2-Hydroxybenzylamine (2-HOBA) to Prevent Early Recurrence of Atrial Fibrillation After Catheter-based Ablation

• ClinicalTrials.gov Identifier: NCT04433091
• Recruitment Status: Active, not recruiting
• First Posted: June 16, 2020
• Last Update Posted: June 2, 2022
• Sponsor: Vanderbilt University Medical Center
• Collaborator: American Heart Association
• Information provided by (Responsible Party): Gregory Michaud, Vanderbilt University Medical Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Atrial Fibrillation	Drug: 2-Hydroxybenzylamine; Other: Placebo	Phase 2

Detailed Description:

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 99 participants
• 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.
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: The participant, care provider and investigator will all be blinded to the assigned treatment arm.
• Primary Purpose: Prevention
• Official Title: 2-Hydroxybenzylamine (2-HOBA) to Prevent Early Recurrence of Atrial Fibrillation After Catheter- Based Ablation
• Actual Study Start Date: May 15, 2020
• Estimated Primary Completion Date: May 15, 2024
• Estimated Study Completion Date: May 15, 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: 2-HOBA; 2-Hydroxybenzylamine(2-HOBA) 250 mg three tabs TID (po) for seven days prior to ablation and 28 days post ablation.	Drug: 2-Hydroxybenzylamine; 2-HOBA (2-Hydroxybenzlamine) 750mg will be given TID seven days prior to ablation and 28 days post ablation.; Other Name: 2- HOBA
Placebo Comparator: Placebo; Placebo- three tabs TID (po) for seven days prior to ablation and 28 days post-ablation	Other: Placebo; Placebo will be given TID for seven days prior to ablation and 28 days post ablation.

Outcome Measures

Primary Outcome Measures :

1. 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 ]

   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

2. 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 ]
   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.

Secondary Outcome Measures :

1. 2-HOBA reduces the change in IsoLG-adduct levels that occurs with AF ablation. [ Time Frame: Pre-ablation and Post-procedure day #1 ]
   AF ablation results in a significant increase in circulating IsoLG-adduct levels.

Other Outcome Measures:

1. 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. ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 22 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• First time AF ablation with radiofrequency or cryo ablation
• Repeat AF ablation if the patient has persistent AF and ablation of non-pulmonary vein substrate is planned (e.g. posterior wall ablation, mitral or roof line, etc)
• Able to provide written, informed consent
• 22 years of age or older

Exclusion Criteria:

• Planned surgical or hybrid (surgical + catheter) ablation
• Amiodarone within past 3 months
• Use of oral steroids or colchicine
• Pro-inflammatory, rheumatologic disorder (e.g. RA, SLE, IBD, psoriasis, ankylosing spondylitis)
• NYHA Class III/IV Heart Failure
• LVEF <35%
• Active ischemia
• Hypertrophic Cardiomyopathy
• Cardiac or thoracic surgery within 6 months
• Expected life span < 1 year
• Creatinine clearance <30 ml/min
• Prior or planned heart transplantation
• Pregnant women
• Aspirin allergy
• Current use of MAO-I

Contacts and Locations

Locations

United States, Tennessee

Vanderbilt University Medical

Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

Vanderbilt University Medical Center

American Heart Association

Investigators

• Principal Investigator: Greg Michaud, MD; Vanderbilt University

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

O'Neill MJ, Yoneda ZT, Crawford DM, Ye F, Ao M, Pitchford LM, Rathmacher JA, Murray KT, Akers WS, Roden DM, Michaud GF, Shoemaker MB. 2-Hydroxybenzylamine (2-HOBA) to prevent early recurrence of atrial fibrillation after catheter ablation: protocol for a randomized controlled trial including detection of AF using a wearable device. Trials. 2021 Aug 28;22(1):576. doi: 10.1186/s13063-021-05553-6.

• Responsible Party: Gregory Michaud, Chief of Arrhythmia Service, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT04433091
• Other Study ID Numbers: 192520
• First Posted: June 16, 2020
• Last Update Posted: June 2, 2022
• Last Verified: June 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Gregory Michaud, Vanderbilt University Medical Center:

Ablation

Additional relevant MeSH terms:

Atrial Fibrillation; Recurrence; Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Disease Attributes