<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/NCT03302715</url>
  </required_header>
  <id_info>
    <org_study_id>KOLBIBAKT; 2017;1</org_study_id>
    <nct_id>NCT03302715</nct_id>
  </id_info>
  <brief_title>The Association Between the Microbiological Environment in Colon and Colorectal Disease</brief_title>
  <official_title>KOLBIBAKT; The Association Between the Microbiological Environment in Colon and Colorectal Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Karolinska Institutet</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Karolinska Institutet</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>
      Colorectal illness contributes significantly to the global burden of disease. Cancer,&#xD;
      inflammatory bowel disease and diverticulosis result in substantial patients suffering and&#xD;
      health care expenditures. The causes of colorectal diseases remain unclear.&#xD;
&#xD;
      New data suggests that intestinal bacteria may play a major role in the causal chain for many&#xD;
      diseases, and the research on the microbial environment in the colon in relation to bowel&#xD;
      disease is increasingly intense although the possibility for analysis of the composition of&#xD;
      bacteria in the gut has so far been limited. However, new analytic methods based on powerful&#xD;
      DNA sequencing, opens new opportunities.&#xD;
&#xD;
      In the surgical clinic at Danderyds hospital, Stockholm, 2500 colonoscopies are performed per&#xD;
      year. The investigators have created a biobank with mucosal samples from patient's large&#xD;
      bowel and will consecutively include all patients scheduled for colonoscopy during one year&#xD;
      (N=2500). Biopsies from the colonic mucosa will be analysed in collaboration with the&#xD;
      Clinical Genomics, Science for Life laboratory (Karolinska Institutet).&#xD;
&#xD;
      In Phase 1, the association between specific bacteria and colorectal disease will be&#xD;
      investigated (hypothesis generating phase). In Phase 2, the investigators aim to identify&#xD;
      specific bacterial biomarkers that could be used as screening tools, and lay the ground for&#xD;
      future new treatments for colorectal disease.&#xD;
&#xD;
      Early detection and new treatment regimes would result in both significant patient benefits&#xD;
      as well as reductions in healthcare costs.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Project description Overall hypothesis: The colonic microbial environment correlates with&#xD;
      bowel pathology and is relevant to development and progress of colorectal disease.&#xD;
&#xD;
      Research questions and outcomes:&#xD;
&#xD;
      In Phase 1 (year 1, hypothesis generating phase), the association between specific bacteria&#xD;
      and the following diseases will be investigated: colorectal disease (colorectal cancer&#xD;
      /polyps, adenomas (pre-cancerous lesions), inflammatory bowel disease (IBD) and&#xD;
      diverticulosis).&#xD;
&#xD;
      Research questions:&#xD;
&#xD;
        1. Is the microenvironment of the gut mucosa in and around tissue with adenomas/colorectal&#xD;
           adenocarcinoma, IBD and diverticulosis colonized with a bacterial set different from&#xD;
           healthy mucosa?&#xD;
&#xD;
        2. Does age, sex and life/dietary habits impact different types of bacterial composition?&#xD;
&#xD;
      In Phase 2 (year 2-3), we aim to identify specific bacterial biomarkers that could be used as&#xD;
      screening tools, and lay the ground for future new treatments for colorectal disease.&#xD;
&#xD;
      Primary research questions:&#xD;
&#xD;
        1. Are specific bacterial sets associated with early formation of adenoma and colorectal&#xD;
           cancer?&#xD;
&#xD;
        2. Can these bacteria be used as faecal biomarkers in a colorectal screening program for&#xD;
           cancer or be identified by serological biomarkers?&#xD;
&#xD;
        3. Can the identification of specific bacteria lead to further studies on the possible&#xD;
           genesis of the emergence and growth of colorectal cancer?&#xD;
&#xD;
      Secondary research questions:&#xD;
&#xD;
        1. Are specific bacterial sets associated with IBD and diverticulosis and can those be used&#xD;
           as faecal or serological biomarkers for disease?&#xD;
&#xD;
        2. Can treatment of these bacteria or their metabolites reduce the incidence of morbidity&#xD;
           in relation to IBD or diverticulitis (inflammation in diverticula)?&#xD;
&#xD;
      Study population and implementation&#xD;
&#xD;
      Phase 1: (2017) -2018. During one year, all patients scheduled for colonoscopy at Danderyd's&#xD;
      Hospital (sample size = 2500 patients) will be consecutively invited to participate in the&#xD;
      study and to give informed consent.&#xD;
&#xD;
      Exclusion criteria: Bleeding risk (defined as a International Normalized Ratio (INR) &gt; 1.6),&#xD;
      severe dementia or inability to understand information and make an informed decision about&#xD;
      participation.&#xD;
&#xD;
      Patients who agree to participate will receive an information letter about the study by mail&#xD;
      (2-3 weeks before colonoscopy). In addition all patients will also receive a phone call as a&#xD;
      reminder of the study. Before bowel preparation, patients will be asked to leave a faeces&#xD;
      sample that will be saved for culture. Study participants will also be asked to complete a&#xD;
      validated questionnaire on medical history, previous illnesses, diet, lifestyle habits,&#xD;
      previous colonoscopies and antibiotic treatment. Immediately before the colonoscopy&#xD;
      examination, four blood samples will be taken: Two for the analysis of HbA1c, haemoglobin and&#xD;
      C-reactive protein (CRP) and two for storage at hospital's biobank robot for later analysis&#xD;
      of biomarkers.&#xD;
&#xD;
      During colonoscopy, tissue samples in addition to routine diagnostic tissue samples will be&#xD;
      taken from the colonic mucosa:&#xD;
&#xD;
        1. Two biopsies (one for DNA sequencing, one for cultivation) will be taken from a healthy&#xD;
           part of colonic mucosa (preferably in the first part of the colon) in all patients.&#xD;
&#xD;
        2. Four biopsies, two (DNA + culture) from pathologic colonic mucosa (polyp (adenomas) /&#xD;
           colorectal cancer / IBD/diverticulosis) and two (DNA + culture) in the nearby area of&#xD;
           the pathologic mucosa.&#xD;
&#xD;
      Phase 2: 2018-2020.&#xD;
&#xD;
        1. Detection and investigation of biologically important bacteria and their metabolites&#xD;
           (metagenomics and metabolomics (studies of chemical processes involving metabolites))&#xD;
           will be carried out for information about specific bacterial genes.&#xD;
&#xD;
        2. This data will then be statistically analysed for any association with various&#xD;
           colorectal conditions, adjusting for confounding and exposures available in medical&#xD;
           records and in the patient questionnaire (See below). These analyses will provide us&#xD;
           with important novel information about the pathogenic mechanisms of relevance for&#xD;
           development of cancer and inflammation.&#xD;
&#xD;
        3. Based on these expected findings of specific bacterial compositions in relation to&#xD;
           colonic disease, specific disease mechanisms can begin to be analysed.&#xD;
&#xD;
        4. The possibilities of using disease-specific bacterial compositions as a clinical marker&#xD;
           of colonic disease will also be explored. During this sub-study we will look at the&#xD;
           association between mucosal microbiota and the microbiota in the feces. Thus, stool&#xD;
           samples from all patients will be will be used to explore whether these correspond to&#xD;
           the bacterial composition of the colonic mucosa sampled from the pathologic and healthy&#xD;
           intestinal area. In addition, serological biomarkers will be examined in relation to&#xD;
           specific bacterial compositions in mucosal samples from pathologic mucosa in all study&#xD;
           patients.&#xD;
&#xD;
      Samples and analysis The samples are first stored and recorded in the Danderyd Hospital&#xD;
      biobank and will thereafter be sent for DNA analysis at the Science for Life laboratory,&#xD;
      Karolinska Institutet. The DNA analysis (primary variables) relates to massive parallel&#xD;
      sequencing of the 16S rRNA gene that gives information about the composition of bacteria in&#xD;
      the sample and the relative amount of bacteria down to the gene level. The results are&#xD;
      presented as a diversity index (Shannon diversity index or alpha diversity within the same&#xD;
      sample) and Unifrac analysis based on the software QIIME. The latter analysis shows&#xD;
      differences in bacterial composition between samples - so-called beta diversity. In addition&#xD;
      to16S sequencing, so called metagenomic sequencing will be performed on selected samples -&#xD;
      with this assay one can also get information about the specific bacterial gene content and&#xD;
      thus gain knowledge of pathogenic mechanisms with relevance to include cancer development.&#xD;
      The validated questionnaire of diet and lifestyle habits will be analysed in relation to the&#xD;
      microbial environment (dependent variable in this laboratory analysis).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 1, 2016</start_date>
  <completion_date type="Actual">July 1, 2019</completion_date>
  <primary_completion_date type="Actual">July 1, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Consecutive cohort study with mucosal samples during colonoscopy</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Bacterial diversity in colorectal disease</measure>
    <time_frame>3 years</time_frame>
    <description>DNA sequencing on mucosal sampling</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">1257</enrollment>
  <condition>Microbial Colonization and Colorectal Disease</condition>
  <arm_group>
    <arm_group_label>Mucosal biopsies</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Only blood samples and mucosal biopsies</description>
  </arm_group>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>Mucosal tissue sampling</intervention_name>
    <description>Mucosal tissue sampling for DNA analysis</description>
    <arm_group_label>Mucosal biopsies</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All colonoscopy cases&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Not able to understand Swedish or to understand patientinformation&#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>Erik Näslund, Professor</last_name>
    <role>Study Chair</role>
    <affiliation>Department of Surgery, Ersta Hospital, &amp; Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden</affiliation>
  </overall_official>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>October 1, 2017</study_first_submitted>
  <study_first_submitted_qc>October 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 5, 2017</study_first_posted>
  <last_update_submitted>October 2, 2019</last_update_submitted>
  <last_update_submitted_qc>October 2, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 4, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Karolinska Institutet</investigator_affiliation>
    <investigator_full_name>Ulf Oskar Gustafsson, MD, PhD</investigator_full_name>
    <investigator_title>Consultant Surgeon, associate professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Infections</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Not decided</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
  </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/NCT03302715
org study id: KOLBIBAKT; 2017;1
nct id: NCT03302715
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Colorectal illness contributes significantly to the global burden of disease. Cancer,
      inflammatory bowel disease and diverticulosis result in substantial patients suffering and
      health care expenditures. The causes of colorectal diseases remain unclear.

      New data suggests that intestinal bacteria may play a major role in the causal chain for many
      diseases, and the research on the microbial environment in the colon in relation to bowel
      disease is increasingly intense although the possibility for analysis of the composition of
      bacteria in the gut has so far been limited. However, new analytic methods based on powerful
      DNA sequencing, opens new opportunities.

      In the surgical clinic at Danderyds hospital, Stockholm, 2500 colonoscopies are performed per
      year. The investigators have created a biobank with mucosal samples from patient's large
      bowel and will consecutively include all patients scheduled for colonoscopy during one year
      (N=2500). Biopsies from the colonic mucosa will be analysed in collaboration with the
      Clinical Genomics, Science for Life laboratory (Karolinska Institutet).

      In Phase 1, the association between specific bacteria and colorectal disease will be
      investigated (hypothesis generating phase). In Phase 2, the investigators aim to identify
      specific bacterial biomarkers that could be used as screening tools, and lay the ground for
      future new treatments for colorectal disease.

      Early detection and new treatment regimes would result in both significant patient benefits
      as well as reductions in healthcare costs.
Project description Overall hypothesis: The colonic microbial environment correlates with
      bowel pathology and is relevant to development and progress of colorectal disease.

      Research questions and outcomes:

      In Phase 1 (year 1, hypothesis generating phase), the association between specific bacteria
      and the following diseases will be investigated: colorectal disease (colorectal cancer
      /polyps, adenomas (pre-cancerous lesions), inflammatory bowel disease (IBD) and
      diverticulosis).

      Research questions:

        1. Is the microenvironment of the gut mucosa in and around tissue with adenomas/colorectal
           adenocarcinoma, IBD and diverticulosis colonized with a bacterial set different from
           healthy mucosa?

        2. Does age, sex and life/dietary habits impact different types of bacterial composition?

      In Phase 2 (year 2-3), we aim to identify specific bacterial biomarkers that could be used as
      screening tools, and lay the ground for future new treatments for colorectal disease.

      Primary research questions:

        1. Are specific bacterial sets associated with early formation of adenoma and colorectal
           cancer?

        2. Can these bacteria be used as faecal biomarkers in a colorectal screening program for
           cancer or be identified by serological biomarkers?

        3. Can the identification of specific bacteria lead to further studies on the possible
           genesis of the emergence and growth of colorectal cancer?

      Secondary research questions:

        1. Are specific bacterial sets associated with IBD and diverticulosis and can those be used
           as faecal or serological biomarkers for disease?

        2. Can treatment of these bacteria or their metabolites reduce the incidence of morbidity
           in relation to IBD or diverticulitis (inflammation in diverticula)?

      Study population and implementation

      Phase 1: (2017) -2018. During one year, all patients scheduled for colonoscopy at Danderyd's
      Hospital (sample size = 2500 patients) will be consecutively invited to participate in the
      study and to give informed consent.

      Exclusion criteria: Bleeding risk (defined as a International Normalized Ratio (INR) > 1.6),
      severe dementia or inability to understand information and make an informed decision about
      participation.

      Patients who agree to participate will receive an information letter about the study by mail
      (2-3 weeks before colonoscopy). In addition all patients will also receive a phone call as a
      reminder of the study. Before bowel preparation, patients will be asked to leave a faeces
      sample that will be saved for culture. Study participants will also be asked to complete a
      validated questionnaire on medical history, previous illnesses, diet, lifestyle habits,
      previous colonoscopies and antibiotic treatment. Immediately before the colonoscopy
      examination, four blood samples will be taken: Two for the analysis of HbA1c, haemoglobin and
      C-reactive protein (CRP) and two for storage at hospital's biobank robot for later analysis
      of biomarkers.

      During colonoscopy, tissue samples in addition to routine diagnostic tissue samples will be
      taken from the colonic mucosa:

        1. Two biopsies (one for DNA sequencing, one for cultivation) will be taken from a healthy
           part of colonic mucosa (preferably in the first part of the colon) in all patients.

        2. Four biopsies, two (DNA + culture) from pathologic colonic mucosa (polyp (adenomas) /
           colorectal cancer / IBD/diverticulosis) and two (DNA + culture) in the nearby area of
           the pathologic mucosa.

      Phase 2: 2018-2020.

        1. Detection and investigation of biologically important bacteria and their metabolites
           (metagenomics and metabolomics (studies of chemical processes involving metabolites))
           will be carried out for information about specific bacterial genes.

        2. This data will then be statistically analysed for any association with various
           colorectal conditions, adjusting for confounding and exposures available in medical
           records and in the patient questionnaire (See below). These analyses will provide us
           with important novel information about the pathogenic mechanisms of relevance for
           development of cancer and inflammation.

        3. Based on these expected findings of specific bacterial compositions in relation to
           colonic disease, specific disease mechanisms can begin to be analysed.

        4. The possibilities of using disease-specific bacterial compositions as a clinical marker
           of colonic disease will also be explored. During this sub-study we will look at the
           association between mucosal microbiota and the microbiota in the feces. Thus, stool
           samples from all patients will be will be used to explore whether these correspond to
           the bacterial composition of the colonic mucosa sampled from the pathologic and healthy
           intestinal area. In addition, serological biomarkers will be examined in relation to
           specific bacterial compositions in mucosal samples from pathologic mucosa in all study
           patients.

      Samples and analysis The samples are first stored and recorded in the Danderyd Hospital
      biobank and will thereafter be sent for DNA analysis at the Science for Life laboratory,
      Karolinska Institutet. The DNA analysis (primary variables) relates to massive parallel
      sequencing of the 16S rRNA gene that gives information about the composition of bacteria in
      the sample and the relative amount of bacteria down to the gene level. The results are
      presented as a diversity index (Shannon diversity index or alpha diversity within the same
      sample) and Unifrac analysis based on the software QIIME. The latter analysis shows
      differences in bacterial composition between samples - so-called beta diversity. In addition
      to16S sequencing, so called metagenomic sequencing will be performed on selected samples -
      with this assay one can also get information about the specific bacterial gene content and
      thus gain knowledge of pathogenic mechanisms with relevance to include cancer development.
      The validated questionnaire of diet and lifestyle habits will be analysed in relation to the
      microbial environment (dependent variable in this laboratory analysis).
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Consecutive cohort study with mucosal samples during colonoscopy
primary purpose: Prevention
masking: None (Open Label)
measure: Bacterial diversity in colorectal disease
time frame: 3 years
description: DNA sequencing on mucosal sampling
arm group label: Mucosal biopsies
arm group type: Experimental
description: Only blood samples and mucosal biopsies
intervention type: Genetic
intervention name: Mucosal tissue sampling
description: Mucosal tissue sampling for DNA analysis
arm group label: Mucosal biopsies
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Erik Näslund, Professor
role: Study Chair
affiliation: Department of Surgery, Ersta Hospital, & Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
responsible party type: Principal Investigator
investigator affiliation: Karolinska Institutet
investigator full name: Ulf Oskar Gustafsson, MD, PhD
investigator title: Consultant Surgeon, associate professor
mesh term: Communicable Diseases
mesh term: Infections
sharing ipd: Yes
ipd description: Not decided
ipd info type: Study Protocol