<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/NCT01671137</url>
  </required_header>
  <id_info>
    <org_study_id>PrevenDAR</org_study_id>
    <secondary_id>Prevent-001</secondary_id>
    <nct_id>NCT01671137</nct_id>
  </id_info>
  <brief_title>Probiotic for the Prevention of Functional Disorders in Childhood</brief_title>
  <official_title>A Randomized Controlled Trial of Lactobacillus Rhamnosus Strain GG for The Prevention of Functional Abdominal Pain Children After Acute Gastroenteritis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Bari</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Bari</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The present study has several aims:&#xD;
&#xD;
        1. Establish whether Lactobacillus Rhamnosus Strain GG is able to prevent the onset of IBS&#xD;
           in a high risk group of children enrolled after an acute gastroenteritis (the study has&#xD;
           been powered to this aim).&#xD;
&#xD;
        2. Establish whether Lactobacillus Rhamnosus Strain GG is able to stabilize the intestinal&#xD;
           microbiota after an acute gastroenteritis.&#xD;
&#xD;
        3. Define the intestinal microbiota of children following an acute gastroenteritis and&#xD;
           identify, if possible, a modification of the microbiota that can predict the emergence&#xD;
           of Irritable Bowel Syndrome.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Design A randomized, double-blind, placebo-controlled, parallel-group trial planned&#xD;
      following the recommendations established by the Consensus report on clinical trial in IBS.&#xD;
&#xD;
      Children during/after an acute episode of gastroenteritis will enter a 12 months treatment&#xD;
      (m1-m12) period followed by a 6 months follow-up phase (m13-m18).&#xD;
&#xD;
      Children will be assigned consecutive numbers, starting with the lowest number available, and&#xD;
      randomly assigned, with the use of a computer generated randomisation list using permuted&#xD;
      block design, to receive orally either LGG (6 × 109 colony forming units) or placebo&#xD;
      (capsules identical in taste and appearance to the active study product except for the&#xD;
      absence of LGG) once a day. Enrolled children will be entered sequentially to receive the&#xD;
      assigned treatment. Boxes containing placebo will have the same shape, dimension, indication&#xD;
      and appearance as those containing the viable LGG and will be provided by the probiotic&#xD;
      producer (Dicofarm SpA, Rome, Italy) which ensure that the study is blinded for investigators&#xD;
      and patients. Group assignment will be concealed from participants and investigators.&#xD;
&#xD;
      Power calculation With the assumption that, in a 12 month period, IBS would be expected in&#xD;
      16% of children after an episode of acute gastroenteritis as opposed to 5% in the general&#xD;
      paediatric population without gastroenteritis, we calculated that a sample of 210 children&#xD;
      per group would be required for the study to have 80% power to show an advantage of LGG over&#xD;
      placebo in reducing the rate of IBS, based on a two-sided type 1 error rate of 5%..&#xD;
&#xD;
      Eligibility of Patients Patients recruited from primary care paediatricians or paediatric&#xD;
      wards during/after (less seven days) an episode of gastroenteritis&#xD;
      (bacteria/viruses/parasites).&#xD;
&#xD;
      Inclusion criteria:&#xD;
&#xD;
        1. Children of 2 - 16 years of age;&#xD;
&#xD;
        2. Either sex.&#xD;
&#xD;
      Exclusion criteria:&#xD;
&#xD;
        1. Chronic disease,&#xD;
&#xD;
        2. Clinical history of abdominal pain history suggestive for functional&#xD;
           dyspepsia/aerophagia/abdominal migraine&#xD;
&#xD;
        3. Growth failure,&#xD;
&#xD;
        4. Alarm signs of organic conditions.&#xD;
&#xD;
      Assessments, Compliance and Adherence. During the duration of the trial (m1-m18) patients&#xD;
      will record gastrointestinal symptoms on monthly bases and the following data will be&#xD;
      collected: a) questionnaire of frequency/severity of pain, b) school absence and c) GI&#xD;
      symptom score by the compilation of the gastrointestinal symptom rating score.&#xD;
&#xD;
      To assess the severity of pain a combination of the self-report Visual Analogue Scale (VAS)&#xD;
      and the Faces Pain Scale (FPS) will be used. The 0-10 mm VAS scale (0 no pain, 10 worst&#xD;
      possible pain) included a horizontal colour gradient (green-red), plus a rating. When asked&#xD;
      to evaluate pain, the child would point to a level and trace a line. This particular VAS is a&#xD;
      validated standard to evaluate pain in children older than five. Assessment was eased&#xD;
      coupling the VAS with the FPS that consists of six faces ranging from a relaxed face to a&#xD;
      face showing intense pain.&#xD;
&#xD;
      Gastrointestinal symptom rating score (GSRS) consists of a 15-point questionnaire to assess&#xD;
      severity and frequency of symptoms validated by Svedlund et al..&#xD;
&#xD;
      During the six months of follow-up the questionnaire will be compiled every other months and&#xD;
      the GSRS at month 18.&#xD;
&#xD;
      The impact on parent's overall assessment of treatment will be obtained by a monthly&#xD;
      interview by the question &quot;how do you feel the medication is affecting the health of your&#xD;
      child?&quot;; possible answers are significant, mild, or no relief.&#xD;
&#xD;
      To ensure compliance one investigator will contact the families every four weeks to monitor&#xD;
      the process of the study. Adherence will be measured by counting the number of capsules&#xD;
      returned at the study visit; children who missed for more than 20% of the medications were&#xD;
      considered noncompliant.&#xD;
&#xD;
      Outcome Measures Primary outcome will be the incidence in IBS in children receiving LGG as&#xD;
      compared to those receiving placebo. We have chosen pain as the primary outcome measure, in&#xD;
      line with the proposed points-to-consider for IBS trials.&#xD;
&#xD;
      IBS or chronic abdominal pain will be diagnosed and categorised according to ROME III&#xD;
      criteria.&#xD;
&#xD;
      Secondary outcomes are: 1) evaluation of frequency/severity of symptoms according to&#xD;
      treatment arm; 2) evaluation of perception of children's health according to parents and 3)&#xD;
      modification of intestinal microbiota.&#xD;
&#xD;
      Intestinal microbiota The intestinal microbiota will be assesses according to methods&#xD;
      published elsewhere.&#xD;
&#xD;
      To define the modification of the intestinal microbiota following an acute gastroenteritis&#xD;
      and to determine whether the onset of the IBS is anticipated by a modification of intestinal&#xD;
      microbiota we will proceed to the collection of faecal samples at entry, after one month and&#xD;
      every two months after enrolment. During the six months of follow-up a fecal sample will be&#xD;
      collected only at month 18.&#xD;
&#xD;
      Bacteria DNA in stools will be extracted and stored at -80°C for future analysis. At the end&#xD;
      of the trial a subset of informative fecal bacterial DNA will be assessed: a) patients that&#xD;
      have NOT developed IBS (LGG and placebo), b) patients that have developed IBS (LGG and&#xD;
      placebo).&#xD;
&#xD;
      The analysis of the intestinal microbiota of these informative cases will help to assess&#xD;
      whether there is a intestinal microbiota suggestive of future inset of IBS and ability of LGG&#xD;
      to stabilize the intestinal microbiota.&#xD;
&#xD;
      Adverse Events and Disallowed Medication Adverse events were monitored throughout the study.&#xD;
      Children will not allowed to consume any probiotic other than those provided (except for a&#xD;
      transient period no longer that 2 weeks) and they will be invited to continue their eating&#xD;
      and physical exercise habits. Concomitant use of medications affecting gastrointestinal&#xD;
      motility and/or pain perception was allowed, providing parents registered the intake.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>September 2012</start_date>
  <completion_date type="Anticipated">September 2014</completion_date>
  <primary_completion_date type="Anticipated">July 2014</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Prevention of Abdominal pain</measure>
    <time_frame>18 months</time_frame>
    <description>Primary outcome will be the incidence in IBS in children receiving LGG as compared to those receiving placebo. We have chosen pain as the primary outcome measure, in line with the proposed points-toconsider for IBS trials (Corazziari E. Consensus report: Clinical trial guidelines for pharmacological treatment of irritable bowel syndrome. Aliment Pharmcol Ther 2003;18:569).&#xD;
IBS or chronic abdominal pain will be diagnosed and categorised according to ROME III criteria (Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006;130).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of IBS</measure>
    <time_frame>6 months</time_frame>
    <description>Evaluation of frequency/severity of symptoms according to treatment arm;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Children's health</measure>
    <time_frame>24 months</time_frame>
    <description>Evaluation of perception of children's health according to parents</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intestinal microbiota</measure>
    <time_frame>24 months</time_frame>
    <description>Investigate the modification of intestinal microbiota.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">400</enrollment>
  <condition>Gastroenteritis</condition>
  <arm_group>
    <arm_group_label>Lactobacillus Rhamnosus Strain GG</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>LGG (6 × 109 colony forming units)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Lactobacillus Rhamnosus Strain GG</intervention_name>
    <description>Lactobacillus Rhamnosus Strain GG</description>
    <arm_group_label>Lactobacillus Rhamnosus Strain GG</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>LGG</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Children of 3 - 16 years of age;&#xD;
&#xD;
          2. Either sex.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Chronic disease,&#xD;
&#xD;
          2. Clinical history of abdominal pain history suggestive for functional&#xD;
             dyspepsia/aerophagia/abdominal migraine&#xD;
&#xD;
          3. Growth failure,&#xD;
&#xD;
          4. Alarm signs of organic conditions.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Years</minimum_age>
    <maximum_age>16 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ruggiero Francavilla</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Bari</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ruggiero FRANCAVILLA</last_name>
    <role>Principal Investigator</role>
    <affiliation>DEPARTMENT OF BIOMEDICINA ETA' EVOLUTIVA</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ruggiero Francavilla</last_name>
    <phone>0805592963</phone>
    <email>rfrancavilla@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Clinica Pediatrica</name>
      <address>
        <city>Bari</city>
        <state>Puglia</state>
        <zip>70125</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>August 2012</verification_date>
  <study_first_submitted>August 16, 2012</study_first_submitted>
  <study_first_submitted_qc>August 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 23, 2012</study_first_posted>
  <last_update_submitted>August 20, 2012</last_update_submitted>
  <last_update_submitted_qc>August 20, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 23, 2012</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Bari</investigator_affiliation>
    <investigator_full_name>Ruggiero Francavilla</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>Lactobacillus GG</keyword>
  <keyword>Functional Abdominal Pain</keyword>
  <keyword>Children</keyword>
  <keyword>Acute</keyword>
  <keyword>Gastroenteritis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gastroenteritis</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/NCT01671137
org study id: PrevenDAR
secondary id: Prevent-001
nct id: NCT01671137
lead sponsor: 
has dmc: Yes
The present study has several aims:

        1. Establish whether Lactobacillus Rhamnosus Strain GG is able to prevent the onset of IBS
           in a high risk group of children enrolled after an acute gastroenteritis (the study has
           been powered to this aim).

        2. Establish whether Lactobacillus Rhamnosus Strain GG is able to stabilize the intestinal
           microbiota after an acute gastroenteritis.

        3. Define the intestinal microbiota of children following an acute gastroenteritis and
           identify, if possible, a modification of the microbiota that can predict the emergence
           of Irritable Bowel Syndrome.
Study Design A randomized, double-blind, placebo-controlled, parallel-group trial planned
      following the recommendations established by the Consensus report on clinical trial in IBS.

      Children during/after an acute episode of gastroenteritis will enter a 12 months treatment
      (m1-m12) period followed by a 6 months follow-up phase (m13-m18).

      Children will be assigned consecutive numbers, starting with the lowest number available, and
      randomly assigned, with the use of a computer generated randomisation list using permuted
      block design, to receive orally either LGG (6 × 109 colony forming units) or placebo
      (capsules identical in taste and appearance to the active study product except for the
      absence of LGG) once a day. Enrolled children will be entered sequentially to receive the
      assigned treatment. Boxes containing placebo will have the same shape, dimension, indication
      and appearance as those containing the viable LGG and will be provided by the probiotic
      producer (Dicofarm SpA, Rome, Italy) which ensure that the study is blinded for investigators
      and patients. Group assignment will be concealed from participants and investigators.

      Power calculation With the assumption that, in a 12 month period, IBS would be expected in
      16% of children after an episode of acute gastroenteritis as opposed to 5% in the general
      paediatric population without gastroenteritis, we calculated that a sample of 210 children
      per group would be required for the study to have 80% power to show an advantage of LGG over
      placebo in reducing the rate of IBS, based on a two-sided type 1 error rate of 5%..

      Eligibility of Patients Patients recruited from primary care paediatricians or paediatric
      wards during/after (less seven days) an episode of gastroenteritis
      (bacteria/viruses/parasites).

      Inclusion criteria:

        1. Children of 2 - 16 years of age;

        2. Either sex.

      Exclusion criteria:

        1. Chronic disease,

        2. Clinical history of abdominal pain history suggestive for functional
           dyspepsia/aerophagia/abdominal migraine

        3. Growth failure,

        4. Alarm signs of organic conditions.

      Assessments, Compliance and Adherence. During the duration of the trial (m1-m18) patients
      will record gastrointestinal symptoms on monthly bases and the following data will be
      collected: a) questionnaire of frequency/severity of pain, b) school absence and c) GI
      symptom score by the compilation of the gastrointestinal symptom rating score.

      To assess the severity of pain a combination of the self-report Visual Analogue Scale (VAS)
      and the Faces Pain Scale (FPS) will be used. The 0-10 mm VAS scale (0 no pain, 10 worst
      possible pain) included a horizontal colour gradient (green-red), plus a rating. When asked
      to evaluate pain, the child would point to a level and trace a line. This particular VAS is a
      validated standard to evaluate pain in children older than five. Assessment was eased
      coupling the VAS with the FPS that consists of six faces ranging from a relaxed face to a
      face showing intense pain.

      Gastrointestinal symptom rating score (GSRS) consists of a 15-point questionnaire to assess
      severity and frequency of symptoms validated by Svedlund et al..

      During the six months of follow-up the questionnaire will be compiled every other months and
      the GSRS at month 18.

      The impact on parent's overall assessment of treatment will be obtained by a monthly
      interview by the question "how do you feel the medication is affecting the health of your
      child?"; possible answers are significant, mild, or no relief.

      To ensure compliance one investigator will contact the families every four weeks to monitor
      the process of the study. Adherence will be measured by counting the number of capsules
      returned at the study visit; children who missed for more than 20% of the medications were
      considered noncompliant.

      Outcome Measures Primary outcome will be the incidence in IBS in children receiving LGG as
      compared to those receiving placebo. We have chosen pain as the primary outcome measure, in
      line with the proposed points-to-consider for IBS trials.

      IBS or chronic abdominal pain will be diagnosed and categorised according to ROME III
      criteria.

      Secondary outcomes are: 1) evaluation of frequency/severity of symptoms according to
      treatment arm; 2) evaluation of perception of children's health according to parents and 3)
      modification of intestinal microbiota.

      Intestinal microbiota The intestinal microbiota will be assesses according to methods
      published elsewhere.

      To define the modification of the intestinal microbiota following an acute gastroenteritis
      and to determine whether the onset of the IBS is anticipated by a modification of intestinal
      microbiota we will proceed to the collection of faecal samples at entry, after one month and
      every two months after enrolment. During the six months of follow-up a fecal sample will be
      collected only at month 18.

      Bacteria DNA in stools will be extracted and stored at -80°C for future analysis. At the end
      of the trial a subset of informative fecal bacterial DNA will be assessed: a) patients that
      have NOT developed IBS (LGG and placebo), b) patients that have developed IBS (LGG and
      placebo).

      The analysis of the intestinal microbiota of these informative cases will help to assess
      whether there is a intestinal microbiota suggestive of future inset of IBS and ability of LGG
      to stabilize the intestinal microbiota.

      Adverse Events and Disallowed Medication Adverse events were monitored throughout the study.
      Children will not allowed to consume any probiotic other than those provided (except for a
      transient period no longer that 2 weeks) and they will be invited to continue their eating
      and physical exercise habits. Concomitant use of medications affecting gastrointestinal
      motility and/or pain perception was allowed, providing parents registered the intake.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Prevention of Abdominal pain
time frame: 18 months
description: Primary outcome will be the incidence in IBS in children receiving LGG as compared to those receiving placebo. We have chosen pain as the primary outcome measure, in line with the proposed points-toconsider for IBS trials (Corazziari E. Consensus report: Clinical trial guidelines for pharmacological treatment of irritable bowel syndrome. Aliment Pharmcol Ther 2003;18:569).
IBS or chronic abdominal pain will be diagnosed and categorised according to ROME III criteria (Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006;130).
measure: Incidence of IBS
time frame: 6 months
description: Evaluation of frequency/severity of symptoms according to treatment arm;
measure: Children's health
time frame: 24 months
description: Evaluation of perception of children's health according to parents
measure: Intestinal microbiota
time frame: 24 months
description: Investigate the modification of intestinal microbiota.
arm group label: Lactobacillus Rhamnosus Strain GG
arm group type: Active Comparator
description: LGG (6 × 109 colony forming units)
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo
intervention type: Other
intervention name: Lactobacillus Rhamnosus Strain GG
description: Lactobacillus Rhamnosus Strain GG
arm group label: Lactobacillus Rhamnosus Strain GG
arm group label: Placebo
other name: LGG
criteria: 
gender: All
minimum age: 3 Years
maximum age: 16 Years
healthy volunteers: No
last name: Ruggiero Francavilla
role: Principal Investigator
affiliation: University of Bari
last name: Ruggiero FRANCAVILLA
role: Principal Investigator
affiliation: DEPARTMENT OF BIOMEDICINA ETA' EVOLUTIVA
last name: Ruggiero Francavilla
phone: 0805592963
email: rfrancavilla@gmail.com
facility: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: University of Bari
investigator full name: Ruggiero Francavilla
investigator title: MD, PhD
mesh term: Gastroenteritis