<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/NCT01703494</url>
  </required_header>
  <id_info>
    <org_study_id>1R21DK093839-01A1</org_study_id>
    <nct_id>NCT01703494</nct_id>
  </id_info>
  <brief_title>Fecal Transplant for Relapsing C. Difficile Infection</brief_title>
  <official_title>Fecal Microbiota Transplantation for Relapsing Clostridium Difficile Infection</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Colleen Kelly</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The Miriam Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      There has been an alarming increase in the incidence and severity of Clostridium difficile&#xD;
      infection (CDI) in North America over the past decade. Relapsing infection is a common&#xD;
      problem in patients treated for CDI, often requiring prolonged and expensive courses of oral&#xD;
      vancomycin with limited alternative treatment options. This study will determine if fecal&#xD;
      microbiota transplantation, which involves administering fecal flora from a healthy stool&#xD;
      donor to a patient with relapsing CDI, is an effective and safe treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Clostridium difficile is an increasingly common infection. The number of hospital discharges&#xD;
      for which C. difficile was listed as the first diagnosis more than doubled between 2000 and&#xD;
      2003. In addition to occurring more frequently, there is an epidemic of serious cases which&#xD;
      are more refractory to therapy and which have high rates of colectomy and death. Most&#xD;
      commonly, C. difficile infection (CDI) is associated with use of antimicrobial agents that&#xD;
      are thought to alter the normal bacterial flora of the gastrointestinal tract so as to permit&#xD;
      colonization and/or proliferation and toxin elaboration by C. difficile. Though the precise&#xD;
      mechanisms by which this occurs are still incompletely understood, depletion of physiologic&#xD;
      microflora, in particular Bacteroides species may play an important role. Most patients with&#xD;
      CDI respond to a course of oral metronidazole or vancomycin, however, up to 20% of patients&#xD;
      relapse after initial treatment. Current guidelines recommend a tapering course of vancomycin&#xD;
      after a second recurrence, however up to 60% of patients still do not respond to this&#xD;
      treatment strategy or develop further recurrence after the vancomycin is stopped. Use of&#xD;
      antimicrobials to treat CDI may predispose these patients to further relapses through the&#xD;
      maintenance of disturbed intestinal flora and may contribute to the emerging problem of drug&#xD;
      resistance.&#xD;
&#xD;
      &quot;Fecal Microbiota Transplantation&quot; (FMT) is a novel treatment approach which involves&#xD;
      administration of feces from a healthy (donor) individual into a patient with relapsing CDI&#xD;
      to promote recolonization with missing components of normal intestinal flora. Numerous case&#xD;
      reports and retrospective case series have suggested benefit of FMT in patients with severe&#xD;
      or recurrent CDI with cure rates as high as 100% and a mean cure rate of 89% for the nearly&#xD;
      300 cases reported in the world literature. Although efficacy has been documented in these&#xD;
      case reports, to date there has not been a published prospective clinical trial of FMT for&#xD;
      CDI.&#xD;
&#xD;
      The proposed study would be the first randomized, double-blind, placebo (sham) controlled&#xD;
      clinical trial to determine whether FMT delivered at colonoscopy is effective at preventing&#xD;
      further relapse in patients who have suffered from at least a 3rd recurrence of CDI despite&#xD;
      receiving standard treatment. The investigators hypothesize that FMT is superior to placebo&#xD;
      in preventing relapse after treatment of CDI with vancomycin. As a result of this study, the&#xD;
      investigators will have preliminary efficacy data for this novel treatment approach for&#xD;
      recurrent CDI. The investigators will be better prepared to test the efficacy of FMT in&#xD;
      future multicenter clinical trials. This research will advance clinical care, potentially&#xD;
      impacting the protocol for treatment of relapsing C. difficile infection worldwide. This&#xD;
      proposal includes collaboration with an investigator capable of performing microbiome&#xD;
      analyses on specimens collected as part of the trial and will further understanding of the&#xD;
      intestinal microflora in health and disease.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>October 2012</start_date>
  <completion_date type="Anticipated">September 2015</completion_date>
  <primary_completion_date type="Actual">May 2015</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>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical Cure</measure>
    <time_frame>8 weeks</time_frame>
    <description>Resolution of diarrhea (i.e., fewer than three unformed stools for two consecutive days), with maintenance of resolution for the duration of the 8 week follow-up period and no further requirements for anti-infective therapy for C. difficile infection). Subjects who meet this definition will be considered cured regardless of results of follow-up stool testing for C. difficile.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical Failure</measure>
    <time_frame>8 weeks</time_frame>
    <description>Persistence or development of diarrhea and the need for additional anti-infective therapy for C. difficile infection with or without positive stool testing (PCR) for C. difficile. Upon clinical failure, subject's treatment will be unblinded and those who received sham Fecal Microbiotia Transplantation (FMT) may chose to receive open label FMT using donor stool. Subjects, who received true FMT and develop clinical failure, may chose to undergo a second FMT using an alternate donor.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Number of Participants with Adverse Events as a Measure of Safety and Tolerability</measure>
    <time_frame>6 months</time_frame>
    <description>Subjects will be followed closely for significant adverse events and adverse events during the 8 week follow up period post-FMT and the development of new medical conditions/diagnoses or changes in medical conditions/medications will be determined at 6 month follow up contact. Adverse events will be tabulated by study arm.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">53</enrollment>
  <condition>Clostridium Difficile</condition>
  <arm_group>
    <arm_group_label>Fecal Microbiota Transplantation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>After completing at least a 10 day course of vancomycin for treatment of the most recent acute C. difficile infection, subjects will receive fecal Microbiota Transplant (FMT) with a 300 mL donor fecal suspension delivered via colonoscopy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham Fecal Microbiota Transplantation</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>After completing at least a 10 day course of vancomycin for treatment of the most recent acute severe C. difficile infection, subjects will receive a 300 mL infusion of a sham (autotransfusion) fecal solution at colonoscopy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Fecal Microbiota Transplantation</intervention_name>
    <description>Fecal microbiota transplantation (FMT) involves administering fecal material from a healthy individual (donor) to a sick patient (with relapsing C. difficile infection) to restore missing components of normal intestinal flora. After completing at least a 10 day course of vancomycin for treatment of the most recent acute C. difficile infection, subjects will receive fecal microbiota transplantation (FMT) with a 300 mL donor fecal suspension delivered via colonoscopy.</description>
    <arm_group_label>Fecal Microbiota Transplantation</arm_group_label>
    <other_name>FMT</other_name>
    <other_name>fecal bacteriotherapy</other_name>
    <other_name>fecal flora reconstitution</other_name>
    <other_name>stool transplant</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Sham Fecal Microbiota Transplantation</intervention_name>
    <description>After completing at least a 10 day course of vancomycin for treatment of the most recent acute C. difficile infection, subjects will receive a sham fecal microbiota transplantation (FMT) with a 300 mL sham fecal suspension delivered via colonoscopy. This sham solution will be a reinfusion of the subject's own stool.</description>
    <arm_group_label>Sham Fecal Microbiota Transplantation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult outpatients (age ≥18 and &lt;75) referred to one of the study centers after&#xD;
             suffering a third (or further) documented episode CDI and&#xD;
&#xD;
          2. who have failed to maintain CDI cure after standard therapy with oral vancomycin.&#xD;
&#xD;
               -  Previous treatment with at least one course of tapered/pulse dose vancomycin as&#xD;
                  per SHEA-IDSA C difficile treatment guidelines or -Inability to taper or stop&#xD;
                  vancomycin without developing diarrhea requiring anti-infective therapy. -&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who are aged 75 years or greater.&#xD;
&#xD;
          -  Patients who are pregnant&#xD;
&#xD;
          -  Patients who are nursing&#xD;
&#xD;
          -  Patients who are incarcerated&#xD;
&#xD;
          -  Patients with cognitive impairment or severe neuropsychiatric co morbidities who are&#xD;
             incapable of giving their own informed consent&#xD;
&#xD;
          -  Patients who are immunocompromised specifically:&#xD;
&#xD;
          -  HIV infection (any CD4 count)&#xD;
&#xD;
          -  AIDS-defining diagnosis or CD4&lt;200/mm3&#xD;
&#xD;
          -  Inherited/primary immune disorders&#xD;
&#xD;
          -  Immunodeficient or Immunosuppressed due to medical condition/medication:&#xD;
&#xD;
          -  Current or recent (&lt;3 most) treatment with anti-neoplastic agent&#xD;
&#xD;
          -  Current or recent (&lt;3 mos) treatment with any immunosuppressant medications (including&#xD;
             but not limited to monoclonal antibodies to B and T cells, anti-TNF agents,&#xD;
             glucocorticoids, antimetabolites (azathioprine, 6-mercaptopurine), calcineurin&#xD;
             inhibitors (tacrolimus, cyclosporine), mycophenolate mofetil). Subjects who are&#xD;
             otherwise immunocompetent and have discontinued any immunosuppressant medications 3 or&#xD;
             more months prior to enrollment may be eligible to enroll.&#xD;
&#xD;
          -  Patients with a history of severe (anaphylactic) food allergy&#xD;
&#xD;
          -  Patients who have previously undergone FMT&#xD;
&#xD;
          -  Patients who are unwilling or unable to undergo colonoscopy&#xD;
&#xD;
          -  Patients with untreated, in-situ colorectal cancer&#xD;
&#xD;
          -  Patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn&quot;s&#xD;
             disease or microscopic colitis) or irritable bowel syndrome&#xD;
&#xD;
          -  Unable to comply with protocol requirements&#xD;
&#xD;
          -  Patients who are American Society of Anesthesiologists (ASA) Physical Status&#xD;
             classification IV and V&#xD;
&#xD;
          -  Patients with acute illness or fever on the day of planned FMT will be excluded (not&#xD;
             undergo randomization or treatment with FMT) with the option of including that subject&#xD;
             at a future date.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Colleen R Kelly, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Lifespan/ The Miriam Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Lawrence J Brandt, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Montefiore Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Montefiore Medical Center</name>
      <address>
        <city>The Bronx</city>
        <state>New York</state>
        <zip>10467</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Miriam Hospital</name>
      <address>
        <city>Providence</city>
        <state>Rhode Island</state>
        <zip>02906</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol. 2010 May-Jun;44(5):354-60. doi: 10.1097/MCG.0b013e3181c87e02.</citation>
    <PMID>20048681</PMID>
  </reference>
  <reference>
    <citation>Persky SE, Brandt LJ. Treatment of recurrent Clostridium difficile-associated diarrhea by administration of donated stool directly through a colonoscope. Am J Gastroenterol. 2000 Nov;95(11):3283-5. doi: 10.1111/j.1572-0241.2000.03302.x. No abstract available.</citation>
    <PMID>11095355</PMID>
  </reference>
  <reference>
    <citation>Yoon SS, Brandt LJ. Treatment of refractory/recurrent C. difficile-associated disease by donated stool transplanted via colonoscopy: a case series of 12 patients. J Clin Gastroenterol. 2010 Sep;44(8):562-6. doi: 10.1097/MCG.0b013e3181dac035.</citation>
    <PMID>20463588</PMID>
  </reference>
  <reference>
    <citation>Kelly CR, de Leon L, Jasutkar N. Fecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results. J Clin Gastroenterol. 2012 Feb;46(2):145-9. doi: 10.1097/MCG.0b013e318234570b.</citation>
    <PMID>22157239</PMID>
  </reference>
  <verification_date>September 2015</verification_date>
  <study_first_submitted>October 4, 2012</study_first_submitted>
  <study_first_submitted_qc>October 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 10, 2012</study_first_posted>
  <last_update_submitted>September 29, 2015</last_update_submitted>
  <last_update_submitted_qc>September 29, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 1, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>The Miriam Hospital</investigator_affiliation>
    <investigator_full_name>Colleen Kelly</investigator_full_name>
    <investigator_title>Clinical Assistant Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>C. difficile</keyword>
  <keyword>fecal transplant</keyword>
  <keyword>stool transplant</keyword>
  <keyword>fecal flora reconstitution</keyword>
  <keyword>fecal microbiota transplant</keyword>
  <keyword>FMT</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Clostridium Infections</mesh_term>
  </condition_browse>
  <!-- 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/NCT01703494
org study id: 1R21DK093839-01A1
nct id: NCT01703494
lead sponsor: 
has dmc: Yes
There has been an alarming increase in the incidence and severity of Clostridium difficile
      infection (CDI) in North America over the past decade. Relapsing infection is a common
      problem in patients treated for CDI, often requiring prolonged and expensive courses of oral
      vancomycin with limited alternative treatment options. This study will determine if fecal
      microbiota transplantation, which involves administering fecal flora from a healthy stool
      donor to a patient with relapsing CDI, is an effective and safe treatment.
Clostridium difficile is an increasingly common infection. The number of hospital discharges
      for which C. difficile was listed as the first diagnosis more than doubled between 2000 and
      2003. In addition to occurring more frequently, there is an epidemic of serious cases which
      are more refractory to therapy and which have high rates of colectomy and death. Most
      commonly, C. difficile infection (CDI) is associated with use of antimicrobial agents that
      are thought to alter the normal bacterial flora of the gastrointestinal tract so as to permit
      colonization and/or proliferation and toxin elaboration by C. difficile. Though the precise
      mechanisms by which this occurs are still incompletely understood, depletion of physiologic
      microflora, in particular Bacteroides species may play an important role. Most patients with
      CDI respond to a course of oral metronidazole or vancomycin, however, up to 20% of patients
      relapse after initial treatment. Current guidelines recommend a tapering course of vancomycin
      after a second recurrence, however up to 60% of patients still do not respond to this
      treatment strategy or develop further recurrence after the vancomycin is stopped. Use of
      antimicrobials to treat CDI may predispose these patients to further relapses through the
      maintenance of disturbed intestinal flora and may contribute to the emerging problem of drug
      resistance.

      "Fecal Microbiota Transplantation" (FMT) is a novel treatment approach which involves
      administration of feces from a healthy (donor) individual into a patient with relapsing CDI
      to promote recolonization with missing components of normal intestinal flora. Numerous case
      reports and retrospective case series have suggested benefit of FMT in patients with severe
      or recurrent CDI with cure rates as high as 100% and a mean cure rate of 89% for the nearly
      300 cases reported in the world literature. Although efficacy has been documented in these
      case reports, to date there has not been a published prospective clinical trial of FMT for
      CDI.

      The proposed study would be the first randomized, double-blind, placebo (sham) controlled
      clinical trial to determine whether FMT delivered at colonoscopy is effective at preventing
      further relapse in patients who have suffered from at least a 3rd recurrence of CDI despite
      receiving standard treatment. The investigators hypothesize that FMT is superior to placebo
      in preventing relapse after treatment of CDI with vancomycin. As a result of this study, the
      investigators will have preliminary efficacy data for this novel treatment approach for
      recurrent CDI. The investigators will be better prepared to test the efficacy of FMT in
      future multicenter clinical trials. This research will advance clinical care, potentially
      impacting the protocol for treatment of relapsing C. difficile infection worldwide. This
      proposal includes collaboration with an investigator capable of performing microbiome
      analyses on specimens collected as part of the trial and will further understanding of the
      intestinal microflora in health and disease.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Clinical Cure
time frame: 8 weeks
description: Resolution of diarrhea (i.e., fewer than three unformed stools for two consecutive days), with maintenance of resolution for the duration of the 8 week follow-up period and no further requirements for anti-infective therapy for C. difficile infection). Subjects who meet this definition will be considered cured regardless of results of follow-up stool testing for C. difficile.
measure: Clinical Failure
time frame: 8 weeks
description: Persistence or development of diarrhea and the need for additional anti-infective therapy for C. difficile infection with or without positive stool testing (PCR) for C. difficile. Upon clinical failure, subject's treatment will be unblinded and those who received sham Fecal Microbiotia Transplantation (FMT) may chose to receive open label FMT using donor stool. Subjects, who received true FMT and develop clinical failure, may chose to undergo a second FMT using an alternate donor.
measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
time frame: 6 months
description: Subjects will be followed closely for significant adverse events and adverse events during the 8 week follow up period post-FMT and the development of new medical conditions/diagnoses or changes in medical conditions/medications will be determined at 6 month follow up contact. Adverse events will be tabulated by study arm.
arm group label: Fecal Microbiota Transplantation
arm group type: Active Comparator
description: After completing at least a 10 day course of vancomycin for treatment of the most recent acute C. difficile infection, subjects will receive fecal Microbiota Transplant (FMT) with a 300 mL donor fecal suspension delivered via colonoscopy.
arm group label: Sham Fecal Microbiota Transplantation
arm group type: Sham Comparator
description: After completing at least a 10 day course of vancomycin for treatment of the most recent acute severe C. difficile infection, subjects will receive a 300 mL infusion of a sham (autotransfusion) fecal solution at colonoscopy.
intervention type: Biological
intervention name: Fecal Microbiota Transplantation
description: Fecal microbiota transplantation (FMT) involves administering fecal material from a healthy individual (donor) to a sick patient (with relapsing C. difficile infection) to restore missing components of normal intestinal flora. After completing at least a 10 day course of vancomycin for treatment of the most recent acute C. difficile infection, subjects will receive fecal microbiota transplantation (FMT) with a 300 mL donor fecal suspension delivered via colonoscopy.
arm group label: Fecal Microbiota Transplantation
other name: FMT
other name: fecal bacteriotherapy
other name: fecal flora reconstitution
other name: stool transplant
intervention type: Biological
intervention name: Sham Fecal Microbiota Transplantation
description: After completing at least a 10 day course of vancomycin for treatment of the most recent acute C. difficile infection, subjects will receive a sham fecal microbiota transplantation (FMT) with a 300 mL sham fecal suspension delivered via colonoscopy. This sham solution will be a reinfusion of the subject's own stool.
arm group label: Sham Fecal Microbiota Transplantation
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Colleen R Kelly, MD
role: Principal Investigator
affiliation: Lifespan/ The Miriam Hospital
last name: Lawrence J Brandt, MD
role: Principal Investigator
affiliation: Montefiore Medical Center
facility: 
facility: 
country: United States
citation: Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol. 2010 May-Jun;44(5):354-60. doi: 10.1097/MCG.0b013e3181c87e02.
PMID: 20048681
citation: Persky SE, Brandt LJ. Treatment of recurrent Clostridium difficile-associated diarrhea by administration of donated stool directly through a colonoscope. Am J Gastroenterol. 2000 Nov;95(11):3283-5. doi: 10.1111/j.1572-0241.2000.03302.x. No abstract available.
PMID: 11095355
citation: Yoon SS, Brandt LJ. Treatment of refractory/recurrent C. difficile-associated disease by donated stool transplanted via colonoscopy: a case series of 12 patients. J Clin Gastroenterol. 2010 Sep;44(8):562-6. doi: 10.1097/MCG.0b013e3181dac035.
PMID: 20463588
citation: Kelly CR, de Leon L, Jasutkar N. Fecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results. J Clin Gastroenterol. 2012 Feb;46(2):145-9. doi: 10.1097/MCG.0b013e318234570b.
PMID: 22157239
responsible party type: Sponsor-Investigator
investigator affiliation: The Miriam Hospital
investigator full name: Colleen Kelly
investigator title: Clinical Assistant Professor of Medicine
mesh term: Clostridium Infections