Non-selective Beta-blocker in Compensated Advanced Chronic Liver Disease

NCT ID: NCT06449339

Last Updated: 2025-06-22

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 474 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-07-17
• Study Completion Date: 2031-07-30

Brief Summary

The goal of this randomised controlled trial is to evaluate the effect of carvedilol (a non-selective beta-blocker) in patients with compensated advanced chronic liver disease under clinically significant portal hypertension or the grey zone of Baveno VII criteria.

The main question it aims to answer is:

Does carvedilol reduce hepatic decompensation and mortality in these patients despite the absence of varices needing treatment.

Researchers will compare carvedilol to no carvedilol to see if carvedilol can prevent hepatic decompensation and mortality.

Participants will either take carvedilol or not taking carvedilol for 5 years with regular clinic visit for checkups and investigations, including blood tests, ultrasonography of the liver, upper gastrointestinal endoscopy, transient elastography.

Detailed Description

The study is a multi-centre, open-label, randomised controlled trial conducted in Prince of Wales Hospital, a tertiary academic hospital in Hong Kong, as well as other international study sites. Eligible patients will be randomised to NSBB arm (i.e. receiving carvedilol) or conventional arm (i.e. not receiving carvedilol), aiming to test the hypothesis that Baveno VII criteria-guided carvedilol treatment in compensated advanced chronic liver disease (cACLD) patients in grey zone or with clinically significant portal hypertension (CSPH) is superior to not treating them in the absence of high-risk varices (HRV), in terms of prevention of first occurrence of hepatic decompensation and mortality. Consecutive patients in the participating study sites with cACLD fulfilling the high-risk grey zone and CSPH criteria by LSM and platelet count will be invited to this study. The patients will undergo oesophagogastroduodenoscopy (OGD) for screening of oesophageal varices (OV). Those without HRV will be randomised into NSBB and conventional arms. Patients in the NSBB arm will be started on carvedilol. Those in the conventional arm will not receive NSBB as per current standard of practice. The expected accrual duration is 24 months with an interim analysis to be performed when all enrolled patients have reached 1 year of follow-up or the primary endpoint. The total follow-up duration is 5 years.

Conditions

Portal Hypertension; Hepatic Decompensation; Advanced Chronic Liver Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

non-selective beta-blocker (NSBB)

oral carvedilol 6.25mg-50mg daily

Group Type: EXPERIMENTAL

Carvedilol

Intervention Type: DRUG

Patients in the NSBB arm will receive generic carvedilol. The starting dose of oral carvedilol is 6.25mg daily (to be taken once or twice per day) and can be adjusted at each scheduled visit (either by increasing the dosage or frequency of dose administration) according to patients' tolerance, as well as the blood pressure and pulse rate that the systolic blood pressure should be not lower than 90 mmHg and pulse rate not lower than 55 beats per minute. The dosage of carvedilol can also be titrated or discontinued at unscheduled visit according to patient's condition. In case carvedilol is discontinued, it can be resumed from the starting dose at next scheduled visit if there is no contraindication for carvedilol. The dose of carvedilol will be kept at 6.25-12.5mg per day unless there are additional non-hepatic indications such as arterial hypertension or cardiac disease warranting higher carvedilol dosage. The maximum allowed dose of carvedilol is 50mg daily as per drug instruction.

Conventional

Not on oral carvedilol

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Carvedilol

Patients in the NSBB arm will receive generic carvedilol. The starting dose of oral carvedilol is 6.25mg daily (to be taken once or twice per day) and can be adjusted at each scheduled visit (either by increasing the dosage or frequency of dose administration) according to patients' tolerance, as well as the blood pressure and pulse rate that the systolic blood pressure should be not lower than 90 mmHg and pulse rate not lower than 55 beats per minute. The dosage of carvedilol can also be titrated or discontinued at unscheduled visit according to patient's condition. In case carvedilol is discontinued, it can be resumed from the starting dose at next scheduled visit if there is no contraindication for carvedilol. The dose of carvedilol will be kept at 6.25-12.5mg per day unless there are additional non-hepatic indications such as arterial hypertension or cardiac disease warranting higher carvedilol dosage. The maximum allowed dose of carvedilol is 50mg daily as per drug instruction.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Aged 18 years of above
• Established diagnosis of chronic liver disease(s) of the following etiologies

• Alcohol-related liver disease (ARLD)
• Chronic hepatitis B (CHB)
• Chronic hepatitis C (CHC)
• Metabolic dysfunction-associated steatotic liver disease (MASLD) § Non-obese (BMI <30kg/m2) and obese (BMI ≥30 kg/m2)
• In high-risk grey zone or CSPH, by Baveno VII criteria (for ARLD, CHB, CHC and non-obese MASLD) or ANTICIPATE-NASH model (for obese MASLD) within 6 months from screening

• Baveno VII criteria (for ARLD, CHB, CHC and non-obese MASLD)

• LSM ≥25 kPa (CSPH)
• LSM ≥20 kPa - <25 kPa and platelet count <150 x 10^9/L; or LSM ≥15 kPa - <20 kPa and platelet count <110 x 10^9/L (high-risk grey zone)
• ANTICIPATE-NASH model (for obese MASLD)

• Predictive probability for CSPH >90% (CSPH)
• Predictive probability for CSPH ≥60% - <90% (high-risk grey zone)

Exclusion Criteria

• Presence of high-risk varices (HRV) (i.e. moderate to large oesophageal varices [OV] or OV with red wale sign) found in OGD
• Current use of non-selective beta-blocker (NSBB) or any use of NSBB within 6 months before

• Use of selective beta blocker, such as atenolol or metoprolol, is not excluded
• Selective beta-blocker will be switched to carvedilol in NSBB arm, and will be kept unchanged in conventional arm if there is clinical need for the selective beta-blocker
• Contraindication to NSBB (e.g. Type II/III heart block or baseline bradycardia <60/minute, hypotension with systolic blood pressure (SBP) <100 mmHg, asthma, poorly controlled chronic obstructive pulmonary disease, and peripheral vascular disease)
• Current use of nitrated drugs or any use of nitrated drugs within 6 months before

o Use of sublingual nitrate, such as glyceryl trinitrate, is not excluded

• Contraindication to OGD (e.g. Intestinal perforation or obstruction)
• Current or history of decompensated liver cirrhosis (i.e. Child's C cirrhosis, prior decompensating events such as ascites, variceal bleeding, hepatic encephalopathy and hepatorenal syndrome)

o Child's B cirrhosis without decompensating events is not excluded

• Current or history of hepatocellular carcinoma (HCC)
• Current or history of portal vein thrombosis
• Transjugular intrahepatic portosystemic shunt (TIPS)
• Liver transplantation
• Serious medical illness with limited life expectancy of less than 6 months
• Pregnancy
• Unable to obtain or refusal of informed consent from patient

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Singapore General Hospital

OTHER

Sponsor Role: collaborator

University of Palermo

OTHER

Sponsor Role: collaborator

University of Malaya

OTHER

Sponsor Role: collaborator

Shanghai Jiao Tong University School of Medicine

OTHER

Sponsor Role: collaborator

Royal Prince Alfred Hospital, Sydney, Australia

OTHER

Sponsor Role: collaborator

Chinese University of Hong Kong

OTHER

Sponsor Role: lead

Responsible Party

Jimmy Che-To Lai

Clinical Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jimmy Che-To Lai, MB ChB

Role: PRINCIPAL_INVESTIGATOR

Chinese University of Hong Kong

Locations

Prince of Wales Hospital, The Chinese University of Hong Kong

Hong Kong, , Hong Kong

Site Status: RECRUITING

Countries

Hong Kong

Central Contacts

Angel Chim, MSc

Role: CONTACT

angelchim@cuhk.edu.hk

+852 3505 4205

Facility Contacts

Jimmy Che-To Lai

Role: primary

jimmyctlai@cuhk.edu.hk

References

de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Baveno VII - Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-974. doi: 10.1016/j.jhep.2021.12.022. Epub 2021 Dec 30.

Reference Type: BACKGROUND

PMID: 35120736 (View on PubMed)

Pons M, Augustin S, Scheiner B, Guillaume M, Rosselli M, Rodrigues SG, Stefanescu H, Ma MM, Mandorfer M, Mergeay-Fabre M, Procopet B, Schwabl P, Ferlitsch A, Semmler G, Berzigotti A, Tsochatzis E, Bureau C, Reiberger T, Bosch J, Abraldes JG, Genesca J. Noninvasive Diagnosis of Portal Hypertension in Patients With Compensated Advanced Chronic Liver Disease. Am J Gastroenterol. 2021 Apr;116(4):723-732. doi: 10.14309/ajg.0000000000000994.

Reference Type: BACKGROUND

PMID: 33982942 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

2023.521-T

Identifier Type: -

Identifier Source: org_study_id