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 (CARVECIR)

Regional University Hospital Center (CHRU)

Status and phase

Not yet enrolling

Phase 3

Conditions

Clinically Significant Portal Hypertension

Asymptomatic Cirrhosis

Treatments

Other: Control group: Patients will receive a placebo.

Drug: Experimental group: Patients will be treated with carvedilol.

Study type

Interventional

Funder types

Other

Identifiers

NCT06263816

CARVECIR

Details and patient eligibility

About

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.

Full 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.

Enrollment

290 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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 Cimétidin
Concomitant use of class I antiarythmic agents (except lidocaïn) (i.e.cibenzoline, disopyramide, flécaïnide, hydroquinidine méxilétine, propafenone, quinidine)
Concomitant use of calcium antagonists: diltiazem, vérapamil and bépridil
Concomitant use of clonidine, méthyldopa, guanfacine, moxonidine, rilménidine
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