Evaluation of Argipressin Adjunctive Therapy in Hyperkinetic Septic Shock: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the effect of adding **vasopressin** in patients with hyperkinetic **septic shock** on organ failure. This is clinically relevant as septic shock is a critical condition characterized by severe infection leading to organ dysfunction, and optimizing treatment strategies can significantly impact patient outcomes.

Secondary objectives include:

• Comparing the 5-day SOFA score between the two groups.
• Comparing mortality rates between the two groups.
• Assessing the decrease in lactatemia in the initial phase between the two groups.
• Evaluating renal function, including the severity of renal failure and the need for extra-renal purification, between the two groups.
• Comparing respiratory function, specifically the need for mechanical ventilation, between the two groups.
• Assessing the use of noradrenaline between the two groups.
• Comparing complications occurring between inclusion and day 28 between the two groups.

The clinical trial focuses on patients diagnosed with **septic shock**, aiming to evaluate the effect of adding vasopressin on organ failure in a hyperkinetic state. The study population includes both male and female participants aged 18 years and older. Participants are required to have a proven or suspected infection necessitating antibiotic therapy, with specific hemodynamic criteria such as lactatemia greater than 2.0 mmol/L and a noradrenaline dosage exceeding 0.3 µg/kg/min for more than one hour to maintain a mean arterial pressure above 65 mmHg. The trial includes individuals with adequate cardiac output, defined by a cardiac index of at least 3.0 L/min/m² or central venous oxygen saturation (ScvO2) of 70% or higher. Participants must be affiliated with a social security system. The trial population is selected based on these criteria, and it includes vulnerable populations. However, the sponsor has not provided information regarding the total number of participants involved in the study.

The clinical trial is designed to evaluate the effect of **vasopressin** in patients experiencing hyperkinetic **septic shock**. This study is a prospective, randomized, double-blind trial, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias. The trial will compare the administration of vasopressin in conjunction with noradrenaline to a control group receiving a placebo, specifically **sodium chloride**. The primary endpoint is the difference in the Sequential Organ Failure Assessment (SOFA) score 48 hours after drug administration between the two groups. Secondary endpoints include various measures of organ function and survival, such as SOFA score at day 5, all-cause mortality in the intensive care unit (ICU) and at day 28, and plasma lactatemia clearance.

The trial is expected to commence recruitment on March 1, 2025, and conclude by April 1, 2027. Participants will be involved in the study for a maximum treatment period of 5 days. The inclusion criteria require participants to be 18 years or older, in septic shock with specific cardiac output parameters, and to have consented to participate. Exclusion criteria are not specified. Study visits will include an initial screening visit to confirm eligibility, followed by regular monitoring visits during the treatment period to assess the primary and secondary endpoints. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Participants may be withdrawn from the study if they experience adverse effects that necessitate discontinuation of the study drug, if they withdraw consent, or if they do not adhere to the study protocol. The trial's design and methodology are structured to ensure rigorous assessment of the therapeutic potential of vasopressin in improving outcomes for patients with septic shock, with a focus on organ failure and survival metrics.

The clinical trial involves the administration of **Reverpleg**, a pharmaceutical product containing the active substance **argipressin**. Reverpleg is formulated as a **solution for infusion** and is intended for **intravenous perfusion use**. The product is supplied as a 40 IU/2 ml solution, with a maximum daily dose of 28.8 IU and a total maximum dose of 144 IU over a treatment period of up to 5 days. The administration of Reverpleg is designed to be continuous, in conjunction with noradrenaline treatment, to assess its effect on organ failure in patients with hyperkinetic septic shock. The product is manufactured by ORPHA-DEVEL HANDELS UND VERTRIEBS GMBH and is authorized under the marketing authorization number BE542195.

In addition to the experimental treatment, the study utilizes **sodium chloride** as a comparator treatment. Sodium chloride is also provided as a **solution for infusion** and administered via **intravenous perfusion use**. The maximum daily dose for sodium chloride is 36 ml, with a total maximum dose of 180 ml over the same 5-day treatment period. Sodium chloride serves as a placebo in this double-blind study, allowing for the evaluation of the efficacy and safety of the experimental treatment. The use of sodium chloride ensures that the study maintains a controlled environment for assessing the primary objective of the trial.

The efficacy of the clinical trial titled "Systematic Adjunction of Vasopressine in hyperkinetic Septic Shock patients: a prospective, randomized, double blind study" will be assessed using both primary and secondary endpoints. The primary endpoint is the difference in the Sequential Organ Failure Assessment (SOFA) score 48 hours after drug administration between the two groups. This endpoint will provide a measure of organ failure improvement or deterioration following the intervention.

Secondary endpoints include a variety of clinical outcomes measured at different time points. These include the SOFA score at day 5 (D5), all-cause mortality in the intensive care unit (ICU) and at day 28 (D28), and plasma lactatemia clearance between the introduction of the experimental drug and 24 and 48 hours post-administration. Additional secondary endpoints involve the Kidney Disease: Improving Global Outcomes (K-DIGO) classification at D28, the use of extrarenal purification at D28, and the number of days alive without extrarenal purification, mechanical ventilation, or noradrenaline infusion at D28.

Further assessments will include the maximum dose of noradrenaline during the first five days of inclusion, and the occurrence of various complications such as myocardial ischemia, cardiogenic shock, mesenteric ischemia, digital ischemia, atrial fibrillation, and thromboembolic events, all evaluated between inclusion and D28. These endpoints will be measured using validated clinical scales and laboratory tests, ensuring a comprehensive evaluation of the treatment's efficacy in improving patient outcomes in hyperkinetic septic shock.