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 controlled trial.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Regional Universitaire De Tours

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]

Trial duration

11 Sep 2025 → ongoing

Decision date (initial)

2025-02-17

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-511663-28-00

ClinicalTrials.gov

NCT06263816

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To evaluate the effect of low dose carvedilol (12.5 mg per day) versus placebo on the occurrence of decompensation of cirrhosis or liverrelated
death at 36 months in patients with asymptomatic Child-Pugh class A5 to B8 cirrhosis clinically significant portal hypertension
(estimated using NITs) without high-risk varices and :
- In virus- and/or alcohol-related and non-obese (BMI <30 kg/m2) MASLD-related cirrhosis,
o liver stiffness measurement (LSM) using transient elastography (TE) (referred as TE-LSM) ≥25 kPa
- in all patients (including patients with obese (BMI ≥30 kg/m2) MASLD-related cirrhosis) :
o estimated probability of CSPH ≥75% by ANTICIPATENASH model (calculated using TE-LSM, platelet count and body mass index) or NICER (calculated using TE-LSM, platelet count and body mass index or
o or spleen stiffness measurement (SSM) using transient elastography (TE) (referred as TE-SSM) (using a 100 Hz device) >55 kPa

Secondary objectives 6

1. 1. To assess safety of low dose carvedilol (<=12.5 mg per day) on (a) systemic hemodynamics (heart rate and blood pressure) and (b) any other adverse effects and reactions
2. 2. To compare the effect of low dose carvedilol (<=12.5 mg per day) versus placebo on the following outcomes, assessed during 36 months of treatment: a. mortality (global and by cause of death: liver related, cardiovascular, non-liver related) b. the composite outcome: mortality or liver transplantation c. decompensation of cirrhosis alone d. each and any event among: overt ascites, overt hepatic encephalopathy, variceal bleeding e. appearance of high-risk varices f. occurrence of acute kidney injury g. occurrence of bacterial infection h. occurrence of hepatocellular carcinoma i. occurrence of portal vein thrombosis j. occurrence of acute-on-chronic liver failure (ACLF) k. number of unplanned hospital admission for any liver related event among overt ascites, overt hepatic encephalopathy, variceal bleeding, acute kidney injury, bacterial infection and portal vein thrombosis l. portal hypertension related features (spleen size, platelet count, size of varices, portal flow velocity, portosystemic collaterals) m. Liver function n. liver and spleen stiffness o. Quality of life
3. 3. To assess treatment compliance
4. 4) To identify potential predictors of decompensation in the control group: - New biomarkers (from ancillary studies) using the biological samples - These results will be adjusted on potential confounding factors, including liver function tests, features of portal hypertension and ethnic origin
5. 5. To identify potential predictors of response to carvedilol (in the group receiving carvedilol): liver and spleen stiffness and its variation over time; cardiac hemodynamics as well as new biomarkers(biological collection).
6. 6) To evaluate the effect of 36 months low dose carvedilol (12.5 mg per day) versus placebo on the occurrence of decompensation of cirrhosis or liver-related death at 36 months in patients with asymptomatic Child- Pugh class A5 to B8 cirrhosis with significant portal hypertension (estimated using NITs) without high-risk varices, according to (i) main cause of cirrhosis, (b) history of previous decompensation, (c) alcohol consumption, (d) presence of metabolic syndrome

Conditions and MedDRA coding

Asymptomatic Child-Pugh A5 to B8 cirrhosis

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 1. Male or female≥ 18 years of age
2. 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)
3. 3. - In virus- and/or alcohol-related and non-obese (BMI <30 kg/m2) MASLD-related cirrhosis, either o 2 TE-LSM ≥25 kPa (measured using the M or XL probe), performed in fasting condition, within 12 months before inclusion - Or (in all patients, including obese (BMI ≥30 kg/m2) MASLDrelated cirrhosis) o 2 estimated probability of CSPH ≥75% assessed by ANTICIPATE- NASH or NICER model, with TE-LSM/TESSM performed in fasting condition, within 12 months before inclusion o 2 TE-SSM ≥55 kPa (measured using the 100 Hz probe) performed in fasting condition, within 12 months before inclusion
4. 4. Absence of medium or large varices or small varices with red signs at endoscopy within 3 months before inclusion
5. 5. Child-Pugh A5 to B8
6. 6. Affiliation to a French social security system.
7. 7. Written informed consent obtained from the participant or guardian/ curator
8. 8. For child-bearing aged women, contraception using oral contraceptive, or intrauterine device or mechanical contraception

Exclusion criteria 19

1. 1. History of overt ascites or encephalopathy <12 months before inclusion
2. 2. Treatment with either diuretics or lactulose or rifaximin <3 months before inclusion
3. 3. Any history of portal hypertension related bleeding
4. 4. Baseline heart rate <65/min or systolic blood pressure <100 mm Hg
5. 5. Previous transjugular intrahepatic portosystemic shunt (TIPSS) or liver transplantation
6. 6. Previous history or active hepatocellular carcinoma
7. 7. Glomerular filtration rate (CKD-Epi) < 30 mL/min
8. 8. Strict indication to selective or nonselective beta-blockers: history of acute myocardial infarction, congestive heart failure
9. 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].
10. 10. Known hypersensitivity to carvedilol
11. 11. Concomitant use of Cimétidin
12. 12. Concomitant use of class I antiarythmic agents (except lidocaïn) (i.e.cibenzoline, disopyramide, flécaı̈nide, hydroquinidine méxilétine, propafenone, quinidine)
13. 13. Concomitant use of calcium antagonists: diltiazem, vérapamil and bépridil
14. 14. Concomitant use of clonidine, méthyldopa, guanfacine, moxonidine, rilménidine
15. 15. Concomitant use of fingolimod
16. 16. Concomitant use of potent inhibitors (e.g. ketoconazole, HIV protease inhibitors) or inductors (e.g. rifampin, carbamazepine, phenytoin) of CYP3A4 (see appendix 7)
17. 17. Pregnancy or breastfeeding
18. 18. Non ability for participant to comply with the requirements of the study
19. 19. Life expectancy <12 months

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary endpoint will be the occurrence, within 36 months after inclusion, of either decompensation of cirrhosis or liver-related death.

Secondary endpoints 6

1. 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
2. Effect of low dose carvedilol (<=12.5 mg per day), within 36 months after randomization
3. 3. To assess treatment compliance: record of unused packaging and information about compliance in a patient notebook
4. 4. To identify potential predictors of decompensation (see primary endpoint for definition) in the control group: - New biomarkers (from ancillary studies) using the biological samples - These results will be adjusted on potential confounding factors, including liver function tests, features of portal hypertension and ethnic origin
5. 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
6. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Regional Universitaire De Tours

Sponsor organisation

Centre Hospitalier Regional Universitaire De Tours

Address

2 Boulevard Tonnelle

City

Tours Cedex 9

Postcode

37044

Country

France

Scientific contact point

Organisation

Centre Hospitalier Regional Universitaire De Tours

Contact name

Coordonateur

Public contact point

Organisation

Centre Hospitalier Regional Universitaire De Tours

Contact name

ARC coordonnateur

Locations

1 EU/EEA country · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications