<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/NCT01709266</url>
  </required_header>
  <id_info>
    <org_study_id>NL40301.081.12</org_study_id>
    <nct_id>NCT01709266</nct_id>
  </id_info>
  <brief_title>The Effect of Probiotics on E. Coli-induced Gastroenteritis</brief_title>
  <acronym>PROTETEC</acronym>
  <official_title>A Randomized, Placebo-controlled, Double Blind Volunteer Study Into the Effect of Probiotics on Gastroenteritis Caused by an Attenuated E. Coli.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>NIZO Food Research</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Lallemand Health Solutions</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>NIZO Food Research</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      The incidence of gastrointestinal infections is very high. In Western countries at least 30%&#xD;
      of the population suffers from at least one food-borne infection per year. Mostly because of&#xD;
      the problem of antibiotic resistance, more emphasis is put on prevention of infections. One&#xD;
      of the possibilities is to strengthen human resistance to gut infections by consumption of&#xD;
      probiotics. A specific blend of probiotic lactic acid bacteria (Lactobacillus helveticus&#xD;
      Rosell-52, Lactobacillus rhamnosus Rosell-11, Bifidobacterium longum Rosell-175) and a&#xD;
      probiotic yeast (Saccharomyces boulardii), improved stool consistency and shortened the&#xD;
      duration of diarrhea in a rat model of E.coli-induced diarrhea. These probiotics showed&#xD;
      synergistic effects compared with administration of solely S. boulardii or a mixture of L.&#xD;
      helveticus Rosell-52, L. rhamnosus Rosell-11, B. longum Rosell-175. Consumption of S.&#xD;
      boulardii and a combination of L. helveticus Rosell-52, L. rhamnosus Rosell-11 reduced&#xD;
      diarrhea in humans.&#xD;
&#xD;
      Aim:&#xD;
&#xD;
      To study whether probiotics improves the resistance of humans to enterotoxigenic E. coli&#xD;
      (ETEC).&#xD;
&#xD;
      Study design:&#xD;
&#xD;
      The PROTETEC study is a parallel, double-blind, placebo-controlled 4-weeks intervention with&#xD;
      probiotics in healthy volunteers. In this study, the effect of probiotic intervention vs&#xD;
      placebo on several infection markers in response to an ETEC challenge is investigated.&#xD;
      Participants will be randomly assigned to the probiotic or placebo group (n=30 per group).&#xD;
      Subjects will be instructed to maintain their usual pattern of physical activity and their&#xD;
      habitual food intake, but to standardize their dietary calcium intake. After an adaptation&#xD;
      period of 2 weeks, subjects will be orally infected with a live, but attenuated, ETEC vaccine&#xD;
      (strain E1392-75-2A; collection NIZO food research; dose 10E10 CFU). Before and after&#xD;
      infection, a diary will be kept to record all food and drinks consumption (2x2 days) to&#xD;
      assess the habitual dietary intake, as well as for daily recording of bowel habits and&#xD;
      frequency and severity of gastrointestinal complaints. The following biological samples will&#xD;
      be collected: 4x10 ml venous blood, a single fecal bolus (for screening) and 7x24 hrs feces.&#xD;
      Blood is sampled for immune response analyses and the fecal samples are collected to quantify&#xD;
      several infection- and immune system markers, to determine probiotic excretion, and to verify&#xD;
      dietary calcium intake.&#xD;
&#xD;
      Study population:&#xD;
&#xD;
      Healthy males of 20-55 yrs of age.&#xD;
&#xD;
      Interventions:&#xD;
&#xD;
      Probiotics (capsules containing freeze-dried powder, probiotic dose per capsule 5x10E9 CFU;&#xD;
      twice daily) or placebo (capsules with carrier material powder of identical appearance)&#xD;
&#xD;
      Primary outcomes:&#xD;
&#xD;
      Fecal ETEC excretion and severity of diarrhea (quantified by fecal output per day).&#xD;
&#xD;
      Secondary outcomes:&#xD;
&#xD;
      Serum immune response to ETEC, self-reported stool consistency scores and gastrointestinal&#xD;
      complaints, relative fecal wet weight.&#xD;
&#xD;
      Tertiary outcomes:&#xD;
&#xD;
      sIgA and calprotectin in feces, probiotic persistence and levels of opportunistic pathogens&#xD;
      in the endogenous microbiota.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">November 2012</completion_date>
  <primary_completion_date type="Actual">November 2012</primary_completion_date>
  <phase>N/A</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>Prevention</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Fecal ETEC excretion curve over time as marker of the colonization resistance</measure>
    <time_frame>Fecal ETEC excretion measured 1-2 days before ETEC infection, and on day 1, 2, 3, 4, 7 and 15 after infection.</time_frame>
    <description>The curve of fecal ETEC excretion over time is compared between verum and placebo group.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Total daily fecal output curve over time as marker of diarrhea</measure>
    <time_frame>Daily fecal output is measured 1-2 days before ETEC infection (baseline), and on day 1, 2, 3, 4, 7 and 15 after infection.</time_frame>
    <description>The curve of daily fecal output over time is compared between verum and placebo group.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Bowel habits</measure>
    <time_frame>Scored daily in a diary during 4 weeks, starting at the day of dietary intervention until 2 weeks after ETEC infection.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency and severity of gastrointestinal symptoms</measure>
    <time_frame>Scored daily by VAS scores in a diary during 4 weeks, starting at the day of dietary intervention until 2 weeks after ETEC infection.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diarrhea severity</measure>
    <time_frame>1-2 days before ETEC infection, and on day 1, 2, 3, 4, 7 and 15 after infection.</time_frame>
    <description>Measured by fecal dry weight excretion and % fecal dry weight.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Specific serum antibody response to CFA-II</measure>
    <time_frame>Before and at day 3 and 15 after ETEC infection.</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Opportunistic pathogens in feces</measure>
    <time_frame>1-2 days before ETEC infection, and on selected time points after infection (day 1, 2, 3, 4, 7 or 15, depending on results of primary and secondary outcomes).</time_frame>
    <description>Measurement of tertiary study outcomes will depend on the results of the primary and secondary study outcomes.</description>
  </other_outcome>
  <other_outcome>
    <measure>Calprotectin in feces</measure>
    <time_frame>1-2 days before ETEC infection, and on selected time points after infection (day 1, 2, 3, 4, 7 or 15, depending on results of primary and secondary outcomes).</time_frame>
    <description>Measurement of tertiary study outcomes will depend on the results of the primary and secondary study outcomes.</description>
  </other_outcome>
  <other_outcome>
    <measure>Total faecal sIgA</measure>
    <time_frame>1-2 days before ETEC infection, and on seleceted time points after infection (day 1, 2, 3, 4, 7 or 15, depending on results of primary and secondary outcomes).</time_frame>
    <description>Measurement of tertiary study outcomes will depend on the results of the primary and secondary study outcomes.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Gastroenteritis</condition>
  <condition>Bacterial Infection</condition>
  <condition>Diarrhea</condition>
  <arm_group>
    <arm_group_label>Probiotics</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Capsule containing 5x10E9 CFU probiotics. Twice daily for 2 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Capsule containing carrier material powder of identical appearance. Twice daily for 2 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Probiotics</intervention_name>
    <arm_group_label>Probiotics</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
          -  Male&#xD;
&#xD;
          -  Age 20-55 yrs&#xD;
&#xD;
          -  Availability of internet connection&#xD;
&#xD;
          -  Willingness to replace habitual dairy product intake with the supplied low-calcium soy&#xD;
             products&#xD;
&#xD;
          -  Willingness to abstain from products with high amounts of prebiotic fibers and from&#xD;
             products with probiotics (except for the supplied one) starting 1 month prior to study&#xD;
             start&#xD;
&#xD;
          -  Willingness to give blood donation from 1 month before the start of the experiment and&#xD;
             during the entire experimental period.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current or previous underlying disease of the GI tract, liver, bile bladder, kidney,&#xD;
             thyroid gland (self-reported)&#xD;
&#xD;
          -  Allergy to milk products or lactose intolerance (self-reported), since the capsules&#xD;
             may contain milk traces from culture media&#xD;
&#xD;
          -  Allergy to soy products (self-reported)&#xD;
&#xD;
          -  Use of antibiotics, norit, laxatives (up till 6 months prior to inclusion),&#xD;
             cholestyramine, acid burn inhibitors or immune suppressive agents (up till 3 months&#xD;
             prior to inclusion), and pre- and probiotics (up till 1 month prior to inclusion).&#xD;
&#xD;
          -  High titer serum antibodies against ETEC (10 ml blood sample collected at screening)&#xD;
&#xD;
          -  Vegetarians&#xD;
&#xD;
          -  Vegans&#xD;
&#xD;
          -  Heavy alcohol use (&gt;4 consumptions/day or &gt;20/week)&#xD;
&#xD;
          -  Drug use&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>NIZO Food Research</name>
      <address>
        <city>Ede</city>
        <state>Utrecht</state>
        <zip>6718 ZB</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <results_reference>
    <citation>Ten Bruggencate SJ, Girard SA, Floris-Vollenbroek EG, Bhardwaj R, Tompkins TA. The effect of a multi-strain probiotic on the resistance toward Escherichia coli challenge in a randomized, placebo-controlled, double-blind intervention study. Eur J Clin Nutr. 2015 Mar;69(3):385-91. doi: 10.1038/ejcn.2014.238. Epub 2014 Nov 5.</citation>
    <PMID>25369827</PMID>
  </results_reference>
  <verification_date>August 2015</verification_date>
  <study_first_submitted>October 11, 2012</study_first_submitted>
  <study_first_submitted_qc>October 16, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 18, 2012</study_first_posted>
  <last_update_submitted>August 26, 2015</last_update_submitted>
  <last_update_submitted_qc>August 26, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 27, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bacterial Infections</mesh_term>
    <mesh_term>Gastroenteritis</mesh_term>
    <mesh_term>Diarrhea</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/NCT01709266
org study id: NL40301.081.12
nct id: NCT01709266
lead sponsor: 
collaborator: 
has dmc: No
Background:

      The incidence of gastrointestinal infections is very high. In Western countries at least 30%
      of the population suffers from at least one food-borne infection per year. Mostly because of
      the problem of antibiotic resistance, more emphasis is put on prevention of infections. One
      of the possibilities is to strengthen human resistance to gut infections by consumption of
      probiotics. A specific blend of probiotic lactic acid bacteria (Lactobacillus helveticus
      Rosell-52, Lactobacillus rhamnosus Rosell-11, Bifidobacterium longum Rosell-175) and a
      probiotic yeast (Saccharomyces boulardii), improved stool consistency and shortened the
      duration of diarrhea in a rat model of E.coli-induced diarrhea. These probiotics showed
      synergistic effects compared with administration of solely S. boulardii or a mixture of L.
      helveticus Rosell-52, L. rhamnosus Rosell-11, B. longum Rosell-175. Consumption of S.
      boulardii and a combination of L. helveticus Rosell-52, L. rhamnosus Rosell-11 reduced
      diarrhea in humans.

      Aim:

      To study whether probiotics improves the resistance of humans to enterotoxigenic E. coli
      (ETEC).

      Study design:

      The PROTETEC study is a parallel, double-blind, placebo-controlled 4-weeks intervention with
      probiotics in healthy volunteers. In this study, the effect of probiotic intervention vs
      placebo on several infection markers in response to an ETEC challenge is investigated.
      Participants will be randomly assigned to the probiotic or placebo group (n=30 per group).
      Subjects will be instructed to maintain their usual pattern of physical activity and their
      habitual food intake, but to standardize their dietary calcium intake. After an adaptation
      period of 2 weeks, subjects will be orally infected with a live, but attenuated, ETEC vaccine
      (strain E1392-75-2A; collection NIZO food research; dose 10E10 CFU). Before and after
      infection, a diary will be kept to record all food and drinks consumption (2x2 days) to
      assess the habitual dietary intake, as well as for daily recording of bowel habits and
      frequency and severity of gastrointestinal complaints. The following biological samples will
      be collected: 4x10 ml venous blood, a single fecal bolus (for screening) and 7x24 hrs feces.
      Blood is sampled for immune response analyses and the fecal samples are collected to quantify
      several infection- and immune system markers, to determine probiotic excretion, and to verify
      dietary calcium intake.

      Study population:

      Healthy males of 20-55 yrs of age.

      Interventions:

      Probiotics (capsules containing freeze-dried powder, probiotic dose per capsule 5x10E9 CFU;
      twice daily) or placebo (capsules with carrier material powder of identical appearance)

      Primary outcomes:

      Fecal ETEC excretion and severity of diarrhea (quantified by fecal output per day).

      Secondary outcomes:

      Serum immune response to ETEC, self-reported stool consistency scores and gastrointestinal
      complaints, relative fecal wet weight.

      Tertiary outcomes:

      sIgA and calprotectin in feces, probiotic persistence and levels of opportunistic pathogens
      in the endogenous microbiota.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Fecal ETEC excretion curve over time as marker of the colonization resistance
time frame: Fecal ETEC excretion measured 1-2 days before ETEC infection, and on day 1, 2, 3, 4, 7 and 15 after infection.
description: The curve of fecal ETEC excretion over time is compared between verum and placebo group.
measure: Total daily fecal output curve over time as marker of diarrhea
time frame: Daily fecal output is measured 1-2 days before ETEC infection (baseline), and on day 1, 2, 3, 4, 7 and 15 after infection.
description: The curve of daily fecal output over time is compared between verum and placebo group.
measure: Bowel habits
time frame: Scored daily in a diary during 4 weeks, starting at the day of dietary intervention until 2 weeks after ETEC infection.
measure: Frequency and severity of gastrointestinal symptoms
time frame: Scored daily by VAS scores in a diary during 4 weeks, starting at the day of dietary intervention until 2 weeks after ETEC infection.
measure: Diarrhea severity
time frame: 1-2 days before ETEC infection, and on day 1, 2, 3, 4, 7 and 15 after infection.
description: Measured by fecal dry weight excretion and % fecal dry weight.
measure: Specific serum antibody response to CFA-II
time frame: Before and at day 3 and 15 after ETEC infection.
measure: Opportunistic pathogens in feces
time frame: 1-2 days before ETEC infection, and on selected time points after infection (day 1, 2, 3, 4, 7 or 15, depending on results of primary and secondary outcomes).
description: Measurement of tertiary study outcomes will depend on the results of the primary and secondary study outcomes.
measure: Calprotectin in feces
time frame: 1-2 days before ETEC infection, and on selected time points after infection (day 1, 2, 3, 4, 7 or 15, depending on results of primary and secondary outcomes).
description: Measurement of tertiary study outcomes will depend on the results of the primary and secondary study outcomes.
measure: Total faecal sIgA
time frame: 1-2 days before ETEC infection, and on seleceted time points after infection (day 1, 2, 3, 4, 7 or 15, depending on results of primary and secondary outcomes).
description: Measurement of tertiary study outcomes will depend on the results of the primary and secondary study outcomes.
arm group label: Probiotics
arm group type: Experimental
description: Capsule containing 5x10E9 CFU probiotics. Twice daily for 2 weeks.
arm group label: Placebo
arm group type: Placebo Comparator
description: Capsule containing carrier material powder of identical appearance. Twice daily for 2 weeks.
intervention type: Dietary Supplement
intervention name: Probiotics
arm group label: Probiotics
intervention type: Dietary Supplement
intervention name: Placebo
arm group label: Placebo
criteria: 
gender: Male
minimum age: 20 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Netherlands
citation: Ten Bruggencate SJ, Girard SA, Floris-Vollenbroek EG, Bhardwaj R, Tompkins TA. The effect of a multi-strain probiotic on the resistance toward Escherichia coli challenge in a randomized, placebo-controlled, double-blind intervention study. Eur J Clin Nutr. 2015 Mar;69(3):385-91. doi: 10.1038/ejcn.2014.238. Epub 2014 Nov 5.
PMID: 25369827
responsible party type: Sponsor
mesh term: Bacterial Infections
mesh term: Gastroenteritis
mesh term: Diarrhea