<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/NCT03008941</url>
  </required_header>
  <id_info>
    <org_study_id>165-16</org_study_id>
    <secondary_id>GESIDA 9116</secondary_id>
    <nct_id>NCT03008941</nct_id>
  </id_info>
  <brief_title>Microbiota Restoration Therapy in HIV With Repeated Low-Dose Interventions</brief_title>
  <acronym>REFRESH</acronym>
  <official_title>A Phase I/II Randomized, Double-Blind, Placebo Controlled Study of Repeated Low-Dose Fecal Microbiota Restoration in HIV-Infected Subjects. The REFRESH Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Altered interplay between gut mucosa and dysbiotic bacteria during HIV infection seems to&#xD;
      contribute to chronic immune dysfunction. Manipulation of the intestinal microbiota with&#xD;
      nutritional interventions exert limited immunologic effects, but a deep understanding of how&#xD;
      these interventions could ameliorate gut dysbiosis and influence health among HIV-infected&#xD;
      individuals remain unexplored. In this Phase I clinical trial, 30 HIV-infected subjects on&#xD;
      effective ART with evidence of persistent immune dysfunction, indicated by a CD4/CD8 ratio&lt;1&#xD;
      will be included and randomized to either repeated low-dose oral fecal microbiota&#xD;
      transplantation or placebo during 8 weeks. The primary outcome will be safety. Secondary&#xD;
      outcomes will include changes in CD4+ T cell counts, CD8+ T cell counts, CD4/CD8 ratio,&#xD;
      inflammatory markers, T cell activation and markers of enterocyte barrier function through&#xD;
      week 48. Engraftment on host microbiota will be examined using Illumina sequencing of the&#xD;
      V3-V4 16S RNA, and changes in bacterial metabolism and in the plasma metabolite fingerprint&#xD;
      will be studied by combination of untargeted mass spectrometry and two different and&#xD;
      complementary separation techniques in bacterial and plasma samples.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 2017</start_date>
  <completion_date type="Actual">October 2018</completion_date>
  <primary_completion_date type="Actual">June 2018</primary_completion_date>
  <phase>Phase 1/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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with treatment-related adverse events as assessed by CTCAE v4.0</measure>
    <time_frame>From baseline through week 48</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in CD4+ T cell counts</measure>
    <time_frame>From baseline through week 48</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in CD8+ T cell counts</measure>
    <time_frame>From baseline through week 48</time_frame>
    <description>Inflammation: interleukin (IL)-6, high sensitivity C reactive protein (hs-CRP), interferon gamma-induced protein (IP)-10.&#xD;
Monocyte/macrophage activation: sCD14, SCD163,&#xD;
Gut epithelial integrity: zonulin-1, intestinal fatty acid binding protein (IFABP).&#xD;
Bacterial translocation: lipoteichoic acid (LTA)&#xD;
Indolamine deoxygenase-1 induction: kynurenine/tryptophan ratio&#xD;
Coagulation: D-dimers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in CD4/CD8 ratio</measure>
    <time_frame>From baseline through week 48</time_frame>
    <description>Inflammation: interleukin (IL)-6, high sensitivity C reactive protein (hs-CRP), interferon gamma-induced protein (IP)-10.&#xD;
Monocyte/macrophage activation: sCD14, SCD163,&#xD;
Gut epithelial integrity: zonulin-1, intestinal fatty acid binding protein (IFABP).&#xD;
Bacterial translocation: lipoteichoic acid (LTA)&#xD;
Indolamine deoxygenase-1 induction: kynurenine/tryptophan ratio&#xD;
Coagulation: D-dimers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in microbiota alpha diversity metrics</measure>
    <time_frame>From baseline through week 48</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in microbiota Unifrac distances</measure>
    <time_frame>From baseline through week 48</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in microbiota Canberra distances</measure>
    <time_frame>From baseline through week 48</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in plasma Interleukin-6 levels</measure>
    <time_frame>From baseline through week 48</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in plasma hs-CRP levels</measure>
    <time_frame>From baseline through week 48</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in plasma lipoteichoic acid levels</measure>
    <time_frame>From baseline through week 48</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in plasma LBP levels</measure>
    <time_frame>From baseline through week 48</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in plasma kynurenine/tryptophan ratio</measure>
    <time_frame>From baseline through week 48</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of HLA-DR+/CD38+ T cells in blood</measure>
    <time_frame>From baseline through week 48</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>HIV Infection</condition>
  <arm_group>
    <arm_group_label>FMT</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fecal microbiota capsules (provided by Openbiome).&#xD;
Dosage:&#xD;
Induction: 10 capsules (single dose)&#xD;
Maintenance: 5 capsules, weekly, during 7 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo capsules (provided by Openbiome).&#xD;
Dosage:&#xD;
Induction: 10 capsules (single dose)&#xD;
Maintenance: 5 capsules, weekly, during 7 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>FMT</intervention_name>
    <description>Capsules with fecal microbiota from healthy donors</description>
    <arm_group_label>FMT</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo capsules</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  On stable antiretroviral therapy with plasma HIV RNA &lt;20 copies/mL during at least 48&#xD;
             weeks.&#xD;
&#xD;
          -  CD4/CD8 ratio &lt;1&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Gastrointestinal diseases, including cirrhosis&#xD;
&#xD;
          -  Active infections, including HCV&#xD;
&#xD;
          -  EBV and/or CMV negative patients (donors are not screened for EBV/CMV).&#xD;
&#xD;
          -  Planned used of chemotherapy or antibiotics&#xD;
&#xD;
          -  Allergy to sodium chloride or glycerol (the former components are capsule ingredients&#xD;
             Generally Recognized As Safe (GRAS)&#xD;
&#xD;
          -  Current or planned use of antimicrobial agents (including prophylactic treatments&#xD;
             against P. jiroveci) other than ART.&#xD;
&#xD;
          -  Neutropenia &lt;500 cells/uL or CD4 counts &lt;350 cells/uL&#xD;
&#xD;
          -  Patients unable to give informed consent&#xD;
&#xD;
          -  Patients unable to comply with the protocol requirements&#xD;
&#xD;
          -  Predicted death within time period of follow-up&#xD;
&#xD;
          -  Any other condition for which the treating physician thinks the treatment may pose a&#xD;
             health risk&#xD;
&#xD;
          -  Dysphagia: oropharyngeal, esophageal, functional, neuromuscular (e.g. stroke, multiple&#xD;
             sclerosis, ALS)&#xD;
&#xD;
          -  History of aspiration&#xD;
&#xD;
          -  History of gastroparesis&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Hospital Ramón y Cajal</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>December 28, 2016</study_first_submitted>
  <study_first_submitted_qc>December 30, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 4, 2017</study_first_posted>
  <last_update_submitted>October 27, 2018</last_update_submitted>
  <last_update_submitted_qc>October 27, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">October 30, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal</investigator_affiliation>
    <investigator_full_name>Sergio Serrano-Villar</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>HIV</keyword>
  <keyword>microbiota</keyword>
  <keyword>inflammation</keyword>
  <keyword>fecal microbiota restoration</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>HIV Infections</mesh_term>
  </condition_browse>
  <!-- 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/NCT03008941
org study id: 165-16
secondary id: GESIDA 9116
nct id: NCT03008941
lead sponsor: 
has dmc: Yes
Altered interplay between gut mucosa and dysbiotic bacteria during HIV infection seems to
      contribute to chronic immune dysfunction. Manipulation of the intestinal microbiota with
      nutritional interventions exert limited immunologic effects, but a deep understanding of how
      these interventions could ameliorate gut dysbiosis and influence health among HIV-infected
      individuals remain unexplored. In this Phase I clinical trial, 30 HIV-infected subjects on
      effective ART with evidence of persistent immune dysfunction, indicated by a CD4/CD8 ratio<1
      will be included and randomized to either repeated low-dose oral fecal microbiota
      transplantation or placebo during 8 weeks. The primary outcome will be safety. Secondary
      outcomes will include changes in CD4+ T cell counts, CD8+ T cell counts, CD4/CD8 ratio,
      inflammatory markers, T cell activation and markers of enterocyte barrier function through
      week 48. Engraftment on host microbiota will be examined using Illumina sequencing of the
      V3-V4 16S RNA, and changes in bacterial metabolism and in the plasma metabolite fingerprint
      will be studied by combination of untargeted mass spectrometry and two different and
      complementary separation techniques in bacterial and plasma samples.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
time frame: From baseline through week 48
measure: Changes in CD4+ T cell counts
time frame: From baseline through week 48
measure: Changes in CD8+ T cell counts
time frame: From baseline through week 48
description: Inflammation: interleukin (IL)-6, high sensitivity C reactive protein (hs-CRP), interferon gamma-induced protein (IP)-10.
Monocyte/macrophage activation: sCD14, SCD163,
Gut epithelial integrity: zonulin-1, intestinal fatty acid binding protein (IFABP).
Bacterial translocation: lipoteichoic acid (LTA)
Indolamine deoxygenase-1 induction: kynurenine/tryptophan ratio
Coagulation: D-dimers
measure: Changes in CD4/CD8 ratio
time frame: From baseline through week 48
description: Inflammation: interleukin (IL)-6, high sensitivity C reactive protein (hs-CRP), interferon gamma-induced protein (IP)-10.
Monocyte/macrophage activation: sCD14, SCD163,
Gut epithelial integrity: zonulin-1, intestinal fatty acid binding protein (IFABP).
Bacterial translocation: lipoteichoic acid (LTA)
Indolamine deoxygenase-1 induction: kynurenine/tryptophan ratio
Coagulation: D-dimers
measure: Changes in microbiota alpha diversity metrics
time frame: From baseline through week 48
measure: Changes in microbiota Unifrac distances
time frame: From baseline through week 48
measure: Changes in microbiota Canberra distances
time frame: From baseline through week 48
measure: Changes in plasma Interleukin-6 levels
time frame: From baseline through week 48
measure: Changes in plasma hs-CRP levels
time frame: From baseline through week 48
measure: Changes in plasma lipoteichoic acid levels
time frame: From baseline through week 48
measure: Changes in plasma LBP levels
time frame: From baseline through week 48
measure: Changes in plasma kynurenine/tryptophan ratio
time frame: From baseline through week 48
measure: Percentage of HLA-DR+/CD38+ T cells in blood
time frame: From baseline through week 48
arm group label: FMT
arm group type: Experimental
description: Fecal microbiota capsules (provided by Openbiome).
Dosage:
Induction: 10 capsules (single dose)
Maintenance: 5 capsules, weekly, during 7 weeks.
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo capsules (provided by Openbiome).
Dosage:
Induction: 10 capsules (single dose)
Maintenance: 5 capsules, weekly, during 7 weeks.
intervention type: Biological
intervention name: FMT
description: Capsules with fecal microbiota from healthy donors
arm group label: FMT
intervention type: Other
intervention name: Placebo
description: Placebo capsules
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
facility: 
country: Spain
responsible party type: Principal Investigator
investigator affiliation: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
investigator full name: Sergio Serrano-Villar
investigator title: MD, PhD
mesh term: HIV Infections