Evaluation of Carvedilol on Portosystemic Gradient in Cirrhotic Portal Hypertension via Endoscopic Ultrasound

Trial ID: 2024-518302-41-00
Protocol: AOI 2023 POINCLOUX
Sponsor: University Hospital Of Clermont-Ferrand

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Diseases & Conditions

Hepatic cirrhosis

Objectives

The primary objective of this study is to evaluate the **efficacy** of Carvedilol 12.5 mg per day in the primary prophylaxis of digestive hemorrhage associated with **cirrhotic portal hypertension**. This is assessed by measuring the portosystemic gradient using echo-endoscopy after one month of treatment. The clinical relevance of this objective lies in its potential to prevent life-threatening hemorrhagic events in patients with cirrhosis, thereby improving patient outcomes and reducing healthcare burdens.

Secondary objectives include:

Assessing the three-month tolerance of Carvedilol 12.5 mg per day as primary prophylaxis of digestive hemorrhage linked to portal hypertension of cirrhotic origin.
Evaluating the three-month efficacy of Carvedilol in preventing the rupture of gastroesophageal varices.
Evaluating the variation of different biological and elastometric parameters measured after taking Carvedilol for three months.

Participants

The clinical trial involves participants diagnosed with **cirrhotic portal hypertension**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have suspected cirrhotic portal hypertension, as defined by the Baveno VII criteria, and must be naïve to any treatment with non-cardioselective beta-blockers. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants' general health status is characterized by the presence of gastroesophageal varices at high risk of rupture, and they must be affiliated with a Social Security scheme. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **Carvedilol** in the primary prophylaxis of digestive hemorrhage associated with **cirrhotic portal hypertension**. This is a Phase 4, randomized, double-blind, controlled trial. The study will involve the administration of Carvedilol at a dose of 12.5 mg per day, with the primary objective being the assessment of the hemodynamic response at one month. The trial is expected to commence on January 15, 2025, and conclude by March 15, 2026, with a maximum treatment period of 97 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as liver elasticity and platelet count, as per the Baveno VII criteria. The inclusion visit will also ensure that participants are naive to non-cardioselective beta-blockers and are affiliated with a Social Security scheme. Following the inclusion visit, participants will attend follow-up visits to monitor the primary endpoint, which is a decrease of at least 10% in the echo-endoscopic portosystemic gradient compared to baseline. Secondary endpoints include the assessment of side effects, incidence of digestive bleeding, and changes in biological and elastometric parameters over a three-month period.

The expected length of participant involvement is approximately three months, with regular follow-up visits scheduled to ensure comprehensive monitoring of treatment effects and safety. Conditions that may lead to early termination from the study include significant adverse effects or the participant's decision to withdraw consent. The trial will adhere to rigorous methodological standards to ensure the reliability and validity of the findings, contributing valuable insights into the management of cirrhotic portal hypertension.

Treatment

The clinical trial involves the administration of **Carvedilol**, marketed under the name **CARVEDILOL ARROW 6,25 mg**, in the form of a **film-coated tablet**. The active substance, **Carvedilol**, is a chemical compound classified under the ATC code **C07AG02**, indicating its role as an alpha and beta-blocker. The pharmaceutical form is a **film-coated tablet**, designed to be taken orally. The dosage regimen for the trial specifies a maximum daily dose of **12.5 mg**, with the treatment period extending up to **97 days**. The primary objective of the trial is to evaluate the efficacy of Carvedilol in the primary prophylaxis of digestive hemorrhage linked to portal hypertension of cirrhotic origin, by measuring the portosystemic gradient via echo-endoscopy.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the source data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not involve a pediatric formulation, and the product is not classified as an orphan drug. The trial is conducted under the authorization of the relevant regulatory body in France, with the product being manufactured by **ARROW GENERIQUES**.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the measurement of the **portosystemic gradient** using echo-endoscopy. The primary endpoint is defined as a hemodynamic response, which is a binary efficacy criterion. This response is characterized by a decrease of at least 10% in the portosystemic gradient at one month compared to the baseline value measured at inclusion. The trial aims to evaluate the efficacy of Carvedilol 12.5 mg per day in the primary prophylaxis of digestive hemorrhage linked to portal hypertension (PH) of cirrhotic origin.

Secondary endpoints include the assessment of the top ten side effects of beta-blockers as reported in the literature, the percentage of patients who discontinue treatment due to side effects, and the occurrence of digestive bleeding linked to the rupture of esophageal or gastric varices within three months of starting treatment. Additionally, biological and elastometric parameters will be measured before and after taking Carvedilol for three months. These assessments will provide a comprehensive evaluation of the treatment's efficacy and safety profile over the course of the trial.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient ≥ 18 years with suspected cirrhotic PH (all causes combined) 1 : according to Baveno VII criteria: Liver elasticity ≥ 25 kPa or Liver elasticity between 20 and 25 kPa with Platelets < 150 G/L or Liver elasticity between 15 and 20 kPa with Platelets < 110 G/L or Liver elasticity > 20 kPa and/or Platelets < 150 G/L for patients with cirrhosis developed from NASH or Gastroesophageal varices at high risk of rupture: Size > 5 mm (stage 2 or 3) or Size ≤ 5 mm and red signs or Size ≤ 5 mm and CHILD-PUGH C. 2. and/or the presence of a radiological sign of PHT: Porto-systemic shunts: rectal varices, splenorenal shunts, re-canalization of the umbilical vein. 3. and/or splenic elasticity > 50 kPa.
Patient naïve to any treatment with non-cardioselective beta-blockers.
Affiliation to a Social Security scheme.

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Exclusion Criteria

Absolute contraindications to beta-blockers: bradycardia ≤ 50 bpm, systolic arterial hypotension (systolic arterial pressure ≤ 90 mmHg), grade II or III atrioventricular block, decompensated heart failure, pulmonary arterial hypertension, severe peripheral arterial disease, Raynaud's syndrome, asthma.
Presence of severe acute alcoholic hepatitis (Madrey score ≥ 32).
Current hepatic encephalopathy ≥ Grade 2.
Hepatorenal syndrome in progress.
Clinical ascites of great abundance: only if bothersome for the feasibility of the EHH.
History of ruptured esophageal varices.
Hepatocellular carcinoma active or in remission for less than six months.
Active or resolved portal vein thrombosis for less than six months.
Digestive surgical history not allowing the feasibility of measuring the portosystemic gradient by echo-endoscopy (gastrectomy, bypass, etc.).
Patients on antiplatelet drugs (except acetylsalicylic acid) or on anticoagulants for emboligenic AC/AF.
Severe chronic renal failure stage 4 or end-stage renal failure stage 5 (clearance < 30 mL/min).
Pregnant or breastfeeding women, or those planning to become pregnant. A pregnancy test will be performed for women of childbearing age.
Patients protected by law (under guardianship, curatorship or legal protection) or deprived of their liberties.