<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/NCT02204891</url>
  </required_header>
  <id_info>
    <org_study_id>LACTO01</org_study_id>
    <nct_id>NCT02204891</nct_id>
  </id_info>
  <brief_title>Probiotics in Intestinal Bacterial Overgrowth</brief_title>
  <official_title>A Clinical Study of the Efficacy of a Formulation of Four Probiotics in Patients With Syndrome of Intestinal Bacterial Overgrowth and Irritable Bowel Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Athens</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Athens</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of the present study is to demonstrate the effect of a mixture of four species of&#xD;
      probiotics (Saccharomyces boulardii, Bifidobacterium lactis BB-12, Lactobacillus acidophilus&#xD;
      LA-5 and Lactobacillus plantarum) in patients with symptomatic irritable bowel syndrome (IBS)&#xD;
      who have culture verified syndrome of intestinal bacterial overgrowth (SIBO) and those who do&#xD;
      not have. This will provide direct evidence for the role of probiotics in treating part of&#xD;
      the pathogenesis of IBS.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder. Pathogenesis&#xD;
      remains multifactorial. Better understanding of the interaction of the host with intestinal&#xD;
      microbiota the last decade led to the knowledge that many of the symptoms of IBS, mainly&#xD;
      bloating and diarrhea, are related with the overgrowth of bacteria of colonic type in the&#xD;
      small intestine. This overgrowth frames the syndrome of intestinal bacterial overgrowth&#xD;
      (SIBO) where colonic type of bacteria predominate in the proximal parts of the small&#xD;
      intestine. Fermentation of dietary carbohydrates by the bacteria colonizers of SIBO ends with&#xD;
      the over-production of gas generating thus symptoms of IBS. The relationship between IBS and&#xD;
      SIBO was found by a series of prospective observational studies using the lactulose and the&#xD;
      glucose tolerance tests for the diagnosis of SIBO. Using this test, the prevalence of SIBO in&#xD;
      patients with IBS ranged between 65 and 85%. The gold-standard technique for the diagnosis of&#xD;
      SIBO is the quantitative culture of the content of the proximal intestine i.e. of the&#xD;
      duodenum after upper GI tract endoscopy. Few studies are available with this design and they&#xD;
      suggest a growth of colonic type of flora at counts equal to or greater than 10^5 cfu/ml as&#xD;
      diagnostic of SIBO. Based on systematic review of the literature but also on data generated&#xD;
      in a cohort of 320 consecutive patients undergoing upper GI tract endoscopy, normal subjects&#xD;
      are never greater than 10^3 cfu/m in the duodenum. In the latter publication coming from&#xD;
      Athens, using variable cut-offs greater than 10^3 or 10^4 or 10^5 cfu/ml for the diagnosis of&#xD;
      SIBO, the frequency of SIBO was significantly greater among sufferers than among&#xD;
      non-sufferers from IBS.&#xD;
&#xD;
      Oral supplementation with probiotics may be a rational approach for the eradication of SIBO&#xD;
      and subsequently of the symptoms of IBS. The majority of probiotic bacteria belong to the&#xD;
      Lactobacillus and Bifidobacterium genera. They are Gram-positive lactic acid-producing&#xD;
      bacteria that constitute a major part of the normal intestinal microflora in animals and&#xD;
      humans. The rationale behind their use as a therapeutic strategy in IBS is that orally&#xD;
      administered probiotics may replace the overgrown enteric-type bacteria of SIBO. Four&#xD;
      randomized clinical trials are available evaluating the efficacy of orally administered&#xD;
      probiotics in IBS. The common findings of these trials are that a) efficacy refers to the&#xD;
      improvement of symptoms of bloating and of diarrhea that are typical symptoms of the presence&#xD;
      of SIBO; and b) efficacy is usually found when mixtures of different species of probiotics&#xD;
      are used. However, no study has ever tested the efficacy of probiotics in patients with IBS&#xD;
      and SIBO proven by small intestinal culture.&#xD;
&#xD;
      The aim of the present study is to demonstrate the effect of a mixture of four species of&#xD;
      probiotics (Saccharomyces boulardii, Bifidobacterium lactis BB-12, Lactobacillus acidophilus&#xD;
      LA-5 and Lactobacillus plantarum) in patients with symptomatic IBS who have culture verified&#xD;
      SIBO and those who do not have. This will provide direct evidence for the role of probiotics&#xD;
      in treating part of the pathogenesis of IBS.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 2014</start_date>
  <completion_date type="Actual">September 2016</completion_date>
  <primary_completion_date type="Actual">June 2016</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>• The efficacy of probiotics in improvement of symptoms of IBS in patients with SIBO compared to their efficacy in patients with IBS without SIBO.</measure>
    <time_frame>30 days</time_frame>
    <description>This will be assessed after 30 days from start of therapy (visit 2) by comparisons of grading of symptoms and results of OLT between the two groups of treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>• The efficacy of probiotics in symptoms of IBS in patients with SIBO compared to their efficacy in patients with IBS without SIBO.</measure>
    <time_frame>60 days</time_frame>
    <description>This will be assessed after 60 days from start of therapy (visit 3) by comparisons of grading of symptoms and results of OLT between the two groups of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The efficacy of probiotics in specific symptoms of IBS both visits 2 and 3.</measure>
    <time_frame>Days 30 and 60</time_frame>
    <description>This will be done by comparing the grading for every symptom of IBS of patients in visits 2 and 3 compared with the baseline visit 1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>• The importance of the inflammation cascade in the pathogenesis of SIBO-related IBS.</measure>
    <time_frame>30 days</time_frame>
    <description>This will be done by comparing the duodenal aspirate cytokines of the two groups of treatment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">26</enrollment>
  <condition>Irritable Bowel Syndrome</condition>
  <arm_group>
    <arm_group_label>Probiotics in SIBO</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Administration of probiotics in patients with IBS and SIBO</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Probiotics</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Administration of probiotics in patients with IBS without SIBO</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Probiotics in SIBO</intervention_name>
    <description>Mixture of the four probiotics in one capsule. One capsule twice daily for 30 days</description>
    <arm_group_label>Probiotics in SIBO</arm_group_label>
    <other_name>Saccharomyces Bifidobacterium Lactobacillus species</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Probiotics</intervention_name>
    <description>One capsule twice daily for 30 days</description>
    <arm_group_label>Probiotics</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥18 years&#xD;
&#xD;
          2. Both genders&#xD;
&#xD;
          3. Written informed consent by study participants&#xD;
&#xD;
          4. Presence of IBS according to Rome III criteria&#xD;
&#xD;
          5. Equal number of SIBO-positive and SIBO-negative patients&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Age &lt;18 years&#xD;
&#xD;
          2. Deny to consent&#xD;
&#xD;
          3. Pregnancy or lactation&#xD;
&#xD;
          4. Presence of inflammatory bowel disease&#xD;
&#xD;
          5. Presence of acute GI tract infection&#xD;
&#xD;
          6. Diabetes mellitus type 1 or type 2&#xD;
&#xD;
          7. Use of laxatives and antibiotics within the preceding 6 weeks&#xD;
&#xD;
          8. Presence of fever, abdominal mass, signs of bowel obstruction and/or leucocytosis&#xD;
&#xD;
          9. Abnormal serum levels of thyroid -stimulating hormone.&#xD;
&#xD;
         10. History of colon cancer or diverticulitis&#xD;
&#xD;
         11. Infection by human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C&#xD;
             virus&#xD;
&#xD;
         12. Patients with celiac disease defined by biopsy of the duodenal mucosa.&#xD;
&#xD;
         13. History of scleroderma and gastroparesis&#xD;
&#xD;
         14. Pregnancy or planning pregnancy the next 3 months&#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>Konstantinos Triantafyllou, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Athens, Medical School</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Evangelos Giamarellos-Bourboulis, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Athens, Medical School</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Gastroenterology, ATTIKON University Hospital</name>
      <address>
        <city>Athens</city>
        <state>Attiki</state>
        <zip>12462</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Greece</country>
  </location_countries>
  <reference>
    <citation>Pyleris E, Giamarellos-Bourboulis EJ, Tzivras D, Koussoulas V, Barbatzas C, Pimentel M. The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: relationship with irritable bowel syndrome. Dig Dis Sci. 2012 May;57(5):1321-9. doi: 10.1007/s10620-012-2033-7. Epub 2012 Jan 20.</citation>
    <PMID>22262197</PMID>
  </reference>
  <reference>
    <citation>Choi CH, Jo SY, Park HJ, Chang SK, Byeon JS, Myung SJ. A randomized, double-blind, placebo-controlled multicenter trial of saccharomyces boulardii in irritable bowel syndrome: effect on quality of life. J Clin Gastroenterol. 2011 Sep;45(8):679-83. doi: 10.1097/MCG.0b013e318204593e. Erratum In: J Clin Gastroenterol. 2011 Oct;45(9):838.</citation>
    <PMID>21301358</PMID>
  </reference>
  <reference>
    <citation>Ringel-Kulka T, Palsson OS, Maier D, Carroll I, Galanko JA, Leyer G, Ringel Y. Probiotic bacteria Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 versus placebo for the symptoms of bloating in patients with functional bowel disorders: a double-blind study. J Clin Gastroenterol. 2011 Jul;45(6):518-25. doi: 10.1097/MCG.0b013e31820ca4d6.</citation>
    <PMID>21436726</PMID>
  </reference>
  <reference>
    <citation>Ki Cha B, Mun Jung S, Hwan Choi C, Song ID, Woong Lee H, Joon Kim H, Hyuk J, Kyung Chang S, Kim K, Chung WS, Seo JG. The effect of a multispecies probiotic mixture on the symptoms and fecal microbiota in diarrhea-dominant irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Clin Gastroenterol. 2012 Mar;46(3):220-7. doi: 10.1097/MCG.0b013e31823712b1.</citation>
    <PMID>22157240</PMID>
  </reference>
  <reference>
    <citation>Yoon JS, Sohn W, Lee OY, Lee SP, Lee KN, Jun DW, Lee HL, Yoon BC, Choi HS, Chung WS, Seo JG. Effect of multispecies probiotics on irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Gastroenterol Hepatol. 2014 Jan;29(1):52-9. doi: 10.1111/jgh.12322.</citation>
    <PMID>23829297</PMID>
  </reference>
  <verification_date>March 2017</verification_date>
  <study_first_submitted>July 28, 2014</study_first_submitted>
  <study_first_submitted_qc>July 28, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 31, 2014</study_first_posted>
  <last_update_submitted>March 17, 2017</last_update_submitted>
  <last_update_submitted_qc>March 17, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">March 20, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Athens</investigator_affiliation>
    <investigator_full_name>Evangelos J. Giamarellos-Bourboulis, M.D.</investigator_full_name>
    <investigator_title>Associate Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>Abdominal pain</keyword>
  <keyword>Abdominal discomfort</keyword>
  <keyword>Flatulence</keyword>
  <keyword>Diarrhea</keyword>
  <keyword>Bacterial overgrowth</keyword>
  <keyword>Cytokines</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Irritable Bowel Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_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/NCT02204891
org study id: LACTO01
nct id: NCT02204891
lead sponsor: 
has dmc: No
The aim of the present study is to demonstrate the effect of a mixture of four species of
      probiotics (Saccharomyces boulardii, Bifidobacterium lactis BB-12, Lactobacillus acidophilus
      LA-5 and Lactobacillus plantarum) in patients with symptomatic irritable bowel syndrome (IBS)
      who have culture verified syndrome of intestinal bacterial overgrowth (SIBO) and those who do
      not have. This will provide direct evidence for the role of probiotics in treating part of
      the pathogenesis of IBS.
Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder. Pathogenesis
      remains multifactorial. Better understanding of the interaction of the host with intestinal
      microbiota the last decade led to the knowledge that many of the symptoms of IBS, mainly
      bloating and diarrhea, are related with the overgrowth of bacteria of colonic type in the
      small intestine. This overgrowth frames the syndrome of intestinal bacterial overgrowth
      (SIBO) where colonic type of bacteria predominate in the proximal parts of the small
      intestine. Fermentation of dietary carbohydrates by the bacteria colonizers of SIBO ends with
      the over-production of gas generating thus symptoms of IBS. The relationship between IBS and
      SIBO was found by a series of prospective observational studies using the lactulose and the
      glucose tolerance tests for the diagnosis of SIBO. Using this test, the prevalence of SIBO in
      patients with IBS ranged between 65 and 85%. The gold-standard technique for the diagnosis of
      SIBO is the quantitative culture of the content of the proximal intestine i.e. of the
      duodenum after upper GI tract endoscopy. Few studies are available with this design and they
      suggest a growth of colonic type of flora at counts equal to or greater than 10^5 cfu/ml as
      diagnostic of SIBO. Based on systematic review of the literature but also on data generated
      in a cohort of 320 consecutive patients undergoing upper GI tract endoscopy, normal subjects
      are never greater than 10^3 cfu/m in the duodenum. In the latter publication coming from
      Athens, using variable cut-offs greater than 10^3 or 10^4 or 10^5 cfu/ml for the diagnosis of
      SIBO, the frequency of SIBO was significantly greater among sufferers than among
      non-sufferers from IBS.

      Oral supplementation with probiotics may be a rational approach for the eradication of SIBO
      and subsequently of the symptoms of IBS. The majority of probiotic bacteria belong to the
      Lactobacillus and Bifidobacterium genera. They are Gram-positive lactic acid-producing
      bacteria that constitute a major part of the normal intestinal microflora in animals and
      humans. The rationale behind their use as a therapeutic strategy in IBS is that orally
      administered probiotics may replace the overgrown enteric-type bacteria of SIBO. Four
      randomized clinical trials are available evaluating the efficacy of orally administered
      probiotics in IBS. The common findings of these trials are that a) efficacy refers to the
      improvement of symptoms of bloating and of diarrhea that are typical symptoms of the presence
      of SIBO; and b) efficacy is usually found when mixtures of different species of probiotics
      are used. However, no study has ever tested the efficacy of probiotics in patients with IBS
      and SIBO proven by small intestinal culture.

      The aim of the present study is to demonstrate the effect of a mixture of four species of
      probiotics (Saccharomyces boulardii, Bifidobacterium lactis BB-12, Lactobacillus acidophilus
      LA-5 and Lactobacillus plantarum) in patients with symptomatic IBS who have culture verified
      SIBO and those who do not have. This will provide direct evidence for the role of probiotics
      in treating part of the pathogenesis of IBS.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: • The efficacy of probiotics in improvement of symptoms of IBS in patients with SIBO compared to their efficacy in patients with IBS without SIBO.
time frame: 30 days
description: This will be assessed after 30 days from start of therapy (visit 2) by comparisons of grading of symptoms and results of OLT between the two groups of treatment.
measure: • The efficacy of probiotics in symptoms of IBS in patients with SIBO compared to their efficacy in patients with IBS without SIBO.
time frame: 60 days
description: This will be assessed after 60 days from start of therapy (visit 3) by comparisons of grading of symptoms and results of OLT between the two groups of treatment.
measure: The efficacy of probiotics in specific symptoms of IBS both visits 2 and 3.
time frame: Days 30 and 60
description: This will be done by comparing the grading for every symptom of IBS of patients in visits 2 and 3 compared with the baseline visit 1.
measure: • The importance of the inflammation cascade in the pathogenesis of SIBO-related IBS.
time frame: 30 days
description: This will be done by comparing the duodenal aspirate cytokines of the two groups of treatment.
arm group label: Probiotics in SIBO
arm group type: Experimental
description: Administration of probiotics in patients with IBS and SIBO
arm group label: Probiotics
arm group type: Active Comparator
description: Administration of probiotics in patients with IBS without SIBO
intervention type: Dietary Supplement
intervention name: Probiotics in SIBO
description: Mixture of the four probiotics in one capsule. One capsule twice daily for 30 days
arm group label: Probiotics in SIBO
other name: Saccharomyces Bifidobacterium Lactobacillus species
intervention type: Dietary Supplement
intervention name: Probiotics
description: One capsule twice daily for 30 days
arm group label: Probiotics
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Konstantinos Triantafyllou, MD, PhD
role: Principal Investigator
affiliation: University of Athens, Medical School
last name: Evangelos Giamarellos-Bourboulis, MD, PhD
role: Principal Investigator
affiliation: University of Athens, Medical School
facility: 
country: Greece
citation: Pyleris E, Giamarellos-Bourboulis EJ, Tzivras D, Koussoulas V, Barbatzas C, Pimentel M. The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: relationship with irritable bowel syndrome. Dig Dis Sci. 2012 May;57(5):1321-9. doi: 10.1007/s10620-012-2033-7. Epub 2012 Jan 20.
PMID: 22262197
citation: Choi CH, Jo SY, Park HJ, Chang SK, Byeon JS, Myung SJ. A randomized, double-blind, placebo-controlled multicenter trial of saccharomyces boulardii in irritable bowel syndrome: effect on quality of life. J Clin Gastroenterol. 2011 Sep;45(8):679-83. doi: 10.1097/MCG.0b013e318204593e. Erratum In: J Clin Gastroenterol. 2011 Oct;45(9):838.
PMID: 21301358
citation: Ringel-Kulka T, Palsson OS, Maier D, Carroll I, Galanko JA, Leyer G, Ringel Y. Probiotic bacteria Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 versus placebo for the symptoms of bloating in patients with functional bowel disorders: a double-blind study. J Clin Gastroenterol. 2011 Jul;45(6):518-25. doi: 10.1097/MCG.0b013e31820ca4d6.
PMID: 21436726
citation: Ki Cha B, Mun Jung S, Hwan Choi C, Song ID, Woong Lee H, Joon Kim H, Hyuk J, Kyung Chang S, Kim K, Chung WS, Seo JG. The effect of a multispecies probiotic mixture on the symptoms and fecal microbiota in diarrhea-dominant irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Clin Gastroenterol. 2012 Mar;46(3):220-7. doi: 10.1097/MCG.0b013e31823712b1.
PMID: 22157240
citation: Yoon JS, Sohn W, Lee OY, Lee SP, Lee KN, Jun DW, Lee HL, Yoon BC, Choi HS, Chung WS, Seo JG. Effect of multispecies probiotics on irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Gastroenterol Hepatol. 2014 Jan;29(1):52-9. doi: 10.1111/jgh.12322.
PMID: 23829297
responsible party type: Principal Investigator
investigator affiliation: University of Athens
investigator full name: Evangelos J. Giamarellos-Bourboulis, M.D.
investigator title: Associate Professor of Medicine
mesh term: Irritable Bowel Syndrome
mesh term: Syndrome
sharing ipd: No