Clinical trial NCT05786859: The Efficacy and Safety of Rifaximin Treatment
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Liver Failure, Acute on Chronic
Hepatic Encephalopathy
HBV
Hepatitis B
Rifaximin
Effect of Drug
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
First posted: 2023-03-28
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single center randomized controlled trial.
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: The reversal rate of hepatic encephalopathy between 2 groups in 4 weeks.
timeFrame: 4 weeks
Secondary outcomes:
measure: The incidence of complications related to liver failure within 12 weeks between 2 groups.
timeFrame: 12 weeks
measure: The survival rate between 2 groups within 12 weeks.
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: The Third Affiliated Hospital of Sun Yat-sen University
state: Guangdong
Study officials:
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