Randomized, Double-Blind, Placebo-Controlled Trial of Zinc Acexamate in Advanced Chronic Liver Disease Patients

The primary objective of this multicenter, randomized, double-blind, comparative clinical trial is to evaluate whether the oral administration of **zinc acexamate** (ACZ) at a dose of 600 mg/day (equivalent to 100 mg/day of elemental zinc) to patients with advanced chronic liver disease (cACLD) improves their prognosis by reducing expected clinical events and the risk of experiencing them during the study follow-up. This is clinically relevant as it aims to enhance the management and outcomes of patients with cACLD, a condition associated with significant morbidity and mortality.

Secondary objectives include:

• Assessing whether ACZ administration improves the risk of first decompensation and its type.
• Evaluating if it reduces the overall risk of clinically significant portal hypertension (CSPH) as estimated by the described model.
• Determining whether it improves the risk of hepatocarcinoma.
• Investigating if it reduces the risk of bacterial infections.
• Assessing improvements in overall transplant-free survival and in relation to liver-related deaths.
• Evaluating improvements in liver function as measured by the Child-Pugh score and the MELD scale.
• Determining if the effects on the main or secondary variables correlate with blood zinc levels during treatment.
• Evaluating the possible adverse effects of treatment with ACZ.

The clinical trial involves participants diagnosed with **chronic liver disease**. The study population includes both male and female subjects, aged between 18 and 80 years. Participants are required to have a diagnosis of compensated advanced chronic liver disease (cACLD) confirmed by hepatic stiffness greater than 15 kPa, as measured by transition elastography. The trial excludes individuals with previous or current decompensation. Women of childbearing potential must undergo a pregnancy test before the study and use effective contraception throughout the trial. The sponsor has not provided information regarding the total number of participants. The trial does not involve a vulnerable population, and participants are expected to maintain their usual lifestyle, with no specific dietary or physical activity requirements mentioned.

The clinical trial is a **randomized**, **double-blind**, and controlled study designed to evaluate the efficacy of **zinc acexamate** in improving the prognosis of patients with advanced **chronic liver disease**. The trial will compare the effects of zinc acexamate against a placebo, with the primary objective of assessing whether the oral administration of zinc acexamate at a dose of 600 mg per day can reduce the occurrence of clinical events and the risk of such events during the study follow-up. The trial is categorized as a low-intervention Phase III study, adhering to the criteria outlined in RD 1090/2015.

The trial is expected to run from July 25, 2022, to January 25, 2028, with participants involved for a maximum treatment period of 66 weeks. Participants will be required to attend several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as hepatic stiffness measured by transition elastography, age between 18 and 80 years, and absence of previous or current decompensation. Women of childbearing age will undergo a pregnancy test and must use effective contraceptive methods throughout the study.

Following the screening, participants will be randomized to receive either zinc acexamate or a placebo. Regular follow-up visits will be scheduled to monitor the occurrence of time-dependent clinical events, including hepatic decompensation, hepatocellular carcinoma, liver-related death, and liver transplant. The end-of-study visit will conclude the participant's involvement, assessing the primary endpoint of the trial. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or withdrawal of consent by the participant.

The clinical trial involves the administration of **zinc acexamate** as the experimental medication. The product, marketed under the name COPINAL 300 mg capsules, is manufactured by Laboratorios Viñas, S.A. The pharmaceutical form of the medication is a hard capsule, intended for **oral use**. Each capsule contains 300 mg of zinc acexamate, and the prescribed dosage for the trial is 600 mg per day, equivalent to 100 mg per day of elemental zinc. This dosage is to be administered in two divided doses, with a maximum treatment period of 66 days. The primary objective of the trial is to evaluate the efficacy of zinc acexamate in improving the prognosis of patients with advanced chronic liver disease by reducing expected clinical events and associated risks during the study follow-up.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, randomized clinical trial. The placebo is designed to match the experimental medication in appearance and administration route to ensure blinding. Participants will receive either the zinc acexamate or the placebo, with neither the participants nor the investigators aware of the treatment allocation. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol. The trial aims to provide a comprehensive assessment of the therapeutic potential of zinc acexamate in the specified patient population.

The efficacy of Zinc Acexamate in patients with advanced chronic liver disease (cACLD) will be assessed through a multicenter, randomized, double-blind, comparative clinical trial. The primary endpoint for evaluating efficacy is the occurrence of time-dependent clinical events during the study follow-up. These clinical events include **hepatic decompensation** (defined as the presence of clinical ascites, gastrointestinal bleeding due to portal hypertension, and hepatic encephalopathy), hepatocellular carcinoma, death from liver causes (considering non-hepatic death as a competitive risk), and liver transplant. The distribution of CSPH risk will be estimated using the ANTICIPATE model.