NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

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1 NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of laparoscopic insertion of a magnetic titanium ring for gastrooesophageal reflux disease Gastro-oesophageal reflux disease is when acid leaks up from the stomach into the oesophagus (gullet) because the ring of muscle around the top of the stomach isn t working properly. This is known as acid reflux and causes heartburn (a burning sensation or pain in the chest) or an acid sensation or taste in the mouth. In this procedure, a small flexible band of interlinked magnetic beads is placed around the outside of the lower oesophagus, just above the stomach. The aim is that the magnetic attraction between the beads will help to keep the sphincter closed to prevent acid reflux, but still allow the person to swallow, belch or vomit. Introduction The National Institute for Health and Care Excellence (NICE) has prepared this interventional procedure (IP) overview to help members of the interventional procedures advisory committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This IP overview was prepared in November Procedure name Laparoscopic insertion of a magnetic titanium ring for gastro-oesophageal reflux disease disease Page 1 of 48

2 Specialist societies Association of Upper Gastrointestinal Surgeons for Great Britain and Ireland (AUGIS) British Society of Gastroenterology (BSG) Royal College of Surgeons of England Description Indications and current treatment Gastro-oesophageal reflux disease (GORD) is a common problem. It is caused by conditions that disturb the sphincter function at the lower end of the oesophagus, such as a hiatus hernia. Symptoms of GORD can be broadly grouped into those directly related to reflux episodes, such as heartburn, regurgitation, chest pain and nausea, and those caused by complications of reflux disease, including dysphagia and respiratory difficulties. Repeated episodes of GORD can damage the lining of the oesophagus and lead to oesophageal ulceration, oesophageal stricture and Barrett's oesophagus. A NICE clinical guideline describes recommendations for the investigation and management of GORD and dyspepsia in adults. The standard treatments for symptomatic GORD are lifestyle modification and drug therapy. Patients who have refractory symptoms, develop complications despite medication or develop intolerance to medication may be considered for anti-reflux surgery (usually laparoscopic fundoplication). Several endoscopic techniques (such as endoscopic radiofrequency ablation or endoscopic injection of bulking agents) have also been used. What the procedure involves The aim of laparoscopic insertion of a magnetic titanium ring for gastrooesophageal reflux is to provide relief of reflux-related symptoms without impeding the ability to swallow, belch or vomit, and with less morbidity than traditional anti-reflux surgery. The procedure is done with the patient under general anaesthesia. Using a laparoscopic approach, a specially designed sizing tool is loosely wrapped around the distal oesophagus to assess the size of implant needed. The sizing tool is then removed and the implant is placed so that it encircles the distal oesophagus at the gastro-oesophageal junction. The ends of the implant are secured together to hold it in place. Intraoperative endoscopy may be used to check that the implant is correctly positioned. disease Page 2 of 48

3 The implant consists of a ring of interlinked titanium beads, each with a weak magnetic force that holds the beads together to keep the distal oesophagus closed. When the patient swallows, the magnetic force is overcome, allowing the ring to open. After swallowing, magnetic attraction brings the beads together and the distal oesophagus is again closed. Outcome measures There are a number of subjective outcome assessment tools for this condition. The gastro-oesophageal reflux disease health-related quality of life (GERD- HRQL) scale assesses patient symptoms and effects on daily living using 10 questions. Scores of 0 50 are recorded; lower scores are better. Literature review Rapid review of literature The medical literature was searched to identify studies and reviews relevant to laparoscopic insertion of a magnetic titanium ring for GORD. The following databases were searched, covering the period from their start to 25 October 2016: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see appendix C for details of search strategy). Relevant published studies identified during consultation or resolution that are published after this date may also be considered for inclusion. The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved. disease Page 3 of 48

4 Table 1 Inclusion criteria for identification of relevant studies Characteristic Publication type Patient Intervention/test Outcome Language Criteria Clinical studies were included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, or a laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Patients with gastro-oesophageal reflux disease. Laparoscopic insertion of a magnetic titanium ring for gastrooesophageal reflux disease Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base. List of studies included in the IP overview This IP overview is based on more than 1,000 patients from 3 non-randomised comparative studies, 4 case series (1 of which is reported in 2 publications) and 1 case report 1 9. Other studies that were considered to be relevant to the procedure but were not included in the main extraction table (table 2) have been listed in appendix A. disease Page 4 of 48

5 Table 2 Summary of key efficacy and safety findings on laparoscopic insertion of a magnetic titanium ring for gastro-oesophageal reflux disease Study 1 Asti E (2016) Details Study type Country Non-randomised comparative study Italy Recruitment period March 2007 to July 2014 Study population and number Age and sex Patient selection criteria n=238 (135 laparoscopic insertion of magnetic bead band versus 103 laparoscopic Toupet fundoplication) Patients with chronic gastro-oesophageal reflux disease. Median 44 years (magnetic bead band); 50 years (fundoplication) 56% female (133/238); 67% (91/135, magnetic bead band) versus 41% (42/103, fundoplication), p<0.001 Age>18 years, chronic gastro-oesophageal reflux disease symptoms despite proton-pump inhibitor (PPI) use for at least 6 months, objective evidence of reflux at ph study, and normal oesophageal motility documented by manometry. Exclusion criteria: hiatal hernia>3 cm, oesophagitis grade C D, ineffective oesophageal motility, body mass index>35 kg/m 2, and previous oesophago-gastric surgery. Technique Laparoscopic insertion of magnetic bead band - LINX device was used. A posterior hiatoplasty was added at the discretion of the surgeon when the hiatus appeared to be markedly enlarged. Follow-up Conflict of interest/source of funding Laparoscopic Toupet fundoplication (upper part of the stomach is partially wrapped around the oesophagus, to 270 rather than the complete 360 wrap of a Nissen fundoplication.) Minimum 1 year. Mean 44 months (magnetic bead band); 42 months (fundoplication) One author has been a consultant for Torax Medical Inc. The authors declared they had no funding and conflicts of interest to disclose. Analysis Follow-up issues: All patients had a minimum of 1 year follow-up. Study design issues: Observational cohort study. Consecutive patients treated by laparoscopic insertion of magnetic bead band or laparoscopic Toupet fundoplication were identified from a prospectively collected database and compared by using the propensity score full matching method and generalised estimating equation. The primary outcome was postoperative quality of life, measured with the validated and disease-specific Gastro-Esophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) questionnaire (scores range from 0 to 75, with lower scores indicating fewer symptoms). Secondary outcomes were PPI use, presence of gas-related symptoms or dysphagia, and reoperation-free probability. Study population issues: A number of baseline characteristics of the study sample differed between the groups. There was a statistically significantly higher proportion of females in the magnetic bead band group (67% versus 41%, p<0.001). There was a higher proportion of patients with anxiety or depression at baseline in the magnetic bead band group (15% [20/135] versus 4% [4/103], p=0.008). The type of symptoms in each group differed, with 32% (43/135) of patients in the magnetic bead band having typical symptoms and 63% (85/135) having mixed typical and atypical symptoms, compared with 54% (56/103) and 45% (46/103) of patients respectively in the fundoplication group (p<0.001 and respectively). The proportion of supine time with ph<4 was 5.8% in the magnetic bead band group and 11.0% in the fundoplication group (p=0.002). In the propensity score full-matched data, preoperative characteristics were similar between the groups. disease Page 5 of 48

6 Key efficacy and safety findings Efficacy Number of patients analysed: 238 (135 versus 103) GERD-HRQL questionnaire scores (lower scores indicating fewer symptoms); median (interquartile range) Follow-up time Magnetic bead band n Toupet fundoplication Preoperative months 3 (4)* (4)* months 2 (5)* (3)* months 2 (4)* 94 3 (2)* months 1 (3)* 59 3 (3)* months 2 (4)* 47 3 (2.5)* months 2 (4)* 30 4 (2.8)* months 0 (4)* 24 2 (2)^ 10 *p<0.001, ^p=0.011 (p values comparing postoperative scores with preoperative scores in each treatment group) There was no statistical difference in the GERD-HRQL scores between the treatment groups. Primary and secondary outcomes over time Outcome Measure Estimate CI p value HRQL Odds ratio to PPI use Odds ratio to Gas-related symptoms Reoperation rate Odds ratio to Hazards ratio to Odds ratios are relative to time procedure interaction of generalised estimating equation. n Safety Complications Magnetic bead band Respiratory arrest, n=1 (within the first hour postoperatively; the patient was successfully resuscitated without consequences.) Toupet fundoplication Atrial fibrillation, n=1 Urinary retention, n=1 Bleeding from trocar site, n=1 The prevalence of dysphagia was statistically significantly greater in patients treated by magnetic bead band at 3- month follow-up (odds ratio 9.42, 95% CI 2.22 to 20.10, p<0.001) (actual rates are not given in the paper). At 1-year follow-up, there was no difference between the groups (interaction time term not statistically significant, treatment term 0.78, 95% CI to 1.57, p=0.357). Reoperation 4 patients in the magnetic bead band needed reoperation for adverse events; 3 had persistent dysphagia and 1 had erosion (no further details were provided). In all these patients, the device was removed through laparoscopy and a standard fundoplication was done. At 80 months, the estimated Kaplan Meier reoperation-free probability survival was 0.94 (95% CI 0.89 to 0.98) for patients treated by magnetic bead band and 0.97 (95% CI 0.88 to 0.99) for patients treated by Toupet fundoplication. Reoperation for recurrent symptoms of heartburn or regurgitation Magnetic bead band=2.2% (3/135) (the device was removed through laparoscopy and a standard fundoplication was done). Toupet fundoplication=3.9% (4/103) (all patients had subsequent Nissen fundoplication) hazard ratio 0.77, 95% CI 0.23 to 2.57, p=0.687 Abbreviations used: CI, confidence intervals; GERD-HRQL, Gastro-Esophageal Reflux Disease-Health Related Quality of Life disease Page 6 of 48

7 Study 2 Warren HF (2016) Details Study type Country Non-randomised comparative study US (3 high-volume centres) Recruitment period April 2007 to December 2014 Study population and number Age and sex Patient selection criteria n=415 (201 laparoscopic insertion of a magnetic bead band versus 214 Nissen fundoplication) Patients with gastro-oesophageal reflux disease. Median 54 years (magnetic bead band) versus 52 years (Nissen fundoplication), p= % female (magnetic bead band) versus 57% female (Nissen fundoplication), p=0.06 Aged between 18 and 85 years; documented history of gastro-oesophageal reflux disease at least partially responsive to PPI treatment, and positive ph testing. Exclusion criteria: prior gastric or oesophageal surgery, hiatal hernia greater than 3 cm, oesophageal dysmotility, and presence of endoscopically visible Barrett s or oesophageal stricture. Patients had to be eligible for both procedures. Technique Laparoscopic insertion of magnetic bead band LINX Reflux Management System was used (Torax Medical, US). Posterior closure of the crura with 1 to 2 sutures was done if indicated. Follow-up Conflict of interest/source of funding Laparoscopic Nissen fundoplication. All procedures included hiatal dissection and closure if indicated, reestablishment of at least 2 cm of intra-abdominal oesophageal length, fundus mobilisation with division of the short gastric vessels, and creation of a symmetrical wrap at the gastro-oesophageal junction. Median 12 months Three authors have received consulting fees from Torax Medical. Analysis Follow-up issues: An additional 40 patients were treated during the study period (21 magnetic bead band and 19 fundoplication) but were excluded because follow-up data were inadequate. A subgroup of 354 patients (169 magnetic bead band and 185 Nissen fundoplication) with a minimum of 1-year follow-up were used to validate clinical outcomes. Study design issues: Retrospective cohort study. Comparisons were made at 1 year for the overall group and for a propensity-matched group (114 matched pairs). Matching was based on preoperative oesophagitis, presence of microscopic Barrett s, hiatal hernia size, Hill grade and body mass index. Clinical symptom severity was measured by the Gastro-Esophageal Reflux Disease Health Related Quality of Life (GERD-HRQL) questionnaire. Study population issues: Overall, the 2 groups were similar in age, sex, and GERD-HRQL scores but statistically significantly different in preoperative obesity (32% versus 40%), dysphagia (27% versus 30%), median DeMeester scores (34 versus 39), presence of microscopic Barrett s (18% versus 31%), and hiatal hernia (55% versus 69%). Other issues: The authors note that there may have been a subtle selection bias with regard to the patients being offered each treatment; there was more microscopically identified Barrett s and more and larger hiatal hernias in patients treated by Nissen fundoplication. disease Page 7 of 48

8 Key efficacy and safety findings Efficacy Number of patients analysed: 415 (201 versus 214) GERD-HRQL questionnaire scores (lower scores indicating fewer symptoms); median values Follow-up period Magnetic bead band n=169 Nissen fundoplication n=185 p value (between groups) Preoperative year p value <0.001 <0.001 Quality of life at 1 year (%) Ability for eructation Ability for emesis Postoperative PPI Magnetic bead band n=169 Nissen fundoplication n=185 p value (between groups) < < Quality of life propensity matched analysis (%) Mean followup GERD-HRQL median score Postoperative PPI Ability for eructation Ability for emesis Magnetic bead band n=114 Nissen fundoplication n=114 p value (between groups) 11 months 16 months < < <0.001 Satisfaction Would have procedure again Safety Adverse events Major complications (30 days) Minor complications (30 days) Magnetic bead band n= % (1/201) GEJ obstruction, treated by surgery to remove a crural stitch. Nissen fundoplication N= % (3/214) 1 GEJ obstruction, treated by revisional surgery; 2 retrooesophageal abscesses, treated by surgical drainage. p value % 9% 0.49 Magnetic bead band device erosion=0.5% (1/201) (the patient presented with dysphagia 20 months after implantation and oesophagogastroduodenoscopy showed a portion of the device within the oesophageal lumen. The exposed magnetic beads were cut with an endoscopic cutter and the rest of the device was removed laparoscopically 90 days later. The patient made a full recovery without any complications.) Dysphagia and gas bloat at 1 year (%) Magnetic bead band n=169 Nissen fundoplication n=185 p value (between groups) No dysphagia Mild dysphagia Moderate dysphagia Severe dysphagia No gas bloat Mild gas bloat Moderate gas bloat Severe gas bloat disease Page 8 of 48

9 Efficacy Revision for recurrent symptoms Magnetic bead band=0.5% (1/201) (1 patient was converted to Nissen fundoplication at 13 months postoperatively for persistent reflux, demonstrated by positive ph testing and clinical symptoms.) Fundoplication=0.9% (2/214) (both revisions were done for recurrence of hiatal hernia with symptomatic gastrooesophageal reflux disease). Operating time (minutes) Magnetic bead band=60 Nissen fundoplication=76, p<0.001 Length of hospital stay (hours) Magnetic bead band=13 Nissen fundoplication=32, p<0.001 Safety Dysphagia propensity matched analysis (%) Magnetic bead band n=114 Nissen fundoplication n=114 p value (between groups) Mean follow-up 11 months 16 months <0.001 No dysphagia Mild dysphagia Moderate dysphagia Severe dysphagia No gas bloat Mild gas bloat Moderate gas bloat Severe gas bloat Hiatal closure (%) Magnetic bead band=19 Nissen fundoplication=83, p<0.001 Abbreviations used: GEJ, gastro-oesophageal junction; GERD-HRQL, Gastro-Esophageal Reflux Disease-Health Related Quality of Life disease Page 9 of 48

10 Study 3 Lipham JC (2015) Details Study type Country Case series US Recruitment period February 2007 to July 2013 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding n=1,048 Patients treated by laparoscopic insertion of a magnetic bead band for gastro-oesophageal reflux disease Not reported Safety related events were collected from 3 primary sources: published clinical literature along with the device s Summary of Safety Effectiveness Data, the FDA MAUDE (Food and Drug Administration Manufacturer and User Facility Device Experience) database for device-related complications, and information provided by the manufacturer. Device: LINX Reflux Management System (Torax Medical) Median implant duration=274 days Not reported Analysis Study design issues: Events included for the analysis were any patient-related experience that resulted in complications during or after surgery, the inability to complete the implantation of the device, a device malfunction that harmed a patient, a device-related event that required an intervention, and a hospital readmission or reoperation. Events were categorised as those that were reported during the clinical trial for regulatory approval and those reported after regulatory approval. The estimated number of implants done worldwide was obtained from the manufacturer. Other issues: Some of the events included in this analysis will also have been reported in other published articles. The single case of erosion is also described in Warren et al., disease 10 of 48 Page

11 Key safety findings Safety Number of patients analysed: 1,048 Summary of events by source Source of data Number of events Breakdown of events Clinical literature 32 9 device removals 20 oesophageal dilation 3 hospital readmissions Food and Drug Administration (FDA) Manufacturer and User device removal Facility Device Experience (MAUDE) database 1 device erosion Manufacturer s database 59 8 device removal 1 intra/perioperative complication 11 hospital readmissions 39 oesophageal dilation Overall summary of reported events Pilot Investigational Device Exemption Pivotal Investigational Device Exemption Outside US post-approval US postapproval Overall Number of patients Number of centres Implant duration (days), median (range) 2,051 (226 to 2,302) 1,448 (21 to 1,614) 325 (2 to 1,308) 139 (3 to 448) 274 (2 to 2,302) Perioperative complications, % 0 (0) 0 (0) 0.2 (1) 0 (0) 0.1 (1) (no.) Readmission, % (no.) 0 (0) 3.0 (3) 1.9 (11) 0 (0) 1.3 (14) Oesophageal dilation, % (no.) 2.3 (1) 19 (19) 4.7 (26) 3.7 (13) 5.6 (59) Device removal, % (no.) 6.3 (3) 6.0 (6) 4.1 (23) 1.4 (4) 3.4 (36) Device erosion, % (no.) 0 (0) 0 (0) 0.2 (1) 0 (0) 0.1 (1) Device migration, % (no.) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Device malfunction, % (no.) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Readmissions and time frame after implant procedure Readmission within 90 days of implant Readmission more than 90 days after implant No. of patients % of total implants No. of patients % of total implants Dysphagia Dilation and dysphagia Pain Nausea and vomiting Overall Device removals and time frame after implant procedure Removal within 90 days of implant Removal more than 90 days after implant No. of patients % of total implants No. of patients % of total implants Dysphagia Gastro-oesophageal reflux symptoms Pain Vomiting MRI planned Erosion Overall All reoperations were done as elective surgery by laparoscopy for device removal, with no complications or conversion to laparotomy. disease 11 of 48 Page

12 Study 4 Ganz RA (2016) and 5 Ganz RA (2013) Details Study type Country Case series US and the Netherlands (14 centres) Recruitment period January to September 2009 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Analysis n=100 Patients with gastro-oesophageal reflux disease Median 53 years (range 18 to 75); 48% female Age 18 to 75 years; at least a 6-month history of gastro-oesophageal reflux disease (GORD); a partial response to proton pump inhibitors (PPIs); pathological oesophageal acid exposure confirmed by ph monitoring. Exclusion criteria included hiatal hernia greater than 3 cm, oesophagitis grade C or D according to the Los Angeles classification, body mass index higher than 35, Barrett s oesophagus, or motility disorder. Device: LINX Reflux Management System (Torax Medical, Inc.). A crural repair was done in 34% of patients. 5 years The study was funded by Torax Medical, Inc. Five authors have served as consultants to Torax Medical, Inc. and have received honoraria. Follow-up issues: 85% (85/100) of patients had a follow-up evaluation at 5 years and 82 patients had an endoscopy at the 5-year follow-up. Study design issues: Prospective, multi-centre, single-arm study. Quality of life was measured with the Gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) questionnaire, with scores ranging from 0 to 50 (higher scores indicate worse symptoms). For patients who had resumed PPIs, the dose and frequency were recorded and the PPI was stopped for at least 7 days before the questionnaire was completed. Oesophageal ph monitoring was done at 1-year follow-up only. The efficacy end points included the following: the number of patients with at least 50% reduction in the GERD-HRQL score compared with baseline (without PPIs); and a reduction of at least 50% in the dose of PPIs compared with baseline. The efficacy endpoint was achieved if it was met by at least 60% of patients. Side-effects and reflux-related symptoms were actively queried before and after treatment using the Foregut Symptoms Questionnaire. The 5-year evaluation included endoscopy to detect oesophagitis, Barrett s oesophagus, or device erosion. Chest radiography was used to confirm the device remained at the gastroesophageal junction. Oesophagitis was graded A to D, according to the Los Angeles classification system (Grade A: 1 or more mucosal breaks no longer than 5 mm that do not extend between the tops of 2 mucosal folds; Grade B: 1 or more mucosal breaks more than 5 mm long that do not extend between the tops of 2 mucosal folds; Grade C: 1 or more mucosal breaks, continuous between the tops of 2 or more mucosal folds but which involve less than 75% of the circumference; Grade D: 1 or more mucosal breaks which involve at least 75% of the oesophageal circumference). Study population issues: The median duration of reflux symptoms at baseline was 10 years (range 1 to 40). The median percentage of time ph was less than 4 was 10.9% (range 4.8% to 25.4%). disease 12 of 48 Page

13 Key efficacy and safety findings Efficacy Number of patients analysed: 100 Components of Oesophageal ph measurements Variable Baseline 1 year follow-up p value No. of patients Median value No. of patients Median value ph<4 Total percentage of time <0.001 ph<4 Percentage of time upright <0.001 ph<4 Percentage of time supine <0.001 Total no. of reflux episodes <0.001 No. of reflux episodes lasting >5 minutes <0.001 Longest reflux episode (minutes) <0.001 DeMeester Score (a score of 14.7 or more indicates abnormal reflux) <0.001 Efficacy at 5-year follow-up 50% or greater reduction in GERD-HRQL score=83% (70/84; 95% CI 73% to 91%) Reduction of 50% or more in average daily dose of PPIs=89.4% (76/85; 95% CI 81% to 95%) Reflux control over time (percentage of patients reporting each outcome) Follow-up Heartburn Regurgitation PPI dependence Dissatisfaction Baseline (n=100) year (n=95) years (n=90) years (n=87) years (n=86) years (n=84) p<0.001 for all comparisons with baseline At 5 years, 75.3% of patients reported complete cessation of PPIs, and 9.4% reported PPI use only as needed. Patients who needed double-dose PPIs decreased from 36% at baseline to 2.4% at 5 years. Of the patients reporting dissatisfaction at 5 years, all but 1 (5 out of 6) reported daily use of PPIs. Median total GERD-HRQL score At baseline, without PPIs=27 At baseline, with PPIs=11 At 5-year follow-up=4 (p<0.001 for both comparisons with baseline) Oesophagitis Healing of oesophagitis occurred in 76.5% (26/34) of patients evaluated at 5 years. Of the 8 patients with ongoing oesophagitis, 6 had Grade A and the others had Grade B. Of the patients without oesophagitis at baseline and evaluated at 5 years, 90% (43/48) continued to have no oesophagitis. Among the 5 patients with de novo oesophagitis, 4 had Grade A and 1 patient had Grade B. No patients developed Barrett s oesophagus during the study. Other symptoms (percentage of patients reporting each outcome) Follow-up Difficulty swallowing Bloating/gassy Diarrhoea Constipation Nausea/vomiting Baseline years p value < Abbreviations used: CI, confidence interval; GERD-HRQL, Gastroesophageal Reflux Disease-Health Related Quality of Life questionnaire; PPI, proton-pump inhibitor disease 13 of 48 Page

14 Safety There were no intraoperative complications. Adverse events and device removal at 3-year follow-up (%) Event Patients (n=100) Maximum level of intensity Mild Moderate Severe Device Removal Dysphagia Bloating Pain Odynophagia Hiccups Nausea Inability to belch or vomit Decreased appetite Flatulence Belching Weight loss Food impaction Globus sensation Irritable bowel syndrome or dyspepsia Regurgitation of sticky mucus Chest discomfort Vomiting Persistent GORD symptoms Serious adverse events occurred in 6% (6/100) of patients and the device was removed in 4 of the 6 patients. The other 2 patients were hospitalised for nausea and vomiting 2 days after surgery; their symptoms resolved with conservative therapy. In 3 patients, the device was removed at 21, 31 and 93 days after implantation for persistent dysphagia. The symptoms resolved after the device was removed. In 1 patient, the device was removed at 357 days because of intermittent vomiting of unknown cause. Symptoms did not resolve after device removal. The device was removed in 2 additional patients, at 489 days and 1,062 days after implantation. One patient had persistent reflux symptoms and the other had persistent chest pain. 3 of the 6 patients in whom the device was removed had a subsequent Nissen fundoplication, with no complications. At 5-year follow-up, there were no new safety concerns. One additional patient had the device removed at 1,807 days after implantation, because of persistent dysphagia. Rate of device removal at 5 years=7% (7/100) There were no device erosions. Abbreviations used: GORD, gastro-oesophageal reflux disease disease 14 of 48 Page

15 Study 6 Saino G (2015) Details Study type Country Case series US, Italy Recruitment period February 2007 to October 2008 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Analysis n=44 Patients with gastro-oesophageal reflux disease Mean 42.8 years (range 19 to 71); 41% (18/44) female Age between 18 and 75 years; abnormal oesophageal ph as measured by ambulatory oesophageal ph monitoring; typical gastro-oesophageal reflux disease symptoms; daily PPI use. Exclusion criteria included hernia greater than 3 cm, oesophagitis of Grade B or higher (Los Angeles Classification), body mass index greater than 35 kg/m 2, Barrett s oesophagus, motility disorders, or gross oesophageal anatomical abnormalities. Patients with a known allergy to titanium, stainless steel, nickel, or ferrous materials were contraindicated for the device and therefore were not eligible for the study. Device: LINX Reflux Management System (Torax Medical, Inc.). 5 years The study was funded by Torax Medical, Inc. Two authors have received payment from Torax Medical, Inc. for consulting. Follow-up issues: Follow-up data to 5 years was available for 75% (33/44) of patients; 2 patients voluntarily withdrew from the study, 4 were lost to follow-up and 3 had the device removed. One clinical site did not follow patients up beyond 1 year and 2 patients completed the study at 1 year follow-up Study design issues: Prospective, multicentre study. Other issues: The patients included in this study were the first in the world to be treated by this procedure. disease 15 of 48 Page

16 Key efficacy and safety findings Efficacy Number of patients analysed: % (31/33) of patients had a greater than 50% reduction in total GERD-HRQL score compared with baseline. Summary of gastro-oesophageal reflux disease health related quality of life scores by question, mean (median) or mean±standard deviation Baseline (n=44) Year 5 (n=33) How bad is your heartburn? 3.7 (4.0) 0.5 (0) Heartburn when lying down? 3.1 (3.0) 0.5 (0) Heartburn when standing up? 3.3 (3.0) 0.4 (0) Heartburn after meals? 3.6 (4.0) 0.8 (1) Does heartburn change your diet? 3.1 (4.0) 0.2 (0) Does heartburn wake you from sleep? 2.5 (3.0) 0.1 (0) Do you have difficulty swallowing? 1.2 (1.0) 0.2 (0) Do you have bloating and gassy feelings? 2.9 (3.0) 0.3 (0) Do you have pain with swallowing? 0.6 (0.0) 0.0 (0) If you take medication, does this affect your 2.0 (2.0) 0.0 (0) daily life? Total GERD-HRQL score 25.7± ±3.0* *p<0.001 NB: the questionnaire was completed while the patient was off PPIs for at least 10 days at both time points. Each question was scored 0 to 5, where 0=no symptoms and 5=incapacitating symptoms). Safety Rate of serious adverse events related to the device or procedure=6.8% (3/44) 1 patient had chest pain shortly after the implant and needed a short stay in hospital; the pain resolved within 1 month. 1 patient had vomiting and nausea immediately after the implant procedure and needed an extended hospital stay; the symptoms resolved after 5 days. 1 patient had persistent dysphagia, which led to device removal 226 after implant. The patient had a Nissen fundoplication and dysphagia resolved approximately 30 days after device removal. Two other patients had an elective device removal: 1 to have an MRI and 1 to have a Nissen fundoplication for ongoing reflux symptoms. There were no reports of death, device erosions, device migrations, device malfunctions, or late-occurring device complications. All serious adverse events occurred and resolved within the first year after implant. Patient satisfaction with current condition Baseline=0% 5-year follow-up=90.9% Oesophageal ph measurements Measure Baseline Year 5 p value (n=44) (n=20) Total time (%) ph< <0.001 Upright time (%) ph< <0.001 Supine time (%) ph< Total number of reflux episodes Episodes lasting >5 minutes Longest time (minutes) DeMeester score < % (17/20) of patients who completed oesophageal ph monitoring at 5 years had either normal oesophageal acid exposure or had at least a 50% reduction from baseline. Normalisation of oesophageal ph (total percentage of time <5.3%) was achieved by 70% (14/20) of patients. PPI use at 5 year follow-up Complete cessation of PPIs=87.8% (29/33) Reduction of 50% or more in average daily dose of PPIs=93.9% (31/33) Abbreviations used: GERD-HRQL, Gastroesophageal Reflux Disease-Health Related Quality of Life questionnaire; PPI, protonpump inhibitor disease 16 of 48 Page

17 Study 7 Riegler M (2015) Details Study type Country Non-randomised comparative study Austria, Germany, Italy and UK Recruitment period Up to July 2013 Study population and number Age and sex Patient selection criteria n=249 (202 magnetic bead band, 47 laparoscopic fundoplication) Patients with moderate or advanced gastro-oesophageal reflux disease (GORD) Mean 47 years (magnetic bead band) versus 53 years (fundoplication), p= % female (magnetic bead band) versus 40% female (fundoplication), p=0.866 Patients who were candidates for a surgical antireflux procedure, including patients with advanced GORD defined as meeting 1 or more of the following conditions: large hiatal hernia (more than 3 cm in diameter of the oesophageal hiatus), Barrett s oesophagus, motility disorder, and grade C or D oesophagitis by Los Angeles classification. All patients had a diagnosis of GORD confirmed by abnormal oesophageal acid exposure on a prolonged ph or ph-impedance study. All patients had chronic reflux symptoms despite the use of medical therapy with PPIs. Patients were excluded if they had known conditions that would make it unlikely for them to complete a 3-year follow-up. Technique Laparoscopic insertion of magnetic bead band - LINX Reflux Management System was used (Torax Medical, US). Follow-up Conflict of interest/source of funding Analysis 1 year Laparoscopic fundoplication Nissen or Toupet Torax Medical, Inc. sponsored and partially funded the study. Two authors have received consulting fees and 1 author has received an unrestricted grant from Torax Medical, Inc. Follow-up issues: Only patients who had completed the 1-year follow-up were included in the study. Study design issues: Prospective, multicentre, observational study. The type of antireflux surgery to be done was provisionally agreed in consultation with the patient and the final decision was made by the surgeon at the time of laparoscopy. A variety of factors were taken into account, including the presence of a large hiatal hernia. Efficacy was assessed using the Gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) questionnaire, an abbreviated Foregut Symptom Questionnaire, and a question about reflux interfering with sleep. Study population issues: Age, large hiatal hernias, and Barrett s oesophagus differed statistically significantly between the 2 treatment groups. At baseline, hiatal hernias greater than 3 cm were diagnosed in 1.6% of patients in the magnetic bead band group compared with 45.7% of patients in the laparoscopic fundoplication group (p<0.001). Fewer patients in the magnetic bead band group had Barrett s oesophagus (1.0% versus 19.1%, p<0.001). 94% of patients in the magnetic bead band group met the definition of moderate GORD compared with 38.3% of patients in the fundoplication group. Severity of symptoms at baseline were similar between the groups. disease 17 of 48 Page

18 Key efficacy and safety findings Efficacy Number of patients analysed: 249 (202 versus 47) Clinical efficacy at 1 year follow-up Measure* GERD-HRQL score (median) Heartburn waking from sleep Reflux interfering with sleep Sleep with bed elevated or in reclining chair Moderate or severe regurgitation Extraoesophageal symptoms Discontinuation of PPIs Magnetic bead band Laparoscopic fundoplication Baseline 1 year Baseline 1 year * Percent of patients unless otherwise noted p value % of patients in the magnetic bead band group and 86.7% of patients in the laparoscopic fundoplication group reported an improvement in their GORD. At least 90% of patients in each group were willing to have antireflux surgery again (actual percentages not reported). Safety Intraoperative complications Magnetic bead band Injury to the pleura, n=1 Minor bleeding (<300 ml), n=2 (there were no clinical consequences) Laparoscopic fundoplication Injury to the pleura, n=1 Procedure related complications Magnetic bead band Postoperative dysphagia (number not stated) Pneumothorax, n=1 Laparoscopic fundoplication Laparoscopic surgical revision for herniation of the fundic wrap, n=1 Side effects evaluated at 1 year follow-up (% of patients) Measure Bloating and gassy feeling^ Difficulty swallowing^ Ability to belch Ability to vomit* Magnetic bead band Laparoscopic fundoplication p value < <0.001 * Based on the patients reporting a need to vomit ^ Percentage of patients reporting a score of 3 or higher for each measure on the GERD-HRQL, indicating the symptoms occurred at least daily and were bothersome Abbreviations used: GERD-HRQL, Gastroesophageal Reflux Disease-Health Related Quality of Life questionnaire; GORD, gastrooesophageal reflux disease; PPI, proton-pump inhibitor disease 18 of 48 Page

19 Study 8 Rona KA (2016) Details Study type Country Case series US Recruitment period May 2009 December 2015 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Analysis n=192 Patients with symptomatic gastro-oesophageal reflux disease (GORD). Median 56 years (range 18 to 81 years) 46% (89/192) female Age 18 years or above; confirmed evidence of GORD by increased oesophageal acid exposure on 24- hour ph monitoring; and persistent reflux symptoms despite maximal proton-pump inhibitor (PPI) therapy. Exclusion criteria: history of oesophageal or gastric surgery, oesophageal or gastric cancer, oesophageal stricture (or other gross anatomical abnormalities of the oesophagus), oesophageal dysmotility, or a known allergy to titanium. Device: LINX Reflux Management System (Torax Medical, Inc.). The size of the hiatal hernia was measured intraoperatively. Hernia repair consisted of dissecting out and reducing the hernia, and posterior closure of the crura using permanent sutures, maintaining 2 to 3 cm of oesophagus in the abdomen. Median 20 months (range 3 to 75 months) One of the authors is a consultant for Torax Medical, Inc. Follow-up issues: Outcomes were assessed at 6 months and yearly thereafter. Patients in the large hiatal hernia group had a shorter follow-up compared to those with smaller hernias (median 12 months versus 20 months). No losses to follow-up were described. Study design issues: Retrospective study. Outcomes consisted of Gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) questionnaire score, appraisal of proton-pump inhibitor requirement, dysphagia needing dilation, change in symptoms, and procedure-related complications. Symptom improvement was based on patient response to verbal inquiry. Study population issues: 27% (52/192) of patients had a hiatal hernia of 3 cm or larger (range 3 to 7 cm). Patients in the large hiatal hernia group were older, had a longer duration of GORD symptoms, a higher preoperative DeMeester score, and a higher incidence of oesophagitis. Barrett s metaplasia was present in 45 patients, none of whom had evidence of dysplasia. Other issues: During the last 2 years of the study, patient selection was expanded to include patients with hiatal hernias of 3 cm or larger. The improved postoperative outcomes with regard to GERD-HRQL and PPI requirement in the large hiatal hernia group may be secondary to the relatively shorter follow-up period. disease 19 of 48 Page

20 Key efficacy and safety findings Efficacy Number of patients analysed: 192 Mean GERD-HRQL score for all patients Baseline=18.9 Follow-up=5.0, p< % of patients had resolution or improvement of their symptoms Comparison of mean GERD-HRQL scores by size of hiatal hernia Hiatal hernia <3 cm, n=140 Hiatal hernia 3 cm, n=52 p value Baseline Follow-up Comparison of postoperative outcomes (% of patients) Postoperative proton-pump inhibitor use Symptom improvement or resolution Hiatal hernia <3 cm, n=140 Hiatal hernia 3 cm, n=52 p value Safety IP 973/2 [IPGXXX] There were no major intraoperative or postoperative complications. Device explants=1.6% (3/192) The reason for removal was the development of a subsequent gastric cancer in 1 patient and persistent GORD symptoms in the other 2 patients. Of the 2 patients with persistent symptoms, 1 patient had a smaller size device implanted and the other had a Nissen fundoplication; symptoms were subsequently controlled in both patients. Comparison of postoperative outcomes (% of patients) Dysphagia needing dilation Hiatal hernia <3 cm, n=140 Hiatal hernia 3 cm, n=52 p value Abbreviations used: GERD-HRQL, Gastroesophageal Reflux Disease-Health Related Quality of Life questionnaire; GORD, gastrooesophageal reflux disease disease 20 of 48 Page

21 Study 9 Stadlhuber RJ (2015) Details Study type Country Recruitment period Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Case report Austria Not reported n=1 Patient with erosive gastro-oesophageal reflux disease refractory to proton-pump inhibitor therapy 60-year-old male Not applicable Laparoscopic insertion of a magnetic sphincter augmentation device 2.5 years Not reported Key safety findings Case report: adenocarcinoma of the distal oesophagus in a patient with a magnetic sphincter augmentation device After the procedure, the patient reported complete resolution of reflux symptoms with occasional bloating and increased flatulence. An upper gastrointestinal endoscopy was done 2.5 years later and an adenocarcinoma was diagnosed in the distal oesophagus. No Barrett s oesophagus had been seen in previous endoscopies. An endoscopic submucosal dissection was done and the patient was subsequently referred to surgery. An open transthoracic en bloc oesophagectomy with gastric pull-up and intrathoracic anastomosis was done. The surgery was uneventful, apart from dense adhesions between the abdominal oesophagus and the left lobe of the liver in the hiatal region. The magnetic bead band was easily removed; almost no foreign body reaction or scar tissue was noted. disease 21 of 48 Page

22 Efficacy Quality of life In a non-randomised comparative study of 238 patients who had laparoscopic insertion of a magnetic titanium ring or Toupet fundoplication, the median Gastro- Esophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) symptom scores improved from 21 and 15 at baseline to 2 and 3 respectively at 3-year follow-up (p<0.001 for both treatment groups); there was no statistically significant difference in the GERD-HRQL scores between the treatment groups 1. In a non-randomised comparative study of 415 patients who had laparoscopic insertion of a magnetic titanium ring or Nissen fundoplication, the median GERD- HRQL) symptom scores improved from 21 and 19 at baseline to 3 and 4 respectively at 1-year follow-up (p<0.001 within groups and p=0.17 for between group comparison) 2. A statistically significantly higher proportion of patients who had a magnetic titanium ring, compared to those treated by Nissen fundoplication, reported ability for eructation (96% versus 69%, p<0.001), ability for emesis (95% versus 43%, p<0.001) and absence of gas bloat (53% versus 41%, p=0.03). In a case series of 100 patients, there was a 50% or greater reduction in the GERD-HRQL score for 83% (70/84; 95% confidence interval [CI] 73% to 91%) of patients at 5-year follow-up; the mean score at baseline (without proton-pump inhibitors [PPIs]) was 27 compared with 4 at 5-year follow-up (p<0.001) 4,5. Oesophageal acid exposure In the case series of 100 patients, the median percentage time that oesophageal ph was less than 4 decreased from 11% at baseline to 3% at 1-year follow-up (p<0.001) 4,5. In the same study, healing of oesophagitis occurred in 77% (26/34) of patients evaluated at 5 years. In a case series of 44 patients, the median percentage time that ph was less than 4 decreased from 12% at baseline (n=44) to 5% at 5-year follow-up (n=20, p<0.001); 85% (17/20) of patients who completed oesophageal ph monitoring at 5 years had either normal oesophageal acid exposure or had at least a 50% reduction from baseline 6. Proton pump inhibitor use In the non-randomised comparative study of 415 patients who had laparoscopic insertion of a magnetic titanium ring or Nissen fundoplication, PPI use was reported by 19% and 14% of patients respectively at 1 year follow-up (p=0.18) 2. In the same study, a propensity matched analysis of 114 patient-pairs showed a statistically significantly higher PPI use in the magnetic titanium ring group (24% versus 12%, p=0.02) but the follow-up periods were different (11 versus 16 months, p<0.001) 2. In the case series of 100 patients, 89% (76/85) of patients had a reduction of 50% or more in their average daily dose of PPIs at 5-year follow-up (95% CI 81% to 95%); 75% of patients reported complete cessation of PPIs and 9% reported PPI use only as needed 4,5. In the case series of disease Page 22 of 48

23 44 patients, 88% (29/33) of patients reported complete cessation of PPIs at 5- year follow-up 6. In a non-randomised comparative study of 249 patients, 82% of patients who had laparoscopic insertion of a magnetic titanium ring reported cessation of PPI use at 1-year follow-up, compared with 63% of patients who had laparoscopic fundoplication (p=0.009) 7. Reoperation In the non-randomised comparative study of 238 patients who had laparoscopic insertion of a magnetic titanium ring or Toupet fundoplication, reoperation for recurrent symptoms of heartburn or regurgitation was reported for 2% (3/135) and 4% (4/103) of patients respectively (hazard ratio 0.77, 95% CI 0.23 to 2.57, p=0.687) 1. In the non-randomised comparative study of 415 patients who had laparoscopic insertion of a magnetic titanium ring or Nissen fundoplication, reoperation for recurrent symptoms was reported in <1% (1/201) and 1% (2/214) of patients respectively 2. Patient satisfaction In the non-randomised comparative study of 415 patients who had laparoscopic insertion of a magnetic titanium ring or Nissen fundoplication, patient satisfaction was 88% and 89% respectively (p=0.61) in a propensity matched analysis of 114 patient pairs; 93% of patients who had a magnetic titanium ring and 83% of patients who had Nissen fundoplication reported that they would have the procedure again (p=0.01) 2. In the case series of 100 patients, 95% of patients were dissatisfied with their current condition at baseline compared with 3.2% of patients at 1-year follow-up (n=95) and 7.1% at 5-year follow-up (n=84) 4,5. In the case series of 44 patients, 91% of patients were satisfied with their current condition at 5-year follow-up, compared with none at baseline 6. Safety Dysphagia Device removal for dysphagia was reported in 1.5% (16/1,048) of patients in a case series of 1,048 patients 3. Oesophageal dilation was needed in 5.6% (59/1,048) of patients in the same study. Dysphagia was reported in a statistically significantly higher proportion of patients who had a magnetic titanium ring than Toupet fundoplication in a non-randomised comparative study of 238 patients at 3-month follow-up (odds ratio 9.42, 95% confidence interval [CI] 2.22 to 20.10, p<0.001) but the difference was no longer statistically significant at 1-year followup 1. Mild dysphagia was reported in a statistically higher proportion of patients who had a magnetic titanium ring than in those treated by Nissen fundoplication (44% versus 32% at 1-year follow-up, p=0.03) in a non-randomised comparative study of 415 patients 2. The rates of moderate and severe dysphagia were similar in the 2 treatment groups (13% versus 11% for moderate dysphagia, p=0.57 and 1% versus 5% for severe dysphagia, p=0.24). Dysphagia was reported in 68% disease Page 23 of 48