<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/NCT01667627</url>
  </required_header>
  <id_info>
    <org_study_id>TASMC-11-RD-0491-CTIL</org_study_id>
    <nct_id>NCT01667627</nct_id>
  </id_info>
  <brief_title>Probiotic in Irritable Bowel Syndrome (IBS) Patients With Diarrhea</brief_title>
  <acronym>IBS-D</acronym>
  <official_title>A Double-blind, Placebo-controlled Study to Assess the Effect of Probiotic on Symptom Relief and Indices of Micro-inflammation and Cholinergic Status in IBS Patients With Diarrhea.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tel-Aviv Sourasky Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Tel-Aviv Sourasky Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      We present the study design of a clinical trial designed to assess the clinical effects of&#xD;
      the multispecies probiotic combination &quot;BIO-25&quot; in IBS-D patients. To this aim the primary&#xD;
      endpoints of the study will be improvement in abdominal pain and stool consistency. The study&#xD;
      will also be designed and powered to investigate the effect of the probiotic BIO-25 on the&#xD;
      putative inflammation-associated parameters related to microinflammation in IBS, using&#xD;
      postulated improvements in Hs-CRP, and calprotectin as markers of that effect. Additional&#xD;
      aims of the study will examine the possible effect of probiotic BIO-25 on the cholinergic&#xD;
      status.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Probiotic treatment in IBS is safe and effective. Probiotics have been shown to improve the&#xD;
      anti-inflammatory/proinflammatory ratio, and may also improve intestinal motility, and the&#xD;
      bacterial composition of the intestines. There is a substantial body of evidence in support&#xD;
      of the use of probiotics in IBS. Probiotics appear to be particularly effective in the&#xD;
      reduction of abdominal bloating and discomfort. The strains of the multispecies probiotic&#xD;
      combination (BIO-25 LR) were tested and found to be beneficial in well-designed studies of&#xD;
      IBS patients. Patients with post-infectious IBS, as well as many patients with &quot;classic&quot; IBS,&#xD;
      manifest a low-grade inflammatory state that may be associated with visceral hypersensitivity&#xD;
      and impaired motility. Probiotics may suppress this low-grade inflammation. In a recent study&#xD;
      we found that highly sensitive CRP (hs-CRP), a serum marker of micro-inflammation, was&#xD;
      significantly higher in patients with diarrhea-predominant IBS than healthy controls,&#xD;
      although within normal limits in both groups. Thus, hs-CRP may serve as a marker of this&#xD;
      low-grade, sub-clinical inflammation. If treatment with probiotic reduces the degree of&#xD;
      low-grade inflammation in IBS, the improvement may be reflected in reduced hs-CRP levels.&#xD;
      This study can contribute to our understanding of the pathophysiology of IBS and provide&#xD;
      further evidence for the effectiveness of probiotic in its treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2014</start_date>
  <completion_date type="Actual">April 2015</completion_date>
  <primary_completion_date type="Actual">April 2015</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Symptom relief (abdominal pain and stool consistency)</measure>
    <time_frame>8 weeks</time_frame>
    <description>Abdominal pain intensity, stool consistency, will be assessed by visual analogue scales (VAS) with scales from 0 (no symptom at all) to 10 (the worst possible symptom.&#xD;
The definition of treatment responders is based on the FDA Draft Guidance for Clinical Evaluation of Products for Treatment of Irritable Bowel Syndrome.&#xD;
A Pain Intensity Responder is a patient who experiences a 30% or greater decrease in the weekly average of worst abdominal pain in past 24 hours in the past 24 hours compared to baseline.&#xD;
A Stool Consistency Responder is a patient who has a greater than 50% decrease in the number of days with at least one stool ≥ type 6 using the Bristol Stool Scale (BSS).&#xD;
A patient will be classified as an overall responder if they achieve the above improvement in pain intensity and stool consistency for at least 50 percent of the time.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Improvement in other specific IBS symptoms, i.e., gas and bloating, feeling of urgency</measure>
    <time_frame>8 weeks</time_frame>
    <description>Specific IBS symptoms, i.e., gas and bloating, feeling of urgency, will be assessed by visual analogue scales (VAS) with scales from 0 (no symptom at all) to 10 (the worst possible symptom).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reduce hs-CRP levels</measure>
    <time_frame>8 weeks</time_frame>
    <description>Blood will be drawn from IBS-D patients after a 12-hour fast and will be analyzed for hs-CRP.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Improve the cholinergic status</measure>
    <time_frame>8 weeks</time_frame>
    <description>Plasma cholinesterase catalytic activity measurements will involve adaptation of a spectrophotometric method to a microtiter plate assay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reduce calprotectin levels</measure>
    <time_frame>8 weeks</time_frame>
    <description>At the beginning and at the end of the treatment period, fecal samples will be obtained for the measurement of calprotectin levels.&#xD;
The quantitative concentration of calprotectin will be determined by enzyme linked immunosorbent assay (ELISA).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">107</enrollment>
  <condition>IBS</condition>
  <arm_group>
    <arm_group_label>BIO-25, Probiotic-mixture</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Two capsules a day.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Identical to the Bio-25 capsule: same taste, same colour, same appearance</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Bio-25</intervention_name>
    <description>Each capsule of the multispecies probiotic combination Bio-25 consists of 25 billion live bacteria.&#xD;
Each type of bio-25 contains billions of live lactic acid bacteria in defined ratios of lyophilized Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasein, Lactobacillus casei, Bifidobacterium bifidum,Lactobacillus lactis, Lactobacillus rhamnosus,and Streptococcus thermophilus.</description>
    <arm_group_label>BIO-25, Probiotic-mixture</arm_group_label>
    <other_name>Probiotic</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Identical placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        A diagnosis of IBS-D according to the Rome III criteria, agreement to participate and the&#xD;
        ability to sign an informed consent. Moreover, the definition of inclusion criteria is&#xD;
        based on the FDA Draft Guidance for Clinical Evaluation of Products (add ref here). Over&#xD;
        the two week run-in period:&#xD;
&#xD;
          -  Pain Intensity: weekly average of worst abdominal pain in past 24 hours score of ≥ 3.0&#xD;
             on a 0 (no pain at all) to 10 (worst possible pain) point scale&#xD;
&#xD;
          -  Stool Consistency: ≥30% of days/week with at least one stool ≥6 using the Bristol&#xD;
             Stool Score (BSS, Fig. 1) (ref).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        1) Hyperthyroidism, 2) celiac disease 3) pregnancy, 4) other gastrointestinal diagnoses&#xD;
        that might interfere with the study (e.g. active peptic disease, inflammatory bowel&#xD;
        disease), 5) a history of malignancy that might, to the best judgment of the doctor,&#xD;
        interfere with the study, 6) any infectious or inflammatory disease within the last month,&#xD;
        7) active medically treated asthma, 8) baseline levels of HsCRP &gt; 10mg/liter, 9) steroid&#xD;
        treatment for any indication, 10) fecal incontinence, and 11) treatment with probiotics or&#xD;
        antibiotics of any kind within the last 4 weeks, 11) Diabetes.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ami Sperber, MD</last_name>
    <role>Study Director</role>
    <affiliation>Tel Aviv Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Roy Dekel, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Tel Aviv Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Tel-Aviv Sourasky Medical Center</name>
      <address>
        <city>Tel-Aviv</city>
        <state>Central Israel</state>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>May 2018</verification_date>
  <study_first_submitted>August 15, 2012</study_first_submitted>
  <study_first_submitted_qc>August 16, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 17, 2012</study_first_posted>
  <last_update_submitted>May 23, 2018</last_update_submitted>
  <last_update_submitted_qc>May 23, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">May 24, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>IBS</keyword>
  <keyword>Probiotic</keyword>
  <keyword>hs-CRP</keyword>
  <keyword>Cholinergic status</keyword>
  <keyword>Micro-inflammation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <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/NCT01667627
org study id: TASMC-11-RD-0491-CTIL
nct id: NCT01667627
lead sponsor: 
has dmc: No
We present the study design of a clinical trial designed to assess the clinical effects of
      the multispecies probiotic combination "BIO-25" in IBS-D patients. To this aim the primary
      endpoints of the study will be improvement in abdominal pain and stool consistency. The study
      will also be designed and powered to investigate the effect of the probiotic BIO-25 on the
      putative inflammation-associated parameters related to microinflammation in IBS, using
      postulated improvements in Hs-CRP, and calprotectin as markers of that effect. Additional
      aims of the study will examine the possible effect of probiotic BIO-25 on the cholinergic
      status.
Probiotic treatment in IBS is safe and effective. Probiotics have been shown to improve the
      anti-inflammatory/proinflammatory ratio, and may also improve intestinal motility, and the
      bacterial composition of the intestines. There is a substantial body of evidence in support
      of the use of probiotics in IBS. Probiotics appear to be particularly effective in the
      reduction of abdominal bloating and discomfort. The strains of the multispecies probiotic
      combination (BIO-25 LR) were tested and found to be beneficial in well-designed studies of
      IBS patients. Patients with post-infectious IBS, as well as many patients with "classic" IBS,
      manifest a low-grade inflammatory state that may be associated with visceral hypersensitivity
      and impaired motility. Probiotics may suppress this low-grade inflammation. In a recent study
      we found that highly sensitive CRP (hs-CRP), a serum marker of micro-inflammation, was
      significantly higher in patients with diarrhea-predominant IBS than healthy controls,
      although within normal limits in both groups. Thus, hs-CRP may serve as a marker of this
      low-grade, sub-clinical inflammation. If treatment with probiotic reduces the degree of
      low-grade inflammation in IBS, the improvement may be reflected in reduced hs-CRP levels.
      This study can contribute to our understanding of the pathophysiology of IBS and provide
      further evidence for the effectiveness of probiotic in its treatment.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Symptom relief (abdominal pain and stool consistency)
time frame: 8 weeks
description: Abdominal pain intensity, stool consistency, will be assessed by visual analogue scales (VAS) with scales from 0 (no symptom at all) to 10 (the worst possible symptom.
The definition of treatment responders is based on the FDA Draft Guidance for Clinical Evaluation of Products for Treatment of Irritable Bowel Syndrome.
A Pain Intensity Responder is a patient who experiences a 30% or greater decrease in the weekly average of worst abdominal pain in past 24 hours in the past 24 hours compared to baseline.
A Stool Consistency Responder is a patient who has a greater than 50% decrease in the number of days with at least one stool ≥ type 6 using the Bristol Stool Scale (BSS).
A patient will be classified as an overall responder if they achieve the above improvement in pain intensity and stool consistency for at least 50 percent of the time.
measure: Improvement in other specific IBS symptoms, i.e., gas and bloating, feeling of urgency
time frame: 8 weeks
description: Specific IBS symptoms, i.e., gas and bloating, feeling of urgency, will be assessed by visual analogue scales (VAS) with scales from 0 (no symptom at all) to 10 (the worst possible symptom).
measure: Reduce hs-CRP levels
time frame: 8 weeks
description: Blood will be drawn from IBS-D patients after a 12-hour fast and will be analyzed for hs-CRP.
measure: Improve the cholinergic status
time frame: 8 weeks
description: Plasma cholinesterase catalytic activity measurements will involve adaptation of a spectrophotometric method to a microtiter plate assay
measure: Reduce calprotectin levels
time frame: 8 weeks
description: At the beginning and at the end of the treatment period, fecal samples will be obtained for the measurement of calprotectin levels.
The quantitative concentration of calprotectin will be determined by enzyme linked immunosorbent assay (ELISA).
arm group label: BIO-25, Probiotic-mixture
arm group type: Active Comparator
description: Two capsules a day.
arm group label: Placebo
arm group type: Placebo Comparator
description: Identical to the Bio-25 capsule: same taste, same colour, same appearance
intervention type: Dietary Supplement
intervention name: Bio-25
description: Each capsule of the multispecies probiotic combination Bio-25 consists of 25 billion live bacteria.
Each type of bio-25 contains billions of live lactic acid bacteria in defined ratios of lyophilized Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasein, Lactobacillus casei, Bifidobacterium bifidum,Lactobacillus lactis, Lactobacillus rhamnosus,and Streptococcus thermophilus.
arm group label: BIO-25, Probiotic-mixture
other name: Probiotic
intervention type: Other
intervention name: Placebo
description: Identical placebo
arm group label: Placebo
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Ami Sperber, MD
role: Study Director
affiliation: Tel Aviv Medical Center
last name: Roy Dekel, MD
role: Principal Investigator
affiliation: Tel Aviv Medical Center
facility: 
country: Israel
responsible party type: Sponsor
mesh term: Diarrhea