The Efficacy and Safety of Rifaximin Treatment

Hepatitis B Clinical Trial

Official title:

The Efficacy and Safety of Rifaximin In The Treatment of HBV Associated Acute-on-Chronic Liver Failure Patients With Mild to Moderate Hepatic Encephalopathy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05786859
• Other study ID #: Efficacy of Rifaximin
• Status: Recruiting
• Phase: Early Phase 1
• Start date: March 9, 2023
• Est. completion date: October 31, 2025

Study information

• Verified date: March 2023
• Source: Sun Yat-sen University
• Contact: Liang Bing Lin, MD
• Phone: 13924129928
• Email: lamikin[@]126.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

There will be 124 patients diagnosed as hepatitis B associated acute on chronic liver failure with mild to moderate hepatic encephalopathy will be enrolled in this study according to the inclusion and exclusion criteria, and will be randomly divided into two groups as 1:1.First group is called Rifaximin group, on the basis of comprehensive treatment of liver failure, Rifaximin (Alfa Sigma S.p.A) is added, three times a day, 400 mg each time, for a total of 4 weeks, and observed until 12 weeks after withdrawal. The other group is called standard treatment group (control group), which will receive routine comprehensive treatment for liver failure. The reversal of mild to moderate hepatic encephalopathy in the two groups of patients will be observed within 4 weeks, then follow up to 12 weeks.

Description:

Liver failure is a common clinical syndrome of severe liver disease, with a high mortality rate. On the basis of chronic liver disease, acute on chronic liver failure is a syndrome characterized by acute jaundice deepening and coagulation dysfunction caused by various inducements, which can be combined with hepatic encephalopathy, ascites, electrolyte disorder, infection, hepatorenal syndrome, hepatopulmonary syndrome and other complications, as well as extrahepatic organ failure. At present, the medical treatment of acute on chronic liver failure is still lacks of efficient drugs and means. On the other hand, the mortality rate of liver transplantation can be as high as 50-70%. The occurrence of bacterial infection, hepatic encephalopathy, hepatorenal syndrome and other complications is significantly related to the high mortality of acute on chronic liver failure. Common causes of liver failure include hepatitis virus, drugs or hepatotoxic substances, autoimmune diseases, etc. In China, hepatitis B virus infection is the main cause of acute on chronic liver failure.

Previous studies have confirmed that intestinal flora imbalance and translocation are important reasons for decompensated cirrhosis complicated with primary bacterial peritonitis. Gram-positive bacteria (including enterococcus, staphylococcus, etc.) and multidrug resistant bacteria have become common pathogenic bacteria of spontaneous bacterial peritonitis. A randomized controlled clinical study on spontaneous bacterial peritonitis in Europe shows that gram-positive bacteria account for 62.5% of bacteria isolated from ascites, enterococcus accounted for the majority. The intestinal flora imbalance and translocation are also important inducements of decompensated cirrhosis complicated with hepatic encephalopathy and hepatorenal syndrome. Patients with acute on chronic liver failure also have intestinal flora imbalance. Recent research shows that the proportion of enterococci in hepatitis B associated acute on chronic liver failure is significantly increased, and during the progress of hepatitis B associated acute on chronic liver failure, enterococcus faecium rapidly increases, which is related to poor prognosis. Due to the severe inflammatory reaction, patients with acute on chronic liver failure are prone to intestinal barrier function defects. Therefore, intestinal flora imbalance and translocation are closely related to the complications of acute on chronic liver failure complicated by bacterial infection and hepatic encephalopathy.

Rifaximin- α (referred to as Rifaximin) is a drug that is not easy to be absorbed and only works locally in the gastrointestinal tract. The concentration in the intestinal tract is much higher than MIC90 of the intestinal flora. It has broad-spectrum antibacterial activity, can cover gram-positive and gram-negative bacteria, and is not conducive to the screening of drug-resistant strains. The efficacy and safety of Rifaximin in the prevention and treatment of hepatic encephalopathy in patients with decompensated cirrhosis have been confirmed by many large randomized controlled clinical trials worldwide, and it is the only drug approved by FDA in the United States for the treatment and prevention of hepatic encephalopathy in the past 30 years. Over the past 10 years, experimental and clinical evidence has shown that Rifaximin may have other beneficial effects on the course of liver cirrhosis by regulating intestinal microflora and affecting the gut-liver axis. Rifaximin has been reported for the prevention of other complications of cirrhosis, including spontaneous bacterial peritonitis, hepatorenal syndrome, reduction of portal pressure, prevention of bleeding from esophageal varices, and treatment of refractory ascites in cirrhosis.

In the drug information about Rifaximin released by the FDA of the United States, it was mentioned that patients with severe liver damage (Child-Pugh C) should be cautious in use, because in the clinical experiment of using rifaximin to prevent and treat hepatic encephalopathy, it was found that rifaximin 550 mg/time, twice a day, for patients with Child-Pugh score A, B and C, the amount of drugs entering the systemic circulation was 10 times higher than that of the healthy control group (12.3 ± 4.8 ng • h/mL), 14 times and 21 times (257 ± 100.2 ng • h/mL).Therefore, most previous clinical trials only included patients with MELD score less than 25. Although the systemic exposure of patients with severe liver damage was higher than that of the healthy control group, due to the low total exposure, the side effects of Rifaximin were rare in the clinical study of decompensated cirrhosis, and the incidence of adverse events was similar to that of the control group. Because Rifaximin mainly takes effect locally in the intestine, the systemic bioavailability is low, and the safety data of Rifaximin in patients with liver cirrhosis, FDA does not recommend adjusting the dose for patients with severe liver damage, and the drug instructions also indicate that dose adjustment is not necessary for patients with liver insufficiency.

A recently published multicenter exploratory study suggested that the use of rifaximin in patients with severe alcoholic hepatitis (MELD score 19-24) was safe, and compared with the control group, the use of Rifaximin could reduce the incidence of infection and the incidence of infection-related acute on chronic liver failure after the use of glucocorticoids in severe alcoholic hepatitis. However, the safety and efficacy of Rifaximin in patients with hepatitis B (HBV) associated acute on chronic liver failure have not been reported. Our study plans to evaluate the safety and effectiveness of Rifaximin in the treatment of hepatitis B(HBV) associated acute on chronic liver failure complicated with mild to moderate hepatic encephalopathy through a randomized controlled study.

There will be 124 patients diagnosed as hepatitis B associated acute on chronic liver failure with mild to moderate hepatic encephalopathy will be enrolled in this study according to the inclusion and exclusion criteria, and will be randomly divided into two groups as 1:1.First group is called Rifaximin group, on the basis of comprehensive treatment of liver failure, Rifaximin (Alfa Sigma S.p.A) is added, three times a day, 400 mg each time, for a total of 4 weeks, and observed until 12 weeks after withdrawal. The other group is called standard treatment group (control group), which will receive routine comprehensive treatment for liver failure. The reversal of mild to moderate hepatic encephalopathy in the two groups of patients will be observed and recorded within 4 weeks, then follow up to 12 weeks. The occurrence of various complications related to liver failure and survival situation will be recorded within 12 weeks, during this time, serum of the two groups of patients will be collected, and the changes of biochemical and coagulation indicators and the changes of serum bacterial translocation-related markers will be recorded. The feces of patients before and after treatment will be collected for intestinal microecological analysis.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 124
• Est. completion date: October 31, 2025
• Est. primary completion date: July 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

1. Inclusion Criteria:

• The confirmed HBsAg positive patients with chronic hepatitis B are defined as HBsAg positive for at least 6 months or evidence of chronic HBV infection;

• Acute onset, progressive deepening of jaundice, serum total bilirubin (TB) = 85umol/L and severe coagulation dysfunction, international standardized ratio (INR) = 1.5 or plasma prothrombin activity (PTA)<40%

• The score of the psychological test scale of hepatic encephalopathy is less than
• 4 points or mild to moderate (degree I or II) manifestations of hepatic encephalopathy, including the decline of computational ability, timing and orientation, personality change, lethargy, and positive flapping wing tremor.

• Be able and willing to provide informed consent and comply with the test requirements.

2. Exclusion Criteria:

• There are definite infections or hepatorenal syndromes during screening;

• Upper gastrointestinal bleeding occurred within 1 week before screening;

• Have used sedative drugs such as "benzodiazepines" or other psychotropic drugs within one week before screening;

• Those with severe primary heart, lung, kidney and other important organ dysfunction affecting life expectancy;

• HIV infection;

• Uncontrolled malignant tumor, nerve and mental abnormality;

• Patients who are allergic to the study drugs and excipients;

• Pregnant or lactating women;

• In the late stage of liver failure, MELD score>35;

• Other circumstances in which the researcher believes that the patient should not participate in this study.

Related Conditions & MeSH terms

• Acute-On-Chronic Liver Failure
• Brain Diseases
• Effect of Drug
• HBV
• Hepatic Encephalopathy
• Hepatic Insufficiency
• Hepatitis B
• Liver Failure
• Liver Failure, Acute
• Liver Failure, Acute on Chronic
• Rifaximin

Intervention

Drug:
• Rifaximin 200 mg
Rifaximin Treatment Group:on the basis of comprehensive treatment of liver failure, Rifaximin will be added, three times a day, 400mg each time, for a total of 4 weeks, and we will observe until 12 weeks after withdrawal.

Other:
• Standard Treatment without Rifaximin
The standard treatment group (control group), which will receive routine comprehensive treatment for liver failure without Rifaximin.

Locations

Country	Name	City	State
China	The Third Affiliated Hospital of Sun Yat-sen University	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Sun Yat-sen University

Country where clinical trial is conducted

China, 

References & Publications (17)

Bajaj JS, Khoruts A. Microbiota changes and intestinal microbiota transplantation in liver diseases and cirrhosis. J Hepatol. 2020 May;72(5):1003-1027. doi: 10.1016/j.jhep.2020.01.017. Epub 2020 Jan 28. — View Citation

Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, Sigal S, Sheikh MY, Beavers K, Frederick T, Teperman L, Hillebrand D, Huang S, Merchant K, Shaw A, Bortey E, Forbes WP. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010 Mar 25;362 — View Citation

Caraceni P, Vargas V, Sola E, Alessandria C, de Wit K, Trebicka J, Angeli P, Mookerjee RP, Durand F, Pose E, Krag A, Bajaj JS, Beuers U, Gines P; Liverhope Consortium. The Use of Rifaximin in Patients With Cirrhosis. Hepatology. 2021 Sep;74(3):1660-1673. — View Citation

Dever JB, Sheikh MY. Review article: spontaneous bacterial peritonitis--bacteriology, diagnosis, treatment, risk factors and prevention. Aliment Pharmacol Ther. 2015 Jun;41(11):1116-31. doi: 10.1111/apt.13172. Epub 2015 Mar 26. — View Citation

Elfert A, Abo Ali L, Soliman S, Ibrahim S, Abd-Elsalam S. Randomized-controlled trial of rifaximin versus norfloxacin for secondary prophylaxis of spontaneous bacterial peritonitis. Eur J Gastroenterol Hepatol. 2016 Dec;28(12):1450-1454. doi: 10.1097/MEG. — View Citation

Goel A, Rahim U, Nguyen LH, Stave C, Nguyen MH. Systematic review with meta-analysis: rifaximin for the prophylaxis of spontaneous bacterial peritonitis. Aliment Pharmacol Ther. 2017 Dec;46(11-12):1029-1036. doi: 10.1111/apt.14361. Epub 2017 Oct 9. — View Citation

Ibrahim ES, Alsebaey A, Zaghla H, Moawad Abdelmageed S, Gameel K, Abdelsameea E. Long-term rifaximin therapy as a primary prevention of hepatorenal syndrome. Eur J Gastroenterol Hepatol. 2017 Nov;29(11):1247-1250. doi: 10.1097/MEG.0000000000000967. — View Citation

Jiang ZD, Ke S, Palazzini E, Riopel L, Dupont H. In vitro activity and fecal concentration of rifaximin after oral administration. Antimicrob Agents Chemother. 2000 Aug;44(8):2205-6. doi: 10.1128/AAC.44.8.2205-2206.2000. — View Citation

Jimenez C, Ventura-Cots M, Sala M, Calafat M, Garcia-Retortillo M, Cirera I, Canete N, Soriano G, Poca M, Simon-Talero M, Altamirano J, Lucey M, Garcia-Tsao G, Brown RS Jr, Schwabe RF, Verna EC, Schnabl B, Bosques-Padilla F, Mathurin P, Caballeria J, Louv — View Citation

Lv XY, Ding HG, Zheng JF, Fan CL, Li L. Rifaximin improves survival in cirrhotic patients with refractory ascites: A real-world study. World J Gastroenterol. 2020 Jan 14;26(2):199-218. doi: 10.3748/wjg.v26.i2.199. — View Citation

Piano S, Fasolato S, Salinas F, Romano A, Tonon M, Morando F, Cavallin M, Gola E, Sticca A, Loregian A, Palu G, Zanus G, Senzolo M, Burra P, Cillo U, Angeli P. The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: Results of — View Citation

Sarin SK, Choudhury A, Sharma MK, Maiwall R, Al Mahtab M, Rahman S, Saigal S, Saraf N, Soin AS, Devarbhavi H, Kim DJ, Dhiman RK, Duseja A, Taneja S, Eapen CE, Goel A, Ning Q, Chen T, Ma K, Duan Z, Yu C, Treeprasertsuk S, Hamid SS, Butt AS, Jafri W, Shukla — View Citation

Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK. Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME Trial). Am J Gastroenterol. 2011 Feb;106(2):307-16. doi: 10. — View Citation

Wang K, Zhang Z, Mo ZS, Yang XH, Lin BL, Peng L, Xu Y, Lei CY, Zhuang XD, Lu L, Yang RF, Chen T, Gao ZL. Gut microbiota as prognosis markers for patients with HBV-related acute-on-chronic liver failure. Gut Microbes. 2021 Jan-Dec;13(1):1-15. doi: 10.1080/ — View Citation

Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol. 2014 Jan;60(1):197-209. doi: 10.1016/j.jhep.2013.07.044. Epub 2013 Aug 28. No abstract available. — View Citation

Wong F, Piano S, Singh V, Bartoletti M, Maiwall R, Alessandria C, Fernandez J, Soares EC, Kim DJ, Kim SE, Marino M, Vorobioff J, Barea RCR, Merli M, Elkrief L, Vargas V, Krag A, Singh SP, Lesmana LA, Toledo C, Marciano S, Verhelst X, Intagliata N, Rabinow — View Citation

Zeng X, Sheng X, Wang PQ, Xin HG, Guo YB, Lin Y, Zhong JW, He CZ, Yin J, Liu TT, Ma WJ, Xiao X, Shi PM, Yuan ZL, Yang L, Ma X, Xu JM, Shen XZ, Yang CQ, Zhu X, Lv NH, Xie WF. Low-dose rifaximin prevents complications and improves survival in patients with — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The reversal rate of hepatic encephalopathy between 2 groups in 4 weeks.	The reversal rate of hepatic encephalopathy in the 2 groups within 4 weeks will be recorded.	4 weeks
Secondary	The incidence of complications related to liver failure within 12 weeks between 2 groups.	The incidence of complications related to liver failure will be recorded in the 2 groups during 12 weeks.	12 weeks
Secondary	The survival rate between 2 groups within 12 weeks.	The survival rate will be observed in the two groups within 12 weeks.	12 weeks

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