Evaluation of Metformin on Hepatic Venous Pressure Gradient in Cirrhotic Patients with Portal Hypertension Under Carvedilol Therapy: A Randomized, Placebo-Controlled Trial

The primary objective of this study is to evaluate the effect of **metformin** versus placebo on the hepatic venous pressure gradient (HVPG) over a 28-day period in patients with cirrhosis and a HVPG of 12 mm Hg or greater, who are already receiving treatment with carvedilol. This is clinically relevant as it aims to determine the potential of metformin to reduce portal hypertension, a significant complication of cirrhosis that can lead to severe outcomes such as variceal bleeding.

Secondary objectives include: - Evaluating the safety and tolerability of metformin in this patient population. - Assessing the rate of change in HVPG after 28 days of treatment. - Determining the rate of patients with a clinically significant improvement in HVPG. - Assessing changes in systemic haemodynamics and liver steatosis after 28 days of treatment. - Evaluating the performance of liver and spleen stiffness measurements using vibration-controlled transient elastography and 2D-shear wave elastography to estimate haemodynamic response. - Investigating the effect of metformin on systemic inflammation, coagulation, hepatocyte stress, and endothelial function.

The clinical trial focuses on patients diagnosed with **portal hypertension** and complications of cirrhosis. The study population includes both male and female participants aged 18 years and older. Participants are required to have a diagnosis of cirrhosis, confirmed through liver biopsy or clinical, biological, endoscopic, and radiological evidence. The trial excludes individuals with hepatocellular carcinoma, except for those with specific nodule criteria. Participants must have been on a stable dose of carvedilol for at least one month and have a high likelihood of hepatic venous pressure gradient (HVPG) ≥ 12 mm Hg. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as alcohol cessation or sustained virological response to antiviral treatment are relevant for inclusion. The study does not specify any particular dietary or physical activity requirements for participants.

The clinical trial is designed to evaluate the effect of **metformin** versus placebo on the hepatic venous pressure gradient (HVPG) in patients with cirrhosis and portal hypertension. This study is a **randomized**, **placebo-controlled** trial, conducted over a period of 28 days. Participants will be randomly assigned to receive either metformin or a placebo, with the primary endpoint being the change in HVPG after the treatment period. The trial is set to begin recruitment on September 2, 2024, and is expected to conclude by September 1, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥18 years), absence of significant hepatocellular carcinoma, and a confirmed diagnosis of cirrhosis. Eligible participants must also have a high likelihood of HVPG ≥ 12 mm Hg and be on a stable dose of carvedilol. Following the screening, participants will attend follow-up visits to monitor their response to the treatment and ensure adherence to the study protocol. The end-of-study visit will occur after 28 days of treatment, where the primary endpoint will be assessed.

The expected length of participant involvement is approximately one month, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with the study protocol. The trial is conducted under a **double-blind** design, ensuring that neither the participants nor the investigators know which treatment is being administered, thereby minimizing bias. The study aims to provide valuable insights into the management of portal hypertension in cirrhosis, with the potential to improve therapeutic strategies for affected patients.

The clinical trial involves the administration of **Metformin**, a pharmaceutical agent classified under the ATC code A10BA02. Metformin is provided in a specific pharmaceutical form denoted as PHF00245MIG. The medication is administered orally, with a maximum daily dose of 1 gram and a total maximum dose of 28 grams over the treatment period. The treatment duration is set for 4 weeks. Metformin is utilized in this study to evaluate its effects on the hepatic venous pressure gradient (HVPG) in patients diagnosed with cirrhosis and portal hypertension, who are already receiving treatment with carvedilol.

In addition to Metformin, a **placebo** is employed as a comparator in this randomized, placebo-controlled study. The placebo, identified as Placebo 515, does not contain any active pharmaceutical ingredients and serves to provide a control for assessing the efficacy of Metformin. The placebo is administered in a manner consistent with the experimental treatment to ensure blinding and maintain the integrity of the study results. The placebo's pharmaceutical form and route of administration are not specified, but it is implied to match the administration method of Metformin to maintain consistency in the trial design.

Efficacy in this clinical trial will be assessed by evaluating the effect of **metformin** compared to placebo on the hepatic venous pressure gradient (HVPG) in patients with cirrhosis and portal hypertension. The primary endpoint for efficacy assessment is the change in HVPG after 28 days of treatment. This parameter will be measured to determine the impact of the intervention on the target population, which includes patients with a baseline HVPG of at least 12 mm Hg who are already receiving carvedilol treatment.