Targeting Hypervigilance and Autonomic Arousal: the Psycho-physiologic Model of Gastroesophageal Reflux Disease (GERD)

NCT04960566 | Enrolling By Invitation DMC

• 2 other identifiers: STU00214532R01DK092217
• Study Type: interventional
• Target: 250
• Locations: 1 country
• Sites: 2

Brief Summary

GERD affects roughly 20% of the U.S. population and the direct and indirect costs of GERD are substantial, totaling close to 50 billion dollars per year. Evidence supports that a large proportion of this cost and poor clinical outcomes in GERD are related to poor healthcare decisions by both the physician and the patient. The problem of inappropriate GERD management stems from three main issues. First, the disease is heterogeneous and requires treatment informed by a precision model. Second, the current paradigm largely ignores the important brain-gut interactions that drive symptoms and healthcare utilization. Third, there is a paucity of well-performed comparative effectiveness trials focused on assessing treatments beyond acid suppression. We will use physiomarkers defined during the previous funding cycle to phenotype the patients and use cognitive behavioral interventions to modulate hypervigilance to test the Psycho-Physiologic Model of GERD. Cognitive Behavioral Therapy (CBT) is able to improve hypervigilance and symptom specific autonomic arousal and thus, we will test our theory that CBT can improve outcomes in GERD by targeting these two important psychologic stressors. We will also continue our focus on the interplay of psychology and physiology by determining whether increased mucosal permeability is associated with reflux perception and whether this is modified by hypervigilance and autonomic disruption.

Conditions

Gastroesophageal Reflux

Outcome Measures

Primary Outcomes (11)

• GERD PROMIS

  25-item measure of GERD symptom severity rated on Likert scale across 4 domains. Higher scores denote more GERD symptoms.

  Week 9

• GERD PROMIS

  25-item measure of GERD symptom severity rated on Likert scale across 4 domains. Higher scores denote more GERD symptoms.

  Week 25

• NEQOL

  14-item measure of HRQoL related to esophageal symptoms, rated on Likert scale. Higher scores denote greater negative impacts on HRQoL.

  Week 9

• NEQOL

  14-item measure of HRQoL related to esophageal symptoms, rated on Likert scale. Higher scores denote greater negative impacts on HRQoL.

  Week 25

• EHAS

  15-item measure of esophageal hypervigilance and symptom specific anxiety rated on Likert scale. Higher scores indicate more hypervigilance and anxiety.

  Week 9

• EHAS

  15-item measure of esophageal hypervigilance and symptom specific anxiety rated on Likert scale. Higher scores indicate more hypervigilance and anxiety.

  Week 25

• Variation in Heart Rate Variability (HRV)

  HRV will be measured using the time domains RMSSD and pNN50 calculated at each time point, as well as daily averages throughout treatment period.

  from the date of randomization through the treatment period, up to 9 weeks

• Heart Rate Variability (HRV)

  HRV will be measured using the time domains RMSSD and pNN50 calculated at each time point, as well as daily averages throughout treatment period.

  Week 9

• Heart Rate Variability (HRV)

  HRV will be measured using the time domains RMSSD and pNN50 calculated at each time point, as well as daily averages throughout treatment period.

  Week 25

• Esophageal Permeability

  Permeability will be measured utilizing Mucosal Impedance (MI) measurement. Higher MI value indicates lower permeability

  Week 9

• Symptom Index

  Symptom index is defined as the number of symptoms associated with reflux divided by the total number of symptoms as determined by pH-Impedance

  Week 9

Secondary Outcomes (2)

• Client Satisfaction Questionnaire - 8

  Week 9

• Sessions completed

  Week 9

Study Arms (2)

eCBT+

EXPERIMENTAL

eCBT+ participants will be enrolled in 6, 45-minute sessions delivered via a secure video platform with a GI psychologist. To reinforce concepts reviewed in the sessions, participants will complete weekly home practice exercises. The targets are 1) improved maladaptive cognitive-affective processes associated with increased hypervigilance and symptom anxiety, 2) reduced behaviors associated with EHA including avoidance, increased medication/healthcare utilization and 3) reduced autonomic nervous system (ANS) arousal by increased HRV. Participants will learn to identify, question, and modify maladaptive thoughts, beliefs, and assumptions related to their symptoms (symptom anxiety). Systematic exposure to feared events are used to reduce maladaptive coping strategies (hypervigilance, PPI overuse, HCU). Specific, paced diaphragmatic breathing exercises (Resonance Frequency Breathing) designed to increase HRV are the last component (visceral hypersensitivity, reflux physiology).

Other: Cognitive Behavioral Therapy

Sham-SOC Lifestyle Coaching

SHAM COMPARATOR

Patients randomized to the SOC condition will receive lifestyle guidance recommended for patients with GERD over a period of 6, 45-minute sessions with the GI psychologist to maintain consistency of delivery between the two intervention arms. Topics include maintaining a healthy weight, identifying triggering food and drink, making healthy food choices, eating behaviors, smoking and/or alcohol use, and timing of meals. The SOC condition will be carefully designed to not include any principles of the eCBT+ condition rather be based solely on patient education and encouragement to practice lifestyle changes on their own.

Other: Sham-SOC Lifestyle Coaching

Interventions

Cognitive Behavioral Therapy OTHER

The CBT intervention is based on the theoretical framework that under stress (reflux symptoms) a person makes a rapid cognitive appraisal of the potential threat (automatic thoughts), leading to both emotional and physical responses in the body, thereby reacting behaviorally (avoidance, increased HCU) in an attempt to mitigate unpleasantness. CBT is a collaborative, present-focused treatment that utilizes a skills-based approach with home practice exercises. CBT targets automatic thoughts and appraisals of threat via education, self-monitoring of stressors and symptoms, and strategies to reframe problematic thinking patterns to more adaptive ones. Resonance frequency breathing (RFB) is achieved when a person breathes at a pace, typically 4 to 6 breaths per minute, that engages the body's baroreflex to modulate arousal. Prior research demonstrates 4 to 6 weeks of RFB training is sufficient to significantly increase baseline HRV with enduring effects for up to 6 months.

eCBT+

Sham-SOC Lifestyle Coaching OTHER

Sham-SOC Lifestyle Coaching

Sham-SOC Lifestyle Coaching

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female subjects (females of childbearing potential should be on highly effective contraceptive methods)
• Aged 18-80 years old
• Mentally capable to provide informed consent
• Fluent in English
• Have symptoms of GERD (heartburn, regurgitation, and non-cardiac chest pain)
• Have failed an appropriate compliant trial of PPI therapy with a GERDQ score ≥6.
• Able to undergo endoscopy, ambulatory reflux monitoring, and manometry
• Be interested in behavioral interventions for ongoing symptoms.

You may not qualify if:

• Participation in a concurrent clinical trial or completed another trial within past 8 weeks.
• Active severe erosive esophagitis (Los Angeles Grade C or D), Long segment Barrett's esophagus (Zap score of 4)
• Prior gastrointestinal surgery of the esophagus and/or stomach
• Current signs or symptoms of heart disease. All patients with non-cardiac chest pain are required to have a cardiologist evaluation as standard of care work up in the evaluation of non-cardiac chest pain.
• Unstable medical illness with ongoing diagnostic work-up and treatment. Patients with well-controlled hypertension, diabetes and a remote history of ischemic heart disease that is deemed stable, as judged by the investigator can be included.
• History of drug addiction, drug abuse or alcoholism.
• Current neurologic or cognitive impairment, which would preclude ability to obtain informed consent.
• Pregnant patients.
• Special vulnerable populations including children, prisoners, institutionalized individuals.
• Bleeding disorder or requirement of NSAID/aspirin during monitoring period.
• Drugs that affect gastrointestinal symptoms (H2 blockers, antacids, metoclopramide, domperidone, erythromycin, anticholinergics \[bentyl, levsin, belladonna etc.\]). Antidepressants can be continued at stable dose.
• Patients found to have achalasia, a spastic disorder, hypercontractile disorder or functional obstruction at the esophagogastric junction will be excluded

Sponsors & Collaborators

• Northwestern University: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator
• Washington University School of Medicine: collaborator
• University of California, San Diego: collaborator
• Vanderbilt University School of Medicine: collaborator

Study Sites (2)

Northwestern University

Chicago, Illinois, 60611, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

MeSH Terms

Conditions

Gastroesophageal Reflux

Interventions

Cognitive Behavioral Therapy

Condition Hierarchy (Ancestors)

Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Gastrointestinal Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Behavior Therapy; Psychotherapy; Behavioral Disciplines and Activities

Study Officials

• John E Pandolfino, MD

  Northwestern University

  PRINCIPAL INVESTIGATOR

• Tifffany Taft, PsyD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Hans Popper Professor of Medicine and Chief

Study Record Dates

• First Submitted: February 17, 2021
• First Posted: July 14, 2021
• Study Start: April 19, 2022
• Primary Completion (Estimated): May 31, 2026
• Study Completion (Estimated): November 30, 2026
• Last Updated: August 11, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)