Clinical Efficacy of Megadose Vitamin C in Sepsis (CEMVIS)

Clinical Efficacy of Megadose Vitamin C in Sepsis (CEMVIS): A Multicenter, Randomized, Single-blind, Placebo-controlled Clinical Trial

In this multicenter, randomized, single-blind, placebo-controlled clinical trial. Patients will be randomly assigned to receive Vitamin C or placebo for 4 days or until ICU discharge (whatever come first). The primary outcome is 28-day all-cause mortality.

Investigational drug: Vitamin C for injection Study title: Clinical efficacy of megadose vitamin C in sepsis (CEMVIS): A Multicenter, Randomized, Single-blind, Placebo-controlled Clinical Trial Principal Investigator: Zhanguo Liu, professor, Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University Study subjects: Adult septic/septic shock patients with procalcitonin(PCT)≥2ng/ml at recruitment. Study phase: Investigator Initiated Trial(IIT) Study objectives: The objective of the study is to determine whether megadose vitamin c, compared to placebo, improve the prognosis of sepsis, including the reduction in mortality, the protection of organ function and reduction of inflammatory response, and to determine the safety of megadose vitamin c in patients with sepsis. Study design: A Multicenter, Randomized, Single-blind, Placebo-controlled Clinical Trial Method： Megadose vitamin C group: routine treatment follow the recommendation of the guidelines for sepsis in 2021+ 12 g vitamin C (48 ml) injection every 12 h for 4 days or until ICU discharge (death or transfer from ICU to general ward or discharge), whatever come first. Placebo control group: routine treatment follow the recommendation of the guidelines for sepsis in 2021 + 48ml 5% glucose injection every 12 h for 4 days or until ICU discharge (death or transfer from ICU to general ward or discharge), whatever come first. Course: 4 days Sample size: 152 The number of study center: 5 Study center: Department of Critical Care Medicine of Zhujiang Hospital,Guangzhou, Guangdong, China Department of Critical Care Medicine of The First People's Hospital of Foshan, Foshan, Guangdong, China Department of Critical Care Medicine of Dongguan People's Hospital, Dongguan, Guangdong,China Department of Critical Care Medicine of Yunfu People' s Hospital, Yunfu, Guangdong, China Department of Critical Care Medicine of Zhongshan People's Hospital, Zhongshan, Guangdong, China Primary endpoint: 28-day all-cause mortality. Secondary endpoints: The state of liver function: the serum level of transaminase(AST、ALT)、total bilirubin at 96 h after randomization The state of lung function: oxygenation index(PaO2/FiO2) at 96h after randomization The state of kidney function: serum level of Creatinine (Cr)、blood urea nitrogen(BUN)、Cystatin(Cys) at 96 h after randomization The state of inflammatory response: the serum level of interleukin-6(IL-6) and C-reactive protein(CRP) at 96 h after randomization. The state of infection: the serum level of procalcitonin(PCT) and white blood cell （WBC） at 96 h after randomization. The state of circulation system: the serum level of lactate at 96 h after randomization Organ dysfunction assessed by Sequential Organ Failure Assessment (SOFA) score at 96 h after randomization The duration of successful cessation of supportive therapies for organ dysfunction including vasoactive agents, mechanical ventilation. The duration of continuous renal replacement therapy(CRRT) The length of stay in ICU Safety endpoints： adverse events Serious adverse events

The participants in treatment group receive intravenous megadose vitamin C. The participants in control group receive 5% glucose injection with same volume.

12 g vitamin C (48 ml) will intravenously injected by a infusion pump every 12 h for 4 days or until ICU discharge

12 g vitamin C (48 ml) will be intravenously injected by a infusion pump every 12 h for 4 days or at ICU discharge

oxygenation index(PaO2/FiO2),the patients treated with extracorporeal membrane oxygenation will not collect this indicator.

Organ dysfunction assessed by Sequential Organ Failure Assessment (SOFA) score. SOFA score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. The highest score for each of the six items is 4 points, and the lowest score is 0 points. Finally, the scores of the six items are summed to get the value of the sofa score. The range of the sofa score is 0-24.Higher values represent a worse outcome.

The duration from the MV administration to the successful cessation in hours( The successful cessation is defined as the termination of MV for more than 48-hours. This outcome measure is intended only for patients receiving MV)

The duration from the vasoactive drugs administration to the successful cessation in hours( The successful cessation is defined as the attainment of a clinician-prescribed mean arterial pressure target for more than 24-hours without the use of vasoactive drugs.This outcome measure is intended only for patients receiving vasoactive drugs)

The duration of CRRT therapy in hours( This outcome measure is intended only for patients receiving CRRT)

A adverse event refers to any adverse medical event that occur after the intervention of trial. The adverse events are not necessarily causally related to the trial treatment.

Any adverse medical event occurs at any dose that meets one or more of the following criteria: 1. causes death 2.life-threatening 3. requires hospitalization or hospitalization for an extended period of time 4. causes permanent or significant disability and functional defects 5. causes deformity.

Inclusion Criteria: Meets the diagnostic criteria for sepsis-3 developed by the American Society of Critical Care Medicine (SCCM)/European Critical Care Medicine Association (ESICM) Age ≥18 years old and age ≤80 years old. Procalcitonin ≥2 ng/ml Exclusion Criteria: Age<18 years, or age>80 years. Pregnancy or lactating A solid-organ or bone marrow transplant patients. Patients with myocardial infarction within the past 3 months. Advanced pulmonary fibrosis . Patients with cardiopulmonary resuscitation before enrollment. HIV-positive patients. granulocyte-deficient patients. blood/lymphatic system tumors are not remission. patients with limited care (lack of commitment to full aggressive life support). patients with long-term use of immunosuppressive drugs or with immunodeficiency. patients with advanced tumors. patients combined with non-infectious factors leading to the death(uncontrollable major bleeding, brain hernia, etc.). surgically unresolved infection sources(such as some intraperitoneal infection etc.) patients allergic to vitamin c. patients with G6PD deficiency.

The datasets generated and analyzed during the study are available from the corresponding author on reasonable request.

Liu F, Zhu Y, Zhang J, Li Y, Peng Z. Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial. BMJ Open. 2020 Jul 8;10(7):e039519. doi: 10.1136/bmjopen-2020-039519.

Chang P, Liao Y, Guan J, Guo Y, Zhao M, Hu J, Zhou J, Wang H, Cen Z, Tang Y, Liu Z. Combined Treatment With Hydrocortisone, Vitamin C, and Thiamine for Sepsis and Septic Shock: A Randomized Controlled Trial. Chest. 2020 Jul;158(1):174-182. doi: 10.1016/j.chest.2020.02.065. Epub 2020 Mar 31.