An Investigation of the EndoStim® Lower Esophageal Sphincter (LES) Stimulation System for the Treatment of Reflux

Study Overview
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Brief Summary
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The purpose of this investigation is to demonstrate the safety and effectiveness of Lower Esophageal Sphincter (LES) Stimulation System in treating gastroesophageal reflux disease (GERD). This investigation is a multicenter, randomized, double-blind, sham-controlled study. After the implant procedure, subjects will be randomized to either the Treatment Group (immediate stimulation) or Control Group (delayed stimulation) for six months followed by an additional open-label phase in which all subjects will receive electrical stimulation. Subjects continue on stimulation treatment in an extended open-label follow-up phase through 5 years post-stimulation.

Detailed Description
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The purpose of this investigation is to demonstrate the safety and effectiveness of the EndoStim® Lower Esophageal Sphincter (LES) Stimulation System in the treatment of subjects with gastroesophageal reflux disease (GERD). This investigation is a multicenter, randomized, double-blind, sham-controlled clinical investigation. After the implant procedure, subjects will be randomized to either the Treatment Group (immediate stimulation) or Control Group (delayed stimulation) for a 6-month, double-blind phase followed by an additional open-label treatment phase in which all subjects will receive electrical stimulation therapy for a total of 12 months. Subjects continue on stimulation treatment and an extended open-label follow-up phase includes an 18 month post-stimulation phone interview followed by annual visits through 5 years post-stimulation.

Official Title
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A Multicenter, Randomized, Double-Blind, Sham-Controlled Clinical Investigation of the EndoStim® Lower Esophageal Sphincter (LES) Stimulation System for the Treatment of Gastroesophageal Reflux Disease (GERD)

Conditions
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Gastroesophageal Reflux Disease (GERD), Reflux, Gastroesophageal, Gastroesophageal Reflux, Acid Reflux

Intervention / Treatment
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* Procedure: Laparoscopic implantation surgery
* Device: EndoStim stimulation for first six months of study
* Device: EndoStim stimulation from Month 6 thru end of study
* Device: Sham EndoStim stimulation for first six months of study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to provide written informed consent Able and willing to comply with required study procedures and follow-up schedule 22 - 75 years of age at the time of informed consent Documented symptoms of gastroesophageal reflux disease (GERD) for longer than 6 months (regurgitation and/or heartburn which is defined as burning epigastric or substernal pain which responds to acid neutralization or suppression) which requires daily use of proton pump inhibitors (PPIs) or other anti-reflux drug therapy, who continue to have symptoms despite maximum medical therapy or are intolerant -severe side-effects (e.g. anaphylaxis or severe allergic reaction, recurrent C. difficile, severe hypomagnesaemia) to one PPI or mild/moderate side effect (e.g. nausea, vomiting, diarrhea or abdominal pain) to at least 2 PPIs of different chemical classes. Symptomatic improvement on PPI therapy demonstrated by a composite GERD-health-related quality of life (HRQL) score of ≥20 off PPI, and a ≥10 point improvement on PPI compared to the off PPI composite GERD-HRQL score. Patients who meet the definition above of PPI intolerant are not required to have ≥10 point improvement. The on-PPI score to satisfy this criterion will be the score from the GERD-HRQL assessment completed after resuming PPIs following the Baseline visit. Excessive lower esophageal acid exposure during pH monitoring (defined as distal esophageal pH < 4 for > 6.0% of the monitoring time) performed after at least 5 days off of PPIs and at least 2 days off of H2 blockers. At least 18 hour of esophageal pH recording will be considered adequate and inclusion will be based on the day (at least 18 hours of valid data) with the highest acid exposure percentage time. Esophagitis ≤ Grade B (Los Angeles (LA) classification) as measured by upper endoscopy off PPI and H2 blockers for 10-14 days Esophageal body contraction amplitude > 30 mmHg for > 30% of swallows and > 30% peristaltic contractions on HRM or ≥ 30% peristaltic contractions with DCI >450. Suitable surgical candidate able to undergo general anesthesia and laparoscopic surgery Exclusion Criteria: Previous EndoStim LES System implant and/or implant attempt Previous surgery involving the gastroesophageal junction or the lead implant site, such as a Nissen fundoplication Previous endoscopic intervention for the treatment of GERD and/or Barrett's esophagus Hiatal hernia larger than 3 cm as determined by endoscopy History of gastroparesis Any non-GERD esophageal motility disorders that in the opinion of investigator precludes an anti-reflux procedure History of or known esophageal stricture or significant esophageal anatomic abnormalities (obstructive lesions, etc.) Barrett's esophagus 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 every week within the last 3 months Unable to tolerate withdrawal from H2 Blockers or PPI medications 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 Significant cardiac arrhythmia or ectopy or significant cardiovascular disease (i.e. unstable angina pectoris, hemodynamically significant valvular disease, severe congestive heart failure), or any 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.) 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 Currently enrolled in other potentially confounding research Active infection as determined by the investigator History of any malignancy, other than basal cell carcinoma, in the last 2 years Life expectancy less than 3 years aa. Diagnosed major psychiatric disorder (bipolar, schizophrenia, etc.) bb. Any condition that, at the discretion of the investigator or sponsor, would interfere with accurate interpretation of the study endpoints or preclude participation in the trial

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 75 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Control Group<br>This group will undergo laparoscopic implantation surgery. The device will not be activated: Sham EndoStim stimulation for first six months of study. It will be activated at the Month 6 visit and provide lower esophageal stimulation from Month 6 thru end of study. | Procedure: Laparoscopic implantation surgery<br>* Laparoscopic surgery to implant the pulse generator and bipolar lead.<br>Device: EndoStim stimulation from Month 6 thru end of study<br>* Lower esophageal stimulation<br>* Other names: lower esophageal stimulation;Device: Sham EndoStim stimulation for first six months of study<br>* EndoStim device remains off (no stimulation delivered)<br>|
| Experimental: Treatment Group<br>The group will undergo laparoscopic implantation surgery. The device will be activated two weeks post-implantation and the subject will receive EndoStim stimulation for first six months of study and continue with EndoStim stimulation from Month 6 thru end of study. | Procedure: Laparoscopic implantation surgery<br>* Laparoscopic surgery to implant the pulse generator and bipolar lead.<br>Device: EndoStim stimulation for first six months of study<br>* Lower esophageal stimulation<br>* Other names: lower esophageal stimulation;Device: EndoStim stimulation from Month 6 thru end of study<br>* Lower esophageal stimulation<br>* Other names: lower esophageal stimulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of device and/or procedure-related serious adverse events | Rate of occurrence of device and/or procedure-related serious adverse events after 12 months | 12 months | 
| Percentage of subjects achieving pH success (pH<4 for mo more than 5.3% of time or at least 50% improvement in pH compared to baseline) | Comparison between treatment and control group: percentage of subjects achieving pH success ((pH<4 for mo more than 5.3% of time or at least 50% improvement in pH compared to baseline) | Comparison of 6 months to baseline data |