<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01686698</url>
  </required_header>
  <id_info>
    <org_study_id>IIBSP-VSL-2012-124</org_study_id>
    <nct_id>NCT01686698</nct_id>
  </id_info>
  <brief_title>Effect of VSL#3 (Original De Simone Formulation) on Cognitive Function, Risk of Falls and Quality of Life in Patients With Cirrhosis</brief_title>
  <official_title>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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Probiotics, due to their ability to modulate intestinal flora, intestinal permeability and&#xD;
      immune response, could decrease bacterial translocation and improve immune system alterations&#xD;
      in cirrhosis. This could lead not only to improvement in liver function and to prevent&#xD;
      bacterial infections and other complications but also to improve CD and to avoid its&#xD;
      consequences falls, HRQoL deterioration).&#xD;
&#xD;
      Recently, the investigators have observed that VSL#3 administration to rats with experimental&#xD;
      cirrhosis decreases bacterial translocation, inflammatory response and ascites formation,&#xD;
      without changes in intestinal flora. This suggests an improvement in intestinal barrier that&#xD;
      deserves further investigation.&#xD;
&#xD;
      VSL#3, through decreasing intestinal bacterial translocation and immune system modulation,&#xD;
      could improve cognitive function and prevent the consequences of CD, including falls and&#xD;
      HRQoL deterioration, in patients with cirrhosis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      OBJECTIVES&#xD;
&#xD;
      Primary endpoint To assess the effect of VSL#3 on cognitive functions in patients with&#xD;
      cirrhosis.&#xD;
&#xD;
      Secondary endpoint&#xD;
&#xD;
      To assess the effect of VSL#3 on:&#xD;
&#xD;
        -  risk of falls&#xD;
&#xD;
        -  HRQoL&#xD;
&#xD;
        -  incidence of complications of cirrhosis and mortality during the study&#xD;
&#xD;
        -  metabolomics in urine&#xD;
&#xD;
        -  endocannabinoid system (MAGL and FAAH enzymes)&#xD;
&#xD;
        -  soluble CD163 in blood as index of macrophage activation and portal hypertension (39)&#xD;
&#xD;
        -  portal hypertension evaluated by abdominal doppler ultrasonography&#xD;
&#xD;
      PATIENTS AND METHODS&#xD;
&#xD;
      Inclusion criteria&#xD;
&#xD;
      Outpatients with cirrhosis cognitive dysfunction and/or falls in the previous year visited at&#xD;
      Hospital de la Santa Creu i Sant Pau.&#xD;
&#xD;
      Cirrhosis will be diagnosed by clinical, analytical and ultrasonographic findings or by liver&#xD;
      biopsy.&#xD;
&#xD;
      Exclusion criteria&#xD;
&#xD;
        -  Hospitalization in the previous month due to decompensation of cirrhosis. Hepatocellular&#xD;
           carcinoma or any other malignancy.&#xD;
&#xD;
        -  Active alcohol intake (in the previous 3 months).&#xD;
&#xD;
        -  Current overt acute or chronic hepatic encephalopathy.&#xD;
&#xD;
        -  Clinically significant cognitive impairment according to Short Portable Mental Status&#xD;
           Questionnaire (SPMSQ) &gt; 5 points.&#xD;
&#xD;
        -  Neurological disease.&#xD;
&#xD;
        -  Inability to perform psychometric tests.&#xD;
&#xD;
        -  Marked symptomatic comorbidities (cardiac, pulmonary, renal, untreated active&#xD;
           depression).&#xD;
&#xD;
        -  Life expectancy less than 6 months.&#xD;
&#xD;
        -  Treatment with non-absorbable disaccharides.&#xD;
&#xD;
        -  Treatment with antiviral drugs.&#xD;
&#xD;
        -  Antibiotic treatment (norfloxacin).&#xD;
&#xD;
      Study Agent&#xD;
&#xD;
      VSL#3 is a probiotic mixture of 8 proprietary strains, namely Streptococcus thermophilus,&#xD;
      bifidobacteria (B. breve, B. longum, B. infantis) and lactobacilli (L. paracasei, L.&#xD;
      acidophilus, L. delbrueckii subsp bulgaricus, L. plantarum) . The active agent will be&#xD;
      supplied as a 4.4g sachet at a dose of 450 billion live bacteria per sachet with maltose and&#xD;
      silicon dioxide as excipients.&#xD;
&#xD;
      Placebo will be formulated as identical in appearance and administered according to the same&#xD;
      schedule as the active agent. Placebo contains maltose and silicon dioxide as inactive agent.&#xD;
&#xD;
      VSL#3 is a food supplement which has been marketed in Europe since 2002. The study agent&#xD;
      needs to be kept refrigerated at all times. It may be kept at room temperature for up to a&#xD;
      week without affecting its potency.&#xD;
&#xD;
      Study agent will be supplied by Actial Farmaceutica Lda, Funchal (Portugal)&#xD;
&#xD;
      Study design&#xD;
&#xD;
      Double-blind placebo-controlled clinical trial.&#xD;
&#xD;
      Forty consecutive patients with cirrhosis and CD (PHES&lt;-4) and/or falls in the previous year&#xD;
      will be randomized to receive VSL#3, sachets containing 450 x 109 bacteria, 1 sachet every 12&#xD;
      hours during 3 months (n=20), or placebo (n=20).&#xD;
&#xD;
      Patients will be randomly assigned either to the active study agent or to the placebo and&#xD;
      randomization list will be elaborated by a specific software and supplied by Actial&#xD;
      Farmaceutica Lda.&#xD;
&#xD;
      The first box with the product (60 sachets) will be given to the patients at the beginning of&#xD;
      the study. Patients will be instructed to take all the doses, to register if they miss some&#xD;
      dose and to bring back the boxes at the next visit.&#xD;
&#xD;
      Patients will also be instructed to bring the urine samples in Falcon tubes that will be&#xD;
      provided in the previous visit.&#xD;
&#xD;
      Then, the patients will give back the boxes and receive the next set of product every month.&#xD;
      The investigators will count the number of remaining sachets in the returned boxes.&#xD;
&#xD;
      Patients will be visited at 0, 4, 6, 8, 12 and 20 weeks.&#xD;
&#xD;
      ASSESSMENTS&#xD;
&#xD;
      Patients will be visited at 0, 4, 6, 8, 12 and 20 weeks. The following patients' assessments&#xD;
      will be performed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>March 2013</start_date>
  <completion_date type="Actual">March 2016</completion_date>
  <primary_completion_date type="Actual">March 2014</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To assess the effect of VSL#3 (Original De Simone formulation) on cognitive function in patients with cirrhosis</measure>
    <time_frame>3 months</time_frame>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Cirrhosis</condition>
  <condition>Cognitive Dysfunction</condition>
  <arm_group>
    <arm_group_label>VSL#3 (Original De Simone formulation)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>VSL#3 (Original De Simone formulation) sachets containing 450 x 109 bacteria, 1 sachet every 12 hours during 3 months (n=20).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo sachets, 1 sachet every 12 hours during 3 months (n=20).</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>VSL#3 (Original De Simone formulation)</intervention_name>
    <description>VSL#3 (Original De Simone formulation) is a probiotic mixture of 8 proprietary strains, namely Streptococcus thermophilus, bifidobacteria and lactobacilli.</description>
    <arm_group_label>VSL#3 (Original De Simone formulation)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>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.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Outpatients with cirrhosis visited at Hospital de la Santa Creu i Sant Pau. Cirrhosis&#xD;
             will be diagnosed by clinical, analytical and ultrasonographic findings or by liver&#xD;
             biopsy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Hospitalization in the previous month due to decompensation of cirrhosis.&#xD;
             Hepatocellular carcinoma or any other malignancy.&#xD;
&#xD;
          -  Active alcohol intake (in the previous 3 months).&#xD;
&#xD;
          -  Current overt acute or chronic hepatic encephalopathy.&#xD;
&#xD;
          -  Clinically significant cognitive impairment according to Short Portable Mental Status&#xD;
             Questionnaire (SPMSQ) &gt; 5 points.&#xD;
&#xD;
          -  Neurological disease.&#xD;
&#xD;
          -  Inability to perform psychometric tests.&#xD;
&#xD;
          -  Marked symptomatic comorbidities (cardiac, pulmonary, renal, untreated active&#xD;
             depression).&#xD;
&#xD;
          -  Life expectancy less than 6 months.&#xD;
&#xD;
          -  Treatment with non-absorbable disaccharides.&#xD;
&#xD;
          -  Treatment with antiviral drugs.&#xD;
&#xD;
          -  Antibiotic treatment (norfloxacin).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>German Soriano, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital de la Santa Creu i Sant Pau</name>
      <address>
        <city>Barcelona</city>
        <zip>08025</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>May 2016</verification_date>
  <study_first_submitted>September 13, 2012</study_first_submitted>
  <study_first_submitted_qc>September 17, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 18, 2012</study_first_posted>
  <last_update_submitted>May 18, 2016</last_update_submitted>
  <last_update_submitted_qc>May 18, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">May 19, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>cirrhosis, VSL#3, cognitive function, falls, quality of life</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Cirrhosis</mesh_term>
    <mesh_term>Fibrosis</mesh_term>
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01686698
org study id: IIBSP-VSL-2012-124
nct id: NCT01686698
lead sponsor: 
has dmc: No
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: To assess the effect of VSL#3 (Original De Simone formulation) on cognitive function in patients with cirrhosis
time frame: 3 months
arm group label: VSL#3 (Original De Simone formulation)
arm group type: Active Comparator
description: VSL#3 (Original De Simone formulation) sachets containing 450 x 109 bacteria, 1 sachet every 12 hours during 3 months (n=20).
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo sachets, 1 sachet every 12 hours during 3 months (n=20).
intervention type: Dietary Supplement
intervention name: VSL#3 (Original De Simone formulation)
description: VSL#3 (Original De Simone formulation) is a probiotic mixture of 8 proprietary strains, namely Streptococcus thermophilus, bifidobacteria and lactobacilli.
arm group label: VSL#3 (Original De Simone formulation)
intervention type: Other
intervention name: Placebo
description: 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.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: German Soriano, PhD
role: Principal Investigator
affiliation: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
facility: 
country: Spain
responsible party type: Sponsor
mesh term: Liver Cirrhosis
mesh term: Fibrosis
mesh term: Cognitive Dysfunction