<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/NCT02226484</url>
  </required_header>
  <id_info>
    <org_study_id>13-0557</org_study_id>
    <secondary_id>1R21DK097529-01A1</secondary_id>
    <nct_id>NCT02226484</nct_id>
  </id_info>
  <brief_title>Can Quercetin Increase Claudin-4 and Improve Esophageal Barrier Function in GERD?</brief_title>
  <official_title>Can Quercetin Increase Claudin-4 and Improve Esophageal Barrier Function in GERD?</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of North Carolina, Chapel Hill</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of North Carolina, Chapel Hill</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Purpose:&#xD;
&#xD;
        1. Determine if oral quercetin increases the expression of claudin-4 in the lining of the&#xD;
           esophagus of patients with a diagnosis of gastroesophageal reflux disease (GERD); and&#xD;
&#xD;
        2. Determine whether the increase in claudin-4 by oral quercetin is accompanied by&#xD;
           improvement in the barrier function and acid resistance of the lining of the esophagus&#xD;
           of patients with a diagnosis of gastroesophageal reflux disease (GERD)&#xD;
&#xD;
      If interested, participants will be consented and provided a questionnaire to complete as&#xD;
      part of the study. Participants will undergo endoscopy for routine care and will have up to 8&#xD;
      esophageal biopsies (small tissue samples) taken for the research study. After endoscopy,&#xD;
      participants will be contacted to begin a 6 week treatment period with study drug (Quercetin,&#xD;
      taken twice daily).&#xD;
&#xD;
      At the end of the 6 week period, participants will be scheduled to have blood drawn and to&#xD;
      have a follow-up endoscopy with biopsies performed for the research study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients must be symptomatic (heartburn) and agree to allow endoscopic biopsies from the&#xD;
      lower 5 cm of esophagus for research purposes. If the endoscopy demonstrates non-erosive&#xD;
      reflux disease, biopsies of Esophageal Squamous Epithelium (ESE) are obtained and placed in&#xD;
      mRNA-Later to assess claudin-4 mRNA by qRT-PCR and protein expression by Western blot (53,&#xD;
      64) while other biopsies of ESE are obtained and handled as in SpAim#2 to assess barrier&#xD;
      function of ESE. After consent, subjects complete a questionnaire assessing demographics,&#xD;
      disease-specific parameters such as duration of symptoms and past treatment, and the&#xD;
      gastroesophageal reflux disease (GERD) Symptom Assessment Scale (GSAS), a validated measure&#xD;
      of GERD severity. Following this, patients in open label fashion are given orally 500 mg&#xD;
      Quercetin (Q) twice daily (bid) [Pure, House of Nutrition, Yonkers, NY] for 6-weeks. Symptoms&#xD;
      are monitored 1 week before and for the 6 week treatment period. At 6 weeks, a blood sample&#xD;
      is obtained for determination of Q and its metabolites by HPLC and endoscopy and biopsies of&#xD;
      ESE are repeated and processed as initially done for claudin-4 levels in ESE.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2014</start_date>
  <completion_date type="Actual">June 2016</completion_date>
  <primary_completion_date type="Actual">May 2016</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Expression of claudin-4 in esophageal squamous epithelium (ESE) of gastroesophageal reflux disease (GERD) in vivo</measure>
    <time_frame>6 weeks</time_frame>
    <description>To assess the change in claudin-4 levels in a given subject before and after administration of Quercetin (Q), our null hypothesis is that there will be no difference in claudin-4 levels (i.e. mean Δ of claudin-4 titer from t0 to t1 is 0) and the alternative hypothesis is that claudin-4 levels following the administration of Q will be significantly different than before administration. To test this hypothesis, we will perform paired Student's t-tests. If data violate normality, Wilcoxon signed-rank test will be used as a nonparametric alternative to the Student's t. Additionally, exploratory analysis will be performed to assess the impact of treatment on reflux scores, as demonstrated by changes in the GERD Symptom Assessment Scale (GSAS) before and after therapy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Barrier function and acid resistance of esophageal squamous epithelium (ESE) as measured by epithelial resistance, RT, and fluorescein flux.</measure>
    <time_frame>6 weeks</time_frame>
    <description>To determine whether the increase in claudin-4 by oral Quercetin (Q) is accompanied by improvement in the barrier function and acid resistance of esophageal squamous epithelium (ESE) in gastroesophageal reflux disease (GERD), we will assess the correlation in claudin-4 expression with our measures of epithelial resistance, RT, and fluorescein flux. Both the predictor variable (claudin-4 expression) and the response variables (RT and fluorescein flux) are continuous variables. Because the correlation between claudin-4 and the response variables is unknown and may not have a linear contour, Spearman's rank correlation coefficient will be used instead of Pearson's correlation, to improve sensitivity to non-linear relationships. Alpha will be set at 0.05.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">26</enrollment>
  <condition>Gastroesophageal Reflux Disease</condition>
  <condition>GERD</condition>
  <condition>Acid Reflux</condition>
  <condition>Reflux</condition>
  <arm_group>
    <arm_group_label>Quercetin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Two 250 mg capsules of oral quercetin (Q) twice-a-day (BID) one hour before meals with a glass of water for 6 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Quercetin</intervention_name>
    <description>Two 250 mg capsules of quercetin twice-a-day one hour before meals with a glass of water.</description>
    <arm_group_label>Quercetin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  English speaking&#xD;
&#xD;
          -  Able to read, comprehend, and complete the consent form.&#xD;
&#xD;
          -  Aged 18 to 80&#xD;
&#xD;
          -  Diagnosed with gastroesophageal reflux disease (GERD) by a physician, defined as:&#xD;
&#xD;
             a. History of heartburn at &gt; 3 times/week for &gt; 4 months AND either: i. Abnormal&#xD;
             24hr-pH monitoring (acid contact time &gt; 4.5% OR ii. Past responsiveness to proton pump&#xD;
             inhibitor (PPI) therapy&#xD;
&#xD;
          -  Willing to undergo esophageal biopsy, endoscopy, and take study medication.&#xD;
&#xD;
          -  Willingness to discontinue or remain off PPIs for the duration of the study (rescue&#xD;
             medication use during the study such as antacids and H2 blockers as needed for&#xD;
             symptoms is permitted)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with a medical condition that makes him/her a poor risk for upper endoscopy,&#xD;
             conscious sedation, esophageal biopsy or ability to comply with study directives&#xD;
&#xD;
          -  Current use of blood thinners such as coumadin, warfarin, heparin and/or low molecular&#xD;
             weight heparin, and rivaroxaban (requires discontinuation of medication 5 days prior&#xD;
             to and 6 days after EGD)&#xD;
&#xD;
          -  Patients with known bleeding disorders&#xD;
&#xD;
          -  Patients who are status post partial or complete esophageal resection&#xD;
&#xD;
          -  Patients with a history of esophageal or gastric surgery, includes fundoplication,&#xD;
             gastric bypass, etc.&#xD;
&#xD;
          -  Patients with a history of esophageal varices, esophageal cancer, achalasia, Barrett's&#xD;
             esophagus, or eosinophilic esophagitis,&#xD;
&#xD;
          -  Current diagnosis of invasive esophageal cancer&#xD;
&#xD;
          -  Current use of calcium channel blockers, estradiol, immune suppressive drugs, aspirin,&#xD;
             non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, and/or taxol/paclitaxel&#xD;
&#xD;
          -  Pregnant women&#xD;
&#xD;
          -  Patients with a history of being intolerant of Quercetin&#xD;
&#xD;
          -  Patients with continued moderate or severe heartburn despite use of twice daily PPIs&#xD;
             (i.e. refractory to twice daily dosing of PPIs)&#xD;
&#xD;
          -  Patients with current active erosive esophagitis (assessed during baseline EGD).&#xD;
&#xD;
          -  Patients with a history of erosive esophagitis requiring PPI to treat. However, if&#xD;
             patients have a history of erosive esophagitis and have discontinued PPI therapy at&#xD;
             least 3 months prior to the baseline EGD, and there is no erosive disease seen during&#xD;
             the baseline EGD, then these patients are eligible.&#xD;
&#xD;
          -  Patients with significant erosive gastropathy on baseline EGD requiring PPI to treat&#xD;
             clinically.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nicholas Shaheen, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>UNC Chapel Hill</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UNC Chapel Hill</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2016</verification_date>
  <study_first_submitted>August 22, 2014</study_first_submitted>
  <study_first_submitted_qc>August 26, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 27, 2014</study_first_posted>
  <last_update_submitted>December 19, 2016</last_update_submitted>
  <last_update_submitted_qc>December 19, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 20, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of North Carolina, Chapel Hill</investigator_affiliation>
    <investigator_full_name>Nicholas Shaheen, MD</investigator_full_name>
    <investigator_title>Professor of Medicine and Epidemiology Chief, Division of Gastroenterology &amp; Hepatology</investigator_title>
  </responsible_party>
  <keyword>Gastroesophageal reflux disease</keyword>
  <keyword>GERD</keyword>
  <keyword>Acid reflux</keyword>
  <keyword>Reflux</keyword>
  <keyword>Quercetin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gastroesophageal Reflux</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Quercetin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>No plans to share data</ipd_description>
  </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/NCT02226484
org study id: 13-0557
secondary id: 1R21DK097529-01A1
nct id: NCT02226484
lead sponsor: 
collaborator: 
has dmc: No
Purpose:

        1. Determine if oral quercetin increases the expression of claudin-4 in the lining of the
           esophagus of patients with a diagnosis of gastroesophageal reflux disease (GERD); and

        2. Determine whether the increase in claudin-4 by oral quercetin is accompanied by
           improvement in the barrier function and acid resistance of the lining of the esophagus
           of patients with a diagnosis of gastroesophageal reflux disease (GERD)

      If interested, participants will be consented and provided a questionnaire to complete as
      part of the study. Participants will undergo endoscopy for routine care and will have up to 8
      esophageal biopsies (small tissue samples) taken for the research study. After endoscopy,
      participants will be contacted to begin a 6 week treatment period with study drug (Quercetin,
      taken twice daily).

      At the end of the 6 week period, participants will be scheduled to have blood drawn and to
      have a follow-up endoscopy with biopsies performed for the research study.
Patients must be symptomatic (heartburn) and agree to allow endoscopic biopsies from the
      lower 5 cm of esophagus for research purposes. If the endoscopy demonstrates non-erosive
      reflux disease, biopsies of Esophageal Squamous Epithelium (ESE) are obtained and placed in
      mRNA-Later to assess claudin-4 mRNA by qRT-PCR and protein expression by Western blot (53,
      64) while other biopsies of ESE are obtained and handled as in SpAim#2 to assess barrier
      function of ESE. After consent, subjects complete a questionnaire assessing demographics,
      disease-specific parameters such as duration of symptoms and past treatment, and the
      gastroesophageal reflux disease (GERD) Symptom Assessment Scale (GSAS), a validated measure
      of GERD severity. Following this, patients in open label fashion are given orally 500 mg
      Quercetin (Q) twice daily (bid) [Pure, House of Nutrition, Yonkers, NY] for 6-weeks. Symptoms
      are monitored 1 week before and for the 6 week treatment period. At 6 weeks, a blood sample
      is obtained for determination of Q and its metabolites by HPLC and endoscopy and biopsies of
      ESE are repeated and processed as initially done for claudin-4 levels in ESE.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Expression of claudin-4 in esophageal squamous epithelium (ESE) of gastroesophageal reflux disease (GERD) in vivo
time frame: 6 weeks
description: To assess the change in claudin-4 levels in a given subject before and after administration of Quercetin (Q), our null hypothesis is that there will be no difference in claudin-4 levels (i.e. mean Δ of claudin-4 titer from t0 to t1 is 0) and the alternative hypothesis is that claudin-4 levels following the administration of Q will be significantly different than before administration. To test this hypothesis, we will perform paired Student's t-tests. If data violate normality, Wilcoxon signed-rank test will be used as a nonparametric alternative to the Student's t. Additionally, exploratory analysis will be performed to assess the impact of treatment on reflux scores, as demonstrated by changes in the GERD Symptom Assessment Scale (GSAS) before and after therapy.
measure: Barrier function and acid resistance of esophageal squamous epithelium (ESE) as measured by epithelial resistance, RT, and fluorescein flux.
time frame: 6 weeks
description: To determine whether the increase in claudin-4 by oral Quercetin (Q) is accompanied by improvement in the barrier function and acid resistance of esophageal squamous epithelium (ESE) in gastroesophageal reflux disease (GERD), we will assess the correlation in claudin-4 expression with our measures of epithelial resistance, RT, and fluorescein flux. Both the predictor variable (claudin-4 expression) and the response variables (RT and fluorescein flux) are continuous variables. Because the correlation between claudin-4 and the response variables is unknown and may not have a linear contour, Spearman's rank correlation coefficient will be used instead of Pearson's correlation, to improve sensitivity to non-linear relationships. Alpha will be set at 0.05.
arm group label: Quercetin
arm group type: Experimental
description: Two 250 mg capsules of oral quercetin (Q) twice-a-day (BID) one hour before meals with a glass of water for 6 weeks.
intervention type: Drug
intervention name: Quercetin
description: Two 250 mg capsules of quercetin twice-a-day one hour before meals with a glass of water.
arm group label: Quercetin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Nicholas Shaheen, MD, MPH
role: Principal Investigator
affiliation: UNC Chapel Hill
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of North Carolina, Chapel Hill
investigator full name: Nicholas Shaheen, MD
investigator title: Professor of Medicine and Epidemiology Chief, Division of Gastroenterology & Hepatology
mesh term: Gastroesophageal Reflux
mesh term: Quercetin
sharing ipd: No
ipd description: No plans to share data