Neuroregulators for the Treatment of Diseases Associated With Esophageal-brain-gut Axis Communication Abnormalities.

Official title

Esophageal Visceral Hypersensitivity and Hypervigilance in Disorders of Gut-brain Interaction: the Roles of Neuromodulators

Overview

Gastroesophageal reflux disease (GERD) poses a challenging medical condition to manage, with up to 40% of patients showing refractory to standard medical intervention, which usually begins with a proton pump inhibitor (PPI). Among these cases, esophageal disorders of gut-brain interaction (DGBI), such as reflux hypersensitivity and functional heartburn, or GERD patients with concurrent occurrences of these conditions, constitute more than 90% of the patients who did not respond to twice-daily PPI treatment. Esophageal visceral hypersensitivity and hypervigilance are the two pathways that drive esophageal DGBI and symptoms. The Rome IV esophageal disorders, encompassing functional chest pain, functional heartburn, globus, functional dysphagia, and reflux hypersensitivity, are defined by present with symptoms originating from the esophagus without detectable evidence of structural, inflammatory, or motor disorders. Diagnosing esophageal DGBI necessitates testing involving endoscopy, pH-impedance monitoring, and high-resolution manometry. Neuromodulators form the basis of the pharmacological strategy for managing various esophageal DGBI and symptoms, modulating both peripheral and central hyperalgesia. Increasing evidence supports the use of brain-gut behavioral therapies, such as gut-directed hypnotherapy and cognitive behavior therapy, as effective treatments for a variety of DGBIs. However, the efficacy of neuromodulators in treating esophageal DGBI and related symptoms remains largely unexplored. The primary objective of this study is to examine the efficacy of neuromodulators in managing esophageal DGBI. Additionally, investigators will explore various classes of neuromodulators and subtypes of esophageal DGBI to ascertain whether there are differing levels of effectiveness across these conditions. The findings from this study will contribute to a better understanding of the pathophysiology of esophageal DGBI and GERD with refractory symptoms. These clinical insights may then offer valuable guidance for future therapeutic approaches in DGBI patients who experience esophageal symptoms and do not respond to PPI treatment.

Detailed description

Procedure steps： n Study One, each participant first completed a questionnaire that included the Gastroesophageal Reflux Disease Questionnaire (GERDQ, PROMIS GERD, DSI \& GSS, RSI), the Brief Esophageal Swallowing Difficulty Scale (BEDQ), the Esophageal Hypersensitivity and Anxiety Scale (EHAS), the Visceral Sensitivity Index (VSI), and the Sleep and Psychosocial Questionnaire (Pittsburgh Sleep Quality Index (PSQI), Taiwanese Depression Questionnaire (TDQ), State-Trait Anxiety Inventory (STAI), Functional Dyspepsia (FD) Questionnaire, Irritable Bowel Syndrome (IBS) Questionnaire, and the Quality of Life Questionnaire (SF-12, Northwest Esophageal Quality of Life Scale (NEQOL)). Completing the questionnaires took approximately 20 to 30 minutes.

Afterward, participants were randomly assigned by computer to receive either 12 weeks of treatment with a neuromodulator-tricyclic antidepressants (TCA), or a neuromodulator-selective serotonin reuptake inhibitors (SSRI), or 12 weeks of the control medication-proton pump inhibitors (PPI). Investigators plan to recruit 70 participants for the TCA group, 70 for the SSRI group, and 70 for the PPI group, with each participant having about a 1/3 chance of being assigned to one of these groups.

The tricyclic antidepressant (TCA) will be administered as 25 mg enteric-coated tablets (Department of Health Drug Code 047966), taken twice daily. The selective serotonin reuptake inhibitor (SSRI) will be administered as 50 mg enteric-coated tablets (Department of Health Drug Code 021780), taken once daily. The control medication, the proton pump inhibitor (PPI), will be given as 30 mg orally dissolving tablets (Department of Health Drug Code 024273), taken once daily.

At the end of the 12-week medication treatment, participants will complete another round of questionnaires to conclude the study.

Interventions

• Drug Takepron
  Participants are expected to take a proton-pump inhibitor (PPI) for 12 weeks, with a dosage of 30 mg taken once a day.
• Drug Zoloft 50Mg Tablet
  Participants are expected to take a selective serotonin reuptake inhibitor (SSRI) for 12 weeks, with a dosage of 50 mg taken once a day.
• Drug Imipramine Pill
  Participants are expected to take tricyclic antidepressants (TCA) for 12 weeks, with a dosage of 25 mg taken twice a day.

Primary outcome measures

• Gastroesophageal Reflux Disease Questionnaire（GERDQ） [Time frame: Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.]
• PROMIS Gastroesophageal Reflux Disease Questionnaire（PROMIS GERD） [Time frame: Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.]
• Disease symptom index(DSI) [Time frame: Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.]
• Reflux Symptom Index(RSI) [Time frame: Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.]
• The Brief Esophageal Dysphagia Questionnaire(BEDQ) [Time frame: Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.]
• Esophageal Hypervigilance and Anxiety Scale(EHAS) [Time frame: Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.]
• Visceral sensitivity index(VSI) [Time frame: Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.]
• Pittsburgh Sleep Quality Index(PSQI) [Time frame: Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.]
• Taiwanese Depression Questionnaire(TDQ) [Time frame: Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.]
• The State-Trait Anxiety Inventory(STAI) [Time frame: Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.]

Eligibility criteria

Inclusion criteria

• Age between 18 and 75 years, with clear consciousness and willingness to sign the informed consent form.
• Subjects with chronic esophageal symptoms related to disorders of the brain-gut axis communication (such as heartburn, acid reflux, sensation of a foreign body in the throat, difficulty swallowing, and chest pain or discomfort).

Exclusion criteria

• Esophageal strictures, or history of surgery on the esophagus, gastrointestinal tract, or throat.
• Structural esophageal diseases (such as diverticula, esophageal rings, etc.), infectious esophagitis, erosive esophagitis, eosinophilic esophagitis.
• Non-erosive gastroesophageal reflux disease or significant esophageal motility disorders.
• History of or current diagnosis of malignancies in the esophagus, gastrointestinal tract, or other organs.
• Significant endocrine or rheumatic immune diseases that may affect gastrointestinal motility.
• Continuous use of medications that may affect esophageal motility within the past month (such as anticholinergics, opioid-like agents, nitrates, calcium channel blockers, etc.).
• Use of or currently taking antidepressants, selective serotonin reuptake inhibitors, or other psychotropic medications within the past three months.
• Pregnant or breastfeeding women.
• Individuals with mental illness or those who are unable to cooperate.
• Known allergy to tricyclic antidepressants.
• Known allergy to selective serotonin reuptake inhibitors.
• Known allergy to any component of proton pump inhibitors.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Taiwan · 1 center

• Hualien Tzu Chi Hospital,Buddhist Tzu Chi Medical Foundation — Hualien City

Identifiers

NCT: NCT06778824 · IRB112-201-A

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗