Clinical trial NCT06263816: 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
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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Asymptomatic Cirrhosis
Clinically Significant Portal Hypertension
Keywords: carvedilol
decompensation
death
asymptomatic cirrhosis
significant portal hypertension
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
Collaborators: name: Centre Hospitalier Universitaire Amiens Picardie
name: Centre Hospitalier Universitaire Angers
name: Assistance Publique Hopitaux Paris BEAUJON
name: Centre Hospitalier Universitaire Caen
name: Centre Hospitalier intercommunal de Créteil
name: Hospices Civils de Lyon
name: Centre Hospitalier Universitaire Grenoble
name: Centre Hospitalier Universitaire Haut Lévêque
name: Centre Hospitalier Régional Universitaire Lille
name: Centre Hospitalier Universitaire Jean Minjoz
name: Assistance Publique Hopitaux Paris AVICENNE
name: Centre Hospitalier Universitaire Clermont Ferrand
name: Assistance Publique Hopitaux Paris LA PITIE SALPETRIERE
name: Centre Hospitalier Universitaire Pontchaillou
name: Assistance Publique Hopitaux Paris ST ANTOINE
name: Assistance Publique Hopitaux Paris PAUL BROUSSE
name: University Hospital, Montpellier
name: Assistance Publique Hopitaux Paris HENRI MONDOR
name: Centre Hospitaliser Départemental de Vendée
name: Nantes University Hospital
name: Centre Hospitalier Universitaire Dijon
name: CHU de Reims
name: Hôpitaux Universitaires de Strasbourg
name: University Hospital, Toulouse
First posted: 2024-02-16
Enrollment: 290
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study will be a national multicentric, phase III, superiority double-blinded randomized controlled trial with two parallel arms: carvedilol versus placebo. The primary end-point will be assessed by the local investigator (hepatologist), blinded of the randomization arm
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: 36 months
Secondary outcomes:
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens Picardie
city: Angers
country: France
facility: CHU Angers
city: Assistance Publique Hôpitaux De Paris
country: France
facility: CHU Beaujon
city: Besançon
country: France
facility: CHU Jean Minjoz
city: Bordeaux
country: France
facility: CHU Haut Lévêque
city: Caen
country: France
facility: CHU Caen
city: CH Intercommunal De Créteil
country: France
facility: CH intercommunal de Créteil
city: Clermont Ferrand
country: France
facility: CHU Clermont Ferrand
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: Hôpital Francois Mitterrand
city: Grenoble
country: France
facility: CHU Grenoble
city: La Roche-sur-Yon
country: France
facility: Centre Hospitalier départemental de Vendée
city: Lille
country: France
facility: Hôpital Huriez
city: Lyon
country: France
facility: CHU la Croix Rousse
city: Montpellier
country: France
facility: CHU de Montpellier
city: Nantes
country: France
facility: CHU Hôtel Dieu
city: Paris
country: France
facility: CHU Avicenne
city: Paris
country: France
facility: CHU Pitié-Salpêtrière
city: Paris
country: France
facility: CHU Saint-Antoin
city: Reims
country: France
facility: CHU de Reims
city: Rennes
country: France
facility: CHU Pontchaillou
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg
city: Toulouse
country: France
facility: CHU de Toulouse
city: Villejuif
country: France
facility: Hôpital Paul Brousse
Study officials:
affiliation: University Hospital, Tours
name: Laure ELKRIEF, MD-PhD
role: STUDY_DIRECTOR
References: