Clinical trial NCT04960566: Targeting Hypervigilance and Autonomic Arousal: the Psycho-physiologic Model of Gastroesophageal Reflux Disease (GERD)
Official title: Targeting Hypervigilance and Autonomic Arousal: the Psycho-physiologic Model of GERD
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: NA
Conditions: Gastroesophageal Reflux
Lead sponsor: Northwestern University
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Washington University School of Medicine
name: University of California, San Diego
name: Vanderbilt University School of Medicine
First posted: 2021-07-14
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: GERD PROMIS
timeFrame: Week 9
measure: GERD PROMIS
timeFrame: Week 25
measure: NEQOL
timeFrame: Week 9
measure: NEQOL
timeFrame: Week 25
measure: EHAS
timeFrame: Week 9
measure: EHAS
timeFrame: Week 25
measure: Variation in Heart Rate Variability (HRV)
timeFrame: from the date of randomization through the treatment period, up to 9 weeks
measure: Heart Rate Variability (HRV)
timeFrame: Week 9
measure: Heart Rate Variability (HRV)
timeFrame: Week 25
measure: Esophageal Permeability
timeFrame: Week 9
measure: Symptom Index
timeFrame: Week 9
Secondary outcomes:
measure: Client Satisfaction Questionnaire - 8
timeFrame: Week 9
measure: Sessions completed
timeFrame: Week 9
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: St. Louis
country: United States
facility: Washington University
state: Missouri
Study officials:
affiliation: Northwestern University
name: John E Pandolfino, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Northwestern University
name: Tifffany Taft, PsyD
role: PRINCIPAL_INVESTIGATOR
References: