Endoscopic and Microbiological Assessment of the Effect of Carvedilol Combined With Berberine on GOV in Cirrhosis

Gastroesophageal Varices Clinical Trial

— CABER  

Official title:

Endoscopic and Microbiological Assessment of the Effect of Carvedilol Combined With Berberine on GOV in Cirrhosis: a Prospective Cohort Study

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04543643
• Other study ID #: Tianjin2PH
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: November 1, 2021
• Est. completion date: October 31, 2023

Study information

• Verified date: October 2021
• Source: Tianjin Second People's Hospital
• Contact: Han Ping, bachelor
• Phone: 13652139315
• Email: 13652139315[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Carvedilol has been shown to be more potent in decreasing portal hypertension to propranolol. A lot of studies have shown that the imbalance of flora and the progress of portal hypertension are mutually causal. Berberine can regulate the intestinal flora.In this study, we evaluated the effect of carvedilol and berberine on reducing portal vein pressure by observing the changes of endoscopy，endoscopic ultrasonography and intestinal flora.

Description:

There is a higher risk of esophageal and gastric varices bleeding in cirrhosis patients with moderate and severe esophageal and gastric varices. Once there is a high mortality rate of esophageal and gastric varices bleeding, it will cause great losses to the family and society. Therefore, it is of great social and economic significance to prevent esophageal and gastric varices bleeding through economic and effective methods. As the third generation of NSBB, carvedilol is more effective in reducing HVPG than propranolol, which is recommended by Baveno VI as the first-line drug for EVB primary prevention. A lot of studies have shown that the imbalance of flora and the progress of portal hypertension are mutually causal. The application of carvedilol can reduce the pressure of portal vein, and when the portal hypertension is improved, the imbalance of intestinal mucosal barrier and flora will also be changed. Berberine can regulate the intestinal flora, which is safe and effective in clinical application. Gastroscopy is still the main method of screening varicose veins. We can determine whether there is GOV in patients and evaluate the risk of varicose vein bleeding. However, gastroscopy can only observe the situation in the digestive tract lumen, and ultrasound endoscopy can scan the outside of the tube wall, so as to more comprehensively evaluate the change of portal hypertension. The purpose of this study is to apply endoscopic ultrasonography to the whole process of the study, which can be used as a more sensitive means to observe the changes of portal hypertension, and to systematically evaluate the continuous changes of portal hypertension. It provides a theoretical basis and measurement means for a more comprehensive and scientific evaluation of portal hypertension.In this study, the patients with GOV who need primary prevention were randomly divided into two groups. Carvedilol or carvedilol combined with berberine were given for 12 months respectively. The degree of varicose vein relief was judged by ES and EUS, and the changes of oral and intestinal flora were detected at the same time To understand the possible mechanism of carvedilol and berberine in reducing portal hypertension.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 288
• Est. completion date: October 31, 2023
• Est. primary completion date: October 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• HBV-related or/and HCV-related liver cirrhotic patients based on pathology or clinical diagnosis;

• Antiviral therapy;

• Male or Female;

• ES showed the presence of esophageal and gastric varices and / or red signs;

• Child-Pugh < 10, and meld < 29;

• Signature of informed consent.

Exclusion Criteria:

• • Used antibiotics, prebiotics, probiotics and proton pump inhibitors within 2 weeks;

• Any contra-indications to beta-blockers including asthma, chronic obstructive pulmonary disease, allergic rhinitis, NYHA (New York Heart Association) class IV heart failure, atrioventricular block, sinus bradycardia (HR < 50 / min), cardiogenic shock, hypotension (SBP < 85mmHg), sick sinus syndrome, insulin dependent diabetes, peripheral vascular disease;

• Unstable high blood pressure and long-term engagement in driving;

• Any malignancy that affects survival, excluding the cured;

• Patients with portal thrombosis;

• PT extension greater than 4 seconds, PLT<30×10^9/L;

• Pregnant and lactating patients;

• History of surgery for portal hypertension;History of prior EVL (endoscopic variceal ligation) or sclerotherapy, history of surgery for portal hypertension including portosystemic shunts, disconnection and spleen resection and transjugular intrahepatic portosystemic shunt;

• Patients with severe diseases of vital organs such as heart, lung, kidney, brain, blood and nervous system;

• Allergic to carvedilol and berberine;

• Severe systemic diseases;

• hemolytic anemia and lack of glucose - 6 - phosphate dehydrogenase patients

• Refusal to participate in the study.

Related Conditions & MeSH terms

• Cirrhosis Due to Hepatitis B
• Cirrhosis Due to Hepatitis C
• Fibrosis
• Gastroesophageal Varices
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis C
• Liver Cirrhosis

Intervention

Drug:
• Carvedilol
As the third generation of NSBB, carvedilol is more effective in reducing HVPG than propranolol, which is recommended by Baveno VI as the first-line drug for EVB primary prevention.
• Berberine
Berberine can regulate the intestinal flora, which is safe and effective in clinical application.

Locations

Country	Name	City	State
China	Tianjin Second People's Hospital	Tianjin	Tianjin

Sponsors (1)

Lead Sponsor	Collaborator
Tianjin Second People's Hospital

Country where clinical trial is conducted

China, 

References & Publications (41)

Abadía M, Montes ML, Ponce D, Froilán C, Romero M, Poza J, Hernández T, Fernández-Martos R, Olveira A; "La Paz Portal Hypertension" Study Group Investigators. Management of betablocked patients after sustained virological response in hepatitis C cirrhosis — View Citation

Aberg F, Helenius-Hietala J, Meurman J, Isoniemi H. Association between dental infections and the clinical course of chronic liver disease. Hepatol Res. 2014 Mar;44(3):349-53. doi: 10.1111/hepr.12126. Epub 2013 Apr 29. — View Citation

Adamberg K, Tomson K, Talve T, Pudova K, Puurand M, Visnapuu T, Alamäe T, Adamberg S. Levan Enhances Associated Growth of Bacteroides, Escherichia, Streptococcus and Faecalibacterium in Fecal Microbiota. PLoS One. 2015 Dec 2;10(12):e0144042. doi: 10.1371/ — View Citation

Arvaniti V, D'Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M, Burroughs AK. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology. 2010 Oct;139(4):1246-56, 1256.e1-5. doi — View Citation

Bajaj JS, Betrapally NS, Hylemon PB, Heuman DM, Daita K, White MB, Unser A, Thacker LR, Sanyal AJ, Kang DJ, Sikaroodi M, Gillevet PM. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology. 2015 Oct;62( — View Citation

Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol. 2015 Nov;63(5):1272-84. doi: 10.1016/j.jhep.2015.07.004 — View Citation

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-con — View Citation

Borzio M, Salerno F, Piantoni L, Cazzaniga M, Angeli P, Bissoli F, Boccia S, Colloredo-Mels G, Corigliano P, Fornaciari G, Marenco G, Pistarà R, Salvagnini M, Sangiovanni A. Bacterial infection in patients with advanced cirrhosis: a multicentre prospectiv — View Citation

Carbonell N, Pauwels A, Serfaty L, Fourdan O, Lévy VG, Poupon R. Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology. 2004 Sep;40(3):652-9. — View Citation

Chen YX, Gao QY, Zou TH, Wang BM, Liu SD, Sheng JQ, Ren JL, Zou XP, Liu ZJ, Song YY, Xiao B, Sun XM, Dou XT, Cao HL, Yang XN, Li N, Kang Q, Zhu W, Xu HZ, Chen HM, Cao XC, Fang JY. Berberine versus placebo for the prevention of recurrence of colorectal ade — View Citation

de Franchis R; Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015 Sep;63(3):743-52. doi: 10.1016/j.jhep.2015.05.022. — View Citation

Ding Q, Tian XG, Li Y, Wang QZ, Zhang CQ. Carvedilol may attenuate liver cirrhosis by inhibiting angiogenesis through the VEGF-Src-ERK signaling pathway. World J Gastroenterol. 2015 Aug 28;21(32):9566-76. doi: 10.3748/wjg.v21.i32.9566. — View Citation

European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol. 2018 Aug;69(2):461-511. doi: 10.1016/j.jhep.2 — View Citation

Feng R, Shou JW, Zhao ZX, He CY, Ma C, Huang M, Fu J, Tan XS, Li XY, Wen BY, Chen X, Yang XY, Ren G, Lin Y, Chen Y, You XF, Wang Y, Jiang JD. Transforming berberine into its intestine-absorbable form by the gut microbiota. Sci Rep. 2015 Jul 15;5:12155. do — View Citation

García-Lezana T, Raurell I, Bravo M, Torres-Arauz M, Salcedo MT, Santiago A, Schoenenberger A, Manichanh C, Genescà J, Martell M, Augustin S. Restoration of a healthy intestinal microbiota normalizes portal hypertension in a rat model of nonalcoholic stea — View Citation

García-Tsao G. Bacterial translocation: cause or consequence of decompensation in cirrhosis? J Hepatol. 2001 Jan;34(1):150-5. — View Citation

Goulis J, Armonis A, Patch D, Sabin C, Greenslade L, Burroughs AK. Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage. Hepatology. 1998 May;27(5):1207-12. — View Citation

Gupta N, Kumar A, Sharma P, Garg V, Sharma BC, Sarin SK. Effects of the adjunctive probiotic VSL#3 on portal haemodynamics in patients with cirrhosis and large varices: a randomized trial. Liver Int. 2013 Sep;33(8):1148-57. doi: 10.1111/liv.12172. Epub 20 — View Citation

Hammoud GM, Ibdah JA. Utility of endoscopic ultrasound in patients with portal hypertension. World J Gastroenterol. 2014 Oct 21;20(39):14230-6. doi: 10.3748/wjg.v20.i39.14230. Review. — View Citation

Hashizume M, Kitano S, Sugimachi K, Sueishi K. Three-dimensional view of the vascular structure of the lower esophagus in clinical portal hypertension. Hepatology. 1988 Nov-Dec;8(6):1482-7. — View Citation

Hoyles L, Fernández-Real JM, Federici M, Serino M, Abbott J, Charpentier J, Heymes C, Luque JL, Anthony E, Barton RH, Chilloux J, Myridakis A, Martinez-Gili L, Moreno-Navarrete JM, Benhamed F, Azalbert V, Blasco-Baque V, Puig J, Xifra G, Ricart W, Tomlins — View Citation

Huang JY, Samarasena JB, Tsujino T, Chang KJ. EUS-guided portal pressure gradient measurement with a novel 25-gauge needle device versus standard transjugular approach: a comparison animal study. Gastrointest Endosc. 2016 Aug;84(2):358-62. doi: 10.1016/j. — View Citation

Kakiyama G, Pandak WM, Gillevet PM, Hylemon PB, Heuman DM, Daita K, Takei H, Muto A, Nittono H, Ridlon JM, White MB, Noble NA, Monteith P, Fuchs M, Thacker LR, Sikaroodi M, Bajaj JS. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis — View Citation

Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K, Bäckhed HK, Gonzalez A, Werner JJ, Angenent LT, Knight R, Bäckhed F, Isolauri E, Salminen S, Ley RE. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell. 2012 Aug 3;150 — View Citation

Mandorfer M, Peck-Radosavljevic M, Reiberger T. Prevention of progression from small to large varices: are we there yet? An updated meta-analysis. Gut. 2017 Jul;66(7):1347-1349. doi: 10.1136/gutjnl-2016-312814. Epub 2016 Sep 30. — View Citation

Moghadamrad S, McCoy KD, Geuking MB, Sägesser H, Kirundi J, Macpherson AJ, De Gottardi A. Attenuated portal hypertension in germ-free mice: Function of bacterial flora on the development of mesenteric lymphatic and blood vessels. Hepatology. 2015 May;61(5 — View Citation

North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med. 1988 Oct 13;319(15) — View Citation

Pascual S, Such J, Esteban A, Zapater P, Casellas JA, Aparicio JR, Girona E, Gutiérrez A, Carnices F, Palazón JM, Sola-Vera J, Pérez-Mateo M. Intestinal permeability is increased in patients with advanced cirrhosis. Hepatogastroenterology. 2003 Sep-Oct;50 — View Citation

Reiberger T, Ferlitsch A, Payer BA, Mandorfer M, Heinisch BB, Hayden H, Lammert F, Trauner M, Peck-Radosavljevic M, Vogelsang H; Vienna Hepatic Hemodynamic Lab. Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP an — View Citation

Reiberger T, Ulbrich G, Ferlitsch A, Payer BA, Schwabl P, Pinter M, Heinisch BB, Trauner M, Kramer L, Peck-Radosavljevic M; Vienna Hepatic Hemodynamic Lab. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non — View Citation

Schwarzer R, Kivaranovic D, Paternostro R, Mandorfer M, Reiberger T, Trauner M, Peck-Radosavljevic M, Ferlitsch A. Carvedilol for reducing portal pressure in primary prophylaxis of variceal bleeding: a dose-response study. Aliment Pharmacol Ther. 2018 Apr — View Citation

Seo YS, Shah VH. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension. Clin Mol Hepatol. 2012 Dec;18(4):337-46. doi: 10.3350/cmh.2012.18.4.337. Epub 2012 Dec 21. Review. — View Citation

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 — View Citation

Sharma M, Singh S, Desai V, Shah VH, Kamath PS, Murad MH, Simonetto DA. Comparison of Therapies for Primary Prevention of Esophageal Variceal Bleeding: A Systematic Review and Network Meta-analysis. Hepatology. 2019 Apr;69(4):1657-1675. doi: 10.1002/hep.3 — View Citation

Silva Santos PS, Fernandes KS, Gallottini MH. Assessment and management of oral health in liver transplant candidates. J Appl Oral Sci. 2012 Mar-Apr;20(2):241-5. — View Citation

Szabo G. Gut-liver axis in alcoholic liver disease. Gastroenterology. 2015 Jan;148(1):30-6. doi: 10.1053/j.gastro.2014.10.042. Epub 2014 Nov 11. Review. — View Citation

Thalheimer U, Triantos CK, Samonakis DN, Patch D, Burroughs AK. Infection, coagulation, and variceal bleeding in cirrhosis. Gut. 2005 Apr;54(4):556-63. Review. — View Citation

Tripathi D, Ferguson JW, Kochar N, Leithead JA, Therapondos G, McAvoy NC, Stanley AJ, Forrest EH, Hislop WS, Mills PR, Hayes PC. Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed. Hepato — View Citation

Wang X, Lin SX, Tao J, Wei XQ, Liu YT, Chen YM, Wu B. Study of liver cirrhosis over ten consecutive years in Southern China. World J Gastroenterol. 2014 Oct 7;20(37):13546-55. doi: 10.3748/wjg.v20.i37.13546. — View Citation

Wang Y, Shou JW, Li XY, Zhao ZX, Fu J, He CY, Feng R, Ma C, Wen BY, Guo F, Yang XY, Han YX, Wang LL, Tong Q, You XF, Lin Y, Kong WJ, Si SY, Jiang JD. Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism. Metabolism. 2017 — View Citation

Yao J, Chang L, Yuan L, Duan Z. Nutrition status and small intestinal bacterial overgrowth in patients with virus-related cirrhosis. Asia Pac J Clin Nutr. 2016;25(2):283-91. doi: 10.6133/apjcn.2016.25.2.06. — View Citation

* Note: There are 41 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The progression Incidence of esophageal varices	progression of esophagogastric varices under gastroscopy and/or endoscopic ultrasound	1 year
Secondary	The incidence of liver cirrhosis decompensation	the occurrence of decompensating events in cirrhosis (decompensating is defined as gastrointestinal bleeding, ascites, or significant hepatic encephalopathy, hepatorenal syndrome, associated with portal hypertension)	1 year
Secondary	HCC, death or liver transplantation	The incidence of hepatic cellular carcinoma, death or liver transplantation	1 year