Evaluation of Argipressin Infusion on Intraoperative Blood Loss in Hepatic Resection for Malignant and Benign Tumors: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate whether the infusion of **Argipressin** during hepatic resection surgery can effectively reduce blood loss compared to a placebo. This is clinically relevant as minimizing blood loss during such surgeries can significantly impact patient outcomes, reducing the need for blood transfusions and associated complications.

Secondary objectives include:

• Determining if the infusion of Argipressin reduces the need for transfusions during and after hepatic resection surgery compared to placebo.
• Assessing whether Argipressin infusion mitigates the postoperative inflammatory response in comparison to placebo.

The clinical trial involves participants undergoing **hepatic resection** due to primary malignant disease, metastasis, or benign tumor. The study population includes both male and female subjects aged 18 years and older, classified under the American Society of Anaesthesiologists (ASA) class I-III, indicating a range from healthy individuals to those with mild systemic disease. Participants are required to have signed an informed consent form. The trial population was selected based on the planned surgical procedure, either open or laparoscopic hepatic resection, regardless of the indication for surgery. The sponsor has not provided the total number of participants involved in the study. The trial includes a vulnerable population, although specific lifestyle considerations such as diet, physical activity, or habits have not been detailed.

The clinical trial is designed to evaluate the efficacy of **argipressin** in reducing blood loss during hepatic resection surgery. This study is a **randomized**, **double-blind**, and **placebo-controlled** trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thus minimizing bias. The trial is categorized as a Phase IV study, focusing on the post-marketing surveillance of the drug's effectiveness and safety. The trial is expected to commence on March 27, 2022, and conclude by February 28, 2025, with the primary objective of determining if the infusion of argipressin during surgery reduces blood loss compared to a placebo.

Participants eligible for inclusion are those aged 18 years or older, scheduled for hepatic resection, and classified as American Society of Anaesthesiologists (ASA) class I-III. The study will involve several key visits, starting with a screening visit to confirm eligibility based on the inclusion criteria and obtain informed consent. Following the screening, participants will undergo the surgical procedure where the investigational product or placebo will be administered intravenously. The primary endpoint is the measurement of blood loss at the end of surgery, assessed by visual inspection of suction devices and gauze, with adjustments for ascites and irrigation fluids.

Secondary endpoints include the volume of blood transfusions required, levels of various biomarkers such as WBC, CRP, and IL-6, and assessments of renal and cardiac function postoperatively. Follow-up visits will occur on postoperative days 1, 2, and 5, with additional assessments on day 30 to document any postoperative complications and the length of hospital stay. The expected duration of participant involvement is approximately 30 days, with conditions for early termination including withdrawal of consent or any adverse events that compromise participant safety.

The clinical trial involves the administration of **Argipressin**, marketed under the name Empressin 40 IE/2 ml, which is a **solution for infusion**. The active substance, **Argipressin**, also known as **Arginine Vasopressin**, is a protein-based compound. The pharmaceutical form is a concentrate for solution for infusion, and it is administered via **intravenous use**. The maximum daily dose is 108 IU/kg, with a total maximum dose of 108 IU/kg over a treatment period of one day. The product is manufactured by ORPHA-DEVEL HANDELS UND VERTRIEBS GMBH and is authorized in Sweden under the marketing authorization number 55407. The ATC code for Argipressin is H01BA01, classified under **Vasopressin**.

The comparator treatment in this study is a **placebo**, specifically a **solution for injection** of **Sodium Chloride**, marketed as Natriumklorid Braun 9 mg/ml. This solution is also administered intravenously. The maximum daily dose for the placebo is 100 ml, with a total maximum dose of 100 ml over a one-day treatment period. The placebo is manufactured by B.BRAUN MELSUNGEN AG and is authorized in Finland under the marketing authorization number 11888. The ATC code for Sodium Chloride is V07AB, which falls under **Solvents and Diluting Agents, Including Irrigating Solutions**.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints related to the influence of **Argipressin** on blood loss during liver resection surgery. The primary endpoint is the measurement of blood loss in milliliters at the end of surgery. This will be determined through visual assessment of suction devices and gauze, with adjustments made for ascites and irrigation fluids, as per the investigator's instructions.

Secondary endpoints include a range of parameters measured at various timepoints. Blood transfusion volumes will be recorded at the end of surgery and on postoperative days 1, 2, or 5. Levels of white blood cells (WBC), C-reactive protein (CRP), platelets (PLT), and albumin will be assessed at the end of surgery and daily up to postoperative day 5. Inflammatory markers such as IL-1b, IL-6, IL-8, IL-10, MCP-1, SDF-1a, ICAM, C3a, and C5b-9 will be measured at the end of surgery and on postoperative days 1 and 2. Coagulation parameters including ROTEM, von Willebrand factor (vWF) activity, and factor VIII will be evaluated at the end of surgery and on postoperative day 1.

Additional assessments include plasma creatinine levels on postoperative days 1, 2, and 5, and urine [TIMP-2] x [IGFBP-7] post-surgery. High-sensitivity troponin I (Hs-TNI) will be monitored at the end of surgery and on postoperative day 1. Arterial lactate levels will be checked at the end of surgery, three hours post-surgery, and on postoperative day 1. Intestinal fatty acid-binding protein (IFABP) will be measured three hours after surgery and on postoperative day 1. Other parameters such as vasopressor use, central venous pressure (CVP) goal achievement, total urine output, and furosemide use will be documented on postoperative day 1.

Hemodynamic measurements including mean arterial blood pressure (MAP), heart rate, CVP, cardiac index (if applicable), and capillary refill time in digits will be assessed at the end of surgery. The total time of surgical hepatic occlusion, radicality of resection, and use of tranexamic acid (TXA) will also be recorded. The length of hospital stay and postoperative complications will be documented up to postoperative day 30.