<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/NCT02970877</url>
  </required_header>
  <id_info>
    <org_study_id>16-5475</org_study_id>
    <nct_id>NCT02970877</nct_id>
  </id_info>
  <brief_title>Stool Transplantation for Treatment of Insulin Resistance in Morbidly Obese Patients</brief_title>
  <official_title>Fecal Microbiota Transplant From Healthy Lean Donors to Morbidly Obese Individuals: Effect on Insulin Resistance and Other Obesity-related Parameters. A Randomized Controlled Trial.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johane Allard</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Canadian Institutes of Health Research (CIHR)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>MOUNT SINAI HOSPITAL</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Toronto</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Health Network, Toronto</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>
      More and more people in Canada and around the world are severely (morbidly) obese, and this&#xD;
      is associated with a high risk for poor blood sugar control (insulin resistance, IR) and&#xD;
      diabetes. Weight loss is often very hard to achieve for morbidly obese patients. Bariatric&#xD;
      surgery is a very effective treatment, but it has some risks and is not available to all&#xD;
      patients. Therefore, alternative treatments are needed.&#xD;
&#xD;
      The gut bacteria (intestinal microbiome) might play a role for the development of obesity and&#xD;
      IR. Several studies in animals have shown that transferring stool from lean mice or humans&#xD;
      into obese animals could lead to weight loss and improve IR. One human study has confirmed&#xD;
      this. The investigators are therefore examining, whether transfer of stool from healthy lean&#xD;
      people into morbidly obese patients with IR will improve blood sugar control, weight, and&#xD;
      other obesity related parameters. This will be done in a randomized controlled trial. Effects&#xD;
      on mental health and the bacterial in the mouth related to gum disease will also be assessed.&#xD;
&#xD;
      If successful, fecal transfer could be a new alternative treatment approach for morbidly&#xD;
      obese patients or those with IR who do not have access to or do not want to undergo bariatric&#xD;
      surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The coupled disorders of morbid obesity and type 2 diabetes (T2D) are a major and growing&#xD;
      public health problem in Canada. The Public Health Agency of Canada 2011 report, Obesity in&#xD;
      Canada, showed that 5.1% and 2.7% of Canadians had obesity class II (body mass index (BMI)&#xD;
      35.0-39.9) and III (BMI &gt;40 kg/m2), respectively. Morbid obesity is associated with not only&#xD;
      T2D (up to 42% of morbidly obese patients), but also cardiovascular complications,&#xD;
      non-alcoholic fatty liver disease and sleep apnea, and the prevalence of psychiatric&#xD;
      disorders, particularly depression and anxiety, is high in this population. As morbid obesity&#xD;
      is very difficult to treat, drastic measures are required, and bariatric surgery is often the&#xD;
      only viable treatment option. Bariatric surgery is nowadays a frequently performed procedure&#xD;
      (about 400 surgeries/year at the University Health Network (UHN)), and there are different&#xD;
      techniques, including gastric banding, sleeve gastrectomy, and Roux-en-Y gastric bypass. Of&#xD;
      these procedures, the Roux-en-Y gastric bypass surgery has become the gold standard, and it&#xD;
      is highly effective in inducing long-term weight loss and improving or even resolving all of&#xD;
      the obesity associated comorbidities. However, bariatric surgery is invasive, costly, has a&#xD;
      risk of complications, and requires life-long commitment to a restricted diet. Therefore, a&#xD;
      significant proportion of patients with morbid obesity is not willing to undergo the&#xD;
      procedure, and a small proportion is excluded from the procedure due to other physical or&#xD;
      mental health problems.In addition, depending on the health care system, bariatric surgery&#xD;
      might not be available to a large proportion of patients. Regarding the growing rates of&#xD;
      obesity and morbid obesity world-wide, less expensive and less invasive alternatives to&#xD;
      bariatric surgery are urgently needed.&#xD;
&#xD;
      Even though obesity largely results from an imbalance between energy intake and energy&#xD;
      expenditure, it has been shown that several factors, including the genetic background can&#xD;
      render individuals susceptible to obesity. Most recently, the role of the intestinal&#xD;
      microbiome has been under investigation. It has been shown that obese people have an&#xD;
      intestinal microbiome and metagenome that is significantly different from lean controls, and&#xD;
      this is even true in identical twins discordant for obesity. In addition, patients with T2D&#xD;
      have a different intestinal microbiome than controls. Work done in rodents showed that fecal&#xD;
      microbiota transplant (FMT) from lean to obese animals (and vice versa) can affect fat mass&#xD;
      and parameters of the metabolic syndrome. It is thus possible that FMT may benefit human&#xD;
      obesity with related metabolic abnormalities. FMT is becoming standard therapy for patients&#xD;
      with refractory Clostridium difficile colitis and may become a treatment option in other&#xD;
      gastrointestinal disorders. Only one human study (n=9) investigated FMT from lean subjects to&#xD;
      obese patients (~BMI 35 kg/m2) with metabolic syndrome and showed improvement in insulin&#xD;
      sensitivity. Taken altogether, these very exciting results led us to hypothesize that that&#xD;
      FMT from healthy lean donors could effectively induce metabolic improvement (i.e. insulin&#xD;
      resistance (IR)) and weight loss) by distinct microbe-specific mediated mechanisms. The&#xD;
      investigators will examine this in a single-center, double-blind, randomized controlled&#xD;
      parallel-group trial (RCT).&#xD;
&#xD;
      Furthermore, emerging evidence shows that the intestinal microbiome, through the gut-brain&#xD;
      axis, can influence mood disorders. First animal studies suggest that FMT can transfer&#xD;
      depression and anxiety and therefore, FMT from healthy individuals may provide some benefits.&#xD;
      Therefore, the investigators will also assess, whether FMT influences depression and anxiety,&#xD;
      which are highly prevalent in obese patients. Finally, our Canadian Institutes for Health&#xD;
      Research (CIHR) Team Grant, which supports this RCT, is also studying the potential&#xD;
      relationship between obesity, T2D and the oral microbiome (OM). Considering that microbes&#xD;
      present in the saliva are swallowed in significant numbers-about 10^12 oral bacteria per&#xD;
      day-and that this may influence the composition of the intestinal microbiome, the&#xD;
      investigators are also exploring the potential relationship between oral and intestinal&#xD;
      microbiome and their associations with obesity and T2D. Having a FMT protocol gives us the&#xD;
      unique opportunity to further assess this potential relationship and determine if FMT may&#xD;
      change OM by improving obesity and metabolic parameters. This has not been previously studied&#xD;
      in animals or humans.&#xD;
&#xD;
      The aims of this RCT are to assess whether FMT from healthy lean individuals into morbidly&#xD;
      obese patients with IR who decline bariatric surgery, leads to 1) improvement in metabolic&#xD;
      parameters: IR, BMI, and other obesity related parameters; 2) improvement in mood disorders:&#xD;
      depression and anxiety scores; 3) changes in the intestinal microbiome and metabolome. 4) In&#xD;
      addition, by assessing the OM through the FMT protocol and by combining these results with&#xD;
      the results of our other protocols in a similar patient population going through bariatric&#xD;
      surgery, the investigators will explore the relationship between oral/intestinal microbiome&#xD;
      and obesity/metabolic parameters. 5) Furthermore, as planned in our CIHR Team Grant, the&#xD;
      investigators will use the FMT from the lean donors and transfer into obese mice to assess&#xD;
      the effect of FMT on mechanisms related to glucose metabolism. These additional experiments&#xD;
      are not part of this protocol but are mentioned briefly, as stool samples and data from the&#xD;
      patients and donors participating in the FMT trial will be used for the other studies in our&#xD;
      CIHR Team Grant.&#xD;
&#xD;
      Significance. The number of obese patients is growing world-wide. The investigators are&#xD;
      examining here a'medical bypass' solutions to treat the 40-50% of obese patients that meet&#xD;
      the criteria set by the National Institutes for Health (NIH) for bariatric surgery (12, 36)&#xD;
      but decline (13), or the much larger population of obese patients (BMI 30-40 kg/m2) who may&#xD;
      not be considered for surgical treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 1, 2017</start_date>
  <completion_date type="Anticipated">November 30, 2022</completion_date>
  <primary_completion_date type="Actual">June 30, 2022</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Insulin Resistance compared to baseline</measure>
    <time_frame>1 month, 3 month</time_frame>
    <description>Homeostasis model of assessment for insulin resistance (HOMA-IR)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Weight</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Body weight (kg)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body mass index</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Weight (kg) / height (m)²</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage weight change compared to baseline</measure>
    <time_frame>1 mo, 3 mo</time_frame>
    <description>% weight change compared to baseline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Appetite score</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Appetite score according to rating scale</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life Questionnaire</measure>
    <time_frame>Baseline, 3 mo</time_frame>
    <description>RAND 36-Item Health Survey 1.0 (SF-36)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Depression score</measure>
    <time_frame>Baseline, 3 mo</time_frame>
    <description>Montgomery-Åsberg Depression Rating Scale (MADRS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anxiety score</measure>
    <time_frame>Baseline, 3 mo</time_frame>
    <description>Hamilton Anxiety Rating Scale (Ham-A)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Hemoglobin A1c</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Blood measurement</description>
  </other_outcome>
  <other_outcome>
    <measure>C-reactive protein</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Blood measurement</description>
  </other_outcome>
  <other_outcome>
    <measure>HOMA-B%</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>HOMA steady state beta cell function (%B)</description>
  </other_outcome>
  <other_outcome>
    <measure>Intestinal microbiome in stool, composition</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Measured by 16S sequencing</description>
  </other_outcome>
  <other_outcome>
    <measure>Intestinal microbiome in stool, function</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Metagenome sequencing</description>
  </other_outcome>
  <other_outcome>
    <measure>Intestinal microbiome in stool, quantitative</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Quantitative real-time polymerase chain reaction (qPCR)</description>
  </other_outcome>
  <other_outcome>
    <measure>Blood lipid profile</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Blood measurement</description>
  </other_outcome>
  <other_outcome>
    <measure>Physical examination performed by the physician</measure>
    <time_frame>Baseline, 3 mo</time_frame>
    <description>All major signs will be checked to see if apparatus are normal or if abnormal findings are present (Head, Ears, Eyes, Nose, Throat, Neck, Lungs, Heart, Abdomen, Skin, Neurological, Anal, Gynecological).</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in food intake</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Total daily energy intake from 3-day food record</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in food intake</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Daily fat intake (amount g/d, energy and % of energy) from 3-day food record</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in food intake</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Daily carbohydrates intake (amount g/d, energy and % of energy) from 3-day food record</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in food intake</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Daily protein intake (amount g/d, energy and % of energy) from 3-day food record</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in food intake</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Daily fiber intake (amount g/d, energy and % of energy) from 3-day food record</description>
  </other_outcome>
  <other_outcome>
    <measure>Physical activity</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Activity log, self-completed</description>
  </other_outcome>
  <other_outcome>
    <measure>Environmental questionnaire</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Questionnaire assessing environmental factors that may influence the intestinal microbiome</description>
  </other_outcome>
  <other_outcome>
    <measure>Stool metabolomics</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Nuclear magnetic resonance spectroscopy</description>
  </other_outcome>
  <other_outcome>
    <measure>Serum metabolomics</measure>
    <time_frame>Baseline, 1 mo, 3 mo</time_frame>
    <description>Nuclear magnetic resonance spectroscopy</description>
  </other_outcome>
  <other_outcome>
    <measure>Oral microbiome</measure>
    <time_frame>Baseline, 3 mo</time_frame>
    <description>16S sequencing, metagenome, quantification by qPCR</description>
  </other_outcome>
  <other_outcome>
    <measure>Dental questionnaire</measure>
    <time_frame>Baseline, 3 mo</time_frame>
    <description>Questionnaire assessing oral health and hygiene</description>
  </other_outcome>
  <other_outcome>
    <measure>Mucosa-associated microbiome</measure>
    <time_frame>Baseline</time_frame>
    <description>Mucosa from intestinal pinch biopsies, taken during colonoscopy 16S sequencing, metagenome, qPCR</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">48</enrollment>
  <condition>Obesity, Morbid</condition>
  <condition>Insulin Resistance</condition>
  <arm_group>
    <arm_group_label>Allogenic treatment group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fecal filtrate from 150 g stool from healthy lean donors</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Autologous control group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Fecal filtrate from 150 g of the recipient's own stool</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Fecal filtrate from 150 g stool from healthy lean donors</intervention_name>
    <description>150 g stool from healthy lean donors will be diluted in 0.9% normal saline to a total volume of 450 mL. Preparation from frozen stool.</description>
    <arm_group_label>Allogenic treatment group</arm_group_label>
    <other_name>Intestinal microbiota from healthy lean donors</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Fecal filtrate from 150 g of the recipient's own stool</intervention_name>
    <description>150 g stool from the recipient will be diluted in 0.9% normal saline to a total volume of 450 mL. Preparation from frozen stool.</description>
    <arm_group_label>Autologous control group</arm_group_label>
    <other_name>Autologous intestinal microbiota</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men and women&#xD;
&#xD;
          -  age 18 years or older&#xD;
&#xD;
          -  morbidly obese (BMI &gt;40 kg/m² or BMI &gt;35-40 kg/m² with other severe weight loss&#xD;
             responsive comorbidities)&#xD;
&#xD;
          -  referred to the Bariatric Clinic at the Toronto Western Hospital for weight loss&#xD;
             surgery, but declining or deferring the surgery&#xD;
&#xD;
          -  insulin resistance (HOMA-IR value &gt;2.73)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  In the 3 months prior to study entry, regular intake of:&#xD;
&#xD;
               -  non-steroidal anti-inflammatory drugs;&#xD;
&#xD;
               -  iron supplements;&#xD;
&#xD;
               -  prebiotics or probiotics from other than food sources;&#xD;
&#xD;
               -  antibiotics; or&#xD;
&#xD;
               -  any experimental drug&#xD;
&#xD;
          -  Type 1 or type 2 diabetes&#xD;
&#xD;
          -  chronic gastrointestinal diseases&#xD;
&#xD;
          -  previous gastrointestinal surgery modifying the anatomy&#xD;
&#xD;
          -  smoking&#xD;
&#xD;
          -  pregnancy or breastfeeding&#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>Johane P Allard, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Health Network, University of Toronto</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Health Network</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2C4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <reference>
    <citation>Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF, Dallinga-Thie GM, Ackermans MT, Serlie MJ, Oozeer R, Derrien M, Druesne A, Van Hylckama Vlieg JE, Bloks VW, Groen AK, Heilig HG, Zoetendal EG, Stroes ES, de Vos WM, Hoekstra JB, Nieuwdorp M. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012 Oct;143(4):913-6.e7. doi: 10.1053/j.gastro.2012.06.031. Epub 2012 Jun 20. Erratum In: Gastroenterology. 2013 Jan;144(1):250.</citation>
    <PMID>22728514</PMID>
  </reference>
  <reference>
    <citation>Kelly CR, Kahn S, Kashyap P, Laine L, Rubin D, Atreja A, Moore T, Wu G. Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms, and Outlook. Gastroenterology. 2015 Jul;149(1):223-37. doi: 10.1053/j.gastro.2015.05.008. Epub 2015 May 15.</citation>
    <PMID>25982290</PMID>
  </reference>
  <reference>
    <citation>Hamilton MJ, Weingarden AR, Unno T, Khoruts A, Sadowsky MJ. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes. 2013 Mar-Apr;4(2):125-35. doi: 10.4161/gmic.23571. Epub 2013 Jan 18.</citation>
    <PMID>23333862</PMID>
  </reference>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>June 17, 2016</study_first_submitted>
  <study_first_submitted_qc>November 18, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2016</study_first_posted>
  <last_update_submitted>November 1, 2022</last_update_submitted>
  <last_update_submitted_qc>November 1, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 2, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University Health Network, Toronto</investigator_affiliation>
    <investigator_full_name>Johane Allard</investigator_full_name>
    <investigator_title>Gastroenterologist, Senior Researcher</investigator_title>
  </responsible_party>
  <keyword>Fecal microbiota transplant</keyword>
  <keyword>Intestinal microbiome</keyword>
  <keyword>Oral microbiome</keyword>
  <keyword>Mucosa associated microbiome</keyword>
  <keyword>Appetite</keyword>
  <keyword>Metabolome</keyword>
  <keyword>Depression</keyword>
  <keyword>Anxiety</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Obesity</mesh_term>
    <mesh_term>Insulin Resistance</mesh_term>
    <mesh_term>Obesity, Morbid</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The current data sharing plans for the current study are unknown and will be made available at a later date</ipd_description>
  </patient_data>
  <pending_results>
    <submitted>December 12, 2022</submitted>
  </pending_results>
  <!-- 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/NCT02970877
org study id: 16-5475
nct id: NCT02970877
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
More and more people in Canada and around the world are severely (morbidly) obese, and this
      is associated with a high risk for poor blood sugar control (insulin resistance, IR) and
      diabetes. Weight loss is often very hard to achieve for morbidly obese patients. Bariatric
      surgery is a very effective treatment, but it has some risks and is not available to all
      patients. Therefore, alternative treatments are needed.

      The gut bacteria (intestinal microbiome) might play a role for the development of obesity and
      IR. Several studies in animals have shown that transferring stool from lean mice or humans
      into obese animals could lead to weight loss and improve IR. One human study has confirmed
      this. The investigators are therefore examining, whether transfer of stool from healthy lean
      people into morbidly obese patients with IR will improve blood sugar control, weight, and
      other obesity related parameters. This will be done in a randomized controlled trial. Effects
      on mental health and the bacterial in the mouth related to gum disease will also be assessed.

      If successful, fecal transfer could be a new alternative treatment approach for morbidly
      obese patients or those with IR who do not have access to or do not want to undergo bariatric
      surgery.
The coupled disorders of morbid obesity and type 2 diabetes (T2D) are a major and growing
      public health problem in Canada. The Public Health Agency of Canada 2011 report, Obesity in
      Canada, showed that 5.1% and 2.7% of Canadians had obesity class II (body mass index (BMI)
      35.0-39.9) and III (BMI >40 kg/m2), respectively. Morbid obesity is associated with not only
      T2D (up to 42% of morbidly obese patients), but also cardiovascular complications,
      non-alcoholic fatty liver disease and sleep apnea, and the prevalence of psychiatric
      disorders, particularly depression and anxiety, is high in this population. As morbid obesity
      is very difficult to treat, drastic measures are required, and bariatric surgery is often the
      only viable treatment option. Bariatric surgery is nowadays a frequently performed procedure
      (about 400 surgeries/year at the University Health Network (UHN)), and there are different
      techniques, including gastric banding, sleeve gastrectomy, and Roux-en-Y gastric bypass. Of
      these procedures, the Roux-en-Y gastric bypass surgery has become the gold standard, and it
      is highly effective in inducing long-term weight loss and improving or even resolving all of
      the obesity associated comorbidities. However, bariatric surgery is invasive, costly, has a
      risk of complications, and requires life-long commitment to a restricted diet. Therefore, a
      significant proportion of patients with morbid obesity is not willing to undergo the
      procedure, and a small proportion is excluded from the procedure due to other physical or
      mental health problems.In addition, depending on the health care system, bariatric surgery
      might not be available to a large proportion of patients. Regarding the growing rates of
      obesity and morbid obesity world-wide, less expensive and less invasive alternatives to
      bariatric surgery are urgently needed.

      Even though obesity largely results from an imbalance between energy intake and energy
      expenditure, it has been shown that several factors, including the genetic background can
      render individuals susceptible to obesity. Most recently, the role of the intestinal
      microbiome has been under investigation. It has been shown that obese people have an
      intestinal microbiome and metagenome that is significantly different from lean controls, and
      this is even true in identical twins discordant for obesity. In addition, patients with T2D
      have a different intestinal microbiome than controls. Work done in rodents showed that fecal
      microbiota transplant (FMT) from lean to obese animals (and vice versa) can affect fat mass
      and parameters of the metabolic syndrome. It is thus possible that FMT may benefit human
      obesity with related metabolic abnormalities. FMT is becoming standard therapy for patients
      with refractory Clostridium difficile colitis and may become a treatment option in other
      gastrointestinal disorders. Only one human study (n=9) investigated FMT from lean subjects to
      obese patients (~BMI 35 kg/m2) with metabolic syndrome and showed improvement in insulin
      sensitivity. Taken altogether, these very exciting results led us to hypothesize that that
      FMT from healthy lean donors could effectively induce metabolic improvement (i.e. insulin
      resistance (IR)) and weight loss) by distinct microbe-specific mediated mechanisms. The
      investigators will examine this in a single-center, double-blind, randomized controlled
      parallel-group trial (RCT).

      Furthermore, emerging evidence shows that the intestinal microbiome, through the gut-brain
      axis, can influence mood disorders. First animal studies suggest that FMT can transfer
      depression and anxiety and therefore, FMT from healthy individuals may provide some benefits.
      Therefore, the investigators will also assess, whether FMT influences depression and anxiety,
      which are highly prevalent in obese patients. Finally, our Canadian Institutes for Health
      Research (CIHR) Team Grant, which supports this RCT, is also studying the potential
      relationship between obesity, T2D and the oral microbiome (OM). Considering that microbes
      present in the saliva are swallowed in significant numbers-about 10^12 oral bacteria per
      day-and that this may influence the composition of the intestinal microbiome, the
      investigators are also exploring the potential relationship between oral and intestinal
      microbiome and their associations with obesity and T2D. Having a FMT protocol gives us the
      unique opportunity to further assess this potential relationship and determine if FMT may
      change OM by improving obesity and metabolic parameters. This has not been previously studied
      in animals or humans.

      The aims of this RCT are to assess whether FMT from healthy lean individuals into morbidly
      obese patients with IR who decline bariatric surgery, leads to 1) improvement in metabolic
      parameters: IR, BMI, and other obesity related parameters; 2) improvement in mood disorders:
      depression and anxiety scores; 3) changes in the intestinal microbiome and metabolome. 4) In
      addition, by assessing the OM through the FMT protocol and by combining these results with
      the results of our other protocols in a similar patient population going through bariatric
      surgery, the investigators will explore the relationship between oral/intestinal microbiome
      and obesity/metabolic parameters. 5) Furthermore, as planned in our CIHR Team Grant, the
      investigators will use the FMT from the lean donors and transfer into obese mice to assess
      the effect of FMT on mechanisms related to glucose metabolism. These additional experiments
      are not part of this protocol but are mentioned briefly, as stool samples and data from the
      patients and donors participating in the FMT trial will be used for the other studies in our
      CIHR Team Grant.

      Significance. The number of obese patients is growing world-wide. The investigators are
      examining here a'medical bypass' solutions to treat the 40-50% of obese patients that meet
      the criteria set by the National Institutes for Health (NIH) for bariatric surgery (12, 36)
      but decline (13), or the much larger population of obese patients (BMI 30-40 kg/m2) who may
      not be considered for surgical treatment.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in Insulin Resistance compared to baseline
time frame: 1 month, 3 month
description: Homeostasis model of assessment for insulin resistance (HOMA-IR)
measure: Weight
time frame: Baseline, 1 mo, 3 mo
description: Body weight (kg)
measure: Body mass index
time frame: Baseline, 1 mo, 3 mo
description: Weight (kg) / height (m)²
measure: Percentage weight change compared to baseline
time frame: 1 mo, 3 mo
description: % weight change compared to baseline
measure: Appetite score
time frame: Baseline, 1 mo, 3 mo
description: Appetite score according to rating scale
measure: Quality of Life Questionnaire
time frame: Baseline, 3 mo
description: RAND 36-Item Health Survey 1.0 (SF-36)
measure: Depression score
time frame: Baseline, 3 mo
description: Montgomery-Åsberg Depression Rating Scale (MADRS)
measure: Anxiety score
time frame: Baseline, 3 mo
description: Hamilton Anxiety Rating Scale (Ham-A)
measure: Hemoglobin A1c
time frame: Baseline, 1 mo, 3 mo
description: Blood measurement
measure: C-reactive protein
time frame: Baseline, 1 mo, 3 mo
description: Blood measurement
measure: HOMA-B%
time frame: Baseline, 1 mo, 3 mo
description: HOMA steady state beta cell function (%B)
measure: Intestinal microbiome in stool, composition
time frame: Baseline, 1 mo, 3 mo
description: Measured by 16S sequencing
measure: Intestinal microbiome in stool, function
time frame: Baseline, 1 mo, 3 mo
description: Metagenome sequencing
measure: Intestinal microbiome in stool, quantitative
time frame: Baseline, 1 mo, 3 mo
description: Quantitative real-time polymerase chain reaction (qPCR)
measure: Blood lipid profile
time frame: Baseline, 1 mo, 3 mo
description: Blood measurement
measure: Physical examination performed by the physician
time frame: Baseline, 3 mo
description: All major signs will be checked to see if apparatus are normal or if abnormal findings are present (Head, Ears, Eyes, Nose, Throat, Neck, Lungs, Heart, Abdomen, Skin, Neurological, Anal, Gynecological).
measure: Change in food intake
time frame: Baseline, 1 mo, 3 mo
description: Total daily energy intake from 3-day food record
measure: Change in food intake
time frame: Baseline, 1 mo, 3 mo
description: Daily fat intake (amount g/d, energy and % of energy) from 3-day food record
measure: Change in food intake
time frame: Baseline, 1 mo, 3 mo
description: Daily carbohydrates intake (amount g/d, energy and % of energy) from 3-day food record
measure: Change in food intake
time frame: Baseline, 1 mo, 3 mo
description: Daily protein intake (amount g/d, energy and % of energy) from 3-day food record
measure: Change in food intake
time frame: Baseline, 1 mo, 3 mo
description: Daily fiber intake (amount g/d, energy and % of energy) from 3-day food record
measure: Physical activity
time frame: Baseline, 1 mo, 3 mo
description: Activity log, self-completed
measure: Environmental questionnaire
time frame: Baseline, 1 mo, 3 mo
description: Questionnaire assessing environmental factors that may influence the intestinal microbiome
measure: Stool metabolomics
time frame: Baseline, 1 mo, 3 mo
description: Nuclear magnetic resonance spectroscopy
measure: Serum metabolomics
time frame: Baseline, 1 mo, 3 mo
description: Nuclear magnetic resonance spectroscopy
measure: Oral microbiome
time frame: Baseline, 3 mo
description: 16S sequencing, metagenome, quantification by qPCR
measure: Dental questionnaire
time frame: Baseline, 3 mo
description: Questionnaire assessing oral health and hygiene
measure: Mucosa-associated microbiome
time frame: Baseline
description: Mucosa from intestinal pinch biopsies, taken during colonoscopy 16S sequencing, metagenome, qPCR
arm group label: Allogenic treatment group
arm group type: Experimental
description: Fecal filtrate from 150 g stool from healthy lean donors
arm group label: Autologous control group
arm group type: Placebo Comparator
description: Fecal filtrate from 150 g of the recipient's own stool
intervention type: Biological
intervention name: Fecal filtrate from 150 g stool from healthy lean donors
description: 150 g stool from healthy lean donors will be diluted in 0.9% normal saline to a total volume of 450 mL. Preparation from frozen stool.
arm group label: Allogenic treatment group
other name: Intestinal microbiota from healthy lean donors
intervention type: Biological
intervention name: Fecal filtrate from 150 g of the recipient's own stool
description: 150 g stool from the recipient will be diluted in 0.9% normal saline to a total volume of 450 mL. Preparation from frozen stool.
arm group label: Autologous control group
other name: Autologous intestinal microbiota
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Johane P Allard, MD
role: Principal Investigator
affiliation: University Health Network, University of Toronto
facility: 
country: Canada
citation: Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF, Dallinga-Thie GM, Ackermans MT, Serlie MJ, Oozeer R, Derrien M, Druesne A, Van Hylckama Vlieg JE, Bloks VW, Groen AK, Heilig HG, Zoetendal EG, Stroes ES, de Vos WM, Hoekstra JB, Nieuwdorp M. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012 Oct;143(4):913-6.e7. doi: 10.1053/j.gastro.2012.06.031. Epub 2012 Jun 20. Erratum In: Gastroenterology. 2013 Jan;144(1):250.
PMID: 22728514
citation: Kelly CR, Kahn S, Kashyap P, Laine L, Rubin D, Atreja A, Moore T, Wu G. Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms, and Outlook. Gastroenterology. 2015 Jul;149(1):223-37. doi: 10.1053/j.gastro.2015.05.008. Epub 2015 May 15.
PMID: 25982290
citation: Hamilton MJ, Weingarden AR, Unno T, Khoruts A, Sadowsky MJ. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes. 2013 Mar-Apr;4(2):125-35. doi: 10.4161/gmic.23571. Epub 2013 Jan 18.
PMID: 23333862
responsible party type: Sponsor-Investigator
investigator affiliation: University Health Network, Toronto
investigator full name: Johane Allard
investigator title: Gastroenterologist, Senior Researcher
mesh term: Obesity
mesh term: Insulin Resistance
mesh term: Obesity, Morbid
sharing ipd: Yes
ipd description: The current data sharing plans for the current study are unknown and will be made available at a later date
submitted: December 12, 2022