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The rapid worldwide spread of COVID-19 has caused a global health crisis. To date, symptomatic supportive care has been the most common treatment. It has been reported that the mechanism of COVID-19 is related to cytokine storms and subsequent immunogenic damage, especially damage to the endothelium and alveolar membrane. Vitamin C (VC), also known as L-ascorbic acid, has been shown to have antimicrobial and immunomodulatory properties. A high dose of intravenous VC (HIVC) was proven to block several key components of cytokine storms, and HIVC showed safety and varying degrees of efficacy in clinical trials conducted on patients with bacterial-induced sepsis and acute respiratory distress syndrome (ARDS). Therefore, we hypothesise that HIVC could be added to the treatment of ARDS and multiorgan dysfunction related to COVID-19.
The investigators designed a multicentre prospective randomised placebo-controlled trial that is planned to recruit 308 adults diagnosed with COVID-19 and transferred into the intensive care unit. Participants will randomly receive HIVC diluted in sterile water or placebo for 7 days once enrolled. Patients with a history of VC allergy, end-stage pulmonary disease, advanced malignancy or glucose-6-phosphate dehydrogenase deficiency will be excluded. The primary outcome is ventilation-free days within 28 observational days. This is one of the first clinical trials applying HIVC to treat COVID-19, and it will provide credible efficacy and safety data. We predict that HIVC could suppress cytokine storms caused by COVID-19, help improve pulmonary function and reduce the risk of ARDS of COVID-19.
The study protocol was approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (identifiers: Clinical Ethical Approval No. 2020001). Findings of the trial will be disseminated through peer-reviewed journals and scientific conferences.
Keywords: infectious diseases, adult intensive & critical care, clinical trials, respiratory infections, adult intensive & critical care
This is one of the first prospective randomised controlled trials applying high dose of intravenous vitamin C (HIVC) to treat COVID-19.
‘High-dose’ vitamin C therapy lacks a universal definition. A previous meta-analysis considered high doses as equal to or greater than 10 g/day. In this trial, we will administer 24 g vitamin C per day for 7 days intravenously.
HIVC has advantages in terms of stability, availability, safety and cost compared with other treatments.
The sample size was calculated in two stages to ensure the calculation is reasonable, maximises the possibility of obtaining significant results and provides credible outcome data.
As the duration and distribution of infected cases are unpredictable geographically and temporally, the number of recruited patients at each centre is also unpredictable, in spite of competitive enrolment.
The COVID-19 pandemic is a threat that has caused panic at the global level. As of 21 June 2020, 8 708 008 cases were confirmed worldwide, resulting in 461 715 deaths. 1 Infected patients presented predominantly with fever and cough as well as dyspnoea and myalgia. 2–4 A meta-analysis 4 concluded that, among the patients, 32.8% presented with acute respiratory distress syndrome (ARDS), 20.3% were transferred to the intensive care unit (ICU) and 13.9% died. According to our previous research, 3 patients with ARDS accounted for 66.1% of patients with COVID-19 in the ICU, and the rates of non-invasive and invasive mechanical ventilation were 41.7% and 47.22%, respectively. However, no specific treatment is currently available because traditional antiviral drugs do not work well against COVID-19. Recent clinical trials exploring new therapies, including remdesivir, 5 hydroxychloroquine 6 and lopinavir-ritonavir, 7 for COVID-19 had negative results. Therefore, it is urgent to explore effective therapies considering the grim situation.
The mechanism of COVID-19 involves a cytokine storm, which is a potentially fatal immune reaction triggered by a variety of factors, including infections. Cytokine storms are associated with the clinical manifestation of severe inflammation and highly elevated levels of proinflammatory cytokines. 8 Previous research 9 suggested that cytokine storms may be the main mechanism of highly pathogenic human coronavirus infected pneumonia, such as severe acute respiratory syndrome and Middle East respiratory syndrome. As a member of the coronavirus family, 10 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits similar clinical features. The clinical characteristics of COVID-19 indicate that cytokine storms may be positively correlated with the severity of the disease. 2 11 12 Moreover, cytokines and T cell subsets may be indicators for predicting prognosis. 12 An immunopathology report 12 speculated that interleukin (IL)-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) were the main cytokines in the hyperinflammatory response caused by COVID-19, while Th1 cells were the key cells involved, especially for patients transferred into ICUs. The findings and speculations were verified by an autopsy study that confirmed that patients with critically ill COVID-19 13 had developed ARDS. In addition, they also found that the overactivation of T cells and the decrease in the cell counts may explain the occurrence of cytokine storms and, to some degree, the severe immune-medicated injury. All these results indicated that decreasing cytokine storms and immunogenetic damage may be the main treatment option for critically ill patients with COVID-19.
Vitamin C (VC), a common and necessary nutrient, is also an antioxidant. In addition to its role in the metabolism of the human body, including energy transformation, collagen biosynthesis and repair, adrenal steroid and catecholamine production, iron absorption and so on, 14–19 VC also possesses antimicrobial properties—thus reducing the risk of infections—and immunomodulatory functions, particularly in high concentrations. 14 First, VC plays a crucial role in immunomodulation. It can inhibit the activation of nuclear factor kappa-B (NFκB), which is a primary proinflammatory transcription factor, and plays a pivotal role in overall immunity, including the genetic regulation of chemokines, cytokines, adhesion molecules, inflammatory mediators and apoptosis inhibitors. 20 VC can inhibit the production of IL-6 and tumor necrosis factor alpha (TNF-α), 21 22 and this effect appears to be a dose dependent. 21 VC can reduce GM-CSF signalling responses, 23 functioning as a regulator of cytokine redox-signal transduction in host defence cells and having a possible role in controlling inflammatory responses. In addition, high-dose VC can regulate the proliferation and function of T cells, B cells and natural killer (NK) cells. 24–27 This may help inhibit the progression of cytokine storms and improve the host’s immunity. Second, previous studies 22 demonstrated that VC can inhibit oxidative stress, an important part of the innate immune response to viral respiratory infection 28 29 and contributes to lung injury and barrier dysfunction. 28 Oxidative stress may also play a role in the mechanism of COVID-19. 29 It has been reported that VC can repair oxidative damage in human bronchial epithelium by modulating reactive oxygen species (ROS) generation and inflammatory expression 30 and can prevent ROS-induced lung damage. 31 Third, VC can regulate alveolar fluid clearance by enhancing lung epithelial barrier function through epigenetic and transcriptional enhancement of protein channels that regulate alveolar fluid clearance. 32 33 VC may help decrease the symptoms of ARDS and improve respiratory function. Fourth, VC may have antiviral effects. VC has been reported to inhibit the replication of herpes simplex virus 1, poliovirus type 1 and influenza A virus in vitro. 34
Previous research 35 demonstrated that intravenous VC (IVC) can achieve a higher plasma concentration than oral VC due to losses during intestinal absorption, tissue transport and renal reabsorption. The efficacy and safety of intravenous high-dose VC (HIVC) in critically ill patients have been investigated via several clinical trials. A recent meta-analysis, 15 of mostly cardiac surgery trials, revealed that VC shortened ICU length of stay and duration of mechanical ventilation in ICU patients. In addition, the effect of VC was significantly greater for patients with more severe illness. 15 36 Regarding patients with sepsis or ARDS, a phase I trial of IVC in patients with severe sepsis 37 reported that VC significantly reduced multiorgan failure scores and circulating injury biomarker levels. Notably, the effect appeared greater in the high-dose group (200 mg/kg) than in the low-dose group (50 mg/kg). However, another study conducted on patients with sepsis and ARDS 38 reported no difference in the primary outcome of organ failure scores and inflammation biomarkers but found a significant reduction in 28-day mortality and long-term prognosis. This study applied 50 mg/kg VC intravenously at a late stage when patients were undergoing mechanical ventilation. In addition, there was also a case report 39 that administered HIVC (200 mg/kg) to successfully treat virus-induced ARDS, with patients making a rapid recovery after receiving extracorporeal membrane oxygenation and without any long-term sequelae.
A major concern regarding the use of high-dose VC is its potential side effects. Many reported side effects of high-dose VC are insignificant and rare and of little consequence. 40 It was reported that high-dose VC was related to haemolysis in glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, acute kidney injury (AKI) and acute oxalate nephropathy. 41–44 However, adverse effects were mostly reported in a few cases and were related to too large of doses, 41–44 non-standard administration 43 or high-risk underlying diseases. 44 Clinical trials with large sample sizes conducted on ICU patients 15 36–38 reported few adverse events (AEs). In addition, a survey 45 also indicated that other than the known complications of kidney damage and G-6-PD deficiency, HIVC appeared to be remarkably safe. For patients with haemochromatosis, G-6-PD deficiency, renal dysfunction, renal stones or oxaluria, VC should be carefully administered; adequate hydration, appropriate dilution and slow infusion rates are recommended for HIVC. 46
Thus, we hypothesise that administering HIVC at an early stage of ARDS in COVID-19 would result in better outcomes. In this trial, we will tentatively explore the safety and efficacy of HIVC used in COVID-19.
The main goal is to investigate a new potential therapy for COVID-19 by clarifying the effect of HIVC on the prognosis of patients with COVID-19, especially on respiratory function assessed by ventilation-free days.
This protocol was written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials guidelines 47 (see attached Research Checklist); the protocol is summarised in figures 1 and 2 .