Efficacy of early intravenous high-dose vitamin C in post-cardiac arrest shock: a multicenter, randomized controled to standard treatment, open label trial.

The primary objective of this study is to evaluate the efficacy of intravenous high-dose **vitamin C** in reducing the need for vasopressor support within the first three days in patients who have experienced an out-of-hospital **cardiac arrest** (OHCA) with subsequent post-cardiac arrest shock. This is clinically relevant as it may offer a therapeutic strategy to improve hemodynamic stability and potentially enhance patient outcomes following cardiac arrest.

Secondary objectives include:

• Comparing hospital mortality related to post-cardiac arrest shock within the first seven days after OHCA between two groups.
• Assessing survival with good neurological outcome at day 28 post-OHCA between the groups.
• Evaluating the maximal dose of catecholamine infusion required within the first three days after OHCA.
• Comparing organ failure progression within the first three days post-OHCA between the groups.
• Assessing arterial lactate levels within the first three days after OHCA between the groups.

The clinical trial focuses on patients who have experienced **cardiac arrest** and are in a post-cardiac arrest shock state. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants are selected based on specific criteria, including being comatose with a Glasgow coma scale score of less than 8, having an out-of-hospital cardiac arrest (OHCA) of presumed cardiac origin with return of spontaneous circulation (ROSC) in less than 60 minutes, and requiring treatment with norepinephrine or epinephrine continuous infusion at a rate of at least 0.2 µg/kg/h within 4 hours after OHCA to maintain a mean arterial pressure of at least 65 mmHg. The trial includes a vulnerable population, indicating that participants may have additional health considerations. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of early intravenous high-dose **vitamin C** in patients experiencing post-cardiac arrest shock. This study is a multicenter, randomized, controlled, open-label trial. The primary objective is to assess the reduction in the need for vasopressors within the first three days following an out-of-hospital cardiac arrest (OHCA) with post-cardiac arrest shock. The trial is expected to commence on April 1, 2023, and conclude by May 1, 2025, with an estimated participant involvement duration of up to 28 days.

Participants will be randomly assigned to receive either the investigational treatment or standard care. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. Inclusion criteria require participants to be comatose with a Glasgow Coma Scale score of less than 8, have experienced an OHCA of presumed cardiac origin with return of spontaneous circulation (ROSC) within 60 minutes, and be receiving continuous infusion of norepinephrine or epinephrine at a specified rate to maintain mean arterial pressure. The primary endpoint is the cumulative incidence of weaning from vasopressors by day three post-OHCA.

Secondary endpoints include the incidence of death due to refractory shock within seven days, neurological outcomes at day 28 assessed using the modified Rankin Scale (mRS), the maximal vasopressor infusion dose within three days, the delta SOFA score, and the arterial lactate level at day three. Participants may be withdrawn from the study early if they experience adverse events that compromise safety or if they withdraw consent. The trial is categorized as low-intervention, with the investigational medicinal products being authorized and supported by scientific evidence, ensuring minimal additional risk to participants compared to standard clinical practice.

The clinical trial involves the administration of several treatments, including both experimental and auxiliary medications. The primary experimental medication is **LAROSCORBINE**, which contains the active substance **ascorbic acid**. This medication is provided as a solution for injection, specifically in the form of a 1 g/5 ml injectable solution in ampoules. The route of administration is intravenous injection, with a maximum daily dose of 200 mg/kg and a total maximum dose of 600 mg/kg over a treatment period of up to 3 days. The pharmaceutical form is a solution for injection, and the medication is manufactured by Bayer Healthcare.

**DOBUTAMINE PANPHARMA** is used as an auxiliary treatment in the trial. It contains the active substance **dobutamine** and is provided as a 250 mg/20 ml solution for infusion. The route of administration is injection, with a maximum daily dose of 36 mg and a total maximum dose of 1.5 mg/kg/h over a treatment period of up to 28 days. The pharmaceutical form is a solution for infusion, and the medication is manufactured by Panpharma.

Another auxiliary treatment is **ADRENALINE AGUETTANT**, which contains the active substance **epinephrine**. This medication is provided as a 1 mg/ml solution for injection without sulfites. The route of administration is injection, with a maximum daily dose of 2400 mg and a total maximum dose of 100 mg/h over a treatment period of up to 28 days. The pharmaceutical form is a solution for injection, and the medication is manufactured by Laboratoire Aguettant.

**NORADRENALINE (TARTRATE) AGUETTANT** is also used as an auxiliary treatment. It contains the active substance **noradrenaline tartrate** and is provided as a 2 mg/ml solution for infusion without sulfites. The route of administration is injection, with a maximum daily dose of 2400 mg and a total maximum dose of 100 mg/h over a treatment period of up to 28 days. The pharmaceutical form is a solution for infusion, and the medication is manufactured by Laboratoire Aguettant.

Lastly, **BEVITINE** is included as an auxiliary treatment. It contains the active substance **thiamine hydrochloride** and is provided as a 100 mg/2 ml solution for injection in ampoules. The route of administration is injection, with a maximum daily dose of 400 mg and a total maximum dose of 1200 mg over a treatment period of up to 3 days. The pharmaceutical form is a solution for injection, and the medication is manufactured by DB Pharma.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the cumulative incidence of weaning from vasopressors at day 3 after out-of-hospital cardiac arrest (OHCA). Secondary endpoints include the cumulative incidence of death by refractory shock within 7 days after OHCA, the neurological outcome at day 28 assessed using the modified Rankin Scale (mRS), the maximal vasopressors infusion dose within 3 days after OHCA, the delta SOFA (sepsis-related organ failure assessment score) defined as the difference between SOFA admission and SOFA at 72 hours after OHCA, and the lower arterial lactate level at day 3 after OHCA.

The neurological outcome will be considered favorable if the mRS ranges from 0 to 3 and unfavorable if it ranges from 4 to 6. The delta SOFA score will account for death within 72 hours as the maximum score of 24 points. These efficacy parameters will be measured and collected at specified timepoints, including day 3, day 7, and day 28 after OHCA. The assessments will utilize validated scales and laboratory tests to ensure accurate and reliable data collection. The analysis of these parameters will provide insights into the efficacy of intravenous high-dose **vitamin C** in reducing the need for vasopressors and improving patient outcomes in post-cardiac arrest shock.