<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/NCT03756454</url>
  </required_header>
  <id_info>
    <org_study_id>2018H0348</org_study_id>
    <nct_id>NCT03756454</nct_id>
  </id_info>
  <brief_title>Comparing the Effectiveness of IV Bezlotoxumab Versus Placebo in Decreasing Morbidity and Mortality in Patients With Fulminant C. Diff Requiring Surgery.</brief_title>
  <official_title>A Prospective, Double-blind, Randomized, and Controlled Clinical Trial to Compare the Effectiveness of Intravenous Bezlotoxumab (10 mg/kg) Versus Placebo in Decreasing Morbidity and Mortality in Patients With Fulminant Clostridioides Difficile Requiring Surgical Intervention.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Michael E Villarreal, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Ohio State University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      A new medication, Bezlotoxumab, has been approved for treatment of recurrent Clostridium&#xD;
      difficile diarrhea by the U.S. Food and Drug Administration. The way this new medication&#xD;
      works, is by binding the toxin produced by C. difficile bacteria and preventing damage to the&#xD;
      large bowel. The toxin, and not the bacteria, is responsible for the damage, resulting in the&#xD;
      clinical symptoms seen in patients. Sometimes, the infection can make a patient severely ill&#xD;
      with organ failure and death. If severe enough, the infection requires surgery to remove the&#xD;
      large bowel and allow the patient a better chance at recovery. Even with surgery and removal&#xD;
      of the bowel, patients can continue to be severely ill and have a very high rate of&#xD;
      mortality. The toxin that injures the large bowel has been shown to obtain access to systemic&#xD;
      circulation because of the injury to the bowel. At this time, the investigators continue&#xD;
      antibiotics and supportive care to help patients recover post-operatively, as the&#xD;
      investigators do not have other interventions in this critical population. Bezlotoxumab is&#xD;
      known to bind this toxin and stop it from causing further injury in the bowel; it has the&#xD;
      potential to bind the systemic toxin to prevent further damage throughout the body. This&#xD;
      study is proposing that this new medication, Bezlotoxumab, can be added to the current&#xD;
      standard of care for severe infection that requires surgery, and result in a decrease of the&#xD;
      complications associated with this disease process. In this study, some patients will receive&#xD;
      the medication after surgery; others will receive extra fluid. The investigators will not&#xD;
      know who received which in order to decrease any bias in the results. All participants will&#xD;
      receive similar post-operative care and be monitored closely. When enough patients are&#xD;
      enrolled in the study, the results will be evaluated.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Design This will be an interventional prospective, randomized, double-blinded&#xD;
      controlled trial performed at a single center. Prospective data will be collected of all&#xD;
      consenting patients with a diagnosis of either initial or recurrent fulminant C. difficile&#xD;
      colitis requiring surgical intervention. The data to be collected includes standard-of-care&#xD;
      blood draws; no extra lab draws are planned for this trial. In the event labs are not drawn,&#xD;
      the investigators will plan to obtain serum creatinine, total bilirubin, and platelet counts&#xD;
      to continue SOFA score evaluations while the patient is in the surgical ICU. Consent will be&#xD;
      obtained either from the patient or their legally authorized representative. Inclusion&#xD;
      criteria will be all patients over the age of eighteen with diagnosed fulminant C. difficile&#xD;
      colitis requiring surgical colectomy with end ileostomy. Surgical intervention will be&#xD;
      determined by the operating surgeon at the time of initial consult assessment and during the&#xD;
      follow-up assessments while the patient is hospitalized. Patients may be excluded on the&#xD;
      account they are pregnant, prisoners/ incarcerated, have a history of congestive heart&#xD;
      failure, or have received IVIG within 30 days of randomization to exclusion criteria.&#xD;
&#xD;
      Randomization will be performed per best common practice guidelines with a computer-generated&#xD;
      randomization process and hospital investigational pharmacy blinding processes into both a&#xD;
      therapeutic arm (Bezlotoxumab) and a placebo (normal saline) arm of the study. All current&#xD;
      standards of care will continue to be administered in these patients, regardless of their&#xD;
      respective study arm. To control for the antibiotics administered, the patients will need to&#xD;
      be stratified according to the standard-of-care antibiotics and balanced in regards to this&#xD;
      variable. Current standard of care therapy at our institution for fulminant C. difficile&#xD;
      colitis includes Vancomycin (both oral and rectal, if needed) and intravenous Metronidazole.&#xD;
      Fulminant C. difficile colitis is defined, per our guidelines, as proven infection with&#xD;
      hypotension/ shock, ileus, or megacolon.&#xD;
&#xD;
      Upon conclusion of the surgical intervention, the Anesthesia or nursing team will administer&#xD;
      the trial medication, Bezlotoxumab, or the placebo, normal saline. Dosing is planned to be&#xD;
      ten milligrams per kilogram, which is standard dosing for therapeutic Bezlotoxumab approved&#xD;
      for use by the U.S. Food and Drug Administration. This dose will be administered as a&#xD;
      one-time single-infusion dose administered over the span of one hour. The placebo&#xD;
      administration of normal saline will be at the same dosing with a single-infusion over one&#xD;
      hour. The patient will receive standard of care post-operative management and the information&#xD;
      obtained from standard-of-care lab draws will be assessed throughout their hospital stay. The&#xD;
      patient will be seen and evaluated in clinic during the post-operative period at the&#xD;
      one-month follow-up and either in clinic or via telephone at their three-month and six-month&#xD;
      follow-up.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Difficulties with enrollment and inability to guarantee further study drug supply after current&#xD;
    supply expired.&#xD;
  </why_stopped>
  <start_date type="Actual">August 19, 2019</start_date>
  <completion_date type="Actual">May 23, 2022</completion_date>
  <primary_completion_date type="Actual">May 23, 2022</primary_completion_date>
  <phase>Phase 4</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>Randomization will be performed per best common practice guidelines with a computer generated randomization process and hospital investigational pharmacy blinding processes into both a therapeutic arm (Bezlotoxumab) and a placebo (normal saline) arm of the study. All current standards of care will continue to be administered in these patients, regardless of their respective study arm. To control for the antibiotics administered, the patients will need to be stratified according to the standard-of-care antibiotics and balanced in regards to this variable. Current standard of care therapy at our institution for fulminant C. difficile colitis includes Vancomycin (both oral and rectal, if needed) and intravenous Metronidazole. Fulminant C. difficile colitis is defined, per our guidelines, as proven infection with hypotension/ shock, ileus, or megacolon.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Upon conclusion of the surgical intervention, the Anesthesia or nursing team will administer the trial medication, Bezlotoxumab, or the placebo, normal saline. Dosing is planned to be ten milligrams per kilogram, which is standard dosing for therapeutic Bezlotoxumab approved for use by the U.S. Food and Drug Administration. This dose will be administered as a one-time single-infusion dose administered over the span of one hour. The placebo administration of normal saline will be at the same dosing with a single-infusion over one hour. The patient will receive standard of care post-operative management and the information obtained from standard-of-care lab draws will be assessed throughout their hospital stay. The patient will be seen and evaluated in clinic in the post-operative period at the one month follow-up and either in clinic or via telephone at their three month and six month follow-up.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Mortality</measure>
    <time_frame>30-days</time_frame>
    <description>Monitor for 30-day mortality</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Heart Failure</measure>
    <time_frame>30-days</time_frame>
    <description>Monitor for development of heart failure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Respiratory Failure</measure>
    <time_frame>30-days</time_frame>
    <description>Monitor for development of respiratory failure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Renal Failure</measure>
    <time_frame>30-days</time_frame>
    <description>Monitor for development of renal failure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hepatic Failure</measure>
    <time_frame>30-days</time_frame>
    <description>Monitor for development of hepatic failure</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Clostridia Difficile Colitis</condition>
  <condition>Clostridium; Sepsis</condition>
  <arm_group>
    <arm_group_label>Bezlotoxumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receiving Bezlotoxumab post-operatively.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Normal Saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients receiving normal saline as a placebo post-operatively.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Bezlotoxumab</intervention_name>
    <description>Patients receiving Bezlotoxumab post-operatively.</description>
    <arm_group_label>Bezlotoxumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Normal Saline</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Normal Saline</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  &gt; 18 years old, diagnosed C diff colitis requiring surgical intervention&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  CHF previously diagnosed, pregnancy, prisoners/ incarcerated, previous administration&#xD;
             of IVIG within 30-days of randomization&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>The Ohio State University</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>November 26, 2018</study_first_submitted>
  <study_first_submitted_qc>November 26, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 28, 2018</study_first_posted>
  <last_update_submitted>May 11, 2023</last_update_submitted>
  <last_update_submitted_qc>May 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 12, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Ohio State University</investigator_affiliation>
    <investigator_full_name>Michael E Villarreal, MD</investigator_full_name>
    <investigator_title>Clinical Instructor House Staff - General Surgery</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colitis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03756454
org study id: 2018H0348
nct id: NCT03756454
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
A new medication, Bezlotoxumab, has been approved for treatment of recurrent Clostridium
      difficile diarrhea by the U.S. Food and Drug Administration. The way this new medication
      works, is by binding the toxin produced by C. difficile bacteria and preventing damage to the
      large bowel. The toxin, and not the bacteria, is responsible for the damage, resulting in the
      clinical symptoms seen in patients. Sometimes, the infection can make a patient severely ill
      with organ failure and death. If severe enough, the infection requires surgery to remove the
      large bowel and allow the patient a better chance at recovery. Even with surgery and removal
      of the bowel, patients can continue to be severely ill and have a very high rate of
      mortality. The toxin that injures the large bowel has been shown to obtain access to systemic
      circulation because of the injury to the bowel. At this time, the investigators continue
      antibiotics and supportive care to help patients recover post-operatively, as the
      investigators do not have other interventions in this critical population. Bezlotoxumab is
      known to bind this toxin and stop it from causing further injury in the bowel; it has the
      potential to bind the systemic toxin to prevent further damage throughout the body. This
      study is proposing that this new medication, Bezlotoxumab, can be added to the current
      standard of care for severe infection that requires surgery, and result in a decrease of the
      complications associated with this disease process. In this study, some patients will receive
      the medication after surgery; others will receive extra fluid. The investigators will not
      know who received which in order to decrease any bias in the results. All participants will
      receive similar post-operative care and be monitored closely. When enough patients are
      enrolled in the study, the results will be evaluated.
Study Design This will be an interventional prospective, randomized, double-blinded
      controlled trial performed at a single center. Prospective data will be collected of all
      consenting patients with a diagnosis of either initial or recurrent fulminant C. difficile
      colitis requiring surgical intervention. The data to be collected includes standard-of-care
      blood draws; no extra lab draws are planned for this trial. In the event labs are not drawn,
      the investigators will plan to obtain serum creatinine, total bilirubin, and platelet counts
      to continue SOFA score evaluations while the patient is in the surgical ICU. Consent will be
      obtained either from the patient or their legally authorized representative. Inclusion
      criteria will be all patients over the age of eighteen with diagnosed fulminant C. difficile
      colitis requiring surgical colectomy with end ileostomy. Surgical intervention will be
      determined by the operating surgeon at the time of initial consult assessment and during the
      follow-up assessments while the patient is hospitalized. Patients may be excluded on the
      account they are pregnant, prisoners/ incarcerated, have a history of congestive heart
      failure, or have received IVIG within 30 days of randomization to exclusion criteria.

      Randomization will be performed per best common practice guidelines with a computer-generated
      randomization process and hospital investigational pharmacy blinding processes into both a
      therapeutic arm (Bezlotoxumab) and a placebo (normal saline) arm of the study. All current
      standards of care will continue to be administered in these patients, regardless of their
      respective study arm. To control for the antibiotics administered, the patients will need to
      be stratified according to the standard-of-care antibiotics and balanced in regards to this
      variable. Current standard of care therapy at our institution for fulminant C. difficile
      colitis includes Vancomycin (both oral and rectal, if needed) and intravenous Metronidazole.
      Fulminant C. difficile colitis is defined, per our guidelines, as proven infection with
      hypotension/ shock, ileus, or megacolon.

      Upon conclusion of the surgical intervention, the Anesthesia or nursing team will administer
      the trial medication, Bezlotoxumab, or the placebo, normal saline. Dosing is planned to be
      ten milligrams per kilogram, which is standard dosing for therapeutic Bezlotoxumab approved
      for use by the U.S. Food and Drug Administration. This dose will be administered as a
      one-time single-infusion dose administered over the span of one hour. The placebo
      administration of normal saline will be at the same dosing with a single-infusion over one
      hour. The patient will receive standard of care post-operative management and the information
      obtained from standard-of-care lab draws will be assessed throughout their hospital stay. The
      patient will be seen and evaluated in clinic during the post-operative period at the
      one-month follow-up and either in clinic or via telephone at their three-month and six-month
      follow-up.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomization will be performed per best common practice guidelines with a computer generated randomization process and hospital investigational pharmacy blinding processes into both a therapeutic arm (Bezlotoxumab) and a placebo (normal saline) arm of the study. All current standards of care will continue to be administered in these patients, regardless of their respective study arm. To control for the antibiotics administered, the patients will need to be stratified according to the standard-of-care antibiotics and balanced in regards to this variable. Current standard of care therapy at our institution for fulminant C. difficile colitis includes Vancomycin (both oral and rectal, if needed) and intravenous Metronidazole. Fulminant C. difficile colitis is defined, per our guidelines, as proven infection with hypotension/ shock, ileus, or megacolon.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: Upon conclusion of the surgical intervention, the Anesthesia or nursing team will administer the trial medication, Bezlotoxumab, or the placebo, normal saline. Dosing is planned to be ten milligrams per kilogram, which is standard dosing for therapeutic Bezlotoxumab approved for use by the U.S. Food and Drug Administration. This dose will be administered as a one-time single-infusion dose administered over the span of one hour. The placebo administration of normal saline will be at the same dosing with a single-infusion over one hour. The patient will receive standard of care post-operative management and the information obtained from standard-of-care lab draws will be assessed throughout their hospital stay. The patient will be seen and evaluated in clinic in the post-operative period at the one month follow-up and either in clinic or via telephone at their three month and six month follow-up.
measure: Mortality
time frame: 30-days
description: Monitor for 30-day mortality
measure: Heart Failure
time frame: 30-days
description: Monitor for development of heart failure
measure: Respiratory Failure
time frame: 30-days
description: Monitor for development of respiratory failure
measure: Renal Failure
time frame: 30-days
description: Monitor for development of renal failure
measure: Hepatic Failure
time frame: 30-days
description: Monitor for development of hepatic failure
arm group label: Bezlotoxumab
arm group type: Experimental
description: Patients receiving Bezlotoxumab post-operatively.
arm group label: Normal Saline
arm group type: Placebo Comparator
description: Patients receiving normal saline as a placebo post-operatively.
intervention type: Biological
intervention name: Bezlotoxumab
description: Patients receiving Bezlotoxumab post-operatively.
arm group label: Bezlotoxumab
intervention type: Other
intervention name: Normal Saline
description: Placebo
arm group label: Normal Saline
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Ohio State University
investigator full name: Michael E Villarreal, MD
investigator title: Clinical Instructor House Staff - General Surgery
mesh term: Colitis
sharing ipd: No