<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/NCT03822819</url>
  </required_header>
  <id_info>
    <org_study_id>N201805035</org_study_id>
    <nct_id>NCT03822819</nct_id>
  </id_info>
  <brief_title>Investigation of the Optimal Cocktailed Probiotics for Decolonization of Vancomycin-resistant Enterococci in Human Gut</brief_title>
  <official_title>Investigation of the Optimal Cocktailed Probiotics for Decolonization of Vancomycin-resistant Enterococci in Human Gut</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Taipei Medical University Shuang Ho Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Taipei Medical University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Delta Electronics</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Taipei Medical University Shuang Ho Hospital</source>
  <oversight_info>
    <has_dmc>No</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>
      Vancomycin-resistant enterococci (VRE) has been a serious public health issue as an&#xD;
      opportunistic pathogen and reservoir of antibiotic resistant genes. To reduce VRE carriage in&#xD;
      human gut, investigators aim to look for effective probiotic cocktail to compete with VRE in&#xD;
      human gut microflora via the technique of microbiome analysis pipeline (MAP). The probiotic&#xD;
      cocktail gave by MAP result will be tested in a clinical trial, in which 80 subjects with VRE&#xD;
      carriage will be enrolled and allocated randomly into two groups. Subjects in first group&#xD;
      will be administered with probiotic cocktail capsules, and placebo capsules will be given to&#xD;
      the second group in a double-blind manner. Stool samples will be collected from subjects&#xD;
      before and after three weeks of probiotic/probiotic capsule uptake, and analyzed for VRE&#xD;
      number and gut microflora changes to evaluate the efficacy of probiotic cocktail.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Enterococci are one of the commensal gut flora in humans and have become an important&#xD;
      pathogenic bacterium of opportunistic infection. Enterococci can cause severe infection when&#xD;
      the patients become immunocompromised and subsequent serious problem in medical therapy&#xD;
      because last line antibiotics could be ineffective. The incidences of vancomycin-resistant&#xD;
      enterococci (VRE) have been increasing all over the world in recent years. VRE have become a&#xD;
      global threat in human health and medical care because of the possible spreading of&#xD;
      antibiotic resistance genes. So far probiotic bacteria have played various important roles in&#xD;
      regulation of gut functions and some positive impact on diabetes, liver function impairment,&#xD;
      and psychiatric disorders. Recently a few probiotic studies indicated that VRE could possibly&#xD;
      be decolonized from human gut. However, it remains controversial because of different&#xD;
      probiotic strains, dosages, durations of administrations, and study designs in these reports.&#xD;
      Therefore, further in vitro studies and clinical trials are warranted for validation of the&#xD;
      hypothesis that VRE could be decolonized by probiotic bacteria from human gut.&#xD;
&#xD;
      In the preliminary study using Microbiome analysis pipeline to dissect the NGS (next&#xD;
      generation sequencing) data from the co-cultures of two VRE strains (Enterococcus faecium,&#xD;
      Enterococcus faecalis) and ten TFDA (Taiwan Food and Drug Administration)-approved probiotic&#xD;
      bacteria, investigators have confirmed that the mixture of the ten probiotic bacteria&#xD;
      significantly suppressed the bacterial amounts of VRE during the in vitro co-cultures. The&#xD;
      results will provide a formula of optimal cocktailed probiotics in which a specific&#xD;
      combination of the selected probiotic bacteria could exert a maximal effect on suppression of&#xD;
      growth of VRE.&#xD;
&#xD;
      First, An in vitro co-culture of VRE and the optimal cocktailed probiotics selected by&#xD;
      Microbiome analysis pipeline will be conducted for validation of the results from the&#xD;
      preliminary study. Gastric acid-resistant capsules containing the probiotic cocktail&#xD;
      validated with in vitro co-culture model, will then be prepared in dosage of 10^10 CFU&#xD;
      (Colony Forming Unit).&#xD;
&#xD;
      Second, in the proposed clinical trial, participants of age between 20 and 90-year-old will&#xD;
      be selected and admitted to Taipei Medical University Hospital with isolated&#xD;
      vancomycin-resistance enterococci (VRE) from their stools after hospitalization. Exclusion&#xD;
      criteria in this study are individuals: (1) with routine probiotic uptake in daily life, or&#xD;
      being prescribed with probiotics in clinic one-week before or in the period of clinical&#xD;
      trial; (2) being prescribed with oral antibiotic uptake in the period of clinical trial; (3)&#xD;
      with diarrhea symptom; (4) in pregnancy; (5) of immuno-compromised conditions or being&#xD;
      prescribed with steroid-type medicines; (6) with diabetes mellitus; (7) critically ill&#xD;
      patients.&#xD;
&#xD;
      When the conditions of their underlying diseases are stabilized, these patients who sign the&#xD;
      informed consents will be randomly assigned into two groups receiving the cocktailed&#xD;
      probiotics or placebo for 3 weeks in double-blind masking. The stool samples will be&#xD;
      collected before and after the 3-week administration of the cocktailed probiotics or placebo.&#xD;
      After completion of enrolling 80 patients in total umber, the double-blinded capsules will be&#xD;
      unlabeled and at least 50 patients with 25 completed paired stool samples in both groups will&#xD;
      be further processed for genomic DNA isolation and 16s rDNA (ribosomal DNA) NGS analysis.&#xD;
      Finally, the quantities of VRE in stool samples will be analyzed with colony formation number&#xD;
      on selective medium, and alterations of gut microbiota will be analyzed through stool&#xD;
      microbiome 16s rDNA NGS. The results will be compared between the cocktailed probiotics group&#xD;
      and the placebo group for evaluation of the VRE decolonization effect of probiotics.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">March 15, 2019</start_date>
  <completion_date type="Anticipated">September 30, 2020</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2020</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>The study is going to be carried out with two groups in which participants are either administered with probiotic cocktail capsules or placebo capsules</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>VRE number change</measure>
    <time_frame>after 30 days of capsules uptake</time_frame>
    <description>Stool samples will be collected from participants before and after capsule uptake and plating out on selective medium for VRE after proper serial dilution. VRE number is defined as VRE CFU per gram of stool sample, and compared between two samples from the same participant.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Vancomycin-Resistant Enterococci</condition>
  <condition>Probiotics</condition>
  <arm_group>
    <arm_group_label>probiotic cocktail capsules uptake</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants take two capsules of probiotic cocktail everyday for 30 days in a double-blinded masking. Stool samples will be collected before and after capsule uptake and be analyzed for VRE number and microbiota change.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo capsules uptake</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants take two capsules of placebo everyday for 30 days in a double-blinded masking. Stool samples will be collected before and after capsule uptake and be analyzed for VRE number and microbiota change.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>probiotic cocktail capsules</intervention_name>
    <description>Daily uptake of probiotic cocktail for three weeks</description>
    <arm_group_label>probiotic cocktail capsules uptake</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>placebo capsules</intervention_name>
    <description>Daily uptake of placebo capsule for three weeks</description>
    <arm_group_label>placebo capsules uptake</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  VRE-carriage&#xD;
&#xD;
          -  of age between 20 and 90-year-old&#xD;
&#xD;
          -  agreeing to participate&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  routine probiotic uptake in daily life, or being prescribed with probiotics in clinic&#xD;
             one- week before or in the period of clinical trial&#xD;
&#xD;
          -  being prescribed with oral antibiotic uptake in the period of clinical trial&#xD;
&#xD;
          -  with diarrhea symptom&#xD;
&#xD;
          -  in pregnancy&#xD;
&#xD;
          -  of immuno-compromised conditions or being prescribed with steroid-type medicines&#xD;
&#xD;
          -  with diabetes mellitus&#xD;
&#xD;
          -  critically ill patients&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Shiuh-Bin Fang, M.D, Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Taipei Medical University-ShuangHo Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Shiuh-Bin Fang, M.D, Ph.D.</last_name>
    <phone>+886 2 22490088</phone>
    <phone_ext>2951</phone_ext>
    <email>sbfang@tmu.edu.tw</email>
  </overall_contact>
  <location>
    <facility>
      <name>Taipei Medical University Hospital</name>
      <address>
        <city>Taipei</city>
        <zip>110</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yuarn-Jang Lee, M.D.</last_name>
      <phone>+886 2 27372181</phone>
      <phone_ext>3979</phone_ext>
      <email>yuarn438@yahoo.com.tw</email>
    </contact>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>January 28, 2019</study_first_submitted>
  <study_first_submitted_qc>January 28, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 30, 2019</study_first_posted>
  <last_update_submitted>March 26, 2020</last_update_submitted>
  <last_update_submitted_qc>March 26, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 30, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>vancomycin-resistant entercocci</keyword>
  <keyword>probiotics</keyword>
  <keyword>microbiome analysis pipeline</keyword>
  <keyword>next generation sequencing</keyword>
  <keyword>decolonization</keyword>
  <keyword>virulence gene</keyword>
  <!-- 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/NCT03822819
org study id: N201805035
nct id: NCT03822819
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Vancomycin-resistant enterococci (VRE) has been a serious public health issue as an
      opportunistic pathogen and reservoir of antibiotic resistant genes. To reduce VRE carriage in
      human gut, investigators aim to look for effective probiotic cocktail to compete with VRE in
      human gut microflora via the technique of microbiome analysis pipeline (MAP). The probiotic
      cocktail gave by MAP result will be tested in a clinical trial, in which 80 subjects with VRE
      carriage will be enrolled and allocated randomly into two groups. Subjects in first group
      will be administered with probiotic cocktail capsules, and placebo capsules will be given to
      the second group in a double-blind manner. Stool samples will be collected from subjects
      before and after three weeks of probiotic/probiotic capsule uptake, and analyzed for VRE
      number and gut microflora changes to evaluate the efficacy of probiotic cocktail.
Enterococci are one of the commensal gut flora in humans and have become an important
      pathogenic bacterium of opportunistic infection. Enterococci can cause severe infection when
      the patients become immunocompromised and subsequent serious problem in medical therapy
      because last line antibiotics could be ineffective. The incidences of vancomycin-resistant
      enterococci (VRE) have been increasing all over the world in recent years. VRE have become a
      global threat in human health and medical care because of the possible spreading of
      antibiotic resistance genes. So far probiotic bacteria have played various important roles in
      regulation of gut functions and some positive impact on diabetes, liver function impairment,
      and psychiatric disorders. Recently a few probiotic studies indicated that VRE could possibly
      be decolonized from human gut. However, it remains controversial because of different
      probiotic strains, dosages, durations of administrations, and study designs in these reports.
      Therefore, further in vitro studies and clinical trials are warranted for validation of the
      hypothesis that VRE could be decolonized by probiotic bacteria from human gut.

      In the preliminary study using Microbiome analysis pipeline to dissect the NGS (next
      generation sequencing) data from the co-cultures of two VRE strains (Enterococcus faecium,
      Enterococcus faecalis) and ten TFDA (Taiwan Food and Drug Administration)-approved probiotic
      bacteria, investigators have confirmed that the mixture of the ten probiotic bacteria
      significantly suppressed the bacterial amounts of VRE during the in vitro co-cultures. The
      results will provide a formula of optimal cocktailed probiotics in which a specific
      combination of the selected probiotic bacteria could exert a maximal effect on suppression of
      growth of VRE.

      First, An in vitro co-culture of VRE and the optimal cocktailed probiotics selected by
      Microbiome analysis pipeline will be conducted for validation of the results from the
      preliminary study. Gastric acid-resistant capsules containing the probiotic cocktail
      validated with in vitro co-culture model, will then be prepared in dosage of 10^10 CFU
      (Colony Forming Unit).

      Second, in the proposed clinical trial, participants of age between 20 and 90-year-old will
      be selected and admitted to Taipei Medical University Hospital with isolated
      vancomycin-resistance enterococci (VRE) from their stools after hospitalization. Exclusion
      criteria in this study are individuals: (1) with routine probiotic uptake in daily life, or
      being prescribed with probiotics in clinic one-week before or in the period of clinical
      trial; (2) being prescribed with oral antibiotic uptake in the period of clinical trial; (3)
      with diarrhea symptom; (4) in pregnancy; (5) of immuno-compromised conditions or being
      prescribed with steroid-type medicines; (6) with diabetes mellitus; (7) critically ill
      patients.

      When the conditions of their underlying diseases are stabilized, these patients who sign the
      informed consents will be randomly assigned into two groups receiving the cocktailed
      probiotics or placebo for 3 weeks in double-blind masking. The stool samples will be
      collected before and after the 3-week administration of the cocktailed probiotics or placebo.
      After completion of enrolling 80 patients in total umber, the double-blinded capsules will be
      unlabeled and at least 50 patients with 25 completed paired stool samples in both groups will
      be further processed for genomic DNA isolation and 16s rDNA (ribosomal DNA) NGS analysis.
      Finally, the quantities of VRE in stool samples will be analyzed with colony formation number
      on selective medium, and alterations of gut microbiota will be analyzed through stool
      microbiome 16s rDNA NGS. The results will be compared between the cocktailed probiotics group
      and the placebo group for evaluation of the VRE decolonization effect of probiotics.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The study is going to be carried out with two groups in which participants are either administered with probiotic cocktail capsules or placebo capsules
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: VRE number change
time frame: after 30 days of capsules uptake
description: Stool samples will be collected from participants before and after capsule uptake and plating out on selective medium for VRE after proper serial dilution. VRE number is defined as VRE CFU per gram of stool sample, and compared between two samples from the same participant.
arm group label: probiotic cocktail capsules uptake
arm group type: Experimental
description: Participants take two capsules of probiotic cocktail everyday for 30 days in a double-blinded masking. Stool samples will be collected before and after capsule uptake and be analyzed for VRE number and microbiota change.
arm group label: placebo capsules uptake
arm group type: Placebo Comparator
description: Participants take two capsules of placebo everyday for 30 days in a double-blinded masking. Stool samples will be collected before and after capsule uptake and be analyzed for VRE number and microbiota change.
intervention type: Dietary Supplement
intervention name: probiotic cocktail capsules
description: Daily uptake of probiotic cocktail for three weeks
arm group label: probiotic cocktail capsules uptake
intervention type: Dietary Supplement
intervention name: placebo capsules
description: Daily uptake of placebo capsule for three weeks
arm group label: placebo capsules uptake
criteria: 
gender: All
minimum age: 20 Years
maximum age: 90 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Shiuh-Bin Fang, M.D, Ph.D.
role: Principal Investigator
affiliation: Taipei Medical University-ShuangHo Hospital
last name: Shiuh-Bin Fang, M.D, Ph.D.
phone: +886 2 22490088
phone ext: 2951
email: sbfang@tmu.edu.tw
facility: 
status: Recruiting
contact: 
country: Taiwan
responsible party type: Sponsor