<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/NCT02188381</url>
  </required_header>
  <id_info>
    <org_study_id>IRB201400233-N</org_study_id>
    <secondary_id>1R01HL132448-01</secondary_id>
    <nct_id>NCT02188381</nct_id>
  </id_info>
  <brief_title>The Role of Gut Microbiota in Hypertension</brief_title>
  <official_title>The Role of Gut Microbiota in Hypertension: Brain-Gut Microbiome-Immune Axis in Hypertension</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Florida</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>
      Hypertension is the single most prevalent risk factor for heart diseases, heart failure,&#xD;
      kidney failure and stroke. About 1 in 3 adults in the United States have hypertension.&#xD;
      Approximately 28-30% of hypertensive patients suffer from resistant hypertension (RH).&#xD;
      Inflammation has been implicated in the pathogenesis of the hypertension. Additional data&#xD;
      suggests the involvement of gut microbiota in host normal cardiovascular functions and&#xD;
      pathophysiology. Accumulating evidence demonstrates that antibiotic treatment benefits&#xD;
      patients with acute coronary syndromes and reduces the incidence of ischemic cardiovascular&#xD;
      events. Even though these studies did not address effects of antibiotic treatment on the gut&#xD;
      microbiota, it is possible that gut microbiota could affect neurologic inflammation. Finally,&#xD;
      intestinal microbiota has recently been proposed to modulate blood pressure (BP) through&#xD;
      production of short-chain fatty acids. In order to investigate this, the investigators&#xD;
      hypothesize that gut microbiota is involved in the neuroinflammation-mediated initiation and&#xD;
      establishment of RH, and targeting gut microbiota by minocycline would produce beneficial&#xD;
      outcomes in RH.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a prospective cohort design. This study will enroll 388 subjects: 81 patients without&#xD;
      HTN as a reference group, 81 patients with controlled HTN, 55 patients with uncontrolled HTN,&#xD;
      55 with remodeled RH, and 81 patients with RH to characterize gut microbiota composition.&#xD;
      Subjects will provide stool samples for analysis. Subjects will also provide a blood sample&#xD;
      for inflammatory marker and stem cell analysis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 2014</start_date>
  <completion_date type="Anticipated">October 2023</completion_date>
  <primary_completion_date type="Anticipated">October 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Characterize gut microbiota composition at phylum level</measure>
    <time_frame>24 hours</time_frame>
    <description>Stool samples to analyze the composition of the microbiota, extracted bacterial genomic DNA will be used as a template for PCR reactions targeting the V4-V5 variable regions of the 16S rRNA gene. Amplicons generated from the PCR will be run on the Illumina MiSeq sequencing platform available in our laboratory to profile microbial communities at phylum level.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Characterize gut microbiota composition at genus level</measure>
    <time_frame>24 hours</time_frame>
    <description>Stool samples to analyze the composition of the microbiota, extracted bacterial genomic DNA will be used as a template for PCR reactions targeting the V4-V5 variable regions of the 16S rRNA gene. Amplicons generated from the PCR will be run on the Illumina MiSeq sequencing platform available in our laboratory to profile microbial communities at genus level.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Reduction in BP is associated with changes in gut microbiota composition in RH subjects.</measure>
    <time_frame>Baseline, 3 months</time_frame>
    <description>Stool samples from patients enrolled in NCT 02133871 that received minocycline medication for resistant hypertension. Will be used to analyze the composition of the microbiota and data (taxonomic assignment) will be analyzed using QIIMEv1.3 pipeline to enumerate microbial population between samples derived from the cohorts.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IS hypertension associated with increased sympathetic activity and decreased parasympathetic activity and whether minocycline or other tetracyclines are effective to improve this balance</measure>
    <time_frame>Baseline and 3 months</time_frame>
    <description>Stool samples from patients enrolled in NCT 02133871 that received minocycline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To determine if characterization of gut microbiota in at risk patients predicts long term care utilization and/or cardiovascular outcomes</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Stool samples</description>
  </secondary_outcome>
  <number_of_groups>5</number_of_groups>
  <enrollment type="Actual">292</enrollment>
  <condition>Hypertension</condition>
  <arm_group>
    <arm_group_label>Normal controls without hypertension</arm_group_label>
    <description>Control subjects will have a systolic BP &lt;140mmHg with no cardiovascular disease. These subjects will provide a one time stool sample and a blood sample.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Controlled hypertension</arm_group_label>
    <description>Subjects with controlled hypertension will provide a one time stool sample and a blood sample.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Resistant hypertension</arm_group_label>
    <description>Resistant hypertension subjects will have systolic blood pressure (BP) ≥140 mmHg despite ≥3 anti-hypertensive medications of different classes. These subjects will provide a one time stool sample and a blood sample.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Prior enrolled in NCT 02133872</arm_group_label>
    <description>These subject will be asked to provide two stool samples and two blood samples. One at baseline and one after 3 months of therapy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Remodeled Resistent Hypertension</arm_group_label>
    <description>Subjects with controlled hypertension will provide a one time stool sample and a blood sample.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Stool Sample and Blood Sample</intervention_name>
    <description>All subjects will provide a stool sample and a blood sample at baseline. Subjects in NCT02133872 will provide a second stool sample and blood sample at their 3 month visit.</description>
    <arm_group_label>Controlled hypertension</arm_group_label>
    <arm_group_label>Normal controls without hypertension</arm_group_label>
    <arm_group_label>Prior enrolled in NCT 02133872</arm_group_label>
    <arm_group_label>Remodeled Resistent Hypertension</arm_group_label>
    <arm_group_label>Resistant hypertension</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Stool Samples&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        This study will initially enroll 10 patients without hypertension as normal controls, and&#xD;
        10 patients with controlled hypertension and 10 patients with resistant hypertension to&#xD;
        characterize gut microbiota. In addition, all patients enrolled in IRB# 102-2013 will be&#xD;
        approached for possible participation.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  age &gt;18 and &lt;80&#xD;
&#xD;
          -  is competent and willing to provide consent&#xD;
&#xD;
        Inclusion criteria for each subject group:&#xD;
&#xD;
          -  Control subjects will have a systolic BP &lt;140mmHg with no cardiovascular disease&#xD;
&#xD;
          -  Patients with controlled hypertension&#xD;
&#xD;
          -  Patients with uncontrolled hypertension&#xD;
&#xD;
          -  Resistant hypertension subjects will have systolic blood pressure (BP) ≥140 mmHg&#xD;
             despite ≥3 anti-hypertensive medications of different classes one of which should be a&#xD;
             diuretic&#xD;
&#xD;
          -  Patients who are no longer RH subjects and have normal blood pressure&#xD;
&#xD;
          -  Subjects participating in NCT 02133872 will be eligible to participate&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  currently pregnant or have been pregnant in the last 6 months;&#xD;
&#xD;
          -  antibiotic treatment within 2 months of study enrollment;&#xD;
&#xD;
          -  currently taking a medication (e.g., antibiotic, anti-inflammatory agents,&#xD;
             glucocorticoids or other immune modulating medications);&#xD;
&#xD;
          -  unwilling to discontinue vitamin or supplements, including probiotics, potentially&#xD;
             affecting gut microbiota (vitamins/supplements and medications that possibly affect&#xD;
             the gut microbiota should be discontinued for at least 2wks prior to stool&#xD;
             collection);&#xD;
&#xD;
          -  history of intestinal surgery, inflammatory bowel disease, celiac disease, lactose&#xD;
             intolerance, chronic pancreatitis or other malabsorption disorder.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Carl Pepline, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Florida</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cardiovascular Clinic at UF Health</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32610</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>July 9, 2014</study_first_submitted>
  <study_first_submitted_qc>July 9, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 11, 2014</study_first_posted>
  <last_update_submitted>May 9, 2023</last_update_submitted>
  <last_update_submitted_qc>May 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Resistant Hypertension (RH)</keyword>
  <keyword>Uncontrolled Hypertension</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</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/NCT02188381
org study id: IRB201400233-N
secondary id: 1R01HL132448-01
nct id: NCT02188381
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Hypertension is the single most prevalent risk factor for heart diseases, heart failure,
      kidney failure and stroke. About 1 in 3 adults in the United States have hypertension.
      Approximately 28-30% of hypertensive patients suffer from resistant hypertension (RH).
      Inflammation has been implicated in the pathogenesis of the hypertension. Additional data
      suggests the involvement of gut microbiota in host normal cardiovascular functions and
      pathophysiology. Accumulating evidence demonstrates that antibiotic treatment benefits
      patients with acute coronary syndromes and reduces the incidence of ischemic cardiovascular
      events. Even though these studies did not address effects of antibiotic treatment on the gut
      microbiota, it is possible that gut microbiota could affect neurologic inflammation. Finally,
      intestinal microbiota has recently been proposed to modulate blood pressure (BP) through
      production of short-chain fatty acids. In order to investigate this, the investigators
      hypothesize that gut microbiota is involved in the neuroinflammation-mediated initiation and
      establishment of RH, and targeting gut microbiota by minocycline would produce beneficial
      outcomes in RH.
This is a prospective cohort design. This study will enroll 388 subjects: 81 patients without
      HTN as a reference group, 81 patients with controlled HTN, 55 patients with uncontrolled HTN,
      55 with remodeled RH, and 81 patients with RH to characterize gut microbiota composition.
      Subjects will provide stool samples for analysis. Subjects will also provide a blood sample
      for inflammatory marker and stem cell analysis.
observational model: Cohort
time perspective: Prospective
measure: Characterize gut microbiota composition at phylum level
time frame: 24 hours
description: Stool samples to analyze the composition of the microbiota, extracted bacterial genomic DNA will be used as a template for PCR reactions targeting the V4-V5 variable regions of the 16S rRNA gene. Amplicons generated from the PCR will be run on the Illumina MiSeq sequencing platform available in our laboratory to profile microbial communities at phylum level.
measure: Characterize gut microbiota composition at genus level
time frame: 24 hours
description: Stool samples to analyze the composition of the microbiota, extracted bacterial genomic DNA will be used as a template for PCR reactions targeting the V4-V5 variable regions of the 16S rRNA gene. Amplicons generated from the PCR will be run on the Illumina MiSeq sequencing platform available in our laboratory to profile microbial communities at genus level.
measure: Reduction in BP is associated with changes in gut microbiota composition in RH subjects.
time frame: Baseline, 3 months
description: Stool samples from patients enrolled in NCT 02133871 that received minocycline medication for resistant hypertension. Will be used to analyze the composition of the microbiota and data (taxonomic assignment) will be analyzed using QIIMEv1.3 pipeline to enumerate microbial population between samples derived from the cohorts.
measure: IS hypertension associated with increased sympathetic activity and decreased parasympathetic activity and whether minocycline or other tetracyclines are effective to improve this balance
time frame: Baseline and 3 months
description: Stool samples from patients enrolled in NCT 02133871 that received minocycline
measure: To determine if characterization of gut microbiota in at risk patients predicts long term care utilization and/or cardiovascular outcomes
time frame: Up to 5 years
description: Stool samples
arm group label: Normal controls without hypertension
description: Control subjects will have a systolic BP <140mmHg with no cardiovascular disease. These subjects will provide a one time stool sample and a blood sample.
arm group label: Controlled hypertension
description: Subjects with controlled hypertension will provide a one time stool sample and a blood sample.
arm group label: Resistant hypertension
description: Resistant hypertension subjects will have systolic blood pressure (BP) ≥140 mmHg despite ≥3 anti-hypertensive medications of different classes. These subjects will provide a one time stool sample and a blood sample.
arm group label: Prior enrolled in NCT 02133872
description: These subject will be asked to provide two stool samples and two blood samples. One at baseline and one after 3 months of therapy.
arm group label: Remodeled Resistent Hypertension
description: Subjects with controlled hypertension will provide a one time stool sample and a blood sample.
intervention type: Other
intervention name: Stool Sample and Blood Sample
description: All subjects will provide a stool sample and a blood sample at baseline. Subjects in NCT02133872 will provide a second stool sample and blood sample at their 3 month visit.
arm group label: Controlled hypertension
arm group label: Normal controls without hypertension
arm group label: Prior enrolled in NCT 02133872
arm group label: Remodeled Resistent Hypertension
arm group label: Resistant hypertension
Stool Samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Carl Pepline, MD
role: Principal Investigator
affiliation: University of Florida
facility: 
country: United States
responsible party type: Sponsor
mesh term: Hypertension