Efficacy of Early Intravenous High-dose Vitamin C in Post-cardiac Arrest Shock.

Study Overview
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Brief Summary
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Among patients admitted after an out-of-hospital cardiac arrest (OHCA) in intensive care unit (ICU), almost two thirds of patients will develop in the first hours a post-cardiac arrest (CA) shock. This post-CA shock, combines cardiac and hemodynamic failure, generally resulting in multi-organ failure and early death in up to 35% of patients. Experimental data suggest that intravenous ascorbic acid (vitamin C) may attenuate inflammation and vascular injury related to sepsis or surgery. Preclinical and clinical studies also provide safety data of high dose intravenous vitamin C (> 200mg/kg/day) with no significant adverse event reported and favorable impact on outcome. Experimental data also suggest beneficial effect of vitamin C in post-CA management with improvement of shock and multi-organ failure with potential benefit on neuroprotection and outcome. The study is a phase II multicenter prospective controlled open-label trial randomized in two parallel groups : Expérimental group: Standard of care care for post-CA shock + Vitamin C (Vit-C) 200mg/kg/d IV (started as early as possible, no later than 1 h after randomization + thiamin (Vit B1) 200mg every 12 h during 3 days. Control group: Standard of care care for post CA shock according international guidelines. Patient number to be enrolled : 234, Study duration :24 months and 28 days, Inclusion duration : 24 months, Patient participation : duration : 28 days

Official Title
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Efficacy of Early Intravenous High-dose Vitamin C in Post-cardiac Arrest Shock: a Multicenter, Randomized Controled Trial.

Conditions
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Cardiac Arrest

Intervention / Treatment
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* Drug: Vitamin C (Laroscorbine) + Vitamin B1 (Bevitine)
* Drug: standard treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients still comatose (Glasgow coma scale < 8) after an OHCA of presumed cardiac origin with ROSC < 60 min; and treated with a norepinephrin or an epinephrin continuous infusion ≥ 0.2µg/kg/h, within 4 hours after OHCA, during at least 30 min/h to maintain mean arterial pressure (MAP) ≥ 65 mmHg. Exclusion Criteria: nclusion criteria: patients still comatose (Glasgow coma scale < 8) after an OHCA of presumed cardiac origin with ROSC < 60 min; and treated with a norepinephrin or an epinephrin continuous infusion ≥ 0.2µg/kg/h, within 4 hours after OHCA, during at least 30 min/h to maintain mean arterial pressure (MAP) ≥ 65 mmHg. Exclusion criteria: minor or pregnant women; OHCA from evident extracardiac cause (trauma, bleeding, poisoning, etc.); interval between OHCA and randomization > 6 hours; extracorporeal circulatory assistance requirement in the first 4 hours after OHCA; history of urolithiasis, oxalate nephropathy or hemochromatosis; glucose-6-phosphate deshydrogenase deficiency; nephrolithiasis, hyperoxalyurie patients already treated with vit-C; known vit-C deficit; inclusion in another study; pre-existent severe chronic kidney disease (glomerular filtration rate < 30ml/min); treatment limitationsor moribound Patient with derpived freedom or with legal protective measures. Patient not covered by French national health insurance

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is a phase II multicenter prospective controlled open-label trial randomized in two parallel groups : Expérimental group Control group Patient number to be enrolled : 234, Study duration :24 months and 28 days, Inclusion duration : 24 months, Patient participation : duration : 28 days
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control group<br>- Control group (standard treatment): post-cardiac arrest care will be provided, including temperature control, according to current international guidelines and local procedures. Standard IV vit-C supplementation will be allowed for dosages up to 1000 mg a day from day 4 after randomization, as well as thiamin supplementation. | Drug: standard treatment<br>* no intervention Standard IV vit-C supplementation will be allowed for dosages up to 1000 mg a day from day 4 after randomization, as well as thiamin supplementation.<br>|
| Experimental: Experimental group<br>- Experimental group (IV high-dose vit-C): in addition of standard post-CA as the control group, patients will receive an IV high-dose vit-C 50mg/kg infusion every 6 hours, started within the hour after randomization, for 3 days. In addition, all patients will receive intravenous thiamine 200 mg twice a day for 3 days to limit the oxalate production. | Drug: Vitamin C (Laroscorbine) + Vitamin B1 (Bevitine)<br>* in addition of standard post-CA as the control group, patients will receive an IV high-dose vit-C 50mg/kg infusion every 6 hours, started within the hour after randomization, for 3 days. In addition, all patients will receive intravenous thiamine 200 mg twice a day for 3 days to limit the oxalate production.<br>* Other names: Laroscorbine + Bevitine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of weaning from vasopressors at day 3 after OHCA. | Cumulative incidence of weaning from vasopressors at day 3 after OHCA. | day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of death by refractory shock within 7 days after OHCA. | Cumulative incidence of death by refractory shock within 7 days after OHCA. | day 7 after OHCA | 
| the neurological outcome at day 28 after OHCA, with mRS range from 0 to 3. | Assessed using the mRS (favorable neurological outcome will be considered if mRS range from 0 to 3; Unfavorable neurological outcome will be considered if mRS range from 4 to 6). | day 28 after OHCA | 
| The maximal vasopressors infusion dose within 3 days after OHCA. | The maximal vasopressors infusion dose within 3 days after OHCA. | 72 hours after OHCA | 
| The delta SOFA (sepsis-related organ failure assessment score) is defined as the difference between SOFA admission and SOFA at 72 hours after OHCA. | Death within 72 hours will be counted as the maximum SOFA score (i.e. 24 points). | 72 hours after OHCA | 
| The lower arterial lactate level at day 3 after OHCA. | The lower arterial lactate level at day 3 after OHCA. | 72 hours after OHCA |