<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/NCT01701297</url>
  </required_header>
  <id_info>
    <org_study_id>10GA021</org_study_id>
    <secondary_id>2010-022886-92</secondary_id>
    <secondary_id>10/H0405/81</secondary_id>
    <nct_id>NCT01701297</nct_id>
  </id_info>
  <brief_title>VSL#3 and Spontaneous Bacterial Peritonitis</brief_title>
  <official_title>The Effect of Probiotics on the Incidence of Spontaneous Bacterial Peritonitis in Patients With Cirrhosis and Ascites</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Nottingham University Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>VSL Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Nottingham University Hospitals NHS Trust</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Research question: Do oral probiotics in patients with cirrhosis and ascites reduce&#xD;
      intestinal bacterial concentrations, ascitic bacterial DNA, SBP and bacteraemia compared to&#xD;
      antibiotics or placebo?&#xD;
&#xD;
      This study is designed to investigate the effects of an oral probiotic (VSL#3; a mixture of&#xD;
      &quot;healthy&quot; bacteria for the intestines) compared to an antibiotic or placebo in preventing&#xD;
      infection developing in the abdominal fluid (&quot;ascites&quot;) that collects in patients with&#xD;
      advanced liver disease (&quot;cirrhosis&quot;). Patients already having had infection will be excluded&#xD;
      from the study. Clear inclusion and exclusion criteria will be met and patients will be&#xD;
      monitored throughout the study to examine whether they have required more hospitalisations,&#xD;
      their rate infection in abdominal fluid or elsewhere and the level of liver function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The prevalence of cirrhosis is increasing in the UK. Decompensation heralds a poor outcome,&#xD;
      with mortality in those developing ascites approximately 50% over the following 1-2 years.&#xD;
      Spontaneous bacterial peritonitis (SBP) in ascitic fluid further reduces survival and occurs&#xD;
      due to a combination of increased intestinal epithelial dysfunction, bacterial translocation&#xD;
      to mesenteric lymph nodes and ascitic fluid, and reduced opsonisation and neutrophil&#xD;
      function. Even with antibiotic treatment, 3-month mortality from SBP is approximately 40% and&#xD;
      results in expensive in-patient care. Several studies have confirmed the benefit of secondary&#xD;
      prophylaxis with long-term oral antibiotics in patients with advanced liver disease (e.g.&#xD;
      norfloxacin, co-trimoxazole) and others suggest that in patients at high risk of developing&#xD;
      SBP, primary antibiotic prophylaxis improves rates of sepsis and survival. Problems with&#xD;
      these strategies include emergence of bacterial resistance, and development of&#xD;
      antibiotic-associated diarrhoea (including C. difficile infection, which has a high&#xD;
      case-fatality rate in those with cirrhosis). Local bacterial resistance profiles and&#xD;
      association with C. difficile infection favour the choice of co-trimoxazole in our study&#xD;
      population. Patients with advanced cirrhosis taking co-trimoxazole have previously&#xD;
      demonstrated reduced liver-related outcomes such as infection and death3. Probiotic&#xD;
      preparations alter intestinal bacterial flora and improve intestinal barrier and neutrophil&#xD;
      function. Faecal bacterial counts of E. coli and Streptococcus (organisms commonly&#xD;
      responsible for SBP) showed a 2-log fall with probiotics, although whether they could reduce&#xD;
      the incidence of SBP remains unexamined.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Unable to obtain QP release certification from the manufacturer (VSL3) for shipment of IMP&#xD;
  </why_stopped>
  <start_date>February 2012</start_date>
  <completion_date type="Actual">October 2014</completion_date>
  <primary_completion_date type="Actual">October 2014</primary_completion_date>
  <phase>Phase 2</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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Liver-related mortality and liver related morbidity</measure>
    <time_frame>12 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of SBP, variceal bleeding, any non-SBP sepsis (e.g. pneumonia, urinary tract infection), clinical episodes of encephalopathy and the incidence of C. difficile infection.</measure>
    <time_frame>12 months</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Decompensated Cirrhosis</condition>
  <condition>Ascites</condition>
  <arm_group>
    <arm_group_label>Co-trimoxazole</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Co-trimoxazole 960mg daily po</description>
  </arm_group>
  <arm_group>
    <arm_group_label>VSL#3 active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>VSL#3 active 2 sachets/daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>VSL#3 placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>VSL#3 placebo 2 sachets/daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>cotrimoxazole</intervention_name>
    <description>Cotrimoxazole 960mg orally each day (two 480mg tablets)</description>
    <arm_group_label>Co-trimoxazole</arm_group_label>
    <other_name>Cotrimoxazole (septrin)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>VSL#3 active</intervention_name>
    <description>The prescribed dose was 2 sachets (containing 900 billion bacteria) orally each day for 48 weeks</description>
    <arm_group_label>VSL#3 active</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>VSL#3 placebo</intervention_name>
    <description>This was two placebo sachets identical to VSL#3 active sachet. The prescribed dose was 2 sachets orally each day for 48 weeks</description>
    <arm_group_label>VSL#3 placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          -  Participant is willing and able to give informed consent for participation in the&#xD;
             study.&#xD;
&#xD;
          -  Male or Female, aged 18 years or above.&#xD;
&#xD;
          -  Diagnosed with required disease/severity/symptoms as outlined in 6.3.1.&#xD;
&#xD;
          -  Stable dose of current regular medication (e.g. diuretics, beta-blockers, vitamin&#xD;
             supplementation) for at least 4 weeks prior to study entry.&#xD;
&#xD;
          -  Female participants of child bearing potential and male participants whose partner is&#xD;
             of child bearing potential must be willing to ensure that they or their partner use&#xD;
             effective contraception during the study and for 3 months thereafter&#xD;
&#xD;
          -  Participants have clinically acceptable laboratory tests and ECG within 14 days of&#xD;
             enrolment.&#xD;
&#xD;
          -  Able (in the Investigators opinion) and willing to comply with all study requirements.&#xD;
&#xD;
        Willing to allow their General Practitioner and consultant&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Female participants who is pregnant, lactating or planning pregnancy during the course&#xD;
             of the study.&#xD;
&#xD;
          -  Presence of hepatocellular carcinoma&#xD;
&#xD;
          -  Scheduled elective surgery or other procedures requiring general anaesthesia during&#xD;
             the study.&#xD;
&#xD;
          -  Participant who is terminally ill&#xD;
&#xD;
          -  Any other significant disease or disorder which, in the opinion of the Investigator,&#xD;
             may either put the participants at risk because of participation in the study, or may&#xD;
             influence the result of the study, or the participant's ability to participate in the&#xD;
             study.&#xD;
&#xD;
          -  Use of antibiotics or probiotics in the last 2 weeks&#xD;
&#xD;
          -  Known hypersensitivity to trimethoprim, sulphonamides or any other ingredients in&#xD;
             co-trimoxazole tablet.&#xD;
&#xD;
          -  History of acute porphyria or serious haematological disorder.&#xD;
&#xD;
          -  Participants who have participated in another research study involving an&#xD;
             investigational product in the past 12 weeks&#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>Martin W James, BM BS FRCP PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>NUH NHS Trust</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>NUH NHS Trust</name>
      <address>
        <city>Nottingham</city>
        <state>Nottinghamshire</state>
        <zip>NG7 2UH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>October 2016</verification_date>
  <study_first_submitted>August 8, 2012</study_first_submitted>
  <study_first_submitted_qc>October 4, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 5, 2012</study_first_posted>
  <last_update_submitted>October 27, 2016</last_update_submitted>
  <last_update_submitted_qc>October 27, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 28, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cirrhosis, ascites, infection</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Peritonitis</mesh_term>
    <mesh_term>Liver Cirrhosis</mesh_term>
    <mesh_term>Fibrosis</mesh_term>
    <mesh_term>Ascites</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Trimethoprim, Sulfamethoxazole Drug Combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT01701297
org study id: 10GA021
secondary id: 2010-022886-92
secondary id: 10/H0405/81
nct id: NCT01701297
lead sponsor: 
collaborator: 
has dmc: Yes
Research question: Do oral probiotics in patients with cirrhosis and ascites reduce
      intestinal bacterial concentrations, ascitic bacterial DNA, SBP and bacteraemia compared to
      antibiotics or placebo?

      This study is designed to investigate the effects of an oral probiotic (VSL#3; a mixture of
      "healthy" bacteria for the intestines) compared to an antibiotic or placebo in preventing
      infection developing in the abdominal fluid ("ascites") that collects in patients with
      advanced liver disease ("cirrhosis"). Patients already having had infection will be excluded
      from the study. Clear inclusion and exclusion criteria will be met and patients will be
      monitored throughout the study to examine whether they have required more hospitalisations,
      their rate infection in abdominal fluid or elsewhere and the level of liver function.
The prevalence of cirrhosis is increasing in the UK. Decompensation heralds a poor outcome,
      with mortality in those developing ascites approximately 50% over the following 1-2 years.
      Spontaneous bacterial peritonitis (SBP) in ascitic fluid further reduces survival and occurs
      due to a combination of increased intestinal epithelial dysfunction, bacterial translocation
      to mesenteric lymph nodes and ascitic fluid, and reduced opsonisation and neutrophil
      function. Even with antibiotic treatment, 3-month mortality from SBP is approximately 40% and
      results in expensive in-patient care. Several studies have confirmed the benefit of secondary
      prophylaxis with long-term oral antibiotics in patients with advanced liver disease (e.g.
      norfloxacin, co-trimoxazole) and others suggest that in patients at high risk of developing
      SBP, primary antibiotic prophylaxis improves rates of sepsis and survival. Problems with
      these strategies include emergence of bacterial resistance, and development of
      antibiotic-associated diarrhoea (including C. difficile infection, which has a high
      case-fatality rate in those with cirrhosis). Local bacterial resistance profiles and
      association with C. difficile infection favour the choice of co-trimoxazole in our study
      population. Patients with advanced cirrhosis taking co-trimoxazole have previously
      demonstrated reduced liver-related outcomes such as infection and death3. Probiotic
      preparations alter intestinal bacterial flora and improve intestinal barrier and neutrophil
      function. Faecal bacterial counts of E. coli and Streptococcus (organisms commonly
      responsible for SBP) showed a 2-log fall with probiotics, although whether they could reduce
      the incidence of SBP remains unexamined.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Liver-related mortality and liver related morbidity
time frame: 12 months
measure: Incidence of SBP, variceal bleeding, any non-SBP sepsis (e.g. pneumonia, urinary tract infection), clinical episodes of encephalopathy and the incidence of C. difficile infection.
time frame: 12 months
arm group label: Co-trimoxazole
arm group type: Active Comparator
description: Co-trimoxazole 960mg daily po
arm group label: VSL#3 active
arm group type: Experimental
description: VSL#3 active 2 sachets/daily
arm group label: VSL#3 placebo
arm group type: Placebo Comparator
description: VSL#3 placebo 2 sachets/daily
intervention type: Drug
intervention name: cotrimoxazole
description: Cotrimoxazole 960mg orally each day (two 480mg tablets)
arm group label: Co-trimoxazole
other name: Cotrimoxazole (septrin)
intervention type: Drug
intervention name: VSL#3 active
description: The prescribed dose was 2 sachets (containing 900 billion bacteria) orally each day for 48 weeks
arm group label: VSL#3 active
intervention type: Drug
intervention name: VSL#3 placebo
description: This was two placebo sachets identical to VSL#3 active sachet. The prescribed dose was 2 sachets orally each day for 48 weeks
arm group label: VSL#3 placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Martin W James, BM BS FRCP PhD
role: Principal Investigator
affiliation: NUH NHS Trust
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Peritonitis
mesh term: Liver Cirrhosis
mesh term: Fibrosis
mesh term: Ascites
mesh term: Trimethoprim, Sulfamethoxazole Drug Combination
sharing ipd: No