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

Portal Hypertension Clinical Trial

— BB_cACLD  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06449339
• Other study ID #: 2023.521-T
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: July 1, 2024
• Est. completion date: June 30, 2031

Study information

• Verified date: June 2024
• Source: Chinese University of Hong Kong
• Contact: Angel Chim, MSc
• Phone: +852 3505 4205
• Email: angelchim[@]cuhk.edu.hk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 varices needing treatment (VNT), in terms of prevention of first occurrence of hepatic decompensation and mortality. Consecutive patients in the participating study sites with cACLD fulfilling the 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 VNT 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 474
• Est. completion date: June 30, 2031
• Est. primary completion date: June 30, 2031
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Aged 18 years of above
• Known chronic liver disease(s)
• In grey zone or clinically significant portal hypertension (CSPH) by Baveno VII criteria (LSM =15 kilopascal [kPa] and/or platelet count <150×10^9/L), with LSM by transient elastography (TE) within 6 months from screening o For patients with platelet count <150 x 10^9/L alone, other non-hepatic causes of thrombocytopenia should have been excluded, such as haematological or rheumatological disorders; and they should have LSM at least =10 kPa to classify as compensated advanced chronic liver disease (cACLD) according to Baveno VII criteria.

Exclusion Criteria:

• Presence of varices needing treatment (VNT) (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
• 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

Related Conditions & MeSH terms

• Advanced Chronic Liver Disease
• Hepatic Decompensation
• Hypertension, Portal
• Liver Diseases
• Liver Failure
• Portal Hypertension

Intervention

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.

Locations

Country	Name	City	State
n/a

Sponsors (6)

Lead Sponsor	Collaborator
Chinese University of Hong Kong	Shanghai Jiao Tong University School of Medicine, Singapore General Hospital, University Hospital, Bordeaux, University of Malaya, University of Palermo

References & Publications (1)

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. Erratum In: J Hepatol. 2022 Apr 14;: — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	composite of incident varices needing treatment (VNT), hepatic decompensation or death	VNT 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, overt hepatic encephalopathy or hepatorenal syndrome.	5 years
Secondary	Number of participants with development of each hepatic decompensation event	Hepatic decompensation events include ascites, variceal bleeding, overt hepatic encephalopathy and hepatorenal syndrome	5 years
Secondary	Number of participants with development of hepatocellular carcinoma	Development of hepatocellular carcinoma	5 years
Secondary	Change in hepatic function in terms of Child-Pugh score	Higher Child-Pugh score indicates poorer liver condition, vice versa	5 years
Secondary	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
Secondary	Change in liver stiffness measurement (LSM) and spleen stiffness measurement (SSM)	Change in liver and spleen stiffness measurements on transient elastography	5 years
Secondary	Adverse events	Any adverse events during the study period	5 years
Secondary	Number of participants who survive until the last clinic visit	Survival until end of study	5 years