Evaluation of Enoxaparin Sodium and Human Serum Albumin Combination Therapy in High-Risk Decompensated Cirrhosis Patients

The primary objective of the COMBAT trial is to assess the **safety** and tolerability of a combinatorial therapy consisting of human albumin and enoxaparin in patients with decompensated **cirrhosis** at high risk of poor outcomes. This evaluation focuses on treatment-emergent adverse events (TEAEs) such as pulmonary edema, major bleeding, and thrombocytopenia. Understanding the safety profile of this therapy is clinically relevant as it may offer a new therapeutic option for managing high-risk cirrhosis patients, potentially improving their prognosis and quality of life.

Secondary objectives include:

• Evaluating signals of efficacy of the combinatorial therapy.
• Exploring the impact of the therapy on pathophysiological mechanisms of cirrhosis through blood samples taken at various time points.
• Investigating the role of selected biomarkers in predicting the response to the therapy using blood samples extracted at several time points.
• Estimating the healthcare costs associated with the combinatorial therapy.

The clinical trial involves a total of **10 participants** diagnosed with **cirrhosis**, specifically those experiencing decompensated cirrhosis. The study population includes both male and female subjects, with an age range of 18 to 80 years. Participants were selected based on their admission to the hospital due to acute decompensation (AD) as per the EASL-CLIF criteria, which includes rapid onset of ascites, hepatic encephalopathy, portal hypertensive-related gastrointestinal bleeding, bacterial infection, or any combination of these. Additionally, participants must have a CLIF-C AD score of 45 or higher at admission or during their hospital stay and are expected to recover from AD and be discharged within 72 hours. The trial does not involve a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

The clinical trial is designed to evaluate the safety and tolerability of a **combinatorial therapy** involving **human serum albumin** and **enoxaparin sodium** in patients with decompensated **cirrhosis**. This trial is a Phase 4, randomized, double-blind, controlled study. The trial is expected to commence on January 22, 2024, and conclude by July 22, 2025, with a maximum treatment period of 90 days for each participant. The study will include a series of visits, starting with an inclusion (screening) visit to assess eligibility based on criteria such as age (18-80 years), diagnosis of decompensated cirrhosis, and a CLIF-C AD score of 45 or higher. Participants must have recovered from acute decompensation and be expected to be discharged within 72 hours.

Following the screening, participants will be randomly assigned to receive either the investigational therapy or a control. The trial will involve regular follow-up visits to monitor treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), with particular attention to pulmonary edema, major bleeding, and thrombocytopenia. The primary endpoint is the percentage of subjects experiencing at least one TEAE or SAE, and the percentage discontinuing the study drug due to specific adverse events. Secondary endpoints include changes in prognostic scores, incidence of hospital readmission, and overall survival rates at 90 and 180 days.

The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted. Participants are expected to be involved in the study for up to 180 days, including follow-up assessments. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or the participant's decision to withdraw consent. The trial aims to provide comprehensive data on the efficacy and safety of the therapy, contributing to the understanding of treatment options for patients with decompensated cirrhosis.

The clinical trial involves the administration of **Enoxaparin Sodium**, marketed under the name Enoxaparina Rovi 4.000 UI (40 mg)/0.4 ml, which is provided as a **solution for injection** in a pre-filled syringe. This medication is administered subcutaneously. The maximum daily dose is 4000 IU, and the treatment period can extend up to 90 days. Enoxaparin Sodium is a low molecular weight heparin used primarily for its anticoagulant properties. The administration of this medication is monitored to ensure compliance and to assess any potential adverse effects, such as major bleeding or thrombocytopenia.

Additionally, the trial includes the use of **Human Serum Albumin**, marketed as Albutein 200 g/l solution for infusion. This medication is administered via infusion, with a maximum daily dose of 60 grams, also over a treatment period of up to 90 days. Human Serum Albumin is a blood-derived product used to restore and maintain blood volume in patients with hypovolemia. The infusion is carefully monitored to evaluate safety and tolerability, particularly concerning potential adverse events like pulmonary edema. Both medications are used in combination to assess their safety and efficacy in patients with decompensated cirrhosis at high risk of poor outcomes.

The efficacy of the combinatorial therapy involving **human serum albumin** and **enoxaparin sodium** in patients with decompensated cirrhosis will be assessed through a series of primary and secondary endpoints. The primary endpoints include the percentage of subjects experiencing at least one treatment-emergent adverse event (TEAE) or serious adverse event (SAE), and the percentage of subjects discontinuing the study drug due to pulmonary edema, severe thrombocytopenia, and/or major bleeding. These events will be evaluated according to the definition by Shulman et al.

Secondary endpoints will be measured at various timepoints, including 30, 90, and 180 days. These include changes in prognostic scores from baseline (CLIF-C AD, MELD, MELD-Na), incidence of hospital and ICU readmissions, incidence of acute-on-chronic liver failure (ACLF), overall and transplant-free survival rates, and incidence of major complications of cirrhosis. Additionally, changes in organ function will be assessed, covering liver, renal, lung, and coagulative variables, as well as hemodynamic parameters. Other secondary endpoints include changes in frailty, quality of life, systemic inflammation, blood and microRNA transcriptome, metabolomic landscape, albumin structure and function, coagulation assays, extracellular vesicles, and endothelial function. These parameters will be collected and analyzed using validated scales and laboratory tests at specified intervals throughout the trial duration.