<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/NCT03827447</url>
  </required_header>
  <id_info>
    <org_study_id>PRO00033844</org_study_id>
    <nct_id>NCT03827447</nct_id>
  </id_info>
  <brief_title>Vancomycin for the Treatment of NAAT(+)/Toxin(-) C. Difficile</brief_title>
  <official_title>Randomized Double Blind Placebo Controlled Trial for the Treatment of NAAT(+)/Toxin EIA(-) Clostridium Difficile</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical College of Wisconsin</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical College of Wisconsin</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>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study proposes to:&#xD;
&#xD;
        1. Characterize the impact of oral vancomycin on C. difficile loads after end of treatment&#xD;
           compared to a placebo group.&#xD;
&#xD;
        2. Determine the effect of oral vancomycin on structural and functional microbiome changes&#xD;
           after end of treatment compared to a placebo group.&#xD;
&#xD;
        3. Characterize the impact of oral vancomycin against a placebo group on the daily&#xD;
           frequency of loose stools by the end of treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Clostridium difficile infection (CDI) is considered the most frequent healthcare associated&#xD;
      infection in the US, causing almost half a million cases per year with an estimated annual&#xD;
      cost of 4.8 billion dollars. Despite the existence of a few treatment options against CDI,&#xD;
      yearly attributable deaths are estimated at 29,300 in the US. From April 2014 to April 2016,&#xD;
      Froedtert Health reported 899 CDIs. Over half of these events are NAAT (Nucleic Acid&#xD;
      Amplification Test)(+)/EIA (Enzyme immunoassay)(-) events. To test for CDI, NAAT followed by&#xD;
      EIA is used in a Multistep algorithmic testing in which a sensitive nucleic acid&#xD;
      amplification test (NAAT) is followed by a specific toxin A and toxin B enzyme immunoassay&#xD;
      (EIA) and are among the most accurate methods for Clostridium difficile infection (CDI)&#xD;
      diagnosis. There is currently uncertainty on how to treat these CDI events.&#xD;
&#xD;
      The primary outcome of this randomized double blind controlled intervention trial will be&#xD;
      changes in C. difficile (Clostridium difficile) loads between day 1 and day 14 and changes in&#xD;
      C. difficile load between day 14 and day 28. Thirty patients with documented C. difficile&#xD;
      will be randomized to either 14 days of vancomycin or placebo capsules. Block randomization&#xD;
      will be used to assign patients to the treatment or placebo arms. Randomized assignments will&#xD;
      be placed in sealed envelopes which will only be handled by the research pharmacist. Study&#xD;
      related stool collections will be obtained on days 1, 7, 14, 21, and 28 (+/- 2days) [Day&#xD;
      1=first day study drug was administered]. Patients will be followed for 90 days starting on&#xD;
      day 1. Patients unable to complete at least 7 days of study treatment will be removed from&#xD;
      analysis and replaced.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 17, 2019</start_date>
  <completion_date type="Actual">June 30, 2021</completion_date>
  <primary_completion_date type="Actual">June 1, 2021</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Patients will be divided into 2 groups, one receiving oral vancomycin and the other placebo.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>After enrollment, patients will be randomized to treatment with vancomycin 125 mg capsules by mouth every 6 hours for 14 days or to placebo with identical looking capsules for the same length of treatment. Block randomization will be used to assign patients to the treatment or placebo arms. Randomized assignments will be placed in sealed envelopes which will only be handled by the research pharmacist. Clinical providers, research team, and patients will remain blinded to allocation</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Determine the change in C. difficile loads between the vancomycin vs. placebo group.</measure>
    <time_frame>Day 1- Day 28</time_frame>
    <description>Compare the impact of vancomycin vs placebo on changes in C. difficile load from stool samples collected on Day 1 to end-of-treatment (Day 14) and to Day 28 using quantitative Polymerase Chain Reaction (qPCR).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Determine the long-term persistence of C. difficile from the change in qPCR levels between the vancomycin vs. placebo group</measure>
    <time_frame>Day 1 - Day 90</time_frame>
    <description>Establish the long-term persistence of C. difficile by qPCR from stool samples collected at Day 1, 7, 14, 21, 28, and 90 between the vancomycin and placebo group.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Characterize the change on structural alterations of the microbiome after end of treatment between the vancomycin vs. placebo groups through 16S rRNA sequencing.</measure>
    <time_frame>Pre-treatment, Day 1 - Day 90 past the beginning of treatment</time_frame>
    <description>Structural alterations of the microbiome after end of treatment will be determined using 16S rRNA sequencing from stool samples collected upon diagnosis, Days 1, 7, 14, 21, 28 &amp; 90. Structural alterations will be defined according to the Shannon Diversity Index.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure the change in bile acids in the oral vancomycin vs. placebo groups by mass spectrometry.</measure>
    <time_frame>Pre-treatment, Day 1 - Day 90 past the beginning of treatment</time_frame>
    <description>Characterize the impact of oral vancomycin against placebo on functional microbiome changes after end of treatment by measuring bile acids. They will be measured via mass spectrometry using stool samples collected upon diagnosis, Days 1, 7, 14, 21, 28 &amp; 90.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure the change in amino acids in the oral vancomycin vs. placebo groups by mass spectrometry.</measure>
    <time_frame>Pre-treatment, Day 1 - Day 90 past the beginning of treatment</time_frame>
    <description>Characterize the impact of oral vancomycin against placebo on functional microbiome changes after end of treatment by measuring amino acids. They will be measured via mass spectrometry using stool samples collected upon diagnosis, Days 1, 7, 14, 21, 28 &amp; 90.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure the change in sugars in the oral vancomycin vs. placebo groups by mass spectrometry.</measure>
    <time_frame>Pre-treatment, Day 1 - Day 90 past the beginning of treatment</time_frame>
    <description>Characterize the impact of oral vancomycin against placebo on functional microbiome changes after end of treatment by measuring sugars. They will be measured via mass spectrometry using stool samples collected upon diagnosis, Days 1, 7, 14, 21, 28 &amp; 90.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure the change in lipids from Day 1 to Day 90 in the oral vancomycin vs. placebo groups by mass spectrometry.</measure>
    <time_frame>Pre-treatment, Day 1 - Day 90 past the beginning of treatment</time_frame>
    <description>Characterize the impact of oral vancomycin against placebo on functional microbiome changes after end of treatment by measuring lipids. They will be measured via mass spectrometry using stool samples collected upon diagnosis, Days 1, 7, 14, 21, 28 &amp; 90.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure the change in frequency of bowel movements in the oral vancomycin vs. placebo groups.</measure>
    <time_frame>Day 1 - Day 90 past the beginning of treatment</time_frame>
    <description>Characterize the impact of oral vancomycin against a placebo group on the daily frequency of bowel movements by the end of treatment. This scale goes from 0 to &gt;20 in increments of 1. Data will be analyzed over time as a slope for each patient. The closer to 1 per 24 hours the better the outcome. Data will be obtained from patient self-reports using study questionnaires on Days 1, 7, 14, 21, 28 &amp; 90.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">7</enrollment>
  <condition>Clostridium Difficile Infection</condition>
  <arm_group>
    <arm_group_label>Drug: Vancomycin Group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subjects will receive oral vancomycin capsules by mouth, 125 mg every 6 hours for 14 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Drug: Placebo Group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects will receive a placebo oral capsule by mouth every 6 hours for 14 days. The placebo oral capsule is manufactured by Study Site's pharmacy to be identical in size, shape, color, appearance and taste as the drug comparator</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vancomycin Oral Capsule</intervention_name>
    <description>125 mg capsules every 6 hours for 14 days.</description>
    <arm_group_label>Drug: Vancomycin Group</arm_group_label>
    <other_name>Vancocin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Capsule</intervention_name>
    <description>Gelatin pill manufactured to mimic 125 mg Vancomycin oral capsule</description>
    <arm_group_label>Drug: Placebo Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Must be at least 18 years of age at time of consent.&#xD;
&#xD;
          -  Presence of loose stools triggering clinical C. difficile NAAT/toxin EIA testing.&#xD;
&#xD;
          -  Having both C. difficile NAAT (+) and C. difficile toxin EIA (-).&#xD;
&#xD;
          -  Admitted outside the hematology-oncology unit.&#xD;
&#xD;
          -  Must be willing to keep a study supplied drug diary&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Presence of sepsis. Sepsis will be defined as a Sequential [Sepsis-related] Organ&#xD;
             Failure Assessment (SOFA) score of 2 points or more as per 2016 definitions.&#xD;
&#xD;
          -  Inability to take oral medications.&#xD;
&#xD;
          -  Unwillingness or inability to provide written informed consent.&#xD;
&#xD;
          -  Has a documented allergy to vancomycin.&#xD;
&#xD;
          -  Has a documented life expectancy shorter than treatment course (14 days).&#xD;
&#xD;
          -  Unwilling or unable to collect stool samples in the outpatient setting after&#xD;
             discharge.&#xD;
&#xD;
          -  Diagnosis of C. difficile colitis [NAAT(+) and toxin EIA(+)] in the preceding 3 months&#xD;
             from enrollment.&#xD;
&#xD;
          -  Received oral vancomycin during their current hospitalization, excluding empiric&#xD;
             treatment given while pending C. difficile NAAT/toxin EIA results. Intravenous&#xD;
             vancomycin is not an exclusion criterion.&#xD;
&#xD;
          -  Women known to be pregnant or lactating during the study.&#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>Silvia Munoz-Price, M.D., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical College of Wisconsin</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Medical College of Wisconsin, Inc.</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>January 21, 2019</study_first_submitted>
  <study_first_submitted_qc>January 31, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 1, 2019</study_first_posted>
  <last_update_submitted>October 12, 2021</last_update_submitted>
  <last_update_submitted_qc>October 12, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 20, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical College of Wisconsin</investigator_affiliation>
    <investigator_full_name>Silvia Munoz-Price</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Clostridium Difficile</keyword>
  <keyword>Metabolomics</keyword>
  <keyword>Vancomycin</keyword>
  <keyword>Microbiome</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Clostridium Infections</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vancomycin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Participant data to be shared would consist of age categories, genders, treatment groups, Clostridium difficile status, microbiome profile and metabolic profile. The data will be anonymized to prevent the identification of individual patients from the data provided. The data would be made available through contacting the principal investigator directly.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03827447
org study id: PRO00033844
nct id: NCT03827447
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This study proposes to:

        1. Characterize the impact of oral vancomycin on C. difficile loads after end of treatment
           compared to a placebo group.

        2. Determine the effect of oral vancomycin on structural and functional microbiome changes
           after end of treatment compared to a placebo group.

        3. Characterize the impact of oral vancomycin against a placebo group on the daily
           frequency of loose stools by the end of treatment.
Clostridium difficile infection (CDI) is considered the most frequent healthcare associated
      infection in the US, causing almost half a million cases per year with an estimated annual
      cost of 4.8 billion dollars. Despite the existence of a few treatment options against CDI,
      yearly attributable deaths are estimated at 29,300 in the US. From April 2014 to April 2016,
      Froedtert Health reported 899 CDIs. Over half of these events are NAAT (Nucleic Acid
      Amplification Test)(+)/EIA (Enzyme immunoassay)(-) events. To test for CDI, NAAT followed by
      EIA is used in a Multistep algorithmic testing in which a sensitive nucleic acid
      amplification test (NAAT) is followed by a specific toxin A and toxin B enzyme immunoassay
      (EIA) and are among the most accurate methods for Clostridium difficile infection (CDI)
      diagnosis. There is currently uncertainty on how to treat these CDI events.

      The primary outcome of this randomized double blind controlled intervention trial will be
      changes in C. difficile (Clostridium difficile) loads between day 1 and day 14 and changes in
      C. difficile load between day 14 and day 28. Thirty patients with documented C. difficile
      will be randomized to either 14 days of vancomycin or placebo capsules. Block randomization
      will be used to assign patients to the treatment or placebo arms. Randomized assignments will
      be placed in sealed envelopes which will only be handled by the research pharmacist. Study
      related stool collections will be obtained on days 1, 7, 14, 21, and 28 (+/- 2days) [Day
      1=first day study drug was administered]. Patients will be followed for 90 days starting on
      day 1. Patients unable to complete at least 7 days of study treatment will be removed from
      analysis and replaced.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Patients will be divided into 2 groups, one receiving oral vancomycin and the other placebo.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: After enrollment, patients will be randomized to treatment with vancomycin 125 mg capsules by mouth every 6 hours for 14 days or to placebo with identical looking capsules for the same length of treatment. Block randomization will be used to assign patients to the treatment or placebo arms. Randomized assignments will be placed in sealed envelopes which will only be handled by the research pharmacist. Clinical providers, research team, and patients will remain blinded to allocation
measure: Determine the change in C. difficile loads between the vancomycin vs. placebo group.
time frame: Day 1- Day 28
description: Compare the impact of vancomycin vs placebo on changes in C. difficile load from stool samples collected on Day 1 to end-of-treatment (Day 14) and to Day 28 using quantitative Polymerase Chain Reaction (qPCR).
measure: Determine the long-term persistence of C. difficile from the change in qPCR levels between the vancomycin vs. placebo group
time frame: Day 1 - Day 90
description: Establish the long-term persistence of C. difficile by qPCR from stool samples collected at Day 1, 7, 14, 21, 28, and 90 between the vancomycin and placebo group.
measure: Characterize the change on structural alterations of the microbiome after end of treatment between the vancomycin vs. placebo groups through 16S rRNA sequencing.
time frame: Pre-treatment, Day 1 - Day 90 past the beginning of treatment
description: Structural alterations of the microbiome after end of treatment will be determined using 16S rRNA sequencing from stool samples collected upon diagnosis, Days 1, 7, 14, 21, 28 & 90. Structural alterations will be defined according to the Shannon Diversity Index.
measure: Measure the change in bile acids in the oral vancomycin vs. placebo groups by mass spectrometry.
time frame: Pre-treatment, Day 1 - Day 90 past the beginning of treatment
description: Characterize the impact of oral vancomycin against placebo on functional microbiome changes after end of treatment by measuring bile acids. They will be measured via mass spectrometry using stool samples collected upon diagnosis, Days 1, 7, 14, 21, 28 & 90.
measure: Measure the change in amino acids in the oral vancomycin vs. placebo groups by mass spectrometry.
time frame: Pre-treatment, Day 1 - Day 90 past the beginning of treatment
description: Characterize the impact of oral vancomycin against placebo on functional microbiome changes after end of treatment by measuring amino acids. They will be measured via mass spectrometry using stool samples collected upon diagnosis, Days 1, 7, 14, 21, 28 & 90.
measure: Measure the change in sugars in the oral vancomycin vs. placebo groups by mass spectrometry.
time frame: Pre-treatment, Day 1 - Day 90 past the beginning of treatment
description: Characterize the impact of oral vancomycin against placebo on functional microbiome changes after end of treatment by measuring sugars. They will be measured via mass spectrometry using stool samples collected upon diagnosis, Days 1, 7, 14, 21, 28 & 90.
measure: Measure the change in lipids from Day 1 to Day 90 in the oral vancomycin vs. placebo groups by mass spectrometry.
time frame: Pre-treatment, Day 1 - Day 90 past the beginning of treatment
description: Characterize the impact of oral vancomycin against placebo on functional microbiome changes after end of treatment by measuring lipids. They will be measured via mass spectrometry using stool samples collected upon diagnosis, Days 1, 7, 14, 21, 28 & 90.
measure: Measure the change in frequency of bowel movements in the oral vancomycin vs. placebo groups.
time frame: Day 1 - Day 90 past the beginning of treatment
description: Characterize the impact of oral vancomycin against a placebo group on the daily frequency of bowel movements by the end of treatment. This scale goes from 0 to >20 in increments of 1. Data will be analyzed over time as a slope for each patient. The closer to 1 per 24 hours the better the outcome. Data will be obtained from patient self-reports using study questionnaires on Days 1, 7, 14, 21, 28 & 90.
arm group label: Drug: Vancomycin Group
arm group type: Active Comparator
description: Subjects will receive oral vancomycin capsules by mouth, 125 mg every 6 hours for 14 days.
arm group label: Drug: Placebo Group
arm group type: Placebo Comparator
description: Subjects will receive a placebo oral capsule by mouth every 6 hours for 14 days. The placebo oral capsule is manufactured by Study Site's pharmacy to be identical in size, shape, color, appearance and taste as the drug comparator
intervention type: Drug
intervention name: Vancomycin Oral Capsule
description: 125 mg capsules every 6 hours for 14 days.
arm group label: Drug: Vancomycin Group
other name: Vancocin
intervention type: Drug
intervention name: Placebo Oral Capsule
description: Gelatin pill manufactured to mimic 125 mg Vancomycin oral capsule
arm group label: Drug: Placebo Group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Silvia Munoz-Price, M.D., Ph.D.
role: Principal Investigator
affiliation: Medical College of Wisconsin
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Medical College of Wisconsin
investigator full name: Silvia Munoz-Price
investigator title: Professor
mesh term: Clostridium Infections
mesh term: Vancomycin
sharing ipd: No
ipd description: Participant data to be shared would consist of age categories, genders, treatment groups, Clostridium difficile status, microbiome profile and metabolic profile. The data will be anonymized to prevent the identification of individual patients from the data provided. The data would be made available through contacting the principal investigator directly.