Electrical Stimulation Therapy (EST) of the Lower Esophageal Sphincter (GERD)

Study Overview
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Brief Summary
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The investigational device that will be used in this trial is the EndoStim® Lower Esophageal Sphincter (LES) Stimulation System. The purpose of this trial is to evaluate the safety and the effectiveness of electrical stimulation therapy (EST) on the lower esophageal sphincter (LES) in the treatment of subjects with gastroesophageal reflux disease (GERD). The study population will consist of subjects diagnosed with pathological GERD as defined by abnormal pH and who complain of heartburn, regurgitation or both for > 6 months, on a daily PPI use.

Detailed Description
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Study Design: Multicenter, randomized, double-blind, sham-controlled study. All subjects undergo screening and baseline visits, followed by system implantation, and randomization after 2 weeks to either a treatment Group (stimulation) or Control Group (delayed stimulation). Randomized subjects complete a 10-week, double-blind phase. At the 14-week visit, subjects are unblinded, control group subjects begin receiving stimulation, and all subjects are followed for an additional 9-month open-label treatment phase. Subjects continue receiving stimulation for an extended follow-up phase involving annual visits through 5 years. Study Visits: Screening and baseline visits. Laparoscopic implantable pulse generator (IPG) and lead implant procedure. Post-implant follow-up office visits at 2 weeks/randomization, 6, 10, 14, 24 and 48 weeks, followed by annual visits through 5 years. Sample Size and Scope: Forty-six subjects will be implanted and followed to 12 months after stimulation treatment at 3 investigational sites.

Official Title
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Electrical Stimulation Therapy (EST) of the Lower Esophageal Sphincter: a Multicenter, Randomized, Double-blind, Sham-controlled Parallel-group Trial Evaluating Short Term Efficacy of EndoStim Device on GERD

Conditions
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GERD

Intervention / Treatment
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* Procedure: Laparoscopic IPG and lead implant procedure
* Device: Active Electric Stimulation Therapy
* Device: Delayed Electric Stimulation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject able and willing to provide written informed consent Subject able and willing to comply with required study procedures and follow-up schedule Typical symptoms of GERD (regurgitation and/or heartburn) for longer than 6 months, heartburn responding to PPI therapy. Subject may also complain of atypical symptoms of GERD that may persist on PPI Daily dose of PPI or other acid neutralization drugs because of PPI intolerance Baseline visit GERD-HRQL score ≥ 20 following 14 days off-PPI and at least 10 points higher than their on-PPI (or other acid-neutralization drugs) GERD-HRQL score recorded during the Screening Visit Excessive lower esophageal acid exposure during pH monitoring (defined as distal esophageal pH < 4 for > 5.0% of the monitoring time) performed after 14 days off PPIs Subject is a suitable surgical candidate able to undergo general anesthesia and laparoscopic surgery. Exclusion Criteria: Previous EndoStim LES System implant and/or implant attempt Previous esophageal surgery, including Nissen fundoplication Previous endoscopic intervention for the treatment of GERD and/or Barrett's esophagus Hiatal hernia larger than 2 cm as determined by any diagnostic investigation (i.e., endoscopy, manometry or laparoscopic visualization) Gastroparesis Any non-GERD esophageal motility disorders Esophageal stricture or significant esophageal anatomic abnormalities Barrett's epithelium or any grade of dysplasia Documented history of esophagitis Grade C or D (LA Classification) History of suspected or confirmed esophageal or gastric cancer Esophageal or gastric varices Symptoms of dysphagia more than once per week within the last 3 months Suspected or known allergies to titanium, platinum, iridium, stainless steel, silicone, epoxy, or nylon Body mass index (BMI) > 35 kg/m2 Any significant multisystem diseases Autoimmune or a connective tissue disorder (scleroderma, dermatomyositis, Calcinosis-Raynaud's-Esophagus Sclerodactyly Syndrome (CREST), Sjogren's Syndrome, Sharp's Syndrome, etc.) requiring therapy in the preceding 2 years Type 1 diabetes mellitus or uncontrolled Type 2 diabetes mellitus (T2DM) defined as HbA1c > 9.5 in the previous 6 months or at screening/baseline, or has T2DM for > 10 years Significant cardiac arrhythmia or ectopy or significant cardiovascular disease (i.e. unstable angina pectoris, hemodynamically significant valvular disease, severe congestive heart failure), or cardiac therapeutic intervention within the last 6 months. Significant cerebrovascular event within the last 6 months Existing implanted electrical stimulator (pacemaker, implantable cardioverter defibrillator, deep brain stimulator (DBS), bone growth or pelvic floor stimulators, drug pumps, etc.) Chronic anticoagulant therapy Female subject of child-bearing potential and is pregnant or nursing, or intends to become pregnant during the trial period, who is not using a reliable form of birth control Subject is currently enrolled in other potentially confounding research Active infection as determined by the investigator History of any malignancy in the last 2 years Life expectancy less than 3 years Diagnosed major psychiatric disorder (bipolar, schizophrenia, etc.)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Electric Stimulation Therapy<br>The subject receives Active Electric Stimulation Therapy for 12 weeks, 2 weeks after laparoscopic IPG and lead implant procedure. The subject and physician will be blinded to the randomization group assignment. The subject continues on stimulation treatment after 14 weeks and an extended open-label follow-up phase includes annual visits through 5 years. | Procedure: Laparoscopic IPG and lead implant procedure<br>* EST placement<br>* Other names: EndoStim;Device: Active Electric Stimulation Therapy<br>* Device programming by the technician to deliver the EST system active (Treatment group) or no stimulation (Control group) for the following 12 weeks, at the 2 weeks visit.<br>* Other names: EndoStim;|
| Sham Comparator: Delayed Electric Stimulation Therapy<br>The subject receives no active Electric Stimulation Therapy for 12 weeks, 2 weeks after laparoscopic IPG and lead implant procedure. The subject and physician will be blinded to the randomization group assignment. The subject will receive Active Electric Stimulation Therapy at week 14 visit, and an extended open-label follow-up phase includes annual visits through 5 years. | Procedure: Laparoscopic IPG and lead implant procedure<br>* EST placement<br>* Other names: EndoStim;Device: Delayed Electric Stimulation Therapy<br>* Device programming by the technician to deliver the EST system no stimulation for the following 12 weeks at the 2 weeks visit. Active Electric Stimulation Therapy will be programmed at the 14 weeks visit.<br>* Other names: EndoStim;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of EST on GERD symptoms (mean improvement in the GERD- health-related quality of life (HRQL) scores from baseline in control and treatment groups) | Comparison between Treatment and Control Groups of the mean improvement in the composite GERD-HRQL scores from baseline measured after at least 14 days off proton pump inhibitors (PPIs) | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (Rate of occurrence of device- and procedure-related adverse events) |  | 12 months | 
| Number of subjects achieving GERD symptom success | Improvement in the total GERD-HRQL score of 50% or more compared to pre-implantation score off PPI | 12 months | 
| Reflux symptoms measured by GERD-HRQL score | Mean improvement in the composite GERD-HRQL scores from baseline measured after at least 14 days off proton pump inhibitors (PPIs) | 6 months | 
| Reflux symptoms measured by GERD-HRQL score | Mean improvement in the composite GERD-HRQL scores from baseline measured after at least 14 days off proton pump inhibitors (PPIs) | 12 months | 
| Number of subjects able to stop regular use of acid-suppression | Defined as 50% or more days without PPI use | 12 months | 
| Number of subjects able to stop all use of acid-suppression medication |  | 12 months | 
| Percentage of asymptomatic patients | Defined as an improvement in their total GERD-HRQL score of 50% or more compared to pre-implantation score off PPI) in treatment and control groups, off-PPI for the last 2 weeks. | 14 weeks | 
| Incidence of reflux esophagitis |  | 12 months | 
| Quality of life measured by EQ-5D EuroQol score | Difference in patient's EQ-5D score, compared to pre-implantation score on and off PPI. | 14 weeks | 
| Quality of life measured by EQ-5D score | Difference in patient's EQ-5D score, compared to pre-implantation score on and off PPI. | 6 months | 
| Quality of life measured by EQ-5D score | Difference in patient's EQ-5D score, compared to pre-implantation score on and off PPI. | 12 months | 
| Efficacy of EST on acid reflux measured by esophageal pH | Difference in % 24 hour esophageal pH<4 in Treatment and Control groups (total, upright, supine, postprandial (2h)). | 14 weeks | 
| Efficacy of EST on acid reflux measured by DeMeester score | Difference in DeMeester score in Treatment and Control groups. | 14 weeks | 
| Percentage of subjects achieving pH success | Defined as normalization (pH < 4 for no more than 4.1% of monitoring time) or > 50% improvement in their distal esophageal acid exposure compared to their baseline off-PPI distal esophageal pH. | 14 weeks | 
| Efficacy of EST on reflux episodes measured by esophageal impedance | Difference in the number of reflux episodes (total, upright, supine, postprandial (2h), acidic, weakly acidic, weakly alkaline, and proximal extent (15 cm) in Treatment and Control groups. | 14 weeks | 
| Difference in lower esophageal sphincter (LOS) pressure and integrated relaxation pressure at 4 seconds (IRP4s) in Treatment and Control groups |  | 14 weeks | 
| Comparison of GERD-HRQL scores in Treatment and Control groups |  | 14 weeks | 
| Comparison of quality of life measured by EQ-5D in Treatment and Control groups |  | 14 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Reflux, Reflux disease, Gastroesophageal reflux disease, Lower esophageal sphincter stimulation