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