Evaluation of Early Vasopressin and Norepinephrine Administration on Renal Replacement Therapy Utilization in Septic Shock Patients

The primary objective of this study is to determine whether the early administration of **vasopressin** in conjunction with norepinephrine affects the utilization of renal function replacement techniques within the first 7 days of hospitalization in the Intensive Care Unit (ICU) for patients with **septic shock**. This is clinically relevant as it may influence treatment protocols and improve patient outcomes by potentially reducing the need for renal replacement therapy.

Secondary objectives include:

• Assessing if early vasopressin administration improves renal function, as indicated by the maximum KDIGO class achieved and its progression during the initial 7 days in the ICU.
• Evaluating whether early vasopressin addition alters renal perfusion, assessed sonographically using the CEUS method.
• Determining if vasopressin affects the water balance of patients within the first 48 and 72 hours post-ICU admission.
• Investigating whether early combined treatment with vasopressin reduces the duration of Continuous Renal Replacement Therapy (CRRT) in patients requiring such support during ICU stay.
• Examining if early vasopressin association decreases the incidence of supraventricular arrhythmias, such as atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia, during vasopressor treatment.
• Evaluating the impact of early vasopressin use on the onset of intestinal, digital, and limb ischemia.
• Assessing the effect of early vasopressin administration on ICU length of stay and mortality at 28 and 90 days.

The clinical trial involves participants diagnosed with **septic shock** and aims to assess the impact of early vasopressin and norepinephrine administration on renal function replacement techniques within the first week of ICU hospitalization. The study population includes both male and female patients aged between 18 and 80 years. Participants are required to have been hospitalized in an intensive setting within 24 hours of their clinical diagnosis and must be capable of providing informed consent. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants must have a norepinephrine dosage of at least 0.25 mcg/kg/min based on their ideal body weight. Lifestyle factors such as diet and physical activity are not specified as part of the study criteria.

The clinical trial is designed to evaluate the renal outcomes associated with the early use of **vasopressin** in the treatment of **septic shock**. This study is a randomized, double-blind, controlled trial, aiming to determine whether the early administration of vasopressin alongside norepinephrine affects the need for renal function replacement techniques within the first seven days of hospitalization in the Intensive Care Unit (ICU). The trial is expected to commence on March 1, 2024, and conclude by March 2, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-80 years), ability to provide informed consent, and specific clinical parameters related to septic shock. Following enrollment, participants will receive intravenous administration of the investigational products, including **sulfur hexafluoride** and **argipressin**, with the treatment period lasting up to four days for sulfur hexafluoride and one day for argipressin. The study will include follow-up visits to monitor renal perfusion and other secondary endpoints, such as the reduction of maximum KDIGO class and water balance assessments at 24, 48, and 72 hours post-ICU admission.

The end-of-study visit will assess the primary endpoint, which is a 30% reduction in patients meeting the criteria for continuous renal replacement therapy (CRRT) within the study group. Secondary endpoints include the evaluation of renal perfusion using contrast-enhanced ultrasound (CEUS) and the incidence of adverse events such as atrial fibrillation and ischemia. Participant involvement is expected to last throughout the ICU stay, with additional monitoring for up to 90 days post-treatment to assess mortality and length of stay in the ICU.

Conditions that may lead to early termination from the study include the development of severe adverse reactions or the participant's withdrawal of consent. The trial is categorized as a Phase IV study, with a low-intervention classification, ensuring that the investigational products are used within their authorized indications and dosages. The trial's design and procedures are structured to maintain scientific rigor while ensuring participant safety and data integrity.

The clinical trial involves the administration of **SonoVue**, a pharmaceutical product formulated as a **powder and solvent for dispersion for injection**. The active substance in SonoVue is **sulfur hexafluoride**, a chemical compound. The product is administered via the **intravenous route**. The maximum daily dose is 4.8 milliliters, with a total maximum dose of 9.6 milliliters over a treatment period of up to 4 days. The product is not a pediatric formulation and is manufactured by Bracco International BV. Participant compliance with the dosing schedule will be monitored throughout the trial.

Additionally, the trial includes the use of **Empressin**, which is provided as a **concentrate for solution for infusion**. The active substance in Empressin is **argipressin**, a protein-based compound. This product is also administered intravenously. The maximum daily dose is 43.2 international units, with a total maximum dose of 302.4 international units over a treatment period of up to 1 day. Empressin is not formulated for pediatric use and is produced by Orpha-Devel Handels und Vertriebs GmbH. The administration of Empressin will be closely monitored to ensure adherence to the prescribed dosing regimen.

The efficacy of the clinical trial titled "Renal Outcomes in the early use of vasopressin in the treatment of septic shock" will be assessed through a series of primary and secondary endpoints. The primary endpoint is a 30% reduction in the number of patients meeting the criteria for continuous renal replacement therapy (CRRT) within the study group. This will be evaluated by comparing the early use of **vasopressin** in conjunction with norepinephrine against its later introduction when norepinephrine reaches a higher dosage.

Secondary endpoints include several parameters: reduction in the maximum Kidney Disease: Improving Global Outcomes (KDIGO) class reached within the first 7 days of hospitalization, assessment of renal perfusion using contrast-enhanced ultrasound (CEUS) within 24 hours of enrollment and 72 hours after the initial evaluation, and water balance measurements at 24, 48, and 72 hours post-admission to the Intensive Care Unit (ICU). Additional secondary endpoints involve the number of patients requiring renal replacement therapy (RRT) during their ICU stay, the incidence of atrial fibrillation (AF), atrial flutter, or paroxysmal supraventricular tachycardia (PSVT) lasting more than 30 minutes, and the occurrence of intestinal or extremity ischemia during or shortly after the infusion of vasoactive drugs. The length of ICU stay and mortality rates at 28 and 90 days will also be recorded.