Rifaximin and Propranolol Combination Therapy Versus Propranolol Monotherapy in Cirrhotic Patients

Study Overview
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Brief Summary
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To reduce portal pressure, the only recommended medication is nonselective beta blocker(NSBB). However, NSBB has some limitation to apply clinically because of poor response rate and compliance. Recent literature has supported the role of bacterial translocation as a mediator of splanchnic vasodilatation and portal hypertension. This stimulates the release of pro-inflammatory cytokines and the activation of the vasodilator NO resulting in a more pronounced deterioration of the baseline hyperdynamic circulatory state. Selective gut decontamination with Rifaximin can induce inhibition of bacterial translocation and associated worsening of portal hypertension. The investigators hypothesized that Rifaximin plus NSBB could result in decrease of portal pressure in cirrhotic patients with esophageal varices.

Official Title
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Hemodynamic Response of Rifaximin and Non-selective β-blocker Combination Therapy Versus Non-selective β-blocker Monotherapy in Cirrhotic Patients With Esophageal Varices

Conditions
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Liver Cirrhosis, Portal Hypertension

Intervention / Treatment
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* Drug: Rifaximin + propranolol
* Drug: Propranolol + Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Liver cirrhosis:diagnosed based on histology or unequivocal clinical, sonographic, and laboratory findings 19≤age≤75 Hepatic venous pressure gradient > 12 mmHg Informed consent Exclusion Criteria: Shock status requiring vasopressor Active infection, for example Spontaneous bacterial peritonitis Acute renal failure patients of any cause Clinically relevant coronary artery disease(NYHA functional angina classification III/IV),congestive heart failure NYHA III/IV), clinically relevant cardiomyopathy, history of myocardial infarction in the past 12 months Poorly controlled hypertension (BP 150/100mmHg) Hepatocellular carcinoma History of another primary malignancy ≤ 3years Medical or psychological conditions that would not permit the subject to complete thte study or sign informed consent Pregnancy or lactation period Serum creatinine ≧ 6mg/dL Involvement in the conduct of other study within 30 days Known hypersensitivity to Rifaximin or propranolol Dysarrhythmia, inappropriate for study on investigator's judgment

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination therapy<br>Rifaximin(normix®)+nonselective beta-blocker(Propranolol) | Drug: Rifaximin + propranolol<br>* Rifaximin : taking 400mg three times a day in the study period (total 1,200 mg per day) Propranolol : taking 40mg twice a day to start. If patient is tolerable and systolic blood pressure is above 90 mmHg, the dosage can be increased by doubling to every other day upto the 360mg per day. (Target heart rate : 25% reduction in baseline heart rate or at least 55 times per minute). If patient is not tolerable, we can reduce the dosage step-by-step until the adverse symptoms is disappeared.<br>* Other names: Propranolol;|
| Placebo Comparator: Monotherapy<br>nonselective beta-blocker(Propranolol) + Placebo(of Rifaximin) | Drug: Propranolol + Placebo<br>* Placebo of Rifaximin : taking 400mg three times a day in the study period (total 1,200 mg per day) Propranolol : taking 40mg twice a day to start. If patient is tolerable and systolic blood pressure is above 90 mmHg, the dosage can be increased by doubling to every other day upto the 360mg per day. (Target heart rate : 25% reduction in baseline heart rate or at least 55 times per minute). If patient is not tolerable, we can reduce the dosage step-by-step until the adverse symptoms is disappeared.<br>* Other names: Placebo of Rifaximin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic vein pressure gradient(HVPG) | After measurement of baseline HVPG, patients will be randomized to treatment group of Rifaximin + Propranolol or Propranolol + Placebo. And 6 weeks after treatment, follow-up measurement of HVPG will be performed to evaluate efficacy of two regimens | Change from baseline heptic vein pressure gradient at 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| occurence of gastrointestinal bleeding | when gastrointestinal bleeding occurs, after initiation of treatment, endoscopy will be performed to evaluate status of bleeding | upto 6 months after initiation of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver cirrhosis, Portal hypertension, Hepatic Venous Pressure Gradient, Rifaximin