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

OVERVIEW: In this randomized, sham-controlled phase II/III adaptive trial, we will randomize 250 subjects with symptoms of GERD to eCBT+ (esophageal Cognitive Behavioral Therapy) or sham-SOC (Standard of Care) Lifestyle Coaching. Each subject will receive 6 sessions of 45 minutes each delivered by telehealth. The study will be conducted at two institutions: Northwestern University and Washington University. The interventions will be delivered by GI Health psychologists based at Northwestern University.

RANDOMIZATION AND BLINDING: Participants will be blinded as to the intervention they will receive. Participants will be randomized in the following manner: In Aim 1, we will block on site (NU or WashU) and randomize patients to eCBT+ or SOC within sites. In Aim 2, we will block on site and whether patients have hypersensitivity. Patients within site and hypersensitivity category (no vs. yes) will be randomized. Note that in randomizing in this way, patients for Aim 3 who exhibit hypersensitivity will also be randomized within site. We will allocate participants to one of 2 study arms in a blinded fashion: eCBT+ (esophageal Cognitive Behavioral Therapy) or sham-SOC Lifestyle Coaching. Subjects will be de-briefed at their week 25 visit.

STUDY PROCEDURES: Study procedures include mucosal impedance (MI) performed during standard of care endoscopy, the use of questionnaires: GERD PROMIS (a measure of symptoms), EHAS (Esophageal Hypervigilance and Anxiety Scale), NEQOL (Northwestern Esophageal Quality of Life), GERDQ (a measure of symptom frequency), and patient satisfaction, as well as measurement of heart rate variability both at the research site and via continuous FitBit usage throughout the treatment period. For Aim 3, repeat endoscopy, mucosal impedance, and pH impedance will be performed on a subset of patients 8 weeks after conclusion of intervention.

ENDPOINTS: Primary endpoints include change in symptoms and quality of life as measured by GERDQ, GERD PROMIS and NEQOL questionnaires, change in hypervigilance and symptom-specific anxiety as measured by EHAS and change in autonomic arousal as measured by HRV before and after treatment with either intervention arm. Secondary endpoints include change in mucosal impedance measurements and symptom index (as determined by pH-Impedance monitoring) before and after treatment, as well as patient satisfaction with treatment and engagement with treatment as defined by the number of sessions completed.

RATIONALE: We selected a parallel design study to explore the treatment effect of eCBT+ compared to a sham-SOC Lifestyle Coaching approach. Power and sample size considerations were based on the primary aim of comparing questionnaire results and HRV measurements in the proposed two-arm clinical trial.

Inclusion criteria

• 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.

Exclusion criteria

• 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