Efficacy of intravenous vitamin C in management of moderate and severe COVID-19: A double blind randomized placebo controlled trial

Abstract

Aim: To study the efficacy of intravenous vitamin C in management of moderate and severe COVID-19. Objective: To determine the efficacy of intravenous vitamin C in reducing in-hospital mortality in moderate and severe cases of COVID-19. Design: Parallel, double-blinded randomized controlled trial with placebo. Ethical clearance was obtained from the institutional ethics committee, AIIMS Patna. The trial was registered with the Clinical Trials Registry – India (registration number- CTRI/2020/11/029230.) Setting: A tertiary care centre in Bihar, India Participants: All patients above the age of 18 years both males and females, admitted in ICU with a diagnosis of moderate and severe COVID-19 (on the basis of a positive reverse transcriptase polymerase chain reaction (RT–PCR) report) at our facility during the study period (01/10/2020–31/12/2020) not having any of the exclusion criteria. Intervention: The patients in the intervention arm were given 1 gram (2 ampoules of 2 ml each containing 500 mg of vitamin C mixed in 100 ml normal saline) intravenous vitamin C 8 hourly for four days. The patients in the placebo arm received similar looking ampoules (2 ampoules of 2 ml sterile water for injection mixed in 100 ml normal saline) intravenously 8 hourly for four days. The rest of the treatment was given as per the standard operating procedure (SOP) of the institute with adjustments as per treating team’s judgement. Outcome Measures: Primary outcome was reduction in in-hospital mortality. Secondary outcomes were improvement in qSOFA score, pO2/fiO2 ratio, fall in inflammatory markers, need for mechanical ventilation and vasopressors. Results: Regarding primary outcome, 10 (33.3%) patients died in intervention group compared to 13 (43.3%) in placebo. Worth noting from baseline characteristics is that 86.7% in intervention arm were of severe category compared to 66.7% severe category patients in placebo group. Though number of severe cases were more in intervention arm there has been comparatively less mortality in this group. Regarding secondary outcomes, amongst 30 patients in vitamin C group, 11 (36.7%) required invasive mechanical ventilation compared to 14 (46.7%) out of 30 in placebo group but the difference was not statistically significant. Although there were a greater number of moderate cases in placebo group, invasive ventilation requirement (and NIV requirement) was more in this group, thus it could be considered that vitamin C might have a role in reducing the severity of disease. The need for vasopressor therapy was higher in intervention arm 33.3% compared to 26.7% in placebo but not significant statistically. The secondary outcomes of the study such as improvement in organ failure score (qSOFA Score), fall in level of inflammatory markers, improvement in respiratory index (pO2/fiO2 ratio), need...

The effect of vitamin C on the risk of mortality in patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials

“…Eight studies were excluded either due to observational study design or reported no mortality events. In total, we included eleven randomized controlled trials (Beigmohammadi et al 2021 ; Cao et al 2020 ; JamaliMoghadamSiahkali et al 2021 ; Kumar et al 2022 ; Kumari et al 2020 ; Labbani-Motlagh et al 2022 ; Leal-Martínez et al 2022 ; Majidi et al 2021 ; Tehrani et al 2022 ; Thomas et al 2021 ; Zhang et al 2021 ) in our systematic review and meta-analysis, with 445 patients randomized to receive vitamin C and 494 patients randomized to receive comparative interventions.…”

“…The regimen of vitamin C in the intervention group differed across the included trials. Most of the included trials (n = 6) (Beigmohammadi et al 2021 ; JamaliMoghadamSiahkali et al 2021 ; Kumar et al 2022 ; Labbani-Motlagh et al 2022 ; Tehrani et al 2022 ; Zhang et al 2021 ) administered vitamin C intravenously at a fixed non–weight-based dose ranging from 2 to 24 g daily for a duration of 4 to 7 days. One trial (Kumari et al 2020 ) administered vitamin C intravenously at a weight-based dose of 50 mg/kg daily.…”

“…We adjudicated five trials (Kumar et al 2022 ; Labbani-Motlagh et al 2022 ; Leal-Martínez et al 2022 ; Majidi et al 2021 ; Thomas et al 2021 ) as having a low risk of bias in all domains and, thus an overall low risk of bias. We rated the remaining trials as having overall some concerns of bias (some concerns of bias in at least one domain): the four trials reported by Zhang et al ( 2021 ), by JamaliMoghadamSiahkali et al ( 2021 ), by Tehrani et al ( 2022 ), and by Beigmohammadi et al ( 2021 ) respectively, had some concerns of bias in the domain of ‘deviations from intervention’ due to open-label/single-blind trial design; the trial reported by Kumari et al ( 2020 ) had some concerns of bias in the domain of ‘randomization’ due to inadequate information on allocation concealment as well as in the domain of ‘deviations from intervention’ due to single-blind trial design; the trial reported by Cao et al ( 2020 ) had some concerns of bias and in the domain of ‘deviations from intervention’ due to single-blind trial design as well as in the domain of ‘selection of the reported results’ since it was unclear whether the trial was analyzed as pre-specified.…”

“…The meta-analysis of eleven trials (Beigmohammadi et al 2021 ; Cao et al 2020 ; JamaliMoghadamSiahkali et al 2021 ; Kumar et al 2022 ; Kumari et al 2020 ; Labbani-Motlagh et al 2022 ; Leal-Martínez et al 2022 ; Majidi et al 2021 ; Tehrani et al 2022 ; Thomas et al 2021 ; Zhang et al 2021 ) using a random-effects model reported reduction in the risk of all-cause mortality with the administration of vitamin C in patients with COVID-19 compared to non-administration of vitamin C; the pooled odds ratio is with significant evidence to indicate mortality benefits, at the current sample size (Fig. 1 ; pooled odds ratio = 0.53; 95% confidence interval 0.30 to 0.92; I 2 = 22%).…”

“…Subgroup analysis of studies (Beigmohammadi et al 2021 ; Cao et al 2020 ; JamaliMoghadamSiahkali et al 2021 ; Kumar et al 2022 ; Kumari et al 2020 ; Leal-Martínez et al 2022 ; Majidi et al 2021 ; Tehrani et al 2022 ; Zhang et al 2021 ) which included patients with severe COVID-19, produced findings of significant mortality reduction with the administration of vitamin C relative to no vitamin C (pooled odds ratio = 0.47; 95% confidence interval 0.26 to 0.84; I 2 = 17%). Likewise, significant evidence of mortality reduction (pooled odds ratio = 0.48; 95% confidence interval 0.27 to 0.87; I 2 = 17%) is observed when an inverse variance heterogeneity (IVhet) model was fitted.…”