Clinical trial NCT06594744: Endoscopic Variceal Ligation vs Carvedilol for the Prevention of First Esophageal Variceal Bleeding in Patients With HCC
Official title: A Randomized Controlled Trial of Endoscopic Variceal Ligation Versus Carvedilol for the Prevention of First Esophageal Variceal Bleeding in Patients With Hepatocellular Carcinoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Hepatocellular Carcinoma (HCC)
Esophageal Varices
Keywords: Endoscopic variceal ligation
Hepatocellular carcinoma
Nonselective beta-blocker
Portal hypertension
Lead sponsor: Taipei Veterans General Hospital, Taiwan
Sponsor class: OTHER_GOV
First posted: 2024-09-19
Enrollment: 120
Sex: ALL
Minimum age (years): 20
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: EVL group:

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.

Carvedilol group:

The initial dosage of carvedilol is set at 6.25 mg daily. In the absence of hypotension (systolic blood pressure \&amp;amp;lt; 90 mmHg), bradycardia (resting heart rate \&amp;amp;lt; 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.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Esophageal variceal bleeding
timeFrame: 3 years
Secondary outcomes:
measure: Other upper gastrointestinal bleeding
timeFrame: 3 years
measure: First/further nonbleeding liver decompensation
timeFrame: 3 years
measure: Overall survival
timeFrame: 3 years
measure: Adverse events
timeFrame: 3 years
Other outcomes:
measure: Primary and secondary outcomes categorized by BCLC staging in the subgroup analysis
timeFrame: 3 years
Locations:
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
Study officials:
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