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Background Vitamin C is an essential water-soluble nutrient that functions as a key antioxidant and has been proven to be effective for boosting immunity. In this study, we aimed to assess the efficacy of adding high-dose intravenous vitamin C (HDIVC) to the regimens for patients with severe COVID-19 disease. Methods An open-label, randomized, and controlled trial was conducted on patients with severe COVID-19 infection. The case and control treatment groups each consisted of 30 patients. The control group received lopinavir/ritonavir and hydroxychloroquine and the case group received HDIVC (6 g daily) added to the same regimen. Results There were no statistically significant differences between two groups with respect to age and gender, laboratory results, and underlying diseases. The mean body temperature was significantly lower in the case group on the 3rd day of hospitalization ( p  = 0.001). Peripheral capillary oxygen saturations (SpO 2 ) measured at the 3rd day of hospitalization was also higher in the case group receiving HDIVC ( p  = 0.014). The median length of hospitalization in the case group was significantly longer than the control group (8.5 days vs. 6.5 days) ( p  = 0.028). There was no significant difference in SpO 2 levels at discharge time, the length of intensive care unit (ICU) stay, and mortality between the two groups. Conclusions We did not find significantly better outcomes in the group who were treated with HDIVC in addition to the main treatment regimen at discharge. Trial registration irct.ir (IRCT20200411047025N1), April 14, 2020

There is limited evidence regarding early treatment of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to mitigate symptom progression. To examine whether high-dose zinc and/or high-dose ascorbic acid reduce the severity or duration of symptoms compared with usual care among ambulatory patients with SARS-CoV-2 infection. This multicenter, single health system randomized clinical factorial open-label trial enrolled 214 adult patients with a diagnosis of SARS-CoV-2 infection confirmed with a polymerase chain reaction assay who received outpatient care in sites in Ohio and Florida. The trial was conducted from April 27, 2020, to October 14, 2020. Patients were randomized in a 1:1:1:1 allocation ratio to receive either 10 days of zinc gluconate (50 mg), ascorbic acid (8000 mg), both agents, or standard of care. The primary end point was the number of days required to reach a 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue (rated on a 4-point scale for each symptom). Secondary end points included days required to reach a total symptom severity score of 0, cumulative severity score at day 5, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements. A total of 214 patients were randomized, with a mean (SD) age of 45.2 (14.6) years and 132 (61.7%) women. The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point. Patients who received usual care without supplementation achieved a 50% reduction in symptoms at a mean (SD) of 6.7 (4.4) days compared with 5.5 (3.7) days for the ascorbic acid group, 5.9 (4.9) days for the zinc gluconate group, and 5.5 (3.4) days for the group receiving both (overall P = .45). There was no significant difference in secondary outcomes among the treatment groups. In this randomized clinical trial of ambulatory patients diagnosed with SARS-CoV-2 infection, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the 2 supplements did not significantly decrease the duration of symptoms compared with standard of care. ClinicalTrials.gov Identifier: NCT04342728.

BackgroundThe LOVIT trial examined the effect of vitamin C on sepsis patients, and concluded that in adults with sepsis receiving vasopressor therapy in the ICU, those who received 4-day intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. The aim of this study was to determine whether the abrupt termination of vitamin C administration could explain the increased mortality in the vitamin C group.MethodsWe used Cox regression with two time periods to model the distribution of deaths over the first 11 days in the LOVIT trial.ResultsCompared with a uniform difference between vitamin C and placebo groups over the 11-day follow-up period, addition of a separate vitamin C effect starting from day 5 improved the fit of the Cox model (p = 0.026). There was no difference in mortality between the groups during the 4-day vitamin C administration with RR = 0.97 (95% CI: 0.65–1.44). During the week after the sudden termination of vitamin C, there were 57 deaths in the vitamin C group, but only 32 deaths in the placebo group, with RR = 1.9 (95% CI: 1.2–2.9; p = 0.004).ConclusionThe increased mortality in the vitamin C group in the LOVIT trial is not explained by ongoing vitamin C administration, but by the abrupt termination of vitamin C. The LOVIT trial findings should not be interpreted as evidence against vitamin C therapy for critically ill patients.

Chronic foot ulcers are associated with a high risk of osteomyelitis, poor quality of life, amputations and disability. Few strategies improve their healing, and amputation rates in high-risk foot services are usually over 30 %. We conducted a randomised, inactive-placebo controlled, double-blind trial of 500 mg of slow-release vitamin C in sixteen people with foot ulcers in the Foot Wound Clinic at Westmead Hospital. Nine were randomised to control and seven to vitamin C. When serum vitamin C results become available at 4 weeks, all people with deficiency were offered both vitamin C and glucosamine tablets for the next 4 weeks. Patients without baseline deficiency continued their original assigned treatment. The primary outcome was percentage ulcer healing (reduction in ulcer size) at 8 weeks. Fifty percentage of subjects had baseline vitamin C deficiency, half having undetectable levels. Healing at 8 weeks was significantly better in the vitamin C group (median 100 v. –14 %, P = 0·041). Healing without amputation occurred in all patients in the vitamin C group. In contrast, 44 % of controls had not healed their ulcer at the end of the study period. Vitamin C improved healing of foot ulcers. Further studies are needed to determine whether there is a threshold effect for serum vitamin C above which therapy is ineffective and whether there are better or lesser responding subgroups. Because of its low cost and ease of access and administration, we recommend offering vitamin C therapy to all people who have chronic foot ulcers and potentially suboptimal vitamin C intake. Trial registration number: ACTRN12617001142325.

Purpose We hypothesised that the biological heterogeneity of sepsis may highlight sepsis subtypes with differences in response to intravenous vitamin C treatment in the Lessening Organ Dysfunction with VITamin C (LOVIT) trial. Our aims were to identify sepsis subtypes and to test whether sepsis subtypes have differences in treatment effect to vitamin C and describe putative biological effects of vitamin C treatment. Methods We measured biomarkers of inflammation, at baseline and at 7 days post-randomisation, in 457/863 (53.0%) of participants with plasma samples in the LOVIT trial. We used agglomerative hierarchical clustering on log 10 -transformed baseline data of 26 biomarkers to identify sepsis subtypes. We analysed differences in vitamin C treatment effect with regression models incorporating robust standard errors to report odds ratio and 95% confidence intervals (OR(95% CI)). All analyses were completed blinded to treatment allocation. Results Our cohort included 233/429 (54.3%) allocated to vitamin C and 224/434 (51.6%) allocated to placebo. A three-subtype model best explained the variance in our data. Subtype-2 had the highest, and subtype-3 had the lowest levels of inflammatory response. In paired longitudinal samples, vitamin C did not have discernible anti-inflammatory effects, with anti-inflammatory effects related to time since randomisation and concomitant hydrocortisone treatment. The treatment effect estimates (OR (95% CI)) for subtype-1, subtype-2 and subtype-3 were 1.04 (0.63–1.73), 1.33 (0.53–3.36) and 1.95 (0.85–4.49), respectively (test of heterogeneity p  = 0.002). Conclusion We report three sepsis subtypes based on inflammatory response profile. No subtype benefitted from vitamin C treatment in the LOVIT trial, with heterogeneity of treatment effect in the magnitude of harm. Trial registration Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.

Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. Supplementation of l-arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis. A single-blind randomized, placebo-controlled trial was conducted in adults aged between 20 and 60 years with persistent fatigue attending a post-acute COVID-19 outpatient clinic. Participants were randomized 1:1 to receive twice-daily orally either a combination of 1.66 g l-arginine plus 500 mg liposomal vitamin C or a placebo for 28 days. The primary outcome was the distance walked on the 6 min walk test. Secondary outcomes were handgrip strength, flow-mediated dilation, and fatigue persistence. Fifty participants were randomized to receive either l-arginine plus vitamin C or a placebo. Forty-six participants (median (interquartile range) age 51 (14), 30 [65%] women), 23 per group, received the intervention to which they were allocated and completed the study. At 28 days, l-arginine plus vitamin C increased the 6 min walk distance (+30 (40.5) m; placebo: +0 (75) m, p = 0.001) and induced a greater improvement in handgrip strength (+3.4 (7.5) kg) compared with the placebo (+1 (6.6) kg, p = 0.03). The flow-mediated dilation was greater in the active group than in the placebo (14.3% (7.3) vs. 9.4% (5.8), p = 0.03). At 28 days, fatigue was reported by two participants in the active group (8.7%) and 21 in the placebo group (80.1%; p < 0.0001). l-arginine plus vitamin C supplementation improved walking performance, muscle strength, endothelial function, and fatigue in adults with long COVID. This supplement may, therefore, be considered to restore physical performance and relieve persistent symptoms in this patient population.

Background Sepsis and septic shock are associated with high mortality and morbidity despite adequate standard care. Vitamin C deficiency is a common, potentially reversible, contributor to morbidity and mortality in sepsis. Previous studies have shown mixed and conflicting results. Our study aimed to determine the potential benefit of early administration (within 6 h after admission) of vitamin C in patients with sepsis or septic shock. Methods This was a phase 3b prospective, multicenter, double-blinded, randomized placebo-controlled trial. Participants were enrolled in the Emergency Departments of 8 hospitals throughout Belgium. Patients were randomized to receive 1.5 g of vitamin C, or matching placebo, every 6 h for 4 days. The primary outcome was the average post-baseline patient Sequential Organ Failure Assessment (SOFA) score on day 2 to 5. Key secondary outcomes were the maximum SOFA score, 28-day mortality and length of ICU and hospital stay. Results A total of 300 patients were recruited between June 4th, 2021, and August 19th, 2023. 292 patients, of which 147 were assigned to the vitamin C and 145 to the placebo group, completed the trial and were included in the analysis. The primary outcome (vitamin C, 1.98; placebo, 2.19) was 8.7% lower in the vitamin C group, but not significantly (ratio 0.91, 95% CI 0.77 to 1.08, P  = 0.30). In a planned subgroup analysis, patients with a baseline SOFA score of 6 or above had a significant lower average post-baseline SOFA score in the vitamin C group (ratio 0.76, 95% CI 0.86 to 0.99, P  = 0.042). Findings were similar in the two groups regarding secondary outcomes and adverse events, except for a lower probability of being on renal replacement therapy in the vitamin C group of the per protocol analysis (ratio 0.28, 95% CI 0.078 to 1.0, P  = 0.05). Conclusions Early treatment with vitamin C did not result in a statistically significant reduction in organ dysfunction. Therefore, this study does not support the use of vitamin C in sepsis patients. Trial registration : ClinicalTrials.gov Identifier: NCT04747795 . Registered 4 February 2021. Key Points Question Does early treatment with vitamin C lead to a less severe disease course in patients with sepsis or septic shock? Findings In this randomized clinical trial that included 292 patients, treatment with intravenous vitamin C compared to placebo did not result in a lower average post-baseline patient Sequential Organ Failure Assessment (SOFA) score on day 2 to 5 (1.98 vs 2.19), except for a subgroup of patients with a baseline SOFA score of 6 or above. Meaning Early treatment with vitamin C did not result in a significant improvement of the disease course.

This study evaluates the efficacy and safety of emulsified microsomal Ferric pyrophosphate (EMFP/SunActive™ Fe, 27 mg elemental iron) versus Ferrous Ascorbate (100 mg elemental iron) in second-trimester pregnant women with iron-deficiency anemia (IDA) for 4 weeks. Pregnant women aged 20–35 years with a singleton pregnancy, hemoglobin (Hb) 9–10.5 g/dL, and ferritin < 15 mcg/L were enrolled. The test group showed zero adverse effects vs. the control group, having 11.1% adverse events. The gastrointestinal(GI) adverse symptoms, including nausea, dark stools, and hyperacidity, were reported only in the Ferrous Ascorbate group, indicating superior tolerability and safety of EMFP tablets. Both groups showed similar improvements in Hb (Δ2.63 g/dL vs. Δ2.62 g/dL) and serum ferritin (61.09% vs. 61.92%). Reticulocyte hemoglobin (RET-He) increased by 20.5% in the test group and 16.2% in the control group, with no significant difference. Clinical symptoms such as dizziness, fatigue, and palpitations improved with greater magnitude in the test group. It was inferred that the test group receiving EMFP was as effective as the control group in improving efficacy endpoints at a significantly lower dose (1/3rd dose compared to ascorbate). EMFP showed better tolerability, safety and compliance, making it a promising option for managing IDA in pregnant women.

Cellular homeostasis is lost or becomes dysfunctional during septic shock due to the activation of the inflammatory response and the deregulation of oxidative stress. Antioxidant therapy administered alongside standard treatment could restore this lost homeostasis. We included 131 patients with septic shock who were treated with standard treatment and vitamin C (Vit C), vitamin E (Vit E), N-acetylcysteine (NAC), or melatonin (MT), in a randomized trial. Organ damage quantified by Sequential Organ Failure Assessment (SOFA) score, and we determined levels of Interleukins (IL) IL1β, Tumor necrosis factor alpha (TNFα), IL-6, monocyte chemoattractant protein-1 (MCP-1), Transforming growth factor B (TGFβ), IL-4, IL-10, IL-12, and Interferon-γ (IFNγ). The SOFA score decreased in patients treated with Vit C, NAC, and MT. Patients treated with MT had statistically significantly reduced of IL-6, IL-8, MCP-1, and IL-10 levels. Lipid peroxidation, Nitrates and nitrites (NO3− and NO2−), glutathione reductase, and superoxide dismutase decreased after treatment with Vit C, Vit E, NAC, and MT. The levels of thiols recovered with the use of Vit E, and all patients treated with antioxidants maintained their selenium levels, in contrast with controls (p = 0.04). The findings regarding oxidative stress markers and cytokines after treatment with antioxidants allow us to consider to future the combined use of antioxidants in a randomized clinical trial with a larger sample to demonstrate the reproducibility of these beneficial effects.

Background Intravenous vitamin C administration in septic shock may have a sparing effect on vasopressor requirements, and vitamin C’s enzyme cofactor functions provide a mechanistic rationale. Our study aimed to determine the effect of intravenous vitamin C administration on vasopressor requirements and other outcomes in patients with septic shock. Methods This was a double-blind, randomised placebo-controlled trial in 40 patients with septic shock who were randomised (1:1) to receive intravenous vitamin C (at a dose of 25 mg/kg of body weight every 6 h) or placebo (intravenous 5% dextrose) for up to 96 h, or until death or discharge. The primary outcome was intravenous vasopressor requirements (dose and duration), and secondary outcomes included Sequential Organ Failure Assessment (SOFA) scores, intensive care unit (ICU) and hospital length of stay, and mortality. In addition, blood samples were collected to determine vitamin C kinetics and inflammatory marker concentrations. Results Median plasma vitamin C concentrations were deficient at baseline (9.2 [4.4, 12] µmol/L) and increased to 408 (227, 560) µmol/L following 72 h of intervention. The mean duration of intravenous vasopressor infusion in the vitamin C group was 48 (95% CI 35–62) hours and in the placebo group was 54 (95% CI 41–62) hours (p = 0.52). The dose of vasopressor delivered over time was comparable between the two groups, as were SOFA scores (p > 0.05). The median ICU length of stay in the intervention group was 3.8 (2.2, 9.8) days versus 7.1 (3.1, 20) days in the placebo group (p = 0.12). The median hospital length of stay for the vitamin C group was 18 (11, 35) days versus 22 (10, 52) days for the placebo group (p = 0.65). Mortality was comparable between the two groups (p > 0.05). Of the inflammatory markers, neutrophil counts were elevated in the vitamin C group relative to placebo by 72 h (p = 0.01). C-reactive protein and myeloperoxidase concentrations were elevated at baseline, however, the two groups were comparable over time (p > 0.05). Conclusions Our pilot study indicated that intravenous vitamin C did not provide significant decreases in the mean dose or duration of vasopressor infusion. Further research that takes into account the potential impact of intervention timing, dose and duration, and location of trial, may provide more definitive evidence. Trial registration ACTRN12617001184369 (11/8/2017).