Effect of Long-term Carvedilol to Prevent Decompensation or Death in Patients With Asymptomatic Child-Pugh A5 to B8 Cirrhosis and Clinically Significant Portal Hypertension: a Multicenter Double-blind Randomized Control Trial

Clinically Significant Portal Hypertension Clinical Trial

— CARVECIR  

Official title:

Effect of Long-term Carvedilol to Prevent Decompensation or Death in Patients With Asymptomatic Child-Pugh A5 to B8 Cirrhosis and Clinically Significant Portal Hypertension: a Multicenter Double-blind Randomized Control Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06263816
• Other study ID #: CARVECIR
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: November 15, 2024
• Est. completion date: June 15, 2030

Study information

• Verified date: February 2024
• Source: University Hospital, Tours
• Contact: Laure ELKRIEF, MD-PhD
• Phone: +33 247475965
• Email: l.elkrief[@]chu-tours.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Decompensation of cirrhosis is a turning point in cirrhosis course, as associated with a marked decrease in life expectancy. Thus, prevention of decompensation is crucial. The usefulness of carvedilol to prevent decompensation of cirrhosis in patients with TE-LSM ≥ 25 kPa as a surrogate marker for clinically significant portal hypertension, has never been evaluated in a clinical trial.

Description:

Decompensation of cirrhosis is a turning point in cirrhosis course, as associated with a marked decrease in life expectancy. Thus, prevention of decompensation is crucial. Portal hypertension (PH) is the strongest predictor of decompensation. Hepatic venous pressure gradient (HVPG) is the reference standard for the evaluation of PH. HVPG ≥10 mm Hg, called "clinically significant portal hypertension", identifies a population with a high risk of decompensation. HVPG measurement is an invasive procedure, only routinely available in expert centers. Liver stiffness measurement (LSM) using transient elastography (TE) (referred as TE LSM) using Fibroscan can provide an indirect estimate of HVPG. TE-LSM ≥ 25 kPa can rule-in HVPG ≥10 mm Hg with a specificity >90%. Nonselective beta-blockers (NSBBs) lower portal pressure by decreasing portal venous inflow. Carvedilol also decreases intrahepatic vascular resistance, and thereby achieves a greater reduction in portal pressure than propranolol. At low-dose (≤12.5 mg/day), carvedilol is safe in patients with compensated cirrhosis. In patients with asymptomatic cirrhosis, NSBBs were recommended when medium or large varices (high-risk varices) are present for prophylaxis of variceal bleeding. In a recent randomized controlled trial, the PREDESCI study (NCT01059396), NSBBs reduced incidence of decompensation or death in patients with compensated cirrhosis with clinically significant portal hypertension. In the PREDESCI study, the diagnosis of clinically significant portal hypertension was based on invasive HVPG measurement, so that its results are not applicable in clinical practice. The usefulness of carvedilol to prevent decompensation of cirrhosis in patients with TE-LSM ≥25 kPa as a surrogate marker for clinically significant portal hypertension, has never been evaluated in a randomized controlled trial.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 290
• Est. completion date: June 15, 2030
• Est. primary completion date: October 15, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or female= 18 years of age
• 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
• 2 TE-LSM (Fibroscan®) performed in fasting conditions, using either the M or the XL probe >=25 kPa, within 12 months before inclusion
• Absence of medium or large varices or small varices with red signs at endoscopy within 3 months before inclusion
• Child-Pugh A5 to B8
• Affiliation to a French social security system.
• Written informed consent obtained from the participant or participant's legal representative
• For child-bearing aged women, contraception using oral contraceptive, or intrauterine device or mechanical contraception

Exclusion Criteria:

• History of overt ascites or encephalopathy <12 months before inclusion
• Treatment with either diuretics or lactulose or rifaximin <3 months before inclusion
• Any history of portal hypertension related bleeding
• Baseline heart rate <65/min or systolic blood pressure <100 mm Hg
• Previous transjugular intrahepatic portosystemic shunt (TIPSS) or liver transplantation
• Previous history or active hepatocellular carcinoma
• Glomerular filtration rate (CKD-Epi) < 30 mL/min
• Strict indication to selective or nonselective beta-blockers: history of acute myocardial infarction, congestive heart failure
• Strict contraindication to selective or nonselective beta-blockers:
• decompensated congestive heart failure
• grade 2 or 3 atrioventricular block
• sinus node dysfunction without pacemaker
• severe asthma according to WHO classification [63]
• 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/)
• 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].
• Known hypersensitivity to carvedilol
• Concomitant use of Cime´tidin
• Concomitant use of class I antiarythmic agents (except lidocaïn) (i.e.cibenzoline, disopyramide, fle´cai¨nide, hydroquinidine me´xile´tine, propafenone, quinidine)
• Concomitant use of calcium antagonists: diltiazem, ve´rapamil and be´pridil
• Concomitant use of clonidine, me´thyldopa, guanfacine, moxonidine, rilme´nidine
• Concomitant use of fingolimod
• Concomitant use of potent inhibitors (e.g. ketoconazole, HIV protease inhibitors) or inductors (e.g. rifampin, carbamazepine, phenytoin) of CYP3A4 (see appendix 7)
• Pregnancy or breastfeeding
• Non ability for participant to comply with the requirements of the study
• Life expectancy <12 months

Related Conditions & MeSH terms

• Clinically Significant Portal Hypertension
• Fibrosis
• Hypertension
• Hypertension, Portal
• Liver Cirrhosis

Intervention

Drug:
• Experimental group: Patients will be treated with carvedilol.
Patients will receive the number of pills of carvedilol corresponding to the dose determined during the titration period (either one pill of 6.25 mg in the morning or 1 pill of 6.25 mg twice a day, 1 in the morning and 1 in the evening.

Other:
• Control group: Patients will receive a placebo.
Patients will receive the number of pills of placebo corresponding to the dose determined during the titration period (either one pill in the morning or 1 pill twice a day: 1 in the morning and 1 in the evening).

Locations

Country	Name	City	State
France	CHU Amiens Picardie	Amiens
France	CHU Angers	Angers
France	CHU Beaujon	Assistance Publique Hôpitaux De Paris
France	CHU Jean Minjoz	Besançon
France	CHU Haut Lévêque	Bordeaux
France	CHU Caen	Caen
France	CH intercommunal de Créteil	CH Intercommunal De Créteil
France	CHU Clermont Ferrand	Clermont Ferrand
France	Hôpital Henri Mondor	Créteil
France	Hôpital Francois Mitterrand	Dijon
France	CHU Grenoble	Grenoble
France	Centre Hospitalier départemental de Vendée	La Roche-sur-Yon
France	Hôpital Huriez	Lille
France	CHU la Croix Rousse	Lyon
France	CHU de Montpellier	Montpellier
France	CHU Hôtel Dieu	Nantes
France	CHU Avicenne	Paris
France	CHU Pitié-Salpêtrière	Paris
France	CHU Saint-Antoin	Paris
France	CHU de Reims	Reims
France	CHU Pontchaillou	Rennes
France	Hôpitaux Universitaires de Strasbourg	Strasbourg
France	CHU de Toulouse	Toulouse
France	Hôpital Paul Brousse	Villejuif

Sponsors (25)

Lead Sponsor

Collaborator

University Hospital, Tours

Assistance Publique Hopitaux Paris AVICENNE, Assistance Publique Hopitaux Paris BEAUJON, Assistance Publique Hopitaux Paris HENRI MONDOR, Assistance Publique Hopitaux Paris LA PITIE SALPETRIERE, Assistance Publique Hopitaux Paris PAUL BROUSSE, Assistance Publique Hopitaux Paris ST ANTOINE, Centre Hospitalier intercommunal de Créteil, Centre Hospitalier Régional Universitaire Lille, Centre Hospitalier Universitaire Amiens Picardie, Centre Hospitalier Universitaire Angers, Centre Hospitalier Universitaire Caen, Centre Hospitalier Universitaire Clermont Ferrand, Centre Hospitalier Universitaire Dijon, Centre Hospitalier Universitaire Grenoble, Centre Hospitalier Universitaire Haut Lévêque, Centre Hospitalier Universitaire Jean Minjoz, Centre Hospitalier Universitaire Pontchaillou, Centre Hospitaliser Départemental de Vendée, CHU de Reims, Hôpitaux Universitaires de Strasbourg, Hospices Civils de Lyon, Nantes University Hospital, University Hospital, Montpellier, University Hospital, Toulouse

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To evaluate the effect of low dose carvedilol (<=12.5 mg per day) versus placebo on the occurrence of decompensation of cirrhosis or liver-related death at 36 months	Primary endpoint will be the occurrence, within 36 months after inclusion, of either decompensation of cirrhosis or liver-related death.; Decompensation of cirrhosis is defined as a composite endpoint including one event among: overt ascites, overt hepatic encephalopathy and variceal bleeding according to Baveno VII consensus conference [1].; Liver-related death is defined as death occurring in the context of complicated ascites (e.g. spontaneous bacterial peritonitis or acute kidney injury), encephalopathy, variceal hemorrhage, or ACLF	36 months