CARVEDILOL for Compensated liver cirrhosis (Child-Pugh A5–B8) | Clinically significant portal hypertension

Inclusion criteria

• {"criterion_text":"- 1. Male or female≥ 18 years of age"}
• {"criterion_text":"- 2. Cirrhosis related to hepatitis C or hepatitis B virus without viral replication for at least 2 years. Or Cirrhosis related to alcohol consumption (active or abstinent) Or Cirrhosis related to metabolic syndrome or cryptogenic with BMI < 30 kg/m2"}
• {"criterion_text":"- 3. 2 TE-LSM (Fibroscan®) performed in fasting conditions, using either the M or the XL probe >=25 kPa, within 12 months before inclusion"}
• {"criterion_text":"- 4. Absence of medium or large varices or small varices with red signs at endoscopy within 3 months before inclusion"}
• {"criterion_text":"- 5. Child-Pugh A5 to B8"}
• {"criterion_text":"- 6. Affiliation to a French social security system."}
• {"criterion_text":"- 7. Written informed consent obtained from the participant or participant’s legal representative"}
• {"criterion_text":"- 8. For child-bearing aged women, contraception using oral contraceptive, or intrauterine device or mechanical contraception"}

Exclusion criteria

• {"criterion_text":"- 1. History of overt ascites or encephalopathy <12 months before inclusion"}
• {"criterion_text":"- 10. Known hypersensitivity to carvedilol"}
• {"criterion_text":"- 11. Concomitant use of Cimétidin"}
• {"criterion_text":"- 12. Concomitant use of class I antiarythmic agents (except lidocaïn) (i.e.cibenzoline, disopyramide, flécaı̈nide, hydroquinidine méxilétine, propafenone, quinidine)"}
• {"criterion_text":"- 13. Concomitant use of calcium antagonists: diltiazem, vérapamil and bépridil"}
• {"criterion_text":"- 14. Concomitant use of clonidine, méthyldopa, guanfacine, moxonidine, rilménidine"}
• {"criterion_text":"- 15. Concomitant use of fingolimod"}
• {"criterion_text":"- 16. Concomitant use of potent inhibitors (e.g. ketoconazole, HIV protease inhibitors) or inductors (e.g. rifampin, carbamazepine, phenytoin) of CYP3A4 (see appendix 7)"}
• {"criterion_text":"- 17. Pregnancy or breastfeeding"}
• {"criterion_text":"- 18. Non ability for participant to comply with the requirements of the study"}
• {"criterion_text":"- 19. Life expectancy <12 months"}
• {"criterion_text":"- 2. Treatment with either diuretics or lactulose or rifaximin <3 months before inclusion"}
• {"criterion_text":"- 3. Any history of portal hypertension related bleeding"}
• {"criterion_text":"- 4. Baseline heart rate <65/min or systolic blood pressure <100 mm Hg"}
• {"criterion_text":"- 5. Previous transjugular intrahepatic portosystemic shunt (TIPSS) or liver transplantation"}
• {"criterion_text":"- 6. Previous history or active hepatocellular carcinoma"}
• {"criterion_text":"- 7. Glomerular filtration rate (CKD-Epi) < 30 mL/min"}
• {"criterion_text":"- 8. Strict indication to selective or nonselective beta-blockers: history of acute myocardial infarction, congestive heart failure"}
• {"criterion_text":"- 9. Strict contraindication to selective or nonselective beta-blockers: o decompensated congestive heart failure o grade 2 or 3 atrioventricular block o sinus node dysfunction without pacemaker o severe asthma according to WHO classification [63] o severe Chronic Obstructive Pulmonary Disease, defined stage 3 or 4 of the GOLD classification, i.e.FEV1<50% of the predicted value (https://goldcopd.org/) o severe Raynaud disease, defined as repetitive episodes of biphasic colour (at least two) of pallor, cyanosis, erythema, in addition to paresthesia or numbness, occurring in both cold and normal environments [64]."}

Primary endpoints

• {"endpoint_text":"- Primary endpoint will be the occurrence, within 36 months after inclusion, of either decompensation of cirrhosis or liver-related death.","definition_or_measurement_approach":"Occurrence within 36 months after inclusion of decompensation of cirrhosis or liver-related death; assessed during scheduled follow-up visits up to 36 months after randomization."}

Secondary endpoints

• {"endpoint_text":"- 1. Safety of carvedilol (<=12.5 mg per day) on: (a) Systemic hemodynamics (heart rate, blood pressure), (b) Cardiac function (c) any other adverse effects and reactions within 36 months after inclusion","definition_or_measurement_approach":"Safety assessed over 36 months by monitoring heart rate, blood pressure, cardiac function and recording adverse events/reactions."}
• {"endpoint_text":"- Effect of low dose carvedilol (<=12.5 mg per day), within 36 months after randomization","definition_or_measurement_approach":"Effect measured during 36 months of treatment on pre-specified clinical outcomes (see main objective and secondary objectives)."}
• {"endpoint_text":"- 3. To assess treatment compliance: record of unused packaging and information about compliance in a patient notebook","definition_or_measurement_approach":"Compliance assessed by return/record of unused packaging and patient notebook entries."}
• {"endpoint_text":"- 4. To identify potential predictors of decompensation in the control group: - Levels of liver and spleen stiffness at baseline and at month 12 - Liver surface nodularity at baseline","definition_or_measurement_approach":"Predictors assessed by measuring liver and spleen stiffness (e.g., TE-LSM) at baseline and month 12 and liver surface nodularity at baseline."}
• {"endpoint_text":"- 5. To identify potential predictors of response to carvedilol (in the group receiving carvedilol): - Levels and variation of liver and spleen stiffness at baseline, and week 2 - Heart rate, systolic and mean blood pressure and its variation at baseline and week 2","definition_or_measurement_approach":"Predictors assessed by measuring liver/spleen stiffness and cardiac hemodynamics at baseline and week 2."}
• {"endpoint_text":"- 6. Occurrence, within 36 months after inclusion, of either decompensation of cirrhosis or liver-related death according to subgroups (a) main etiology of cirrhosis (alcohol, viral, or metabolic) (b) history of previous decompensation (c) alcohol consumption (d) features of metabolic syndrome","definition_or_measurement_approach":"Subgroup analyses of the primary outcome across pre-specified subgroups during 36 months follow-up."}

Methods

• Patients will be preincluded at each investigator center by the investigator and/or the study coordinator by reading medical records to check inclusion and non-inclusion criteria.

France

Earliest CTIS Part Ii Submission Date

30-01-2025

Latest Decision Or Authorization Date

17-02-2025

Processing Time Days

18

Number Of Sites

25

Number Of Participants

300

Primary sponsor

Full Name

Centre Hospitalier Regional Universitaire De Tours

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France