<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/NCT04410003</url>
  </required_header>
  <id_info>
    <org_study_id>115450</org_study_id>
    <nct_id>NCT04410003</nct_id>
  </id_info>
  <brief_title>Metabolic and Metagenomic Effects of Intestinal Microbiome Repopulation in Unexplained Atherosclerosis</brief_title>
  <official_title>Metabolic and Metagenomic Effects of Repopulation of the Intestinal Microbiome in Patients With Severe Unexplained Atherosclerosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Western University, Canada</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>European Bioinformatics Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Western University, Canada</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Patients with unexplained atherosclerosis (severe atherosclerosis not explained by&#xD;
      traditional risk factors) will receive fecal microbial transplants (FMT) from patients with a&#xD;
      Protected phenotype (patients who have high levels of risk factors but little or no carotid&#xD;
      atherosclerosis). The objective is to determine what changes in the intestinal microbiome are&#xD;
      associated with a decline in plasma levels of toxic metabolites of the itnestinal microbiome&#xD;
      such as trimethylamine N-oxide (TMAO) and p-cresylsulfate. The intention is to develop an&#xD;
      ecosystem therapeutic of cultured bacteria to treat atherosclerosis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      100 patients with Unexplained Atherosclerosis, and 5 donors with the protected phenotype will&#xD;
      be recruited; there will be extensive microbial, viral and parasitic screening of the donors.&#xD;
      Recipients will be randomized to receive capsules of stool from the donors, or cellulose&#xD;
      placebo. Recipients will take cloxacillin 500 mg 4 times daily for 5 days before the FMT, and&#xD;
      will undergo purging with an electrolyte solution, (PegLyte) the day before the FMT.&#xD;
      Metagenomic analysis of the recipient stool will be performed before FMT, 6 weeks later and&#xD;
      after 12 months.Plasma levels of toxic intestinal metabolites will be measured before FMT, at&#xD;
      6 weeks and 12 months after FMT; the levels to be measured will be TMAO, P-cresylsulfate,&#xD;
      Hippuric acid. Indoxyl sulfate, P-cresyl glucuronide. Phenyl acetyl glutamine, and Phenyl&#xD;
      sulfate.&#xD;
&#xD;
      The investigators will analyze the metagenomic changes in the intestinal microbiome of&#xD;
      recipients that are associated with decline in the plasma levels of the metabolic products of&#xD;
      the intestinal microbiome to identify candidate bacteria for an &quot;ecosystem therapeutic for&#xD;
      atherosclerosis. Based on previous experience of designing such a therapeutic for clostridium&#xD;
      difficile, it is anticipated that ~ 40 bacterial species would be needed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">June 2, 2020</start_date>
  <completion_date type="Anticipated">April 30, 2022</completion_date>
  <primary_completion_date type="Anticipated">April 30, 2022</primary_completion_date>
  <phase>Phase 1</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>Randomized controlled trial</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Patients and persons involved in the followup and assessment of the participants will be blinded to the randomized assignment.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in plasma levels of metabolites of the intestinal microbiome</measure>
    <time_frame>6 weeks and 12 months</time_frame>
    <description>The primary outcome is changes in plasma levels of trimethylamine N-oxide and p-cresylsulfate</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Metagenomic changes of the intestinal microbiome</measure>
    <time_frame>6 weeks and 12 months</time_frame>
    <description>Metagenomic changes in the stool of transplant recipients will be analyzed to determine what changes in the intestinal bacteria are associated with changes in the plasma levels of the intestinal metabolites.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Atherosclerosis</condition>
  <condition>Intestinal Microbiome</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Cellulose capsules, cloxacillin, electrolyte purgative (Peglyte)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Active</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Capsules of stool from Protected donors, cloxacillin, electrolyte purgative (Peglyte)</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Fecal microbial transplant</intervention_name>
    <description>Fecal microbial transplant</description>
    <arm_group_label>Active</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Severe atherosclerosis, with total plaque area in the top quartile (&gt;119 mm2), not&#xD;
             explained by traditional risk factors in linear regression (residual score &gt;= 2)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Excluded will be patients unwilling/unable to provide informed consent, unwilling to&#xD;
             ingest the stool capsules at baseline, patients with moderate to severe renal failure&#xD;
             (eGFR&lt;50), immunosuppressed patients, and patients with cancer, unstable angina,&#xD;
             planned carotid revascularization or other conditions that might be expected to reduce&#xD;
             their survival to &lt; 1 year (including age &gt;80).&#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>J. David Spence, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Western Ontario, Canada</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>J. David Spence, M.D.</last_name>
    <phone>1-519-931-5731</phone>
    <email>dspence@robarts.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Tisha Mabb</last_name>
    <phone>1-519=931-5731</phone>
    <email>tisha@robarts.ca</email>
  </overall_contact_backup>
  <reference>
    <citation>Bogiatzi C, Gloor G, Allen-Vercoe E, Reid G, Wong RG, Urquhart BL, Dinculescu V, Ruetz KN, Velenosi TJ, Pignanelli M, Spence JD. Metabolic products of the intestinal microbiome and extremes of atherosclerosis. Atherosclerosis. 2018 Jun;273:91-97. doi: 10.1016/j.atherosclerosis.2018.04.015. Epub 2018 Apr 17.</citation>
    <PMID>29702430</PMID>
  </reference>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>February 24, 2020</study_first_submitted>
  <study_first_submitted_qc>May 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 1, 2020</study_first_posted>
  <last_update_submitted>May 27, 2020</last_update_submitted>
  <last_update_submitted_qc>May 27, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 1, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atherosclerosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Data might be made available with approval of the ethics committee</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/NCT04410003
org study id: 115450
nct id: NCT04410003
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Patients with unexplained atherosclerosis (severe atherosclerosis not explained by
      traditional risk factors) will receive fecal microbial transplants (FMT) from patients with a
      Protected phenotype (patients who have high levels of risk factors but little or no carotid
      atherosclerosis). The objective is to determine what changes in the intestinal microbiome are
      associated with a decline in plasma levels of toxic metabolites of the itnestinal microbiome
      such as trimethylamine N-oxide (TMAO) and p-cresylsulfate. The intention is to develop an
      ecosystem therapeutic of cultured bacteria to treat atherosclerosis.
100 patients with Unexplained Atherosclerosis, and 5 donors with the protected phenotype will
      be recruited; there will be extensive microbial, viral and parasitic screening of the donors.
      Recipients will be randomized to receive capsules of stool from the donors, or cellulose
      placebo. Recipients will take cloxacillin 500 mg 4 times daily for 5 days before the FMT, and
      will undergo purging with an electrolyte solution, (PegLyte) the day before the FMT.
      Metagenomic analysis of the recipient stool will be performed before FMT, 6 weeks later and
      after 12 months.Plasma levels of toxic intestinal metabolites will be measured before FMT, at
      6 weeks and 12 months after FMT; the levels to be measured will be TMAO, P-cresylsulfate,
      Hippuric acid. Indoxyl sulfate, P-cresyl glucuronide. Phenyl acetyl glutamine, and Phenyl
      sulfate.

      The investigators will analyze the metagenomic changes in the intestinal microbiome of
      recipients that are associated with decline in the plasma levels of the metabolic products of
      the intestinal microbiome to identify candidate bacteria for an "ecosystem therapeutic for
      atherosclerosis. Based on previous experience of designing such a therapeutic for clostridium
      difficile, it is anticipated that ~ 40 bacterial species would be needed.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized controlled trial
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Patients and persons involved in the followup and assessment of the participants will be blinded to the randomized assignment.
measure: Changes in plasma levels of metabolites of the intestinal microbiome
time frame: 6 weeks and 12 months
description: The primary outcome is changes in plasma levels of trimethylamine N-oxide and p-cresylsulfate
measure: Metagenomic changes of the intestinal microbiome
time frame: 6 weeks and 12 months
description: Metagenomic changes in the stool of transplant recipients will be analyzed to determine what changes in the intestinal bacteria are associated with changes in the plasma levels of the intestinal metabolites.
arm group label: Placebo
arm group type: Placebo Comparator
description: Cellulose capsules, cloxacillin, electrolyte purgative (Peglyte)
arm group label: Active
arm group type: Active Comparator
description: Capsules of stool from Protected donors, cloxacillin, electrolyte purgative (Peglyte)
intervention type: Biological
intervention name: Fecal microbial transplant
description: Fecal microbial transplant
arm group label: Active
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: J. David Spence, M.D.
role: Principal Investigator
affiliation: University of Western Ontario, Canada
last name: J. David Spence, M.D.
phone: 1-519-931-5731
email: dspence@robarts.ca
last name: Tisha Mabb
phone: 1-519=931-5731
email: tisha@robarts.ca
citation: Bogiatzi C, Gloor G, Allen-Vercoe E, Reid G, Wong RG, Urquhart BL, Dinculescu V, Ruetz KN, Velenosi TJ, Pignanelli M, Spence JD. Metabolic products of the intestinal microbiome and extremes of atherosclerosis. Atherosclerosis. 2018 Jun;273:91-97. doi: 10.1016/j.atherosclerosis.2018.04.015. Epub 2018 Apr 17.
PMID: 29702430
responsible party type: Sponsor
mesh term: Atherosclerosis
sharing ipd: No
ipd description: Data might be made available with approval of the ethics committee