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.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Septic Shock
• Intervention / Treatment: Drug: Vitamin C; Drug: 5% glucose injection

Detailed Description

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: 234

The number of study center: 4

Study center:

1. Department of Critical Care Medicine of Zhujiang Hospital,Guangzhou, Guangdong, China
2. Department of Critical Care Medicine of The First People's Hospital of Foshan, Foshan, Guangdong, China
3. Department of Critical Care Medicine of Dongguan People's Hospital, Dongguan, Guangdong,China
4. Department of Critical Care Medicine of Yunfu People' s Hospital, Yunfu, Guangdong, China
5. Department of Critical Care Medicine of Zhongshan People's Hospital, Zhongshan, Guangdong, China

Primary endpoint: 28-day all-cause mortality.

Secondary endpoints:

1. The state of liver function: the serum level of transaminase(AST、ALT)、total bilirubin at 96 h after randomization
2. The state of lung function: oxygenation index(PaO2/FiO2) at 96h after randomization
3. The state of kidney function: serum level of Creatinine (Cr)、blood urea nitrogen(BUN)、Cystatin(Cys) at 96 h after randomization
4. The state of inflammatory response: the serum level of interleukin-6(IL-6) and C-reactive protein(CRP) at 96 h after randomization.
5. The state of infection: the serum level of procalcitonin(PCT) and white blood cell （WBC） at 96 h after randomization.
6. The state of circulation system: the serum level of lactate at 96 h after randomization
7. Organ dysfunction assessed by Sequential Organ Failure Assessment (SOFA) score at 96 h after randomization
8. The duration of successful cessation of supportive therapies for organ dysfunction including vasoactive agents, mechanical ventilation.
9. The duration of continuous renal replacement therapy(CRRT)
10. The length of stay in ICU

Safety endpoints：

1. adverse events
2. Serious adverse events

• Study Type: Interventional
• Enrollment (Estimated): 234
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: zhanguo Liu, M.D.PhD; Phone Number: +862062782927; Email: zhguoliu@163.com

Study Locations

• China
  • Guanzhou, China
    • Recruiting
    • Department of Critical Care Medicine of Nanfang Hospital of Southern Medical University
    • Contact: zhenhua zeng; Email: zhenhuazeng.2008@163.com
  • Guangdong
    • Guanzhou, Guangdong, China
      • Recruiting
      • Department of Critical Care Medicine of Zhujiang Hospital,Southern Medical University
      • Contact: zhanguo Liu, M.D.PhD; Phone Number: +862062782927; Email: zhguoliu@163.com
    • Yunfu, Guangdong, China, 527300
      • Recruiting
      • Department of Critical Care Medicine of Yunfu People's Hospital
      • Contact: Bihua Mo, MD; Email: mobihua2013@163.com
  • Guangzhou
    • Zhongshan, Guangzhou, China, 528403
      • Recruiting
      • Department of Critical Care Medicine of Zhongshan People's Hospital
      • Contact: Jianwei Li, MD; Email: likenwei@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Megadose vitamin C group; 12 g vitamin C (48 ml) will intravenously injected by a infusion pump every 12 h for 4 days or until ICU discharge	Drug: Vitamin C; 12 g vitamin C (48 ml) will be intravenously injected by a infusion pump every 12 h for 4 days or at ICU discharge
Placebo Comparator: Placebo group; 5% glucose solution 48 ml every 12 h for 4 days or until ICU discharge.	Drug: 5% glucose injection; 5% glucose solution 48 ml every 12 h for 4 days or at ICU discharge.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-day all-cause mortality	All-cause mortality from the enrollment to the 28th days	The outcome will be assessed at the 28 day after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
liver function(1)	the serum level of Alanine transaminase(ALT)	The outcome will be assessed at the 0, 1 ,2 ,4 day after enrollment
liver function(2)	the serum level of Aspartate transaminase (AST)	The outcome will be assessed at the 0, 1 ,2 ,4 day after enrollment
liver function(3)	the serum level of total bilirubin	The outcome will be assessed at the 0, 1 ,2 ,4 day after enrollment
lung function	oxygenation index(PaO2/FiO2),the patients treated with extracorporeal membrane oxygenation will not collect this indicator.	The outcome will be assessed at the 0, 1 ,2 ,4 day after enrollment
kidney function(1)	serum level of Creatinine (Cr)	The outcome will be assessed at the 0, 1 ,2 ,4 day after enrollment
kidney function(2)	serum level of blood urea nitrogen(BUN)	The outcome will be assessed at the 0, 1 ,2 ,4 day after enrollment
kidney function(3)	serum level of Cystatin(Cys)	The outcome will be assessed at the 0, 1 ,2 ,4 day after enrollment
inflammatory response(1)	the serum level of interleukin-6(IL-6)	The outcome will be assessed at the 0, 1 ,2 ,4 day after enrollment
inflammatory response(2)	the serum level of C-reactive protein(CRP)	The outcome will be assessed at the 0, 1 ,2 ,4 day after enrollment
Indicators of infection(1)	the serum level of procalcitonin(PCT)	The outcome will be assessed at the 0, 1 ,2 ,4 day after enrollment
Indicators of infection(2)	the level of white blood cell count(WBC)	The outcome will be assessed at the 0, 1 ,2 ,4 day after enrollment
The level of lactate	the serum level of lactic acid	The outcome will be assessed at the 0, 1 ,2 ,4 day after enrollment
Sequential Organ Failure Assessment (SOFA) score	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 outcome will be assessed at the 0, 1 ,2 ,4 day after enrollment
The cessation of mechanical ventilation(MV) administration	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 outcome will be assessed at the 28 day after enrollment
The cessation of vasoactive drugs administration	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 outcome will be assessed at the 28 day after enrollment
The duration of CRRT	The duration of CRRT therapy in hours( This outcome measure is intended only for patients receiving CRRT)	The outcome will be assessed at the 28 day after enrollment
ICU length of stay	ICU length of stay	The outcome will be assessed at the 28 day after enrollment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	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.	The outcome will be assessed at the 28 day after enrollment
Incidence of serious adverse events	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.	The outcome will be assessed at the 28 day after enrollment

Collaborators and Investigators

• Sponsor: Zhujiang Hospital
• Investigators: Principal Investigator: Zhanguo Liu, M.D.PhD, Department of Critical Care Medicine of Zhujiang Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2022
• Primary Completion (Estimated): December 4, 2024
• Study Completion (Estimated): December 4, 2024

Study Registration Dates

• First Submitted: January 3, 2022
• First Submitted That Met QC Criteria: January 3, 2022
• First Posted (Actual): January 18, 2022

Study Record Updates

• Last Update Posted (Actual): March 19, 2024
• Last Update Submitted That Met QC Criteria: March 17, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: megadose vitamin C
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• Other Study ID Numbers: 2020-KY-069-05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: The datasets generated and analyzed during the study are available from the corresponding author on reasonable request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No