<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/NCT03029689</url>
  </required_header>
  <id_info>
    <org_study_id>RAGTIME</org_study_id>
    <nct_id>NCT03029689</nct_id>
  </id_info>
  <brief_title>Clinical Trial to Evaluate the Effect of Raltegravir Intensification (1.200 mg QD) on the Gut Microbiota of Chronically HIV-1 Infected Subject Over Time: THE RAGTIME STUDY</brief_title>
  <official_title>Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Effect of Raltegravir Intensification (1.200 mg QD) on the Gut Microbiota of Chronically HIV-1 Infected Subject Over Time: THE RAGTIME</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia</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>
      The project presented here will be the first prospective, randomized evaluation of the effect&#xD;
      of ART on the structure and function of the gut microbiome. This study provides a unique&#xD;
      opportunity to understand the benefits of ART with high intestinal penetration on the gut&#xD;
      microbiome. It is thus a key study to understand the bidirectional interactions between the&#xD;
      microbiome and the host in people living with HIV/AIDS.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The gut microbiome is essential for the maturation of the neonatal immune system and the&#xD;
      adequate development and function of adult immune responses. HIV-1 infection in children and&#xD;
      adults exerts a rapid and severe depletion of gut-associated lymphoid tissue, which damages&#xD;
      the intestinal barrier, allowing translocation of gut commensal bacteria into the systemic&#xD;
      circulation. Bacterial translocation causes chronic inflammation and immune activation, which&#xD;
      lead to immune deterioration and premature aging of HIV-1-infected subjects, including&#xD;
      metabolic disturbances, cardiovascular diseases, cognitive disorders and HIV-associated&#xD;
      cancers. Persistence of residual HIV-1 replication in the presence of ART has been associated&#xD;
      to incomplete HIV-1 suppression in gut lymphatic tissues due to suboptimal tissular&#xD;
      penetration of PI/s or NNRTIs.&#xD;
&#xD;
      In previous work in our institute, the investigators have observed that HIV-1 infection is&#xD;
      independently associated with significant reductions in the gut microbiome richness, which&#xD;
      is, in turn, are inversely correlated with systemic inflammation. Reduced microbial richness,&#xD;
      for example, has been associated with intestinal inflammatory diseases and well as with&#xD;
      metabolic syndrome, diabetes and obesity and correlated with metabolic markers.&#xD;
&#xD;
      Recovering bacterial richness might thus have a positive impact on immune activation, chronic&#xD;
      inflammation and the overall health of HIV-infected individuals. However, achieving that goal&#xD;
      will possibly require, alongside potential bacterial supplementations, the use of ART with&#xD;
      high penetration into gut lymphoid tissue to limit as much as possible the continued damage&#xD;
      exerted by residual HIV replication on the GALT. Antiretroviral drugs with higher intestinal&#xD;
      penetration like raltegravir may be more effective at recovering the intestinal microbiome&#xD;
      composition and function than those with lower gut penetration like darunavir or the NNRTIs.&#xD;
      Thereby, raltegravir intensification could be associated with increases in intestinal&#xD;
      microbial richness, implying an improvement on intestinal and overall health.&#xD;
&#xD;
      Despite the lack of evidence on that regard, previous studies from our group and others would&#xD;
      favor that hypothesis. Residual HIV-1 replication in plasma can be deterred by ART&#xD;
      intensification with raltegravir, which is, in part, due to the high penetration of&#xD;
      raltegravir in intestinal tissues. Moreover, raltegravir intensification decreases peripheral&#xD;
      CD8 T-cell activation CD45RA (-) and creates a transient CD4 T-cell redistribution, which&#xD;
      revert after raltegravir withdrawal.&#xD;
&#xD;
      The project presented here will be the first prospective, randomized evaluation of the effect&#xD;
      of ART on the structure and function of the gut microbiome. This study provides a unique&#xD;
      opportunity to understand the benefits of ART with high intestinal penetration on the gut&#xD;
      microbiome. It is thus a key study to understand the bidirectional interactions between the&#xD;
      microbiome and the host in people living with HIV/AIDS&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 28, 2017</start_date>
  <completion_date type="Actual">April 30, 2020</completion_date>
  <primary_completion_date type="Actual">April 30, 2020</primary_completion_date>
  <phase>Phase 3</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>Basic Science</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>bacterial richness (observed species). Analysis of the composition, structure and function of the intestinal microbiome. *</measure>
    <time_frame>From baseline to 48 weeks</time_frame>
    <description>-* Structure and composition of the microbiome. DNA will be extracted and purified from fecal samples and cryopreserved at -80ºC until amplification. The purified DNA will be amplified using Illumina-tagged primers to amplify the V3 and V4 16S ribosomal DNA (rDNA) regions. PCR reactions will be performed in triplicate to preserve diversity. Pooled triplicates will be sequenced ensuring adequate sampling depth.&#xD;
-Function of the bacteriome. The gene content will be inferred from the abundance of each bacteria in the intestinal bacteriome according to the 16S rDNA information</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Association of the gut microbiome composition and richness with inflammation</measure>
    <time_frame>From baseline to 48 weeks</time_frame>
    <description>IL-6, IP-10</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association of the gut microbiome composition and richness with coagulation</measure>
    <time_frame>From baseline to 48 weeks</time_frame>
    <description>D-Dimer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association of the gut microbiome composition and richness with Enterocyte damage</measure>
    <time_frame>From baseline to 48 weeks</time_frame>
    <description>Intestinal Fatty Acid Binding Protein (I-FABP)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association of the gut microbiome composition and richness with Bacterial translocation and monocyte activation</measure>
    <time_frame>From baseline to 48 weeks</time_frame>
    <description>LPS-binding protein (LBP), soluble CD14</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association of the gut microbiome composition and richness with Maturation, activation, exhaustion and immune senescence in CD4+ and CD8+ T-cells</measure>
    <time_frame>From baseline to 48 weeks</time_frame>
    <description>CD3+, CD4+, CD8+, CD45RA, CCR7, CD28, CD27, HLA-DR, CD38, PD-1, CD57</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association of the gut microbiome composition and richness with CD4 and CD8+ counts and ratio.</measure>
    <time_frame>From baseline to 48 weeks</time_frame>
    <description>CD4 and CD8+ counts and ratio</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gut bacterial composition*</measure>
    <time_frame>From baseline to 48 weeks</time_frame>
    <description>Longitudinal changes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gut bacterial function*</measure>
    <time_frame>From baseline to 48 weeks</time_frame>
    <description>Longitudinal changes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Other estimators of richness and diversity</measure>
    <time_frame>From baseline to 48 weeks</time_frame>
    <description>1/Simpson</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Other estimators of richness and diversity</measure>
    <time_frame>From baseline to 48 weeks</time_frame>
    <description>ACE</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Other estimators of richness and diversity</measure>
    <time_frame>From baseline to 48 weeks</time_frame>
    <description>Shannon</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>In case of changes in the microbiome, the quantification of viral reservoir will be done in PBMCs</measure>
    <time_frame>From baseline to 48 weeks</time_frame>
    <description>quantification of viral reservoir</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>HIV</condition>
  <arm_group>
    <arm_group_label>Current ART + Raltegravir</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Current ART + Raltegravir</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Current ART + placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Current ART + placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Raltegravir</intervention_name>
    <description>Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization</description>
    <arm_group_label>Current ART + Raltegravir</arm_group_label>
    <other_name>NP</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.</description>
    <arm_group_label>Current ART + placebo</arm_group_label>
    <other_name>NP</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Current ART</intervention_name>
    <description>3-drug antiretroviral treatment including PI/r/c or NNRTI</description>
    <arm_group_label>Current ART + Raltegravir</arm_group_label>
    <arm_group_label>Current ART + placebo</arm_group_label>
    <other_name>NP</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥18 years old&#xD;
&#xD;
          2. Documented HIV infection&#xD;
&#xD;
          3. Stable 3-drug antiretroviral treatment including PI/r/c or NNRTI for at least 6&#xD;
             months.&#xD;
&#xD;
          4. Plasma HIV-1 RNA load &lt;50 copies/mL for at least 12 months.&#xD;
&#xD;
          5. Signed Informed Consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. PI/r monotherapy&#xD;
&#xD;
          2. INSTI therapy during the previous 6 months&#xD;
&#xD;
          3. Evidence of previous INSTI resistance&#xD;
&#xD;
          4. Creatine clearance &lt;50 mL/min&#xD;
&#xD;
          5. Child- Pugh B or C&#xD;
&#xD;
          6. History of active uncontrolled GI disorders or diseases including:&#xD;
&#xD;
             6.1. Major surgery of the GI tract, with the exception of cholecystectomy and&#xD;
             appendectomy, in the previous 5 years.&#xD;
&#xD;
             6.2. Any major bowel resection at any time.&#xD;
&#xD;
             6.3. Any chronic digestive disease such as peptic ulcer, Crohn's disease, ulcerative&#xD;
             colitis, coeliac disease, confirmed intolerance to lactose or indeterminate colitis.&#xD;
&#xD;
             6.4. Persistent infectious gastroenteritis, colitis or gastritis; persistent or&#xD;
             chronic diarrhea of unknown etiology; Clostridium difficile infection (recurrent) or&#xD;
             Helicobacter pylori infection (untreated)&#xD;
&#xD;
             6.5. Irritable bowel syndrome (moderate-severe)&#xD;
&#xD;
             6.6. Chronic constipation&#xD;
&#xD;
             6.7. Active proctitis&#xD;
&#xD;
          7. Antibiotic therapy within the previous 2 months&#xD;
&#xD;
          8. In women, pregnancy or breastfeeding*.&#xD;
&#xD;
               -  Female subjects of childbearing potential must not be pregnant, not be planning a&#xD;
                  pregnancy or breast-feeding. Sexually active women must be willing to use two&#xD;
                  approved methods of contraception (including condoms, diaphragm, spermicides,&#xD;
                  hormonal methods and/or intrauterine devices) from baseline until the end of the&#xD;
                  clinical trial. Sexually active men in heterosexual relationships must be willing&#xD;
                  to use two approved method of contraception with their partners from baseline&#xD;
                  until the end of the clinical trial.&#xD;
&#xD;
               -  condom use is considered as an additional method of contraception only and cannot&#xD;
                  be the only method of contraception used as not been considered an effective&#xD;
                  method by the Clinical Trial Facilitation Group (CTFG) guidelines.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Germans Trias i Pujol Hospital</name>
      <address>
        <city>Badalona</city>
        <state>Barcelona</state>
        <zip>08916</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>January 11, 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>July 24, 2020</last_update_submitted>
  <last_update_submitted_qc>July 24, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 27, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HIV infection</keyword>
  <keyword>Gut microbiome</keyword>
  <keyword>Raltegravir</keyword>
  <keyword>Raltegravir intensification</keyword>
  <keyword>Bacterial richness</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Raltegravir Potassium</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03029689
org study id: RAGTIME
nct id: NCT03029689
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The project presented here will be the first prospective, randomized evaluation of the effect
      of ART on the structure and function of the gut microbiome. This study provides a unique
      opportunity to understand the benefits of ART with high intestinal penetration on the gut
      microbiome. It is thus a key study to understand the bidirectional interactions between the
      microbiome and the host in people living with HIV/AIDS.
The gut microbiome is essential for the maturation of the neonatal immune system and the
      adequate development and function of adult immune responses. HIV-1 infection in children and
      adults exerts a rapid and severe depletion of gut-associated lymphoid tissue, which damages
      the intestinal barrier, allowing translocation of gut commensal bacteria into the systemic
      circulation. Bacterial translocation causes chronic inflammation and immune activation, which
      lead to immune deterioration and premature aging of HIV-1-infected subjects, including
      metabolic disturbances, cardiovascular diseases, cognitive disorders and HIV-associated
      cancers. Persistence of residual HIV-1 replication in the presence of ART has been associated
      to incomplete HIV-1 suppression in gut lymphatic tissues due to suboptimal tissular
      penetration of PI/s or NNRTIs.

      In previous work in our institute, the investigators have observed that HIV-1 infection is
      independently associated with significant reductions in the gut microbiome richness, which
      is, in turn, are inversely correlated with systemic inflammation. Reduced microbial richness,
      for example, has been associated with intestinal inflammatory diseases and well as with
      metabolic syndrome, diabetes and obesity and correlated with metabolic markers.

      Recovering bacterial richness might thus have a positive impact on immune activation, chronic
      inflammation and the overall health of HIV-infected individuals. However, achieving that goal
      will possibly require, alongside potential bacterial supplementations, the use of ART with
      high penetration into gut lymphoid tissue to limit as much as possible the continued damage
      exerted by residual HIV replication on the GALT. Antiretroviral drugs with higher intestinal
      penetration like raltegravir may be more effective at recovering the intestinal microbiome
      composition and function than those with lower gut penetration like darunavir or the NNRTIs.
      Thereby, raltegravir intensification could be associated with increases in intestinal
      microbial richness, implying an improvement on intestinal and overall health.

      Despite the lack of evidence on that regard, previous studies from our group and others would
      favor that hypothesis. Residual HIV-1 replication in plasma can be deterred by ART
      intensification with raltegravir, which is, in part, due to the high penetration of
      raltegravir in intestinal tissues. Moreover, raltegravir intensification decreases peripheral
      CD8 T-cell activation CD45RA (-) and creates a transient CD4 T-cell redistribution, which
      revert after raltegravir withdrawal.

      The project presented here will be the first prospective, randomized evaluation of the effect
      of ART on the structure and function of the gut microbiome. This study provides a unique
      opportunity to understand the benefits of ART with high intestinal penetration on the gut
      microbiome. It is thus a key study to understand the bidirectional interactions between the
      microbiome and the host in people living with HIV/AIDS
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Double (Participant, Investigator)
measure: bacterial richness (observed species). Analysis of the composition, structure and function of the intestinal microbiome. *
time frame: From baseline to 48 weeks
description: -* Structure and composition of the microbiome. DNA will be extracted and purified from fecal samples and cryopreserved at -80ºC until amplification. The purified DNA will be amplified using Illumina-tagged primers to amplify the V3 and V4 16S ribosomal DNA (rDNA) regions. PCR reactions will be performed in triplicate to preserve diversity. Pooled triplicates will be sequenced ensuring adequate sampling depth.
-Function of the bacteriome. The gene content will be inferred from the abundance of each bacteria in the intestinal bacteriome according to the 16S rDNA information
measure: Association of the gut microbiome composition and richness with inflammation
time frame: From baseline to 48 weeks
description: IL-6, IP-10
measure: Association of the gut microbiome composition and richness with coagulation
time frame: From baseline to 48 weeks
description: D-Dimer
measure: Association of the gut microbiome composition and richness with Enterocyte damage
time frame: From baseline to 48 weeks
description: Intestinal Fatty Acid Binding Protein (I-FABP)
measure: Association of the gut microbiome composition and richness with Bacterial translocation and monocyte activation
time frame: From baseline to 48 weeks
description: LPS-binding protein (LBP), soluble CD14
measure: Association of the gut microbiome composition and richness with Maturation, activation, exhaustion and immune senescence in CD4+ and CD8+ T-cells
time frame: From baseline to 48 weeks
description: CD3+, CD4+, CD8+, CD45RA, CCR7, CD28, CD27, HLA-DR, CD38, PD-1, CD57
measure: Association of the gut microbiome composition and richness with CD4 and CD8+ counts and ratio.
time frame: From baseline to 48 weeks
description: CD4 and CD8+ counts and ratio
measure: Gut bacterial composition*
time frame: From baseline to 48 weeks
description: Longitudinal changes
measure: Gut bacterial function*
time frame: From baseline to 48 weeks
description: Longitudinal changes
measure: Other estimators of richness and diversity
time frame: From baseline to 48 weeks
description: 1/Simpson
measure: Other estimators of richness and diversity
time frame: From baseline to 48 weeks
description: ACE
measure: Other estimators of richness and diversity
time frame: From baseline to 48 weeks
description: Shannon
measure: In case of changes in the microbiome, the quantification of viral reservoir will be done in PBMCs
time frame: From baseline to 48 weeks
description: quantification of viral reservoir
arm group label: Current ART + Raltegravir
arm group type: Experimental
description: Current ART + Raltegravir
arm group label: Current ART + placebo
arm group type: Placebo Comparator
description: Current ART + placebo
intervention type: Drug
intervention name: Raltegravir
description: Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
arm group label: Current ART + Raltegravir
other name: NP
intervention type: Drug
intervention name: Placebo
description: Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
arm group label: Current ART + placebo
other name: NP
intervention type: Drug
intervention name: Current ART
description: 3-drug antiretroviral treatment including PI/r/c or NNRTI
arm group label: Current ART + Raltegravir
arm group label: Current ART + placebo
other name: NP
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
facility: 
country: Spain
responsible party type: Sponsor
mesh term: Raltegravir Potassium
sharing ipd: No