Hernia Reduction Prior to Scheduled TIF Completion- The HEURISTIC Study
Phase: NA
Conditions: Fundoplication
Sponsor: EndoGastric Solutions

 
The HEURISTIC Study (D031517 – Rev C) 
December 19, 2017 
Page 1 of 61 
CLINICAL INVESTIGATION PLAN (CIP) 
The HEURISTIC Study 
HErnia RedUction PRIor to Scheduled TIF Completion 
 
This document complies with requirements of the Declaration of Helsinki, International Harmonized 
Standards: EN ISO 14155-1 and ISO 14155-2:2003(E) and with 21 CFR Parts 50, 54, 56, and 812. 
Sponsor: 
EndoGastric Solutions, Inc. 
18109 NE 76th Street, Suite 100 
Redmond, WA 98052 
Phone: 425-307-9200 
Study 
Responsibility: 
Investigator Initiated 
Each study investigator is responsible for institutional and protocol compliance 
CRO 
Daniel & Daniel Consulting, LLC 
http://www.clinregconsult.com 
Principal 
Investigator: 
Michael J. Murray, M.D. 
Northern Nevada Medical Group 
2385 E Prater Way Ste 205 
Sparks, NV  89434 
CO- Investigators: 
Medhat Fanous, MD (Iron River Hospital, Iron 
River, MI) 
 
Mamoon Raza, MD (Indiana 
Medical Research, Elkhart, IN) 
 
Date of Issue: 
December 19, 2017 
 
 
This protocol contains confidential information for use by the Investigators and their designated representatives 
participating in this clinical investigation. It should be held confidential and maintained in a secure location. 
Do not copy or distribute without written permission. 

 
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December 19, 2017 
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Protocol Approval Page 
 
STUDY TITLE: 
HErnia RedUction PRIor to Scheduled TIF Completion  
- The HEURISTIC Study 
PROTOCOL NUMBER: 
D031517 
VERSION NUMBER: 
C 
DATE: 
December 19, 2017 
 
We, the undersigned, have read and approve the protocol specified above and agree on its content.  
 
 
 
Adrian Lobontiu, MD 
 
Date:  
Michael A. Daniel 
CRO 
 
Date: 

 
The HEURISTIC Study (D031517 – Rev C) 
December 19, 2017 
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Investigator’s Signature Page 
 
STUDY TITLE: 
HErnia RedUction PRIor to Scheduled TIF Completion  
- The HEURISTIC Study 
STUDY CENTER: 
_____________________________________________ 
 (Print name of study center) 
 
We, the undersigned, have read and understand the protocol specified above and agree on its content. 
We agree to perform and conduct the study as described in the protocol.  
 
 
Investigator 
 
Print name: 
 
 
 
Date 
 
 
 
Investigator  
 
Print name: 
 
 
 
Date 
 
 
 
Investigator 
 
Print name: 
 
 
 
Date 
 
 
 
Investigator  
 
Print name: 
 
 
 
Date 
 
 

 
The HEURISTIC Study (D031517 – Rev C) 
December 19, 2017 
Page 4 of 61 
Protocol Synopsis 
The HEURISTIC Study  
HErnia RedUction PRIor to Scheduled TIF Completion  
 
Primary 
Objective 
Evaluation of the relative merits, safety and effectiveness of the EsophyX ZR 
transoral device in performing the standardized TIF 2.0 procedure preceded by 
laparoscopic Hiatal Hernia repair in PPI-prescribed patients with persistent 
“troublesome symptoms” per the Montreal consensus definition. 
Test Device 
EsophyX ZR System 
Principal 
Investigator 
Michael J. Murray, M.D. 
Northern Nevada Medical Group 
2385 E Prater Way Ste 205 
Sparks, NV  89434 
Co-
Investigators 
 
,  
Medhat Fanous, MD (Iron River Hospital, 
MI) 
 
Mamoon Raza, MD (Elkhart Hospital, IN) 
 
Type of Study 
Prospective, investigator initiated, multicenter, non-randomized single arm, open 
label. 
Study Duration 6 Months for primary endpoint.  1 and 2 year follow-up for QOL per SOC. 
Number of 
Patients 
Number of 
Sites 
50 patients from 3 sites 
 
Follow-Up 
Schedule 
Following TIF procedure, patients will be expected to complete follow-up visits 
at the 2-Week, 3-Month, and 6-Month time points.  Additional follow-up to be 
completed at 12 and 24 months to assess long-term symptom relief.  
Consideration will be given to extending follow-up with questionnaires to 3, 4 
and 5 years. 
The study will be considered complete (with regard to the primary effectiveness 
endpoint) after all patients have completed the 6-Month follow-up visit. 

 
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Inclusion 
Criteria 
1. 
Age 18-80 years 
2. 
Dependent upon daily PPIs for > 6 months. Daily use is defined as a double dose, or full 
dose or half dose taken daily for more than 80% of the total number of days during the 
proceeding evaluation period 
3. 
Troublesome symptoms, specifically heartburn or regurgitation, while on optimized 
dose of PPI’s 
Troublesome heartburn or regurgitation symptoms are those which occur a minimum 
of 2 days a week and are mild to severe in severity 
4. Abnormal ambulatory (Bravo) pH study after off PPI therapy for 7 days, i.e. > 5.3% 
of the time with pH < 4 in a 48-hour monitoring period 
5. Normal or near normal esophageal motility (by Upper GI/ esophagram or 
manometry as required) 
6. Pre-enrollment Hiatal Hernia (axial height and transverse dimension) from > 2 cm 
up to 4 cm inclusive. 
7. Patient willing to cooperate with post-operative dietary recommendations and 
assessment tests at the requisite follow-up visits 
8. Signed informed consent 
Pre-enrollment 
Exclusion 
Criteria 
 
1. 
BMI > 35 
2. 
Hiatal hernia ≤ 2 and > 4 cm 
3. 
Esophagitis Los Angeles grade C or D 
4. 
Esophageal ulcer 
5. 
Esophageal stricture 
6. 
Long-segment Barretts esophagus (Prague: C > 1, M > 3) 
7. 
Esophageal motility disorder 
8. 
Pregnancy or plans for pregnancy in the next 12 months (in females) 
9. 
Immunosuppression 
10. ASA > 2 
11. Portal hypertension and/or varices 
12. History of previous resective gastric or esophageal surgery, cervical spine fusion, 
Zenker’s diverticulum, esophageal epiphrenic diverticulum, achalasia, scleroderma 
or dermatomyositis, eosinophilic esophagitis, or cirrhosis 
13. Active gastro-duodenal ulcer disease 
14. Gastric outlet obstruction or stenosis 
15. Severe gastroparesis or delayed gastric emptying confirmed by solid-phase gastric 
emptying study if patient complains of postprandial satiety during assessment 
16. Coagulation disorders  
17. Atypical symptoms including gas bloat and dysphagia.   
18. Any other presenting condition that in the opinion of the investigator would not 
make participation in this study in the patient’s best interest. 

 
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Post 
Enrollment 
Exclusion 
1. Inability to repair Hiatal hernia with at least 2cm of intra-abdominal esophagus length. 
Intervention 
Treatment:   
Standardized Transoral Incisionless Fundoplication (TIF 2.0) using EsophyX ZR 
system with SerosaFuse fasteners (EndoGastric Solutions, Inc., Redmond, WA, 
USA) preceded by Hiatal Hernia repair. 
Control:   
Each patient will serve as his/her own control (condition prior to HH repair  and 
TIF 2.0) 
Evaluation 
Criteria  
 
Primary Effectiveness Endpoint:   
Normalization in esophageal acid exposure is defined by ≤ 5.3% of total time pH 
< 4 in a 48-hour monitoring period. 
Secondary Effectiveness Endpoint 1:   
Per Montreal Consensus definition, troublesome symptoms are mild symptoms 
occurring two (2) or more days per week, or moderate/severe symptoms 
occurring more than 1 day per week. 
Secondary Effectiveness Endpoint 2:   
Clinically significant PPI consumption reduction is defined as from daily use to 
occasional use or none at all. Daily use is defined as a double dose, or full 
dose or half dose taken daily for more than 80 % of the total number of 
days during the proceeding evaluation period.  

 
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Study 
Hypotheses 
Primary Effectiveness hypothesis 
At 6-month follow-up, the proportion of TIF patients with normalized 
esophageal acid exposure will be statistically non-inferior to results from the 
EGS RESPECT study. 
Secondary Effectiveness hypothesis 1 
The proportion of TIF patients who are free of “troublesome” symptoms will be 
the same as or higher than the EGS RESPECT study. 
Secondary Effectiveness hypothesis 2  
At 6-month follow-up, ≥ 50% of the TIF patients will have a clinically 
significant reduction in PPI consumption as compared with their pre-TIF 
consumption. 
Primary Safety hypothesis 1 
At 6-month follow-up, no increase in medically significant AE’s as compared 
with the RESPECT study 
Secondary Safety hypothesis 1 
At 6-month follow-up, no new onset symptoms and side effects frequently 
associated with Nissen fundoplication procedures including dysphagia and gas 
bloat.  
 

 
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Table of Contents 
Protocol Approval Page .............................................................................................................. 2 
Investigator’s Signature Page ..................................................................................................... 3 
Table of Contents ........................................................................................................................ 8 
1. 
Introduction and History of Prior Investigations ............................................................... 11 
2. 
Device Description ............................................................................................................ 13 
3. 
Study Design Rationale ..................................................................................................... 14 
4. 
Study Objective ................................................................................................................. 15 
5. 
Study Hypotheses .............................................................................................................. 15 
5.1. 
Primary Efficacy Hypothesis 1 ................................................................................... 15 
5.2. 
Secondary Efficacy Hypothesis 1 ............................................................................... 15 
5.3. 
Secondary Efficacy Hypothesis 2 ............................................................................... 15 
5.4. 
Primary Safety Hypothesis 1 ...................................................................................... 15 
5.5. 
Secondary Safety Hypotheses 1 ................................................................................. 16 
6. 
Study Design ..................................................................................................................... 16 
6.1. 
Study Population......................................................................................................... 16 
6.2. 
Study Schematic Design ............................................................................................. 16 
7. 
Study Population ............................................................................................................... 18 
7.1. 
Selection Criteria ........................................................................................................ 18 
7.2. 
Withdrawal ................................................................................................................. 19 
8. 
Study Methods and Techniques ........................................................................................ 19 
8.1. 
Clinical Symptom Assessments.................................................................................. 19 
8.2. 
PPI Usage ................................................................................................................... 19 
8.3. 
Upper GI Endoscopy .................................................................................................. 20 
8.4. 
BRAVO pH Studies.................................................................................................... 21 
8.5. 
Esophageal Motility .................................................................................................... 21 
9. 
Study Procedures ............................................................................................................... 21 
9.1. 
Determination of Patient Eligibility – Screening Process .......................................... 23 
Initial Screening - .............................................................................................................. 23 
Final Screening -: .............................................................................................................. 23 
9.2. 
Prior to the Study Procedure ....................................................................................... 23 
9.3. 
During the Study Procedure ....................................................................................... 23 
TIF Procedure (Treatment)................................................................................................ 24 
9.4. 
Post-Procedure / Hospital Discharge .......................................................................... 25 
9.5. 
Follow-up.................................................................................................................... 25 
10. Statistical Considerations .................................................................................................. 26 
10.1. Analysis Populations and Missing Data Handling ..................................................... 26 
10.2. Statistical Analysis Plan ............................................................................................. 26 
10.1. Sample Size and Power Estimation ............................................................................ 27 
11. Clinical Effectiveness Endpoints and Evaluation Criteria ................................................ 27 

 
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11.1. Clinical effectiveness .................................................................................................. 27 
12. Risks .................................................................................................................................. 28 
13. Adverse Events .................................................................................................................. 29 
13.1. Causality and Seriousness Assessment ....................................................................... 29 
13.2. Reporting Serious Adverse Events ............................................................................. 30 
13.3. Withdrawal of Subjects Due to Adverse Events ........................................................ 31 
13.4. Device Failures and Malfunctions .............................................................................. 31 
14. Data Management .............................................................................................................. 31 
14.1. Data Collection ........................................................................................................... 31 
14.2. Data Processing .......................................................................................................... 31 
15. Monitoring Procedures ...................................................................................................... 31 
15.1. Monitoring and Auditing ............................................................................................ 31 
15.2. Device Accountability ................................................................................................ 32 
16. Ethical Considerations ....................................................................................................... 32 
16.1. Declaration of Helsinki ............................................................................................... 32 
16.2. Institutional Review Board ......................................................................................... 32 
16.3. Informed Consent Form.............................................................................................. 32 
16.4. Amending the Protocol ............................................................................................... 33 
16.5. Emergency Actions ..................................................................................................... 33 
16.6. Protocol Deviations .................................................................................................... 33 
17. Study Administration ........................................................................................................ 33 
17.1. Pre-Study Documentation Requirements ................................................................... 33 
17.2. Record Retention ........................................................................................................ 33 
17.3. Criteria for Terminating Study ................................................................................... 34 
17.4. Criteria for Suspending/Terminating a Study Center ................................................. 34 
17.5. Investigator Responsibilities....................................................................................... 34 
18. Bibliography ...................................................................................................................... 36 
 

 
The HEURISTIC Study (D031517 – Rev C) 
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Appendix 
 
A 
Sample Informed Consent Form 
B 
Declaration of Helsinki 
C 
GSRS-HRQL Quality of Life Assessment 
D 
GERD-HRQL Quality of Life Assessment 
E 
Reflux Disease Questionnaire 
F 
Reflux Symptom Index 
 
 

 
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1. Introduction and History of Prior Investigations 
The need for a safe, effective, and durable treatment of gastroesophageal reflux disease 
(GERD) has become increasingly apparent in the past 15 years as a result of a growing 
prevalence and incidence of this chronic disease.1-6  The likelihood of developing GERD 
increases with the severity of anatomical change and dysfunction of the gastroesophageal 
(GE) junction, which represents the primary defense against reflux of gastric content into the 
esophagus. 7-12, 13 Restoration of the gastroesophageal junction competence at the anatomic, 
mechanic and physiologic levels is critical for an effective long-term treatment of GERD.2  
At the same time, complications and new onset symptoms associated with traditional 
laparoscopic Nissen fundoplication, including dysphagia and gas bloat must be avoided. 
A novel transoral incisionless device was developed in an attempt to mimic well established 
and long term proven principles of antireflux surgery via constructing a fundoplication at the 
gastroesophageal junction, restoring the angle of His, increasing sphincter augmentation, 
recreating the high pressure zone and reducing small hiatal hernia, but with fewer side 
effects. The EsophyX™ system with SerosaFuse fasteners (EndoGastric Solutions, 
Redmond, WA, USA) has been cleared by the U.S. FDA for treatment of GERD and 
reduction of ≤2 cm hiatal hernia and has been successfully used to reconstruct the 
gastroesophageal junction through  partial fundoplication with tailored delivery of multiple 
fasteners during a single-device insertion (Figures 1,2,3). 14  
The technique has been refined resulting in a significantly higher normalization rate of 
esophageal acid exposure and a significant increase of LES pressure and length, combined 
with long term symptom control. 
 
 
 

 
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The Esophyx device has been well-established for the indication of GERD treatment by the 
U.S. FDA through numerous Class II device 510(k) pre-market clearances dating back to 
2009 (and most recently K160960).  A summary of past clinical trials has been provided in 
Table 2. Based on the success of prior TIF surgeries, EndoGastric Solutions has recently 
fine-tuned the Esophyx device allowing for more user-friendly and automatic, stapler-like 
reliable fastener deployment, as stylet manipulation is no longer required (See “3. Device 
Description” section).  Neither the initial Intended Use nor the Indications for Use have been 
altered as a result of this design refinement.  The FDA cleared Indications for Use is 
provided below. 
“The EndoGastric Solutions EsophyX Z System with SerosaFuse Fastener and Accessories 
is indicated for use in transoral tissue approximation, full thickness plication and ligation in 
the GI tract and is indicated for the treatment of symptomatic chronic gastroesophageal 
reflux disease in patients who require and respond to pharmacological therapy. It is also 
indicated to narrow the gastroesophageal junction and reduce hiatal hernia ≤ 2cm in size in 
patients with symptomatic chronic gastroesophageal reflux disease.” 
The current ≤ 2cm hiatal hernia size limitation presents a problem for treating patients  with 
hiatal hernias >2 cm.  Traditionally, these patients, with more advanced anatomical defects, 
have been surgically treated via a laparoscopic Nissen Fundoplication (NF). Although 
laparoscopic, the NF is a complex and relatively invasive  procedure best performed by very 
experienced surgeons in order to increase the probability of achieving the desired repair of 
the hiatal hernia and completion of a total circumferential  360 degree “floppy” wrap 
without the complications of dysphagia and gas bloat. 
A recent n=64, 10-year follow-up study showed a 10.9% defective fundic wrap in 
laparoscopic Nissen candidates.1  Due to the fundamentally different approaches between 
TIF and Nissen procedures, the serious risks associated with Nissen that are inherently 
absent from the EsophyX TIF 2.0 technique include: excessive scarring, vagus nerve injury, 
dysphagia, gas bloat, and vomiting/ eructation inhibition from supra-physiological fundic 
overwrapping.2  
Historically, clinical results, with patients presenting with ≤2cm hiatal hernias, have 
demonstrated that the TIF procedures using the EsophyX system with SerosaFuse fasteners 
is effective in eliminating symptoms, decreasing the need for daily PPIs, normalizing 
esophageal acid exposure, increasing LES resting pressure, and promoting healing of 
esophagitis in more than 80% of patients with chronic GERD.  The obtained improvement in 
clinical and pathophysiological outcomes correlated significantly with the quality of the 
anatomic reconstruction. This clinical study is designed to explore use of the TIF procedure 
in patients who have had their hiatal hernias reduced from between >2cm and ≤4 cm to 
≤2cm.  Demonstration that TIF results with these patients are similar to TIF results from 
patients initially presenting with ≤2cm hiatal hernias while avoiding traditional NF 
complications could provide expanded patient choices in the minimally invasive treatment 
of GERD.  
                                                 
1 Neuvonen, Perttu, Mauri Iivonen, and Tuomo Rantanen. "Endoscopic evaluation of laparoscopic nissen 
fundoplication: 89% success rate 10 years after surgery." World journal of surgery 38.4 (2014): 882-889. 
2 Waring JP (1999). "Postfundoplication complications. Prevention and management". Gastroenterol. Clin. 
North Am. 28 (4): 1007–19, viii–ix. doi:10.1016/S0889-8553(05)70102-3. PMID 10695014. 

EndoGastric Solutions, Inc. 
 
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The HEURISTIC Study (D031517 – Rev C) 
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RESPECT16 
TEMPO17,18,19 
TIF vs. Sham20 
TIF 
Registry21,22,23 
STAR 
Registry 
Design  
A multi-center, 
randomized, single-
blind, controlled 
TIF/Placebo vs. 
Sham/PPIs trial  
A multi-center, 
randomized, 
open-label, 
controlled TIF vs. 
PPI trial  
A multi-center, 
double-blind, 
sham controlled 
randomized trial  
A multi-center, 
prospective, open-
label, post market 
registry  
An AGA-
sponsored, 
multi-center, 
prospective, 
open-label, post 
market registry  
Objective  
To compare safety 
and effectiveness of 
TIF vs. Sham/PPIs in 
patients with 
“troublesome 
symptoms” 
specifically 
regurgitation  
To compare safety 
and efficacy of TIF 
vs. PPIs for the 
treatment of 
chronic medically 
refractory GERD  
To gauge the time 
to ‘treatment 
failure’ during the 
first 6 months 
after intervention  
To evaluate the 
safety and efficacy of 
TIF in a broad range 
of GERD patients 
treated in routine 
clinical practice  
To compare the 
safety and 
efficacy of TIF 
procedure vs. 
Laparoscopic 
Nissen 
Fundoplication 
Surgery (LNF)  
Patients  
2:1 ratio 
TIF/Placebo group 
(n=80) vs. Sham/PPI 
group (n=40)  
2:1 ratio TIF group 
(n=28) vs. PPIs 
group (n=14)  
1:1 ratio TIF group 
(n=22) vs. sham 
group (n=22)  
274 patients treated 
with TIF procedure  
1:1 ratio TIF 
group (n=250) 
vs. LNF group 
(n=250)  
Duration(s)  
6 months, 1 year w/ 
crossover (abstract)  
6 months, 1 year 
w/ crossover, 3 
years  
6 months  
6 months, 1 year, 2 
years  
Ongoing  
Key Outcomes  
 
 Troublesome 
regurgitation was 
eliminated in 72% of 
TIF patients at > 1Y  
 Median heartburn 
score decreased from 
17 to 5 at 6 months 
and to 3, at > 1Y post-
TIF  
 Complete 
cessation of PPI 
therapy was achieved 
in 72% of TIF patients 
> 1Y  
 
 
 All symptomatic 
outcome measures 
were stable between 
1Y, 2Y and 3Y follow-
up  
 Esophagitis was 
healed in 86% of 
patients at 3Y follow-
up  
 71% of patients 
completely off PPIs 
at 3Y follow-up  
 Improvement in 
pH parameters 
remained stable at 
3Y follow-up  
 
 
 Average of 197 
days “time in 
remission” post-TIF 
vs. 107 days post-
sham  
 Six months post-
op 13/22 (59%) of TIF 
patients were in 
clinical remission 
with complete 
cessation of PPIs 
consumption.  
 69% of the TIF 
group normalized 
esophageal acid 
exposure vs. 20% of 
the sham group  
 
At 2Y follow-up:  
 65% normalization 
in the Reflux Symptom 
Index score  
 74% normalization 
of Gastroesophageal 
Reflux Symptom Score  
 A decrease from 
91% to 29% in daily PPI 
use  
 75% of patients 
had esophagitis healed  
 
In enrollment  
 
Table 2. Summary of Level I and II Clinical Studies (TIF 2.0) 
 
2.  Device Description  
The EsophyX® Z device is a single use, hand-held flexible instrument that is introduced transorally with a 
flexible endoscope in the center of the device, so the entire procedure can be done safely under direct 
visualization. The device is designed so the physician can manipulate esophageal and gastric tissue, creating a 
partial fundoplication, secured by and deploy strong, H-shaped fasteners in order to reconfigure lower 
esophageal anatomy to prevent GERD.  
 

EndoGastric Solutions, Inc. 
 
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3. Study Design Rationale 
In spite of the promising results described in the previous section, the TIF 2.0 procedure with 
EsophyX Z is not an ideal option for all GERD patients. Early GERD syndrome and disease 
is clearly best medically treated with antacids, H2 blockers and/or Proton Pump Inhibitors 
(PPIs).  These pharmacological approaches may be palliative but are both highly effective and 
believed to be very safe at labeled dosages and durations, in early stage of the disease.  The 
current 
general 
Gastroenterology 
consensus, 
as 
documented 
in 
the 
American 
Gastroenterological Association (AGA) Medical Position Statement on “The Management of 
Gastroesophageal Reflux Disease”, is that only patients who are either intolerant of PPIs, or 
who have persistent troublesome symptoms while on properly adjusted doses of PPIs should 
be considered for antireflux surgery. “Troublesome” symptoms in this context are defined by 

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The HEURISTIC Study (D031517 – Rev C) 
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the “Montreal Consensus”1 as mild symptoms occurring two (2) or more days per week, or 
moderate/severe symptoms occurring more than 1 day per week. 
Frequently, patients exhibiting GERD symptoms and Hiatal Hernias are treated with Nissen 
fundoplications. However, the Nissen technique is complex, and requires significant training 
and expertise to perform.  Many surgeons lack the requisite experience and resources to 
perform such a procedure safely and effectively. Demonstration of TIF effectiveness post 
hiatal hernia reduction from up to 4 cm, gastroenterologists would have an option as opposed 
to referring patients to select hospitals for a Nissen.  
As in RESPECT RCT, patients are required to cease PPI intake 7 days prior to the procedure 
to ensure of accurate pH measurement via the BRAVO capsule. 
In this context, an ideal study would consist of enrolling patients who suffered from persistent 
troublesome symptoms while on optimized dose of PPIs. The prospective study is open-label, 
non-randomized, and investigator initiated at multiple (3) sites (n=50).  The primary endpoint 
is a clinically significant pH improvement, i.e. normalization, at the 6 month post-op mark.  
The proportion of patients with normalized esophageal acid exposure after 6 months will be 
compared to that of the previous EsophyX RESPECT trial to demonstrate equivalent (non-
inferior) effectiveness.  A sequence of follow-up visits will be required (2 week, 3 month, 6 
month) to monitor symptom presence and PPI intake via Quality of Life surveys in addition 
to the primary endpoint.  This follow-up and symptom monitoring will include evaluation of 
potentially new onset symptoms such as dysphagia and gas bloating commonly associated 
with the NF procedure.  
4.  Study Objective  
Evaluation of the relative merits, safety and effectiveness of the EsophyX Z transoral device 
in performing an advanced TIF procedure preceded by laparoscopic Hiatal Hernia repair 
(hiatal hernias >2cm and ≤4 cm) in PPI- prescribed patients with “troublesome symptoms” 
per the Montreal consensus definition.  
5. Study Hypotheses 
5.1. 
Primary Efficacy Hypothesis 1 
At 6-month follow-up, the proportion of TIF patients with normalized esophageal acid exposure will be 
statistically non-inferior to results from the EGS RESPECT study. 
5.2. 
 Secondary Efficacy Hypothesis 1 
The proportion of TIF2 patients who are free of “troublesome” symptoms will be the same as or higher 
than the results from the EGS RESPECT study. 
5.3. 
 Secondary Efficacy Hypothesis 2  
At 6-month follow-up, ≥ 50% of the TIF patients will have a clinically significant reduction in PPI 
consumption as compared with their pre-TIF consumption  
5.4. 
 Primary Safety Hypothesis 1 
At 6-month follow-up, no increase in medically significant adverse events as compared with the RESPECT study 

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5.5. 
Secondary Safety Hypotheses 1  
At 6-month follow-up, no new onset symptoms and side effects frequently associated with Nissen 
fundoplication procedures including dysphagia and gas bloat. 
6. Study Design 
6.1. 
Study Population  
The study population will consist of patients with chronic “troublesome” GERD symptoms while 
on PPIs and proven anatomic deterioration of the gastroesophageal junction who prefer a 
laparoscopic Hiatal Hernia Repair followed by an endoscopic intervention (TIF 2.0) over the long 
term treatment of PPIs.  These patients should have well documented GERD with or without 
endoscopic signs of esophagitis, hiatal hernia >2cm and up to 4 cm and a history of > 6 months of 
daily use of PPI to control major GERD symptoms.  
6.2. 
Study Schematic Design 
 
Please see next page. 

EndoGastric Solutions, Inc. 
 
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Figure 6.  
Schematic of Study Design  

EndoGastric Solutions, Inc. 
 
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7. Study Population 
7.1. 
Selection Criteria 
The table on the following pages outlines the specific inclusion and exclusion criteria for 
the study.  Before randomization in the study, a patient must meet all of the inclusion and 
exclusion criteria. 
 
Inclusion Criteria: 
1. 
Age 18-80years 
2. 
Dependent upon daily PPIs for > 6 months. Daily use is defined as a double dose, or full dose or half 
dose taken daily for more than 80 % of the total number of days during the proceeding evaluation period 
3. 
Troublesome symptoms, specifically heartburn or regurgitation, while on optimized dose of PPI’s. 
Troublesome heartburn or regurgitation symptoms are those which occur a minimum of 2 days a 
week and are mild to severe in severity.  
4. 
Abnormal ambulatory (Bravo) pH study after off PPI therapy for 7 days, i.e. >5.3% of the time with 
pH < 4 in a 48-hour monitoring period 
5. 
Normal or near normal esophageal motility (by Upper GI/ esophagram or manometry as required) 
6. 
Pre-enrollment Hiatal Hernia (axial height and transverse dimension) from > 2cm and up to 4 cm 
inclusive 
7. 
Patient willing to cooperate with post-procedure dietary recommendations and assessment tests at 
the requisite follow-up visits 
8. 
Signed informed consent 
Pre-enrollment Exclusion Criteria: 
1. 
BMI > 35 
2. 
Hiatal hernia ≤ 2 and > 4 cm 
3. 
Esophagitis Los Angeles grade C or D 
4. 
Esophageal ulcer 
5. 
Esophageal stricture 
6. 
Long-segment  Barretts esophagus (Prague: C > 1, M > 3) 
7. 
Esophageal motility disorder 
8. 
Pregnancy or plans for pregnancy in the next 12 months (in females) 
9. 
Immunosuppression 
10. ASA > 2 
11. Portal hypertension and/or varices 
12. History of previous resective gastric or esophageal surgery, cervical spine fusion, Zenker’s 
diverticulum, esophageal epiphrenic diverticulum, achalasia, scleroderma or dermatomyositis, 
eosinophilic esophagitis, or cirrhosis 
13. Active gastro-duodenal ulcer disease 
14. Gastric outlet obstruction or stenosis 
15. Severe gastroparesis or delayed gastric emptying confirmed by solid-phase gastric emptying study 
if patient complains of postprandial satiety during assessment 
16. Coagulation disorders  
17. Symptoms including gas bloat and dysphagia. 
18. Any other presenting condition that in the opinion of the investigator would not make participation 
in this study in the patients best interest. 
Post-enrollment Exclusion Criteria: 
1.  Inability to repair Hiatal hernia with at least 2cm of intra-abdominal esophagus length. 

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7.2. 
Withdrawal  
While study withdrawal is discouraged, patients may withdraw from the study at any 
time, with or without reason and without prejudice to further treatment. Withdrawn 
patients will not undergo any additional follow-up.  In all cases of withdrawal, the 
reason(s) for withdrawal (if given) will be recorded upon study termination. 
8. Study Methods and Techniques 
8.1. 
Clinical Symptom Assessments 
The following four GERD-specific questionnaires will be used to assess typical and 
atypical symptoms, their frequency and intensity, as well as their impact on daily life, 
relationships, quality of life, state of mind, worries and concerns, sleep and diet. 
- Reflux Disease Questionnaire (RDQ) 
- GERD HRQL Quality of life assessment 
- GERD GSRS Quality of life assessment 
- RSI Questionnaire for atypical symptoms 
 
• 
The time needed for completion of all four questionnaires is estimated for 35 
minutes maximum. 
• 
A ≥ 50% improvement in the total GERD-HRQL and GERD-GSRS scores 
compared to the baseline off PPIs will be considered clinically significant. 
• 
A reduction in severity from ≥ moderate to ≤ mild and/or a reduction in frequency 
from ≥ 2 days per week to ≤ 1 day per week is indicative of a clinically significant 
result as measured by the Reflux Disease Questionnaire (RDQ). 
8.2. 
PPI Usage 
The use of PPIs plus other GERD medication such as histamine receptor antagonists 
(H2RA) and antacids will be recorded in a medication diary using generic names (Table 
3) and classified according to the daily dose and frequency. 18, 21 
 
Usage will be defined as “Daily” if a double dose, full dose or half dose is taken daily for 
more than 80% of the total number of days during the proceeding follow-up period. 
 
Note: “Full Dose” is defined as the first number of mg listed for each PPI in the following 
table. 

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Table 3.  Proton Pump Inhibitors (PPI) 
Generic Name 
Brand Names 
Available 
Pill Sizes 
(mg) 
Esomeprazole 
Nexium 
20, 40 
Lansomeprazole 
Prevacid, Dakar, Lanso, Lanzor, Prezal, 
Lanzol 
15, 30 
Omeprazole 
Prilosec, Losec, Logastric 
10, 20, 
40 
Pantoprazole 
Protonix, Zurcal, Pantozol, Zurcale 
20, 40 
Rabeprazole 
Aciphex, Pariet 
20 
 
8.3. 
Upper GI Endoscopy 
• 
Diagnosis of esophagitis according to the Los Angeles classification confirmed by 
esophageal biopsy. 22 
• 
Hiatal hernia size will be diagnosed based on the distance from Z-line to 
diaphragmatic impression measured in cm at retraction of the endoscope without 
insufflation. 
• 
Geometrical aspects of the TIF valves will be assessed by evaluating their: 
- 
Length, defined as the length in cm from the apex of the fundus to the 
valve lip as demonstrated in Figure 7;23 
- 
Circumference, defined as the distance in degrees between the two most 
distant fasteners as demonstrated in Figure 4; 
- 
Adherence to the endoscope defined as tight, moderate or loose;  
- 
Grade using Hill classification system,24 defining grade I by the presence 
of a prominent tissue fold surrounding the endoscopic shaft; grade II by the 
presence of a moderately prominent tissue fold which rarely opens with 
respiration and closes promptly; grade III by a barely present fold which 
fails to close around the endoscope; and grade IV by the lack of a muscular 
fold with lumen of esophagus staying open all the time allowing the 
squamous epithelium to be viewed from below. 
 

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Figure 7.  Schematic drawing of TIF valve and its 
geometric aspects (Illustration from Cadiere et al 
2008 16) 
8.4. 
BRAVO pH Studies 
Acid reflux (off all antisecretory compounds for a minimum of 7 days) will be 
documented using pH-metry techniques utilizing BRAVO system.  The BRAVO system 
will be used both at baseline/screening and at 6 monts post procedure to document in a 
consistent way, across all sites for an ambulatory 48 hour pH.  
Normal pH will be considered if pH < 4 lasts for ≤ 5.3% of the time in a 48-hour 
monitoring period. 
8.5. 
Esophageal Motility 
• 
Measures LES resting pressure following standard protocol 
• 
> 50% peristalsis with > 30% distal amplitudes  
• 
10 consecutive water swallows allows the assessment of propulsive motor function of 
the esophagus 
• 
High-resolution motility is optional  
9.  Study Procedures 
The schedule of observations and assessments to take place during the study follows on the 
next page. (Table 4) 
 

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Table 4. Study Events Schedule 
 
Initial 
Screening 
Final 
Screening 
 
 
Procedure 
Post-Procedure/ 
Hospital 
Discharge 
2-Week 
±3 days 
3-Month 
± 15days 
6-Month 
± 20 days 
12 and 24  
Months 
± 20 days 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
Sign Informed Consent Form 
 
X 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
X 
 
 
 
 
Record concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
Recording of GERD Medications 
X 
 
 
 
X 
X 
X 
X 
Recording of duration of GERD Symptoms 
X 
 
 
 
X 
X 
X 
X 
Recording of type of GERD Symptoms 
X 
 
 
 
X 
X 
X 
X 
Recording of PPI Use; except for 2-week and 
3-month visits, discontinue PPI usage for 7 
days to evaluate study endpoints  
X 
 
 
X 
X 
X 
X 
X 
RDQ, atypical symptom RSI, Quality of Life 
questionnaires GSRS, HRQL after being off 
PPI for at least 7 days 
X 
 
 
 
 
 
X 
X 
Discontinuation of anticoagulants if applicable 
(at least 10 days before scheduled TIF) 
X 
 
 
 
 
 
 
 
EGD with optional biopsy 
 
X 
 
 
 
 
X 
 
Motility studies (High resolution optional) 
 
X 
 
 
 
 
 
 
BRAVO pH study (at least 7 days after 
stopping all antisecretory compounds) 
 
X 
 
 
 
 
X 
 
Study Enrollment 
 
X 
 
 
 
 
 
 
Hiatal Hernia Repair 
 
 
X 
 
 
 
 
 
TIF 
2.0 
Procedure 
(if 
Hiatal 
Hernia 
successfully repaired with at least 2 cm of 
intra-abdominal esophagus) 
 
 
X 
 
 
 
 
 
Adverse Event Reporting  
 
 
X 
X 
X 
X 
X 
 

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9.1. 
Determination of Patient Eligibility – Screening Process  
Initial Screening -  
The following pre-procedure data must be collected in order to determine patient 
eligibility:  
 
• 
Demographics and medical history, to include age, weight, gender, and 
race 
• 
Usage of GERD medication (medication, dosage, frequency and duration) 
• 
Duration of GERD symptoms 
• 
Type of GERD symptoms 
• 
Duration of PPI Use 
• 
Clinical symptom assessments (RDQ) and Quality of Life questionnaires 
(GSRS,  HRQL, Atypical Symptom RSI) 
• 
All general inclusion/exclusion criteria have been met 
 
Upon completion of the Initial Screening Process, if it is determined that the 
patient does not have “troublesome” symptoms while on PPIs, they are NOT 
eligible for the study 
 
Final Screening -: 
The following pre-procedure data must be collected in order to determine 
eligibility: 
 
• Informed consent signing 
• Physical Examination 
• Days since last PPI intake (prior to BRAVO pH study) 
• EGD with optional biopsy 
• High resolution motility studies (optional)  
• Upper GI endoscopy 
• Bravo pH studies (48 hours) 
 
Patients who have met all entry criteria are enrolled to the study.  
9.2. 
Prior to the Study Procedure 
• 
The usage of any anticoagulants will be discontinued before TIF for at 
least 10 days. 
• 
12-hours before the procedure, the patient is expected to be fasting. 
• 
Immediately before the procedure, each patient will undergo an 
endoscopic examination of the stomach and esophagus.   
 
9.3. 
During the Study Procedure 
A Transoral Incisionless Fundoplication will be performed following the standard laparoscopic 
Hiatal Hernia Repair and closure of the diaphragmatic defect (crura closure will be made 

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posterior with 2-3 separate stitches). The patient will be terminated from the study if hiatal 
hernia cannot be repaired, with at least 2 cm intra-abdominal esophageal length. 
TIF Procedure (Treatment) 
The TIF procedure (treatment) will be conducted under continuous 
visualization following a standard TIF2.0 protocol (Figures 8).  
 
 
 
 
Figure 8.  Standard TIF2 protocol 
The usage of any anticoagulants will be discontinued before HHR and TIF 2.0 for 
at least 10 days.  Patients are expected to fast for 12 hours before the procedure.  
Antibiotic prophylaxis will be administered during induction of general 
anesthesia 
(oro-tracheal 
intubation 
and 
anti-emetic 
protocol; 
dehydrobenzoperidol, dexamethasone, Zofran, Primperan). 
As stated in Section 10.2, immediately before the procedure, each patient will 
undergo an endoscopic examination of the stomach and esophagus.  The 
EsophyX ZR will be inserted transorally through a bite-block into the esophagus 
with the patient in either in supine, or 45 degrees or left lateral position. 
During a single insertion of the device, a valve similar to that created through 
antireflux surgery will be reconstructed by retraction of full-thickness plications 
and tailored placement of multiple fasteners circumferentially 1-3 cm above the 
Z-line. The procedure is expected to last for 30-45 minutes.  The quality of the 

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created valve will be evaluated by an endoscopic examination immediately after 
the procedure.  Any complications related to the procedure will be recorded. 
In the event of patient complaint of significant unmanaged GERD symptoms 14 
days post procedure, the patient will be offered continued PPI therapy.  (See 
below) 
9.4. 
Post-Procedure / Hospital Discharge 
Patients will be released the next day after a complete physical examination and 
instructed to consume a liquid diet during the first two weeks and a soft diet 
during the following four weeks.  The liquid diet will consist of strained soups, 
pudding, milk, gelatin, yogurt, well-cooked and puréed vegetables, and chewable 
multivitamins.  During weeks 3 to 6, patients will introduce a soft diet consisting 
of moist fish, canned fruits, bananas, berries, soft eggs, cooked vegetables, 
mashed potatoes, pasta, moist rice, and cereals (softened in milk).  After the six-
week healing time, patients can then incorporate fresh vegetables, meats, bread, 
citrus and alcohol back into their diet. 
The usage of PPIs will be continued for 14 days following the procedure to allow 
healing of the gastric mucosa around the fasteners and to reduce patients’ post 
procedure anxiety.  In the event of the recurrence of troublesome symptoms, 
patients will be encouraged to contact the study coordinator.  The nature, 
intensity and frequency of these symptoms will be assessed during in-office 
visits. 
The designated staff at the clinical site will review the study requirements with 
the patient to maximize compliance with the follow-up schedule and the required 
medication regimen. Patients will be instructed to return for follow-up 
assessments according to the study event schedule in Section 8.  A date for the 
follow-up visit (office or phone as appropriate) should be established between the 
patient and Investigator, and if possible the visits scheduled at the time of hospital 
discharge. 
9.5. 
Follow-up 
All enrolled patients will be evaluated at 2-weeks, 3-, 6-, and 12-Months and 24 
months post TIF- procedure.  
The study will be considered complete (with regard to the primary endpoint) 
after all patients have completed the 6-Month follow-up period. 
Consultations may become necessary if major reflux symptoms emerge.  Before 
each follow up time point the patient will be contacted by telephone in order to 
enhance clinical assessments and data compliance.  Refer to the Schedule of 
Events (Table 4) for a comprehensive outline of protocol requirements. 

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10. Statistical Considerations 
10.1. 
Analysis Populations and Missing Data Handling 
Effectiveness Population - Per the Intent-to-Treat principle, all enrolled patients 
who receive the protocol TIF 2.0 procedure will be included in the effectiveness 
analysis.  
Safety Population - Safety analysis will include all enrolled patients who receive 
any portion of the protocol required Hiatal Hernia Repair or TIF 2.0 procedures.  
Missing data: All analyses will be based on available data.  Missing data will not 
be imputed by methods. 
  
10.2. 
Statistical Analysis Plan 
10.2.1 General Methodology 
Patient demographics and key baseline and disease characteristics at screening 
will be summarized by descriptive statistics. Mean, standard deviation, median, 
minimum and maximum will be reported for continuous variables.   Frequency 
counts and proportions will be presented for categorical variables.  Effectiveness 
and Safety endpoints will be similarly summarized with 95% confidence intervals 
for means and proportions of interest. 
10.2.2 Effectiveness Analysis 
The primary analysis timepoint for effectiveness is 6 months post TIF procedure. 
Descriptive summaries as described in 10.2.1 General Methodology will be 
provided for the primary effectiveness endpoint of proportion of patients with 
normalized esophageal acid exposure, and secondary endpoints of proportion of 
patients free of “troublesome” symptoms and proportion of patients with a 
clinically significant reduction in PPI consumption from their pre-TIF screening 
consumption.   
At each assessment time point, RDQ, atypical symptom RSI, Quality of Life 
questionnaires GSRS, HRQL will summarized as continuous measures. At 6 
months, changes from baseline will be similarly summarized for each of these 
instruments.  As defined in Section 8.1, portions of patients with clinically 
significant improvements will also be reported with 95% confidence intervals for 
GERD-HRQL, GERD-GSRS, RSI, and RDQ.  
In addition, for the primary endpoint, proportion of patients with normalized 
esophageal acid exposure, 44% was observed in the EGS RESPECT study.  Non-
inferiority testing will be conducted for the same proportion observed in the 
HEURISTIC study vs. the RESPECT result.  The hypotheses are as follows.  
H0: HEURISTIC 6-month normalization rate ≤ 44% − 20% = 24% 
HA: HEURISTIC 6-month normalization rate > 44% − 20% = 24% 
The HEURISTIC normalization rate will be considered non-inferior to the 44% 
RESPECT rate if H0 can be rejected at a 1-sided p<0.05 level by exact binomial 

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probability calculation.  To achieve this goal in 50 evaluable patients, the 
observed 6-month normalization rate in HEURISTIC must be 18/50 (36%) or 
higher. 
10.2.3 Safety Analysis 
Treatment emergent adverse events, i.e. adverse events occurring during or after the 
first protocol procedure (i.e. hiatal hernia reduction), will be summarized.  The 
proportion of patients with medically significant adverse events will be compared to the 
same proportions observed in the RESPECT study. 
In addition, the number and proportion of subjects reporting any given adverse event, 
including any clinically significant hiatal hernia repair complications and new onset 
symptoms (dysphagia, gas bloat) should they occur, will be tabulated.  Separate tables 
will be constructed for (a) all reported treatment emergent adverse events, (b) protocol 
procedures (hiatal hernia reduction, TIF) related adverse events, and (c) serious adverse 
events.  
10.1. 
Sample Size and Power Estimation 
For the primary endpoint, proportion of patients with normalized esophageal acid 
exposure at 6 months post TIF procedure, 44% was observed in the EGS RESPECT 
study.  It is assumed that the true underlying rate for HEURISTIC treatment would be 
the same, i.e. 44%.  In order to reject an inferior normalization rate of 24% at a 1-sided 
p < 0.05 level, the observed 6-month normalization rate in HEURISTIC must be 18/50 
(36%) or higher. With 50 evaluable subjects, the chance (power) for successfully 
reaching this goal is 0.90. 
 
11. Clinical Effectiveness Endpoints and Evaluation Criteria 
11.1. Clinical effectiveness 
Primary effectiveness endpoint and evaluation criterion  
The primary efficacy endpoint is normalization in esophageal acid exposure at 6 
months post TIF procedure.  Normalization in esophageal acid exposure is 
defined as ≤ 5.3% of time with pH < 4 in a 48-hour monitoring period. 
Secondary effectiveness measures and evaluation criteria 
Secondary effectiveness measures include free of “troublesome” heartburn and/or 
regurgitation symptoms and a clinically significant reduction in PPI use.   
Per Montreal Consensus definition, troublesome symptoms are mild to severe 
symptoms which occur a minimum of 2 days a week.  
A clinically significant PPI consumption reduction is defined as from daily use to 
occasional use or none at all. Daily use is defined as a double dose, or full dose or 
half dose taken daily for more than 80 % of the total number of days during the 
proceeding follow-up period. 

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Table 5.  Study Effectiveness Endpoints and Success Criteria 
Study 
Endpoints/Outcomes 
Control 
Pre-procedure 
Value 
Post-
procedure 
Value 
Success Criteria 
PRIMARY EFFECTIVENESS  
Normalized acid 
exposure 
Self-
Compar
ison 
BRAVO Ph 
studies after 
off anti-
secretory meds 
≥7 days 
BRAVO Ph 
studies at 6 
months after off 
anti-secretory 
meds ≥7 days 
Treatment success will be defined by a 
proportion of TIF patients with 
normalized acid exposure that is non-
inferior to the RESPECT result as defined 
in 10.2.2.  
SECONDARY EFFECTIVENESS 
GERD symptoms 
Self-
Compar
ison 
 
Reflux Disease  
Questionnaire 
(RDQ) scores 
Reflux Disease  
Questionnaire 
(RDQ) scores at 
and 6 months 
Treatment success will be defined by a 
proportion of TIF patients free of 
troublesome symptoms at 6 months that is 
≥ the same proportion in RESPECT Trial 
(67%) 
PPI usage 
Self-
Compar
ison 
PPI usage 
(must be 
“daily”) 
PPI usage at 6 
months 
Treatment success will be defined by 
≥50% of TIF patients that has a clinically 
significant reduction, i.e.  from "daily"  
PPI use to "none" or "occasional’ use, at 6 
months. 
 
 
12. Risks  
The following risks are anticipated and can result from the TIF procedure or 
general anesthesia: 
Expected typical risks or discomfort: 
• Pharyngolaryngeal pain (e.g., sore throat) 
• Musculoskeletal pain (e.g., left shoulder pain) 
• 
Temporary epigastric or abdominal pain, which can be treated with 
standard pain medication 
• Temporary dysphagia (i.e., difficulty swallowing) due to swelling 
• Nausea or vomiting 
Unusual risks or discomfort: 
• Oral or dental injury 
• Bleeding  
• Bloating sensation 
• Hematoma 
Rare risks:  
• Esophageal perforation, laceration or tear 
• Aspiration, hypoxia, achalasia 

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• Nerve damage  
• Arrhythmia 
• Pneumothorax, chest pain 
• Pneumoabdomen 
• Fistula 
• Infection of the mediastinal space 
Additional risks: 
• Operation to remove a defective device or its parts 
• Reoperation after a failed procedure (insufficient symptom relief) 
 
13. 
Adverse Events 
All adverse events will be monitored from the time of enrolling through the 6-
month follow-up visit. Unanticipated adverse device effects (UADE) and SAEs 
will be monitored through the 12-month follow-up.  
An AE is defined as any undesirable clinical occurrence in a patient whether or 
not it is considered to be device related. In addition, the definition of AE applies 
to any event with an onset post study treatment or to any underlying diseases, 
present at baseline, that exacerbate in severity post study treatment. Therefore, an 
underlying disease that was present at the time of enrollment is not reported as an 
AE, but any increase in the severity of the underlying disease is to be reported as 
an AE. This definition includes events occurring during the follow-up period. 
All AEs must be recorded in the electronic database. A description of the event, 
including the start date, resolution date, action taken, and the outcome should be 
provided, along with the Investigator’s assessment of the relationship between the 
AE and the study treatment.  
A serious adverse event (SAE) is defined as an event which leads to:   
• Death due to any cause 
• Life-threatening condition 
• Results in persistent or significant disability/incapacity 
• Requires in-patient hospitalization or prolonged hospitalization 
• Necessitates an intervention to prevent a permanent impairment of a body 
function or permanent damage to a body structure 
• Results in congenital abnormality 
13.1. Causality and Seriousness Assessment 
The Investigator and Sponsor will bring all expertise to bear on determining 
adverse event relationship to investigational device or other study treatment. The 
Investigator and Sponsor will promptly review documented adverse events and 
abnormal test findings to determine if the:  

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• Abnormal test finding or experience should be classified as an adverse 
event 
• Adverse event was definitely, probably, possibly, unlikely or not related 
to the, and 
• Adverse event meets the criteria for a serious adverse event. 
 
Causality/Relationship Definitions: 
Definitely 
Clear-cut temporal association and no other possible cause. 
Probably 
Clear-cut temporal association and a potential alternative etiology is 
not apparent. 
Possibly 
Less clear temporal association; other etiologies are also possible, but 
there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the drugs, devices or procedures 
involved in the research 
Unlikely 
Does not follow a reasonable temporal association; or causal 
relationship with the drugs, devices or procedures involved in the 
research is unlikely but cannot be completely ruled out 
Not related AE is completely independent of study product administration; 
and/or evidence exists that the event is definitely related to another 
etiology. 
 
13.2. 
Reporting Serious Adverse Events  
Study personnel must report to the EndoGastric Solutions Clinical Affairs 
Team any SAE by telephone, fax, or electronic data capture entry within 24 
hours of learning of the event. When telephoning in notification of an event, a 
telephone log or other source record should be retained at site as adequate 
documentation of timely event reporting. When faxing in notification of an event, 
a fax confirmation report must be retained at site as adequate documentation of 
timely event reporting.  
Attention: Adrian Lobontiu, MD, FACS 
Telephone Reporting: 650-474-9259 
E-mail Reporting: 
alobontiugsahyun@endogastricsolutions.com 
Study personnel must forward follow-up information as the event continues 
and/or resolves. 
It is the responsibility of the Site Principal Investigator to inform the IRB of SAE 
and events as required by local procedure. EndoGastric Solutions is responsible 
for relaying adequate information on SAEs/UADEs to  all participating 
investigators and regulatory authorities. 
 

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13.3. Withdrawal of Subjects Due to Adverse Events 
Patients who experience adverse events during or after the procedure will remain 
enrolled in the study. Once enrolled, all patients will be followed for safety and 
efficacy evaluations with the exception of consent withdrawals by patient. 
13.4. Device Failures and Malfunctions 
All failures and malfunctions of the study device will be documented in the 
electronic database, and the device will be returned to EndoGastric Solutions for 
analysis. Device failures and malfunctions should also be documented in the 
patient’s medical record. 
NOTE:     Device failures or malfunctions are NOT to be reported as adverse 
events. However, if there is an adverse event that results from a 
device failure or malfunction, that specific event would be 
recorded in the usual way. 
14. 
Data Management 
14.1. Data Collection 
Data will be collected via a standard paper-based system of CRFs.  In addition to 
collecting data as required per this protocol, various cost and reimbursement 
information will be captured on a per-patient and per-site basis.  All data will be 
treated confidentially and exported only in the aggregate non-identifiable form. 
14.2. Data Processing  
Data will be entered into a spreadsheet based database by the CRO.  Visual and 
computer error checks will be carried out. The Investigator will be queried on 
errors concerning completeness and consistency. 
Audits may be performed for quality assurance of the electronic database. 
15. Monitoring Procedures 
15.1. Monitoring and Auditing 
Monitoring visits to the clinical sites will be made periodically during the study, 
to ensure that all aspects of the current, approved protocol/amendment(s) are 
followed. Original source documents will be reviewed for verification of data.. 
The Investigator/institution guarantees direct access to original source documents 
by EndoGastric Solutions personnel, their designees, and appropriate regulatory 
authorities. In the event that the original medical records cannot be obtained for a 
patient that is seen by a non-study physician at a non-study institution, 
photocopies of the original source documents must be made available for review. 
The study may also be subject to a quality assurance audit by EndoGastric 
Solutions or its designees, as well as inspection by appropriate regulatory 
authorities. 

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It is important that the Investigator and relevant study personnel are available 
during the monitoring visits and possible audits and that sufficient time is devoted 
to the process. 
15.2. Device Accountability 
Device accountability records must be maintained at the study site.  Each site will 
purchase the devices from EGS. 
16. Ethical Considerations 
16.1. Declaration of Helsinki 
The Investigator will ensure that this study is conducted in full conformity with 
the current revision of the Declaration of Helsinki, and with the regulations and 
guidelines of FDA; whichever affords the greater protection to the patient. 
16.2. Institutional Review Board 
A copy of the protocol, proposed Informed Consent form, other written patient 
information and any proposed advertising material must be submitted to the IRB 
for written approval. A copy of the written IRB approval of the protocol and 
Informed Consent form must be received by EndoGastric Solutions before 
recruitment of patients into the study. 
The Investigator must submit and, where necessary, obtain approval from the 
IRB for all subsequent protocol amendments and changes to the Informed 
Consent form. The Investigator should notify the IRB of deviations from the 
protocol or SAEs/UADEs occurring at the site and other SAE/UADE reports 
received from EndoGastric Solutions in accordance with local procedures. 
The Investigator will be responsible for obtaining annual IRB approval and 
renewal throughout the duration of the study. Copies of the Investigator’s reports 
and the IRB continuance of approval must be sent to EndoGastric Solutions.  
16.3. Informed Consent Form 
A sample Informed Consent form is provided in Appendix A for the Investigator 
to prepare for use at his/her site. The written Informed Consent documents should 
be prepared in the language(s) of the potential patient population. 
The reviewing IRB and the sponsor must first approve the Informed Consent 
forms that are used. The Informed Consent forms that are used should be in 
accordance with the current guidelines as outlined by the Good Clinical Practices 
(GCP) guidelines, Declaration of Helsinki and the International Conference on 
Harmonization (ICH).  
Prior to participation in the clinical trial, each patient must give written Informed 
Consent after the context of the study has been fully explained to the patient in 
language that is easily understood by the patient. The patients must also be given 
the opportunity to ask questions and have those questions answered to their 
satisfaction. 

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Written Informed Consent must be recorded appropriately by means of the 
patient’s, or their legal representative’s dated signature. The patient will receive a 
copy of the Informed Consent form. 
16.4. Amending the Protocol 
This protocol is to be followed exactly, and will only be altered by written 
amendments. Administrative changes that do not affect the patient benefit/risk 
ratio (e.g., editorial changes for clarity) may be made without any further 
approvals. Any change that would require alteration of the Informed Consent 
form must receive approval from appropriate EndoGastric Solutions personnel 
and from the IRB prior to implementation. Following approval, the protocol 
amendment(s) will be distributed to all protocol recipients with instructions to 
append them to the protocol. 
16.5. Emergency Actions 
EndoGastric Solutions accepts the right of the Investigator to deviate from the 
protocol in an emergency when necessary to safeguard the life or the physical 
well being of a study patient. The Investigator must give notice of any emergency 
deviations and justification for the deviation to EndoGastric Solutions and the 
IRB as quickly as possible after the episode, in any event no later than 24 hours 
after the emergency. 
16.6. Protocol Deviations 
Deviations from clinical protocol requirements, including ICH/GCP guidelines, 
will be reviewed and evaluated on an ongoing basis and, as necessary, 
appropriate corrective actions put into place. 
 
17. Study Administration 
EndoGastric Solutions will make necessary efforts to ensure that this study is 
conducted in compliance with GCPs and all applicable regulatory requirements. 
17.1. Pre-Study Documentation Requirements 
Prior to shipment of investigational product, the following documents must be 
provided to CRO / EGS: 
• Signed and dated Investigator Agreement 
• A copy of the written IRB approval of the protocol  
• A copy of the written IRB approval of the Informed Consent Form  
• A copy of the curriculum vitae of the Coordinating Investigator and Co-
Coordinating Investigator (if applicable) 
17.2. Record Retention 
The Investigator will maintain all essential trial documents and source documentation, 
in original format, that support the data collected on the study patients in compliance 
with the ICH/GCP guidelines. Documents must be retained for at least 2 years after the 

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last approval of marketing application or until at least 2 years have elapsed after last 
enrolled patient. These documents will be retained for a longer period of time by 
agreement with EndoGastric Solutions or in compliance with other regulatory 
requirements. When these documents no longer need to be maintained, it is 
EndoGastric Solutions responsibility to inform the Investigator. The Investigator will 
take measures to ensure that these essential documents are not accidentally damaged or 
destroyed. If for any reason the Investigator withdraws responsibility for maintaining 
these essential documents, custody must be transferred to an individual who will 
assume responsibility. EndoGastric Solutions must receive written notification of this 
custodial change.  
17.3. Criteria for Terminating Study 
EndoGastric Solutions reserves the right to terminate the study but intends only to 
exercise this right for valid scientific or administrative reasons and reasons related to 
protection of patients. Investigators and associated IRB will be notified in writing in the 
event of termination. 
Possible reasons for study termination include (but are not limited to): 
• The discovery of an unexpected, significant, or unacceptable risk to the 
patients enrolled in the study. 
17.4. Criteria for Suspending/Terminating a Study Center 
EndoGastric Solutions reserves the right to stop enrolling of patients at a study center at 
any time after the study initiation visit if no patients have been enrolled or if the center 
has multiple or severe protocol violations without justification or fails to follow 
remedial actions. 
Possible reasons for suspending/terminating a study center include: 
• Repeated failure to complete case report forms prior to scheduled 
monitoring visits. 
• Failure to obtain written Informed Consent. 
• Failure to report SAE/UADE to EndoGastric Solutions within 24 hours of 
knowledge. 
17.5. Investigator Responsibilities 
• Agree to sign and adhere to the Investigator Agreement 
• Agree to participate in Investigator meetings as scheduled by EndoGastric 
Solutions 
• Be willing to perform and be capable of performing treatment procedures as 
outlined in this protocol 
• Comply with all required elements of this protocol Agree to obtain 
written Informed Consent before any study specific procedures are 
performed in accordance with GCP 
• Complete all data modules prior to scheduled monitoring visits 

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• Be willing to change hospital routine if required by protocol (as long 
as patient safety and well-being is not compromised) 

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18. Bibliography 
 
1. El-Serag HB. Time trends of gastroesophageal reflux disease: a systematic review. Clin 
Gastroenterol Hepatol 2007;5:17-26. 
2. Lundell L. Surgery of gastroesophageal reflux disease: a competitive or complementary 
procedure? Dig Dis 2004;22:161-170. 
3. Metz DC. Managing gastroesophageal reflux disease for the lifetime of the patient: 
evaluating the long-term options. Am J Med 2004;117 Suppl 5A:49S-55S. 
4. Moayyedi P, Talley NJ. Gastro-oesophageal reflux disease. Lancet 2006;367:2086-2100. 
5. Nandurkar S, Talley NJ. Epidemiology and natural history of reflux disease. Best Pract Res 
Clin Gastroenterol 2000;14:743-757. 
6. Smout AJ. The patient with GORD and chronically recurrent problems. Best Pract Res Clin 
Gastroenterol 2007;21:365-378. 
7. Stylopoulos N, Rattner DW. The history of hiatal hernia surgery: from Bowditch to 
laparoscopy. Ann Surg 2005;241:185-193. 
8. Jones MP, Sloan SS, Rabine JC, Ebert CC, Huang CF, Kahrilas PJ. Hiatal hernia size is the 
dominant determinant of esophagitis presence and severity in gastroesophageal reflux 
disease. Am J Gastroenterol 2001;96:1711-1717. 
9. Mittal RK. Hiatal hernia: myth or reality? Am J Med 1997;103:33S-39S. 
10. Mittal RK. Hiatal hernia and gastroesophageal reflux: another attempt to resolve the 
controversy. Gastroenterol 1993;105:941-943. 
11. Moss SF, Kidd M, Modlin IM. The status of the hiatus:  the role of hernia in 
gastroesophageal reflux disease. J Clin Gastroenterol 2007;41:S144-S153. 
12. Rydberg L, Ruth M, Lundell L. Mechanism of action of antireflux procedures. Br J Surg 
1999;86:405-410. 
13. Ahroni JH, Montgomery KF, Watkins BM. Laparoscopic adjustable gastric banding: 
weight loss, co-morbidities, medication usage and quality of life at one year. Obes Surg 
2005;15:641-7. 
14. Cadiere GB, Rajan A, Rqibate M, Germay O, Dapri G, Himpens J, Gawlicka AK. 
Endoluminal fundoplication (ELF) - evolution of EsophyXTM, a new surgical device for 
transoral surgery. Minim Invasive Ther Allied Technol 2006;15:348-355. 
15. Jobe BA, O'Rourke RW, McMahon BP, Gravesen F, Lorenzo C, Hunter JG, Bronner M, 
Kraemer SJ. Transoral endoscopic fundoplication in the treatment of gastroesophageal 
reflux disease: the anatomic and physiologic basis for reconstruction of the esophagogastric 
junction using a novel device. Ann Surg 2008;248:69-76. 
16. Cadiere GB, Rajan A, Germay O, Himpens J. Endoluminal fundoplication by a transoral 
device for the treatment of GERD: A feasibility study. Surg Endosc 2008;22:333-42. 

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17. Cadiere GB, Van Sante N, Graves JE, Gawlicka AK, Rajan A. Two-year results of a 
feasibility study on antireflux transoral incisionless fundoplication (TIF) using EsophyX. 
Surg Endosc 2009;(in press). 
18. Cadiere GB, Buset M, Muls V, Rajan A, Rosch T, Eckardt AJ, Weerts J, Bastens B, 
Costamagna G, Marchese M, Louis H, Mana F, Sermon F, Gawlicka AK, Daniel MA, 
Deviere J. Antireflux transoral incisionless fundoplication using EsophyX: 12-month 
results of a prospective multicenter study. World J Surg 2008;32:1676-88. 
19. Huber-Lang M, Henne-Bruns D, Schmitz B, Wuerl P. Esophageal perforation: principles of 
diagnosis and surgical management. Surg Today 2006;36:332-340. 
20. Bouvy ND, Witteman BPL, Jobe BA, Lorenzo C, Kraemer SJM, Gawlicka AK, McMahon 
B, Gravesen FH, Masclee A, Hameeteman W, Koek GH, Perry K. Tailored reconstruction 
of the esophagogastric junction using transoral incisionless fundoplication: a feasibility 
study. Surg Endosc 2008;(submitted). 
21. Bouvy ND, Witteman BPL, de Vries E, van Dam JW, Greve JW, Gawlicka AK, Masclee 
A, Hameeteman W, Koek GH. EsophyX transoral incisionless fundoplication for the 
treatment of GERD in clinical practice. Surg Endosc 2008;submitted. 
22. Lundell LR, Dent J, Bennett JR, Blum AL, Armstrong D, Galmiche JP, Johnson F, Hongo 
M, Richter JE, Spechler SJ, Tytgat GN, Wallin L. Endoscopic assessment of oesophagitis: 
clinical and functional correlates and further validation of the Los Angeles classification. 
Gut 1999;45:172-180. 
23. Jobe BA, Kahrilas PJ, Vernon AH, Sandone C, Gopal DV, Swanstrom LL, Aye RW, Hill 
LD. Endoscopic appraisal of the gastroesophageal valve after antireflux surgery. Am J 
Gastroenterol 2004;99:233-243. 
24. Hill LD, Kozarek RA, Kraemer SJ, Aye RW, Mercer CD, Low DE, Pope CE, 2nd. The 
gastroesophageal flap valve: in vitro and in vivo observations. Gastrointest Endosc 
1996;44:541-547. 
25 Nimish Vakil, M.D., F.A.C.G.,1 Sander V. van Zanten, M.D.,2 Peter Kahrilas, M.D.,3 John 
Dent, M.D.,4 Roger Jones, M.D.,5 and the Global Consensus Group American Journal of 
Gastroenterology The Montreal Definition and Classification of Gastroesophageal Reflux 
Disease: A Global Evidence-Based Consensus ISSN 0002-9270 C_ 2006 by Am. Coll. of 
Gastroenterology doi: 10.1111/j.1572-0241.2006.00630.x Published by Blackwell 
Publishing  
 
 
 
 
 

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 APPENDIX 
A 
 Sample Informed Consent Form 
 
RESEARCH SUBJECT INFORMATION AND CONSENT FORM 
 
TITLE:   
 
 
 
 
The HEURISTIC Study 
HErnia RedUction PRIor to Scheduled TIF 
Completion 
 
 
PROTOCOL NO.: 
 D031517 
 
 
WIRB® Protocol #xxxxxx 
PRINCIPAL  
INVESTIGATOR: 
Michael J. Murray, M.D. 
 
 
 
Northern Nevada Medical Group 
 
 
 
2385 E Prater Way Ste 205 
 
 
 
Sparks, NV  89434  
United States 
 
STUDY SITE(S):  
 
 
 
Medhat Fanous, MD (Iron River Hospital, Iron River, 
MI) 
 
 
 
 
 
Mamoon Raza, MD (Elkhart Hospital, Elkhart, IN) 
 
 
 
 
SPONSOR:  
EndoGastric Solutions, Inc. 
Redmond, Washington 
United States 
STUDY-RELATED  
PHONE NUMBERS: 
[Principal Investigator’s name] 
[Phone number] 

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CO- PRINCIPAL 
INVESTIGATOR(S): 
 
 
 
 
Medhat Fanous, MD (Iron River Hospital, MI) 
 
 
 
 
 
 
 
Mamoon Raza, MD (Elkhart Hospital, IN) 
  
                                              
 
 
United States 
STUDY-  
COORDINATOR: 
Adrian Lobontiu, MD, FACS 
 
Medical Director, EndoGastric Solutions 
 
650 474 9259 
 
This consent form may contain words that you do not understand.  Please ask the study doctor 
or the study coordinator to explain any words or information that you do not clearly 
understand.  You may take home an unsigned copy of this consent form to think about or 
discuss with family or friends before making your decision. 
 
SUMMARY 
You are being asked to be in a research study.  The purpose of this consent form is to help you 
decide if you want to be in the research study.  Please read this form carefully.  To be in a 
research study, you must give your informed consent.  “Informed consent” includes: 
• Reading this consent form, 
• Having the study doctor or staff explain the research study to you, 
• Asking questions about anything that is not clear, and 
• Taking home an unsigned copy of this consent form.  This gives you time to think 
about it and to talk to family or friends before you make your decision. 
You should not join this research study until all of your questions are answered. 
 
Things to know before deciding to take part in a research study: 
• The main goal of a research study is to learn things to help patients in the future. 
• The main goal of regular medical care is to help each patient. 
• Taking part in a research study is entirely voluntary.  No one can make you take part. 
• If you decide to take part, you can change your mind later on and withdraw from the 
research study. 

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• The decision to join or not join the research study will not cause you to lose any 
medical benefits.  If you decide not to take part in this study, your doctor will continue 
to treat you. 
• Parts of this study do  involve standard medical care.  Standard care is the treatment 
normally given for a certain condition or illness. 
• Your medical records may become part of the research record.  If that happens, your 
medical records may be looked at and/or copied by the sponsor of this study and 
government agencies or other groups associated with the study. 
• Your insurance provider may be billed for the costs of any of the procedures performed 
for the research study (for example, upper gastrointestinal (GI) endoscopy and 
radiography, or follow-up procedures).   
After reading and discussing the information in this consent form, you should know: 
• Why this research study is being done; 
• What will happen during the research; 
• What drug or device or procedures will be used; 
• Any possible benefits to you; 
• The possible risks to you; 
• The other medical procedures, drugs, or devices that could be used instead of being in 
this research study; and 
• How any problems you may have will be treated during the study and after the study is 
over. 
If you take part in this research study, you will be given a copy of this signed and dated 
consent form. 
 
PURPOSE OF THE STUDY 
You are being asked to voluntarily be in a research study to evaluate  the relative merits, safety 
and effectiveness of the EsophyX ZR transoral device in performing the standardized an 
advanced TIF 2.0  procedure preceded by laparoscopic Hiatal Hernia repair  (≤4cm) in PPI-
prescribed patients with persistent “troublesome symptoms” per the Montreal consensus 
definition will be evaluated. The EsophyX ZR device was cleared by the U.S. FDA in 2016 for 
treatment of symptomatic chronic GERD, after it was proven safe and effective.   
 
Who is being asked to take part in this research study? 
You are invited to participate in a research study of the EndoGastric Solutions Inc., EsophyX 
ZR System.  You were selected as a possible subject because your diagnostic tests, endoscopy, 
manometry or pH-metry, have indicated you are suffering from Gastro-esophageal Reflux 
Disease (GERD) .You also have a hiatal hernia greater than 2 but less or equal to 4 cm.,  
are intolerant onPPIs or have troublesome heartburn or regurgitation symptoms which occur at 
a minimum of 2-3 days a week and are having laparoscopic Hiatal Hernia repair. You have 
been recommended for antireflux surgery. 
 

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 Currently your GERD is treated with medication, proton pump inhibitors (PPI’s), but you have 
indicated that either you continue to experience symptoms despite taking PPI medication or 
you prefer an alternative treatment.   
 
The study is being performed on 50 patients by several doctors across the U.S. and will last for 
6 months. 
 
PROCEDURES 
Subjects will undergo the standardized laparoscopic Hiatal Hernia Repair and closure of the 
diaphragmatic defect (crural closure) followed by the TIF 2.0 procedure with EsophyX ZR 
device, which consists of inserting the EsophyX ZR device through your mouth, down the 
esophagus and into your stomach.  The surgeon will use prolene  fasteners to create an 
effective  flap valve between your stomach and the esophagus to help prevent acid reflux.  The 
device will be removed and the plastic fasteners will remain in the tissue of your esophagus to 
hold the flap valve.  
If you decide to take part in this research study, you will undergo the following procedures that 
are not part of your standard medical care: 
 
Screening Procedures: 
 
Procedures to determine if you are eligible to take part in a research study are called “screening 
procedures.” For this research study, the screening procedures include the following: 
 
• You will have a physical exam. 
 
• You must answer questions about your general medical history, symptoms and history 
of GERD, medication history, surgical history, the food you commonly eat and what 
activities you do.  Additionally, you will be asked to fill out three short questionnaires 
to determine your frequency and intensity of your GERD symptoms and to evaluate 
their impact on your quality of life.  Your name will not be associated with these 
questions, so no one outside of your study doctor’s office will be able to connect you 
with your answers.  This visit will require about 1 hour of your time. 
 
• You will undergo an upper GI radiography (optional).  Before the test, you will drink 
barium (a chalky liquid) and possibly some gas-making crystals.  The doctor will watch 
the movement of the barium through your esophagus.  Several x-rays will be taken at 
different times and from different views.  This will allow the study doctor to look at 
your esophagus and make sure you are a good candidate for the EsophyX procedure. 
 
• An upper gastrointestinal endoscopy is a procedure that allows your doctor to look at 
the interior lining of your esophagus, your stomach, and the first part of your small 
intestine through a thin, flexible viewing instrument called an endoscope. The tip of the 

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endoscope is inserted through your mouth and then gently moved down your throat into 
the esophagus, stomach, and duodenum (upper gastrointestinal tract). 
 
• You will undergo an esophageal manometry test which is used to identify swallowing 
problems (optional, only if dismotility is suspected). It measures the strength and 
muscle coordination of your esophagus when you swallow. The esophagus is the "food 
pipe" leading from the mouth to the stomach. During the manometry test, a tube is 
passed through the nose, along the back of the throat, down the esophagus, and into the 
stomach. 
 
• You will undergo pH studies to measure the level of acidity in your esophagus coming 
from the stomach.  It will require placing a small capsule with pH sensor into your 
esophagus.  The capsule placement will be performed under local sedation.  The 
capsule attaches temporarily to the esophageal wall and transmits esophageal pH data 
wirelessly to a portable receiver.  You will be instructed to eat and live normally during 
the pH monitoring and to record times where you eat, sleep and experience symptoms.  
You will be required to carry around the receiver for the data from this detector for two 
days and then return to the doctor’s office for the removal of the device.  The capsule 
will naturally detach within 3-4 days and will come out with the stool.  This test may 
cause some discomfort in your esophagus and chest.  It will allow the doctor to see how 
much acid moves from your stomach into your esophagus on a daily basis and how that 
correlates with your symptoms.   
 
In the event that a clinically significant, unsuspected disease or condition is identified during 
this screening, the standard diagnostics and/or treatments will be applied.   
 
The Proposed  Procedure: 
 
If you qualify to take part in this research study, you will undergo the standard of care 
procedures listed below.   
 
• You are required to not eat anything for 12 hours before the procedure.  
 
• Before the Laparoscopic Hiatal Hernia repair followed by the TIF 2.0 procedure and 
immediately after the procedure, you will undergo endoscopy.  It will allow us to 
measure your gastroesophageal valve before and after the procedure. 
 
The TIF 2.0 procedure is performed under general anesthesia.  The EsophyX ZR device will be 
inserted through your mouth, down the esophagus and into your stomach.  The surgeon will 
use prolene  fasteners to create a small flap valve between your stomach and the esophagus to 
help prevent acid reflux.  The device will be removed, while  the plastic fasteners will remain 
in the tissue of your esophagus to hold the flap valve.  This procedure was invented based upon 
other surgical treatments for GERD but does not include incisions in the abdomen and has 

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fewer side effects. The only small abdominal incisions you will have are from the standard of 
care laparoscopic Hiatal Hernia Repair (HHR).  
• Before you are discharged from the hospital, you may have an upper GI radiography.  
This requires you to drink a liquid that will be tracked through your esophagus and 
stomach by X-ray to verify that there are no leaks from the procedure.   
 
• After the procedure, you will be on a diet of liquid foods for two weeks and a diet of 
soft foods for an additional four weeks.  This reduces the pressure on the new valve and 
allows for adequate healing time.   
 
• The Laparoscopic Hiatal Hernia Repair followed by the TIF 2.0 procedure is a one time 
(two steps) procedure and will take place at the surgery department of the <NAME OF 
INSTITUTION>.  Duration will approximately be 30-45 minutes and it will require a 
one night hospital stay.   
 
Follow-up Procedures: 
Procedures to evaluate the safety and effectiveness of the experimental TIF procedure are 
called “follow-up” procedures.  For this research study, the follow-up procedures will include: 
 
• The morning after the Laparoscopic Hiatal Hernia Repair and EsophyX ZR TIF 2.0 
procedure, the nurse will give you after surgery instructions and a physical exam.  You 
will meet with the study doctor or the study coordinator to discuss a new diet plan, and 
then you will be discharged from the hospital. 
 
• 2-Weeks after your procedure, you will return to the study doctor’s office.  You will be 
asked a few questions about how you feel after the procedure and you will 
progressively stop  taking GERD medication.    
 
•  3 and 6 months after your procedure, you will return to the study doctor’s office.  You 
will be asked a few questions about how you are feeling after the procedure and you 
will then be asked to complete questionnaires to determine the frequency and intensity 
of your GERD symptoms and to evaluate their impact on your quality of life. 12 and 24 
Month surveys will be sent but an office visit is not required.    
 
 
• At the follow-up 6-Month visit, you will be asked how you are feeling and asked to 
complete questionnaires just as you have done at previous office visits.  You will also 
undergo a pH study just as you did at your screening visit.  The pH study measures the 
level of acidity in your esophagus coming from stomach, as described above. 
 
 

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In addition to the listed procedure, you may also undergo any of the following procedures 
during follow-up visits per your study doctor recommendation:  
 
• Endoscopy - to determine the current status of your esophagus and the junction between 
your esophagus and stomach.  This is performed under sedation.  The doctor will put a 
camera through your mouth, down the esophagus, into the stomach and back out.  A 
small esophageal biopsy will be taken for tissue evaluation. 
 
• Manometry (optional) - to verify your swallowing pattern and identify important 
aspects of the valve between your stomach and esophagus.  A tube will be inserted 
through your nose into your stomach and you will be asked to swallow some water.   
 
• Upper GI radiography - to determine the current status of your esophagus and the 
junction between your esophagus and stomach.  Before the test, you will drink barium 
(a chalky liquid) and possibly some gas-making crystals.  The doctor will watch the 
movement of the barium through your esophagus and the junction on a video screen.  
Several x-rays will be taken at different times and from different view. 
• pH Studies - You will undergo pH studies to measure the level of acidity in your 
esophagus coming from the stomach. 
 
What are the possible risks, side effects, and discomforts of this research study? 
 
The possible risks of this research study may be due to the surgical procedure, the anesthesia, 
the follow-up tests, and/or the use of proton pump inhibitors PPI (standard medical treatment 
for GERD). 
 
Risks of the TIF procedure: 
 
Previous human research studies using the Laparoscopic Hiatal hernia Repair  procedure have 
shown that the nature and number of adverse events associated with its use are similar to other 
procedures that involve acid reflux surgery.   
 
Previous human research studies using the TIF 2.0 procedure have shown that the nature and 
number of adverse events associated with its use are significantly lower than other procedures 
that involve acid reflux surgery.  
 
Likely risks or discomforts (occur in greater than 10%, or more than 10 out of 100 people): 
Sore throat, left shoulder pain (from lying on your shoulder during surgery), temporary 
abdominal or esophageal pain that can be treated with standard pain medication or temporary 
difficulty swallowing due to swelling.  These adverse events are usually mild in severity. 
 

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Infrequent adverse events (occur in 1-10%, or 1-10 out of 100 people): Oral or dental injury, 
bleeding, bloating sensation or bruising.  These adverse events are usually mild in severity. 
 
Rare adverse events (occur in less than 0.5% , or less than 1 out of 200 people): Nerve damage, 
perforation of the esophagus, chest pain, gastric ulcer, infection, long-term swallowing 
disorders, foreign material entering the lungs, or arrhythmia (abnormal heartbeat).  Rarely, 
additional surgeries may be needed to repair an adverse event from the first procedure 
including: operation to repair an above-mentioned adverse event or operation to remove a 
defective device or its parts.  These adverse events can be moderate to severe.   
 
As with any new surgical procedure, there may be adverse events or side effects that are 
currently unknown and certain of these unknown risks could be permanent, severe, or life 
threatening. 
 
A physician, emergency drugs and equipment will be readily available should you experience 
any adverse events from the surgical procedure.   
 
If you are a woman of child-bearing potential, you will undergo a pregnancy test prior to your 
exposure to the TIF procedure.  Tests have not been done to determine the risk of the TIF 
procedure to pregnant women.  To avoid risks to the fetus, it is important that you not be 
pregnant when we conduct this study.  We also advise that you not become pregnant for at 
least six months after the procedure, as it may impact the outcome of the procedure.  Avoiding 
sexual activity is the only certain method to prevent pregnancy.   However, if you choose to be 
sexually active, you should use an appropriate “double barrier” method of birth control (such 
as female use of a diaphragm, intrauterine device (IUD), or contraceptive sponge, in addition to 
male use of a condom) or the female should be using prescribed “birth control” pills, 
injections, or implants.  If you choose to be sexually active during this study, pregnancy could 
still result even with the use of these birth control methods.   
 
Risks of the Anesthesia: 
 
Any time you undergo a procedure that requires general anesthesia, there are risks involved.  
Some of the mild to moderate risks include headache, vision problems, muscle pain, dizziness, 
drowsiness, mood changes, nausea or vomiting. Additionally serious and possibly life-
threatening reactions can occur while under anesthesia.  It is very important that your doctor is 
aware of any and all medications before undergoing this procedure to help prevent serious 
reactions.     
 
Risks of the follow-up tests: 
 
• -pH-Metry – can cause in some patients a discomfort felt in the upper chest.   
 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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• Endoscopy - A temporary, mild throat irritation sometimes occurs after the exam.  
Serious risks are very uncommon but include bleeding, fever, infection, breathing 
difficulty and heartbeat irregularity.  In extremely rare instances, a perforation, or tear, 
in the esophagus or stomach wall can occur.  This may require hospitalization and, 
rarely, surgery. 
 
• Manometry - can sometimes cause coughing or vomiting during tube placement or 
removal. 
 
• Upper GI radiography - participation will also involve radiation exposure.  The amount 
of radiation exposure that you will receive from this procedure is about 0.245 rem (a 
unit of radiation exposure) to the chest with minimal exposure of other body areas.  For 
comparison, radiation workers are permitted, by federal regulation, a maximum 
radiation exposure of 50 rems per year to any single body organ.  There is no minimum 
amount of radiation exposure that is recognized as being totally free of the risk of 
causing genetic mutations (abnormal cells) or cancer.  However, the risk associated 
with the amount of radiation exposure that you will receive from taking part in this 
study is felt to be low and comparable to everyday risks.   
 
Risks of the long-term use of PPIs: 
 
If PPIs are used over a long period of time, the following risks have been shown to be a 
possibility: gastric polyps, gastroenteritis, osteoporosis, hip fracture, dementia, kidney failure, 
c. difficile infection.   
 
If I agree to take part in this research study, will I be told of any new risks that may be found 
during the course of the study? 
 
You will be promptly notified if any new information develops during the conduct of this 
research study which may cause you to change your mind about continuing to participate.   
 
What are possible benefits from taking part in this study? 
 
Your GERD symptoms may improve or even go away as a result of your participation in this 
study.  However, there is no guarantee that you will receive such a benefit.   
 
The information from this research study may lead to a better treatment in the future for people 
with GERD. 
 
Who will pay for the surgery? 
 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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The costs of the study procedure and study-related tests will be billed to your insurance 
company.  Ask your study doctor what costs will or will not be covered by the insurance.  This 
discussion should include the costs of treating possible side effects.  Otherwise, you might 
have unexpected expenses from being in this study. 
 
Will I be paid if I take part in this research study? 
 
You will receive a compensation of $200 for completing each 6-month and 12-month follow-
up visit. 
 
Who will pay if I am injured as a result of taking part in this study? 
 
This research study involves the FDA- approved EsophyX ZR device, being evaluated for its 
FDA- approved use in the treatment of symptomatic chronic gastro- esophageal reflux disease 
(GERD).  If you should suffer an injury related to the evaluation of this device in this research 
study, you should immediately contact the Principal Investigator listed on the first page of this 
consent form.  Necessary medical care will be provided to you.  The costs of this medical care 
will be billed to you or your insurance company in the usual manner (as per the costs of an 
injury that you may have suffered from any FDA- approved device).  In the event that your 
insurance company does not pay for these costs or you do not have insurance, the costs of 
injury treatment will be billed directly to you.  If you have concerns about this, you should 
discuss these concerns with the study doctor.  The surgical device company, EndoGastric 
Solutions, Inc., that developed the EsophyX ZR device and the TIF 2.0 procedure, will not 
provide additional care for injuries related to this research.  There is no plan to provide you 
with other payments for or related to your injury.  However, you do not give up your legal right 
by signing this form. 
  
Who will know about my participation in this research study? 
 
Any information about you obtained from this research will be kept as confidential (private) as 
possible.  All records related to your involvement in this research study will be stored in a 
locked file cabinet.  Your identity on these records will be indicated by a case number rather 
than by your name, and the information linking these case numbers with your identity will be 
kept separate from the research records.  You will not be identified by name in any publication 
of the research results unless you sign a separate consent form giving your permission 
(release). 
 
Will this research study involve the use or disclosure of my identifiable medical information? 
 
This research study will involve the recording of current and/or future identifiable medical 
information from your hospital and/or other (e.g., doctor’s office) records.  The information 
that will be recorded will be limited to information concerning your GERD symptoms and the 
effect on your life, the procedure itself, your medication history, the follow-up exams 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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December 19, 2017 
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previously listed in this document, and any adverse events that may have been associated with 
the TIF procedure.   
 
The nature of the identifiable information resulting from your participation in this research 
study that will be recorded in your medical record includes the results of the additional follow-
up tests performed for research purposes and information related to any adverse events you 
may suffer following the TIF surgical procedure. 
 
Who will have access to identifiable information related to my participation in this research 
study? 
 
In addition to your study doctor listed on the first page of this authorization (consent) form and 
their research staff, the following individuals will or may have access to identifiable 
information (which may include your identifiable medical information) related to your 
participation in this research study:  
Authorized representatives of the WIRB may review your identifiable research information 
(which may include your identifiable medical information) for the purpose of monitoring the 
appropriate conduct of this research study.   
 
In unusual cases, the investigators may be required to release identifiable information (which 
may include your identifiable medical information) related to your participation in this research 
study in response to an order from a court of law.   
 
Authorized representatives of the sponsor of this research study, EndoGastric Solutions, Inc., 
will review and/or obtain identifiable information (which may include your identifiable 
medical information) related to your participation in this research study for the purpose of 
monitoring the accuracy and completeness of the research data and for performing required 
scientific analyses of the research data.  Authorized representatives of the study sponsor may 
also be present during your participation in the TIF procedure performed as part of this 
research study.  While the study sponsor understands the importance of maintaining the 
confidentiality of your identifiable research and medical information. 
 
The investigators involved in the conduct of this research study may receive funding from the 
sponsor to perform the research procedures and to provide the sponsor with identifiable 
research and medical information related to your participation in the study.   
 
Authorized representatives of the U.S. Food and Drug Administration may review and/or 
obtain identifiable information (which may include your identifiable medical information) 
related to your participation in this research study for the purpose of monitoring the accuracy 
of the research data.  While the U.S. Food and Drug Administration understands the 
importance of maintaining the confidentiality of your identifiable research and medical 
information. 
 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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Authorized representatives of <NAME OF INSTITUTION> or other affiliated health care 
providers may have access to identifiable information (which may include your identifiable 
medical information) related to your participation in this research study for the purpose of (1) 
fulfilling orders made by the investigators for hospital and health care services (e.g., laboratory 
tests, diagnostic procedures) associated wit-h research study participation; (2) addressing 
correct payment for tests and procedures ordered by the investigators; and/or (3) for internal 
hospital operations (i.e., quality assurance). 
 
For how long will the investigators be permitted to use and disclose identifiable information 
related to my participation in this research study? 
 
The investigators may continue to use and disclose, for the purposes described above, 
identifiable information (which may include your identifiable medical information) related to 
your participation in this research study for a minimum of seven years after final reporting or 
publication of a project.   
 
May I have access to my medical information that results from my participation in this 
research study? 
 
In accordance with the Notices of Privacy Practices document that you have been provided, 
you are permitted access to information (including information resulting from your 
participation in this research study) contained within your medical records filed with your 
health care provider. 
 
Is my participation in this research study voluntary? 
 
Your participation in this research study, to include the use and disclosure of your identifiable 
information for the purposes described above, is completely voluntary.  (Note, however, that if 
you do not provide your consent for the use and disclosure of your identifiable information for 
the purposes described above, you will not be allowed to participate in the research study.)  
Whether or not you provide your consent for participation in this research study will have no 
effect on your current or future relationship with the provider.  Whether or not you provide 
your consent for participation in this research study will have no effect on your current or 
future medical care at your provider  or affiliated health care provider or your current or future 
relationship with a health care insurance provider. 
 
Your study doctor is involved as an investigator in this research study.  As both your doctor 
and a research investigator, he is interested both in your medical care and the conduct of this 
research study.  Before agreeing to participate in this research study, or at any time during your 
study participation, you may discuss your care with another doctor who is not associated with 
this research study.  You are not under any obligation to participate in any research study 
offered by your doctor. 
 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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December 19, 2017 
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May I withdraw, at a future date, my consent for participation in this research study? 
 
You may withdraw, at any time, your consent for participation in this research study, to include 
the use and disclosure of your identifiable information for the purposes described above.  
(Note, however, that if you withdraw your consent for the use and disclosure of your 
identifiable information for the purposes described above, you will also be withdrawn, in 
general, from further participation in this research study.)  Any identifiable research or medical 
information recorded for, or resulting from, your participation in this research study prior to the 
date that you formally withdrew your consent may continue to be used and disclosed by the 
investigators for the purposes described above. 
 
To formally withdraw your consent for participation in this research study, you should provide 
a written and dated notice of this decision to the principal investigator of this research study at 
the address listed on the first page of this form. 
 
Your decision to withdraw your consent for participation in this research study will have no 
effect on your current or future medical care institutions or your current or future relationship 
with a health care insurance provider. 
 
If I agree to take part in this research study, can I be removed from the study without my 
consent? 
 
It is possible that you may be removed from the research study by the researchers if you do not 
meet the criteria for entry into the study; for example, your pregnancy test proves to be 
positive, you do not follow the instructions of your doctor regarding this study or you will not 
be able to participate in all monitoring/follow up visits for any reason, 
 
If you are withdrawn from participation in this research study, your doctor will continue 
providing you with the standard of medical care for your GERD and may discuss other options 
with you.  The described monitoring/follow- up procedures for your safety and the 
effectiveness evaluation of your GERD treatment will also be available to you after withdraw 
from study participation.   
 
Any identifiable research or medical information recorded for, or resulting from, your 
participation in this research study prior to the date that you formally withdrew your consent 
may continue to be used and disclosed by the investigators for the purposes described above. 
 
What are alternatives to participating in this study? 
If you choose to not to take part in this research study, you may consult your doctor for 
standard alternatives to the medication you are currently on for GERD or remain on your 
current medication.  
 
 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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December 19, 2017 
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SOURCE OF FUNDING FOR THE STUDY 
The sponsor, EndoGastric Solutions, Inc., will pay for this research study. 
 
QUESTIONS 
Contact: 
 
Michael J. Murray, M.D. 
Northern Nevada Medical Group 
2385 E Prater Way Ste 205 
Sparks, NV  89434  
for any of the following reasons: 
 
• if you have any questions about this study or your part in it, 
• if you feel you have had a research-related injury, or  
• if you have questions, concerns, or complaints about the research. 
 
If you have questions about your rights as a research subject or if you have questions, 
concerns, or complaints about the research, you may contact: 
 
Western Institutional Review Board® (WIRB®) 
3535 Seventh Avenue, SW 
Olympia, Washington 98502 
Telephone:  1-800-562-4789 or 360-252-2500 
E-mail:  Help@wirb.com. 
 
WIRB is a group of people who independently review research. 
 
WIRB will not be able to answer some types of questions, such as questions about appointment 
times.  You may contact WIRB if you cannot reach the research team or if you want to talk to 
someone else. 
 
Do not sign this consent form unless you have had a chance to ask questions and have gotten 
satisfactory answers. 
 
If you agree to be in this study, you will receive a signed and dated copy of this consent form for 
your records. 
 
************************************************************************ 
VOLUNTARY CONSENT 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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December 19, 2017 
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The above information has been explained to me and all of my current questions have been 
answered.  I understand that I am encouraged to ask questions, voice concerns or complaints 
about any aspect of this research study during the course of this study and that such future 
questions, concerns or complaints will be answered by a qualified individual or by the 
investigator(s) listed on the first page of this consent document at the telephone number(s) 
given.  I understand that I may always request that my questions, concerns or complaints be 
addressed by a listed investigator.  I understand that I may contact [Add name], Chairman of 
the WIRB office, at 360-252-2500 to discuss problems, concerns, and questions, obtain 
information, offer input, or discuss situations in the event that the research team is unavailable.   
 
By signing this form, I agree to participate in this research study.  A copy of this consent form 
will be given to me. 
 
____________________________  
____________________________ ____________ 
Signature of Subject  
 
 
Printed Name of Participant  
Date 
 
 
CERTIFICATION of INFORMED CONSENT 
 
I certify that I have explained the nature and purpose of this research study to the above-named 
individual(s), and I have discussed the potential benefits and possible risks of study 
participation.  Any questions the individual(s) have about this study have been answered, and 
we will always be available to address future questions, concerns or complains as they arise.  I 
further certify that no research component of this protocol was begun until after this consent 
form was signed. 
 
___________________________________  
________________________ 
Printed Name of Person Obtaining Consent  
Role in Research Study 
 
_________________________________ 
 
____________ 
Signature of Person Obtaining Consent 
 
 
Date  
 
 
  
 
 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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B 
Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
 
Ethical Principles for Medical Research Involving Human Subjects Adopted by the 18th 
WMA General Assembly Helsinki, Finland, June 1964 and amended by the: 
 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. 
INTRODUCTION 
1. 
The World Medical Association has developed the Declaration of Helsinki as a statement 
of ethical principles to provide guidance to physicians and other participants in medical 
research involving human subjects. Medical research involving human subjects includes 
research on identifiable human material or identifiable data. 
2. 
It is the duty of the physician to promote and safeguard the health of the people. The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty. 
3. 
The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my patient will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act only in the patient's interest 
when providing medical care which might have the effect of weakening the physical and 
mental condition of the patient." 
4. 
Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
5. 
In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society. 
6. 
The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the etiology 
and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and 
therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality. 
7. 
In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
8. 
Medical research is subject to ethical standards that promote respect for all human beings 
and protect their health and rights. Some research populations are vulnerable and need 
special protection. The particular needs of the economically and medically disadvantaged 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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December 19, 2017 
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must be recognized. Special attention is also required for those who cannot give or refuse 
consent for themselves, for those who may be subject to giving consent under duress, for 
those who will not benefit personally from the research and for those for whom the 
research is combined with care. 
9. 
Research Investigators should be aware of the ethical, legal and regulatory requirements 
for research on human subjects in their own countries as well as applicable international 
requirements. No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this 
Declaration. 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
10. 
It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject. 
11. 
Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and on adequate laboratory and, where appropriate, 
animal experimentation. 
12. 
Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
13. 
The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol. This protocol should be 
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the 
investigator, the sponsor or any other kind of undue influence. This independent 
committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed. The committee has the right to monitor ongoing 
trials. The researcher has the obligation to provide monitoring information to the 
committee, especially any serious adverse events. The researcher should also submit to 
the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
14. 
The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration. 
15. 
Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. 
The responsibility for the human subject must always rest with a medically qualified 
person and never rest on the subject of the research, even though the subject has given 
consent. 
16. 
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to 
the subject or to others. This does not preclude the participation of healthy volunteers in 
medical research. The design of all studies should be publicly available. 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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17. 
Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and can 
be satisfactorily managed. Physicians should cease any investigation if the risks are 
found to outweigh the potential benefits or if there is conclusive proof of positive and 
beneficial results. 
18. 
Medical research involving human subjects should only be conducted if the importance 
of the objective outweighs the inherent risks and burdens to the subject. This is especially 
important when the human subjects are healthy volunteers. 
19. 
Medical research is only justified if there is a reasonable likelihood that the populations 
in which the research is carried out stand to benefit from the results of the research. 
20. 
The subjects must be volunteers and informed participants in the research project. 
21. 
The right of research subjects to safeguard their integrity must always be respected. 
Every precaution should be taken to respect the privacy of the subject, the confidentiality 
of the patient's information and to minimize the impact of the study on the subject's 
physical and mental integrity and on the personality of the subject. 
22. 
In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and 
the discomfort it may entail. The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without 
reprisal. After ensuring that the subject has understood the information, the physician 
should then obtain the subject's freely-given informed consent, preferably in writing. If 
the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
23. 
When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or 
may consent under duress. In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
24. 
For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law. 
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons. 
25. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent 
to decisions about participation in research, the investigator must obtain that assent in 
addition to the consent of the legally authorized representative. 
26. 
Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population. The 
specific reasons for involving research subjects with a condition that renders them unable 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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December 19, 2017 
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to give informed consent should be stated in the experimental protocol for consideration 
and approval of the review committee. The protocol should state that consent to remain 
in the research should be obtained as soon as possible from the individual or a legally 
authorized surrogate. 
27. 
Both authors and publishers have ethical obligations. In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results. Negative as 
well as positive results should be published or otherwise publicly available. Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared 
in the publication. Reports of experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication. 
 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
1. 
The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value. 
When medical research is combined with medical care, additional standards apply to 
protect the patients who are research subjects. 
2. 
The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods. This does not 
exclude the use of placebo, or no treatment, in studies where no proven prophylactic, 
diagnostic or therapeutic method exists. 
3. 
At the conclusion of the study, every patient entered into the study should be assured of 
access to the best proven prophylactic, diagnostic and therapeutic methods identified by 
the study. 
4. 
The physician should fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship. 
5. 
In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from 
the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic 
measures, if in the physician's judgement it offers hope of saving life, re-establishing 
health or alleviating suffering. Where possible, these measures should be made the object 
of research, designed to evaluate their safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, published. The other relevant guidelines of 
this Declaration should be followed. 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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C 
Appendix C – GSRS-Quality of Life Assessment  
 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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Appendix D – GERD- HRQL Quality of life assessment 
 
Patient Name:_______________________________   Date ___/___/___ 
 
Check the box to the right of each question that best describes your experience over the past 
two weeks. 
 
0 = No symptom 
1 = Symptoms noticeable but not bothersome 
2 = Symptoms noticeable and bothersome but not every day 
3 = Symptoms bothersome every day 
4 = Symptoms affect daily activity 
5 = Symptoms are incapacitating to do daily activities 
 
1. 
How bad is the heartburn? 
 
 
 
 
□0  □1  □2  □ 3  □4  □5 
2. 
Heartburn when lying down? 
 
 
 
 
□0  □1  □2  □ 3  □4  □5 
3. 
Heartburn when standing up? 
 
 
 
 
□0  □1  □2  □ 3  □4  □5 
4. 
Heartburn after meals? 
 
 
 
 
 
□0  □1  □2  □ 3  □4  □5 
5. 
Does heartburn change your diet? 
 
 
 
□0  □1  □2  □ 3  □4  □5 
6. 
Does heartburn wake you from sleep?  
 
 
□0  □1  □2  □ 3  □4  □5 
7.  
How bad is the regurgitation?  
 
 
 
□0  □1  □2  □ 3  □4  □5 
8. 
Regurgitation when lying down? 
 
 
 
□0  □1  □2  □ 3  □4  □5 
9. 
Regurgitation when standing up? 
 
 
 
□0  □1  □2  □ 3  □4  □5 
10. 
Regurgitation after meals? 
 
 
 
 
□0  □1  □2  □ 3  □4  □5 
11. 
Does regurgitation change your diet?  
 
 
□0  □1  □2  □ 3  □4  □5 
12. 
Does regurgitation wake you from sleep? 
 
 
□0  □1  □2  □ 3  □4  □5 
13. 
Do you have difficulty swallowing?  
 
 
□0  □1  □2  □ 3  □4  □5 
14. 
Do you have pain with swallowing?  
 
 
□0  □1  □2  □ 3  □4  □5 
15. 
If you take medication, does this affect your daily life? 
□0  □1  □2  □ 3  □4  □5 
16. 
How satisfied are you with your present condition? 
□  Satisfied  
□  Neutral  
□  Dissatisfied 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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Appendix E – Reflux Disease Questionnaire 
 

EndoGastric Solutions, Inc.                                                                                                                     CONFIDENTIAL  
 
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Appendix F. – RSI (Reflux Symptom Index 
 
REFLUX SYMPTOM INDEX 
Name: _____________________________________ Date: ___/___/___ 
Within the last month, how did the following problems affect you? 
(0-5 rating scale with 0 = No problem and 5 = Severe) 
1. Hoarseness or a problem with your voice 0 1 2 3 4 5 
2. Clearing your throat 0 1 2 3 4 5 
3. Excess throat mucous or postnasal drip 0 1 2 3 4 5 
4. Difficulty swallowing food, liquids or pills 0 1 2 3 4 5 
5. Coughing after you ate or after lying down 0 1 2 3 4 5 
6. Breathing difficulties or choking episodes 0 1 2 3 4 5 
7. Troublesome or annoying cough 0 1 2 3 4 5 
8. Sensations or something sticking in your throat 0 1 2 3 4 5 
9. Heart burn, chest pain, indigestion, or stomach 0 1 2 3 4 5 
acid coming up 
TOTAL: _________ 
 
Normative data suggests that a RSI of greater than or equal to 13 is 
clinically significant. Therefore a RSI > 13 may be indicative of significant 
reflux disease.