<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/NCT03030248</url>
  </required_header>
  <id_info>
    <org_study_id>PRO00028749</org_study_id>
    <nct_id>NCT03030248</nct_id>
  </id_info>
  <brief_title>Vancomycin for C Difficile NAAT+/EIA- Hematology Oncology Patients</brief_title>
  <official_title>Randomized Double Blind Controlled Trial for the Treatment of Nucleic Acid Amplification Test (NAAT)+/Toxin Enzyme Immunoassay (EIA)- Clostridium Difficile in the Hematology Oncology Population</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>Yes</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>
      This study will randomized hematology oncology patients with active diarrhea and a NAAT&#xD;
      positive/toxin EIA negative to either 14 days of oral vancomycin capsules or placebo. The&#xD;
      study is designed to include 30 patients (15 per arm).&#xD;
&#xD;
      Outcomes will include C. difficile load using qPCR, VRE loads, structural and functional&#xD;
      microbiome changes and frequency of bowel movements. All endpoints will be measured at&#xD;
      several time points including days 0, 14, 21 and 90.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The adverse health consequences resulting from antibiotic overtreatment of NAAT(+), toxin(-)&#xD;
      patients may be particularly important in transplant recipients. The usual treatment&#xD;
      prescribed for CDI at the Froedtert Memorial Lutheran Hospital is oral vancomycin. While this&#xD;
      drug has excellent activity against C. difficile and commonly suppresses its growth to&#xD;
      non-detection, it does not eradicate carriage and its use results in marked and prolonged&#xD;
      disruption of the lower intestinal microbiota. Meanwhile, the degree of lower intestinal&#xD;
      microbiota disruption at the time of HSCT engraftment has been demonstrated to be an&#xD;
      independent predictor (controlling for other markers of underlying disease) of overall and&#xD;
      transplant-related 3-year mortality.14 In addition, recent findings suggest that bone marrow&#xD;
      suppressive effects of antibiotics, in this case potentially unnecessary oral vancomycin&#xD;
      (which is not appreciably absorbed), may be solely mediated via microbiota disruption. All&#xD;
      these data supports the notion that antibiotic treatment of NAAT(+), toxin(-) C. difficile&#xD;
      patients might have significant negative repercussions without a clear clinical benefit.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 1, 2018</start_date>
  <completion_date type="Actual">June 30, 2020</completion_date>
  <primary_completion_date type="Actual">June 30, 2020</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>
    <intervention_model_description>Patients will be divided into two groups, one receiving oral vancomycin capsules, the other receiving oral placebo capsules.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>The allocation status of patients within this study will be held in sealed envelopes by the unblinded research pharmacist on the team. Neither the main care provider, study physicians, or the patient will know of their group, until either the end of the study (after data analysis). We will also have a blinded pharmacist.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in Clostridium difficile bacterial loads in the stool</measure>
    <time_frame>Pre-treatment, 1, 7, 14, 21, 28, and 90 days past the beginning of treatment</time_frame>
    <description>Changes in Clostridium difficile bacterial counts from stool as determined by quantitative polymerase chain reaction (PCR)</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Clostridium Difficile Infection</condition>
  <condition>Hematologic Diseases</condition>
  <condition>Bone Marrow Transplant</condition>
  <condition>Oncologic Disorders</condition>
  <arm_group>
    <arm_group_label>Vancomycin treated group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This group will be given vancomycin oral capsules, 125 mg, every 6 hours, for 14 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>This group will be given placebo oral capsules every 6 hours for 14 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vancomycin Oral Capsule</intervention_name>
    <description>We have chosen oral vancomycin capsules as it is currently a standard of care for Clostridium difficile infections, is poorly absorbed by the intestines, and is easier to blind compared to oral vancomycin solution.</description>
    <arm_group_label>Vancomycin treated group</arm_group_label>
    <other_name>Vancocin hydrochloride Oral Capsule</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Capsule</intervention_name>
    <description>A capsule containing gelatin, polyethylene glycol, titanium dioxide, iron oxide, and FD&amp;C blue No. 2. Contains the inactive ingredients of the vancomycin oral capsule, as mixed by the Froedtert Health Research Pharmacy.</description>
    <arm_group_label>Placebo group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients admitted to the hematology oncology inpatient units at Froedtert Memorial&#xD;
             Lutheran Hospital&#xD;
&#xD;
          -  New onset of diarrhea during hospitalization&#xD;
&#xD;
          -  C. difficile clinical testing showing NAAT positive EIA negative results&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Being unable to consent for self&#xD;
&#xD;
          -  Inability to take enteral medications&#xD;
&#xD;
          -  Unwillingness to enroll in study&#xD;
&#xD;
          -  Patient has a documented allergy to vancomycin&#xD;
&#xD;
          -  Patient has a documented life expectancy shorter than treatment course (14 days)&#xD;
&#xD;
          -  Patient is unwilling or unable to provide stool samples in the outpatient setting&#xD;
             after discharge&#xD;
&#xD;
          -  Diagnosis of C. difficile colitis [NAAT (+) and toxin EIA (+) within 3 months of&#xD;
             enrollment).&#xD;
&#xD;
          -  New onset of abdominal distention within 24 hours prior to the onset of diarrhea&#xD;
             during index admission&#xD;
&#xD;
          -  Presence of toxic megacolon&#xD;
&#xD;
          -  Presence of clinical sepsis. Sepsis will be defined as a Sequential [Sepsis-related]&#xD;
             Organ Failure Assessment (SOFA) score of 2 points or more as per 2016 definitions&#xD;
&#xD;
          -  Pregnancy or lactating&#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>Froedtert and the Medical College of Wisconsin</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>
  <reference>
    <citation>Lessa FC, Winston LG, McDonald LC; Emerging Infections Program C. difficile Surveillance Team. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015 Jun 11;372(24):2369-70. doi: 10.1056/NEJMc1505190. No abstract available.</citation>
    <PMID>26061850</PMID>
  </reference>
  <reference>
    <citation>Martin JS, Monaghan TM, Wilcox MH. Clostridium difficile infection: epidemiology, diagnosis and understanding transmission. Nat Rev Gastroenterol Hepatol. 2016 Apr;13(4):206-16. doi: 10.1038/nrgastro.2016.25. Epub 2016 Mar 9.</citation>
    <PMID>26956066</PMID>
  </reference>
  <reference>
    <citation>Theriot CM, Koenigsknecht MJ, Carlson PE Jr, Hatton GE, Nelson AM, Li B, Huffnagle GB, Z Li J, Young VB. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat Commun. 2014;5:3114. doi: 10.1038/ncomms4114.</citation>
    <PMID>24445449</PMID>
  </reference>
  <reference>
    <citation>Theriot CM, Bowman AA, Young VB. Antibiotic-Induced Alterations of the Gut Microbiota Alter Secondary Bile Acid Production and Allow for Clostridium difficile Spore Germination and Outgrowth in the Large Intestine. mSphere. 2016 Jan 6;1(1):e00045-15. doi: 10.1128/mSphere.00045-15. eCollection 2016 Jan-Feb.</citation>
    <PMID>27239562</PMID>
  </reference>
  <reference>
    <citation>Sethi AK, Al-Nassir WN, Nerandzic MM, Bobulsky GS, Donskey CJ. Persistence of skin contamination and environmental shedding of Clostridium difficile during and after treatment of C. difficile infection. Infect Control Hosp Epidemiol. 2010 Jan;31(1):21-7. doi: 10.1086/649016.</citation>
    <PMID>19929371</PMID>
  </reference>
  <results_reference>
    <citation>Aldrete SD, Kraft CS, Magee MJ, Chan A, Hutcherson D, Langston AA, Greenwell BI, Burd EM, Friedman-Moraco R. Risk factors and epidemiology of Clostridium difficile infection in hematopoietic stem cell transplant recipients during the peritransplant period. Transpl Infect Dis. 2017 Feb;19(1). doi: 10.1111/tid.12649.</citation>
    <PMID>27943501</PMID>
  </results_reference>
  <results_reference>
    <citation>Isaac S, Scher JU, Djukovic A, Jimenez N, Littman DR, Abramson SB, Pamer EG, Ubeda C. Short- and long-term effects of oral vancomycin on the human intestinal microbiota. J Antimicrob Chemother. 2017 Jan;72(1):128-136. doi: 10.1093/jac/dkw383. Epub 2016 Oct 5.</citation>
    <PMID>27707993</PMID>
  </results_reference>
  <results_reference>
    <citation>Polage CR, Gyorke CE, Kennedy MA, Leslie JL, Chin DL, Wang S, Nguyen HH, Huang B, Tang YW, Lee LW, Kim K, Taylor S, Romano PS, Panacek EA, Goodell PB, Solnick JV, Cohen SH. Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era. JAMA Intern Med. 2015 Nov;175(11):1792-801. doi: 10.1001/jamainternmed.2015.4114.</citation>
    <PMID>26348734</PMID>
  </results_reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>January 19, 2017</study_first_submitted>
  <study_first_submitted_qc>January 20, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 24, 2017</study_first_posted>
  <last_update_submitted>September 8, 2020</last_update_submitted>
  <last_update_submitted_qc>September 8, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 10, 2020</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>microbiome</keyword>
  <keyword>bone marrow transplantation</keyword>
  <keyword>Clostridium difficile</keyword>
  <keyword>metabolomics</keyword>
  <keyword>vancomycin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Clostridium Infections</mesh_term>
    <mesh_term>Hematologic Diseases</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>
  <pending_results>
    <submitted>November 22, 2021</submitted>
    <returned>December 21, 2021</returned>
    <submitted>May 17, 2022</submitted>
    <returned>June 10, 2022</returned>
  </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/NCT03030248
org study id: PRO00028749
nct id: NCT03030248
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This study will randomized hematology oncology patients with active diarrhea and a NAAT
      positive/toxin EIA negative to either 14 days of oral vancomycin capsules or placebo. The
      study is designed to include 30 patients (15 per arm).

      Outcomes will include C. difficile load using qPCR, VRE loads, structural and functional
      microbiome changes and frequency of bowel movements. All endpoints will be measured at
      several time points including days 0, 14, 21 and 90.
The adverse health consequences resulting from antibiotic overtreatment of NAAT(+), toxin(-)
      patients may be particularly important in transplant recipients. The usual treatment
      prescribed for CDI at the Froedtert Memorial Lutheran Hospital is oral vancomycin. While this
      drug has excellent activity against C. difficile and commonly suppresses its growth to
      non-detection, it does not eradicate carriage and its use results in marked and prolonged
      disruption of the lower intestinal microbiota. Meanwhile, the degree of lower intestinal
      microbiota disruption at the time of HSCT engraftment has been demonstrated to be an
      independent predictor (controlling for other markers of underlying disease) of overall and
      transplant-related 3-year mortality.14 In addition, recent findings suggest that bone marrow
      suppressive effects of antibiotics, in this case potentially unnecessary oral vancomycin
      (which is not appreciably absorbed), may be solely mediated via microbiota disruption. All
      these data supports the notion that antibiotic treatment of NAAT(+), toxin(-) C. difficile
      patients might have significant negative repercussions without a clear clinical benefit.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Patients will be divided into two groups, one receiving oral vancomycin capsules, the other receiving oral placebo capsules.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: The allocation status of patients within this study will be held in sealed envelopes by the unblinded research pharmacist on the team. Neither the main care provider, study physicians, or the patient will know of their group, until either the end of the study (after data analysis). We will also have a blinded pharmacist.
measure: Changes in Clostridium difficile bacterial loads in the stool
time frame: Pre-treatment, 1, 7, 14, 21, 28, and 90 days past the beginning of treatment
description: Changes in Clostridium difficile bacterial counts from stool as determined by quantitative polymerase chain reaction (PCR)
arm group label: Vancomycin treated group
arm group type: Active Comparator
description: This group will be given vancomycin oral capsules, 125 mg, every 6 hours, for 14 days.
arm group label: Placebo group
arm group type: Placebo Comparator
description: This group will be given placebo oral capsules every 6 hours for 14 days.
intervention type: Drug
intervention name: Vancomycin Oral Capsule
description: We have chosen oral vancomycin capsules as it is currently a standard of care for Clostridium difficile infections, is poorly absorbed by the intestines, and is easier to blind compared to oral vancomycin solution.
arm group label: Vancomycin treated group
other name: Vancocin hydrochloride Oral Capsule
intervention type: Drug
intervention name: Placebo Oral Capsule
description: A capsule containing gelatin, polyethylene glycol, titanium dioxide, iron oxide, and FD&C blue No. 2. Contains the inactive ingredients of the vancomycin oral capsule, as mixed by the Froedtert Health Research Pharmacy.
arm group label: 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
citation: Lessa FC, Winston LG, McDonald LC; Emerging Infections Program C. difficile Surveillance Team. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015 Jun 11;372(24):2369-70. doi: 10.1056/NEJMc1505190. No abstract available.
PMID: 26061850
citation: Martin JS, Monaghan TM, Wilcox MH. Clostridium difficile infection: epidemiology, diagnosis and understanding transmission. Nat Rev Gastroenterol Hepatol. 2016 Apr;13(4):206-16. doi: 10.1038/nrgastro.2016.25. Epub 2016 Mar 9.
PMID: 26956066
citation: Theriot CM, Koenigsknecht MJ, Carlson PE Jr, Hatton GE, Nelson AM, Li B, Huffnagle GB, Z Li J, Young VB. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat Commun. 2014;5:3114. doi: 10.1038/ncomms4114.
PMID: 24445449
citation: Theriot CM, Bowman AA, Young VB. Antibiotic-Induced Alterations of the Gut Microbiota Alter Secondary Bile Acid Production and Allow for Clostridium difficile Spore Germination and Outgrowth in the Large Intestine. mSphere. 2016 Jan 6;1(1):e00045-15. doi: 10.1128/mSphere.00045-15. eCollection 2016 Jan-Feb.
PMID: 27239562
citation: Sethi AK, Al-Nassir WN, Nerandzic MM, Bobulsky GS, Donskey CJ. Persistence of skin contamination and environmental shedding of Clostridium difficile during and after treatment of C. difficile infection. Infect Control Hosp Epidemiol. 2010 Jan;31(1):21-7. doi: 10.1086/649016.
PMID: 19929371
citation: Aldrete SD, Kraft CS, Magee MJ, Chan A, Hutcherson D, Langston AA, Greenwell BI, Burd EM, Friedman-Moraco R. Risk factors and epidemiology of Clostridium difficile infection in hematopoietic stem cell transplant recipients during the peritransplant period. Transpl Infect Dis. 2017 Feb;19(1). doi: 10.1111/tid.12649.
PMID: 27943501
citation: Isaac S, Scher JU, Djukovic A, Jimenez N, Littman DR, Abramson SB, Pamer EG, Ubeda C. Short- and long-term effects of oral vancomycin on the human intestinal microbiota. J Antimicrob Chemother. 2017 Jan;72(1):128-136. doi: 10.1093/jac/dkw383. Epub 2016 Oct 5.
PMID: 27707993
citation: Polage CR, Gyorke CE, Kennedy MA, Leslie JL, Chin DL, Wang S, Nguyen HH, Huang B, Tang YW, Lee LW, Kim K, Taylor S, Romano PS, Panacek EA, Goodell PB, Solnick JV, Cohen SH. Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era. JAMA Intern Med. 2015 Nov;175(11):1792-801. doi: 10.1001/jamainternmed.2015.4114.
PMID: 26348734
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: Hematologic Diseases
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.
submitted: November 22, 2021
returned: December 21, 2021
submitted: May 17, 2022
returned: June 10, 2022