Effect of VSL#3 (Original De Simone Formulation) on Cognitive Function, Risk of Falls and Quality of Life in Patients With Cirrhosis

Study of the Effect of VSL#3 (Original De Simone Formulation) on Cognitive Function, Risk of Falls and Quality of Life in Patients With Cirrhosis

Probiotics, due to their ability to modulate intestinal flora, intestinal permeability and immune response, could decrease bacterial translocation and improve immune system alterations in cirrhosis. This could lead not only to improvement in liver function and to prevent bacterial infections and other complications but also to improve CD and to avoid its consequences falls, HRQoL deterioration).

Recently, the investigators have observed that VSL#3 administration to rats with experimental cirrhosis decreases bacterial translocation, inflammatory response and ascites formation, without changes in intestinal flora. This suggests an improvement in intestinal barrier that deserves further investigation.

VSL#3, through decreasing intestinal bacterial translocation and immune system modulation, could improve cognitive function and prevent the consequences of CD, including falls and HRQoL deterioration, in patients with cirrhosis.

Study Overview

• Status: Completed
• Conditions: Cognitive Dysfunction; Cirrhosis
• Intervention / Treatment: Dietary supplement: VSL#3 (Original De Simone formulation); Other: Placebo

Detailed Description

OBJECTIVES

Primary endpoint To assess the effect of VSL#3 on cognitive functions in patients with cirrhosis.

Secondary endpoint

To assess the effect of VSL#3 on:

• risk of falls
• HRQoL
• incidence of complications of cirrhosis and mortality during the study
• metabolomics in urine
• endocannabinoid system (MAGL and FAAH enzymes)
• soluble CD163 in blood as index of macrophage activation and portal hypertension (39)
• portal hypertension evaluated by abdominal doppler ultrasonography

PATIENTS AND METHODS

Inclusion criteria

Outpatients with cirrhosis cognitive dysfunction and/or falls in the previous year visited at Hospital de la Santa Creu i Sant Pau.

Cirrhosis will be diagnosed by clinical, analytical and ultrasonographic findings or by liver biopsy.

Exclusion criteria

• Hospitalization in the previous month due to decompensation of cirrhosis. Hepatocellular carcinoma or any other malignancy.
• Active alcohol intake (in the previous 3 months).
• Current overt acute or chronic hepatic encephalopathy.
• Clinically significant cognitive impairment according to Short Portable Mental Status Questionnaire (SPMSQ) > 5 points.
• Neurological disease.
• Inability to perform psychometric tests.
• Marked symptomatic comorbidities (cardiac, pulmonary, renal, untreated active depression).
• Life expectancy less than 6 months.
• Treatment with non-absorbable disaccharides.
• Treatment with antiviral drugs.
• Antibiotic treatment (norfloxacin).

Study Agent

VSL#3 is a probiotic mixture of 8 proprietary strains, namely Streptococcus thermophilus, bifidobacteria (B. breve, B. longum, B. infantis) and lactobacilli (L. paracasei, L. acidophilus, L. delbrueckii subsp bulgaricus, L. plantarum) . The active agent will be supplied as a 4.4g sachet at a dose of 450 billion live bacteria per sachet with maltose and silicon dioxide as excipients.

Placebo will be formulated as identical in appearance and administered according to the same schedule as the active agent. Placebo contains maltose and silicon dioxide as inactive agent.

VSL#3 is a food supplement which has been marketed in Europe since 2002. The study agent needs to be kept refrigerated at all times. It may be kept at room temperature for up to a week without affecting its potency.

Study agent will be supplied by Actial Farmaceutica Lda, Funchal (Portugal)

Study design

Double-blind placebo-controlled clinical trial.

Forty consecutive patients with cirrhosis and CD (PHES<-4) and/or falls in the previous year will be randomized to receive VSL#3, sachets containing 450 x 109 bacteria, 1 sachet every 12 hours during 3 months (n=20), or placebo (n=20).

Patients will be randomly assigned either to the active study agent or to the placebo and randomization list will be elaborated by a specific software and supplied by Actial Farmaceutica Lda.

The first box with the product (60 sachets) will be given to the patients at the beginning of the study. Patients will be instructed to take all the doses, to register if they miss some dose and to bring back the boxes at the next visit.

Patients will also be instructed to bring the urine samples in Falcon tubes that will be provided in the previous visit.

Then, the patients will give back the boxes and receive the next set of product every month. The investigators will count the number of remaining sachets in the returned boxes.

Patients will be visited at 0, 4, 6, 8, 12 and 20 weeks.

ASSESSMENTS

Patients will be visited at 0, 4, 6, 8, 12 and 20 weeks. The following patients' assessments will be performed.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08025
    • Hospital De La Santa Creu I Sant Pau

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Outpatients with cirrhosis visited at Hospital de la Santa Creu i Sant Pau. Cirrhosis will be diagnosed by clinical, analytical and ultrasonographic findings or by liver biopsy.

Exclusion Criteria:

• Hospitalization in the previous month due to decompensation of cirrhosis. Hepatocellular carcinoma or any other malignancy.
• Active alcohol intake (in the previous 3 months).
• Current overt acute or chronic hepatic encephalopathy.
• Clinically significant cognitive impairment according to Short Portable Mental Status Questionnaire (SPMSQ) > 5 points.
• Neurological disease.
• Inability to perform psychometric tests.
• Marked symptomatic comorbidities (cardiac, pulmonary, renal, untreated active depression).
• Life expectancy less than 6 months.
• Treatment with non-absorbable disaccharides.
• Treatment with antiviral drugs.
• Antibiotic treatment (norfloxacin).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: VSL#3 (Original De Simone formulation); VSL#3 (Original De Simone formulation) sachets containing 450 x 109 bacteria, 1 sachet every 12 hours during 3 months (n=20).	Dietary supplement: VSL#3 (Original De Simone formulation); VSL#3 (Original De Simone formulation) is a probiotic mixture of 8 proprietary strains, namely Streptococcus thermophilus, bifidobacteria and lactobacilli.
Placebo Comparator: Placebo; Placebo sachets, 1 sachet every 12 hours during 3 months (n=20).	Other: Placebo; Placebo will be formulated as identical in appearance and administered according to the same schedule as the active agent. Placebo contains maltose and silicon dioxide as inactive agent.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To assess the effect of VSL#3 (Original De Simone formulation) on cognitive function in patients with cirrhosis	3 months

Collaborators and Investigators

• Sponsor: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
• Investigators: Principal Investigator: German Soriano, PhD, Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: September 13, 2012
• First Submitted That Met QC Criteria: September 17, 2012
• First Posted (Estimate): September 18, 2012

Study Record Updates

• Last Update Posted (Estimate): May 19, 2016
• Last Update Submitted That Met QC Criteria: May 18, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: cirrhosis, VSL#3, cognitive function, falls, quality of life
• Additional Relevant MeSH Terms: Mental Disorders; Digestive System Diseases; Pathologic Processes; Neurocognitive Disorders; Liver Diseases; Cognition Disorders; Fibrosis; Liver Cirrhosis; Cognitive Dysfunction
• Other Study ID Numbers: IIBSP-VSL-2012-124