3.1 Study subjects
The 50 subjects had the procedure performed at four different sites and have been followed for 1 year. Device implantation was attempted and performed in all subjects. Three subjects had discontinued the study by 1 year:
- 2 subjects with successful treatment results discontinued the study at 3 months and 6 months, respectively, with the following results at the time of discontinuation:
- No Dysphagia, no Odynophagia, no Regular Daily PPI consumption, no Regurgitation and subjects Satisfied
- 1 subject had the device placed too low at surgery – refused re-surgery and discontinued at 6-months with the following results at the time of discontinuation:
- Moderate Dysphagia, no Odynophagia, no Regular Daily PPI consumption, minimal Regurgitation and subject Dissatisfied
3.2 Baseline characteristics
Subject mean age was: 51.5 (SD 11.8) years. Of the 50 subjects, 28 (56%) were men and 22 (44%) women. PPI consumption was halted for all subjects at least 1 week prior to the baseline visit. 24-h pH monitoring (percentage of overall time pH <4) at baseline showed acid reflux in all subjects; mean result 16.35%. The mean score for the GERD-HRQL questionnaire (questions 1-10) one week off PPI at baseline was 28.8 (SD 7.3). Before surgery, all subjects took PPIs. At baseline endoscopy, 13 subjects (26.0%) had Grade A esophagitis and 9 subjects (18.0%) had Grade B esophagitis. At baseline, 26 subjects reported severe regurgitation in the foregut questionnaire. Forty-five of 50 subjects were Dissatisfied, 4 subjects Neutral and 1 subject Satisfied at baseline. The median score for severity of heartburn (GERD-HRQL question 1) was 4.0 at baseline (range 0 to 5). When assessed by the GERD-HRQL questionnaire at baseline, 15 subjects had difficulty swallowing (dysphagia) and 13 subjects had pain at swallowing (odynophagia). The median score for bloating or a gassy feeling was 4.0 (range 0 to 5) at baseline.
3.3 Safety Parameters
No serious adverse events related to the RefluxStop™ device were reported during the 6-month and 1-year follow-up periods. No deaths, no device deficiencies and no device explantations were reported/performed during this period.
The following presentation of the adverse events has been divided into events related to the device, anti-reflux surgery or surgical procedure in general (Table 1). Further division of events with respect to seriousness aims to facilitate an overview of the safety profile of the device.
Table 1. Adverse Events related to the device, anti-reflux surgery or surgery in general
3.4.1 Serious Adverse Events related to surgery – none device related
Six serious adverse events (SAEs) were reported for 4 subjects at 6 months. All but one of the events described above were resolved at the time of the 6-months analysis cut-off date. The subject diagnosed with an abdominal wall hernia unrelated to surgery may eventually undergo surgical repair.
Two of these adverse events above were more serious, directly correlated to surgery in general belonging to the two most common adverse events in surgery, namely one infection and one bleeding. The bleeding lead to a second look. It probably originated from the divided short gastric vessel, was self-limiting and clot evacuation and drainage was performed. The infection included both mediastinal abscess and empyema, probably due to the infected mediastinal haematoma. However, due to a well-performed invagination of the device the infection did not spread to the pouch with the device, and the subject healed completely with an excellent treatment result.
One serious adverse event (SAE) was reported in 1 subject between the 6-month and 1-year visit due to the release of fundoplication sutures. Reoperation was performed, and the subject had a successful 1-year follow-up visit. This confirms the treatment principle and reinforces the importance of positioning the device high up.
3.4.2 Complications and side effects related to the procedure
Dysphagia and Odynophagia
Two important complications related to anti-reflux surgery are dysphagia and odynophagia [1, 2, 3, 20]. Fifteen subjects had dysphagia at baseline, whereof in 11 completely resolved and 4 subjects continued to have reduced swallowing problems at the 6-month visit (GERD-HRQL score above 1) (Table 2). At the 1-year visit, 2 subjects reported minimal dysphagia. No new cases of dysphagia were recorded at either visit.
Thirteen subjects had pain at swallowing before surgery and none of the subjects reported pain at swallowing at the 6-month visit, while at the 1-year visit, one subject reported pain at swallowing at the same minimal level as at baseline. No new cases of odynophagia were recorded at the 6-month or 1-year visits (Table 2).
Table 2. Dysphagia and Odynophagia at Baseline, 6-months and 1-year post-operation.
3.5 Efficacy Parameters
3.5.1 Reduction from baseline of GERD symptoms based on the GERD-HRQL score
The mean total GERD-HRQL score at baseline was 28.8 (SD 7.3), n=50. At 6 months (n=47), the score had decreased to 3.4 (SD 6.0) (p<0.001), reflecting an improvement in GERD symptoms of 88%. One subject discontinued the study with successful 3-month score (Figure 6 and Table 3).
Figure 6. Total GERD-HRQL score at Baseline, 6 months and 1 year post-operation.
Table 3. GERD-HRQL total score at 6 months and 1 year post-operation
Forty-five out of 47 subjects had at least 50% improvement of the GERD-HRQL total score from baseline. Two subjects are defined as a failure not having a 50% improvement in the GERD-HRQL score. Both these subjects had the device positioned too low, prohibiting the device to function as intended. One subject had the device placed too low at surgery and refused re-surgery (representing proof of concept since an incorrectly placed device does not treat the subject). In the second subject, the suture line between the stomach and esophagus failed which is believed to be due to fat in the suture line attachment. The subject was well treated during the 3-month follow-up and was recorded as a failure after 6 months because the fundus with the intact invaginated device had slipped down due to the stomach-to-fundus suture line failing, resulting in the device being positioned too low, hindering its function. The subject was reoperated after 8 months with resuturing and was immediately treated with optimal results (GERD-HRQL total score zero points) supporting once again that the new treatment principle works.
At the 1-year follow-up visit (n=47), >50% improvement in GERD symptoms compared to baseline was reported in 44 subjects. Two subjects with <50% improvement were shown to not have GERD and one subject had the device positioned improperly too low. The average score improvement when deducting the two subjects with failed results for reasons other than GERD was 89% and average score was 3.2. Full results in Figure 6 and Table 3.
3.5.1 24-hour pH monitoring
pH testing at the 6 months study visit was completed by 45 subjects. The esophageal pH was monitored using Bravo Capsules during a 24-hour period at baseline and again at 6 months post-implantation (Figure 7 and Table 4). The results show a mean reduction from baseline of percentage of overall time with pH <4 from 16.35% to 0.80% at the 6-month visit (p<0.001) reflecting a 95% improvement of the mean value. Normal 24-h pH results in 98% of subjects.
Two of the subjects refused the burdensome pH-monitoring test whereof one had a successful GERD-HRQL questionnaire score and one subject had the device positioned too low at surgery, prohibiting the function of the device. The latter subject refused reoperation and the pH monitoring test, but notable that this subject did not take any PPIs.
Figure 7. 24-hour pH monitoring at Baseline and 6 months post-operation
Table 4. 24-hour pH monitoring at Baseline and 6 months post-operation
3.5.2 PPI medication
PPI consumption/reuse is often used as an indicator for success in reflux surgery. Before surgery all 50 subjects were taking PPI drugs. Six months after implantation no subject (0%), n=47, took PPI medication. At the 1-year follow-up visit, 1 subject (2.1%), n=47, who had the device positioned too low, took regular daily PPIs (Table 5).
Table 5. PPI consumption before surgery and at follow up visits.
3.5.1 Gas bloating
Gas bloating often occurs in anti-reflux surgery [1, 2, 3, 17] and in the investigation the question about gas bloating in the GERD-HRQL (score above 2) was present in 84.0% of the subjects at baseline and in 19.1% of the subjects at 1 year. Gas bloating at 1 year compared to baseline: disappeared in 30 subjects; improved in 7 subjects; remained unchanged in 2 subjects; and no subject had their gas bloating symptoms worsen (Table 6).
Table 6. Gas bloating including change between Baseline and 1-year
Daily regurgitation is common in acid reflux subjects  and occurred in 44 subjects (88%) at baseline in the investigation, whereof 33 subjects had moderate to severe regurgitation. At 1-year follow-up 46 out of 47 evaluable subjects (97.8%) operated with RefluxStop™ had none or minimal occasional episodes of regurgitation (Table 7).
Table 7. Daily regurgitation before surgery and at 1-year follow up visit.
3.5.3 Subject Satisfaction
Forty-five subjects at baseline indicated that they were dissatisfied with their present condition whereas at follow-up six months after implantation 44 subjects (93.6%) were satisfied, one subject was neutral (2.1%) and two subjects dissatisfied (4.3%) (n=47) (Table 8). The two dissatisfied subjects were the same subjects as discussed previously with the device placed too low, hindering its function. Out of these, one subject was reoperated between 6 months and 1 year to improve the positioning of the device by placing it higher up and was thereafter immediately satisfied again (HRQL total score zero).
At the 1-year follow-up, one subject was still neutral (2.1%) and one subject was dissatisfied due to the device being positioned too low. In addition, two subjects (4.3%) were dissatisfied for reasons other than GERD: one subject had all tests performed with a normal outcome and one (1) subject had short-term gastritis and was satisfied at the subsequent follow-up visit and 2-year visit.
So far, no correctly operated subject has failed, which means that there is a 100% success rate for the treatment principle of RefluxStop™, supporting a possible shift in acid reflux treatment.
Table 8. Subject satisfaction before surgery and at follow-up visits.
3.5 Summary of the safety endpoint
No device related serious or non-serious adverse events occurred during the study. The surgery related serious adverse events were all resolved with satisfactory results.
3.6 Summary of the main efficacy endpoint
- 86% score reduction from baseline at 1-year follow up visit
- 95% confidence interval: 94.1– 79.4%
- Lower limit of confidence interval was above 60%
- Percent of subjects with at least 50% improvement: 93.6%
- 3 subjects had <50% improvement, whereof:
- 2 were shown not to have GERD
- 1 due to too low position of the device thereby prohibiting its function
24-hour pH Monitoring:
- 98% of subjects had normal 24-h pH monitoring (percentage of total time) at 6-months
- 95% improvement at 6-months on mean value
- 35% at Baseline reduced to 0.80% at 6-months (p<0.001)