports on a clinical trial.
- The author has confirmed that this trial has been registered with an ICMJE-approved registry, and the trial registration ID has been provided in the text. If the article reports on a study that was registered retrospectively, a statement explaining why the study was not registered in advance has been provided in the text.
- The author has confirmed that a statement listing potential conflicts of interest or lack thereof is included in the text.
The COVID A to Z trial (JAMA Netw Open. 2021;4:e210369) is important as it focused specifically on SARS-CoV-2 coronavirus patients and examined a high dose of vitamin C which was previously predicted to reduce the duration of respiratory virus infections by about 20%. Unfortunately, there are several limitations in the trial methods. The COVID A to Z trial was “stopped early for futility”. In the sample size calculation, the authors assumed a 1.0 day shorter symptoms by intervention. Duration of symptoms was reduced by 1.2 days in the vitamin C arm compared with the usual care arm. Given that the observed vitamin C effect was 20% greater than the expected effect (1.2 vs. 1.0), it is illogical to have stopped the trial early because of “futility”. In this reanalysis we calculated the rate ratio of recovery between the vitamin C and usual care arms and found that vitamin C increased the rate of recovery by 70% (95% CI 6.8% to 170%, P = 0.025). Furthermore, we calculated quantile treatment effect of vitamin C. At the 60th percentile level of symptom distribution, duration was 9 days in the usual care arm, and 6 days in the vitamin C arm, which corresponds to reduction in symptom duration by 3 days (95% CI 3 to 4.6 days; P < 0.001). The analysis of the quantile treatment effect indicates that there may be around 30% reduction in symptom duration in patients with the longest symptoms. Our reanalysis indicates a need for methodologically sound trials with larger numbers of patients to investigate the treatment effects of vitamin C against SARS-CoV-2.
Keywords
Ascorbic acid, COVID-19, Common cold, Randomized controlled trials, SARS-CoV-2, Statistics, Time factors, Treatment outcome, Zinc
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This is a preprint. It has not completed peer review.
Research Article
Harri Hemilä
University of Helsinki, Helsinki, Finland
Corresponding Author
ORCiD: https://orcid.org/0000-0002-4710-307X
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 01 Mar, 2021
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Declarations:
Declarations
- This study involved human subjects.
- The author confirmed that all appropriate ethical guidelines for the use of human subjects have been followed, any necessary IRB and/or ethics committee review has been obtained, and information about the IRB/ethics committee is included in the manuscript.
- The author has confirmed that all necessary patient/participant consent or assent has been obtained and the appropriate institutional forms have been archived. If the IRB/ethics committee waived the requirement for patient/participant consent or assent, an explanation for the waiver is included in the text.
- This study reports on a clinical trial.
- The author has confirmed that this trial has been registered with an ICMJE-approved registry, and the trial registration ID has been provided in the text. If the article reports on a study that was registered retrospectively, a statement explaining why the study was not registered in advance has been provided in the text.
- The author has confirmed that a statement listing potential conflicts of interest or lack thereof is included in the text.
The COVID A to Z trial (JAMA Netw Open. 2021;4:e210369) is important as it focused specifically on SARS-CoV-2 coronavirus patients and examined a high dose of vitamin C which was previously predicted to reduce the duration of respiratory virus infections by about 20%. Unfortunately, there are several limitations in the trial methods. The COVID A to Z trial was “stopped early for futility”. In the sample size calculation, the authors assumed a 1.0 day shorter symptoms by intervention. Duration of symptoms was reduced by 1.2 days in the vitamin C arm compared with the usual care arm. Given that the observed vitamin C effect was 20% greater than the expected effect (1.2 vs. 1.0), it is illogical to have stopped the trial early because of “futility”. In this reanalysis we calculated the rate ratio of recovery between the vitamin C and usual care arms and found that vitamin C increased the rate of recovery by 70% (95% CI 6.8% to 170%, P = 0.025). Furthermore, we calculated quantile treatment effect of vitamin C. At the 60th percentile level of symptom distribution, duration was 9 days in the usual care arm, and 6 days in the vitamin C arm, which corresponds to reduction in symptom duration by 3 days (95% CI 3 to 4.6 days; P < 0.001). The analysis of the quantile treatment effect indicates that there may be around 30% reduction in symptom duration in patients with the longest symptoms. Our reanalysis indicates a need for methodologically sound trials with larger numbers of patients to investigate the treatment effects of vitamin C against SARS-CoV-2.
Figure 1
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