Evaluation of VS-01 Efficacy and Safety in Overt Hepatic Encephalopathy with Acute Decompensation or ACLF Grade 1: A Phase 2 Randomized Controlled Study

The primary objective of this study is to evaluate the **efficacy** of two different dwell times (3 hours and 4 hours) of intraperitoneal VS-01, administered once daily for up to 4 days, in addition to standard of care (SOC), compared to SOC alone in treating patients with **overt hepatic encephalopathy** (OHE) and acute decompensation (AD) of liver cirrhosis or acute-on-chronic liver failure (ACLF) grade 1. The efficacy is measured by the time to improvement of OHE, which is clinically relevant as it addresses the need for effective treatment strategies in managing OHE, a serious complication of liver disease.

Secondary objectives include:

• Evaluating the safety and tolerability of the two different dwell times of VS-01 when administered on top of SOC compared to SOC alone in the specified patient population.
• Assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of the two different dwell times of VS-01.

The clinical trial involves a total of **21 participants** diagnosed with **overt hepatic encephalopathy** (OHE) and acute decompensation (AD) of liver cirrhosis or acute-on-chronic liver failure (ACLF) grade 1. The study population includes both male and female subjects aged between 18 and 79 years. Participants were selected based on their diagnosis of liver cirrhosis of any underlying etiology, confirmed by standard clinical criteria, imaging findings, and/or histology. The trial includes individuals with a dry body weight ranging from 40 kg to less than 140 kg. Participants are required to have fasting blood ammonia levels above the upper limit of normal at baseline. The study population is characterized by the presence of ascites necessitating diagnostic or therapeutic paracentesis. Both genders are represented, and the trial includes a vulnerable population. Participants were required to provide written informed consent, or if unable, consent was obtained from a legally authorized representative in accordance with local regulations.

The clinical trial is a **Phase 2**, randomized, controlled, open-label study designed to evaluate the efficacy, safety, and pharmacokinetics of the investigational medicinal product VS-01 in patients with **overt hepatic encephalopathy** (OHE) and acute decompensation (AD) of liver cirrhosis or acute-on-chronic liver failure (ACLF) grade 1. The trial aims to compare two different dwell times of VS-01, administered intraperitoneally, on top of standard of care (SOC) versus SOC alone. The primary endpoint is the time to improvement of OHE, assessed by the Hepatic Encephalopathy Grading Instrument (HEGI), with improvement defined as a reduction in HE grades. Secondary endpoints include safety and tolerability, as well as pharmacokinetic and pharmacodynamic assessments.

The trial is expected to commence recruitment on September 6, 2025, and conclude by December 24, 2025. Participants will be involved in the study for a maximum of four days, during which VS-01 will be administered once daily. The study includes several key visits: an initial screening visit to confirm eligibility based on inclusion criteria such as the presence of liver cirrhosis and OHE, and a dry body weight between 40 kg and 140 kg. Follow-up visits will monitor the participants' response to treatment and assess any adverse events. The end-of-study visit will evaluate the overall outcomes and collect final data.

Participants may be withdrawn from the study if they experience severe adverse events or if they no longer meet the inclusion criteria. The trial is not considered low intervention due to its investigational nature and the administration of a new treatment modality. The study is conducted under the sponsorship of Versantis AG, with VS-01 being a suspension for infusion containing **citric acid, anhydrous**. The trial's design and methodology ensure rigorous assessment of the investigational product's efficacy and safety in the target patient population.

The clinical trial involves the administration of the experimental medication **VS-01**, which is a **suspension for infusion**. The active substance in VS-01 is **citric acid, anhydrous Ph. Eur.** The pharmaceutical form of VS-01 is specifically designed for **intraperitoneal use**. The medication is administered once daily, with two different dwell times being evaluated: 3 hours and 4 hours. The treatment period for VS-01 is up to 4 days. The dosage is measured in milliliters, and the maximum daily and total dose amounts are not specified, indicating flexibility in dosing based on the study protocol. The administration of VS-01 is conducted on top of standard-of-care (SOC) therapy, which serves as the comparator treatment in this study.

The standard-of-care therapy, which is used as a non-experimental treatment in this trial, is administered to all participants. This therapy is the current standard treatment for patients with overt hepatic encephalopathy (OHE) in the context of acute decompensation (AD) of liver cirrhosis or acute-on-chronic liver failure (ACLF) grade 1. The study aims to compare the efficacy of VS-01 in combination with SOC against SOC alone. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial is designed to evaluate the efficacy, safety, and pharmacokinetics of VS-01 in this patient population.

The efficacy of the investigational product VS-01 in the treatment of **Overt Hepatic Encephalopathy (OHE)** will be assessed through a primary endpoint focused on the time to improvement of OHE. Improvement is defined as a reduction in hepatic encephalopathy (HE) grades, specifically from grades 4 or 3 to grade ≤2, or from grade 2 to grade <2, as assessed by the Hepatic Encephalopathy Grading Instrument (HEGI). This endpoint will provide a quantitative measure of the therapeutic effect of VS-01 when administered intraperitoneally with two different dwell times (3 hours and 4 hours) on top of standard of care (SOC) compared to SOC alone.

Secondary endpoints will include safety and tolerability assessments, which will be determined by the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Additionally, pharmacokinetic (PK) and pharmacodynamic (PD) parameters will be analyzed. PK assessments will involve the blood and peritoneal fluid concentration-time profile of baseline-corrected citric acid and lipids in patients treated with VS-01. PD assessments will focus on changes from baseline in fasting blood and peritoneal fluid ammonia levels across all study arms.