Effects of Plasma Exchange with Human Serum Albumin 5% (PE-A 5%) on Short-term Survival in Subjects with Acute-On-Chronic Liver Failure" (ACLF) at High Risk of Hospital Mortality

The primary objective of this clinical study is to evaluate the effect of **standard medical treatment** (SMT) plus Plasma Exchange with Human Serum Albumin 5% (SMT+PE-A 5%) on 90-day overall survival in subjects with **Acute-On-Chronic Liver Failure** (ACLF) at high risk of hospital mortality. This objective is clinically relevant as it aims to determine the potential benefit of this combined treatment approach in improving survival outcomes for patients with severe liver conditions, which could inform future therapeutic strategies.

Secondary objectives include:

• To evaluate the effect of SMT+PE-A 5% on 90-day transplant-free survival.
• To evaluate the effect of SMT+PE-A 5% on 28-day overall survival.

These secondary objectives are important for understanding the broader impact of the treatment on patient outcomes, including the potential to delay or avoid liver transplantation and improve short-term survival rates.

The clinical trial involves a total of **214 participants** diagnosed with cirrhosis and presenting with **ACLF-1b, ACLF-2, or ACLF-3a**, either at admission or during hospitalization. The study population comprises both male and female subjects, aged between 18 and 79 years. Participants were selected based on their diagnosis of acute-on-chronic liver failure (ACLF) within a specified screening period. The trial includes a vulnerable population, as it involves individuals with potentially compromised decision-making capacity due to hepatic encephalopathy, where consent may be provided by a legally authorized representative. The study does not specify particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are willing and able to provide informed consent, or have an authorized representative to do so on their behalf, in accordance with local laws and institutional policies.

The clinical trial is designed to evaluate the effect of standard medical treatment (SMT) combined with **human serum albumin** 5% (PE-A 5%) on the 90-day overall survival of subjects with acute-on-chronic liver failure (ACLF). This is a Phase II, exploratory confirmatory trial, which is not classified as low intervention. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from September 1, 2018, to September 30, 2025, with the primary endpoint being the comparison of 90-day overall survival between the SMT+PE-A 5% treatment group and the SMT control group. Secondary endpoints include assessing the effects of PE-A 5% on 90-day transplant-free survival and 28-day overall survival versus SMT alone.

Participants will be involved in the study for a maximum treatment period of 17 days, with the treatment administered intravenously. The study includes several key visits: an initial screening visit to confirm eligibility, follow-up visits to monitor the treatment's effects, and an end-of-study visit to assess the final outcomes. The inclusion criteria specify that participants must be male or female cirrhotic subjects aged between 18 and 79 years, with ACLF-1b, ACLF-2, or ACLF-3a detected either at admission or during hospitalization. Participants must be willing and able to provide written informed consent, or have an authorized representative do so on their behalf. In cases of hepatic encephalopathy, consent will be obtained from a relative or legally authorized representative if the subject is deemed incompetent to consent.

Participants may be terminated early from the study if they do not adhere to the protocol, experience adverse effects that necessitate withdrawal, or if they choose to withdraw consent. The trial aims to provide valuable insights into the potential benefits of PE-A 5% in improving survival outcomes for patients with ACLF, thereby contributing to the advancement of treatment options for this condition.

The clinical trial involves the administration of **Albutein 50 g/l solución para perfusión**, a pharmaceutical product containing **human serum albumin** as the active substance. This experimental medication is presented in the form of a **solution for infusion** and is administered via the **intravenous** route. The maximum daily dose of Albutein is 1.2 units, with a total maximum dose of 10.8 units over the course of the treatment. The treatment period is limited to a maximum of 17 days. The product is derived from blood, specifically categorized as a structurally diverse substance. The manufacturer of Albutein is Instituto Grifols, S.A., and it is authorized for use in Spain under the marketing authorization number 46964.

In addition to the experimental treatment, participants in the study will receive standard medical treatment (SMT) as part of the trial protocol. The combination of SMT and Albutein 5% (PE-A 5%) is being evaluated for its effect on 90-day overall survival in subjects with acute-on-chronic liver failure (ACLF) at high risk of hospital mortality. The study does not include a placebo or comparator treatment, focusing solely on the efficacy of the experimental medication in conjunction with standard care. Compliance with the dosing schedule and administration will be monitored throughout the trial to ensure adherence to the protocol.

Efficacy in this clinical trial will be assessed by evaluating the impact of Plasma Exchange with **Human Serum Albumin** 5% (PE-A 5%) on short-term survival in subjects with Acute-on-Chronic Liver Failure (ACLF) at high risk of hospital mortality. The primary efficacy endpoint is the comparison of 90-day overall survival between the treatment group receiving standard medical treatment plus PE-A 5% (SMT+PE-A 5%) and the control group receiving standard medical treatment (SMT) alone. Secondary efficacy endpoints include the assessment of 90-day transplant-free survival and 28-day overall survival in the treatment group versus the control group.