<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/NCT03798210</url>
  </required_header>
  <id_info>
    <org_study_id>ATCC PTA 4659</org_study_id>
    <nct_id>NCT03798210</nct_id>
  </id_info>
  <brief_title>Lactobacillus Reuteri ATCC PTA 4659 in Ulcerative Colitis</brief_title>
  <acronym>COLUS</acronym>
  <official_title>The Effect of Lactobacillus Reuteri ATCC PTA 4659 in Patients With Ulcerative Colitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Uppsala University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Uppsala University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Explorative investigation to study the effect of the endogenous bacterium Lactobacillus&#xD;
      reuteri ATCC PTA 4659 as a nutrient additive against relapse in ulcerative colitis. Forty&#xD;
      patients will be studied with a randomized parallel design over one year. Patients with&#xD;
      established treatment against relapse of ulcerative colitis with mesalazine ≤4 grams will be&#xD;
      requested to participate in the study, allocated to 20 patients with placebo and 20 with&#xD;
      active treatment L. reuteri as an &quot;add-on&quot;. Inklusion: 18-80 years of age, ≥1 relapse with&#xD;
      bleeding during previous 12 months with a disease activity Mayo Clinical Score ≤2, treatment&#xD;
      with mesalazine ≤4,0 g daily. Exklusion: &gt;80 years of age, no registered bleeding during&#xD;
      recent 12 months, on-going steroid treatment, immunosuppressives, biologics or adhesion&#xD;
      inhibitors, antibiotics or other clinical trial. behandling med probiotika. Disease&#xD;
      monitoring will be done with:&#xD;
&#xD;
      Time to disease relapse with macroscopic bleeding and Mayo score ≥5, blood chemistry and CRP,&#xD;
      lipopolysaccharides and gut permeability, fecal calprotectin, and short health scale at 4&#xD;
      weeks, 26 weeks and 52 weeks.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Research question To study whether dietary supplementation with L. reuteri ATCC PTA 4659&#xD;
      (Lr4659) is safe and can reduce the relapse rate and have a positive effect in patients with&#xD;
      ulcerative colitis (UC).&#xD;
&#xD;
      Lr4659 is a naturally occurring strain of human origin. It is a typical member of the L.&#xD;
      reuteri species, with typical sugar fermentation patterns, reuterin production and growth&#xD;
      characteristics. Identification using 16SrRNA gene analysis shows that it has 99% similarity&#xD;
      with the type strain of L. reuteri thus confirming that it belongs to this well-known and&#xD;
      well-studied species that is considered safe for human consumption. In vitro studies indicate&#xD;
      that this strain has strong tolerance to acid environments, as do many other L. reuteri&#xD;
      strains and that it has the unusual ability to interfere with TNFalpha mediated propagation&#xD;
      of inflammatory responses in human macrophages.&#xD;
&#xD;
      Treatment with the probiotic bacterium L. reuteri has been shown to prevent dextran sodium&#xD;
      sulfate (DSS)-induced colitis in rats. During DSS-induced colitis, the number of bacteria in&#xD;
      the inner firmly-adherent mucus layer increased and bacterial composition of the two layers&#xD;
      no longer differed. However, L. reuteri decreased the bacterial translocation from the&#xD;
      intestine to mesenteric lymph nodes during DSS treatment, which might be an important part of&#xD;
      the mechanisms by which L. reuteri ameliorates DSS-induced colitis in rats.&#xD;
&#xD;
      Study design This is a double-blind randomized clinical trial. Randomization will be done to&#xD;
      either mesalazine plus Lr4659, or to mesalazine plus placebo for a continuous treatment until&#xD;
      new bleeding episode or a maximum of 52 weeks.&#xD;
&#xD;
      Forty patients with UC in remission, medicated with &lt;4 g mesalazine and aged over 18 years&#xD;
      will be recruited. After written consent to the study the subjects in whom the eligibility&#xD;
      criteria are confirmed the subjects will be randomized to receive either 2 daily doses of&#xD;
      Lr4659 (n=15) or the corresponding placebo. The total length of study treatment is 52 weeks.&#xD;
&#xD;
      Concomitant treatment During the period of the study, the subjects will refrain from&#xD;
      ingestion of any kind of probiotic or bacterial preparation.&#xD;
&#xD;
      The objective is to determine whether dietary supplementation with Lr4659 is able to: Prolong&#xD;
      time in remission and Time from last bleeding episode until re-bleeding, Time from start of&#xD;
      study treatment until re-bleeding, Reduce Mayo score reduction by at least 50%, Reduce&#xD;
      f-calprotectin, Reduce recovered sucralose in the sucralose gut permeability test, Reduce&#xD;
      zonulin expression from gut mucosa, Impact microflora composition&#xD;
&#xD;
      Study Product and Dosage Lr4659, consisting of L. reuteri ATCC PTA 4659 will be delivered at&#xD;
      a dose of 5x108 colony forming units (CFU) as a powder in capsules. One dose is to be taken&#xD;
      in the morning and one in the evening yielding a total daily dose of 1x109 CFU/day. Placebo&#xD;
      capsules are identical to Lr4659 except for the active ingredient. The study products will be&#xD;
      taken daily throughout the entire 52-week study-period.&#xD;
&#xD;
      Inclusion criteria for study: UC confirmed by biopsy, Mayo full score &lt; 2, Total or&#xD;
      left-sided UC, Stable diagnose of UC &gt;1 year, History of more than 1 yearly recurrence,&#xD;
      Current remission period exceeding 2 months, 18-80 years of age, Baseline 5-ASA ≤4g daily,&#xD;
      Mentally fit to participate, Informed consent obtained Exclusion criteria: Crohn's disease,&#xD;
      Ulcerative proctitis, Infective colitis, Liver disease, Current use of probiotics, Current&#xD;
      medication acetylsalicylic acid (ASA), non-steroidal antiinflammatory drugs (NSAID),&#xD;
      corticosteroids, anticoagulants, serotonin-selective re-uptake inhibitors (SSRI),&#xD;
      serotonin-noradrenaline re-uptake inhibitors (SNRI), azathioprine (AZA), 6-mercaptopurin&#xD;
      (6-MP), thioguanin (TG), anti-TNF-alpha biologicals, Participation in other clinical trials&#xD;
&#xD;
      Analyses Evaluation of the clinical Mayo score will be done by ocular inspection and&#xD;
      immediate recording in the CRF.&#xD;
&#xD;
      C-reactive protein (CRP) will be locally analysed according to clinical routine by Department&#xD;
      of clinical chemistry, Uppsala University Hospital.&#xD;
&#xD;
      Fecal calprotectin will be analysed according to local routines (Bühlmann, Schönenbuch,&#xD;
      Switzerland) by Department of clinical chemistry, Uppsala University Hospital).&#xD;
&#xD;
      &quot;Gut&quot; permeability focuses on colonic permeability as studied with recovery of different&#xD;
      sugar components in the urine. 24-hour urine will be analysed by an in-house high performance&#xD;
      liquid chromatography (HPLC) method by GastroLab, Uppsala University Hospital.&#xD;
&#xD;
      Fecal microbiology, alfa-diversity, beta-diversity&#xD;
&#xD;
      Expected findings: Prolonged interval to next flare of UC with rectal bleeding. Reduced&#xD;
      calprotectin and CRP levels.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 1, 2017</start_date>
  <completion_date type="Anticipated">March 1, 2019</completion_date>
  <primary_completion_date type="Anticipated">January 31, 2019</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>
    <intervention_model_description>Lactobacillus reuteri versus placebo on prevention of flare in ulcerative colitis/proctosgmoiditis</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Pre-masked randomized tablet vials with Lactobacillus reuteri, or corresponding placebo</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Rectal bleeding with Mayo score ≥5</measure>
    <time_frame>12 months</time_frame>
    <description>Rectal bleeding as sign of increased inflammatory activity as determined by the Mayor Clinic Score for evaluation of disease activity in ulcerative colitis</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Increased fecal calprotectin</measure>
    <time_frame>12 months</time_frame>
    <description>Gut inflammatory biomarker</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Increased CRP</measure>
    <time_frame>12 months</time_frame>
    <description>General inflammatory biomarker</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Serum Zonulin</measure>
    <time_frame>12 months</time_frame>
    <description>Gut permeability biomarker</description>
  </other_outcome>
  <other_outcome>
    <measure>Gut permeability</measure>
    <time_frame>12 months</time_frame>
    <description>Recovery of sugar molecules in urine as marker of increased permeability</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Ulcerative Colitis Flare</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Look and taste-alike placebo tablets in white plastic vials.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Lactobacillus reuter's</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Lactobacillus reuteri tablets in white plastic vials.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Lactobacillus reuteri</intervention_name>
    <description>Study group split in two arms for experimental treatment with Lactobacillus reuteri or placebo.</description>
    <arm_group_label>Lactobacillus reuter's</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of UC confirmed by biopsy&#xD;
&#xD;
          -  Mayo full score &lt; 2&#xD;
&#xD;
          -  Total or left-sided UC&#xD;
&#xD;
          -  Stable diagnose of UC &gt;1 year&#xD;
&#xD;
          -  History of more than 1 yearly recurrence&#xD;
&#xD;
          -  Current remission period exceeding 2 months&#xD;
&#xD;
          -  18-75 years of age&#xD;
&#xD;
          -  Baseline 5-ASA ≤2g daily&#xD;
&#xD;
          -  Mentally fit to participate&#xD;
&#xD;
          -  Informed consent obtained&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Crohn's disease&#xD;
&#xD;
          -  Ulcerative proctitis&#xD;
&#xD;
          -  Infective colitis&#xD;
&#xD;
          -  Liver disease&#xD;
&#xD;
          -  Current use of probiotics&#xD;
&#xD;
          -  Current medication acetylsalicylic acid (ASA), non-steroidal antiinflammatory drugs&#xD;
             (NSAID), corticosteroids, anticoagulants, serotonin-selective re-uptake inhibitors&#xD;
             (SSRI), serotonin-noradrenaline re-uptake inhibitors (SNRI), azathioprine (AZA),&#xD;
             6-mercaptopurin (6-MP), thioguanin (TG), anti-TNF-alpha biologicals&#xD;
&#xD;
          -  Participation in other clinical trials&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Per M Hellström, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>Uppsala University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Per M Hellström, Prof</last_name>
    <phone>+46 70 3727423</phone>
    <email>per.hellstrom@medsci.uu.se</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Peter Benno, MD, PhD</last_name>
    <phone>+46 70 579554</phone>
    <email>peter.benno@endoskopienheten.se</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Uppsala University</name>
      <address>
        <city>Uppsala</city>
        <zip>75185</zip>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Per M Hellström, Prof</last_name>
      <phone>+46 70 3727423</phone>
      <email>per.hellstrom@medsci.uu.se</email>
    </contact>
    <contact_backup>
      <last_name>Peter Benno, MD, PhD</last_name>
      <phone>+46 70 5795554</phone>
      <email>peter.benno@endoskopienheten.se</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 7, 2019</study_first_submitted>
  <study_first_submitted_qc>January 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 9, 2019</study_first_posted>
  <last_update_submitted>January 10, 2019</last_update_submitted>
  <last_update_submitted_qc>January 10, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 14, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Uppsala University</investigator_affiliation>
    <investigator_full_name>Per Hellström</investigator_full_name>
    <investigator_title>Prof, MD, PhD</investigator_title>
  </responsible_party>
  <keyword>ulcerative colitis</keyword>
  <keyword>prevention</keyword>
  <keyword>microbiota</keyword>
  <keyword>Lactobacillus</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colitis</mesh_term>
    <mesh_term>Colitis, Ulcerative</mesh_term>
    <mesh_term>Ulcer</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Shared at publication.</ipd_description>
  </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/NCT03798210
org study id: ATCC PTA 4659
nct id: NCT03798210
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Explorative investigation to study the effect of the endogenous bacterium Lactobacillus
      reuteri ATCC PTA 4659 as a nutrient additive against relapse in ulcerative colitis. Forty
      patients will be studied with a randomized parallel design over one year. Patients with
      established treatment against relapse of ulcerative colitis with mesalazine ≤4 grams will be
      requested to participate in the study, allocated to 20 patients with placebo and 20 with
      active treatment L. reuteri as an "add-on". Inklusion: 18-80 years of age, ≥1 relapse with
      bleeding during previous 12 months with a disease activity Mayo Clinical Score ≤2, treatment
      with mesalazine ≤4,0 g daily. Exklusion: >80 years of age, no registered bleeding during
      recent 12 months, on-going steroid treatment, immunosuppressives, biologics or adhesion
      inhibitors, antibiotics or other clinical trial. behandling med probiotika. Disease
      monitoring will be done with:

      Time to disease relapse with macroscopic bleeding and Mayo score ≥5, blood chemistry and CRP,
      lipopolysaccharides and gut permeability, fecal calprotectin, and short health scale at 4
      weeks, 26 weeks and 52 weeks.
Research question To study whether dietary supplementation with L. reuteri ATCC PTA 4659
      (Lr4659) is safe and can reduce the relapse rate and have a positive effect in patients with
      ulcerative colitis (UC).

      Lr4659 is a naturally occurring strain of human origin. It is a typical member of the L.
      reuteri species, with typical sugar fermentation patterns, reuterin production and growth
      characteristics. Identification using 16SrRNA gene analysis shows that it has 99% similarity
      with the type strain of L. reuteri thus confirming that it belongs to this well-known and
      well-studied species that is considered safe for human consumption. In vitro studies indicate
      that this strain has strong tolerance to acid environments, as do many other L. reuteri
      strains and that it has the unusual ability to interfere with TNFalpha mediated propagation
      of inflammatory responses in human macrophages.

      Treatment with the probiotic bacterium L. reuteri has been shown to prevent dextran sodium
      sulfate (DSS)-induced colitis in rats. During DSS-induced colitis, the number of bacteria in
      the inner firmly-adherent mucus layer increased and bacterial composition of the two layers
      no longer differed. However, L. reuteri decreased the bacterial translocation from the
      intestine to mesenteric lymph nodes during DSS treatment, which might be an important part of
      the mechanisms by which L. reuteri ameliorates DSS-induced colitis in rats.

      Study design This is a double-blind randomized clinical trial. Randomization will be done to
      either mesalazine plus Lr4659, or to mesalazine plus placebo for a continuous treatment until
      new bleeding episode or a maximum of 52 weeks.

      Forty patients with UC in remission, medicated with <4 g mesalazine and aged over 18 years
      will be recruited. After written consent to the study the subjects in whom the eligibility
      criteria are confirmed the subjects will be randomized to receive either 2 daily doses of
      Lr4659 (n=15) or the corresponding placebo. The total length of study treatment is 52 weeks.

      Concomitant treatment During the period of the study, the subjects will refrain from
      ingestion of any kind of probiotic or bacterial preparation.

      The objective is to determine whether dietary supplementation with Lr4659 is able to: Prolong
      time in remission and Time from last bleeding episode until re-bleeding, Time from start of
      study treatment until re-bleeding, Reduce Mayo score reduction by at least 50%, Reduce
      f-calprotectin, Reduce recovered sucralose in the sucralose gut permeability test, Reduce
      zonulin expression from gut mucosa, Impact microflora composition

      Study Product and Dosage Lr4659, consisting of L. reuteri ATCC PTA 4659 will be delivered at
      a dose of 5x108 colony forming units (CFU) as a powder in capsules. One dose is to be taken
      in the morning and one in the evening yielding a total daily dose of 1x109 CFU/day. Placebo
      capsules are identical to Lr4659 except for the active ingredient. The study products will be
      taken daily throughout the entire 52-week study-period.

      Inclusion criteria for study: UC confirmed by biopsy, Mayo full score < 2, Total or
      left-sided UC, Stable diagnose of UC >1 year, History of more than 1 yearly recurrence,
      Current remission period exceeding 2 months, 18-80 years of age, Baseline 5-ASA ≤4g daily,
      Mentally fit to participate, Informed consent obtained Exclusion criteria: Crohn's disease,
      Ulcerative proctitis, Infective colitis, Liver disease, Current use of probiotics, Current
      medication acetylsalicylic acid (ASA), non-steroidal antiinflammatory drugs (NSAID),
      corticosteroids, anticoagulants, serotonin-selective re-uptake inhibitors (SSRI),
      serotonin-noradrenaline re-uptake inhibitors (SNRI), azathioprine (AZA), 6-mercaptopurin
      (6-MP), thioguanin (TG), anti-TNF-alpha biologicals, Participation in other clinical trials

      Analyses Evaluation of the clinical Mayo score will be done by ocular inspection and
      immediate recording in the CRF.

      C-reactive protein (CRP) will be locally analysed according to clinical routine by Department
      of clinical chemistry, Uppsala University Hospital.

      Fecal calprotectin will be analysed according to local routines (Bühlmann, Schönenbuch,
      Switzerland) by Department of clinical chemistry, Uppsala University Hospital).

      "Gut" permeability focuses on colonic permeability as studied with recovery of different
      sugar components in the urine. 24-hour urine will be analysed by an in-house high performance
      liquid chromatography (HPLC) method by GastroLab, Uppsala University Hospital.

      Fecal microbiology, alfa-diversity, beta-diversity

      Expected findings: Prolonged interval to next flare of UC with rectal bleeding. Reduced
      calprotectin and CRP levels.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Lactobacillus reuteri versus placebo on prevention of flare in ulcerative colitis/proctosgmoiditis
primary purpose: Prevention
masking: Triple (Participant, Care Provider, Investigator)
masking description: Pre-masked randomized tablet vials with Lactobacillus reuteri, or corresponding placebo
measure: Rectal bleeding with Mayo score ≥5
time frame: 12 months
description: Rectal bleeding as sign of increased inflammatory activity as determined by the Mayor Clinic Score for evaluation of disease activity in ulcerative colitis
measure: Increased fecal calprotectin
time frame: 12 months
description: Gut inflammatory biomarker
measure: Increased CRP
time frame: 12 months
description: General inflammatory biomarker
measure: Serum Zonulin
time frame: 12 months
description: Gut permeability biomarker
measure: Gut permeability
time frame: 12 months
description: Recovery of sugar molecules in urine as marker of increased permeability
arm group label: Placebo
arm group type: Placebo Comparator
description: Look and taste-alike placebo tablets in white plastic vials.
arm group label: Lactobacillus reuter's
arm group type: Experimental
description: Lactobacillus reuteri tablets in white plastic vials.
intervention type: Dietary Supplement
intervention name: Lactobacillus reuteri
description: Study group split in two arms for experimental treatment with Lactobacillus reuteri or placebo.
arm group label: Lactobacillus reuter's
intervention type: Dietary Supplement
intervention name: Placebo
description: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Per M Hellström, Prof
role: Principal Investigator
affiliation: Uppsala University
last name: Per M Hellström, Prof
phone: +46 70 3727423
email: per.hellstrom@medsci.uu.se
last name: Peter Benno, MD, PhD
phone: +46 70 579554
email: peter.benno@endoskopienheten.se
facility: 
status: Recruiting
contact: 
contact backup: 
country: Sweden
responsible party type: Principal Investigator
investigator affiliation: Uppsala University
investigator full name: Per Hellström
investigator title: Prof, MD, PhD
mesh term: Colitis
mesh term: Colitis, Ulcerative
mesh term: Ulcer
sharing ipd: Undecided
ipd description: Shared at publication.