Non-selective Beta-blocker in Compensated Advanced Chronic Liver Disease (BB_cACLD)

Baveno VII Criteria-guided Initiation of Non-selective Beta Blocker in Patients With Compensated Advanced Chronic Liver Disease to Reduce Hepatic Decompensation: an Open-label Randomised Controlled Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Portal Hypertension; Advanced Chronic Liver Disease; Hepatic Decompensation
• Intervention / Treatment: Drug: Carvedilol

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.

• Study Type: Interventional
• Enrollment (Estimated): 474
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Angel Chim, MSc; Phone Number: +852 3505 4205; Email: angelchim@cuhk.edu.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • Prince of Wales Hospital, The Chinese University of Hong Kong
    • Contact: Jimmy Che-To Lai; Email: jimmyctlai@cuhk.edu.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: non-selective beta-blocker (NSBB); oral carvedilol 6.25mg-50mg daily	Drug: 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.
No Intervention: Conventional; Not on oral carvedilol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
composite of incident high-risk varices (HRV), hepatic decompensation or death	HRV is defined by moderate to large oesophageal varices (OV) or OV with red wale sign. Hepatic decompensation is defined by the presence of ascites, variceal bleeding or overt hepatic encephalopathy	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with development of hepatocellular carcinoma	Development of hepatocellular carcinoma	5 years
Change in liver stiffness measurement (LSM) and spleen stiffness measurement (SSM)	Change in liver and spleen stiffness measurements on transient elastography	5 years
Adverse events	Any adverse events during the study period	5 years
Number of participants who survive until the last clinic visit	Survival until end of study	5 years
Change in hepatic function in terms of Child-Pugh score	Higher Child-Pugh score indicates poorer liver condition, vice versa	5 years
Change in hepatic function in terms of model for end-stage liver disease (MELD) score	Higher MELD score indicates poorer liver condition, vice versa	5 years
Number of participants with development of each hepatic decompensation event	Hepatic decompensation events include ascites, variceal bleeding and overt hepatic encephalopathy	5 years

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong
• Collaborators: University of Palermo; University of Malaya; Singapore General Hospital; Shanghai Jiao Tong University School of Medicine; Royal Prince Alfred Hospital, Sydney, Australia
• Investigators: Principal Investigator: Jimmy Che-To Lai, MB ChB, Chinese University of Hong Kong

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2024
• Primary Completion (Estimated): July 30, 2031
• Study Completion (Estimated): July 30, 2031

Study Registration Dates

• First Submitted: May 29, 2024
• First Submitted That Met QC Criteria: June 7, 2024
• First Posted (Actual): June 10, 2024

Study Record Updates

• Last Update Posted (Actual): June 22, 2025
• Last Update Submitted That Met QC Criteria: June 17, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: non-selective beta-blocker; hepatic decompensation; compensated advanced chronic liver disease; Baveno VII
• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Liver Diseases; Hypertension, Portal; Liver Failure; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Membrane Transport Modulators; Antioxidants; Protective Agents; Adrenergic Agents; Calcium Channel Blockers; Vasodilator Agents; Antihypertensive Agents; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Carvedilol
• Other Study ID Numbers: 2023.521-T

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data may be shared upon reasonable request.
• IPD Sharing Time Frame: 6 months after the first publication until 15 years after the end of the study
• IPD Sharing Access Criteria: By email communication
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No