<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/NCT04433091</url>
  </required_header>
  <id_info>
    <org_study_id>192520</org_study_id>
    <nct_id>NCT04433091</nct_id>
  </id_info>
  <brief_title>2-Hydroxybenzylamine (2-HOBA) to Prevent Early Recurrence of Atrial Fibrillation After Catheter-based Ablation</brief_title>
  <official_title>2-Hydroxybenzylamine (2-HOBA) to Prevent Early Recurrence of Atrial Fibrillation After Catheter- Based Ablation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>American Heart Association</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The proposed studies will test this hypothesis by randomizing patients with AF to 2-HOBA or&#xD;
      placebo 7 days prior to AF ablation to allow 2-HOBA to reach steady-state levels. We&#xD;
      hypothesize that tissue injury from AF ablation causes a large release of ROS that react with&#xD;
      lipids to generate IsoLGs (Figure 2). In the absence of 2-HOBA, IsoLGs will react within&#xD;
      seconds to form IsoLG-macromolecule adducts in atrial tissue, promoting early recurrence of&#xD;
      AF. In the presence of 2-HOBA, IsoLGs will rapidly react to form IsoLG-macromolecule adducts&#xD;
      in atrial tissue, promoting early recurrence of AF. In the presence of 2-HOBA, IsoLG will&#xD;
      preferentially bind to and therefore be inactivated by 2-HOBA thereby sparing injury to the&#xD;
      atrial tissue caused by oxidative stress and its contribution to early recurrence of AF.&#xD;
      Early recurrence of AF will be measured by ECGs that are recorded once per day by a&#xD;
      smartwatch (Apple Watch, Apple Inc., Cupertino, CA) with additional ECGs recorded by the&#xD;
      participant if they experience symptoms of AF, or if the smartwatch alerts the participant of&#xD;
      a possible AF episode via its auto-detection AF monitoring algorithm. The Apple Watch's AF&#xD;
      algorithm is based on sampling of heart rate and variability and will give an audible alarm&#xD;
      if those parameters indicate a possible episode of AF. The smartwatch records a single-lead&#xD;
      ECG if the participant touches the watch with their contralateral hand. The day and time of&#xD;
      the episode is also stored by the smartwatch. At the end of the 28-day follow-up period,&#xD;
      study personnel will review the stored ECGs. Blood will be drawn prior to ablation and on&#xD;
      post-procedure Day 1 for measurement of IsoLG-adduct levels. DNA will be extracted to explore&#xD;
      a pharmacogenomic interaction with haplotypes at the chromosome 4q25 AF risk locus, which: 1)&#xD;
      is strongly associated with the development of AF and the early recurrence of AF after&#xD;
      ablation27; and 2) has been reported to be a regulator of an anti-oxidant gene program in&#xD;
      response to cardiac injury.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The proposed double-blind, randomized, placebo-controlled trial of 2-HOBA in patients&#xD;
      undergoing AF ablation is designed to address the following Specific Aims:&#xD;
&#xD;
      Specific Aim 1: To test the hypothesis that treatment with 2-HOBA reduces early recurrence of&#xD;
      AF (clinical endpoint)&#xD;
&#xD;
      Specific Aim 2: To test the hypothesis that treatment with 2-HOBA reduces circulating levels&#xD;
      of IsoLG-adducts (biochemical endpoint)&#xD;
&#xD;
      Specific Aim 3: To explore the idea that genetic variation at the 4q25 (PITX2) AF&#xD;
      susceptibility locus modulates the clinical and biochemical response to 2-HOBA&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">May 15, 2020</start_date>
  <completion_date type="Anticipated">May 14, 2024</completion_date>
  <primary_completion_date type="Anticipated">August 16, 2023</primary_completion_date>
  <phase>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>
    <intervention_model_description>This will be a double-blind, randomized study. Eligible subjects will be randomized according to a permuted block scheme with a block size of balancing interval, varying randomly according to the outcome of a computer-generated random number. This ensures that the cumulative number of assignments to each treatment (2-HOBA or placebo) will be in balance after each block of assignments had been made. A statistician will design the randomization table and enable the randomization tool within REDCap. After a patient enrolls for the study, the study nurse will determine the treatment assignment using the randomization tool in REDCap.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>The participant, care provider and investigator will all be blinded to the assigned treatment arm.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>2-HOBA reduces the rate of early recurrence of AF, atrial tachycardia, or atrial flutter following AF ablation within 28 days follow-up</measure>
    <time_frame>Post-ablation for 28 days</time_frame>
    <description>Participants will wear a smartwatch linked to an iPhone to continually record heart rate, variability and detection of arrhythmias.&#xD;
Participants will record a daily ECG each morning upon waking via the watch. In addition, participants will be notified by the smartwatch of 1) detection of atrial fibrillation or atrial flutter, 2) persistent high HR (&gt; 110 bpm) outside of exercise</description>
  </primary_outcome>
  <primary_outcome>
    <measure>A secondary analysis will analyze a surrogate of AF burden as the endpoint and designed to account for the impact of cardioversion on AF burden assessment</measure>
    <time_frame>Post-ablation for 28 days</time_frame>
    <description>A continuous heart rate monitor is provided by the smartwatch.which will be assessed by the AF burden and whether or not a cardioversion was performed.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>2-HOBA reduces the change in IsoLG-adduct levels that occurs with AF ablation.</measure>
    <time_frame>Pre-ablation and Post-procedure day #1</time_frame>
    <description>AF ablation results in a significant increase in circulating IsoLG-adduct levels.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>An interaction will exist between the 4q25 GRS and the treatment group for an association with the early recurrence of AF.</measure>
    <time_frame>Pre-ablation.</time_frame>
    <description>DNA will be extracted and genotyping will be performed on a GWAS chip that includes the 3 SNPs located at chromosome 5125 that are independently associated with AF risk.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">99</enrollment>
  <condition>Atrial Fibrillation</condition>
  <arm_group>
    <arm_group_label>2-HOBA</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>2-Hydroxybenzylamine(2-HOBA) 250 mg three tabs TID (po) for seven days prior to ablation and 28 days post ablation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo- three tabs TID (po) for seven days prior to ablation and 28 days post-ablation</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>2-Hydroxybenzylamine</intervention_name>
    <description>2-HOBA (2-Hydroxybenzlamine) 750mg will be given TID seven days prior to ablation and 28 days post ablation.</description>
    <arm_group_label>2-HOBA</arm_group_label>
    <other_name>2- HOBA</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo will be given TID for seven days prior to ablation and 28 days post ablation.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  First time AF ablation with radiofrequency or cryo ablation&#xD;
&#xD;
          -  Repeat AF ablation if the patient has persistent AF and ablation of non-pulmonary vein&#xD;
             substrate is planned (e.g. posterior wall ablation, mitral or roof line, etc)&#xD;
&#xD;
          -  Able to provide written, informed consent&#xD;
&#xD;
          -  22 years of age or older&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Planned surgical or hybrid (surgical + catheter) ablation&#xD;
&#xD;
          -  Amiodarone within past 3 months&#xD;
&#xD;
          -  Use of oral steroids or colchicine&#xD;
&#xD;
          -  Pro-inflammatory, rheumatologic disorder (e.g. RA, SLE, IBD, psoriasis, ankylosing&#xD;
             spondylitis)&#xD;
&#xD;
          -  NYHA Class III/IV Heart Failure&#xD;
&#xD;
          -  LVEF &lt;35%&#xD;
&#xD;
          -  Active ischemia&#xD;
&#xD;
          -  Hypertrophic Cardiomyopathy&#xD;
&#xD;
          -  Cardiac or thoracic surgery within 6 months&#xD;
&#xD;
          -  Expected life span &lt; 1 year&#xD;
&#xD;
          -  Creatinine clearance &lt;30 ml/min&#xD;
&#xD;
          -  Prior or planned heart transplantation&#xD;
&#xD;
          -  Pregnant women&#xD;
&#xD;
          -  Aspirin allergy&#xD;
&#xD;
          -  Current use of MAO-I&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>22 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ben Shoemaker, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Vanderbilt University Medical</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>June 3, 2020</study_first_submitted>
  <study_first_submitted_qc>June 11, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>July 25, 2023</last_update_submitted>
  <last_update_submitted_qc>July 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>M. Benjamin Shoemaker</investigator_full_name>
    <investigator_title>Assoc Professor</investigator_title>
  </responsible_party>
  <keyword>Ablation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atrial Fibrillation</mesh_term>
    <mesh_term>Recurrence</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/NCT04433091
org study id: 192520
nct id: NCT04433091
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The proposed studies will test this hypothesis by randomizing patients with AF to 2-HOBA or
      placebo 7 days prior to AF ablation to allow 2-HOBA to reach steady-state levels. We
      hypothesize that tissue injury from AF ablation causes a large release of ROS that react with
      lipids to generate IsoLGs (Figure 2). In the absence of 2-HOBA, IsoLGs will react within
      seconds to form IsoLG-macromolecule adducts in atrial tissue, promoting early recurrence of
      AF. In the presence of 2-HOBA, IsoLGs will rapidly react to form IsoLG-macromolecule adducts
      in atrial tissue, promoting early recurrence of AF. In the presence of 2-HOBA, IsoLG will
      preferentially bind to and therefore be inactivated by 2-HOBA thereby sparing injury to the
      atrial tissue caused by oxidative stress and its contribution to early recurrence of AF.
      Early recurrence of AF will be measured by ECGs that are recorded once per day by a
      smartwatch (Apple Watch, Apple Inc., Cupertino, CA) with additional ECGs recorded by the
      participant if they experience symptoms of AF, or if the smartwatch alerts the participant of
      a possible AF episode via its auto-detection AF monitoring algorithm. The Apple Watch's AF
      algorithm is based on sampling of heart rate and variability and will give an audible alarm
      if those parameters indicate a possible episode of AF. The smartwatch records a single-lead
      ECG if the participant touches the watch with their contralateral hand. The day and time of
      the episode is also stored by the smartwatch. At the end of the 28-day follow-up period,
      study personnel will review the stored ECGs. Blood will be drawn prior to ablation and on
      post-procedure Day 1 for measurement of IsoLG-adduct levels. DNA will be extracted to explore
      a pharmacogenomic interaction with haplotypes at the chromosome 4q25 AF risk locus, which: 1)
      is strongly associated with the development of AF and the early recurrence of AF after
      ablation27; and 2) has been reported to be a regulator of an anti-oxidant gene program in
      response to cardiac injury.
The proposed double-blind, randomized, placebo-controlled trial of 2-HOBA in patients
      undergoing AF ablation is designed to address the following Specific Aims:

      Specific Aim 1: To test the hypothesis that treatment with 2-HOBA reduces early recurrence of
      AF (clinical endpoint)

      Specific Aim 2: To test the hypothesis that treatment with 2-HOBA reduces circulating levels
      of IsoLG-adducts (biochemical endpoint)

      Specific Aim 3: To explore the idea that genetic variation at the 4q25 (PITX2) AF
      susceptibility locus modulates the clinical and biochemical response to 2-HOBA
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This will be a double-blind, randomized study. Eligible subjects will be randomized according to a permuted block scheme with a block size of balancing interval, varying randomly according to the outcome of a computer-generated random number. This ensures that the cumulative number of assignments to each treatment (2-HOBA or placebo) will be in balance after each block of assignments had been made. A statistician will design the randomization table and enable the randomization tool within REDCap. After a patient enrolls for the study, the study nurse will determine the treatment assignment using the randomization tool in REDCap.
primary purpose: Prevention
masking: Triple (Participant, Care Provider, Investigator)
masking description: The participant, care provider and investigator will all be blinded to the assigned treatment arm.
measure: 2-HOBA reduces the rate of early recurrence of AF, atrial tachycardia, or atrial flutter following AF ablation within 28 days follow-up
time frame: Post-ablation for 28 days
description: Participants will wear a smartwatch linked to an iPhone to continually record heart rate, variability and detection of arrhythmias.
Participants will record a daily ECG each morning upon waking via the watch. In addition, participants will be notified by the smartwatch of 1) detection of atrial fibrillation or atrial flutter, 2) persistent high HR (> 110 bpm) outside of exercise
measure: A secondary analysis will analyze a surrogate of AF burden as the endpoint and designed to account for the impact of cardioversion on AF burden assessment
time frame: Post-ablation for 28 days
description: A continuous heart rate monitor is provided by the smartwatch.which will be assessed by the AF burden and whether or not a cardioversion was performed.
measure: 2-HOBA reduces the change in IsoLG-adduct levels that occurs with AF ablation.
time frame: Pre-ablation and Post-procedure day #1
description: AF ablation results in a significant increase in circulating IsoLG-adduct levels.
measure: An interaction will exist between the 4q25 GRS and the treatment group for an association with the early recurrence of AF.
time frame: Pre-ablation.
description: DNA will be extracted and genotyping will be performed on a GWAS chip that includes the 3 SNPs located at chromosome 5125 that are independently associated with AF risk.
arm group label: 2-HOBA
arm group type: Active Comparator
description: 2-Hydroxybenzylamine(2-HOBA) 250 mg three tabs TID (po) for seven days prior to ablation and 28 days post ablation.
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo- three tabs TID (po) for seven days prior to ablation and 28 days post-ablation
intervention type: Drug
intervention name: 2-Hydroxybenzylamine
description: 2-HOBA (2-Hydroxybenzlamine) 750mg will be given TID seven days prior to ablation and 28 days post ablation.
arm group label: 2-HOBA
other name: 2- HOBA
intervention type: Other
intervention name: Placebo
description: Placebo will be given TID for seven days prior to ablation and 28 days post ablation.
arm group label: Placebo
criteria: 
gender: All
minimum age: 22 Years
maximum age: N/A
healthy volunteers: No
last name: Ben Shoemaker, MD
role: Principal Investigator
affiliation: Vanderbilt University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: M. Benjamin Shoemaker
investigator title: Assoc Professor
mesh term: Atrial Fibrillation
mesh term: Recurrence