Endoscopic Variceal Ligation vs Carvedilol for the Prevention of First Esophageal Variceal Bleeding in Patients With HCC (P-HCC-CVL)

February 11, 2025 updated by: Taipei Veterans General Hospital, Taiwan

A Randomized Controlled Trial of Endoscopic Variceal Ligation Versus Carvedilol for the Prevention of First Esophageal Variceal Bleeding in Patients With Hepatocellular Carcinoma

The goal of this clinical trial is to evaluate whether endoscopic variceal ligation (EVL) or carvedilol is more effective at preventing the first esophageal variceal bleeding (EVB) in patients with hepatocellular carcinoma (HCC). It will also learn about the safety of EVL and carvedilol in patients with HCC. The main questions it aims to answer are:

Whether EVL or carvedilol is more effective at preventing initial EVB in patients with HCC with high-risk EVs.

What medical problems do participants have when undergoing EVL or taking carvedilol? Researchers will compare the efficacy and safety of EVL to carvedilol for the prevention of first EVB in patients with HCC.

Participants will:

Undergo EVL every 3-4 weeks until variceal eradication and then receive regular endoscopic follow-up according to the protocol, or Take carvedilol every day (start from 6.25 mg/d and then titrate to 12.5 mg/d if tolerable).

Visit the clinic once every 2-3 months for checkups and tests. Keep a diary of their vital signs (SBP, DBP, and HR) as well as symptoms.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Gastro-esophageal variceal bleeding is a major complication of portal hypertension (PHT) and carries a high rate of rebleeding and mortality. Hepatocellular carcinoma (HCC), a special subgroup of PHT, is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide. The presence of esophageal varices (EVs) in more than half of patients with HCC is associated with poor survival. Furthermore, without primary prevention strategies, nearly half of these HCC patients experience esophageal variceal bleeding (EVB). The prognosis of HCC patients with EVB is extremely poor, with a rebleeding rate of 50% and a six-week mortality rate of 26-48%, both of which are higher than those of non-HCC patients.

However, there is still a lack of evidence on how to prevent first EVB in patients with HCC with high-risk EVs. AASLD practice guidance recommends prevention of EVB and hepatic decompensation in patients with HCC should follow the same principles as those for patients without HCC, that is, nonselective beta-blocker (NSBB) therapy is recommended in patients with HCC with clinically significant portal hypertension (CSPH). Endoscopic variceal ligation (EVL) is recommended for compensated patients with high-risk EVs who have contraindications to NSBBs. However, this recommendation lacks randomized controlled trial (RCT) to support it. Our recently published RCT showed that EVL is superior to propranolol (PPL) in the primary prevention of EVB in patients with HCC with high-risk EVs. In the subgroup analysis, EVL reduces EVB and improves OS in patients with BCLC stage A/B but not in those with BCLC stage C/D.

Carvedilol, an NSBB that additionally exerts intrinsic anti-alpha-1-adrenergic activity, has been shown to reduce hepatic venous pressure gradient more than propranolol and is currently the first-line treatment for primary prophylaxis in patients with CSPH. Nevertheless, the superiority of EVL versus carvedilol as a primary prevention strategy in patients with HCC with high-risk EVs is still unknown. In this project, we will initiate an open-label RCT aiming at comparing the efficacy of EVL and carvedilol in the primary prevention of EVB in patients with HCC with high-risk EVs. We will also explore if there is any difference between the two groups in terms of other upper gastrointestinal bleeding, nonbleeding liver decompensation (such as new onset/worsening ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome), overall survival, adverse events, tolerability and safety. We will also compare the efficacy of EVL and carvedilol in the primary prevention of EVB in patients with HCC at different BCLC stage.

Study Type

Interventional

Enrollment (Estimated)

120

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Taiwan
      • Taipei, Taiwan, 11217
        • Recruiting
        • Taipei Veterans General Hospital
        • Principal Investigator:
          • Tsung-Chieh Yang, MD
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

- Patients with HCC and high-risk EVs, confirmed through imaging and clinical data (classified as F2 or F3 EVs according to Beppu et al. classification)

Exclusion Criteria:

  • Age less than 20 years or greater than 90 years.
  • History of esophageal variceal bleeding.
  • Previous treatment for EVs, including EVL, endoscopic sclerotherapy, transjugular intrahepatic portosystemic shunt (TIPS), or surgical interventions.
  • Use of non-selective β-blockers within two weeks prior to enrollment.
  • Contraindications for non-selective β-blockers, including severe atrioventricular block, chronic obstructive pulmonary disease (COPD), asthma, poorly controlled diabetes, and severe peripheral artery disease.
  • Presence of other end-stage organ diseases, including terminal cancers other than HCC, heart failure, and renal failure.
  • Pregnant women.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Endoscopic variceal ligation
EVL will be performed and repeated every 3 to 4 weeks until the EVs are eradicated. Following this, patients will undergo regular upper gastrointestinal endoscopic surveillance, initially every three months for a total of two sessions, then every six months for a total of two sessions, and subsequently annually. If EVs are found to recur during surveillance, additional EVL will be performed every 3 to 4 weeks until the varices are again eradicated endoscopically.
Procedure: Endoscopic variceal ligation
EVL will be performed and repeated every 3 to 4 weeks until the EVs are eradicated. Following this, patients will undergo regular upper gastrointestinal endoscopic surveillance, initially every three months for a total of two sessions, then every six months for a total of two sessions, and subsequently annually. If EVs are found to recur during surveillance, additional EVL will be performed every 3 to 4 weeks until the varices are again eradicated endoscopically.
Placebo Comparator: Carvedilol
The initial dosage of carvedilol is set at 6.25 mg daily. In the absence of hypotension (systolic blood pressure < 90 mmHg), bradycardia (resting heart rate < 55 beats per minute), or other adverse effects, hospitalized patients may have their dosage increased to 12.5 mg daily after 3 days, while outpatient patients may increase their dosage to 12.5 mg daily after 7 days. This dosage represents the target dose for the trial.
Drug: Carvedilol
The initial dosage of carvedilol is set at 6.25 mg daily. In the absence of hypotension (systolic blood pressure < 90 mmHg), bradycardia (resting heart rate < 55 beats per minute), or other adverse effects, hospitalized patients may have their dosage increased to 12.5 mg daily after 3 days, while outpatient patients may increase their dosage to 12.5 mg daily after 7 days. This dosage represents the target dose for the trial.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Esophageal variceal bleeding
Time Frame: 3 years
The cumulative incidence of esophageal variceal bleeding
3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: 3 years
3 years
Adverse events
Time Frame: 3 years
3 years
Other upper gastrointestinal bleeding
Time Frame: 3 years
The cumulative incidence of other upper gastrointestinal bleeding
3 years
First/further nonbleeding liver decompensation
Time Frame: 3 years
Events that defined first/further nonbleeding liver decompensation were based on the Baveno VII consensus
3 years

Other Outcome Measures

Outcome Measure
Time Frame
Primary and secondary outcomes categorized by BCLC staging in the subgroup analysis
Time Frame: 3 years
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Taipei Veterans General Hospital, Taiwan

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2024

Primary Completion (Estimated)

October 1, 2030

Study Completion (Estimated)

October 1, 2030

Study Registration Dates

First Submitted

September 10, 2024

First Submitted That Met QC Criteria

September 10, 2024

First Posted (Actual)

September 19, 2024

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

February 11, 2025

Last Verified

February 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2024-02-016B

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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