Clinical trial NCT06449339: Non-selective Beta-blocker in Compensated Advanced Chronic Liver Disease
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Portal Hypertension
Hepatic Decompensation
Advanced Chronic Liver Disease
Keywords: compensated advanced chronic liver disease
non-selective beta-blocker
Baveno VII
hepatic decompensation
Lead sponsor: Chinese University of Hong Kong
Sponsor class: OTHER
Collaborators: name: Singapore General Hospital
name: University of Palermo
name: University of Malaya
name: University Hospital, Bordeaux
name: Shanghai Jiao Tong University School of Medicine
First posted: 2024-06-10
Enrollment: 474
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: composite of incident high-risk varices (HRV), hepatic decompensation or death
timeFrame: 5 years
Secondary outcomes:
measure: Number of participants with development of each hepatic decompensation event
timeFrame: 5 years
measure: Number of participants with development of hepatocellular carcinoma
timeFrame: 5 years
measure: Change in hepatic function in terms of Child-Pugh score
timeFrame: 5 years
measure: Change in hepatic function in terms of model for end-stage liver disease (MELD) score
timeFrame: 5 years
measure: Change in liver stiffness measurement (LSM) and spleen stiffness measurement (SSM)
timeFrame: 5 years
measure: Adverse events
timeFrame: 5 years
measure: Number of participants who survive until the last clinic visit
timeFrame: 5 years
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital, The Chinese University of Hong Kong
Study officials:
affiliation: Chinese University of Hong Kong
name: Jimmy Che-To Lai, MB ChB
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.