Evaluation of Carvedilol for Prevention of Decompensation or Mortality in Asymptomatic Child-Pugh A5-B8 Cirrhosis with Clinically Significant Portal Hypertension

The primary objective of this study is to evaluate the effect of low-dose **carvedilol** (≤12.5 mg per day) compared to placebo on the occurrence of decompensation of cirrhosis or liver-related death at 36 months in patients with asymptomatic Child-Pugh class A5 to B8 cirrhosis with TE-LSM ≥ 25 kPa without high-risk varices. This is clinically relevant as it aims to determine the potential of carvedilol in preventing progression to more severe liver disease or mortality in this patient population.

Secondary objectives include:

• Assessing the safety of low-dose carvedilol on systemic hemodynamics and other adverse effects.
• Comparing the effect of carvedilol versus placebo on various outcomes over 36 months, including mortality, liver transplantation, decompensation events, and quality of life.
• Evaluating treatment compliance.
• Identifying potential predictors of decompensation in the control group, such as liver and spleen stiffness and new biomarkers.
• Identifying potential predictors of response to carvedilol in the treatment group, including changes in liver and spleen stiffness and cardiac hemodynamics.
• Evaluating the effect of carvedilol on decompensation or liver-related death in specific patient subgroups based on cirrhosis cause, previous decompensation history, alcohol consumption, and metabolic syndrome presence.

The clinical trial involves participants diagnosed with **asymptomatic Child-Pugh A5 to B8 cirrhosis**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have cirrhosis related to hepatitis C or B virus without viral replication for at least two years, alcohol consumption, metabolic syndrome, or cryptogenic causes with a BMI of less than 30 kg/m². The trial does not include a vulnerable population. Participants must have undergone two TE-LSM (Fibroscan®) assessments in fasting conditions, with results of at least 25 kPa within 12 months prior to inclusion. Additionally, the absence of medium or large varices or small varices with red signs at endoscopy within three months before inclusion is necessary. The trial population was selected based on these criteria, and all participants are required to be affiliated with the French social security system. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the effect of low-dose **carvedilol** (≤12.5 mg per day) compared to placebo on the occurrence of decompensation of cirrhosis or liver-related death over a period of 36 months in patients with asymptomatic Child-Pugh class A5 to B8 cirrhosis and clinically significant portal hypertension. This is a multicenter, double-blind, randomized controlled trial. The trial will involve two parallel arms: one receiving carvedilol and the other receiving a placebo. The primary endpoint is the occurrence of either decompensation of cirrhosis or liver-related death within 36 months after inclusion. Secondary endpoints include the safety of carvedilol on systemic hemodynamics and cardiac function, treatment compliance, and identification of potential predictors of decompensation and response to carvedilol.

Participants will be involved in the study for a maximum of 36 months. The trial will begin with a screening visit to confirm eligibility based on criteria such as age, cirrhosis etiology, and absence of high-risk varices. Following randomization, participants will attend regular follow-up visits to monitor health status, medication compliance, and any adverse effects. These visits will include assessments of liver and spleen stiffness, heart rate, and blood pressure. The end-of-study visit will occur at the conclusion of the 36-month period or upon early termination. Conditions that may lead to early termination include significant adverse reactions or withdrawal of consent.

The clinical trial involves the administration of **Carvedilol**, marketed as Carvedilol NORMON 6.25 mg tablets EFG, which is an experimental medication used in this study. Carvedilol is a **beta-blocker** with vasodilating properties, indicated for the management of certain cardiovascular conditions. The pharmaceutical form of the medication is a tablet, and it is administered orally. The dosage for this trial is set at a maximum of 12.5 mg per day, with the treatment period extending up to 36 months. The active substance, carvedilol, is of chemical origin, and the tablets contain additional excipients such as lactose monohydrate and saccharose. The administration schedule is designed to ensure participant compliance, with regular monitoring throughout the study duration.

The study also includes a **placebo** comparator, which is a white, oval, film-coated tablet, measuring 8 mm in length, with an engraving of F57 on one side and a score line on the other. This placebo does not contain any active substance. The excipients in the placebo include Prosolv Easytab SP, which consists of microcrystalline cellulose, colloidal silica, sodium starch glycolate, and sodium stearyl fumarate. The film coating solution comprises hypromellose, PEG 3350, and Candurin silver sheen. The placebo is administered in a manner identical to the experimental medication to maintain the double-blind nature of the trial.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint, which is the occurrence of either decompensation of **cirrhosis** or liver-related death within 36 months after inclusion. This endpoint will be measured to determine the effect of low-dose carvedilol (≤12.5 mg per day) compared to placebo in patients with asymptomatic Child-Pugh class A5 to B8 cirrhosis and clinically significant portal hypertension. Secondary endpoints include the safety of carvedilol on systemic hemodynamics, cardiac function, and any other adverse effects within the same timeframe. Additionally, treatment compliance will be assessed through the record of unused packaging and patient-reported compliance in a notebook.

Potential predictors of decompensation in the control group will be identified by measuring liver and spleen stiffness levels at baseline and at month 12, as well as liver surface nodularity at baseline. For the group receiving carvedilol, predictors of response will be evaluated by assessing levels and variations of liver and spleen stiffness at baseline and week 2, along with heart rate, systolic, and mean blood pressure and their variations at these timepoints. The occurrence of decompensation or liver-related death will also be analyzed according to subgroups based on the main etiology of cirrhosis, history of previous decompensation, alcohol consumption, and features of metabolic syndrome.