Hybrid Argon Plasma Coagulation and Endoscopic Sleeve Gastroplasty Trial (HAPCET): A Single-center Randomized Controlled Trial
Phase: NA
Conditions: Obesity
Sponsor: Mayo Clinic

HAPCET 
V3 09/24/2024 
1 
 
 
 
 
 
 
 
 
Title: Hybrid Argon Plasma Coagulation and Endoscopic Sleeve Gastroplasty 
Trial (HAPCET): A Single-Center Randomized Control Trial  
 
NCT Number: NCT05559866  
 
Document Date: 09/24/2024 
 

HAPCET 
V3 09/24/2024 
2 
 
 
Hybrid Argon Plasma Coagulation and Endoscopic Sleeve 
Gastroplasty Trial (HAPCET): A Single-Center Randomized 
Control Trial 
 
Principal Investigator 
 
 
 
 
Site Investigators 
Omar Ghanem, MD 
Surgery – Metabolic Surgery 
200 1st St SW, Rochester, MN 55905  
507-266-4347  
 
Omar Ghanem, MD  
Associate Professor of Surgery, Mayo Clinic 
 
Jeff L. Fidler, M.D. 
Professor of Radiology, Mayo Clinic 
 
 
 
Legal Sponsor 
Mayo Clinic 
201 1st St SW 
Rochester, Minnesota 55902 
507-284-2511 
Funding Partner: 
Erbe USA, Incorporated 
2225 Northwest Parkway 
Marietta, Georgia 30067 
770-955-4400 
 
Erbe Elektromedizin GmbH 
Waldhörnlestr. 17 · 72072 Tübingen, Deutschland 
+49 7071 7550 
 
Study Product: 
Hybrid Argon Plasma Coagulation (HAPC) 
System Accounts:  
IRBe 
PLM 
 
 
22-001202 
2022-307124-H01 
 
 
 

HAPCET 
V3 09/24/2024 
3 
 
Contents 
LIST OF ABBREVIATIONS ......................................................................................................................... 6 
1. ................................................................................................................................................................ ABSTRACT
 ...................................................................................................................................................................... 8 
2. ....................................................................................................................................................... INTRODUCTION
 ...................................................................................................................................................................... 9 
BACKGROUND ........................................................................................................................................................... 9 
CLINICAL DATA TO DATE ........................................................................................................................................ 10 
RATIONALE ............................................................................................................................................................. 10 
STUDY OBJECTIVES ................................................................................................................................ 12 
STUDY DESIGN ......................................................................................................................................... 13 
GENERAL DESCRIPTION ........................................................................................................................................... 13 
ENDPOINTS .............................................................................................................................................................. 13 
Effectiveness 
13 
Safety 
14 
STUDY SETTING ....................................................................................................................................................... 14 
SUBJECTS ................................................................................................................................................................. 14 
INCLUSION CRITERIA ............................................................................................................................................... 14 
EXCLUSION CRITERIA .............................................................................................................................................. 15 
TRIAL PROCEDURES ............................................................................................................................... 17 
INFORMED CONSENT ............................................................................................................................................... 17 
STUDY TIMELINE ..................................................................................................................................................... 17 
SCREENING AND ELIGIBILITY ASSESSMENT ............................................................................................................. 19 
RANDOMIZATION ..................................................................................................................................................... 20 
TRIAL INTERVENTION .............................................................................................................................................. 20 
SCHEDULE OF EVENTS (SOE) .................................................................................................................................. 22 
PARTICIPANT RETENTION ........................................................................................................................................ 24 
REPLACEMENT OF WITHDRAWN SUBJECTS ............................................................................................................... 24 
SOURCE DOCUMENTATION ...................................................................................................................................... 24 
PROTOCOLS FOR PROCEDURE AND IMAGING ................................................................................... 25 
DATA MONITORING AND SAFETY REPORTING ................................................................................... 28 
DATA AND SAFETY MONITORING ............................................................................................................................ 28 
ADVERSE EVENTS.................................................................................................................................................... 28 
PROTOCOL DEVIATION ............................................................................................................................................ 30 
RISK/BENEFIT EVALUATION .................................................................................................................................... 30 
STATISTICAL ANALYSIS .......................................................................................................................... 31 
POWER AND SAMPLE SIZE ....................................................................................................................................... 31 
STATISTICAL ANALYSIS ........................................................................................................................................... 31 
MISSING DATA ........................................................................................................................................................ 32 
RANDOMIZATION AND DATA COLLECTION .............................................................................................................. 32 
INTERIM ANALYSIS .................................................................................................................................................. 32 
ETHICAL CONSIDERATIONS ................................................................................................................... 33 
STUDY FINANCES ..................................................................................................................................... 34 
FUNDING SOURCE .................................................................................................................................................... 34 
CONFLICT OF INTEREST ........................................................................................................................................... 34 
SUBJECT STIPENDS OR PAYMENTS ........................................................................................................................... 34 

HAPCET 
V3 09/24/2024 
4 
 
REFERENCES ............................................................................................................................................ 35 
 
 
 
 
 
 

HAPCET 
V3 09/24/2024 
5 
 
 
 
Protocol Signature Page 
 
Study Title:  HYBRID ARGON PLASMA COAGULATION AND ENDOSCOPIC SLEEVE 
GASTROPLASTY TRIAL (HAPCET): A SINGLE-CENTER RANDOMIZED CONTROLLED TRIAL 
 
Protocol Version Number: Version 2  
 
Protocol Date:  10AUG2022 
 
Sponsor: Mayo Clinic, Rochester, MN 
 
 
 
The undersigned have read and understand the Protocol specified above and agree on its content. I agree to 
conduct the study according to this protocol, its amendments, the clinical trial agreement and the applicable 
regulatory requirements.   I understand that said study will not be initiated without appropriate Institutional 
Review Board (IRB) approval and that the administrative requirements of the governing body will be fully 
complied with. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________  
 
_____________________ 
Principal Investigator’s Printed Name and Signature 
 
 
Date 
 
 
 
 
 
_______________________________________________ 
 
_____________________ 
Site Name 
 
 
 
 
 
 
 
Site Number 
 
 

HAPCET 
V3 09/24/2024 
6 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event/Adverse Experience 
ANCOVA 
Analysis of covariance 
APC 
Argon Plasma Coagulation 
APMC 
Argon Plasma Mucosal Coagulation 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CO2 
Carbon dioxide 
COPD 
Chronic Obstructive Pulmonary Disease 
CPE 
Complete Physical Exam 
CRF 
Case Report Form 
DSMP 
Data safety monitoring plan 
DRAE 
Device-Related Adverse Event 
DVT 
Deep Vein Thrombosis 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EGD 
Upper endoscopy/esophagogastroduodenoscopy 
EKG 
Electrocardiogram 
EMR 
Electronic medical record 
ESG 
Endoscopic Sleeve Gastroplasty 
EWL 
Excess Weight Loss 
GE 
Gastric Emptying 
GERD 
Gastroesophageal reflux disease 
GI 
Gastrointestinal 
GLP-1 
HAPC 
Glucagon-like peptide 
Hybrid Argon Plasma Coagulation 
HDL 
High-Density Lipoprotein 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
IWQOL-lite 
Intravenous 
Impact of Weight on Quality of Life - Lite 
LDL  
Low-Density Lipoprotein 
MAR 
Missing at random 
mITT 
Modified intent-to-treat 
MRI 
Magnetic Resonance Imaging 
NAFLD 
Non-Alcoholic Fatty Liver Disease 
NES 
Night Eating Syndrome 
NPO 
Nothing by mouth 
NSAID 
Non-steroidal anti-inflammatory drug 
PCP 
Primary Care Provider 
PE 
PHQ-9 
Pulmonary Embolism 
Patient Health Questionnaire 
PI 
Principal Investigator 
PTT 
Partial Thromboplastin Time 
RGYB 
Roux-En-Y Gastric Bypass 
SAE 
Serious Adverse Event/Serious Adverse Experience 

HAPCET 
V3 09/24/2024 
7 
 
SCD 
Sequential Compression Device 
SGOT/AST 
Serum Glutamic-Oxaloacetic Transaminase /Aspartate 
Aminotransferase 
SGPT/ALT 
Serum Glutamic-Pyruvic Transaminase /Alanine Aminotransferase 
SDRAE 
SF-36 
Serious Device-Related Adverse Event 
Short Form Health Survey 
TBWL 
TFEQ 
Total Body Weight Loss 
Three-Factor Eating Questionnaire 
TORe 
Transoral outlet reduction 
UADE 
Unanticipated Adverse Device Effects 
 
 
 
 
 
 
 
 
 
 

HAPCET 
V3 09/24/2024 
8 
 
1. 
ABSTRACT 
 
The obesity epidemic continues to grow in the United States with the prevalence of obesity increasing up 
to nearly 43% in 2019 with current projections estimating one in every two US Adults by 2030.1, 2 Obesity 
is associated with type 2 diabetes, coronary artery disease, chronic joint disease, obstructive sleep apnea, 
nonalcoholic fatty liver disease (NAFLD), and malignancy. Obesity is associated with an increased risk of 
all-cause and cardiovascular mortality and accounts for about 2.5 million preventable deaths annually. 3-5 
Obesity treatment is limited as lifestyle modifications provide only a modest total body weight loss with a 
high rate of weight recidivism.6 Widely available medical therapies are plagued by intolerance, cost, 
attenuated response, and weight regain after cessation of pharmacotherapy7. Newer GLP-1 analogues while 
providing significant weight loss require further investigation to determine if the weight loss effect is 
durable long term.8-11 Bariatric surgical interventions have been associated with significant side effects, 
micronutrient deficiencies and weight regain, however they have proven to be the most durable and 
effective12. Unfortunately, they are usually unavailable to patients with Class 1 to Class 2 obesity (BMI 30-
40 kg/m)13. This has led to a significant management gap for patients with mild to moderate obesity. 
Endoscopic sleeve gastroplasty (ESG) is an endoscopic, minimally invasive intervention that has 
demonstrated clinically significant, sustained, weight loss ranging between 15-19%.14 However, given lack 
of approximation of submucosal structures with ESG to enhance wound healing and fibrogen deposits at 
the gastroplasty construct, durability of the gastroplasty construct is not maximized15. We have shown 
enhanced durability of ESG when combining it with endoscopic submucosal resection techniques16. 
However, this is technically challenging and only allows treatment in the distal stomach. Argon plasma 
coagulation is effective in the transoral outlet reduction (TORe) procedure to help reduce the gastric outlet 
aperture in patients with weight regain after bariatric surgery by creating a focal coagulation injury in a 
circumferential manner that ablates the mucosal layer and aids in wound healing17. One case report 
evaluation using APC at time of ESG which demonstrated enhanced fibrosis at the site of endoscopically 
placed sutures potentially improving the durability and of the ESG and reducing complications of more 
invasive mucosal ablation methods such as endoscopic submucosal dissection or endoscopic mucosal 
resection techniques.18 Furthermore, APC application is technically easy with scalable skill-set to the 
average endoscopist19. Hybrid APC (HAPC) with submucosal lift offers enhanced safety; especially in 
ablating the mucosa in the proximal stomach, where the gastric wall is thin, to minimize risk of deep gastric 
wall injury. While this is hybrid approach is promising, controlled proof of concept evidence is required. 
Therefore, we propose a pilot randomized control trial evaluating the safety, durability of ESG in 
combination with HAPC and its effect on weight loss compared against traditional ESG alone in patients 
with obesity and body mass index (BMI) between 30-40 kg/m2.  
 
 
 
 
 
 
 
 
 
 
 

HAPCET 
V3 09/24/2024 
9 
 
2. 
INTRODUCTION 
 
Background  
 
The obesity epidemic continues to grow unabated in the United States20. The prevalence of obesity has 
increased from 30.5% to 42.4% with the prevalence of severe obesity increasing from  4.7% to 9.2% from 
the year 2000 until 2019 and continues to rise.1 Currently projections show about one in two United States 
(US) adults will have obesity, with one in four afflicted by severe disease by 2030.2 Obesity has significant 
implications on public health as it is associated with type 2 diabetes, coronary artery disease, chronic joint 
disease, obstructive sleep apnea, nonalcoholic fatty liver disease (NAFLD), and malignancy. Obesity is 
associated with an increased risk of all-cause and cardiovascular mortality and accounts for about 2.5 
million preventable deaths annually. 3-5 Furthermore, the worldwide economic impact of obesity has been 
estimated to be $2.0 trillion USD or 2.8% of the global gross domestic product (GDP) and continues to 
rise.21  
 
This problem of obesity is compounded by a lack of sufficient therapeutics. Currently patients with obesity 
are treated with a combination of lifestyle modifications, medication therapy and in certain instances 
surgical intervention. While lifestyle modification remains the foundation for successful obesity 
management, alone it yields only about a 3% total body weight loss.22-24 Furthermore weight regain is a 
problem with lifestyle modifications25.  Studies have shown that 1 year following dietary and lifestyle 
modification therapy, 20%-25% of patient's have weight regain.  This number swells to more than 50% at 
5 years.6 The development of GLP 1 agonists used alone or in conjunction with other medications such as 
amylin analogues has shown promise for treatment of obesity as these medications produced between 8% 
and 16% with a favorable side effect profile.8-11 However, there are no long terms studies evaluating weight 
regain after cessation of these medications26. Prior generations of obesity pharmacotherapy were plagued 
by intolerance, cost, attenuated response, and weight regain after cessation of the pharmacotherapy27. 
 
Bariatric surgical interventions are the most effective and durable therapies for management of obesity28.  
However they are limited by invasiveness, expense, long-term risks, and patients’ acceptance.29  Moreover, 
in younger patients, desire for bariatric surgery is quelled by concerns regarding long-term nutrient 
deficiencies and need for invasive revisions30.  Bariatric surgery is only available to about one percent of 
eligible patients and is not considered for the majority of patients with class I and II obesity without 
comorbid conditions.31  
 
The current obesity management paradigm involves an intervention to provide a robust initial weight loss 
followed by lifelong engagement of the patient in continued lifestyle modifications32.  With the weight 
recidivism seen with obesity pharmacotherapy, and limited availability and cost of bariatric surgical 
interventions, this has led to the development of endoscopic bariatric therapies to address this gap in 
treatment33.  Intragastric balloons have shown promise in inducing weight loss, however intolerance is an 
issue as side effects such as nausea, vomiting, abdominal pain are commonly seen.34  Furthermore, more 
serious side effects such as gastric ulceration, gastric perforation and pancreatitis are recognized side 
effects.34-36 Also the limited dwelling time of these intragastric balloons leads to weight recidivism and the 
need for combination therapies to help ensure continued weight loss37.  
 

HAPCET 
V3 09/24/2024 
10 
 
Since it was first demonstrated as a feasible therapy in humans in 2013, the most commonly performed 
endoscopic bariatric therapy has been the endoscopic sleeve gastroplasty (ESG).38  This is a minimally 
invasive endoscopic technique that involves creation of full-thickness plications of the stomach using 
endoscopic suturing creating a tubular shape to the stomach limiting gastric volume and accommodation 
similar shape created with surgical sleeve gastrectomy.39  Multiple studies have shown up to 15% to 18% 
TBWL with sustenance of this weight loss up to 24 months.14 Furthermore, studies have demonstrated 
physiologic perturbations resulting from creation of the ESG and its association with increased satiation 
and metabolic effects that are important to control the metabolic dysregulation associated with obesity.40 
The ESG procedure is associated with fewer complications than bariatric surgical procedures.41 However, 
complications of the ESG procedure include pain, nausea, upper gastrointestinal bleeding, gastric 
ulceration, and peri-gastric leak or fluid collection.14 Suture dehiscence and enlargement of the stomach 
within months requiring revisional procedures have also been seen.18 Revision is usually performed using 
a combination of endoscopic suturing as well as argon plasma coagulation42.  
 
Argon plasma coagulation (APC) is a method of non-contact thermal hemostasis initially created to assist 
in inducing hemostasis43. APC utilizes high-frequency current which applied to the target tissue through an 
argon plasma jet inducing hemostasis and a homogenous surface coagulation with a limited depth of 
penetration. This technology has also been used in bariatric endoscopy for patients requiring revision after 
bariatric surgical procedure44.  Endoscopic transoral outlet reduction (TORe) is a commonly performed 
procedure to help manage weight regain after bariatric surgical intervention45. The two most commonly 
performed techniques for TORe are full-thickness suturing with plus argon plasma mucosal coagulation (ft-
TORe) and argon plasma mucosal coagulation alone (APMC-TORe). Both of these techniques utilize APC 
creates a focal coagulation injury in a circumferential manner causing edema, ulceration and fibrosis 
reducing the aperture of the gastrojejunal anastomosis.46, 47 This causes a physical reduction in the size of 
the stoma as well as a delay in gastric emptying48. One study showed a reduction in the diameter of the 
gastrojejunal anastomosis of 67% with approximately 15kg weight loss with APC in patients with weight 
regain after RGYB.49 While APC is a useful tool in patients with weight regain following bariatric surgical 
procedure, it can be combined with ESG to provide enhanced fibrosis along the gastric plications.18 
 
Clinical Data to Date  
 
ESG was proven to be feasible in human subjects in 2013 and since then it has become the most commonly 
performed endoscopic bariatric procedure.38 Multiple studies have demonstrated significant and sustained 
weight loss. However, the durability of the plication construct could be enhanced with addition of HAPC. 
One case report combined the use of ESG and APC and found to have enhanced fibrosis along the site of 
endoscopic plications potentially providing an avenue for longer and more durable ESG while minimizing 
these associated complications. Furthermore, with enhanced fibrosis this could decrease the incidence of 
weight regain in patients undergoing ESG and capitalize on the metabolic benefits of gastric mucosal 
revitalization reported with APC alone. However, to date no prospective controlled studies have been done 
comparing traditional ESG to a hybrid ESG and APC procedure. 
 
Rationale 
 

HAPCET 
V3 09/24/2024 
11 
 
ESG is a commonly performed procedure that has been shown to demonstrate significant weight loss. 
However, combining it with HAPC technique to enable approximation of submucosal surfaces for enhanced 
gastroplasty healing, durability of this procedure could be enhanced. This could help maximize the 
metabolic benefits of gastric mucosal revitalization in conjunction with the restrictive effects of ESG for 
enhanced weight loss, durability, and metabolic benefits of the combined procedure while minimizing the 
risk of weight recurrence previously reported with the traditional ESG.    

HAPCET 
V3 09/24/2024 
12 
 
 
STUDY OBJECTIVES 
Assess the safety and durability of combined HAPC and ESG compared to traditional ESG 
Assess weight loss and improvement in obesity related co-morbidities in combined HAPC and ESG 
compared to ESG alone. 

HAPCET 
V3 09/24/2024 
13 
 
 
STUDY DESIGN 
General Description 
 
This is a single-center, randomized, single-blinded clinical trial evaluating the efficacy and safety of 
combined HAPC and ESG for weight loss and improvement in obesity-related co-morbidities compared to 
ESG alone in participants with a BMI ≥ 30 and ≤40 kg/m² who have failed to achieve and maintain weight 
loss with a non-surgical management.  
 
Participants will be recruited from outpatient clinical weight loss clinics and from study-related institutional 
review board (IRB) approved advertisements.  
 
Twenty-four eligible participants will be block-randomized 1 to 1 treatment (12 participants) and control 
(12 participants) groups. All participants will undergo endoscopy and those without endoscopic 
contraindications will be eligible. All treatment group subjects will undergo combined HAPC and ESG 
where APC is applied according to on-label use prior to the standard ESG technique for enhanced fibrosis 
along the site of the plications potentially providing an avenue for longer and more durable ESG while 
minimizing the associated complications. Control subjects will undergo traditional ESG alone. All 
participants will undergo a repeat upper endoscopy at 26 weeks (6 months) +/- 2 weeks to evaluate the 
durability of the endoscopic sutures. All subjects will undergo research MRI at baseline and 26 weeks +/- 
2 weeks to evaluate and grade the durability of the created gastroplasty, gastric motility, and gastric 
accommodation. This specially developed MRI protocol at Mayo offers a gold standard in evaluating 
gastroplasty durability. Additionally, at both baseline and 26 weeks +/- 2 weeks, all patients will undergo 
gastric scintigraphy to evaluate and measure gastric emptying. 
Endpoints 
Effectiveness 
Primary: 
• 
Assess durability of endoscopic plications and sutures 26 weeks (6 months) +/- 2 weeks 
post procedure between patients receiving HAPC/ ESG vs traditional ESG alone. 
 
Secondary: 
• 
%TBWL in the combined HAPC and ESG group compared to traditional ESG at 6 and 12 
months. 
• 
Assess the procedure safety. 
• 
% Excess weight loss (EWL) at 6 and 12 months between both groups.  
• 
Proportion with ≥25% EWL at 6 and 12 months by randomized arm. 
• 
% of patients in the combined HAPC and ESG group achieving ≥ 5% TBWL at 6 and 12 
months compared to ESG alone. 
• 
% of patients in the combined HAPC and ESG group achieving ≥ 10% TBWL at 6 and 12 
months compared to ESG alone. 
• 
Changes in quality of life assessed using standard validated questionnaires (IWQOL-lite 
and SF-36) at 6 and 12 months compared to baseline. 
• 
Changes in depression assessed using PHQ-9 questionnaire at 6 and 12 months compared 
to baseline. 

HAPCET 
V3 09/24/2024 
14 
 
• 
Improvement/reduction of hunger and desire to eat evaluated using validated self-reported 
ratings of appetite based on a 100-mm visual-analogue scale at 6 and 12 months compared 
to baseline. 
• 
Improvement in eating behaviors evaluated using the Three Factor Eating Questionnaire 
(TFEQ) at 6 and 12 months compared to baseline. 
• 
Improvement in obesity related comorbidities (blood pressure, fasting glucose, Hba1c, lipid 
panel, liver enzymes) at 6 and 12 months compared to baseline. 
• 
Changes in gastric motility, volume, accommodation, and constructed gastroplasty on MRI 
at 6 months compared to baseline. 
• 
Changes in gastric emptying evaluated by gastric emptying study at 6 months compared to 
baseline.  
• 
Changes in liver biochemical panel, and glucose homeostasis parameters at 6 months 
compared to baseline between the two groups.    
 
Safety 
• 
The incidence, frequency, and severity of adverse events related to treatment with the 
device will be reported throughout the duration of the study. 
• 
Goal is <5% rate of serious adverse events related to the device or procedure (as 
determined by the site PI). Serious adverse events will be classified in the Adverse Events 
table. 
 Study Setting  
 
The study will be conducted at 1 US center, Mayo Clinic in Rochester, MN. The maximum enrollment will 
be limited to 24 participants. The expected enrollment period is 6 months.   
 
 Subjects 
 
Participants will be adult patients (Ages 21 ≥ and ≤ 65) with a BMI ≥ 30 and ≤ 40 kg/m2 that meet the 
eligibility criteria below. All eligibility criteria must be met at the time of randomization. 
 
 Inclusion Criteria 
 
1. Age 21-65 
2. BMI ≥ 30 and ≤40 kg/m² 
3. Willingness to comply with the substantial lifelong dietary restrictions required by the 
procedure. 
4. History of failure with non-surgical weight-loss methods. 
5. Willingness to follow protocol requirements, including signed informed consent, routine 
follow-up schedule, completing laboratory tests, and completing diet counseling. 

HAPCET 
V3 09/24/2024 
15 
 
6. Residing within a reasonable distance from the investigator’s office and able to travel to the 
investigator to complete all routine follow-up visits. 
7. Ability to give informed consent. 
8. Women of childbearing potential (i.e., not post-menopausal or surgically sterilized) must 
agree to use adequate birth control methods. 
 
Exclusion Criteria 
 
1. History of foregut or gastrointestinal (GI) surgery (except uncomplicated cholecystectomy or 
appendectomy). 
2. Prior gastrointestinal surgery with sequelae, i.e. obstruction, and/or adhesive peritonitis or 
known abdominal adhesions. 
3. Prior open or laparoscopic bariatric surgery.  
4. Prior surgery of any kind on the esophagus, stomach, or any type of hiatal hernia surgery. 
5. Any inflammatory disease of the gastrointestinal tract including severe (LA Grade C or D) 
esophagitis, Barrett’s esophagus, gastric ulceration, duodenal ulceration, cancer, or specific 
inflammatory disease such as Crohn’s disease or celiac disease.  
6. Potential upper gastrointestinal bleeding conditions such as esophageal or gastric varices, 
congenital or acquired intestinal telangiectasis, or other congenital anomalies of the 
gastrointestinal tract such as atresias or stenoses. 
7. Gastrointestinal stromal tumors, history of premalignant gastric lesions (intestinal 
metaplasia), history of familial and nan-familial adenomatous syndromes.  
8. A gastric mass or gastric polyps > 1 cm in size.  
9. A hiatal hernia > 4cm of axial displacement of the z-line above the diaphragm or severe or 
intractable gastro-esophageal reflux symptoms.  
10. A structural abnormality in the esophagus or pharynx such as a stricture or diverticulum that 
could impede passage of the endoscope.  
11. Achalasia or any other severe esophageal motility disorder  
12. Severe coagulopathy. 
13. Insulin-dependent diabetes (either Type 1 or Type 2) or a significant likelihood of requiring 
insulin treatment in the following 12 months or a HgbA1C≥9. 
14. Subjects with any serious health condition unrelated to their weight that would increase the 
risk of endoscopy. 
15. Chronic abdominal pain. 
16. Motility disorders of the GI tract such as gross esophageal motility disorders, gastroparesis 
or intractable constipation. 

HAPCET 
V3 09/24/2024 
16 
 
17. Hepatic insufficiency or cirrhosis. 
18. Use of an intragastric device prior to this study due to the increased thickness of the stomach 
wall preventing effective suturing.  
19. Active psychological issues preventing participation in a life-style modification program as 
determined by a psychologist. 
20. Patients unwilling to participate in an established medically supervised diet and behavior 
modification program, with routine medical follow-up.  
21. Patients receiving daily prescribed treatment with high dose aspirin (> 81mg daily), anti-
inflammatory agents, anticoagulants, or other gastric irritants.  
22. Patients who are unable or unwilling to take prescribed proton pump inhibitor medication.  
23. Patients who are pregnant or breast-feeding.  
24. Patients currently taking weight-loss medications or other therapies for weight loss within 
the prior 6 months.  
25. Subjects with severe cardiopulmonary disease or other serious organic disease which might 
include known history of coronary artery disease, myocardial infarction within the past 6 
months, poorly controlled hypertension, required use of NSAIDs. 
26. Subjects taking medications on specified hourly intervals that may be affected by changes to 
gastric emptying, such as anti-seizure or anti-arrhythmic medications. 
27. Subjects who are taking corticosteroids, immunosuppressants, and narcotics.  
28. Symptomatic congestive heart failure, cardiac arrhythmia, or unstable coronary artery 
disease.  
29. Pre-existing respiratory disease such as moderate or severe chronic obstructive pulmonary 
disease (COPD) requiring steroids, pneumonia, or cancer.  
30. Diagnosis of autoimmune connective tissue disorder (e.g.  Systemic lupus erythematosus, 
scleroderma) or immunocompromised.  
31. Specific diagnosed genetic disorder such as Prader Willi syndrome. 
32. Eating disorders including night eating syndrome (NES), bulimia, binge eating disorder, or 
compulsive overeating. 
33. Known history of endocrine disorders affecting weight such as uncontrolled 
hypothyroidism. 
34. At the discretion of the PI for subject safety 
35. If minority inclusion population target of 10% has not been reached by the 90% enrollment 
mark (example 21 of 24 subjects), the remaining enrollments will be reserved for minority 
subjects (example 3 of 24 subjects). 

HAPCET 
V3 09/24/2024 
17 
 
 
TRIAL PROCEDURES 
Informed Consent 
 
Prior to being enrolled in the trial, study participants must consent to participate after the nature, scope, and 
possible risks of the trial have been explained and outlined in an understandable form to them per the 
requirements of the IRB. Participants are free to withdraw consent at any time. 
 
After reading the Informed Consent Form (ICF) document, the participant must sign and date the latest 
approved version of the ICF before any study procedures are performed (electronic via compliant system 
such as Docusign, or wet-signed copy prepared in Participant Tracking System (Ptrax). A copy of the signed 
consent document will be accessible for the participant, and the original signed consent form will be 
retained by the study team.  
 
Where possible, “remote” visits such as via phone or video call will be acceptable across the schedule of 
events to streamline coordination efforts and adapt to any unexpected conditions such as isolation protocol.  
Study Timeline 
 
 
The study timeline is depicted in Figure 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

HAPCET 
V3 09/24/2024 
18 
 
Figure 1. Study Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

HAPCET 
V3 09/24/2024 
19 
 
Screening and Eligibility assessment 
 
Screening will be conducted by the investigator or the co-investigator and documented on the Investigator 
delegated/medically qualified team member intake form (conventionally known as PI Intake Form) and 
Screening Labs form. Screening must occur no more than 45 days prior to randomization.  
 
Screening will include the following: 
1. Sign informed consent form 
2. Screening exam and intake by the investigator or co-investigator 
3. Height, weight, and BMI; waist and hip circumference; vital signs (blood pressure and pulse) 
4. Dietary screening intake and approval 
5. Laboratory tests (after 8 hours fasting) 
• 
CBC: hemoglobin, hematocrit, white blood cell count, mean corpuscular volume, 
platelets 
• 
Chemistry panel:  sodium, potassium, chloride, CO2, BUN, creatinine, fasting glucose, 
fasting insulin, SGOT/AST, SGPT/ALT, alkaline phosphatase, total bilirubin, direct 
bilirubin, albumin, fasting lipids profile (total cholesterol, triglyceride, LDL cholesterol, 
HDL cholesterol), Ferritin, B12, C-reactive protein.  
• 
Coag:  INR, PTT 
• 
Urinalysis 
• 
HgbA1C  
• 
H. Pylori Breath Test. **Patients with a positive h-pylori breath test will be treated and 
eradication must be confirmed with a stool antigen after treatment and prior to 
randomization** 
• 
EKG for all patients 
• 
Urine pregnancy test for women of child-bearing potentiala 
• 
MRI at baseline to evaluate gastric anatomy, gastric motility, and gastric accommodation.   
• 
Gastric emptying scintigraphy at baseline to evaluate gastric emptying. Gastric 
emptying scintigraphy will be conducted according to current Mayo Clinic Rochester 
clinical protocol. 
 
6. Questionnaires 
7. Psychological evaluation and approval: Study psychologists will use their standard clinical 
evaluations for bariatric interventions. 
 
 
Within one week (7 calendar days) of completion of the screening tests, the PI will review the results and 
determine the participant’s eligibility. The center will inform the participant of their screening results within 
10 days of completing testing. Any abnormal lab results will be communicated to the participant by 
delegated personnel, and they will be required to notify their primary care provider (PCP) for any further 
action that may be necessary. All potential participants who qualify for randomization based on the initial 
 
a Childbearing potential to be defined as women who are not yet post-menopausal who are not consistently 
utilizing an acceptable form of contraception. Acceptable forms of contraception to include hormonal 
methods such as oral contraceptives, patches, injections, vaginal ring, or implants, hormonal or copper 
intrauterine device, or history of surgical sterilization including tubal ligation or hysterectomy. 

HAPCET 
V3 09/24/2024 
20 
 
screening assessments will have the chance to review any questions with the study staff, as well as a recap 
of the follow-up schedule, and they will then receive their randomization assignment.  
 
Recruitment efforts will be made by working with Mayo Clinic’s Research Recruitment Services to develop 
marketing materials including a recruitment flyer in both print and digital formats, a social media 
recruitment plan leveraging Mayo Clinic’s enterprise social media accounts for recruitment and other 
potential tactics to be determined after recruitment begins, directed towards the goal of boosting minority 
inclusion to be at least representative of the local population. Data will be pulled during the time of IRB 
submission and included to establish general targets justifying Exclusion #35 to help reserve spots for 
enrollment that are in-line with a representative population if they are not met by a certain threshold. At the 
time of this writing, Rochester, MN has demonstrated approximately 10% minority population.  
Randomization 
 
Participants will be randomly assigned to treatment or control group with a 1:1 allocation per a computer-
generated randomization using variable block randomization.  
 
Participants will be blinded to the results of randomization. They will remain blinded until the end of the 
study, or if there is medical or surgical safety concern. If any SAEs occur, subjects may be unblinded as 
defined by the Clavien-Dindo Grade III or above. Unblinding of subjects will be reported to IRB per local 
site IRB guidelines, if not meeting the criteria above. Measures will be taken to minimize or avoid bias in 
the study using “masking/blinding procedures.”  Randomization assignment will be recorded in the EDC 
and subject tracking, but will not be recorded within the EMR to reduce clinical team exposure to their 
randomized status for follow-up care. Research teams will not be blinded to the randomization results. 
Subjects will be asked to confirm with their study team if they have become aware of the procedure.  
 
Participants will proceed to a brief visit with the dietician to review the post-op liquid diet, and the 
procedure (ESG or HAPC/ESG) will be scheduled within 60 days of randomization.  
Trial Intervention 
 
Participants will report to the procedure suite within 60 days of randomization. Participants of child-bearing 
potential will be required to have a pregnancy test within 7 days of the scheduled ESG or combined HAPC 
and ESG. Participants taking medications for hypertension and/or type II diabetes will be instructed to 
notify their prescribing physician of their procedure and to discuss any necessary medication changes for 
the post-op period.  
 
The ESG or combined HAPC and ESG will be conducted in Saint Marys Hospital at the Mayo Clinic in 
Rochester, Minnesota. Within two hours prior to the procedure, IV access will be obtained, IV hydration 
initiated, and a transdermal scopolamine patch placed for patients 65 years of age or younger (this will be 
removed in 24 to 48 hours after the procedure). Scopolamine can precipitate delirium in elderly patients, 
and hence we will avoid using them in patients older than 65 years of age. After Hybrid ESG or traditional 
ESG patient will be monitored for 24-48 hours to ensure patient is able to tolerate liquid diet and discharge 
timing is to be determined on individual basis per the site primary investigator.  
 
Prior to ESG or combined HAPC and ESG, a standard upper endoscopy is performed to rule out any 
contraindications. All procedures will be done under general anesthesia with endotracheal intubation and 
utilizing CO2 insufflation. During the procedure, IV hydration will be continued, and patients will be given 
the following: one dose of IV antibiotics (Zosyn, Ceftriaxone, or Ciprofloxacin), 8 mg of IV Zofran, and 8 
mg of Decadron. A minimum of two liters of IV hydration (either normal saline or lactate ringers) should 
be administered in the perioperative recovery period before discharge. Sequential compression devices 

HAPCET 
V3 09/24/2024 
21 
 
(SCDs) will be used perioperatively to decrease the risk of deep vein thrombosis (DVT) and pulmonary 
embolism (PE).  
 
Patients will be prescribed the following medications or equivalent after the procedure to manage expected 
post-procedural symptoms: 
• 
Zofran 4mg rapid dissolving pills taken every 6 hours as needed for nausea for 7 days 
• 
Phenergan 25mg suppositories taken twice daily as needed for nausea for 7 days  
• 
Low dose liquid narcotic taken every 6 hours as needed for pain for 5 days 
• 
Omeprazole 40mg capsule to be opened and mixed with smooth, semi-liquid food for the first 7 
days after ESG or combined HAPC and ESG, then taken as whole capsule daily for 12 months 
from date of ESG or combined HAPC and ESG.  
• 
Ativan 0.5 mg taken orally once daily for up to 3 days as needed for intractable nausea or anxiety.  
 
Admission for a 23-hour observation for symptom management is optional but permissible. All patients 
will be given instructions prior to being discharged from the facility to help manage post-procedural 
symptoms, including nausea, vomiting and/or abdominal pain. Study staff will call patients once between 
18-36 hours after the procedure to assess symptoms and to relay any issues to the PI. If the PI feels it is 
necessary to see a patient in clinic, an unscheduled visit will be scheduled appropriately. 
 
All patients will go on a 6-week transitional diet consisting of 4 weeks of full liquid protein shakes and 2 
weeks of soft pureed diet. The transitional diet is designed to allow suture healing and incorporation within 
the plicated gastric wall. After the transitional diet period, all patients will be on a low-calorie healthy diet 
personalized by the dietician according to individual patients’ needs conducive to weight loss. Physical 
activity, including 150 minutes of aerobic exercise per week, will be encouraged and assessed for 
compliance during the study. It may be recommended for patients to take two chewable multivitamins and 
one calcium plus vitamin D supplement daily starting within 1 week of the ESG or combined HAPC and 
ESG.  
 
All patients will undergo a standard moderate intensity life-style intervention administered over 12 visits 
in the first year after procedure. Participants will be required to follow up with their prescribing physician 
to make any necessary changes to their hypertension and/or type II diabetes medications at 3, 6, 9 and 12 
months. Completion of patient follow-up with providers for medication adjustment will be captured with 
completion of the appropriate CRF at the corresponding visits. In the event that participants are unable to 
contact their physician or participants are experiencing symptoms related to the medication dosing requiring 
urgent action, the study team will make any necessary changes in their medication dosing and document 
these changes appropriately in the relevant CRFs.  Any medication changes will be monitored and recorded 
by the study team. Laboratory testing will be obtained as detailed in the study schedule of events    
 
Participants will return for follow-up visits per the schedule of events below. For all visits with the exception 
of weeks 1 and 4, an in-window visit will be considered as reporting for follow-up visits within a two-week 
window of the visit date. 
 
At the time of the 6-month visit, each subject’s 6-month de-identified EGD video will be shared with an 
external center for an additional blinded assessment of the primary endpoint (suture durability) by a 
qualified endoscopist. Each video will be classified objectively according to the aspect of the gastric tissue 
and the sutures (intact, partially intact, or open). This sharing will take place through Mayo SimpleShare  
system.

HAPCET 
V3 09/24/2024 
22 
 
Schedule of Events (SOE) 
Study Activity 
Screening & 
Enroll. 
Rand. 
Procedure 
Post-Op 
Call 
Week 
1 
Week 
4 
Week 
8 
Week 12 
Weeks 
16, 20 
Week 26 
(Month 6) 
Weeks  
30, 36, 42, 48 
Week 52 
(Year 1) 
Unscheduled 
Visit 
Visit Number 
-2 
-1 
0 
1 
2 
3 
4 
5 
6,7 
8 
9,10,11,12 
13 
 
In-Window Day Range 
45 to Rand. 
60 to 
Proc. 
0◊ 
+/- 2 
+/- 3 
+/- 14 
 
Informed Consent Form (ICF) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Exam (CPE)* 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
Focused Physical Exam * 
 
 
 
 
X 
 
 
 
 
 
 
 
 
EKG  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Formal nutritional assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Formal psychology evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test ** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory tests + 
H-Pylori breath test (baseline only) 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Questionnaires ++ 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure Assessment Form 
 
 
X 
 
 
 
 
 
 
 
 
 
 
GERD Questionnaire & Activity Assessment 
Form 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight, Height (Screening only), BMI, Waist 
and Hip Circumference Form 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs Form 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Form 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Form 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization (ESG vs Hybrid ESG/APC) † 
 
X 
 
 
 
 
 
 
 
 
 
 
 
EGD 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
MRI 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Gastric emptying scintigraphy*** 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Post-enrollment Nutrition/Exertion/Satiety 
counseling and assessment †† 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Subject Satisfaction Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Inter-observation of EGD 
 
 
 
 
 
 
 
 
 
X 
 
 
 
* Performed by Investigator or delegated medically qualified team member 
** Females of childbearing potential only 
***POC Urine Pregnancy Test required 48 hours prior to procedure (if not within window from blood test) 
+ CBC, electrolytes, BUN, creatinine, HbA1c, fasting blood sugar, fasting insulin, fasting lipids profile (total cholesterol, LDL, HDL, triglycerides), INR, PTT, ALT, AST, ALP, total bilirubin, direct bilirubin, albumin, CRP, B12, ferritin 
++Eating and weight patterns questionnaire + hospital anxiety and depression questionnaires (only at baseline), Impact of Weight on Quality of Life-Lite (IWQOL-Lite), Short Form (36) Health Survey (SF36), Patient Health Questionnaire 9 (PHQ9), Pittsburg Sleep 
Quality Index (PSQI), Three Factor Eating Questionnaire (TFEQ) 
†To occur after all screening assessments are complete; within 45 days of screening evaluations 

HAPCET 
V3 09/24/2024 
23 
 
††To discuss upcoming post-op diet and exertion 
◊ If the procedure is unable to be performed within the 105 day in-window range due to factors outside the control of the study team (patient testing positive for COVID-19, delays associated with H. pylori eradication testing, or limitations of the procedural schedule), 
the PI will assess if any baseline laboratory tests must be repeated prior to the procedure for subject safety. 

 
 24 
 
Participant Retention 
All patients will be encouraged to complete study follow-up, and all reasonable efforts will be made to 
ensure completeness of follow-up. 
It is understood that study participants may withdraw consent for study participation at any time irrespective 
of their reasons.  The investigators may also withdraw a participant from the study in order to protect their 
safety, and/or if they are unwilling or unable to comply with the required study procedures. 
In the event of a patient withdrawing from the trial, the reason for withdrawal must be documented on the 
CRF.    
Replacement of withdrawn subjects 
 
Patients withdrawn prior to undergoing combined HAPC and ESG or ESG alone will count towards the 
target accrual. Screen failed patients will not count towards target accrual. New patients will be randomized 
to target accrual of 24 total patients receiving combined HAPC and ESG or ESG alone. The power and 
sample size calculation includes sufficient patients to yield power assuming some post-intervention 
dropout. 
 
Source Documentation 
Study source worksheets and/or electronic documentation in the medical record will be used as source 
documentation for the trial for all participant follow-up visits. Source documentation from the electronic 
medical record will be required for the procedure(s), medications, and any serious adverse medical events. 
REDCap will be used for collection of electronic sources and verified by PI attestation as the eCRF. If 
unavailable to conduct electronic source, physical CRF source worksheets will be available and can be 
added to the eCRF for investigator attestation.  

 
 25 
 
PROTOCOLS FOR PROCEDURE AND IMAGING 
HybridAPC (HAPC) Application 
HAPC will be performed in conjunction with ESG in patients in the treatment group. The location is from 
the level of the incisura all the way to the fundus. The pattern includes 3 rectangular APC ablation zones 
created on the anterior, greater curvature and posterior surface of the stomach. The HAPC is composed of 
a submucosal lift followed by ablation. The default setting of the APC is 50 Watts, 1 L/min flow, but it 
may be adjusted within normal clinical limits dependent on participant anatomy and tissue response. After 
ablation, ESG will be performed in standard fashion. 
 
Measurement of Gastric Accommodation by Dynamic MRI 
Gastric MRI will only be performed in patients who can safely undergo MRI. It will be performed at both 
baseline and 6 months for subjects randomized to either study arm. Subjects will be kept NPO after 
midnight and scanned with MRI using a torso phased array coil. If the 3T magnet (Phillips) is not 
available, a 1.5T magnet will be used. Before, and after a meal (296 ml Ensure mixed with 4ml 
gadolinium, i.e., 300 ml), static and dynamic imaging sequences will be acquired using available MR 
sequences to assess respectively gastric volumes and motility. No intravenous contrast will be 
administered. Postprandial accommodation will be calculated as the difference between postprandial and 
fasting volumes (Neurogastroenterol Motil 2009; 21:42–51; American Journal of Physiology. 
2014;307:G582-G587). Likewise, gastric motility (i.e., contractile frequency, amplitude and velocity) will 
be analyzed with established approaches (Neurogastroenterol Motil 2011;23(7):617-e252).  
 
Gastric Emptying Scintigraphy 
Gastric emptying scintigraphy will be performed at baseline and at 6 months for subjects 
randomized to either study arm. Imaging will begin immediately after consumption of a 
standardized meal including 1 mCi Tc-99m labeled sulfur colloid in two eggs accompanied by one 
slice of white bread and a glass of skim milk. For patients unable to consume any individual 
component of the meal substitutions will be made according to clinical protocol. Dual isotope 
acquisition of anterior and posterior views of the abdomen will be acquired, with view times to be 
within +/- 15 minutes of the hour. Images will be acquired Baseline (0), 1, 2, 3 and 4 hours 
following ingestion of the radiolabeled meal. Results will be interpreted according to institutionally 
established normal ranges. Geometric means of decay-corrected counts in anterior and posterior 
gastric regions of interest will be used to estimate the proportion of 99mTc emptied at each time 
point. 
 
Screening & Enrollment 
This will include a patient visit for procedures mentioned in section 5.3. This includes: 
Signing informed consent form 
 
Screening exam and intake by the investigator or co-investigator 
 
Baseline anthropomorphic and vital signs data 
 
Baseline laboratory testing, including pregnancy test if female of childbearing potential 
 
Baseline EKG 
 
Baseline MRI 
 
Baseline gastric emptying scintigraphy  
 
Baseline questionnaires.  
 
Baseline nutritional assessment 
 
Baseline psychological evaluation and approval 
 
Randomization 
 
After randomization, patients will have a brief post-enrollment nutrition/exertion/satiety counseling and 
assessment.  

 
 26 
 
Procedure 
 
This includes a patient visit for procedure which may or may not include an admission for a 23-hour 
observation for symptom management, further elaborated in section 5.5. 
Anthropomorphic and vital signs data will also be collected on procedure day.  
 
Post-Op Call  
This is a telephone visit which will include review of adverse events and medications. 
 
Week 1 
This will include: 
• 
Focused physical examination 
• 
Anthropomorphic and vital signs data 
• 
Review of adverse events and medications 
• 
Nutritional counseling and assessment. 
 
Week 4 (Month 1) 
This will include: 
• 
Anthropomorphic and vital signs data 
• 
Review of adverse events and medications 
• 
Nutritional counseling and assessment. 
 
 
Week 8 (Month 2) 
This will include: 
• 
Anthropomorphic and vital signs data 
• 
Review of adverse events and medications 
• 
Nutritional counseling and assessment. 
 
 
Week 12 (Month 3) 
 
This will include: 
• 
 
• 
Questionnaires 
• 
Anthropomorphic and vital signs data 
• 
Review of adverse events and medications 
• 
Nutritional counseling and assessment. 
 
 
Weeks 16, 20  
These will include: 
• 
Anthropomorphic and vital signs data 
• 
Review of adverse events and medications 
• 
Nutritional counseling and assessment. 
 
 
Week 26 (Month 6) 
 

 
 27 
This will be a comprehensive visit, including: 
• 
Complete physical examination 
• 
Anthropomorphic and vital signs data 
• 
Review of adverse events and medications 
• 
Laboratory testing 
• 
Questionnaires 
• 
EGD, to be performed clinically  
• 
MRI  
• 
Gastric emptying scintigraphy 
• 
Nutritional counseling and assessment. 
• 
Inter-observation of deidentified EGD video by qualified endoscopist 
 
Weeks 30, 36, 42, 48 
 
These will include: 
• 
Anthropomorphic and vital signs data 
• 
Review of adverse events and medications 
• 
Nutritional counseling and assessment. 
 
 
Week 52 (Year 1) 
 
This will include: 
• 
Complete physical examination 
• 
Anthropomorphic and vital signs data 
• 
Review of adverse events and medications 
• 
Laboratory testing 
• 
Questionnaires 
• 
Nutritional counseling and assessment.  
 
 
Unscheduled Visit 
Any unscheduled visits will include a complete physical examination collection of anthropomorphic 
and vital signs data and review of adverse events and medications. 
 

 
 28 
 
DATA MONITORING AND SAFETY REPORTING  
Data and Safety Monitoring 
This study will adhere to an IRB approved data safety monitoring plan (DSMP) to ensure sufficient 
oversight of the following areas of study conduct: subject safety, data integrity, subject privacy, data 
confidentiality, product accountability, study documentation and study coordination. Monthly meetings 
will be held with the Principal Investigator in attendance to review study conduct, with additional 
meetings to occur as needed to address time sensitive matters including adverse events or any deviations. 
Internal monitoring will be conducted following the accrual of the first subject, with additional 
monitoring to be undertaken on a quarterly basis thereafter. All adverse events, deviations and 
unanticipated problems affecting subject safety will be reported according to the requirements of the IRB 
of record. Ongoing assessment of AEs by the PI will determine if any of the stopping rules have been 
triggered. 
 
7.11 Stopping rules 
The study will be stopped if a) one death attributed to the procedure or the device, b) >2 of Grade IV AEs 
has occurred, and c) > 4 Grade III or more AEs occur.   
Adverse Events 
7.2.1 Definitions 
The following definitions will be used: 
7.2.1.1 Adverse Events: 
Only untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) related to the study intervention.  Each subject will be followed closely to 
ensure safety. 
Adverse events will be classified using the Clavien-Dindo classification in Figure 2. 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Adverse Event (AE) Clavien-Dindo Classification Grading 

 
 29 
 
 
 
7.2.1.2. Serious Adverse Event (SAE): 
An adverse event that meets one of the following criteria 
• 
Led to death 
• 
Resulted in serious deterioration in the health of the subject that results in: 
o Life-threatening illness or injury 
o Permanent impairment of a body structure or a body function 
o The need for in-patient care or prolongation of hospitalization (this does not include the 
optional 23 hours observation admission after ESG or re-tightening procedure).  
o Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function. 
• 
**Planned hospitalization for a pre-existing condition, or a procedure required by the trial protocol, 
without serious deterioration in health, is not considered a serious adverse event** 
 
Unanticipated problems, SAEs and AEs will be reported to governing IRBs per local guidelines. 
 
For the purpose of the study, an adverse event is considered severe if it is grade ≥ 3 on the Clavien-Dindo 
classification. 
 
7.2.1.3 Device-Related Adverse Event (DRAE): 
An adverse event related to the use of the medical device. This definition includes any events resulting from 
incorrect delivery and operation of the device and/or of its approved accessories, or any malfunction of the 
device or its components. This definition also includes any event resulting from user error or from 
intentional misuse of the device. 

 
 30 
 
7.2.1.4 Serious Device-Related Adverse Event (SDRAE): 
Any untoward medical occurrence that can be attributed wholly or partly to the device, which resulted in 
any of the characteristics of a serious adverse event as described above. 
 
7.2.1.5 Unanticipated Adverse Device Effects (UADE):  
Any adverse device effect which by its nature, incidence, severity, or outcome, has not been identified 
under the SAE section 6.2. 
 
Protocol Deviation 
All protocol deviations will be documented with the subject number and date of the protocol deviation. 
The following information will be documented for each protocol deviation: 
• 
Inclusion/Exclusion exceptions or violations, including subject did not sign informed consent 
prior to study admission  
• 
Follow-up visit not performed or Follow-up outside of window  
• 
Required testing or questionnaire not performed  
• 
Other (Describe)  
 
Protocol deviations will be reported to the IRB at the time of continuing review unless they are determined 
to rise to the level of a major deviation and/or impact subject safety. In the event of a major deviation a 
report is to be made to the IRB within 5 working days. All deviations are to be recorded in the EDC.  
 
Risk/Benefit evaluation 
ESG is an established procedure that has an excellent safety profile and has been shown to demonstrate 
significant weight loss. APC is approved for use in the GI tract and has also been shown to have a good 
safety profile. Combining ESG with HAPC technique could enhance the durability of this procedure by 
enabling approximation of submucosal surfaces for enhanced gastroplasty healing. This could help 
maximize the metabolic benefits of gastric mucosal revitalization in conjunction with the restrictive effects 
of ESG for enhanced weight loss, durability, and metabolic benefits of the combined procedure while 
minimizing the risk of weight recurrence previously reported with the traditional ESG. Since both 
procedures have an established good safety profile, hence minimizing the risks about using them in 
conjunction. 
 
 

 
 31 
 
STATISTICAL ANALYSIS 
 
Power and Sample Size 
The primary endpoint for power and sample size is durability of plications on repeat endoscopy 6 months 
after initial procedure with HAPC and ESG and ESG alone. Another primary endpoint for power and 
sample size is %TBWL at 6 and 12 months.   
 
We plan a 1:1 randomization scheme that allocates to either HAPC ESG (12 patients) or ESG alone (12 
patients). Given the pilot nature of this trial, no formal power calculation is feasible or warranted.   
  
Statistical Analysis 
Statistical analyses of randomized groups at 6 and 12 months will be performed based on a modified intent-
to-treat (mITT) principle for efficacy analyses. Patients randomized but subsequently withdrawn or 
identified as meeting exclusion criteria prior to intervention (as applied to both the treatment and control 
arms) will be excluded from the analysis if the reason for exclusion is documented and unrelated to the 
randomized arm.  
 
8.2.1 Primary Aim 
 
The primary outcomes are durability of plications and endoscopic sutures on repeat endoscopy at 6 
months, in the two randomized arms.  
 
 
8.2.2 Secondary Aims 
 
Continuous secondary outcomes, including %TBWLb, %EWLc, change in systolic and diastolic blood 
pressure and change in HbA1c, QOL questionnaires such as the SF-36, IWQOL, PHQ-9, and eating 
behavior scores will be compared between treatment arms using ANCOVA with adjustment for the same 
variables specified in the primary analysis. 
 
Binary outcomes, including proportion with ≥25% reduction in %EWL and incidence of esophagitis will 
be compared between treatment arms by Pearson Chi-square test.  
 
Among all subjects, %EWL will be compared at 6 and 12 months between both arms of the study.   
 
8.2.3 Secondary Analyses 
A per-protocol analysis will compare randomized groups among protocol adherent patients – here, defined 
among as those actually receiving the procedure and making ≥ 80% follow-up visit in both groups. Modified 
ITT will be considered the primary approach for all efficacy analyses and will include patients who actually 
received the intervention regardless of adherence to follow-up visits. Safety endpoints and adverse events 
may be evaluated based on treated group (per-protocol). 
 
Additional outcomes and analyses not specified here are considered exploratory and post-hoc and will be 
clearly identified as such in any publications. 
 
b %TBWL defined as [(pre-operative weight - post-operative weight)/(pre-operative weight)] x 100 
c % EWL defined as [(pre-op weight – follow up weight)/(pre-op weight – ideal body weight)] X 100 
Note: "Ideal body weight" of BMI 25 

 
 32 
Missing Data 
The primary analysis uses a hierarchical regression model, assuming post-randomization dropout is missing 
at random (MAR) among subjects completing at least 1 of the planned follow up visits. 
Patients excluded after randomization and before intervention on the basis of identified exclusion criteria 
will be excluded from analyses; reasons for meeting exclusion criteria will be documented.  Patients that 
withdraw/dropout between randomization and intervention are assumed to be missing completely at 
random.  However, a sensitivity analysis will compare withdrawn subjects to participating subjects and 
perform analyses under MAR (including multiple imputation) assumptions if these subjects appear different 
or if dropout occurs at substantially different rate in one arm compared to the other.  Participating patients 
who dropout prior to the first follow up visit will be analyzed similarly. 
 
Randomization and Data Collection 
Stratified block randomization schedules will be uploaded to REDCap. Data will be collected in REDCap 
data collection forms. 
 
Interim Analysis 
No interim analysis will be performed for efficacy endpoints.  Adverse events will be monitored throughout 
and discussed with the data monitoring committee. 
 

 
 33 
 
ETHICAL CONSIDERATIONS 
This study is to be conducted according to United States government regulations and Institutional 
research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional Review 
Board (IRB), in agreement with local legal prescriptions, for formal approval of the study.  The decision 
of the IRB concerning the conduct of the study will be made in writing to the sponsor-investigator before 
commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  This 
consent form will be submitted with the protocol for review and approval by the IRB for the study.  The 
formal consent of a subject, using the Approved IRB consent form, must be obtained before that subject 
undergoes any study procedure.  The consent form must be signed and dated by the subject or the 
subject’s legally authorized representative, and the individual obtaining the informed consent. 
 

 
 34 
 
STUDY FINANCES 
 
Funding Source 
The study is financed through the funding partner, Erbe Elektromedizin GmbH, and the Mayo Clinic 
Rochester.  
 
Conflict of Interest 
 
Any study team member who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict 
management plan that has been reviewed and approved by the study sponsor-investigator prior to 
participation in this study. 
 
Subject Stipends or Payments 
Subjects will not receive remuneration for taking part in this study. 
The procedure costs and all other costs associated with imaging, testing, procedure day, and follow-up 
visits will be covered by the funding partner, Erbe Elektromedizin GmbH, and Mayo clinic Rochester. 
Subjects will not pay for any procedure or test performed as part of the study and outlined in the protocol.  
 
 
 

 
 35 
 
REFERENCES   
 
1. 
Hales CM, Carroll MD, Fryar CD, et al. Prevalence of Obesity and Severe Obesity Among Adults: 
United States, 2017-2018. NCHS Data Brief 2020:1-8. 
2. 
Ward ZJ, Bleich SN, Cradock AL, et al. Projected U.S. State-Level Prevalence of Adult Obesity 
and Severe Obesity. N Engl J Med 2019;381:2440-2450. 
3. 
Flegal KM, Kit BK, Orpana H, et al. Association of all-cause mortality with overweight and obesity 
using standard body mass index categories: a systematic review and meta-analysis. JAMA 
2013;309:71-82. 
4. 
Adams KF, Schatzkin A, Harris TB, et al. Overweight, obesity, and mortality in a large prospective 
cohort of persons 50 to 71 years old. The New England journal of medicine 2006;355:763-78. 
5. 
Whitlock G, Lewington S, Sherliker P, et al. Body-mass index and cause-specific mortality in 900 
000 adults: collaborative analyses of 57 prospective studies. Lancet 2009;373:1083-96. 
6. 
Wadden TA, Butryn ML, Wilson C. Lifestyle Modification for the Management of Obesity. 
Gastroenterology 2007;132:2226-2238. 
7. 
Kheniser K, Saxon DR, Kashyap SR. Long-Term Weight Loss Strategies for Obesity. The Journal 
of Clinical Endocrinology & Metabolism 2021;106:1854-1866. 
8. 
Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with 
Overweight or Obesity. New England Journal of Medicine 2021;384:989-1002. 
9. 
Wadden TA, Bailey TS, Billings LK, et al. Effect of Subcutaneous Semaglutide vs Placebo as an 
Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: 
The STEP 3 Randomized Clinical Trial. JAMA 2021;325:1403-1413. 
10. 
Davies M, Færch L, Jeppesen OK, et al. Semaglutide 2·4 mg once a week in adults with overweight 
or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-
controlled, phase 3 trial. Lancet 2021;397:971-984. 
11. 
Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of concomitant administration of multiple doses of cagrilintide with 
semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet 
2021;397:1736-1748. 
12. 
Bal BS, Finelli FC, Shope TR, et al. Nutritional deficiencies after bariatric surgery. Nature Reviews 
Endocrinology 2012;8:544-556. 
13. 
Proietto J. Why is treating obesity so difficult? Justification for the role of bariatric surgery. Medical 
Journal of Australia 2011;195:144-146. 
14. 
Hedjoudje A, Abu Dayyeh BK, Cheskin LJ, et al. Efficacy and Safety of Endoscopic Sleeve 
Gastroplasty: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2020;18:1043-
1053.e4. 
15. 
Itani MI, Farha J, Sartoretto A, et al. Endoscopic sleeve gastroplasty with argon plasma 
coagulation: a novel technique. Journal of Digestive Diseases 2020;21:664-667. 
16. 
Mahmoud T, Vargas EJ, Ghazi R, et al. The Osculating Circles Gastroplasty: A Novel Endoscopic 
Submucosal Resection Enhanced Endoluminal Suturing for Obesity. Gastroenterology 
2021;161:1806-1808. e1. 
17. 
Jirapinyo P, de Moura DTH, Dong WY, et al. Dose response for argon plasma coagulation in the 
treatment of weight regain after Roux-en-Y gastric bypass. Gastrointestinal Endoscopy 
2020;91:1078-1084. 
18. 
Itani MI, Farha J, Sartoretto A, et al. Endoscopic sleeve gastroplasty with argon plasma 
coagulation: A novel technique. J Dig Dis 2020;21:664-667. 
19. 
Lee JH, Johannes RS, Van Dam J, et al. 7087 Argon plasma coagulation in endoscopic therapy. 
Gastrointestinal Endoscopy 2000;51:AB264. 
20. 
Mitchell NS, Catenacci VA, Wyatt HR, et al. Obesity: overview of an epidemic. The Psychiatric 
clinics of North America 2011;34:717-732. 

 
 36 
21. 
Tremmel M, Gerdtham U-G, Nilsson PM, et al. Economic Burden of Obesity: A Systematic 
Literature Review. International Journal of Environmental Research and Public Health 
2017;14:435. 
22. 
Stevens VJ, Obarzanek E, Cook NR, et al. Long-term weight loss and changes in blood pressure: 
results of the Trials of Hypertension Prevention, phase II. Annals of Internal Medicine 2001;134:1-
11. 
23. 
Gregg EW, Chen H, Wagenknecht LE, et al. Association of an intensive lifestyle intervention with 
remission of type 2 diabetes. JAMA 2012;308:2489-96. 
24. 
Pi-Sunyer X, Blackburn G, Brancati FL, et al. Reduction in weight and cardiovascular disease risk 
factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes care 
2007;30:1374-83. 
25. 
Dalle Grave R, Calugi S, Centis E, et al. Lifestyle modification in the management of the metabolic 
syndrome: achievements and challenges. Diabetes, metabolic syndrome and obesity : targets and 
therapy 2010;3:373-385. 
26. 
Kheniser K, Saxon DR, Kashyap SR. Long-Term Weight Loss Strategies for Obesity. J Clin 
Endocrinol Metab 2021;106:1854-1866. 
27. 
Kheniser K, Saxon DR, Kashyap SR. Long-Term Weight Loss Strategies for Obesity. The Journal 
of clinical endocrinology and metabolism 2021;106:1854-1866. 
28. 
Bult MJ, van Dalen T, Muller AF. Surgical treatment of obesity. Eur J Endocrinol 2008;158:135-
45. 
29. 
Chang S-H, Stoll CRT, Song J, et al. The effectiveness and risks of bariatric surgery: an updated 
systematic review and meta-analysis, 2003-2012. JAMA surgery 2014;149:275-287. 
30. 
Lupoli R, Lembo E, Saldalamacchia G, et al. Bariatric surgery and long-term nutritional issues. 
World journal of diabetes 2017;8:464-474. 
31. 
English WJ, DeMaria EJ, Brethauer SA, et al. American Society for Metabolic and Bariatric 
Surgery estimation of metabolic and bariatric procedures performed in the United States in 2016. 
Surgery for obesity and related diseases : official journal of the American Society for Bariatric 
Surgery 2018;14:259-263. 
32. 
Wadden TA, Tronieri JS, Butryn ML. Lifestyle modification approaches for the treatment of 
obesity in adults. The American psychologist 2020;75:235-251. 
33. 
Brunaldi VO, Neto MG. Endoscopic Procedures for Weight Loss. Current Obesity Reports 
2021;10:290-300. 
34. 
Courcoulas A, Abu Dayyeh BK, Eaton L, et al. Intragastric balloon as an adjunct to lifestyle 
intervention: a randomized controlled trial. Int J Obes (Lond) 2017;41:427-433. 
35. 
Aljiffry M, Habib R, Kotbi E, et al. Acute Pancreatitis: A Complication of Intragastric Balloon. 
Surg Laparosc Endosc Percutan Tech 2017;27:456-459. 
36. 
Rahman AA, Loi K. Gastric Perforation as a complication of intragastric balloon. Surg Obes Relat 
Dis 2018;14:719-722. 
37. 
Gleysteen JJ. A history of intragastric balloons. Surg Obes Relat Dis 2016;12:430-5. 
38. 
Abu Dayyeh BK, Rajan E, Gostout CJ. Endoscopic sleeve gastroplasty: a potential endoscopic 
alternative to surgical sleeve gastrectomy for treatment of obesity. Gastrointestinal Endoscopy 
2013;78:530-5. 
39. 
Sharaiha RZ, Kedia P, Kumta N, et al. Initial experience with endoscopic sleeve gastroplasty: 
technical success and reproducibility in the bariatric population. Endoscopy 2015;47:164-6. 
40. 
Abu Dayyeh BK, Acosta Cardenas AJ, Camilleri M, et al. Endoscopic Sleeve Gastroplasty Alters 
Gastric Physiology and Induces Loss of Body Weight in Obese Individuals. Clinical 
gastroenterology and hepatology : the official clinical practice journal of the American 
Gastroenterological Association 2015. 
41. 
Sharaiha R. Managing Obesity With Endoscopic Sleeve Gastroplasty. Gastroenterology & 
hepatology 2017;13:547-549. 

 
 37 
42. 
Jirapinyo P, de Moura DTH, Thompson CC. Endoscopic submucosal dissection with suturing for 
the treatment of weight regain after gastric bypass: outcomes and comparison with traditional 
transoral outlet reduction (with video). Gastrointestinal endoscopy 2020;91:1282-1288. 
43. 
Zenker M. Argon plasma coagulation. GMS Krankenhaushygiene interdisziplinar 2008;3:Doc15-
Doc15. 
44. 
Marchesini SD, Baretta GAP, Cambi MPC, et al. Endoscopic plasma argon coagulation in 
treatment of weight regain after bariatric surgery: what does the patient think about this? Arquivos 
brasileiros de cirurgia digestiva : ABCD = Brazilian archives of digestive surgery 2014;27 Suppl 
1:47-50. 
45. 
Dhindsa BS, Saghir SM, Naga Y, et al. Efficacy of transoral outlet reduction in Roux-en-Y gastric 
bypass patients to promote weight loss: a systematic review and meta-analysis. Endoscopy 
international open 2020;8:E1332-E1340. 
46. 
Storm AC, Thompson CC. Endoscopic Treatments Following Bariatric Surgery. Gastrointest 
Endosc Clin N Am 2017;27:233-244. 
47. 
Jaruvongvanich V, Vantanasiri K, Laoveeravat P, et al. Endoscopic full-thickness suturing plus 
argon plasma mucosal coagulation versus argon plasma mucosal coagulation alone for weight 
regain after gastric bypass: a systematic review and meta-analysis. Gastrointest Endosc 
2020;92:1164-1175.e6. 
48. 
Catalano MF, Rudic G, Anderson AJ, et al. Weight gain after bariatric surgery as a result of a large 
gastric stoma: endotherapy with sodium morrhuate may prevent the need for surgical revision. 
Gastrointestinal Endoscopy 2007;66:240-245. 
49. 
Baretta GAP, Alhinho HCAW, Matias JEF, et al. Argon Plasma Coagulation of Gastrojejunal 
Anastomosis for Weight Regain After Gastric Bypass. Obesity Surgery 2015;25:72-79.