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)

February 16, 2024 updated by: University Hospital, Tours

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

290

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
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).
Experimental: Carvédilol
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Time Frame: 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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Tours

Collaborators

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

Investigators

  • Study Director: Laure ELKRIEF, MD-PhD, University Hospital, Tours

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

November 15, 2024

Primary Completion (Estimated)

October 15, 2029

Study Completion (Estimated)

June 15, 2030

Study Registration Dates

First Submitted

February 8, 2024

First Submitted That Met QC Criteria

February 8, 2024

First Posted (Actual)

February 16, 2024

Study Record Updates

Last Update Posted (Actual)

February 20, 2024

Last Update Submitted That Met QC Criteria

February 16, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CARVECIR

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Clinically Significant Portal Hypertension

Clinical Trials on Experimental group: Patients will be treated with carvedilol.

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Madagascar

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe