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