Transcutaneous Electrical Acustimulation (TEA) for the Treatment of Non-Erosive Gastroesophageal Reflux Disease (NERD)

Study Design

This is a prospective, multicenter, randomized, double-blind, sham-controlled, parallel-group clinical trial conducted at multiple centers in China. A total of 204 eligible participants with non-erosive gastroesophageal reflux disease (NERD) will be enrolled and randomly assigned in a 1:1 ratio to receive either active transcutaneous electrical acustimulation (TEA) or sham stimulation for 4 weeks. Randomization will be performed centrally using a computer-generated permuted block design (fixed block size of 4), stratified by study site. Due to differences in stimulation location, treatment administrators will be aware of group assignment; however, participants, outcome assessors, and data analysts will remain blinded to treatment allocation. Group labels (Group A / Group B) will be used in the electronic case report form (eCRF) to maintain blinding.

Study Population

Participants will be recruited from gastroenterology clinics. Eligible participants must meet all of the following criteria: age 18-75 years; typical heartburn symptoms for ≥3 months; heartburn on ≥2 days during the run-in diary period; endoscopically confirmed NERD (no esophageal erosions, Los Angeles grade N/M) within 12 months; and willingness to discontinue acid-suppressive therapy during the study. Key exclusion criteria include familiarity with acupuncture points, presence of esophageal structural or mucosal diseases (e.g., Barrett's esophagus, erosive esophagitis LA grade A-D), gastric or duodenal ulcers, functional heartburn or dyspepsia by Rome IV criteria, uncontrolled systemic diseases, implanted electronic devices (e.g., pacemaker), pregnancy, and participation in other interventional trials within the past 3 months.

All enrolled participants will be categorized based on heartburn frequency during the baseline run-in period (electronic diary) into two subgroups: Subgroup A (heartburn ≥4 days/week) and Subgroup B (heartburn 2-3 days/week). This stratification will be used for prespecified subgroup analyses to explore potential differences in treatment effects across symptom frequency populations.

Intervention and Study Procedures

The total study duration is 10 weeks, consisting of a washout period (Week -2 to Week -1), a baseline run-in period (Week -1 to Week 0), a treatment period (Week 0 to Week 4), and a follow-up period (Week 4 to Week 8).

Active TEA Group: Electrical stimulation will be applied unilaterally at the ST36 (Zusanli) acupoint, located on the anterolateral aspect of the leg, about one finger breadth lateral to the anterior crest of the tibia and just below the tibial tuberosity. One electrode will be placed at ST36 and the other 3-5 cm vertically down from ST36. Stimulation parameters are: 25 Hz pulse frequency, 0.5 ms pulse width, 2 seconds on and 3 seconds off. Current amplitude will range from 1 to 9.5 mA and will be gradually adjusted to the maximum level tolerated by the participant. Participants will self-administer TEA for 1 hour twice daily (morning and evening, within a flexible time window from 6:00 AM to 9:00 PM) for 4 consecutive weeks.

Sham TEA Group: Electrodes will be placed unilaterally at the olecranon and 3-5 cm vertically down from the olecranon, an area not associated with known acupoints for gastrointestinal regulation. The same stimulation device and parameters (including visual and auditory signals) will be used, but the electrical output will not exceed the sensory threshold, providing an identical user experience without active therapeutic stimulation.

Assessments and Outcome Measures

Participants will complete daily electronic symptom diaries from Week -1 through Week 4 and at Week 8. Heartburn severity is assessed using a 0-3 scale (0=none; 1=mild, noticed but does not affect activities; 2=moderate, interferes with daily activities; 3=severe, significantly affects daily life or sleep). A heartburn-free day is defined as a day with a heartburn score of 0 and no use of rescue antacids.

Clinic visits will occur at Week 0 (baseline), Week 4 (end of treatment), and Week 4 (end of treatment). At each visit, participants will complete the Gastroesophageal Reflux Disease Questionnaire (GERD-Q) and the GERD-Health Related Quality of Life (GERD-HRQL) questionnaire. The Patient Global Impression of Change (PGI-C) will be assessed at Week 4. Patient Global Impression of Severity (PGI-S) will be assessed at Week 0, Week 4, and Week 8. Rescue medication use will be recorded from Week 0 to Week 4. Treatment acceptability and persistence of efficacy after TEA discontinuation will be evaluated at Week 8. Safety assessments, including adverse event monitoring, will be conducted throughout the study from Week 0 to Week 8.

Sample Size

The primary endpoint is the proportion of 24-hour heartburn-free days during the 4-week treatment period. Based on prior randomized GERD trials and published TEA studies, the expected proportion of heartburn-free days is estimated at 45% in the TEA group and 25% in the sham group (absolute difference 20%). With a two-sided alpha of 0.05 and 80% power, 86 participants per group are required. Allowing for an anticipated dropout rate of approximately 15%, 102 participants per group will be enrolled, for a total sample size of 204 participants.

Statistical Analysis

Primary analyses will follow the intention-to-treat (ITT) principle, including all randomized participants who received at least one treatment session and provided at least one post-baseline assessment. Per-protocol (PP) analysis will be conducted as a sensitivity analysis. The primary outcome (proportion of heartburn-free days) will be compared between groups using the chi-square test, and further analyzed using logistic regression models adjusting for study site and baseline symptom measures. Secondary continuous outcomes measured repeatedly over time will be analyzed using mixed-effects models. In the ITT analysis, missing primary outcome data will be handled using conservative non-responder imputation (missing diary days considered as non-heartburn-free days). All statistical tests will be two-sided with a significance level of 0.05. Secondary outcome analyses will be interpreted as exploratory and will not be adjusted for multiple comparisons.

Prespecified subgroup analyses will be conducted based on baseline heartburn frequency (≥4 days/week vs. 2-3 days/week). An interaction term "group × heartburn frequency subgroup" will be included to test heterogeneity of treatment effect across subgroups (P_interaction < 0.10 considered significant). All subgroup analyses are exploratory and will not serve as evidence for primary conclusions.

Safety Monitoring

Adverse events (AEs) will be collected systematically throughout the treatment and follow-up periods. Expected AEs based on TEA intervention characteristics include local skin reactions (itching, redness, rash, tingling, burning sensation, mild swelling), electrical stimulation-related discomfort (intolerable tingling, involuntary muscle twitching, dizziness, nausea), and device-related issues. Severity will be graded as mild (no effect on daily activities), moderate (affects daily activities, may require intervention), or severe (significantly affects daily life or requires active medical intervention). Serious adverse events (SAEs) will be reported to the principal investigator within 24 hours and to the ethics committee in accordance with regulatory requirements.

Study Period

The total study duration is from April 1, 2026, to March 31, 2028. Patient recruitment and intervention will occur from April 1, 2026, to December 31, 2027. Data management and statistical analysis will be conducted from January 1, 2028, to January 31, 2028. Study report writing will be completed from February 1, 2028, to March 31, 2028.