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Hepatocellular Carcinoma (HCC)Phase 4P-HCC-CVLNCT06594744

Endoscopic Variceal Ligation vs Carvedilol for the Prevention of First Esophageal Variceal Bleeding in Patients With HCC

A Phase 4 study testing Endoscopic variceal ligation and Carvedilol in people with Hepatocellular Carcinoma (HCC) and Esophageal Varices, run by Taipei Veterans General Hospital, Taiwan at 1 site in Taiwan.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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. Read more about this study

Who is it for?
Ages 20 to 90 years
What is being tested?
Endoscopic variceal ligation and Carvedilol
Type of treatment
Surgery or procedure
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
120 participants
Where
1 siteTaiwan
Study dates
1 Oct 2024to Oct 2030
Phase
Phase 4
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 20 to 90 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)

Who cannot join

  • 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.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Tsung-Chieh Yang, MD contact

+886-2-28712121 ext. 7506

tcyang@vghtpe.gov.tw

Ming-Chih Hou, MD contact

+886-2-28712121 ext. 7053

mchou@vghtpe.gov.tw

Taiwan1 site, 1 recruiting

  • Taipei Veterans General Hospital

    Taipei, 11217

    Tsung-Chieh Yang, MD, +886-2-28712121 ext. 7506, tcyang@vghtpe.gov.tw

    Ming-Chih Hou, MD, +886-2-28712121 ext. 7053, mchou@vghtpe.gov.tw

    Recruiting

Other trials in Taiwan

About this study

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

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.

Read more

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.

Read the 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.

Being tested
Endoscopic variceal ligation, Carvedilol
Keywords
Endoscopic variceal ligation, Hepatocellular carcinoma, Nonselective beta-blocker, Portal hypertension
Medical subject headings
Carcinoma, Hepatocellular, Esophageal and Gastric Varices, Hypertension, Portal

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Endoscopic variceal ligationProcedure or surgery

    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.

  • CarvedilolDrug

    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.

Study groups in NCT06594744
Study groupRoleWhat they receive
Endoscopic variceal ligationActive comparatorEVL 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.
Receives: Procedure: Endoscopic variceal ligation
CarvedilolPlacebo comparatorThe 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.
Receives: Drug: Carvedilol

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Esophageal variceal bleeding

    The cumulative incidence of esophageal variceal bleeding

    Measured: 3 years

Secondary outcomes (4)

  1. Other upper gastrointestinal bleeding

    The cumulative incidence of other upper gastrointestinal bleeding

    Measured: 3 years

  2. First/further nonbleeding liver decompensation

    Events that defined first/further nonbleeding liver decompensation were based on the Baveno VII consensus

    Measured: 3 years

  3. Overall survival

    Measured: 3 years

  4. Adverse events

    Measured: 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Sep 2024
  2. Study start1 Oct 2024
  3. Primary completionOct 2030 (estimated)
  4. Study completionOct 2030 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
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.
Masking
None (open label)
Enrolment
120 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06594744
Sponsor's protocol ID
2024-02-016B
Acronym
P-HCC-CVL
Status last verified
Feb 2025
First submitted
10 Sep 2024
Last updated
13 Feb 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Kaplan DE, Ripoll C, Thiele M, Fortune BE, Simonetto DA, Garcia-Tsao G, Bosch J. AASLD Practice Guidance on risk stratification and management of portal hypertension and varices in cirrhosis. Hepatology. 2024 May 1;79(5):1180-1211. doi: 10.1097/HEP.0000000000000647. Epub 2023 Oct 23. No abstract available.

    PubMed 37870298

  • Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19(3):329-38. doi: 10.1055/s-2007-1007122.

    PubMed 10518312

  • Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973 Aug;60(8):646-9. doi: 10.1002/bjs.1800600817. No abstract available.

    PubMed 4541913

  • Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology. 1992 Dec;16(6):1343-9. doi: 10.1002/hep.1840160607.

    PubMed 1446890

  • Beppu K, Inokuchi K, Koyanagi N, Nakayama S, Sakata H, Kitano S, Kobayashi M. Prediction of variceal hemorrhage by esophageal endoscopy. Gastrointest Endosc. 1981 Nov;27(4):213-8. doi: 10.1016/s0016-5107(81)73224-3.

    PubMed 6975734

  • Serper M, Kaplan DE, Taddei TH, Tapper EB, Cohen JB, Mahmud N. Nonselective beta blockers, hepatic decompensation, and mortality in cirrhosis: A national cohort study. Hepatology. 2023 Feb 1;77(2):489-500. doi: 10.1002/hep.32737. Epub 2022 Oct 17.

    PubMed 35984731

  • Kalambokis GN, Christaki M, Tsiakas I, Despotis G, Fillipas-Ntekouan S, Fotopoulos A, Tsiouris S, Xourgia X, Lakkas L, Pappas K, Michalis LK, Sergianiti F, Baltayiannis G, Christodoulou D, Koustousi C, Aggelis N, Milionis H. Conversion of Propranolol to Carvedilol Improves Renal Perfusion and Outcome in Patients With Cirrhosis and Ascites. J Clin Gastroenterol. 2021 Sep 1;55(8):721-729. doi: 10.1097/MCG.0000000000001431.

    PubMed 32991355

  • Totzeck M, Mincu RI, Rassaf T. Cardiovascular Adverse Events in Patients With Cancer Treated With Bevacizumab: A Meta-Analysis of More Than 20 000 Patients. J Am Heart Assoc. 2017 Aug 10;6(8):e006278. doi: 10.1161/JAHA.117.006278.

    PubMed 28862931

  • Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, Sukeepaisarnjaroen W, Kang YK, Van Dao T, De Toni EN, Rimassa L, Breder V, Vasilyev A, Heurgue A, Tam VC, Mody K, Thungappa SC, Ostapenko Y, Yau T, Azevedo S, Varela M, Cheng AL, Qin S, Galle PR, Ali S, Marcovitz M, Makowsky M, He P, Kurland JF, Negro A, Sangro B. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022 Aug;1(8):EVIDoa2100070. doi: 10.1056/EVIDoa2100070. Epub 2022 Jun 6.

    PubMed 38319892

  • Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Lim HY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Ma N, Nicholas A, Wang Y, Li L, Zhu AX, Finn RS. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022 Apr;76(4):862-873. doi: 10.1016/j.jhep.2021.11.030. Epub 2021 Dec 11.

    PubMed 34902530

  • Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745.

    PubMed 32402160

  • Allaire M, Thabut D. Portal hypertension and variceal bleeding in patients with liver cancer: Evidence gaps for prevention and management. Hepatology. 2024 Jan 1;79(1):213-223. doi: 10.1097/HEP.0000000000000291. Epub 2023 Jan 13.

    PubMed 36631021

  • Thabut D, Kudo M. Treatment of portal hypertension in patients with HCC in the era of Baveno VII. J Hepatol. 2023 Mar;78(3):658-662. doi: 10.1016/j.jhep.2022.11.019. Epub 2022 Nov 30.

    PubMed 36460163

  • Shah HA, Azam Z, Rauf J, Abid S, Hamid S, Jafri W, Khalid A, Ismail FW, Parkash O, Subhan A, Munir SM. Carvedilol vs. esophageal variceal band ligation in the primary prophylaxis of variceal hemorrhage: a multicentre randomized controlled trial. J Hepatol. 2014 Apr;60(4):757-64. doi: 10.1016/j.jhep.2013.11.019. Epub 2013 Nov 28.

    PubMed 24291366

  • Bhardwaj A, Kedarisetty CK, Vashishtha C, Bhadoria AS, Jindal A, Kumar G, Choudhary A, Shasthry SM, Maiwall R, Kumar M, Bhatia V, Sarin SK. Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: a randomised placebo-controlled trial. Gut. 2017 Oct;66(10):1838-1843. doi: 10.1136/gutjnl-2016-311735. Epub 2016 Jun 13.

    PubMed 27298379

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Endoscopic variceal ligation and Carvedilol in people with Hepatocellular Carcinoma (HCC) and Esophageal Varices, run by Taipei Veterans General Hospital, Taiwan at 1 site in Taiwan.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 13 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Tsung-Chieh Yang, MD (+886-2-28712121 ext. 7506, tcyang@vghtpe.gov.tw), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Esophageal variceal bleeding (time frame: 3 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06594744, which also lists 42 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Feb 2025.

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