<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/NCT03279224</url>
  </required_header>
  <id_info>
    <org_study_id>STAN-FMT-WCH-2016</org_study_id>
    <nct_id>NCT03279224</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of Fecal Microbiota Transplantation in a Population With Bipolar Disorder</brief_title>
  <official_title>A Randomized Controlled Trial of the Safety and Efficacy of Fecal Microbiota Transplantation in a Population With Bipolar Disorder</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Valerie Taylor</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Women's College Hospital</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>
      Every human harbors complex microbial communities (collectively, the human 'microbiome') that&#xD;
      cover the skin and the body's mucosal surfaces. There is mounting evidence of an interaction&#xD;
      between the intestinal microbiota, the gut, and the central nervous system (CNS) in what is&#xD;
      recognized as the microbiome-gut-brain axis. Based on this compelling body of evidence, there&#xD;
      is growing enthusiasm for work that is focused on translating this emerging association into&#xD;
      novel therapies for psychiatric illness.&#xD;
&#xD;
      Fecal microbiota transplantation(FMT) is a technique in which gut bacteria are transferred&#xD;
      from a healthy screened donor to a patient, with the goal to introduce or restore a stable&#xD;
      microbial community in the gut.There are no clinical trials examining the impact of FMT on&#xD;
      Bipolar Disorder (BD). However, there is biological rationale to support this type of&#xD;
      treatment, given the known inflammatory underpinnings of this illness.&#xD;
&#xD;
      The objective of this study is to assess the effectiveness of this very novel therapy&#xD;
      targeting the gut-brain axis, FMT, to treat bipolar depression.&#xD;
&#xD;
      Study Hypotheses:&#xD;
&#xD;
      Main hypothesis: FMT from healthy donors to patients with BD depression will improve&#xD;
      depression symptoms as an adjunct to approved medication.&#xD;
&#xD;
      Secondary hypotheses:&#xD;
&#xD;
        1. FMT will also reduce anxiety and global function&#xD;
&#xD;
        2. FMT is safe and will be well tolerated by the patients&#xD;
&#xD;
        3. Improvements in clinical parameters will be associated with specific changes in the&#xD;
           intestinal microbiome and/or metabolites in stool and serum&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary goals of this proof of concept study are to determine the effectiveness, safety&#xD;
      and tolerability of FMT in adults with BD depression.&#xD;
&#xD;
      Objective 1: To evaluate the effectiveness of the combination of a currently accepted&#xD;
      approved therapy for BD depression + FMT in individuals with BD depression. This will be&#xD;
      assessed through a change in the Montgomery-Ãsberg Depression Rating Scale (MADRS) total&#xD;
      score from baseline (pre-intervention) to the final visit (week 24). The investigators will&#xD;
      also assess the proportion of patients withdrawing from study due to inadequate control of&#xD;
      depressive symptoms.&#xD;
&#xD;
      Secondary objective 2: To evaluate the effectiveness of FMT on anxiety symptoms and global&#xD;
      function/overall improvement in participants with BD depression. Secondary objective 3: To&#xD;
      determine the safety and tolerability of FMT in individuals with BD depression. Safety will&#xD;
      be evaluated by solicited and unsolicited adverse events, including serious adverse events,&#xD;
      throughout the study period. Tolerability will be assessed using the Toronto Side Effect&#xD;
      Scale (TSES). This is a 32-item instrument that is designed to establish incidence,&#xD;
      frequency, and severity of CNS, gastrointestinal, and sexual side effects.&#xD;
&#xD;
      Secondary objective 4: To assess the effect of FMT on microbiome profile (community structure&#xD;
      and functional metagenome) and fecal metabolome. Changes in fecal microbiome profile and&#xD;
      fecal metabolome from baseline to the final visit will be assessed using next generation&#xD;
      sequencing and nuclear magnetic resonance (NMR) spectrometry, respectively. Changes in mood&#xD;
      rating scales will be correlated with a specific microbiome and metabolome signature.&#xD;
      Intestinal microbiome and metabolome of healthy donors will also be assessed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 1, 2018</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Actual">March 15, 2022</primary_completion_date>
  <phase>Phase 2/Phase 3</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>Adults with BD depression being treated with an approved medication will be assigned to either allogenic FMT (from a healthy, screened individual with no personal or family history of an Axis 1 disorder) or autologous FMT (re-infusion of own feces)</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Both the patient and the study team (clinical team, study coordinator, data analyst) will be blinded to group assignments.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in the MADRS total score from baseline (pre-intervention) to the final visit (week 24).</measure>
    <time_frame>Every 2 weeks for 24 weeks</time_frame>
    <description>The MADRS score will be used to assess the effectiveness of the combination of a currently accepted approved therapy plus FMT on depression symptoms. The MADRS score will also help assess the percentage of patients who show inadequate control of depressive symptoms</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in the the Clinical Global Impression (CGI) scale</measure>
    <time_frame>Every 2 weeks for 24 weeks</time_frame>
    <description>The effectiveness of Approved treatment + FMT in controlling anxiety symptoms and global function/Overall improvement will be assessed through the CGI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the the World Health Organization Quality of life (WHOQOL-BREF) rating</measure>
    <time_frame>Every 2 weeks for 24 weeks</time_frame>
    <description>The effectiveness of Approved treatment + FMT in improving the quality of life of bipolar depression patients will be assessed through the World Health Organization Quality of life (WHOQOL-BREF) questionnaire.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Side effects as reported on the Toronto Side Effect Scale (TSES)</measure>
    <time_frame>Every 2 weeks for 24 weeks</time_frame>
    <description>The tolerability of FMT will be assessed using the Toronto Side effects Scale (TSES)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in fecal microbiome profile</measure>
    <time_frame>stool sample collected at Baseline (Visit 2), week 12 and at week 24</time_frame>
    <description>Stool samples will be collected and analysed using next generation sequencing to examine changes in Changes in fecal microbiome profile</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in fecal Metabolome</measure>
    <time_frame>stool sample collected at Baseline (Visit 2), week 12 and at week 24</time_frame>
    <description>Stool samples will be collected and analysed using nuclear magnetic resonance (NMR) spectrometry</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">35</enrollment>
  <condition>Bipolar Depression</condition>
  <arm_group>
    <arm_group_label>Allogenic FMT</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants Randomized to this arm will receive FMT (Fecal Microbiota Transplantation) from a healthy, screened individual with no personal or family history of an Axis 1 disorder.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Autologous FMT</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants Randomized to this arm will receive FMT (Fecal Microbiota Transplantation) by re-infusion of their own feces donated earlier in the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Allogenic FMT</intervention_name>
    <description>Fifty (50) g of screened donor feces will be weighed and homogenized with 30 mL of sterile 0.9 N NaCl + 10% glycerol using a sterile 330 micron micro-filter-separated double-compartment polyethylene bag in the Stomacher® Paddle Blender.&#xD;
2.The volume of fecal filtrate corresponding to fifty (50) g of donor stools will be transferred into a 50 mL Falcon tube with screw top and frozen at -80oC.&#xD;
3. For colonoscopy administration, three (3) Falcon tubes of thawed FMT concentrated will be diluted to a total volume of 300 mL with 0.9N NaCl and will be transported to the endoscopy suite. In the endoscopy suite, the FMT product will be packaged into 6 x 50 ml syringes for patient delivery by colonoscopy.</description>
    <arm_group_label>Allogenic FMT</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Autologous FMT</intervention_name>
    <description>1. Fifty (50) g of the participant's feces will be weighed and homogenized with 30 mL of sterile 0.9 N NaCl + 10% glycerol using a sterile 330 micron micro-filter-separated double-compartment polyethylene bag in the Stomacher® Paddle Blender.&#xD;
3.The volume of fecal filtrate corresponding to fifty (50) g of participant's stools will be transferred into a 50 mL Falcon tube with screw top and frozen at -80oC.&#xD;
3. For colonoscopy administration, three (3) Falcon tubes of thawed FMT concentrated will be diluted to a total volume of 300 mL with 0.9N NaCl and will be transported to the endoscopy suite. In the endoscopy suite, the FMT product will be packaged into 6 x 50 ml syringes for patient delivery by colonoscopy.</description>
    <arm_group_label>Autologous FMT</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Between 18-65 years of age&#xD;
&#xD;
          2. Outpatient status&#xD;
&#xD;
          3. Have a diagnosis of bipolar disorder (BD) (type I or II) according to the Mini&#xD;
             International Neuropsychiatric Interview (MINI)&#xD;
&#xD;
          4. Have been on a stable first line treatment for BD depression at an adequate dose for&#xD;
             at least 8 weeks prior to study entry&#xD;
&#xD;
          5. Suffer from a current depressive episode (Montgomery-Åsberg Depression Rating Scale&#xD;
             (MADRS) score at screening and baseline of ≥ 12)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. DSM-IV criteria for substance abuse within the last 6 months or lifetime dependency&#xD;
&#xD;
          2. Active eating disorders&#xD;
&#xD;
          3. Schizophrenia or schizoaffective disorder&#xD;
&#xD;
          4. Current psychotic symptoms&#xD;
&#xD;
          5. A Young Mania Rating Scale (YMRS) score of ≥12 at screening&#xD;
&#xD;
          6. Active suicidality&#xD;
&#xD;
          7. Regular intake of non-steroidal anti-inflammatory drugs or iron supplements in the 3&#xD;
             months prior to study entry&#xD;
&#xD;
          8. Use of prebiotics or probiotics for medical purposes, use of antibiotics or any&#xD;
             experimental drug in the 3 months prior to study entry&#xD;
&#xD;
          9. Chronic gastrointestinal diseases&#xD;
&#xD;
         10. Conditions causing immunosuppression&#xD;
&#xD;
         11. A significant bleeding disorder&#xD;
&#xD;
         12. Any contraindication to colonoscopy&#xD;
&#xD;
         13. Pregnancy or breastfeeding&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Valerie Taylor, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Women's College Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Women's college Research Institute</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G1N8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <link>
    <url>https://mtop.ca/funded-projects/</url>
    <description>Microbiota Therapeutics Outcomes Program (MTOP)</description>
  </link>
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  <verification_date>April 2022</verification_date>
  <study_first_submitted>September 5, 2017</study_first_submitted>
  <study_first_submitted_qc>September 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 12, 2017</study_first_posted>
  <last_update_submitted>April 27, 2022</last_update_submitted>
  <last_update_submitted_qc>April 27, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Women's College Hospital</investigator_affiliation>
    <investigator_full_name>Valerie Taylor</investigator_full_name>
    <investigator_title>Psychiatrist-in-Chief</investigator_title>
  </responsible_party>
  <keyword>Bipolar, Depression, FMT, Microbiome</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depression</mesh_term>
    <mesh_term>Bipolar Disorder</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>both the descriptive and analyzed data, including individual patient data, will be submitted to the National Database for Clinical Trials related to Mental Illness (NDCT), which is part of the National Institute of Mental Health Data Archive (NDA). The data are de-identified and will be made available to qualified researchers, who have to request access to the dataset.</ipd_description>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>Data will be uploaded every 6 months through the study and released Within 4 months</ipd_time_frame>
    <ipd_access_criteria>Researchers approved for access to NDCT have the ability to download shared data from all clinical trials available in the repository</ipd_access_criteria>
    <ipd_url>https://nda.nih.gov/</ipd_url>
  </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/NCT03279224
org study id: STAN-FMT-WCH-2016
nct id: NCT03279224
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Every human harbors complex microbial communities (collectively, the human 'microbiome') that
      cover the skin and the body's mucosal surfaces. There is mounting evidence of an interaction
      between the intestinal microbiota, the gut, and the central nervous system (CNS) in what is
      recognized as the microbiome-gut-brain axis. Based on this compelling body of evidence, there
      is growing enthusiasm for work that is focused on translating this emerging association into
      novel therapies for psychiatric illness.

      Fecal microbiota transplantation(FMT) is a technique in which gut bacteria are transferred
      from a healthy screened donor to a patient, with the goal to introduce or restore a stable
      microbial community in the gut.There are no clinical trials examining the impact of FMT on
      Bipolar Disorder (BD). However, there is biological rationale to support this type of
      treatment, given the known inflammatory underpinnings of this illness.

      The objective of this study is to assess the effectiveness of this very novel therapy
      targeting the gut-brain axis, FMT, to treat bipolar depression.

      Study Hypotheses:

      Main hypothesis: FMT from healthy donors to patients with BD depression will improve
      depression symptoms as an adjunct to approved medication.

      Secondary hypotheses:

        1. FMT will also reduce anxiety and global function

        2. FMT is safe and will be well tolerated by the patients

        3. Improvements in clinical parameters will be associated with specific changes in the
           intestinal microbiome and/or metabolites in stool and serum
The primary goals of this proof of concept study are to determine the effectiveness, safety
      and tolerability of FMT in adults with BD depression.

      Objective 1: To evaluate the effectiveness of the combination of a currently accepted
      approved therapy for BD depression + FMT in individuals with BD depression. This will be
      assessed through a change in the Montgomery-Ãsberg Depression Rating Scale (MADRS) total
      score from baseline (pre-intervention) to the final visit (week 24). The investigators will
      also assess the proportion of patients withdrawing from study due to inadequate control of
      depressive symptoms.

      Secondary objective 2: To evaluate the effectiveness of FMT on anxiety symptoms and global
      function/overall improvement in participants with BD depression. Secondary objective 3: To
      determine the safety and tolerability of FMT in individuals with BD depression. Safety will
      be evaluated by solicited and unsolicited adverse events, including serious adverse events,
      throughout the study period. Tolerability will be assessed using the Toronto Side Effect
      Scale (TSES). This is a 32-item instrument that is designed to establish incidence,
      frequency, and severity of CNS, gastrointestinal, and sexual side effects.

      Secondary objective 4: To assess the effect of FMT on microbiome profile (community structure
      and functional metagenome) and fecal metabolome. Changes in fecal microbiome profile and
      fecal metabolome from baseline to the final visit will be assessed using next generation
      sequencing and nuclear magnetic resonance (NMR) spectrometry, respectively. Changes in mood
      rating scales will be correlated with a specific microbiome and metabolome signature.
      Intestinal microbiome and metabolome of healthy donors will also be assessed.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Adults with BD depression being treated with an approved medication will be assigned to either allogenic FMT (from a healthy, screened individual with no personal or family history of an Axis 1 disorder) or autologous FMT (re-infusion of own feces)
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Both the patient and the study team (clinical team, study coordinator, data analyst) will be blinded to group assignments.
measure: Change in the MADRS total score from baseline (pre-intervention) to the final visit (week 24).
time frame: Every 2 weeks for 24 weeks
description: The MADRS score will be used to assess the effectiveness of the combination of a currently accepted approved therapy plus FMT on depression symptoms. The MADRS score will also help assess the percentage of patients who show inadequate control of depressive symptoms
measure: Changes in the the Clinical Global Impression (CGI) scale
time frame: Every 2 weeks for 24 weeks
description: The effectiveness of Approved treatment + FMT in controlling anxiety symptoms and global function/Overall improvement will be assessed through the CGI
measure: Changes in the the World Health Organization Quality of life (WHOQOL-BREF) rating
time frame: Every 2 weeks for 24 weeks
description: The effectiveness of Approved treatment + FMT in improving the quality of life of bipolar depression patients will be assessed through the World Health Organization Quality of life (WHOQOL-BREF) questionnaire.
measure: Side effects as reported on the Toronto Side Effect Scale (TSES)
time frame: Every 2 weeks for 24 weeks
description: The tolerability of FMT will be assessed using the Toronto Side effects Scale (TSES)
measure: Changes in fecal microbiome profile
time frame: stool sample collected at Baseline (Visit 2), week 12 and at week 24
description: Stool samples will be collected and analysed using next generation sequencing to examine changes in Changes in fecal microbiome profile
measure: Changes in fecal Metabolome
time frame: stool sample collected at Baseline (Visit 2), week 12 and at week 24
description: Stool samples will be collected and analysed using nuclear magnetic resonance (NMR) spectrometry
arm group label: Allogenic FMT
arm group type: Active Comparator
description: Participants Randomized to this arm will receive FMT (Fecal Microbiota Transplantation) from a healthy, screened individual with no personal or family history of an Axis 1 disorder.
arm group label: Autologous FMT
arm group type: Placebo Comparator
description: Participants Randomized to this arm will receive FMT (Fecal Microbiota Transplantation) by re-infusion of their own feces donated earlier in the study.
intervention type: Biological
intervention name: Allogenic FMT
description: Fifty (50) g of screened donor feces will be weighed and homogenized with 30 mL of sterile 0.9 N NaCl + 10% glycerol using a sterile 330 micron micro-filter-separated double-compartment polyethylene bag in the Stomacher® Paddle Blender.
2.The volume of fecal filtrate corresponding to fifty (50) g of donor stools will be transferred into a 50 mL Falcon tube with screw top and frozen at -80oC.
3. For colonoscopy administration, three (3) Falcon tubes of thawed FMT concentrated will be diluted to a total volume of 300 mL with 0.9N NaCl and will be transported to the endoscopy suite. In the endoscopy suite, the FMT product will be packaged into 6 x 50 ml syringes for patient delivery by colonoscopy.
arm group label: Allogenic FMT
intervention type: Biological
intervention name: Autologous FMT
description: 1. Fifty (50) g of the participant's feces will be weighed and homogenized with 30 mL of sterile 0.9 N NaCl + 10% glycerol using a sterile 330 micron micro-filter-separated double-compartment polyethylene bag in the Stomacher® Paddle Blender.
3.The volume of fecal filtrate corresponding to fifty (50) g of participant's stools will be transferred into a 50 mL Falcon tube with screw top and frozen at -80oC.
3. For colonoscopy administration, three (3) Falcon tubes of thawed FMT concentrated will be diluted to a total volume of 300 mL with 0.9N NaCl and will be transported to the endoscopy suite. In the endoscopy suite, the FMT product will be packaged into 6 x 50 ml syringes for patient delivery by colonoscopy.
arm group label: Autologous FMT
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Valerie Taylor, MD, PhD
role: Principal Investigator
affiliation: Women's College Hospital
facility: 
country: Canada
url: https://mtop.ca/funded-projects/
description: Microbiota Therapeutics Outcomes Program (MTOP)
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responsible party type: Sponsor-Investigator
investigator affiliation: Women's College Hospital
investigator full name: Valerie Taylor
investigator title: Psychiatrist-in-Chief
mesh term: Depression
mesh term: Bipolar Disorder
sharing ipd: Yes
ipd description: both the descriptive and analyzed data, including individual patient data, will be submitted to the National Database for Clinical Trials related to Mental Illness (NDCT), which is part of the National Institute of Mental Health Data Archive (NDA). The data are de-identified and will be made available to qualified researchers, who have to request access to the dataset.
ipd info type: Clinical Study Report (CSR)
ipd time frame: Data will be uploaded every 6 months through the study and released Within 4 months
ipd access criteria: Researchers approved for access to NDCT have the ability to download shared data from all clinical trials available in the repository
ipd url: https://nda.nih.gov/