The Effect of Autonomic Modulation on Symptoms in Patients With Reflux Hypersensitivity

A Randomized Single Blinded Parallel Study to Investigate the Physiological Modulation of the Autonomic Nervous System on Symptoms in Patients With Reflux Hypersensitivity

Reflux hypersensitivity is the disease that causes chest pain, heartburn and regurgitation and can impair patients' quality of life. Pain modulators are often used for the treatment of reflux hypersensitivity, but the effect is not enough and more effective therapy is needed.

Slow deep breathing is the validated method to modulate the autonomic nervous system. In our previous study, slow deep breathing could increase the threshold of oesophageal pain in healthy volunteers. Therefore, slow deep breathing has the potential to be an effective treatment for reflux hypersensitivity and further study is warranted in the patient group.

The aims of this study are (1) to evaluate the feasibility of slow deep breathing and (2) to investigate the effect of autonomic nerve modulation by slow deep breathing on symptoms in patients with reflux hypersensitivity.

Study Overview

• Status: Completed
• Conditions: Gastro Esophageal Reflux
• Intervention / Treatment: Behavioral: slow deep breathing; Behavioral: sham breathing

Detailed Description

This is a randomized single-blinded parallel study and the investigators aim to recruit 40 participants.

Patients will be enrolled for a period of 4 weeks and don't have to attend our institution. A video chat on day 1 will consist of confirming eligibility, after which the patient will be randomised to follow either the slow deep breathing protocol or the sham breathing protocol in a single blinded fashion. That is, the patient will be unaware of which the active breathing exercise is. Once randomised during a video chat, they will undergo baseline heart rate variability (HRV) measurements using a smartphone app, answer the questionnaires on Research Electronic Data Capture (REDCap), and then practice the relevant breathing exercise with an instruction video. The patient will then be trained to self-administer the breathing exercise during a video chat, which will be used twice a day for 10 minutes over the next 4 weeks with a standardized instruction video.

This study finishes when participants answer the online questionnaire and record HRV on day 29.

The investigators will set up this questionnaire on our electronic data capture system (Research Electronic Data Capture: REDCap). Participants will answer questionnaires using this online system on day 1, day 8, day15, day 22, and day 29 (end of the study).

Therefore, participants will also be trained on how to use REDCap and answer questionnaires under supervision on day 1 during a video chat. Questionnaires on day 8, 15, 22, and 29 will be answered at home. The investigators will send a reminder message to participants using a REDCap system the day before they answer the questionnaire.

Participants will be asked to record their HRV using a smartphone app on day 1, 8, 15, 22, and 29.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, E1 2AJ
    • Queen Mary University of London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female patients over the age of 18 years.
• Women in the follicular phase of the menstrual cycle (visits will be arranged so that in menstruating women, the study will be started in the follicular phase of the menstrual cycle to standardise for possible confounding effects of the menstrual cycle on symptom perception).
• Able to give informed consent
• Able to speak and understand English without the need for an interpreter
• No evidence of erosive esophagitis by OGD
• Presence of chest pain, heartburn, and/or regurgitation ≥ 3 days/week
• Normal acid exposure on MII-pH
• Positive symptom reflux association on MII-pH (symptom index ≥ 50% and symptom association probability ≥ 95%)
• OGD is performed within 2 years before the enrolment
• MII-pH study is performed within 2 year before the enrolment

Exclusion Criteria:

• Current or previous GI or medical illnesses that may affect ANS / GI function
• Current or previous significant CNS illness
• Current medications affecting the CNS, GI or ANS systems
• Pregnancy and lactation
• Cardiac dysrhythmias

• Those who do not have access to the internet-based questionnaire

  • The use of acid suppression therapies (e.g. proton pump inhibitor or H2 blocker) or pain modulators (e.g. low-dose Tricyclic Antidepressants, TCAs or Selective Serotonin Reuptake Inhibitors, SSRI) does not change the decision of participation as long as above-mentioned symptoms remain.

Patients are asked to refrain from smoking for 12 hours and drinking alcohol as well as using recreational drugs for 48 hours prior to study visit.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: slow deep breathing; Patients are instructed to do deep breathing at full inspiratory capacity for 4 seconds followed by forced expiration in 6 seconds (forced vital capacity) for 10 minutes.	Behavioral: slow deep breathing; Participants in this arm will be asked to do slow deep breathing (4 seconds inhalation and 6 seconds exhalation) for 10 minutes twice a day during the study period.
SHAM_COMPARATOR: sham breathing; Patients are instructed to count 10 breaths and tick a box every time they count ten breaths. The counting distracts the patient reducing the effect of focussing of breathing on their autonomic nervous system.	Behavioral: sham breathing; Participants in this arm will be asked to do sham breathing for 10 minutes twice a day during the study period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The feasibility of 10 minutes twice a day for 4 weeks of slow deep breathing	Compliance and acceptability are evaluated by the Global or general acceptability of treatment questionnaire. This is recorded as 'very good', 'good', 'fair', or 'poor'.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The effect of slow deep breathing on anxiety	State and Trait Anxiety Inventory state (Maximun and minimum values are 80 and 20, respectively. The higher value indicates more nervous status.) and State and Trait Anxiety Inventory trait (Maximun and minimum values are 80 and 20, respectively. The higher value indicates more nervous trait) are used.	4 weeks
The effect of slow deep breathing on personality states.	Big five inventory questionnaire (44 items) is used. This is a self-report inventory designed to measure the personality type.	4 weeks
The effect of slow deep breathing on depression.	Hospital Anxiety and Depression Scale is used. The maximun and minimum values are 21 and 0, respectively (0-7 = Normal, 8-10 = Borderline,11-21 = Abnormal).	4 weeks
Changes in vagal nerve activity before and after slow deep breathing protocol	Cardiac vagal tone, which is an indicator of vagal nerve activity and caluculated from R-R interval of electrocardiogram, is used for the evaluation.	4 weeks
Changes in symptoms before and after slow deep breathing	Reflux symptom questionnaire, 7 day recall is used for the evaluation. This can categorize the symptom into 'did not have', 'very mild', 'mild', 'moderate', 'moderately severe', or 'severe'.	4 weeks

Collaborators and Investigators

• Sponsor: Queen Mary University of London

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 16, 2020
• Primary Completion (ACTUAL): October 31, 2022
• Study Completion (ACTUAL): October 31, 2022

Study Registration Dates

• First Submitted: January 27, 2020
• First Submitted That Met QC Criteria: January 30, 2020
• First Posted (ACTUAL): February 5, 2020

Study Record Updates

• Last Update Posted (ESTIMATE): February 14, 2023
• Last Update Submitted That Met QC Criteria: February 13, 2023
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: reflux hypersensitivity; vagal nerve stimulation; slow deep breathing
• Additional Relevant MeSH Terms: Digestive System Diseases; Immune System Diseases; Gastrointestinal Diseases; Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Hypersensitivity; Gastroesophageal Reflux
• Other Study ID Numbers: 278533

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No