Probiotics and Hemodynamic Changes in Cirrhosis

Study Overview
=================
Brief Summary
-----------------
This is a single-center blinded randomized interventional placebo-controlled study of the effect of probiotics on hemodynamic parameters and liver function in cirrhosis.

Detailed Description
-----------------
Forty patients with Child-Pugh class B and C cirrhosis will be randomized in a 1.5:1 ratio to test and control arms. Patients in the test arm will receive probiotic Saccharomyces boulardii (A07FA02 - Saccharomyces (Enterol) Biocodex Ltd, France, registration number LP-000622 from 21.09.2011) for 3 months, patients in the control arm will receive placebo for 3 months. All patients also will receive standard treatment: spironolactone 100 mg/day in ascites and carvedilol 12.5 mg/day in esophageal varices. The patients will be blinded. At inclusion and after 3 months after starting of probiotic/placebo treatment, systemic hemodynamics parameters (cardiac output and systemic vascular resistance), liver function (serum albumin and total bilirubin level, international normalized ratio, presence and degree of ascites or hepatic encephalopathy), the gut microbiome, biomarkers of bacterial translocation (presepsin, lipopolysaccharide), intestinal permeability (claudin 3), systemic inflammation (tumor necrosis factor alpha ) and endothelial dysfunction (nitrites, endothelin) will be assessed. After the end of the study, an interim analysis of the effect of the probiotic on aforementioned systemic hemodynamics and liver function indicators will be carried out. If there is a positive effect, a full analysis of all the aforementioned factors contributing to its development will be performed.

Official Title
-----------------
The Effect of Probiotics on Hemodynamic Changes and Complications of Cirrhosis

Conditions
-----------------
Cirrhosis

Intervention / Treatment
-----------------
* Drug: Saccharomyces Boulardii Probiotic Supplement
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Cirrhosis Child-Pugh class B or C; Age between 18 and 70 years; Signed informed consent. Exclusion Criteria: Use of lactulose, lactitol, or other prebiotics, probiotics, antibiotics, or metformin in the past 6 weeks before inclusion; Alcohol consumption in the past 6 weeks before inclusion; Inflammatory bowel disease; Cancer; Prematurely discontinuation of the consumption of tested probiotic/placebo; Started taking antibiotics, other probiotics, or prebiotics during the follow-up period; Refusal to participate during the follow-up period.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiotics<br>Patients in the Test arm will receive Saccharomyces boulardii (Saccharomyces), (Enterol), Biocodex Ltd, France, registration number LP-000622 from 21.09.2011 at a dose of 250 mg 2 times a day for 3 months. | Drug: Saccharomyces Boulardii Probiotic Supplement<br>* Probiotic yeast<br>* Other names: Enterol;|
| Placebo Comparator: Placebo<br>Patients in the Placebo arm will receive the placebo at a dose of 250 mg 2 times a day for 3 months. | Drug: Placebo<br>* Placebo<br>* Other names: No other name;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the change in cardiac output | Transthoracic echocardiography (with Acuson S2000 by Siemens Ltd, USA, registration number 2017/6109 from 24.07.2018) according to the guidelines of the American Society of Echocardiography (published in 2015) with a simultaneous assessment of blood pressure (with semi-automatic tonometer UA-604 by AND Ltd, Japan, registration number 2011/09642 from 10.10.2018) and heart rate will be performed to assess systemic hemodynamics. Cardiac output will be calculated as (stroke volume) × (heart rate). | at inclusion and 3 months after the start of the study | 
| the change in number of points on the Child-Pugh scale | The scale assesses the degree of hyperbilirubinemia (1 point - serum total bilirubin level is less than 2 mg / dl, 2 points - 2-3 mg / dl, 3 points - above 3 mg / dl), hypoalbuminemia (1 point - serum albumin level above 35 g / l, 2 points - 28-35 g / l, 3 points - less than 28 g / l), hypocoagulation (1 point - international normalized ratio less than 1.7, 2 points - 1.7-2.3, 3 points - above 2.3) degree of ascites (1 points - no ascites, 2 points - ascites detected only with ultrasound, 3 points - large ascites visible to the eyes) of hepatic encephalopathy (1 point - no hepatic encephalopathy; 2 points - hepatic encephalopathy without severe manifestations (stupor or coma); 3 points - severe hepatic encephalopathy (stupor or coma)). | at inclusion and 3 months after the start of the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the change in the serum albumin level | venous blood will be take on an empty stomach at 7-9 am without any special preparation | at inclusion and 3 months after the start of the study | 
| the change in the serum total bilirubin level | venous blood will be take on an empty stomach at 7-9 am without any special preparation | at inclusion and 3 months after the start of the study | 
| the change in the international normalized ratio | venous blood will be take on an empty stomach at 7-9 am without any special preparation | at inclusion and 3 months after the start of the study | 
| the change in the serum C-reactive protein level | venous blood will be take on an empty stomach at 7-9 am without any special preparation | at inclusion and 3 months after the start of the study | 
| the change in systemic vascular resistance | systemic vascular resistance will be calculated as mean arterial pressure/cardiac output | at inclusion and 3 months after the start of the study | 
| the change in the degree of hepatic encephalopathy | 0 - no hepatic encephalopathy, 1 - minimal hepatic encephalopathy (normal neurological status but abnormal number connection test), 2 - overt hepatic encephalopathy (abnormal neurological status) | at inclusion and 3 months after the start of the study | 
| the change in the degree of ascites | 0 points - no ascites, 1 points - ascites detected only with ultrasound, 2 points - ascites detected with the shifting dullness method; 3 point - gross refractory ascites. | at inclusion and 3 months after the start of the study | 
| the change in the presence of small intestinal bacterial overgrowth | lactulose hydrogene breath test with Gastro+Gastrolyzer (by Bedfont Ltd, the United kingdom, registration number 2010/06253 from 17.09.2020) in accordance with the North American Consensus: the presence of small intestinal bacterial overgrowth is considered when there was an increase in breath hydrogen of at least 20 ppm above the baseline value within 90 minutes after taking 10 ml of lactulose dissolved in 200 ml of water. | at inclusion and 3 months after the start of the study | 
| the change in the serum presepsin level | venous blood will be take on an empty stomach at 7-9 am without any special preparation | at inclusion and 3 months after the start of the study | 
| the change in the serum lipopolysaccharide level | venous blood will be take on an empty stomach at 7-9 am without any special preparation | at inclusion and 3 months after the start of the study | 
| the change in the serum claudin 3 level | venous blood will be take on an empty stomach at 7-9 am without any special preparation | at inclusion and 3 months after the start of the study | 
| the change in the serum tumor necrosis factor alpha level | venous blood will be take on an empty stomach at 7-9 am without any special preparation | at inclusion and 3 months after the start of the study | 
| the change in the serum nitrites level | venous blood will be take on an empty stomach at 7-9 am without any special preparation | at inclusion and 3 months after the start of the study | 
| the change in the serum big endothelin level | venous blood will take on an empty stomach at 7-9 am without any special preparation | at inclusion and 3 months after the start of the study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
microbiota, gut-liver axis, microbiome, liver, cirrhosis, hemodynamics