Evaluation of Argipressin Efficacy in Adult Intensive Care Patients with Norepinephrine-Refractory Vasoplegic Shock: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of early Argipressin (arginine vasopressin) treatment compared to placebo in adult patients with norepinephrine-refractory vasoplegic shock. This includes assessing the reduction of mortality, reduction of renal replacement therapy duration, and reduction of vasopressor administration. The clinical relevance of this objective lies in potentially improving survival rates and reducing the need for intensive interventions in critically ill patients experiencing vasoplegic shock, which is resistant to standard norepinephrine treatment.

Secondary objectives focus on further efficacy and safety assessments of Argipressin compared to placebo. These include:

• A decrease in all-cause mortality in the intensive care unit (ICU) at day 30 (D30) and day 90 (D90).
• A lower risk of renal failure at D30 and D90.
• A lower incidence of cardiac complications within 7 days.
• A lower overall dose of concomitant inotropic and vasopressor agents within 7 days.
• A lower need for organ support at D30 and D90.
• A shorter duration of hospitalization in the ICU.
• A shorter overall hospital stay.
• To evaluate the safety of Argipressin in adult patients with refractory vasoplegia.

These secondary objectives aim to provide a comprehensive understanding of the potential benefits and safety profile of Argipressin, which could inform clinical practice and improve patient outcomes in the management of vasoplegic shock.

The clinical trial involves **adult patients** diagnosed with **norepinephrine-refractory vasoplegic shock**. The study population includes both male and female participants aged 18 years and older. Participants are required to have a cardiac index of at least 2.3 L/min/m² and hyperlactatemia greater than 2 mmol/l, with vasopressor doses expressed as norepinephrine base equivalent at or above 0.25 µg/kg/min to maintain perfusion pressure. The trial does not include a vulnerable population. Participants must be covered by French national health insurance and have vasoplegia primarily caused by conditions such as sepsis, post-operative vasoplegia, post hemorrhage, sterile systemic inflammation, anaphylaxis, liver failure, or other causes. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. The selection criteria emphasize early intervention, with criteria for refractory and vasoplegic shock reached for less than 12 hours. Informed consent is required from the patient or a surrogate, with emergency consent as a possible option if necessary.

The clinical trial is designed to evaluate the efficacy of early **Argipressin** treatment in adult patients with norepinephrine-refractory vasoplegic shock. This is a multicentric, randomized, double-blind, placebo-controlled superiority trial. The trial aims to assess the reduction of mortality, renal replacement therapy duration, and vasopressor administration. The study will involve two groups: one receiving the experimental treatment with Argipressin and the other receiving a placebo, both administered via intravenous perfusion. The trial is expected to commence recruitment in September 2025 and conclude by June 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), presence of vasoplegic shock, and refractory shock conditions. Informed consent will be obtained from participants or their surrogates. The trial will include follow-up visits to monitor the primary and secondary endpoints, such as mortality at 30 days, use of renal replacement therapy, and persistence of vasopressor use. The end-of-study visit will occur after the final assessment of the primary and secondary endpoints.

The expected length of participant involvement is up to 90 days, with the maximum treatment period being 7 days. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or any situation where continued participation is deemed unsafe by the investigator. The primary endpoint is a composite score evaluating mortality, renal replacement therapy, and vasopressor use. Secondary endpoints include ICU length of stay, renal failure, arrhythmia, and serious adverse events. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of **Argipressin**, marketed under the name REVERPLEG 40 U.I./2 mL, as the experimental medication. This pharmaceutical product is presented as a **solution for infusion** and is intended for **intravenous perfusion use**. The active substance, Argipressin, also known as **arginine vasopressin**, is classified under the ATC code H01BA01. The maximum daily dose of Argipressin is 0.4 U/mL, with a total maximum dose of 2.8 U/mL over a treatment period not exceeding 7 days. The product is manufactured by ORPHA-DEVEL HANDELS UND VERTRIEBS GMBH and is not a pediatric formulation. Compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol.

The study also includes a non-experimental treatment, which serves as a placebo comparator. This is the CHLORURE DE SODIUM 0.9% VIAFLO, a **sodium chloride** solution for infusion, used as a standard electrolyte solution. It is also administered via **intravenous perfusion**. The maximum daily dose for this solution is 100 mL, with a total maximum dose of 700 mL over the same 7-day treatment period. This product is manufactured by BAXTER SAS and is classified under the ATC code B05XA03. The sodium chloride solution is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment allocation.

The efficacy of early **Argipressin** treatment in the management of patients with norepinephrine-refractory vasoplegic shock will be assessed through a multicentric randomized, double-blind placebo-controlled superiority trial. The primary endpoint for evaluating efficacy is a composite score that includes three criteria, ordered by importance: mortality at day 30 (D30), use of renal replacement therapy (RRT) within 30 days post-inclusion, and persistence of vasopressor use within 15 days post-inclusion. This score will be calculated using a stratified win-ratio analysis, comparing each patient from one group to all patients from the other group within the concerned strata.

Secondary endpoints will further assess efficacy by comparing the experimental group to the placebo group across several parameters: the number of all-cause deaths in the intensive care unit (ICU) at D30 and D90, renal failure as indicated by a score of 2 or higher on the Kidney Disease Improving Global Outcome (KDIGO) classification at D30 and D90, arrhythmia requiring treatment, myocardial injury within 7 days, and the Vasoactive Inotropic Score (VIS) between day 0 (D0) and day 7 (D7). Additional measures include renal replacement therapy-free days, vasopressor-free days, ventilator-free days at D30 and D90, length of stay in the ICU, and length of stay until discharge from the hospital. Safety will also be monitored by recording the number of serious adverse events according to the MedDRA classification in both groups.