Probiotics and Hemodynamic Changes in Cirrhosis (PrBHCCir)

The Effect of Probiotics on Hemodynamic Changes and Complications of Cirrhosis

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

Study Overview

• Status: Completed
• Conditions: Cirrhosis
• Intervention / Treatment: Drug: Placebo; Drug: Saccharomyces Boulardii Probiotic Supplement

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 119435
    • Clinic for Internal Diseases, Gastroenterology and Hepatology at Sechenov University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Probiotics; 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; Probiotic yeast; Other Names: Probiotics; Enterol
Placebo Comparator: Placebo; Patients in the Placebo arm will receive the placebo at a dose of 250 mg 2 times a day for 3 months.	Drug: Placebo; Placebo; 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

Collaborators and Investigators

• Sponsor: I.M. Sechenov First Moscow State Medical University
• Investigators: Principal Investigator: Vladimir Ivashkin, Prof., I.M. Sechenov First Moscow State Medical University (Sechenov University)

Publications and helpful links

General Publications

• Maslennikov R, Ivashkin V, Efremova I, Poluektova E, Shirokova E. Gut-liver axis in cirrhosis: Are hemodynamic changes a missing link? World J Clin Cases. 2021 Nov 6;9(31):9320-9332. doi: 10.12998/wjcc.v9.i31.9320.
• Maslennikov R, Ivashkin V, Efremova I, Alieva A, Kashuh E, Tsvetaeva E, Poluektova E, Shirokova E, Ivashkin K. Gut dysbiosis is associated with poorer long-term prognosis in cirrhosis. World J Hepatol. 2021 May 27;13(5):557-570. doi: 10.4254/wjh.v13.i5.557.
• Maslennikov R, Ivashkin V, Efremova I, Poluektova E, Shirokova E. Probiotics in hepatology: An update. World J Hepatol. 2021 Sep 27;13(9):1154-1166. doi: 10.4254/wjh.v13.i9.1154.
• Ivashkin V, Fomin V, Moiseev S, Brovko M, Maslennikov R, Ulyanin A, Sholomova V, Vasilyeva M, Trush E, Shifrin O, Poluektova E. Efficacy of a Probiotic Consisting of Lacticaseibacillus rhamnosus PDV 1705, Bifidobacterium bifidum PDV 0903, Bifidobacterium longum subsp. infantis PDV 1911, and Bifidobacterium longum subsp. longum PDV 2301 in the Treatment of Hospitalized Patients with COVID-19: a Randomized Controlled Trial. Probiotics Antimicrob Proteins. 2021 Oct 13:1-9. doi: 10.1007/s12602-021-09858-5. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2021
• Primary Completion (Actual): March 29, 2022
• Study Completion (Actual): March 29, 2022

Study Registration Dates

• First Submitted: January 27, 2022
• First Submitted That Met QC Criteria: February 7, 2022
• First Posted (Actual): February 9, 2022

Study Record Updates

• Last Update Posted (Actual): March 31, 2022
• Last Update Submitted That Met QC Criteria: March 29, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: gut-liver axis; hemodynamics; cirrhosis; liver; microbiome; microbiota
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis
• Other Study ID Numbers: 2533644

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data disclosure is not permitted by the Local Ethics Committee of I.M. Sechenov First Moscow State Medical University. For more information about the study, you need to contact the principal investigator.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No