<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/NCT04431934</url>
  </required_header>
  <id_info>
    <org_study_id>PI19/00842</org_study_id>
    <nct_id>NCT04431934</nct_id>
  </id_info>
  <brief_title>Efficacy of a Probiotic or Fecal Microbiota Transplantation (FMT) on the Eradication of Rectal Multidrug-resistant Gram-negative Bacilli (MDR-GNB) Carriage (PROFTMDECOL)</brief_title>
  <acronym>PROFTMDECOL</acronym>
  <official_title>Open-label, Randomized Study to Assess the Efficacy of a Probiotic or Fecal Microbiota Transplantation (FMT) on the Eradication of Rectal Multidrug-resistant Gram-negative Bacilli (MDR-GNB) Carriage (PROFTMDECOL)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital Clinic of Barcelona</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fundacion Clinic per a la Recerca Biomédica</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institut d'Investigacions Biomèdiques August Pi i Sunyer</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Fondo de Investigacion Sanitaria</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hospital Clinic of Barcelona</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The working hypothesis is that in patients who are rectal carriers of MDR-GNB (Multi&#xD;
      drug-resistant gram negative bacilli), the rate and speed of eradication of the carrier&#xD;
      status obtained with NAA regimens are insufficient and could be improved with additional&#xD;
      interventions directed to restore a healthy fecal microbiota or to increase the colonization&#xD;
      resistance by the putative beneficial activity of lactate-producing bacteria and&#xD;
      bifidobacteria. A healthier colonic microbiota environment is expected not only to promote&#xD;
      the eradication of the existing MDR organisms but also to hinder the subsequent&#xD;
      recolonization and hopefully the risk of infection with gut dysbiosis -associated pathogens&#xD;
      (MDR-GNB, C. difficile and Candida).&#xD;
&#xD;
      The principal objective of the study is To compare the decolonization efficacy at the end of&#xD;
      the study (60 ± 7 days after randomization) of the administration of a probiotic (&quot;Vivomixx®&quot;&#xD;
      2 sachets/12h for 2 weeks) versus the administration of two doses (administered a week apart)&#xD;
      of a fecal microbiota transplantation preparation (equivalent to 50 g of healthy donor feces)&#xD;
      and no treatment (control arm) in patients with rectal colonization with MDRGNB&#xD;
      (ESBL-producing Klebsiella pneumoniae, CPE and MDR/XDR (multi drug-resistant/ extensively&#xD;
      drug-resistant Pseudomonas aeruginosa).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Data Collection and Processing&#xD;
&#xD;
      Recording of data All data required for the study will be recorded in the participating&#xD;
      center using a case report form (CRF). Completeness and plausibility checks will ensure the&#xD;
      collection of high quality data.&#xD;
&#xD;
      A CRF for each patient will be completed by authorized personnel who must be identified and&#xD;
      authorized in writing by the Principal Investigator before they conduct any study related&#xD;
      tasks.&#xD;
&#xD;
      A delegation of responsibility log identifying who can enter data and/or sign off a CRF will&#xD;
      be maintained by the Principal Investigator.&#xD;
&#xD;
      The subject's number and date of entry into the study, along with a study identifier, should&#xD;
      be recorded in the subject's study records. The following should also be recorded in the&#xD;
      study records: confirmation of written consent, the subject's clinical status, date of every&#xD;
      study visit, copies of all relevant reports, comments on results and reference to serious&#xD;
      adverse events and related adverse events.&#xD;
&#xD;
      Direct access to source data/documents Investigators will ensure access to the source&#xD;
      documents of the staff responsible for guaranteeing data quality and data analysis. In&#xD;
      addition, access to documentation will be provided, if necessary, to the staff duly&#xD;
      authorized by the sponsor (study monitors).&#xD;
&#xD;
      Data management The Investigator must ensure the accuracy, completeness, legibility and&#xD;
      timelines of data reported in the CRF and all required reports.&#xD;
&#xD;
      Archiving and storage of data The investigator is responsible for maintaining all records&#xD;
      which enable the conduct of the study at the site to be fully documented, in accordance&#xD;
      applicable national regulatory requirements. Timeliness and completeness of the documentation&#xD;
      will be regularly checked by the clinical monitor. All completed study related documents&#xD;
      (e.g. eletronic CRF, Informed consent forms, Subject identification log, etc) must be&#xD;
      archived at site.&#xD;
&#xD;
      QUALITY CONTROL The purpose of monitoring is to verify that the rights and wellbeing of human&#xD;
      subjects are protected; that the study is accurate, complete and verifiable with source data&#xD;
      and that the study is conducted in compliance with the protocol, and the applicable&#xD;
      regulatory requirements. A monitoring plan will be designed. The monitoring plan will&#xD;
      establish the guideline for conducting all the monitoring activities. Source data will be&#xD;
      verified during on-site monitoring visits. During the visits, the monitor will compare the&#xD;
      data entered into the CRF with the source documents. The nature and location of all source&#xD;
      documents will be identified to ensure that all sources of original data required to complete&#xD;
      the eCRF are known to the monitor and study-site personnel and are accessible for&#xD;
      verification. During monitoring visits, the relevant study-site personnel should be&#xD;
      available, the source documentation accessible, and a suitable environment provided for&#xD;
      review of study related documents.&#xD;
&#xD;
      Criteria for termination and /or discontinuation The participants will discontinue study&#xD;
      participation if they are unwilling or unable to meet the protocol requirements in terms of&#xD;
      the visit schedule or if the patient or the investigator considers it is best to end their&#xD;
      participation in the study. All participants have the right to withdraw their consent at any&#xD;
      time during the study without prejudice to them.&#xD;
&#xD;
      All follow-up terminations of study subjects and the reasons for them must be reported&#xD;
      immediately to the study monitor and be duly documented both in the medical records and the&#xD;
      case report form.&#xD;
&#xD;
      Drug accountability Drug accountability will be carried out at each study visit for those&#xD;
      patients assigned to the Probiotic arm. FMT administration will always be performed under&#xD;
      direct observation of one of the investigators and if ambulatory, the patient will remain&#xD;
      under observation in the outpatient clinic during at least 2 hours after the procedure.&#xD;
&#xD;
      Source data verification Source documents are defined as all observations or notes recorded&#xD;
      on the clinical interventions, and all reports and notes required for assessment and&#xD;
      reconstruction of the research study.&#xD;
&#xD;
      Whenever possible the original document should be kept as the source document; however,&#xD;
      provision of a photocopy which is clear, legible and an exact duplicate of the original&#xD;
      document and signed by the principal investigator is acceptable.&#xD;
&#xD;
      End of the clinical research The end of the clinical research is defined as the date of the&#xD;
      last visit of last subject undergoing the study.&#xD;
&#xD;
      Statistical analysis For the primary outcome the main analysis will be performed according to&#xD;
      the intention to treat principle, considering as intention-to-treat population all randomized&#xD;
      patients. Missing RS will be considered as positive. In addition, the investigators intend to&#xD;
      do a per protocol analysis, evaluating only the patients who end the treatment and end the&#xD;
      study. Categorical variables will be compared by the Fisher exact test and continuous ones&#xD;
      the the student t-test or Mann-Whitney test. Univariate logistic regression with group&#xD;
      assignment as predictor variable and clinical characteristics and decolonization as outcome&#xD;
      will be performed to calculate OR and 95% confidence intervals. In the event of imbalance in&#xD;
      the distribution of potential confounder despite randomization, a multivariate logistic&#xD;
      regression analysis with decolonization as de dependent variable and group assignment as one&#xD;
      of the explanatory variables will be carried out.&#xD;
&#xD;
      All randomised patients will be included in the &quot;intention-to-treat population&quot; for analysis.&#xD;
&#xD;
      Patients withdrawn for any reason or lost to follow-up will be considered as treatment&#xD;
      failure in this analysis.&#xD;
&#xD;
      Subgroup analyses An analysis of efficacy for each bacterial species/resistance determinant&#xD;
      (ESBL-producing K.pneumoniae, carbapenemase-producing enterobacteriaceae, MDR-P. aeruginosa)&#xD;
      are planned&#xD;
&#xD;
      Interim analysis A safety interim analysis is planned after inclusion of the first 100&#xD;
      individuals in the study.&#xD;
&#xD;
      Analysis Centre Data will be analyzed in the &quot;Institut Clinic de Medicina Interna,&#xD;
      Dermatologia I Infeccions del Hospital Clinic de Barcelona&quot;.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">November 16, 2020</start_date>
  <completion_date type="Anticipated">July 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2022</primary_completion_date>
  <phase>N/A</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>This is an investigator-initiated, single center, parallel-group, randomized, open-label, clinical research with non pharmacological products.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of patients with digestive decolonization rate</measure>
    <time_frame>At the end of study (60 ± 7 days after the randomization).</time_frame>
    <description>Proportion of patients with digestive decolonization rate defined as negative rectal swab (RS) for the target MDR-GNB (ESBL-producing Klebsiella pneumoniae, CPE and MDR/XDR Pseudomonas aeruginosa) at the end of study (60 ± 7 days after the randomization).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Digestive decolonization rate defined as a negative fecal sample</measure>
    <time_frame>At the end of study treatment (3 weeks after randomization).</time_frame>
    <description>Proportion of patients with digestive decolonization rate defined as a negative fecal sample for the target MDR-GNB at the end of study treatment (3 weeks after randomization).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Digestive decolonization rate defined as a negative rectal swab</measure>
    <time_frame>(week 1 after randomization).</time_frame>
    <description>Proportion of patients with digestive decolonization rate defined as a negative rectal swab for the target MDR-GNB after the decontamination period with non-absorbable antibiotics (week 1 after randomization).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>target MDR-GNB or any other MDR-GNB in any control RS or fecal sample</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>Proportion of patients with target MDR-GNB or any other MDR-GNB in any control RS or fecal sample during the study period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>clinical infections</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>Proportion of patients with clinical infections during the study period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>development of resistance to colistin or amikacin</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>Proportion of patients with development of resistance to colistin or amikacin in any strain isolated in control RS or fecal sample during the study period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in fecal microbiota composition</measure>
    <time_frame>At the end of study treatment (3 weeks after randomization).</time_frame>
    <description>Changes from baseline in fecal microbiota composition at the end of study treatment.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">437</enrollment>
  <condition>CARRIER STATE</condition>
  <arm_group>
    <arm_group_label>CONTROL</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>No intervention arm</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PROBIOTIC</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>FMT REGIMEN</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>PROBIOTIC</intervention_name>
    <description>Participants assigned to the probiotic arm will receive 2 sachets of &quot;Vivomixx®&quot; dissolved in 50 L of warm water (according to the manufacturer indications) every 12 h orally or through a nasogastric tube (in this case the tube will be flushed with 50 mL of water after the administration). The probiotic will be started 24 h after the last dose of NAA and will be administered for 14 consecutive days. Each sachet of &quot;Vivomixx®&quot; contains a combination of 4 Lactobacillus (L. paracasei 24733, L. acidophilus 24735, L. delbrueckii ssp bulgaricus 24734, L. plantarum 24730), 3 Bifidobacteria (B. brief 24732, B. longum 24736, B. infantis 24737), and Streptococcus thermophilus 24731 at a concentration of 450 billion (45x1010) live lyophilized bacteria per sachet.</description>
    <arm_group_label>PROBIOTIC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>FMT REGIMEN</intervention_name>
    <description>The FMT preparation will be administered as 2 doses, once a week, of 14-17 capsules per dose. Each dose (14-17 capsules) will contain the fecal microbiota equivalent to 50 gr of stools from a healthy donor. If the patient is carrying a nasogastric tube, the content of capsules will be decapsulized (~27 gr of powder), diluted in 50 mL of water and passed through it, followed by the administration of 50 mL of water to flush the tube. The first dose will be administered 24 h after the last dose of NAA and the second dose one week later. Whenever possible, the two doses of FMT will be originated from the same donor. According to our data done by flow cytometry and bacterial culture in three replicates, each absorbate capsule contains approximately 1.12x1010 live bacteria.</description>
    <arm_group_label>FMT REGIMEN</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult patients (≥18 years-old).&#xD;
&#xD;
          2. Admitted to the Hospital Clinic of Barcelona with documented rectal colonization&#xD;
             whitin the previous 7 days by rectal swabbing with MDR-GNB (ESBL-producing Klebsiella&#xD;
             pneumoniae, carbapenemase-producing Enterobacterial (CPE) and MDR/XDR Pseudomonas&#xD;
             aeruginosa).&#xD;
&#xD;
          3. Eligible for routine digestive decolonization (7 days oral administration of&#xD;
             nonabsorbable antibiotics (NAA).&#xD;
&#xD;
          4. Capable to provide informed consent (by themselves or through their legal&#xD;
             representatives).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnant women or breastfeeding.&#xD;
&#xD;
          2. Neutropenic patients (total neutrophil count &lt;500 cell/mm3)*.&#xD;
&#xD;
          3. HIV-infected patients with CD4(cluster of differentiation 4) count &lt;200 cell/mm3.&#xD;
&#xD;
          4. Patients with active C. difficile infection.&#xD;
&#xD;
          5. Patients with ileus or bowel obstruction.&#xD;
&#xD;
          6. Patients with documented or suspected bowel perforation.&#xD;
&#xD;
          7. Patients with a colistin-resistant MDR-GNB.&#xD;
&#xD;
               -  Solid organ or hematopoietic organ transplant recipients without neutropenia will&#xD;
                  qualify for inclusion in the study. This is based on preliminary data on the&#xD;
                  safety of probiotics without Saccharomyces boulardii/cerevisae in transplant&#xD;
                  recipients of several organs (hematopoietic precursors, liver, kidney, small&#xD;
                  intestine) and on the preliminary safety data of FMT in nonneutropenic patients&#xD;
                  with hematological disorders including hematopoietic cell transplantation&#xD;
                  (25,42,43). However, the condition of transplant recipients will be assessed inan&#xD;
                  individual basis and only those patients that by consensus with their attending&#xD;
                  physician will be judged to be at a very low risk of complications derived from&#xD;
                  the use of the probiotic o fecal microbiota will be considered for inclusion in&#xD;
                  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>Jose Antonio Martinez, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>senior consultant</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ana del rio, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>senior consultant</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jose Antonio JA Martinez, PhD</last_name>
    <phone>+34648521868</phone>
    <email>jamarti@clinic.cat</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Fernanda Meira, MD</last_name>
    <phone>+34666368934</phone>
    <email>fandrade@clinic.cat</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Hospital Clinic</name>
      <address>
        <city>Barcelona</city>
        <zip>08003</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ana delRio, phD</last_name>
      <phone>659108052</phone>
      <phone_ext>380377</phone_ext>
      <email>adelrio@clinic.cat</email>
    </contact>
    <contact_backup>
      <last_name>Fernanda Meira, MD</last_name>
      <phone>932275400</phone>
      <phone_ext>5767</phone_ext>
      <email>fandrade@clinic.cat</email>
    </contact_backup>
    <investigator>
      <last_name>José Antonio Martinez, phD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
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  <verification_date>February 2021</verification_date>
  <study_first_submitted>June 5, 2020</study_first_submitted>
  <study_first_submitted_qc>June 11, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>February 11, 2021</last_update_submitted>
  <last_update_submitted_qc>February 11, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 12, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hospital Clinic of Barcelona</investigator_affiliation>
    <investigator_full_name>José Antonio Martinez</investigator_full_name>
    <investigator_title>MD, PhD, Senior Consultor, Assistant Profesor of Medicine (University of Barcelona)</investigator_title>
  </responsible_party>
  <keyword>fecal microbiota transplantation</keyword>
  <keyword>probiotics</keyword>
  <keyword>carbapenemase-producing Enterobacteriaceae</keyword>
  <keyword>multiple-drug resistant Pseudomonas aeruginosa</keyword>
  <keyword>ESBl-producing Klebsiella pneumoniae</keyword>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>It is not yet known if there will be a plan to make individual participant data available</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 2, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/34/NCT04431934/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT04431934
org study id: PI19/00842
nct id: NCT04431934
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The working hypothesis is that in patients who are rectal carriers of MDR-GNB (Multi
      drug-resistant gram negative bacilli), the rate and speed of eradication of the carrier
      status obtained with NAA regimens are insufficient and could be improved with additional
      interventions directed to restore a healthy fecal microbiota or to increase the colonization
      resistance by the putative beneficial activity of lactate-producing bacteria and
      bifidobacteria. A healthier colonic microbiota environment is expected not only to promote
      the eradication of the existing MDR organisms but also to hinder the subsequent
      recolonization and hopefully the risk of infection with gut dysbiosis -associated pathogens
      (MDR-GNB, C. difficile and Candida).

      The principal objective of the study is To compare the decolonization efficacy at the end of
      the study (60 ± 7 days after randomization) of the administration of a probiotic ("Vivomixx®"
      2 sachets/12h for 2 weeks) versus the administration of two doses (administered a week apart)
      of a fecal microbiota transplantation preparation (equivalent to 50 g of healthy donor feces)
      and no treatment (control arm) in patients with rectal colonization with MDRGNB
      (ESBL-producing Klebsiella pneumoniae, CPE and MDR/XDR (multi drug-resistant/ extensively
      drug-resistant Pseudomonas aeruginosa).
Data Collection and Processing

      Recording of data All data required for the study will be recorded in the participating
      center using a case report form (CRF). Completeness and plausibility checks will ensure the
      collection of high quality data.

      A CRF for each patient will be completed by authorized personnel who must be identified and
      authorized in writing by the Principal Investigator before they conduct any study related
      tasks.

      A delegation of responsibility log identifying who can enter data and/or sign off a CRF will
      be maintained by the Principal Investigator.

      The subject's number and date of entry into the study, along with a study identifier, should
      be recorded in the subject's study records. The following should also be recorded in the
      study records: confirmation of written consent, the subject's clinical status, date of every
      study visit, copies of all relevant reports, comments on results and reference to serious
      adverse events and related adverse events.

      Direct access to source data/documents Investigators will ensure access to the source
      documents of the staff responsible for guaranteeing data quality and data analysis. In
      addition, access to documentation will be provided, if necessary, to the staff duly
      authorized by the sponsor (study monitors).

      Data management The Investigator must ensure the accuracy, completeness, legibility and
      timelines of data reported in the CRF and all required reports.

      Archiving and storage of data The investigator is responsible for maintaining all records
      which enable the conduct of the study at the site to be fully documented, in accordance
      applicable national regulatory requirements. Timeliness and completeness of the documentation
      will be regularly checked by the clinical monitor. All completed study related documents
      (e.g. eletronic CRF, Informed consent forms, Subject identification log, etc) must be
      archived at site.

      QUALITY CONTROL The purpose of monitoring is to verify that the rights and wellbeing of human
      subjects are protected; that the study is accurate, complete and verifiable with source data
      and that the study is conducted in compliance with the protocol, and the applicable
      regulatory requirements. A monitoring plan will be designed. The monitoring plan will
      establish the guideline for conducting all the monitoring activities. Source data will be
      verified during on-site monitoring visits. During the visits, the monitor will compare the
      data entered into the CRF with the source documents. The nature and location of all source
      documents will be identified to ensure that all sources of original data required to complete
      the eCRF are known to the monitor and study-site personnel and are accessible for
      verification. During monitoring visits, the relevant study-site personnel should be
      available, the source documentation accessible, and a suitable environment provided for
      review of study related documents.

      Criteria for termination and /or discontinuation The participants will discontinue study
      participation if they are unwilling or unable to meet the protocol requirements in terms of
      the visit schedule or if the patient or the investigator considers it is best to end their
      participation in the study. All participants have the right to withdraw their consent at any
      time during the study without prejudice to them.

      All follow-up terminations of study subjects and the reasons for them must be reported
      immediately to the study monitor and be duly documented both in the medical records and the
      case report form.

      Drug accountability Drug accountability will be carried out at each study visit for those
      patients assigned to the Probiotic arm. FMT administration will always be performed under
      direct observation of one of the investigators and if ambulatory, the patient will remain
      under observation in the outpatient clinic during at least 2 hours after the procedure.

      Source data verification Source documents are defined as all observations or notes recorded
      on the clinical interventions, and all reports and notes required for assessment and
      reconstruction of the research study.

      Whenever possible the original document should be kept as the source document; however,
      provision of a photocopy which is clear, legible and an exact duplicate of the original
      document and signed by the principal investigator is acceptable.

      End of the clinical research The end of the clinical research is defined as the date of the
      last visit of last subject undergoing the study.

      Statistical analysis For the primary outcome the main analysis will be performed according to
      the intention to treat principle, considering as intention-to-treat population all randomized
      patients. Missing RS will be considered as positive. In addition, the investigators intend to
      do a per protocol analysis, evaluating only the patients who end the treatment and end the
      study. Categorical variables will be compared by the Fisher exact test and continuous ones
      the the student t-test or Mann-Whitney test. Univariate logistic regression with group
      assignment as predictor variable and clinical characteristics and decolonization as outcome
      will be performed to calculate OR and 95% confidence intervals. In the event of imbalance in
      the distribution of potential confounder despite randomization, a multivariate logistic
      regression analysis with decolonization as de dependent variable and group assignment as one
      of the explanatory variables will be carried out.

      All randomised patients will be included in the "intention-to-treat population" for analysis.

      Patients withdrawn for any reason or lost to follow-up will be considered as treatment
      failure in this analysis.

      Subgroup analyses An analysis of efficacy for each bacterial species/resistance determinant
      (ESBL-producing K.pneumoniae, carbapenemase-producing enterobacteriaceae, MDR-P. aeruginosa)
      are planned

      Interim analysis A safety interim analysis is planned after inclusion of the first 100
      individuals in the study.

      Analysis Centre Data will be analyzed in the "Institut Clinic de Medicina Interna,
      Dermatologia I Infeccions del Hospital Clinic de Barcelona".
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is an investigator-initiated, single center, parallel-group, randomized, open-label, clinical research with non pharmacological products.
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of patients with digestive decolonization rate
time frame: At the end of study (60 ± 7 days after the randomization).
description: Proportion of patients with digestive decolonization rate defined as negative rectal swab (RS) for the target MDR-GNB (ESBL-producing Klebsiella pneumoniae, CPE and MDR/XDR Pseudomonas aeruginosa) at the end of study (60 ± 7 days after the randomization).
measure: Digestive decolonization rate defined as a negative fecal sample
time frame: At the end of study treatment (3 weeks after randomization).
description: Proportion of patients with digestive decolonization rate defined as a negative fecal sample for the target MDR-GNB at the end of study treatment (3 weeks after randomization).
measure: Digestive decolonization rate defined as a negative rectal swab
time frame: (week 1 after randomization).
description: Proportion of patients with digestive decolonization rate defined as a negative rectal swab for the target MDR-GNB after the decontamination period with non-absorbable antibiotics (week 1 after randomization).
measure: target MDR-GNB or any other MDR-GNB in any control RS or fecal sample
time frame: through study completion, an average of 1 year
description: Proportion of patients with target MDR-GNB or any other MDR-GNB in any control RS or fecal sample during the study period.
measure: clinical infections
time frame: through study completion, an average of 1 year
description: Proportion of patients with clinical infections during the study period.
measure: development of resistance to colistin or amikacin
time frame: through study completion, an average of 1 year
description: Proportion of patients with development of resistance to colistin or amikacin in any strain isolated in control RS or fecal sample during the study period.
measure: Changes in fecal microbiota composition
time frame: At the end of study treatment (3 weeks after randomization).
description: Changes from baseline in fecal microbiota composition at the end of study treatment.
arm group label: CONTROL
arm group type: No Intervention
description: No intervention arm
arm group label: PROBIOTIC
arm group type: Active Comparator
arm group label: FMT REGIMEN
arm group type: Active Comparator
intervention type: Dietary Supplement
intervention name: PROBIOTIC
description: Participants assigned to the probiotic arm will receive 2 sachets of "Vivomixx®" dissolved in 50 L of warm water (according to the manufacturer indications) every 12 h orally or through a nasogastric tube (in this case the tube will be flushed with 50 mL of water after the administration). The probiotic will be started 24 h after the last dose of NAA and will be administered for 14 consecutive days. Each sachet of "Vivomixx®" contains a combination of 4 Lactobacillus (L. paracasei 24733, L. acidophilus 24735, L. delbrueckii ssp bulgaricus 24734, L. plantarum 24730), 3 Bifidobacteria (B. brief 24732, B. longum 24736, B. infantis 24737), and Streptococcus thermophilus 24731 at a concentration of 450 billion (45x1010) live lyophilized bacteria per sachet.
arm group label: PROBIOTIC
intervention type: Dietary Supplement
intervention name: FMT REGIMEN
description: The FMT preparation will be administered as 2 doses, once a week, of 14-17 capsules per dose. Each dose (14-17 capsules) will contain the fecal microbiota equivalent to 50 gr of stools from a healthy donor. If the patient is carrying a nasogastric tube, the content of capsules will be decapsulized (~27 gr of powder), diluted in 50 mL of water and passed through it, followed by the administration of 50 mL of water to flush the tube. The first dose will be administered 24 h after the last dose of NAA and the second dose one week later. Whenever possible, the two doses of FMT will be originated from the same donor. According to our data done by flow cytometry and bacterial culture in three replicates, each absorbate capsule contains approximately 1.12x1010 live bacteria.
arm group label: FMT REGIMEN
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jose Antonio Martinez, PhD
role: Principal Investigator
affiliation: senior consultant
last name: Ana del rio, PhD
role: Principal Investigator
affiliation: senior consultant
last name: Jose Antonio JA Martinez, PhD
phone: +34648521868
email: jamarti@clinic.cat
last name: Fernanda Meira, MD
phone: +34666368934
email: fandrade@clinic.cat
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: Spain
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responsible party type: Principal Investigator
investigator affiliation: Hospital Clinic of Barcelona
investigator full name: José Antonio Martinez
investigator title: MD, PhD, Senior Consultor, Assistant Profesor of Medicine (University of Barcelona)
sharing ipd: Undecided
ipd description: It is not yet known if there will be a plan to make individual participant data available
provided document: 