Effects of the Transcutaneous Electrical Stimulation System on Heartburn, Regurgitation and Esophageal Acid Exposure in GERD Patients—An Uncontrolled Feasibility Study

ABSTRACT

Background

Proton pump inhibitors (PPI) for gastroesophageal reflux disease (GERD) are associated with a high failure rate. Our uncontrolled feasibility study aimed determining the effect of a transcutaneous electrical stimulation system (TESS) on GERD symptoms and acid exposure time (AET).

Methods

Recruited patients with heartburn and regurgitation. During the first phase (one‐week, run‐in period, off‐PPI's), patients completed symptom diaries and demographic questionnaires. Thereafter, all patients underwent gastroscopy with subsequent placement of a wireless esophageal pH capsule, off‐PPI. Based on pH analysis in the first 24 h, only those with increased AET (percent total time pH < 4 above 6%) continued to the next phase. During that phase, patients were treated for up to 3 weeks with TESS and documented their symptoms. The Primary endpoint was the magnitude of reduction in GERD‐related symptoms. The secondary endpoints were the magnitude of reduction of AET and DeMeester score, as compared with their baseline values.

Results

Included 31 patients and of those, 26 patients (42% females, aged 49 ± 15 years, mean BMI 25 ± 3 kg/m²) completed the first two phases of the study.

At baseline, mean number of daily heartburn and regurgitation episodes was 2.55 ± 1.79 and 1.40 ± 1.73, respectively. Following TESS, mean number of daily heartburn and regurgitation episodes dropped to 0.77 ± 0.75 and 0.36 ± 0.8, respectively (p < 0.001). At base line, mean AET and DeMeester score were 12.4 ± 5.6 and 32.1 ± 12.7, respectively. Following TESS mean AET dropped to 6.0 ± 3.5 and DeMeester score dropped to 16.2 ± 8.2 (p < 0.001).

Conclusions

TESS is effective in reducing both symptoms and esophageal AET in GERD patients.

Following TESS treatment, reported number of heartburn and regurgitation events in patients with GERD decreased by 68.3% and 78.5%, respectively. Esophageal AET and DeMeester score decreased by 74.5% (SD 31.9%) and 82.3% (SD 26.8%), respectively. TESS is a useful, safe device, effectively reduces both symptoms and AET in GERD patients.

Summary.

• Aims/goals: To determine the effect of transcutaneous electrical stimulation system on gastroesophageal reflux disease related symptoms and esophageal acid exposure time (AET) as primary outcomes.

• Basic methodology: A multi‐center study that included 31 patients with classic GERD‐related symptoms. Patients underwent wireless pH testing and were subsequently treated with TESS. AET and reports of symptoms' number were recorded during the study. Primary end points included a significant (at least 50%) reduction in mean reported number of heartburn and/or regurgitation events and in mean AET at the end of phase 2 compared to baseline.

• Brief results: Following TESS treatment, reported number of heartburn and regurgitation events decreased by 68.3% and 78.5%, respectively. Esophageal AET and DeMeester score decreased by 74.5% (SD 31.9%) and 82.3% (SD 26.8%), respectively. TESS appears to be a useful and safe device.

1. Introduction

GERD is a persistent and common medical disorder, affecting up to 13% of the adults worldwide [1, 2]. The most effective treatments for GERD include PPIs and laparoscopic fundoplication as both reduce gastroesophageal reflux, control symptoms, heal esophageal erosions, and decrease complications. Nevertheless, patients' satisfaction with PPIs is limited by diverse factors that lead to PPI failure in up to 44% of patients.

[3, 4, 5] and by patient's concerns regarding PPI safety issues [6, 7, 8]. Thus, identifying validated, safe and non‐invasive alternative therapies for GERD is clearly needed in patients who didn't respond to medical treatment and for those who decline such treatment [9, 10]. In fact, in the case of PPI failure, except those with severe erosive esophagitis, there are currently no satisfactory, non‐invasive alternative treatment options [11, 12]. Laparoscopic fundoplication is another possible therapeutic modality for patients with proven pathologic acid exposure despite doubling the dose of PPI. Nevertheless, less than 1% of eligible patients eventually undergo fundoplication due to its invasive nature and related adverse events [9, 13, 14, 15, 16].

Transcutaneous electrical stimulation system (TESS) is a novel device developed by GerdCare Medical Ltd. (Yokneam, Israel), for the treatment of GERD. The device is noninvasive and designed for self‐use in the home environment. TESS is applied by the patient on the abdominal skin at a specific location (over the external oblique and rectus abdominus muscles) and electrically stimulates these muscles.

For optimized effect, stimulation is synchronized with the breathing phase (active only during inhalation) and provokes asymmetrical contractions of these muscles. In a previously published, preliminary proof of concept (POC) study we evaluated the effects of an earlier version of the TESS on esophageal acid exposure in seven GERD patients who continued to be symptomatic despite standard dose PPI [17].

Study results indicated that TESS significantly reduced esophageal acid exposure within a very short period of time in all patients. Additionally, TESS was found to be safe and well tolerated. However, due to its short duration, the effect of TESS treatment on heartburn and regurgitation was not assessed in that study.

How TESS reduced esophageal acid exposure is not completely understood. However, based on studies that investigated mucous transport within the bronchial tree [18, 19, 20, 21], dynamic asymmetrical movements are equivalent to the well‐known mechanism of vibrating conveyer, used in industry [18, 19, 20, 21, 22, 23]. As the static friction is higher than the dynamic friction, materials (solids or liquids) move toward the direction of slow slope. Hence, TESS may reduce esophageal acid exposure by accelerating the downstream clearance of acid refluxate from the esophagus or by accelerating gastric emptying. Another hypothesis is that TESS may augment lower esophageal sphincter (LES) tone and reduce transient LES relaxations. Evaluation of each such putative mechanisms on GERD related symptoms and acid exposure are clearly needed.

The aforementioned preliminary data demonstrated that TESS reduced esophageal acid exposure and that a symptomatic response to TESS treatment has yet to be shown. Therefore, the primary endpoint of this study was to determine the efficacy of TESS on GERD related symptoms throughout a treatment period of 3 weeks. The Secondary endpoints were the magnitude of reduction of AET and DeMeester score, as compared with their baseline (pretreatment) values.

2. Patients and Methods

2.1. Patients

In this multicenter, interventional study, adult patients (age > 18 years) who were suffering from GERD‐related symptoms (heartburn and/or regurgitation) more than 3 days per week, over at least 3 months were invited to participate. Potential participants were recruited from clinics of gastroenterology and by online public advertisement. To increase recruitment, potential participants were firstly interviewed by phone to assess preliminary eligibility. A subsequent, in‐depth evaluation of inclusion and exclusion criteria was performed during the screening face‐to‐face interview meeting with the study coordinator and the chief investigator in each site. Exclusion criteria included gastric or esophageal surgery, active peptic ulcer disease, malignancy, pregnancy, uncontrolled diabetes mellitus, severe cardiac conditions, implanted electrical devices including cardiac pacemaker or defibrillator, skin allergy to the study device electrodes, severe pulmonary disease, obesity (BMI > 30 kg/m²), gastroparesis, contraindications to Bravo capsule, upper endoscopy or sedation, and inability to provide informed consent or to comply with the study requirements.

2.2. Study Design

This prospective, interventional, open‐label, multi‐center clinical study, was conducted in five medical centers in Israel between January 2019 and March 2023. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice, and was approved by the Human Subjects Protection Program of each site (MOH_2019‐02‐27_006003 and MOH_2019‐02‐24_004798). All patients provided written informed consent before enrollment into the study.

Study design included two consecutive phases: phase 1 consisted of a 1‐week off‐PPI run‐in period, during which patients were using neither PPIs nor the study device and phase 2 that consisted of TESS treatment for almost 3 weeks.

During phase 1 patients were requested to use a smartphone application to report their daily number and severity of GERD‐related symptom episodes (heartburn and regurgitation). Number of symptoms and symptom severity averaged over phase 1 were defined as baseline values.

During the subsequent week all patients underwent gastroscopy with the placement of a wireless 96‐h pH monitoring capsule (Bravo, Medtronic, Minneapolis, USA) (off PPI). Thus, the PPI treatment was stopped between 1 week and 2 weeks, before the gastroscopy. The findings of the gastroscopies were as follows: 14 patients had normal gastroscopy, 13 patients had gastroscopy who demonstrated hihatal hernia or reflux esophagitis or both, two patients had gastritis, one patients had duodenitis and another one had barrett's esophagus and hiatal hernia. The mean acid exposure time (AET) and DeMeester score after the first 24‐h monitoring were defined as baseline values. Patients with pathological baseline AET (i.e., percent total time pH < 4 above 6%) were invited to continue to phase 2 (TESS treatment phase). Patients with baseline AET equal to or less than 6% were excluded from the study. During phase 2, participants were treated with TESS at home for 17 consecutive days (off PPI), while continuing to report GERD‐related symptoms by using the smartphone application. The first 3 days of phase 2 consisted of TESS treatment in parallel to the ongoing last 72 h of the pH monitoring. At the end of each day of pH monitoring, the study technician downloaded and analyzed the pH monitoring data, and ensured correct position and function of the TESS device. After the last day of pH monitoring, the Bravo recorder was collected and patients continued to be treated with TESS and to report their daily symptoms until the end of phase 2. Study phases and design are shown in Figure 1.

FIGURE 1.

Study design.

2.3. Study Equipment and Measurements

2.3.1. Wireless pH Monitoring

The wireless pH monitoring capsule system (Bravo, Medtronic, PLC, USA) is attached to the esophageal wall 6 cm. above the esophagogastric junction and records AET for up to 96 h [24]. In this study, AET was determined every 24 h and up to 4 days, using commercially available computer software (Bravo, Medtronic, Minneapolis, USA). The first day (24 h) of pH monitoring (Day 0) was completed before starting TESS treatment and served as a baseline. The remaining three pH monitoring days were performed in parallel with TESS treatment.

2.3.2. Stimulation Device

TESS (GerdCare Medical, Yokneam, Israel) is a novel, non‐invasive, electrical stimulation system for GERD treatment. TESS comprises a sealed, external, rechargeable pulse generator, a pair of electrodes connected to the skin (through conductive adhesive hydrogel), and a piezoelectric breathing sensor. The device delivers low‐current electrical pulses during inhalation and is simply mounted on a belt (Figure 2A,B). TESS stimulates the abdomen at the areas of external oblique and rectus abdominis muscles with modulated asymmetrical sawtooth bursts of symmetric biphasic current waves (Figure S1.). The current level is between 5 and 50 mA (user controlled) and the stimulation voltage is up to 120 V (base to peak). Stimulation waveform comprises bursts of multiple rectangular bi‐phasic pulses with a duration of 200 μS and frequency of 35 Hz. As a result, the external oblique and rectus abdominis muscles are electrically stimulated, resulting in asymmetrical contractions. The device is synchronized with patient's breathing by means of integrated respiration sensors and dedicated software algorithms, such that the stimulation bursts are active mainly during the inhalation phase. The user can activate the stimulation and control its intensity (current level) via the smartphone application or an embedded two‐button keypad.

FIGURE 2.

(A) TESS comprises a sealed plastic case, software‐driven electrical circuitry with an internal processor, pulse generator, rechargeable battery, and a low energy Bluetooth (BLE) communication module. A pair of disposable electrodes coated with conductive, biocompatible adhesive are connected to the device via magnetic studs. (B) The electrodes are applied over the skin of the abdominal peripheral muscles (left external oblique and rectus abdominus) and held by a dedicated belt. Low energy electrical current is applied transcutaneously, stimulating the abdominal musculature.

2.3.3. Symptom Assessment

GERD‐related symptoms were reported by the patients using the TESS smartphone application. Patients were requested to report symptoms as they occur and at most, during the 24‐h after. Each symptom report included time of occurrence and symptom severity, using a 5‐point Likert scale (0 = none, 1 = minimal, easily held, 2 = mild, can be held and does not influence doings, 3 = moderate, cannot be held, occasionally influences doings, 4 = severe, cannot be held and markedly limits doings). Thus, analysis included both the daily numbers of reported heartburn and regurgitation episodes and their ranked severity.

Clinical endpoints included: The primary endpoint of a significant (at least 50%) reduction in mean reported number and/or severity scores of heartburn and/or regurgitation and the secondary endpoints of a significant reduction in mean AET and DeMeester score at the end of phase 2 compared to baseline.

Tolerability and safety assessments: Device safety was assessed by number and severity of adverse device effects (ADEs) occurring throughout the study. Adverse events were assessed by both the study coordinator and the principal investigators at each site, weekly during the treatment period and at the end of study. All adverse events were summarized and tabulated, including severity and relationship to the study device, for each patient.

2.4. Statistical Analysis

We analyzed symptoms at two time frames: a. at baseline, which refers to the run‐in, first week of the study (phase 1); and b. during treatment with TESS (phase 2). Symptoms that were reported during pH monitoring were excluded from analysis. Thus, symptoms were analyzed right after the completion of pH monitoring till the last day of phase 2. Results from phase 2 were compared to those at baseline using a paired samples t‐test. Cohen's d effect size was used to evaluate the magnitude of the change. In the latter metric, values ≥ 0.8 are commonly considered large.

The post‐treatment and baseline (pre‐treatment) values of AET and DeMeester score were compared. Due to detachment of the Bravo capsule from the esophageal wall, the number of patients with valid monitoring data gradually decreased from the 2nd monitoring day (Day 1) to the 4th monitoring day (Day 3). AET and DeMeester scores at Days: 1, 2, 3 and at the last monitoring day (LMD), defined as the last day in which there was a valid monitoring data, were compared to their baseline levels (BL) using a paired‐sample t‐test. The analysis comprised separate tests calculated for the following data sets: BL to Day 1, BL to Day 2, BL to Day 3, BL to LMD. The non‐parametric Wilcoxon signed‐rank test was used in addition, for data sets in which the sample size was small. The magnitude of decrease from the baseline level was calculated using the Cohen's d test.

Changes in AET and DeMeester score were also expressed as the ratio between the actual change and the decrease required for achieving normal values. In this analysis, 100% change implies a decrease from baseline to within normal limits, whereas negative change represents deterioration in the measured values.

We calculated these changes using the following formula:

$$\text{Change}=\min \left(100\%-\frac{X_{\mathrm{LMD}}-X_{\text{normal}}}{X_{\mathrm{BL}}-X_{\text{normal}}},100\%\right)$$

where: $X_{\mathrm{BL}}$ = Baseline value, $X_{\mathrm{LMD}}$ = Measured value on LMD. And $X_{\text{normal}}$ = Normal values (normal values were taken as $X_{\text{normal}}$ = 6% for AET and $X_{\text{normal}}$ = 14.7 for DeMeester score).

3. Results

Eighty‐eight patients were eligible for enrollment and underwent pre‐screening. Of those, 23 were excluded due to noncompliance with study inclusion or exclusion criteria, such as high BMI, pregnancy, allergy to skin patches, foregut surgery and refusal to sign an informed consent. Sixty‐five patients were enrolled into phase 1 and completed baseline (Day 0) pH monitoring. Of those, 34 were excluded due to a normal AET (27 patients) and pH technical difficulties (seven patients). Thirty‐one patients with a pathological AET continued to phase 2. Of those, four were excluded due to insufficient pH data and reports of daily symptoms. Overall, a total of 26 patients (42% females, aged 49 ± 15 years, mean BMI 25 ± 3 kg/m²) completed the first two phases of the study and had a complete set of symptom's reports and pH data. Table 1 shows the Demographic characteristics and baseline AET and DeMeester score (DM) of the 31 patients with a pathological AET who continued to phase 2 of the study.

TABLE 1.

Demographic characteristics and baseline acid exposure time (AET) and DeMeester score (DM) of the patients.

Patient	Age, years	BMI	Gender	Baseline AET×, %	Baseline DM
1	66	28.9	Female	8.2	21.8
2	46	29.3	Male	14.8	36.5
3	32	28.0	Female	9.3	34
4	64	29.8	Female	11.3	28.2
5	50	30.1	Female	15.7	40.7
6	47	29.1	Male	7.3	20.4
7	32	23.0	Male	11.6	30.8
8	25	20.4	Female	6.6	17.2
9	73	27.2	Female	15.5	38.4
10	43	26.2	Male	9.2	23.9
11	66	27.5	Female	7.8	21.5
12	38	a	Male	9.2	23.6
13	64	26.0	Male	11.8	36.4
14	75	21.3	Male	14.2	36.9
15	72	29.2	Female	6.7	17.8
16	44	21.0	Male	27	63.4
17	48	20.4	Male	9.3	24.6
18	56	22.0	Female	13.4	34.8
19	34	24.4	Male	18.4	45.1
20	61	25.5	Male	12.1	29.6
21	50	25.9	Male	6.3	14.1
22	29	21.9	Female	6.4	19.2
23	28	19.9	Male	8.2	21.8
24	60	28.1	Male	10.9	28.6
25	47	22.8	Male	19.4	49.1
26	21	25.3	Male	12.8	36.5
27	35	28.7	Male	25.2	60
28	69	19.9	Female	11.6	27.6
29	38	24.9	Male	10.1	26.7
30	54	25.5	Female	9.1	26.8
31	61	28.9	Female	25.6	58.5

^a Missing data; × AET is assessed by percent total time of pH < 4.

3.1. Effects on Number and Severity of Symptoms

We analyzed the number of heartburn and regurgitation events in each phase of the study. Completion rate of symptom's reports during phase 1 and 2 was high.

Results of changes from baseline to treatment in the number of symptoms (heartburn and regurgitation) and symptom severity scores are presented in Table 2. During phase 1, the mean number of heartburn events was 2.55 ± 1.79 and following TESS treatment it dropped to 0.77 ± 0.75 (p < 0.001). Results of daily number and sum of severities for heartburn are presented in Figure 3. The mean number of regurgitation events during phase 1 was 1.4 ± 1.73 and following TESS treatment it dropped to 0.36 ± 0.80 (p < 0.001). Results of daily number and sum of severities for regurgitation are presented in Figure 4. Overall, following TESS, reported number of heartburn and regurgitation events decreased by 68.3% and 78.5%, respectively.

TABLE 2.

Changes from baseline to treatment period in number of symptoms (heartburn and regurgitation) (1) and symptom severity scores (2).

1. No. of Symptoms	Heartburn			Regurgitation			All symptoms
Mean (SD)	2.55 (1.79)	➔	0.77 (0.75)	1.40 (1.73)	➔	0.36 (0.80)	6.90 (6.15)	➔	1.86 (2.38)
p‐value	< 0.001			< 0.001			< 0.001
Effect size (Cohen's d)	1.34			0.96			1.25
Sample size (n)	26			26			26

2. Severity of symptoms	Heartburn			Regurgitation			All symptoms
Mean sum (SD)	7.38 (4.88)	➔	1.94 (2.02)	3.75 (3.93)	➔	0.75 (1.32)	18.79 (14.80)	➔	4.45 (5.11)
p‐value	< 0.001			< 0.001			< 0.001
Effect size (Cohen's d)	1.31			1.00			1.32
Sample size (n)	26			26			26

Note: Sample size includes only patients for whom both baseline and treatment data is available.

FIGURE 3.

Daily number of heartburn events and daily sum of heartburn severities. Broken lines indicate raw data, whereas rigid lines indicate smoothened data using a 3‐day moving average (i.e., the rigid lines comprise the average of the previous, current, and subsequent raw data points). Vertical bars represent standard error.

FIGURE 4.

Daily number of regurgitation events and daily sum of regurgitation severities. Broken lines indicate raw data, whereas rigid lines indicate smoothened data using a 3‐day moving average (i.e., the rigid lines comprise the average of the previous, current, and subsequent raw data points). Vertical bars represent standard error.

3.2. Effects on Esophageal Acid Exposure

Acid exposure data as assessed by AET and DeMeester scores, were obtained on a daily basis from the Bravo data analysis software. The first 24 h of pH monitoring was completed just before starting the TESS treatment and served as baseline. In the remaining 72 h of pH monitoring, acid exposure was evaluated under TESS treatment. All patients (n = 31) completed 48 h of pH monitoring, while 26 and 17 patients completed 72 and 96 h, respectively. Mean results, averaged over the last 1, 2, and 3 monitoring days, are presented in Figure 5 and in Table 3. For example, baseline AET (off TESS) was 12.4 ± 5.6 and dropped to 7.62 ± 4.36, 8.18 ± 5.33, 7.19 ± 4.26, and 6.03 ± 3.47 in Day 1, Day 2, Day 3, and LMD, respectively (p < 0.001). Additionally, pH data for each individual patient (AET and DeMeester scores), as measured on LMD, (defined as the last day for which monitoring data exists), were compared to baseline values and are presented in Figure 6A (for AET) and in Figure 6B (for DeMeester scores).

FIGURE 5.

Change from baseline to treatment period in AET [%] and DeMeester scores. Mean results, averaged over the last 1, 2, and 3 monitoring days are presented.

TABLE 3.

Changes from baseline to first 3 treatment days in AET (1) and DeMeester score (2).

1. AET changes	BL ➔ Day 1			BL ➔ Day 2			BL ➔ Day 3			BL ➔ LMD
Mean (SD)	12.42 (5.63)	➔	7.62 (4.36)	12.42 (5.97)	➔	8.18 (5.33)	12.42 (6.61)	➔	7.19 (4.26)	12.42 (5.63)	➔	6.03 (3.47)
p‐value	< 0.001			< 0.001			< 0.001			< 0.001
Effect size (Cohen's d)	1.2			0.93			1.47			1.37
Sample size (n)	31			26			17			9

2. DeMeester score changes	BL ➔ Day 1			BL ➔ Day 2			BL ➔ Day 3			BL ➔ LMD
Mean (SD)	32.08 (12.6)	➔	20.62 (11.0)	32.06 (13.4)	➔	21.50 (12.8)	36.32 (14.4)	➔	18.47 (10.0)	32.08 (12.6)	➔	16.24 (8.2)
p‐value	< 0.001			< 0.001			< 0.001			< 0.001
Effect size (Cohen's d)	1.25			1.13			1.63			1.51
Sample size (n)	31			26			17			9

Note: Sample size varies since each column includes only patients for whom both baseline and treatment monitoring data is available. In Cohen's d test (measures magnitude of decrease in AET) values ≥ 0.8 are commonly considered large.

Abbreviations: AET, acid exposure time; BL, base line; LMD, last monitoring day; SD, standard deviation.

FIGURE 6.

(A) AET in each individual patient, was measured during the last monitoring day (LMD), defined as the last day for which monitoring data exists, and compared to baseline values. (B) DeMeester score in each individual patient, was measured. During the last treatment day (LMD), defined as the last day for which monitoring data exists, and compared to baseline values.

Changes in esophageal acid exposure (AET and DeMeester scores) were also expressed as the ratio between the actual decrease and the decrease required for achieving normal values. Utilizing this change analysis, AET and DeMeester scores have decreased by 74.5% ± 31.9% and 82.3% ± 26.8%, respectively.

3.3. Tolerability and Safety Assessments

No severe adverse events were reported during the study. 8 (26%) patients report mild erythema or itching beneath electrodes. All events were relieved without treatment in a short period of time (typically 2–3 h, max. 3 days). 1 (3%) patient reported epigastric pain related to the Bravo capsule and 1 (4%) felt the electrical current. None of these mild adverse events affected compliance with study requirements. Overall, TESS was well tolerated by all patients.

4. Discussion

This multicenter study is in continuation with our previous POC study that showed a favorable effect of TESS in reducing esophageal acid exposure in patients who have failed standard dose PPI [17]. In the present study we measured acid exposure but in addition, evaluated the effects of TESS on symptoms, which was not evaluated in the POC study. Study results showed significant improvement in both acid exposure and symptoms, indicating a positive reaction to treatment with regard to both primary and secondary endpoints. To our knowledge, this is the first study to explore the effect of a noninvasive, safe and easy‐to‐use device on AET and GERD‐related symptoms.

These promising results deserve explanation regarding the mechanism of action of this novel device. As mentioned, we hypothesized that mechanism of action of TESS may involve several routs. Firstly, TESS may strength esophageal secondary peristalsis that can clear gastroesophageal refluxate. Secondly, TESS may accelerate the rate of gastric empting and by that reduces acid reflux. Thirdly, it may strength LES tone, decreasing the occurrence of transient LES relaxation (TLESR) and may strength the gastroesophageal junction (GEJ), creating a stronger barrier between the stomach and the esophagus. Physiologically, the high pressure zone at the GEJ is determined by both LES and the diaphragmatic crura. An association between rapid increase in abdominal pressure and increased GEJ pressure was studied by Mittal et al. more than three decades ago [24]. In a recent study, Shafik A et al. evaluated the effect of straining on the diaphragmatic crura (DC), identifying a straining‐crural reflex [25]. In that study, straining and coughing via laryngeal and tracheal stimulation provoked increased electromyographic (EMG) activity of the DC and the LES. Furthermore, on sustained straining, an increased EMG activity was coupled with significant increase in GEJ pressure (four times as compared to baseline) [25, 26]. Thus, the so‐called “straining‐crural reflex” may support our hypothesis that TESS induces repeated contractions of the rectus abdominis and external oblique muscle, and by that increase GEJ pressure. It is yet to be proven in our patients whether that “straining‐crural reflex” actually increases EMG activity and pressure at the GEJ and by that reduces AET and related symptoms. Although the present study focused only on TESS effectiveness and safety we do intend to perform a physiological evaluation in the near future. Esophageal high‐resolution manometry (HRM) and pH monitoring before and under TESS treatment is just an example.

In this study, TESS was found to be safe, well tolerated, and significantly reduced AET and symptom's burden within a relatively short period of time. In addition, it was found that symptom's report showed an approximately 1‐week phase of constant decrease before stabilizing.

This observation suggests that the decrease in AET would have been even larger than observed if it could be applicable to prolong the pH monitoring for more than 4 days.

The strengths of this study were the equal sex distribution, the highly selected patient population and the simple and clear design and outcome measures. Acid exposure was rigorously evaluated every 24 h, comparing two well‐defined and distinct periods: The first 24 h off‐PPI and off‐TESS (baseline) and the subsequent 72 h under TESS treatment. In addition, by using a wireless system to measure acid exposure at home, we could minimize changes in real lifestyle or eating behaviors that occur with catheter‐based ambulatory pH monitoring. Another point in favor of a wireless system if the prolonged monitoring duration (96 h compared to 24 h).

Limitations of this study were the small sample size and the lack of a controlled group (e.g., a sham treatment arm). The small number of participants was due to our difficulty in identifying and enrolling true nonerosive reflux disease (NERD) patients (typical symptoms and an abnormal esophageal acid exposure). In fact, we had to exclude a significant number of screened patients that completed phase 1, as more than half of those were excluded because of a non‐pathologic AET at Day 0. It is now recognized that the cumulative incidence of functional heartburn is quite high among patients with NERD. Consequently, the number of patients who fulfilled inclusion and exclusion criteria was lower than expected. Regarding the lack of a controlled group, this study results demonstrated a significant effect of TESS that may surpass potential placebo effects. In one meta‐analysis it was found that the placebo response was 18.85% [13].

Another limitation of this study regards esophageal acid exposure in the supine and upright positions as well as during the post prandial periods. Unfortunately, not all the patients completed their diaries in this regard and therefore this information was not included into the analysis. Finally, and as was discussed physiological data that could assess TESS mechanism of action (esophageal peristalsis, GEJ high‐pressure zone and gastric empting) at baseline and at the end of the study was not collected in this study.

Our study suggests that TESS may be safe and effective in reducing esophageal acid exposure and improving GERD‐related symptoms in GERD patients. We believe that our results provide justification for performing a larger sham‐controlled clinical trial to assess the effectiveness and safety of the TESS treatment, and to conduct a physiological investigation of the underlying mechanism of action.

In summary, TESS appears to be safe and effective in reducing esophageal acid exposure and improving heartburn and regurgitation in GERD patients. A larger prospective, sham controlled study is currently designed to verify these early results.

Author Contributions

R.G.‐B. planned and conducted the study, and drafted the manuscript. T.R., T.N., Y.R. planned and conducted the study. S. L. and T.T.P. interpreted the data. M.S. interpreted the data and drafted the manuscript. M.H.‐P., R.G.‐B. planned and conducted the study. D.B. drafted the manuscript. R.F. planned the study and drafted the manuscript. R.D. planned and conducted the study, and drafted the manuscript. All authors read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Figure S1. TESS generates electrical stimulation in the form of asymmetrical saw‐tooth wave bursts. Each burst comprises multiple rectangular biphasic pulses with a duration of 0.2 ms and frequency of 35 Hz.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.