Efficacy and Safety of Intraperitoneal VS-01 with Standard Care in Acute-on-Chronic Liver Failure with Ascites: A Phase 2a Randomized Controlled Study

The primary objective of this study is to evaluate the **efficacy** of VS-01, administered intraperitoneally (i.p.) daily over 4 days, in conjunction with standard of care (SOC) compared to SOC alone in patients with acute-on-chronic liver failure (ACLF) grades 1 and 2. This will be measured by the Chronic Liver Failure Consortium Acute on-Chronic Liver Failure (CLIF-C ACLF) score at Day 7. The clinical relevance of this objective lies in its potential to improve outcomes in a patient population with a high mortality rate, as ACLF is a major cause of death in cirrhosis.

Secondary objectives include:

• Evaluating the efficacy of VS-01 on mortality rate, time to death, ACLF grade change, time to ACLF resolution, and transplant-free survival in patients with ACLF grades 1 and 2.
• Characterizing the safety and tolerability of VS-01 following i.p. administration in ACLF patients.

The clinical trial involves a total of **13 participants** diagnosed with **acute-on-chronic liver failure (ACLF)**, specifically targeting those with ACLF grades 1 and 2 accompanied by ascites. 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, confirmed through standard clinical criteria, imaging, or histology, with any underlying etiology. The trial includes individuals with a dry body weight ranging from 40 kg to less than 140 kg. The onset of ACLF in participants must not exceed 7 days prior to screening, and the presence of ascites requiring paracentesis is mandatory. The trial population is considered vulnerable, and informed consent is required, either directly from the participant or through a legal representative. The selection process ensures that participants can understand and comply with the protocol, as evidenced by the signing of the Patient Informed Consent Document. The sponsor has not provided specific information regarding lifestyle considerations such as diet or physical activity.

The clinical trial is a **Phase 2a**, open-label, randomized, controlled, multi-center study designed to evaluate the efficacy, safety, and tolerability of the investigational product VS-01, administered **intraperitoneally** as a **suspension for infusion**. The trial targets adult patients with **acute-on-chronic liver failure (ACLF)** grades 1 and 2, who also present with ascites. The primary objective is to assess the efficacy of VS-01 on top of standard of care (SOC) compared to SOC alone, as measured by the Chronic Liver Failure Consortium Acute on-Chronic Liver Failure (CLIF-C ACLF) score at Day 7. The trial is expected to run until June 30, 2025, with recruitment having commenced on July 2, 2023.

Participants will be involved in the study for a maximum of 4 days of treatment, with the primary endpoint being evaluated on Day 7. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as liver cirrhosis diagnosis and ACLF grade, followed by daily treatment visits over the 4-day period. The end-of-study visit will occur on Day 7 to assess the primary endpoint. Follow-up visits will be conducted to evaluate secondary endpoints, including mortality rates at 28 and 90 days, and transplant-free survival.

Inclusion criteria require participants to be adults aged 18 to 79 years with a dry body weight between 40 kg and 140 kg, and with the onset of ACLF not more than 7 days prior to screening. Exclusion criteria are not specified in the provided data. Participants may be withdrawn from the study if they experience adverse drug reactions or if they fail to comply with the study protocol. The study is not a low-intervention trial and is classified as a proof of concept study, emphasizing its exploratory nature in evaluating the potential benefits of VS-01 in this patient population.

The clinical trial involves the administration of **VS-01**, an experimental medication formulated as a **suspension for infusion**. The active substance in VS-01 is **citric acid, anhydrous Ph. Eur.**, which is classified under Specified Substance Group 3. The pharmaceutical form of VS-01 is designed for **intraperitoneal use**, and it is administered daily over a period of four days. The dosage is calculated in milligrams per kilogram (mg/kg), although the specific maximum daily and total dose amounts are not defined in the trial documentation. The treatment is intended for adult patients with acute-on-chronic liver failure (ACLF) grades 1 and 2, and it is administered in conjunction with standard-of-care (SOC) therapy.

The standard-of-care therapy serves as the comparator treatment in this study. It is administered to all participants, with one group receiving SOC alone and the other group receiving VS-01 in addition to SOC. The SOC regimen is not specified in the provided data, but it typically includes treatments that are widely accepted and used in clinical practice for managing ACLF. The trial aims to assess the efficacy, safety, and tolerability of VS-01 when used alongside SOC, with the primary endpoint being the change in the Chronic Liver Failure Consortium Acute on-Chronic Liver Failure (CLIF-C ACLF) score at Day 7.

Participant compliance with the dosing schedule is monitored throughout the trial, ensuring adherence to the administration protocol. The trial is designed as a Phase 2a, open-label, randomized, controlled, multi-center study, providing a proof of concept for the use of VS-01 in this patient population. The investigational product, VS-01, is designated as an orphan drug, highlighting its potential use in treating a rare condition. The trial is conducted under the sponsorship of Versantis AG, with the product authorized for use in the study under specific regulatory approvals.

The efficacy of the investigational product VS-01 in the clinical trial will be assessed by evaluating its impact on patients with acute-on-chronic liver failure (ACLF) grades 1 and 2. The primary endpoint for efficacy evaluation is the **Chronic Liver Failure Consortium Acute on-Chronic Liver Failure (CLIF-C ACLF) score** at Day 7. This score will be used to measure the effect of VS-01 administered intraperitoneally on top of standard of care (SOC) compared to SOC alone.

Secondary endpoints include various outcome measures such as 90-day and 28-day mortality rates, time to death through Day 90 and Day 28, and changes in ACLF grade at Days 7 and 28. These changes will be assessed by the rate and time to ACLF resolution, as well as the rate and time to regression of at least one ACLF grade. Additionally, transplant-free survival will be evaluated through Day 90 and Day 28. Safety assessments will include the incidence rate, severity, and relationship to VS-01 of adverse drug reactions and serious adverse drug reactions.