Combined Endoscopic Ultrasound Guided Core Liver Biopsy and Intragastric Balloon Placement for the Diagnosis and Management of Nonalcoholic Steatohepatitis and Obesity
Phase: NA
Conditions: Obesity, Non-Alcoholic Steatohepatitis
Sponsor: Mayo Clinic

 
 
A Pilot Combined Endoscopic 
Ultrasound Guided Core Liver 
Biopsy and Intragastric Balloon 
Placement for Management of 
Nonalcoholic Steatohepatitis 
and Obesity 
 
NCT# 02880189 
 
June 23, 2017 

EUS and IGB for Management of NASH and Obesity  
 
 
 
 
Version 3.0 
 
 
Revised 6/23/2017 
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A Pilot Combined Endoscopic Ultrasound Guided Core Liver Biopsy and Intragastric 
Balloon Placement for Management of Nonalcoholic Steatohepatitis and Obesity 
 
 
Principal Investigator 
 
 
 
 
 
 
 
Barham Abu Dayyeh M.D. MPH 
Division of Gastroenterology and Hepatology 
Mayo Clinic 
200 First Street SW, Rochester MN 55905 
Phone: 507-266-6931 
Email: abudayyeh.barham@mayo.edu 
 
 
 
Study Product: 
Orbera Intragastric Balloon (Apollo Endosurgery, Austin, 
TX) 
Protocol Number: (IRBe) 
IRB 15-009262 
IDE Number: 
G160077 
 
 
 
Initial version: 
05/03/16 Version (1.0) 
Revised: 
 
6/23/2017 (3.0) 
 
 

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Table of Contents 
STUDY SUMMARY ................................................................................................................................4 
1 
INTRODUCTION ...........................................................................................................................6 
1.1 
BACKGROUND ............................................................................................................................................. 6 
1.2 
INVESTIGATIONAL DEVICE .......................................................................................................................... 8 
1.3 
PRECLINICAL DATA .................................................................................................................................... 8 
1.4 
CLINICAL DATA TO DATE ........................................................................................................................... 8 
1.5 
STUDY RATIONALE AND RISK/BENEFITS .................................................................................................... 9 
1.5.1 
Study Rationale ....................................................................................................................9 
1.5.2 
Anticipated Risks .............................................................................................................. 10 
1.5.3 
Potential Benefits .............................................................................................................. 12 
2 
STUDY OBJECTIVES ................................................................................................................. 12 
3 
STUDY DESIGN .......................................................................................................................... 13 
3.1 
GENERAL DESIGN ..................................................................................................................................... 13 
3.2 
PRIMARY STUDY ENDPOINT ...................................................................................................................... 14 
3.3 
SECONDARY STUDY ENDPOINTS ............................................................................................................... 14 
3.4 
PRIMARY SAFETY ENDPOINTS ................................................................................................................... 15 
4 
SUBJECT SELECTION, ENROLLMENT AND WITHDRAWAL .............................................. 15 
4.1 
INCLUSION CRITERIA ................................................................................................................................ 16 
4.2 
.EXCLUSION CRITERIA .............................................................................................................................. 16 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ......................................................................... 17 
4.4 
EARLY WITHDRAWAL OF SUBJECTS.......................................................................................................... 17 
4.4.1 
When and How to Withdraw Subjects ................................................................................. 17 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ....................................................... 18 
5 
STUDY DEVICE ......................................................................................................................... 18 
5.1 
DESCRIPTION ............................................................................................................................................ 18 
5.2 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS .................................................................. 18 
5.3 
PREPARATION AND ADMINISTRATION/IMPLANTATION OF INVESTIGATIONAL DEVICE .............................. 19 
5.4 
SUBJECT COMPLIANCE MONITORING ........................................................................................................ 19 
5.5 
PRIOR AND CONCOMITANT THERAPY ....................................................................................................... 19 
5.6 
PACKAGING AND LABELING ...................................................................................................................... 20 
5.7 
MASKING/BLINDING OF STUDY ................................................................................................................ 20 
5.8 
RECEIVING, STORAGE, DISTRIBUTION AND RETURN ................................................................................. 20 
5.8.1 
Receipt of Investigational Devices ...................................................................................... 20 
5.8.2 
Storage ............................................................................................................................ 20 
5.8.3 
Distribution of Study Device .............................................................................................. 20 
5.8.4 
Return or Destruction of Study Device ................................................................................ 20 
6 
STUDY PROCEDURES............................................................................................................... 20 
6.1 
FOLLOW UP FOR PATIENTS WITH DEVICE-RELATED ADVERSE EVENTS AT THE TIME OF DEVICE 
REMOVAL ................................................................................................................................................................ 22 
6.2 
SCHEDULE OF EVENTS .............................................................................................................................. 23 
6.3 
TISSUE LIPIDOMICS WORKUP ..................................................................................................................... 24 
7 
STATISTICAL PLAN .................................................................................................................. 24 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................ 24 
8.1 
DEFINITIONS ............................................................................................................................................. 24 
8.2 
ADVERSE EVENT REPORTING PERIOD ....................................................................................................... 26 
8.3 
RECORDING OF ADVERSE EVENTS ............................................................................................................ 26 

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8.4 
SPONSOR-INVESTIGATOR REPORTING OF UNANTICIPATED ADVERSE DEVICE EFFECTS 
AND 
UNANTICIPATED PROBLEMS .................................................................................................................................... 27 
8.4.1 
Sponsor-Investigator Reporting, Notifying Mayo IRB ........................................................... 27 
8.4.2 
Sponsor-Investigator Reporting: Notifying the FDA ............................................................. 27 
8.5 
UNBLINDING PROCEDURES ....................................................................................................................... 28 
8.6 
STOPPING RULES ....................................................................................................................................... 28 
8.7 
MEDICAL MONITORING ............................................................................................................................ 28 
8.7.1 
Internal Data and Safety Monitoring Board ........................................................................ 28 
8.8 
CONFIDENTIALITY..................................................................................................................................... 29 
8.9 
SOURCE DOCUMENTS................................................................................................................................ 29 
8.10 
CASE REPORT FORMS ............................................................................................................................... 29 
8.11 
RECORDS RETENTION ............................................................................................................................... 30 
9 
STUDY MONITORING, AUDITING, AND INSPECTING ......................................................... 30 
9.1 
STUDY MONITORING PLAN ....................................................................................................................... 30 
9.2 
AUDITING AND INSPECTING ...................................................................................................................... 31 
10 
ETHICAL CONSIDERATIONS .................................................................................................. 31 
11 
STUDY FINANCES ..................................................................................................................... 31 
11.1 
FUNDING SOURCE ..................................................................................................................................... 31 
11.2 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................................ 31 
12 
PUBLICATION PLAN ................................................................................................................ 31 
13 
REFERENCES ............................................................................................................................ 32 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
EUS 
Endoscopic Ultrasound 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IDE 
Investigational Device Exemption 
IGB 
Intragastric Balloon 
IRB 
Institutional Review Board 
MRE 
Magnetic Resonance Elastography 
MRS 
Magnetic Resonance Spectroscopy 
NAFLD 
Non-alcoholic Fatty Liver Disease 
NAS 
Non-alcoholic Steatohepatitis Score 
NASH 
Non-alcoholic Steatohepatitis 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
TBWL 
Total Body Weight Loss 
UADE 
Unanticipated Adverse Device Effect 
 
 
Study Summary 
Title 
A Pilot Combined Endoscopic Ultrasound Guided Core Liver Biopsy 
and Intragastric Balloon Placement for Management of Nonalcoholic 
Steatohepatitis and Obesity 
Running Title 
EUS and IGB for Management of NASH and Obesity 
IRB Protocol 
Number 
15-009262 
Phase 
Pilot 
Methodology 
Open Label  

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Overall Study 
Duration 
60-64 Weeks 
Subject Participation 
Duration 
12 months 
Objectives 
Significant weight loss achieved with the IGB in NASH patients with 
BMI between 30 – 55 kg/m2 and early fibrosis based on MRE is 
associated with ≥ 2 points improvement in NAS and regression of 
fibrosis on paired EUS guided liver core biopsies. 
Number of Subjects 
25 
Diagnosis and Main 
Inclusion Criteria 
Inclusion criteria to our study include NASH patients with evidence 
of early fibrosis (excluding advanced fibrosis or cirrhosis) by baseline 
liver biopsy when available, and/or  MRE (magnetic resonance 
elastography), who are referred for an intragastric balloon placement 
for weight loss. 
Study Device 
Orbera Intragastric Balloon (Apollo Endosurgery Austin, TX) 
Duration of 
Exposure 
6 months  
Statistical 
Methodology 
We have the resources to enroll at total of 20 patients (additional 5 in 
case of early withdrawal) to this study. With a sample size of 20 we 
will have 80% power to detect a medium to large (effect size 0.66) 
improvement in NASH activity scores on paired liver biopsies using a 
paired t-test with a two sides p-value < 0.05. The table below shows 
that sample size needed to detect small, medium, or large 
improvement in NAS scores on paired liver biopsies at 80% power. 
 
 

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1 Introduction 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the procedures described in this protocol, applicable United States 
government regulations and Mayo Clinic policies and procedures. 
1.1 
Background 
Obesity has reached pandemic proportions.[1] Mirroring this rise in obesity prevalence is 
a rise in its associated co-morbid conditions including metabolic syndrome and non-alcoholic 
fatty liver disease (NAFLD). [2] Indeed, NAFLD is thought to afflict about 70% and 50% of 
obese adults and children, respectively.[3] Of those, about 5% will progress to cirrhosis and 
end stage liver disease. Non-alcoholic steatohepatitis (NASH) is projected to be the leading 
cause of liver transplantation in the United States by 2020. [4]  
 
Hepatic fibrosis regardless of etiology progresses to cirrhosis if the etiological agent is 
not removed or treated. [5] There is growing evidence for reversibility of steatohepatitis and 
hepatic fibrosis especially in early stages and with significant weight loss. [5] In a seminal 
study of 293 patients with histologically proven NASH who had life-style modification to 
reduce their weight over 52 weeks, 72 (25%) achieved resolution of steatohepatitis, 138 
(47%) had reductions in nonalcoholic fatty liver disease activity score (NAS), and 56 (19%) 
had regression of fibrosis. [5] The degree of weight loss was independently associated with 
improvements in all NASH-related histologic parameters with all patients who lost ≥ 10% of 
their total body weight (%TBWL) had reductions in NAS, 90% had resolution of NASH, and 
45% had regression of fibrosis, compared to 32% (reduction in NAS), 10% (resolution of 
NASH), and 16% (regression of fibrosis) in those who lost ≤5%. Life-style interventions for 
obesity; however, are associated with poorly sustained effects and relatively weak efficacy. 
Indeed, in this study less than 10% of the cohort achieved ≥ 10% TBWL with life-style 
modification alone and the majority (70%) achieved less than 5% TBWL.[5] 
 
The Orbera™ Intragastric Balloon (Apollo Endosurgery, Austin, TX), previously known 
as the BioEnterics Intragastric Balloon (BIB) (Allergan, Irvine, CA) is an elastic spherical 
balloon made from silicone, filled with about 600 ml of saline and is placed in the stomach 
via upper endoscopy. This IGB is designed to stay in place for 6 months prior to endoscopic 
removal and has been widely used in Europe, South America, and the Middle East with 
excellent safety profile. In an ASGE Bariatric Endoscopy Task Force systematic review and 
meta-analysis the pooled %TBWL after the Orbera IGB implantation was 12.3% (95% CI, 
7.91–16.73), 13.16% (95% CI, 12.37–13.95), and 11.27% (95% CI, 8.17–14.36) at 3, 6, and 
12 months after implantation, respectively.[6] This was based on a review of 55 studies. This 
balloon is currently FDA approved for use in the United States after a US randomized 
multicenter pivotal trial demonstrated similar efficacy.  
 
The rates of adverse events after implantation of the Orbera balloon are pooled from a 
manual review of 68 studies (8500 implantations) and are summarized in Figure 1. Pain and 
nausea are frequent side-effects after Orbera balloon implantation, occurring in up to 33.7% 
of subjects. Medications such as proton pump inhibitors, antispasmodic drugs, and 
antiemetics are usually prescribed prophylactically before, during, and after balloon 

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placement to prevent or minimize these expected common side effects. Serious side-effects 
with Orbera balloon are rare with an incidence of migration and gastric perforation of 1.4% 
and 0.1%, respectively. Most of the reported perforations with the Orbera were in patients 
who had undergone previous gastric surgeries, which is a contraindication for use in the 
US.[6]  
 
More particularly, the safety and efficacy of the Orbera intragastric balloon has been 
previously demonstrated in patients with suspected NASH. A small study randomized 18 
obese or overweight patients with histologically proven nonalcoholic steatohepatitis (NASH) 
to lifestyle modification plus Orbera balloon placement or to lifestyle modification plus a 
sham procedure. Weight and liver histology were assessed before and 6 months after balloon 
insertion or the sham procedure. The Orbera balloon placement group had a significantly 
higher reduction in mean BMI (1.52 vs 0.8; P = .0008) and a superior improvement in 
nonalcoholic fatty liver disease activity scores at the end of treatment (2 [SD 0.75] vs 4 [SD 
2.25]; P = .03).[7] Three other single arm studies demonstrated improvement in liver 
steatosis by cross sectional imaging and liver biochemical testing with the Orbera balloon in 
patient with suspected NASH. [8-10] 
 
The detection of early fibrosis with steatohepatitis is critical given the more aggressive 
nature of disease, which requires a more aggressive treatment plan. However, early fibrosis is 
difficult to diagnose with non-invasive imaging modalities without the need for a liver 
biopsy. Although modalities such as transient elastography (Fibroscan) have good diagnostic 
accuracy for cirrhosis, its performance is suboptimal for earlier stages of fibrosis. [11] 
Several studies have established that liver magnetic resonance elastography (MRE) is an 
accurate technique for the detection of earlier stages of liver fibrosis and steatosis. MRE has 
therefore emerged as a potential alternative to liver biopsy in establishing the diagnosis of 
NASH. [12, 13] However, despite MRE accuracy in establishing the diagnosis, there are 
no studies to demonstrate its sensitivity to change in response to an intervention such as 
weight loss. Furthermore, there are no standardized validated criteria to objectively 
assess improvement in NASH and fibrosis with MRE as exit for liver biopsy, which 
remains the gold standard in clinic trial evaluating the impact of intervention on 
NASH.[14]  
 
Endoscopic ultrasound guided liver biopsy has been shown to be very safe and capable of 
adequately and reproducibly sampling widely separated liver regions under direct guidance; 
thus yielding more representative and suitable liver tissue for the staging and 
histopathological follow-up of NASH, especially in the confounds of clinical trial.[15-17] 
EUS-guided core liver biopsy can produce equal or higher number of complete portal tracts 
compared to traditional percutaneous approach, while avoiding sampling error in a paired 
liver biopsy design (pre and post intervention), which is currently a pitfall of the precautious 
liver biopsy approach given the patchy nature of non-alcoholic fatty liver disease. [18]  
 
Given the limited data of the impact of weight loss produced by the intragastric balloon 
on NASH with early fibrosis, we propose a prospective study to evaluate the impact of 
weight loss produced the Orbera intragastric balloon on objective NASH histopathological 
parameters.  

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1.2 
Investigational Device 
The Orbera (Apollo Endosurgery, Austin Tx) is an elastic spherical balloon made of 
silicone, filled with 450 to 700 mL of saline solution, and is FDA approved for weight loss in 
adult US patients with body mass index between 30 to 40 kg/m2.  The deflated balloon comes 
preloaded on a catheter, which is blindly advanced transorally into the stomach. An 
endoscope is then advanced alongside it to ensure accurate placement of the balloon in the 
fundus. Under direct visualization, the balloon is then inflated by injecting saline solution 
through the external portion of the catheter. The Orbera balloon is currently used in many 
countries outside the United States and is typically implanted for 6 months and then retrieved 
endoscopically. 
1.3 
Preclinical Data 
See PMA study of the Orbera intragastric balloon  
1.4 
Clinical Data to Date 
The Orbera™ Intragastric Balloon (Apollo Endosurgery, Austin, TX), previously known 
as the BioEnterics Intragastric Balloon (BIB) (Allergan, Irvine, CA) is an elastic spherical 
balloon made from silicone, filled with about 600 ml of saline and is placed in the stomach 
via upper endoscopy. This IGB is designed to stay in place for 6 months prior to endoscopic 
removal and has been widely used in Europe, South America, and the Middle East with 
excellent safety profile. In an ASGE Bariatric Endoscopy Task Force systematic review and 
meta-analysis the pooled %TBWL after the Orbera IGB implantation was 12.3% (95% CI, 
7.91–16.73), 13.16% (95% CI, 12.37–13.95), and 11.27% (95% CI, 8.17–14.36) at 3, 6, and 
12 months after implantation, respectively.[6] This was based on a review of 55 studies. This 
balloon is currently FDA approved for use in the United States after a US randomized 
multicenter pivotal trial demonstrated similar efficacy. 
 
The rates of adverse events after implantation of the Orbera balloon are pooled from a 
manual review of 67 studies (8500 implantations) and are summarized in Figure 1. Pain and 
nausea are frequent side-effects after Orbera balloon implantation, occurring in up to 33.7% 
of subjects. Medications such as proton pump inhibitors, antispasmodic drugs, and 
antiemetics are usually prescribed prophylactically before, during, and after balloon 
placement to prevent or minimize these expected common side effects. Serious side-effects 
with Orbera balloon are rare with an incidence of migration and gastric perforation of 1.4% 
and 0.1%, respectively. Most of the reported perforations with the Orbera were in patients 
who had undergone previous gastric surgeries, which is a contraindication for use in the 
US.[6]  
 
More particularly, the safety and efficacy of the Orbera intragastric balloon has been 
previously demonstrated in patients with suspected NASH. A small study randomized 18 
obese or overweight patients with histologically proven nonalcoholic steatohepatitis (NASH) 
to lifestyle modification plus Orbera balloon placement or to lifestyle modification plus a 
sham procedure. Weight and liver histology were assessed before and 6 months after balloon 
insertion or the sham procedure. The Orbera balloon placement group had a significantly 

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higher reduction in mean BMI (1.52 vs 0.8; P = .0008) and a superior improvement in 
nonalcoholic fatty liver disease activity scores at the end of treatment (2 [SD 0.75] vs 4 [SD 
2.25]; P = .03).[7] Three other single arm studies demonstrated improvement in liver 
steatosis by cross sectional imaging and liver biochemical testing with the Orbera balloon in 
patient with suspected NASH. [8-10] 
1.5 
Study Rationale and Risk/Benefits 
1.5.1 Study Rationale 
NASH with early fibrosis is serious condition that afflicts a significant portion of patients 
with obesity with the potential to progress to cirrhosis. Weight loss of ≥ 10 % TBWL has 
been definitively shown to be an effective treatment of NASH with regression of early 
fibrosis, however, this magnitude of weight loss is only achieved in the minority (≤ 10%) of 
patients with life style modification. The IGB achieves a mean %TBWL weight loss of about 
13% at 6 months, and has previously shown efficacy in management of NASH in a small 
cohort outside the US.  In 8 patients with biopsy proven NASH and obesity, who underwent 
the Orbera IGB placement and  paired percutaneous liver biopsies before and 6 months after 
Orbera placement, the NAS significantly improved with IGB placement group compared to 
the life-style intervention alone (4 ±2.25 vs. 2 ± 0.75 vs. P = .03). However, this study 
demonstrated no improvement in fibrosis scores as only the minority of the cohort had true 
early fibrosis. From a recent seminal paper we know that achieving ≥ 10% TBWL is clearly 
associated with regression in fibrosis, although this magnitude of weight loss is difficult to 
achieve with life-style modification only. Thus, in this protocol we will be selecting patients 
with NASH and early fibrosis diagnosed by MRE for placement of intragastric balloon and 
concomitant EUS guide liver biopsies at the time of balloon placement and removal (6 
months after) to evaluate the impact of weight loss achieved by the Orbera IGB on NAS and 
fibrosis regression.  
 
The use of paired EUS guided liver biopsies is crucial for our study design as despite 
MRE accuracy in establishing the diagnosis of NASH with early fibrosis for patient 
inclusion to our study, there are no studies to demonstrate its sensitivity to change in 
response to an intervention such as weight loss. Furthermore, there are no standardized 
validated criteria to objectively assess improvement in NASH and fibrosis with MRE as 
exists for liver biopsy, which remains the gold standard in clinic trial evaluating the 
impact of intervention on NASH.  
 
Spectroscopic and biochemical hepatic fat quantitative assessment pre- and post-
intervention – Rationale:  
 
The degree of lipid saturation and polyunsaturation can be measured noninvasively by 
proton magnetic resonance spectroscopy [19]. This technique adds no cost, as the series can 
be simultaneously captured during MRE acquisition session, adding few minutes to the 
procedure. Evidence suggests that depletion of hepatic polyunsaturated fatty acids (PUFAs) 
reduces hepatic fatty acid oxidation and triglyceride export. Furthermore, it is associated with 
augmentation in in hepatic fatty acid and triglyceride synthesis, leading to increased 
triglyceride aggregation. Moreover, this process has been thought to increase inflammation 
and facilitates the development of steatohepatitis. Indeed, studies have shown that alterations 

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in tissue lipid saturation may portend sinister clinical outcomes more reliably than simple 
means of fatness measurements [20]. 
 
To the best of our knowledge, no studies have corroborated the sensitivity of H-MRS 
detection of SI and PUI changes, as well as other indices of hepatic lipid composition, with 
weight loss, and its correlation to decrease in total steatosis, changes in liver stiffness, as well 
as changes in fibrosis scores on histology.  
 
Our current study offers a rare window to accurately examine and capture these changes 
due to the availability of liver tissue histology pre- and post-intervention. This will allow the 
determination H-MRS reliability in predicting lipidomic analysis changes in a NASH 
afflicted liver, obviating the need of invasive testing. 
 
Furthermore, an unmet need in the understanding of nonalcoholic fatty liver disease is the 
determination of the interactions between the changes in hepatic lipid polyunsaturated fatty 
acids (PUFA) depletion and liver injury; considering the expected improvement in liver 
histology parameters with our proposed intervention, our study would offer a unique 
opportunity to correlate these improvements with PUFA depletion[19, 21, 22]. 
 
1.5.2 Anticipated Risks 
The rates of adverse events after implantation of the Orbera balloon are pooled from a 
manual review of 68 studies (8500 implantations) and are summarized in Figure 1. Pain and 
nausea are frequent side-effects after Orbera balloon implantation, occurring in up to 33.7% 
of subjects. Medications such as proton pump inhibitors, antispasmodic drugs, and 
antiemetics are usually prescribed prophylactically before, during, and after balloon 
placement to prevent or minimize these expected common side effects. Serious side-effects 
with Orbera balloon are rare with an incidence of migration and gastric perforation of 1.4% 
and 0.1%, respectively. Most of the reported perforations with the Orbera were in patients 
who had undergone previous gastric surgeries, which is a contraindication for use in the 

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US.[6] 
 
 
Figure 1. Pooled Orbera Complications from 68 studies (8500 patients) [6] 
 
More particularly, the safety of the Orbera intragastric balloon has been previously 
demonstrated in patients with suspected NASH. A small study randomized 18 obese or 
overweight patients with histologically proven nonalcoholic steatohepatitis (NASH) to 
lifestyle modification plus Orbera balloon placement or to lifestyle modification plus a sham 
procedure. Weight and liver histology were assessed before and 6 months after balloon 
insertion or the sham procedure. The Orbera balloon placement group had a significantly 
higher reduction in mean BMI (1.52 vs 0.8; P = .0008) and a superior improvement in 
nonalcoholic fatty liver disease activity scores at the end of treatment (4 [SD 2.5] vs 2 [SD 
20.75]; P = .03), with no increased incidence of adverse events.[7] Three other single arm 
studies demonstrated improvement in liver steatosis by cross sectional imaging and liver 
biochemical testing with the Orbera balloon in patient with suspected NASH with excellent 
safety profile in these cohorts with suspected NASH. [8-10] 
 
EUS guided core liver biopsy has been established as a safe, adequate, and cost effective 
mean to obtain diagnostic liver tissue to diagnose and stage chronic liver disease. In more 
than 200 patients reported in the literature, EUS guided liver biopsy was capable in providing 
similar or more adequate liver sample than percutaneous or trans-jugular approach with no 
reported incidence of any adverse events. [15-17, 23] Our EUS group has conducted over 
800 EUS guided liver biopsies, with no reported incidence of immediate or delayed adverse 
events. In this protocol using paired EUS guided liver biopsies at the time of balloon 
insertion and removal will be cost effective, safe, only add few extra minutes to the 
procedure, and will allow us to minimize sampling error and isolate the effects of weight loss 
achieved by the intragastric balloon on gold standard histological endpoints.  

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1.5.3 Potential Benefits 
Hepatic fibrosis regardless of etiology progresses to cirrhosis if the etiological agent is 
not removed or treated. [5] There is growing evidence for reversibility of steatohepatitis and 
hepatic fibrosis especially in early stages and with significant weight loss. [5] In a seminal 
study of 293 patients with histologically proven NASH who had life-style modification to 
reduce their weight over 52 weeks, 72 (25%) achieved resolution of steatohepatitis, 138 
(47%) had reductions in nonalcoholic fatty liver disease activity score (NAS), and 56 (19%) 
had regression of fibrosis. [5] The degree of weight loss was independently associated with 
improvements in all NASH-related histologic parameters with all patients who lost ≥ 10% of 
their total body weight (%TBWL) had reductions in NAS, 90% had resolution of NASH, and 
45% had regression of fibrosis, compared to 32% (reduction in NAS), 10% (resolution of 
NASH), and 16% (regression of fibrosis) in those who lost ≤5%. Life-style interventions for 
obesity; however, are associated with poorly sustained effects and relatively weak efficacy. 
Indeed, in this study less than 10% of the cohort achieved ≥ 10% TBWL with life-style 
modification alone and the majority (70%) achieved less than 5% TBWL.[5] 
 
The Orbera intragastric balloon is expected to results in 12.3% (95% CI, 7.91–16.73), 
13.16% (95% CI, 12.37–13.95), and 11.27% (95% CI, 8.17–14.36) TBWL at 3, 6, and 12 
months after implantation, respectively.[6] This was based on a review of 55 studies. This 
balloon is currently FDA approved for use in the United States after a US randomized 
multicenter pivotal trial demonstrated similar efficacy. Thus, with the anticipated weight loss 
seen with the Orbera Intragastric balloon, we expect improvement in histological NASH 
parameters and regression of fibrosis with the weight loss achieved with the intragastric 
balloon.  
 
The ability to quantify and capture hepatic fat change, and correlate it to spectroscopic 
changes could offer important non-invasive means of NASH progression/regression in 
afflicted individuals. This study would offer a unique opportunity to corroborate the utility of 
MRS in accurate and reliable evaluation of this parameter.  
2 Study Objectives 
 
2.1 Primary Objective 
NASH with early fibrosis is serious condition that afflicts a significant portion of patients 
with obesity with the potential to progress to cirrhosis. Weight loss of ≥ 10 % TBWL has 
been definitively shown to be an effective treatment of NASH with regression of early 
fibrosis, however, this magnitude of weight loss is only achieved in the minority (≤ 10%) of 
patients with life style modification. The IGB achieves as mean %TBWL of 13%. Therefore, 
we aim to study the impact of weight loss achieved by the Orbera intragastric balloon on 
NAS and liver fibrosis in a cohort selected by MRE to have NASH with early fibrosis but not 
cirrhosis.  This will be assessed with a paired EUS guided biopsies at the time of balloon 
placement and removal after six months.  
 
Hypothesis 1: Significant weight loss achieved with the IGB in NASH patients with BMI 
between 30 – 55 kg/m2 and fibrosis based on MRE is associated with ≥ 2 points improvement 
in NAS and regression of fibrosis on paired EUS guided liver core biopsies.  

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2.2 Secondary Objective 
- 
Evaluate safety and tolerance of the Orbera intragastric balloon and concomitant 
paired EUS guided liver biopsy at time of balloon placement and removal.  
- 
Obtaining lipid saturation (SI) and polyunsaturation (PUI) indices via H-MRS 
technology pre- and post-intervention 
- 
Obtaining hepatic triglycerides content (HTGC) via H-MRS technology pre- and 
post-intervention. 
- 
Obtaining percent unsaturated fatty acyl chains present in this cohort of NASH 
patients, as well as changes that occur in the setting of weight loss. 
- 
Obtaining percent polyunsaturated fatty acyl chains present in this cohort of NASH 
patients, as well as changes that occur in the setting of weight loss.  
- 
Measurement of hepatic lipid composition by needle biopsy and lipidomic analysis 
techniques before and after weight loss.  
- 
Correlation of MRS obtained lipid composition to lipidomic analysis composition. 
 
3 Study Design 
3.1 
General Design 
 Patients with suspicion for NASH at our center undergo a combined MRE/MRS 
(magnetic resonance elastography/magnetic resonance spectroscopy) sequence to classify 
their disease according to four stages. These stages 
are numbered from 1-4 with stage 4 signifying 
more advanced fibrosis. The MRE/MRS sequence 
also quantifies hepatic fat content. Those with 
stage 1-3 fibrosis will be referred for IGB 
placement for weight loss as a management 
strategy for NASH. Once referred to the 
endoscopic bariatric clinic a multidisciplinary 
team 
that 
includes 
endocrinology, 
gastroenterology, psychology, and nutrition will 
evaluate them. If found to be appropriate 
candidates, they will be enrolled in this study by a 
member of the study team who will discuss the study protocol, risks, benefits, and 
alternatives with patients and have them sign an informed consent.  Patient will undergo 
intragastric balloon placement and an EUS guided liver biopsy during the same endoscopy 
session will be performed under monitored anesthesia sedation at our outpatient endoscopy 
unit. The EUS guided liver biopsy will be performed before balloon insertion from the left 
liver lobe under EUS guidance using a 22 gauge core needle (Sharkcore, Covidien, 
Minneapolis, MN). Three passes will be performed from two separate liver segments (Figure 
2). An additional pass may be performed at the discretion of the PI if the three performed 
passes do not yield enough tissue on visual inspection of the core to ensure adequate 
histology analysis. The maximum number of passes will not exceed four. Doppler ultrasound 
will be used to exclude intervening vessels.  Two samples will be submitted for 
histopathology review in formalin, and one or two will be submitted for total fat 
Figure 2.  

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quantification analysis. After the EUS guided liver biopsy (usually take 10 minutes to 
perform), the Orbera intragastric balloon will be advanced to the stomach under endoscopy 
guidance and inflated with 600 ml of normal saline. Patient transient nausea and pain 
symptoms will be managed with few days course of antiemetic and antispasmodics as per our 
clinical protocol, and patients will be required to take a daily proton pump inhibitor if not 
already taking. Patient will then undergo a moderate intensity life-style intervention 
consisting of daily phone call for the first week (nurse and or study coordinator) then 
monthly group visits with a health-care coach / nutrition to administer the life-style 
intervention program over 6 months period as per our clinical protocol for the intragastric 
balloon. At 6 months patients will return for balloon removal at our complex endoscopy unit 
under monitored anesthesia care. The balloon will be removed using the standard balloon 
retrieval kit approved by the FDA. After balloon removal a second EUS guided liver biopsy 
from two separate liver segments similar to the first biopsies site will be obtained with three 
or four passes with the 22 gauge core liver biopsy needle (Sharckcore, Covidien, 
Minneapolis, MN). The anticipated procedural length for both the EUS guided liver biopsy 
and balloon insertion and removal is less than 6 minutes. After balloon removal, all patients 
will be offered additional six months of moderate life-style intervention program 
administered as monthly group or individual visits with a health care coach to emphasize 
healthy lifestyle intervention and behaviors. Weight, height, waist circumference, and 
demographic information will be collected a baseline, time of balloon removal (6 months), 
and at 12 months (6months after balloon removal). Of note the cost of balloon placement, 
removal, medications to manage symptoms after balloon placement, EUS guided liver biopsy 
and pathologic interpretation, and the 12 months life-style intervention program will be 
covered by the study. The initial evaluation at the obesity clinic prior to enrollment in the 
study will be part regular clinical care.  
 
Of note in this protocol will include patients with diagnosis of NASH with fibrosis (stage 
1-3) on MRE/MRS (magnetic resonance elastography/magnetic resonance spectroscoy), 
which has demonstrated high accuracy in making the diagnosis, but has unknown sensitivity 
and specificity to detect change over time and has no standardized validated criteria to 
objectively assess improvement in NASH and fibrosis as exists for liver biopsy, which 
remains the gold standard in clinic trial evaluating the impact of intervention on NASH. In 
the rare instance that the MRE result was falsely positive and the patient was not found 
to have NASH on liver biopsy. The patient will continue with balloon therapy for 
weight loss, but we will not repeat liver biopsy at 6 months, since the balloon is 
indicated for obesity with or without NASH with clear health benefits to weight loss in 
this cohort. The balloon cost will remain covered by the study under these rare 
circumstances. 
3.2 
Primary Study Endpoint 
Number of subjects with ≥ 2 points improvement in NASH activity scores on paired liver 
biopsies before and 6 months after intragastric balloon placement.  
3.3 
Secondary Study Endpoints 
 
• Regression of fibrosis on paired EUS guided liver core biopsies.  

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• Percent total body weight loss at 6 months after Orbera balloon placement. 
• Obtaining lipid saturation (SI) and polyunsaturation (PUI) indices via H-MRS 
technology pre- and post-intervention 
• Obtaining hepatic triglycerides content (HTGC) via H-MRS technology pre- and 
post-intervention. 
• Obtaining percent unsaturated fatty acyl chains present in this cohort of NASH 
patients, as well as changes that occur in the setting of weight loss. 
• Obtaining percent polyunsaturated fatty acyl chains present in this cohort of NASH 
patients, as well as changes that occur in the setting of weight loss.  
• Measurement of hepatic lipid composition by needle biopsy and lipidomic analysis 
techniques before and after weight loss.  
• Correlation of MRS obtained lipid composition to lipidomic analysis composition 
3.4 
Primary Safety Endpoints 
 
• Incidence of all serious adverse events including unanticipated adverse effects  
(balloon migration, small bowel obstruction, luminal GI perforation, ulcer formation, 
liver abscess formation, bleeding, biliary obstruction or injury, aspiration, infection, 
abdominal pain requiring hospitalization, nausea and dehydration requiring 
intravenous fluids, and death). All adverse events will be captured and graded for 
severity using standardized scales. [24] 
 
• Early balloon intolerance requiring removal.  
 
• Balloon deflation rates (see Orbera PMA)  
 
4 Subject Selection, Enrollment and Withdrawal 
We plan to enroll patients with obesity and NASH with fibrosis but no advanced fibrosis 
or cirrhosis as diagnosed by MRE/MRS . We are expanding the cohort of patient with obesity 
to include patients with BMI between 30 to 55 kg/m2 given recent meta-analysis 
demonstrating similar weight loss with the Orbera intragastric balloon in obese patients with 
higher BMIs (Figure 3).[6] Given that more than 10% TBWL is associated with 
improvement in NASH [5], we feel that including patients with higher BMI will be important 
in this pilot study.   

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Figure 3. Meta-regression linear plot depicting the best-fit regression line of the association 
between baseline body mass indexes (BMIs) and percentage of excess weight loss (%EWL) 
at 6 months after Orbera intragastric balloon (IGB) implantation. The sample size of 
individual studies is proportional to the diameter of the circle by which it is represented on 
the graph. [6] 
4.1 
Inclusion Criteria 
 
• Age 21 – 70 years 
• Male and Female  
• BMI between 30 to 55 kg/m2 
• NASH with fibrosis (excluding advanced fibrosis or cirrhosis). This is determined by 
a baseline liver biopsy when available showing stage 1-3 fibrosis, but not stage 4 
(advance fibrosis or cirrhosis), and / or magnetic resonance elastography (MRE) 
showing a liver stiffness measurement range that spans a score of ≥ 3.0kPa and with a 
mean liver stiffness value of < 5 kPa.  Both of these tests are valid for study inclusion 
within 6 months of enrollment. When both a biopsy and MRE are available prior to 
study enrollment the fibrosis designation will be based on the gold standard histology.  
• Subjects will have attempted and failed more conservative weight reduction 
alternatives, such as supervised diet, exercise and behavior modification programs 
(per Orbera’s approved PMA: P140008) 
• Able to provide a written informed consent 
4.2 
Exclusion Criteria 
 
• Age <21 or >70 years 
• Pregnancy or plan for pregnancy during study period  
• Lactation 
• Previous history of gastric surgery 

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• Hiatus hernia > 5cm 
• Current or recent (within 6 months) gastric or duodenal ulcers  
• Gastroparesis 
• Liver cirrhosis 
• Coagulopathy or active use of anticoagulation 
• Inflammatory bowel disease involving the upper GI tract.  
• Active substance abuse  
• Active psychiatric condition deemed as a contraindication by our psychology team 
evaluation 
• Concomitant chronic liver disease other than NASH 
• 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 stenosis  
• Hiatal hernia with associated severe or intractable gastro-esophageal reflux symptoms 
• Structural abnormality in the esophagus or pharynx such as a stricture or diverticulum 
that could impede passage of the delivery catheter and/or an endoscope 
• Achalasia 
• Gastric mass 
• Patients receiving aspirin, anti-inflammatory agents, anticoagulants or other gastric 
irritants, not under medical supervision  
• Patients who are unable or unwilling to take prescribed proton pump inhibitor 
medication for the duration of the device implant. 
4.3 
Subject Recruitment, Enrollment and Screening 
Patients with suspicion for NASH at our center undergo MRE (magnetic resonance 
elastography) sequence to classify their disease as grade 0 (simple steatosis), grade 1 
(steatohepatitis with no fibrosis), grade 2 (steatohepatitis with early fibrosis), grade 3 
(steatohepatitis with advance fibrosis/cirrhosis). Those with stage 1-3 fibrosis and interested 
in weight loss with the intragastric balloon will be referred for the intragastric balloon clinic 
evaluation, which consist of one day evaluation by nutrition, psychology, and 
gastroenterology in the obesity clinic. Those who meet the inclusion / exclusion criteria will 
be consented to participate in the study after discussion of risk, benefits, and alternatives by 
one of our study team members and a written consent is provided. Those who do not qualify 
for the study will be offered other alternatives for weight loss as per out clinical protocol. Of 
note the cost of balloon placement, removal, medications to manage symptoms after balloon 
placement, EUS guided liver biopsy and pathologic interpretation, and the 12 months life-
style intervention program will be covered by the study. The initial evaluation at the obesity 
clinic prior to enrollment in the study will be part regular clinical care. 
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Study will be stopped:  
• 1 death  

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• 2 or more severe adverse events or unanticipated adverse device effects deemed of 
enough severity to stop the study by an independent data safety and monitoring board 
consisting of three Mayo consultants independent from the study 
 
Patient will be withdrawn from the study:  
• Subject safety issues, adverse device effects 
• Failure of subject to adhere to protocol requirements 
• Disease progression to cirrhosis within the time frame of the study 
• Subject decision to withdraw from the study (withdrawal of consent) 
 
Replacement of withdrawn subjects: 
If a patient is withdrawn from the study for reasons other than severe adverse events, the 
intragastric balloon will be removed from the patient at a time that works for the patient and 
within six months of insertion. The patient will be followed as per the standard clinical 
protocol for the intragastric balloon to ensure safety. Weight and safety data will be collected 
until the intragastric balloon is removed. After balloon removal subjected will be followed 
clinically as per our protocol for additional three months to ensure safety. We will replace up 
to 5 subjects withdrawn for reasons other than severe adverse events.  
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
If a patient is withdrawn from the study for reasons other than severe adverse events, the 
intragastric balloon will be removed from the patient at a time that works for the patient and 
within six months of insertion. The patient will be followed as per the standard clinical 
protocol for the intragastric balloon to ensure safety. Weight and safety data will be collected 
until the intragastric balloon is removed. After balloon removal subjected will be followed 
clinically as per our protocol for additional three months to ensure safety. We will replace up 
to 5 subjects withdrawn for reason other than severe adverse events.  
5 Study Device 
5.1 
Description 
The Orbera (Apollo Endosurgery, Austin Tx) is an elastic spherical balloon made of 
silicone, filled with 450 to 700 mL of saline solution, and is FDA approved for weight loss in 
adult US patients with body mass index between 30 to 40 kg/m2.  The deflated balloon comes 
preloaded on a catheter, which is blindly advanced transorally into the stomach. An 
endoscope is then advanced alongside it to ensure accurate placement of the balloon in the 
fundus. Under direct visualization, the balloon is then inflated by injecting saline solution 
through the external portion of the catheter. The Orbera balloon is currently used in many 
countries outside the United States and is typically implanted for 6 months and then retrieved 
endoscopically. 
5.2 
Method for Assigning Subjects to Treatment Groups 
All enrolled subjects will get the Orbera intragastric balloon and paired EUS guided liver 
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5.3 
Preparation and Administration/Implantation of Investigational Device 
The intragastric balloon will be used as described by the Orbera PMA application 
approved by the FDA.  
5.4 
Subject Compliance Monitoring 
Patient will undergo intragastric balloon placement and an EUS guided liver biopsy 
during the same endoscopy session will be performed under monitored anesthesia sedation at 
our outpatient endoscopy unit. The EUS guided liver biopsy will be performed before 
balloon insertion from the left liver lobe under EUS guidance using a 22 gauge core needle 
(Sharkcore, Covidien, Minneapolis, MN). Three passes will be performed from two separate 
liver segments (Figure 2). An additional pass may be performed at the discretion of the PI if 
the three performed passes do not yield enough tissue on visual inspection of the core to 
ensure adequate histology analysis. The maximum number of passes will not exceed four. 
Doppler ultrasound will be used to exclude intervening vessels.  Two samples will be 
submitted for histopathology review in formalin, and one or two will be submitted for total 
fat quantification analysis. After the EUS guided liver biopsy (usually take 10 minutes to 
perform), the Orbera intragastric balloon will be advanced to the stomach under endoscopy 
guidance and inflated with 600 ml of normal saline. Patient transient nausea and pain 
symptoms will be managed with few days course of antiemetic and antispasmodics as per our 
clinical protocol. Patient will also be required to take a proton pump inhibitor -if not already 
taking- throughout the 6 months of balloon therapy. Patient will then undergo a moderate 
intensity life-style intervention consisting of daily phone call for the first week (nurse and or 
study coordinator) then monthly group visits with a health-care coach / nutrition to 
administer the life-style intervention program over 6 months period as per our clinical 
protocol for the intragastric balloon. At 6 months patients will return for balloon removal at 
our complex endoscopy unit under monitored anesthesia care. The balloon will be removed 
using the standard balloon retrieval kit approved by the FDA. After balloon removal a second 
EUS guided liver biopsy from two separate liver segments similar to the first biopsies site 
will be obtained with three or four passes with the 22 gauge core liver biopsy needle 
(Sharckcore, Covidien, Minneapolis, MN). The anticipated procedural length for both the 
EUS guided liver biopsy and balloon insertion and removal is less than 6 minutes. After 
balloon removal, all patients will be offered additional six months of moderate life-style 
intervention program administered as monthly group or individual visits with a health care 
coach to emphasize healthy lifestyle intervention and behaviors. Weight, height, waist 
circumference, and demographic information will be collected a baseline, time of balloon 
removal (6 months), and at 12 months (6 months after balloon removal). Of note the cost of 
balloon placement, removal, medications to manage symptoms after balloon placement, EUS 
guided liver biopsy and pathologic interpretation, and the 12 months life-style intervention 
program will be covered by the study. The initial evaluation at the obesity clinic prior to 
enrollment in the study will be part of regular clinical care. The PI will evaluate all patients 
within 1 week of balloon placement and removal.  
5.5 
Prior and Concomitant Therapy 
Not applicable  

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5.6 
Packaging and Labeling 
Upon receipt of the IGB devices from Apollo Endosurgery, assurance of the 
investigational device label will be affixed to the packaging of each device. See below: 
 
“CAUTION – Investigational Device. Limited by Federal (or United States) law to 
investigational use” 
5.7 
Masking/Blinding of Study 
Not applicable  
5.8 
Receiving, Storage, Distribution and Return 
5.8.1 Receipt of Investigational Devices 
The Orbera intragastric balloon devices will be shipped to the study coordinator from 
Apollo Endosurgery in Austin, Texas. Upon receipt of the devices, the study coordinator will 
perform an inventory and fill out a device accountability log to ensure that all devices are 
accounted for. Any discrepancies, damaged, or unusable devices in a given shipment will be 
documented in the study files and the company will be notified. The devices will then be 
taken by the study coordinator to where they will be stored in the Operating Room Core.  
5.8.2 Storage 
The Orbera intragastric balloons will be stored with the rest of the supplies that will be 
stored in the Operating Room Core which is a secure location with limited access to prevent 
unintended or unauthorized use of the device.  
5.8.3 Distribution of Study Device 
The Orbera intragstric balloons will be distributed according to the clinical protocol of 
how clinical intragastric balloons are distributed. The serial number on the Orbera 
intragastric balloon will be matched up to a subject’s medical record number. This de-
identified data will then be recorded on the device accountability log using subject number 
instead of medical record number.  
5.8.4 Return or Destruction of Study Device 
At routine intervals and at the completion of the study, there will be a reconciliation of 
devices shipped, devices utilized, and devices remaining.  This reconciliation will be logged 
on the Device Accountability form, signed and dated.  Any discrepancies noted will be 
documented, the sponsor-investigator will be notified and an investigation will be conducted 
to determine the cause of the discrepancy.  Devices destroyed on site will be documented in 
the study files. 
6 Study Procedures 
Patients with suspicion for NASH at our center undergo a combined MRE/MRS 
(magnetic resonance elastography/magnetic resonance spectroscopy) sequence to classify 
their disease according to four stages. These stages are numbered from 1-4 with stage 4 
signifying more advanced fibrosis. The MRE/MRS sequence also quantifies hepatic fat 
content. Those with stage 1-3 fibrosis and interested in weight loss with the intragastric 

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balloon will be referred for the intragastric balloon clinic evaluation, which consist of one 
day evaluation by nutrition, psychology, and gastroenterology in the obesity clinic. Those 
who meet the inclusion / exclusion criteria will be consented to participate in the study after 
discussion of risk, benefits, and alternatives by one of our study team members and a written 
consent is provided. Following this, patients will be scheduled for their intragastric balloon 
placement and EUS guided liver biopsy. 
 
Patients will undergo intragastric balloon placement and an EUS guided liver biopsy 
during the same endoscopy session will be performed under monitored anesthesia sedation at 
our outpatient endoscopy unit. The EUS guided liver biopsy will be performed before 
balloon insertion from the left liver lobe under EUS guidance using a 22 gauge core needle 
(Sharkcore, Covidien, Minneapolis, MN). Three passes will be performed from two separate 
liver segments (Figure 2). An additional pass may be performed at the discretion of the PI if 
the three performed passes do not yield enough tissue on visual inspection of the core to 
ensure adequate histology analysis. The maximum number of passes will not exceed four. 
Doppler ultrasound will be used to exclude intervening vessels.  Two samples will be 
submitted for histopathology review in formalin, and one or two will be submitted for total 
fat quantification analysis. After the EUS guided liver biopsy (usually take 10 minutes to 
perform), the Orbera intragastric balloon will be advanced to the stomach under endoscopy 
guidance and inflated with 600 ml of normal saline. Patient transient nausea and pain 
symptoms will be managed with few days course of antiemetic and antispasmodics as per our 
clinical protocol. Patient will also be required to take a proton pump inhibitor -if not already 
taking- throughout the 6 months of balloon therapy.  Patient will then undergo a moderate 
intensity life-style intervention consisting of daily phone call for the first week (nurse and or 
study coordinator) then monthly group visits with a health-care coach / nutrition to 
administer the life-style intervention program over 6 months period as per our clinical 
protocol for the intragastric balloon. At 6 months patients will return for balloon removal at 
our complex endoscopy unit under monitored anesthesia care. The balloon will be removed 
using the standard balloon retrieval kit approved by the FDA. After balloon removal a second 
EUS guided liver biopsy from two separate liver segments similar to the first biopsies site 
will be obtained with three or four passes with the 22 gauge core liver biopsy needle 
(Sharckcore, Covidien, Minneapolis, MN). The anticipated procedural length for both the 
EUS guided liver biopsy and balloon insertion and removal is less than 6 minutes. After 
balloon removal, all patients will be offered additional six months of moderate life-style 
intervention program administered as monthly group or individual visits with a health care 
coach to emphasize healthy lifestyle intervention and behaviors. Weight, height, waist 
circumference, and demographic information will be collected a baseline, time of balloon 
removal (6 months), and at 12 months (6 months after balloon removal). Of note the cost of 
balloon placement, removal, medications to manage symptoms after balloon placement, EUS 
guided liver biopsy and pathologic interpretation, and the 12 months life-style intervention 
program will be covered by the study. The initial evaluation at the obesity clinic prior to 
enrollment in the study will be part of regular clinical care. The PI will evaluate all patients 
within 1 week of balloon placement and removal.  

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6.1 
Follow up for Patients with Device-Related Adverse Events at the Time of Device 
Removal 
Patients with any device related adverse events (AE) or gastric ulcerations at the time of 
device removal will continue on medical proton pump inhibitors therapy with dose and 
duration of therapy determined by the study PI. These patients will be followed clinically 
until complete resolution. Repeat endoscopy to assess for resolution will be done at the 
discretion of the study PI depending on the severity of endoscopic finding at the time of 
removal and the clinical need based on best clinical guidelines and practices. 

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6.2 
Schedule of Events 
 
 
Study Activity 
Screening 
Visit 
Procedure 
Week 1 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Months 
7-11 
Month 
12 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
History and demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
Physical exama  
X 
 
 
 
 
 
 
 
 
 
 
MRE/MRSb (magnetic 
resonance 
elastography/spectroscopy) 
X 
 
 
 
 
 
 
 
X 
 
 
One day evaluation in 
obesity clinicc 
X 
 
 
 
 
 
 
 
 
 
 
B-HCGd 
X 
 
 
 
 
 
 
 
 
 
 
Endoscopic ultrasound 
(EUS) 
 
X 
 
 
 
 
 
 
X 
 
 
EUS guided liver biopsy 
 
 
X 
 
 
 
 
 
 
X 
 
 
Placement of 
intragastric balloon 
 
X 
 
 
 
 
 
 
 
 
 
Daily phone calls life 
Style Intervention  
 
 
X 
 
 
 
 
 
 
 
 
Monthly group visit 
health-care 
coach/nutrition 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up phone calls 
by bariatric clinic 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Removal of intragastric 
balloon 
 
 
 
 
 
 
 
 
X 
 
 
a Weight, height, waist circumference, demographic information 
b MRE=Magnetic Resonance Elastography, MRS=Magnetic Resonance Spectroscopy 
c Nutrition, psychology, gastroenterology 
d Serum pregnancy test (women of childbearing potential) 
 

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6.3 
Tissue lipidomics workup  
A total of 50 mg of liver tissue will be collected via EUS-guided biopsy. Sharkcore 
needle is 22 gauge. Diameter is ~0.7 mm. ~270 mm of tissue length will be acquired 
and will deliver a volume of ~50 mg. The sample will  be frozen in liquid nitrogen 
immediately upon harvesting in the endoscopy suite and placed in a 1.5 conical 
Eppendorf tube. Samples shall not sit more than few minutes before flash freezing to 
ensure adequate analysis. Also, inspection before freezing will occur to ensure that 
the tissue is relatively clean specimen on inspection. 
 
7 Statistical Plan 
Baseline subject characteristics will be described by their means, medians and and/or 
frequencies. For our primary study endpoint of improvement in NASH activity scores on 
paired liver biopsies at baseline and after 6 months, we will be using a paired t-test with two 
sided alpha <0.05. With a sample size of 20 subjects, we will have 80% power to detect a 
medium to large difference in activity scores (0.66). Please see table below for minimum 
sample size needed for each desired effect size.   
 
 
 
Small effect size  
0.5 
Medium effect size 
0.66 
Large effect size  
0.8 
Sample (N) 
34 
20 
15 
 
Additionally, we will run a linear regression analysis with the change in NASH 
activity scores as the outcome with baseline BMI and diabetes as the covariates on a 
univariable and multivariable fashion to investigate their effects on the primary outcome. 
 
For our secondary endpoint of number of subjects with regression of fibrosis in paired 
liver biopsies, we will be reporting the percentage of subjects with regression. As far as the 
secondary endpoint of percent total body weight 6 months after Orbera balloon placement, 
we will be reporting the mean or median percent total body weight loss at 6 months. 
 
For our secondary endpoint of quantifying total fat liver and triglycerides content, we will 
be reporting the mean and median percent of change at 6 months.  
8 Safety and Adverse Events 
All adverse events occurring during the study, including those not meeting the criteria of 
an Unanticipated Adverse Device Effect (UADE) will be recorded on the appropriate case 
report form.  Records of these events will be maintained and reports submitted to the FDA 
and IRB according to the regulatory requirements.  Expected clinical adverse events and 
nonsignificant (not serious) clinical adverse events will not be reported. Expected clinical 
adverse events and anticipated adverse device effects are those listed in Section 1.5.2. 
8.1 
Definitions 
 

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Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device if that effect, problem or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or 
IDE application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
 
 
Adverse Effect (Event) 
Any untoward medical occurrence in a subject involved in clinical study of an 
investigational device; regardless of the causal relationship of the problem with the device or, 
if applicable, other study related treatment(s). 
 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event. 
 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as an unanticipated adverse device effect unless specifically 
instructed otherwise in this protocol.  Any condition responsible for surgery should be 
documented as an adverse event if the condition meets the criteria for an adverse event. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances:  
 
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the 
last scheduled visit, the local investigator should instruct each subject to report, to the local 
investigator, any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  The local investigator 
should notify the study regulatory sponsor of any death or adverse event occurring at any 
time after a subject has discontinued or terminated study participation that may reasonably be 
related to this study.  The sponsor should also be notified if the local investigator should 
become aware of the development of problems, cancer or of a congenital anomaly in a 
subsequently conceived offspring of a subject that has participated in this study. 
 
Preexisting Condition 

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A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the character 
of the condition worsens during the study period. 
 
 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets all of the following three criteria: 
• 
Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: 
(1) death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, 
or prolonged; (4) disability/incapacity - persistent or significant; (5) birth 
defect/anomaly; (6) breach of confidentiality and (7) other problems, events, or new 
information (i.e. publications, DSMB reports, interim findings, product labeling 
change) that in the opinion of the local investigator may adversely affect the rights, 
safety, or welfare of the subjects or others, or substantially compromise the research 
data, AND 
• 
Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• 
Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
 
8.2 
Adverse Event Reporting Period 
For this study, the study treatment follow-up period is defined from enrollment in the 
study to 6 months after balloon removal (12 months from balloon insertion). Adverse events 
will be captured and reported from enrollment to the end of the study treatment follow-up.  
8.3 
Recording of Adverse Events 
Adverse events will be solicited at each study visit or contact with patient. All adverse 
events will be recorder on the below case report form:  
 
• Subject Study Number/Identifier 
• Device information (model and serial number) 
• Date of event onset 
• Description of the event 
• Indication if study treatment was discontinued, or if investigational device was 
removed 
• Subject current status, or if the event was resolved 
• Principal Investigator assessment of if the event was serious and justification for 
determination 

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• Principal Investigator assessment of causality and relationship to study treatment. 
8.4 
Sponsor-Investigator Reporting of Unanticipated Adverse Device Effects and 
Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event 
Worksheet and log.  The sponsor-investigator will evaluate the event and determine the 
necessary follow-up and reporting required. 
 
The sponsor-investigator will promptly review documented Unanticipated Adverse 
Device Effects and as necessary shall report the results of such evaluation to FDA within 10 
working days and Mayo IRB within 5 working days of initial notice of the effect.  Thereafter 
the sponsor-investigator will submit such additional reports concerning the effect as 
requested. 
8.4.1 Sponsor-Investigator Reporting, Notifying Mayo IRB  
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-
UPIRTSOs according to the Mayo IRB Policy and Procedures. 
8.4.2 Sponsor-Investigator Reporting: Notifying the FDA 
The sponsor-investigator will report to the FDA all unanticipated adverse device effects 
according to the required reporting timelines, formats and regulations. 
 
The sponsor-investigator will submit a completed FDA Form 3500A to the FDA’s Center 
for Devices and Radiological Health for any observed or reported adverse effect that is 
determined to be an unanticipated adverse device effect.  A copy of this completed form will 
be provided to all participating sub-investigators. (Note: DSMP)  
 
The completed FDA Form 3500A will be submitted to the FDA as soon as possible and, 
in no event, later than 10 working days after the sponsor-investigator first receives notice of 
the adverse effect. 
 
If the results of the sponsor-investigator’s follow-up evaluation shows that an adverse 
effect that was initially determined to not constitute an unanticipated adverse device effect 
does, in fact, meet the requirements for reporting; the sponsor-investigator will submit a 
completed FDA Form 3500A as soon as possible, but in no event later than 10 working days, 
after the determination was made. 
 
For each submitted FDA Form 3500A, the sponsor-investigator will identify all 
previously submitted reports that that addressed a similar adverse effect experience and will 
provide an analysis of the significance of newly reported adverse effect in light of any 
previous, similar report(s). 
 
Subsequent to the initial submission of a completed FDA Form 3500A, the sponsor-
investigator will submit additional information concerning the reported adverse effect as 
requested by the FDA. 

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Reporting Process 
Unanticipated Adverse Device Effect reports will be submitted on FDA Form 3500A. 
The contact information for submitting reports is: 
 
Food and Drug Administration 
Center for Devices and Radiological Health 
Document Mail Center - WO66-G609 
10903 New Hampshire Avenue 
Silver Spring, Maryland 20993-0002 
 
Deviations from the investigational plan 
The sponsor-investigator shall notify Mayo IRB (see 21 CFR 56.108(a) (3) and (4)) of 
any deviation from the investigational plan to protect the life or physical well-being of a 
subject in an emergency. Such notice shall be given as soon as possible, but in no event later 
than 5 working days after the emergency occurred. Except in such an emergency, prior 
approval by the sponsor-investigator is required for changes in or deviations from a plan, and 
if these changes or deviations may affect the scientific soundness of the plan or the rights, 
safety, or welfare of human subjects, FDA and IRB notification in accordance with 21 CFR 
812.35(a) also is required. 
8.5 
Unblinding Procedures 
Not applicable  
 
8.6 
Stopping Rules 
• 1 death  
• 2 or more severe adverse events or severe unanticipated adverse device effect deemed 
of enough severity by the primary investigator and co-investigator to stop the study 
due to safety concerns that can’t be mitigated by the study team. In that case the study 
will not resume until approval is obtained from the FDA and IRB.  
8.7 
Medical Monitoring 
It is the responsibility of the sponsor-investigator to oversee the safety of the study.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events 
as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see Section 10 Auditing, Monitoring and Inspecting).  Medical monitoring 
will include a regular assessment of the number and type of serious adverse events. 
8.7.1 Internal Data and Safety Monitoring Board 
The data safety will be monitored directly by the primary investigator.    

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8.8 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following: 
 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (long term 
survival status that the subject is alive) at the end of their scheduled study period. 
8.9 
Source Documents  
Source data comprise all information, original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial.  Source data are contained in source documents.  Examples of these original documents, 
and data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification 
as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. When applicable, information 
recorded on the CRF shall match the Source Data recorded on the Source Documents. 
8.10 Case Report Forms  
A Case Report Form (CRF) will be completed for each subject enrolled into the clinical 
study.  The investigator-sponsor will review, approve and sign/date each completed CRF; the 
investigator-sponsor’s signature serving as attestation of the investigator-sponsor’s 
responsibility for ensuring that all clinical and laboratory data entered on the CRF are 
complete, accurate and authentic. 
 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  If a 
space on the CRF is left blank because the procedure was not done or the question was not 
asked, write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All 
entries should be printed legibly in black ink.  If any entry error has been made, to correct 
such an error, draw a single straight line through the incorrect entry and enter the correct data 
above it.  All such changes must be initialed and dated.  Do not obliterate, erase, or use 
“white-out” for errors.  For clarification of illegible or uncertain entries, print the clarification 
above the item, then initial and date it.  If the reason for the correction is not clear or needs 

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additional explanation, neatly include the details to justify the correction. Any missed, 
unused, corrected and/or spurious data will be discarded in HIPPA compliant manner. 
 
Data Management 
A database will be created and maintained by the study coordinator in order to ensure all 
data on case report forms are completed and accurate. This database will be stored on a 
secure Mayo Clinic computer and not be accessible to anyone outside the institution.  
 
Data Security and Confidentiality 
Any study data with identifiers will be kept in a locked file cabinet and stored 
electronically on a password protected server. 
 
Data Quality Assurance 
Source documents will be verified to ensure they align with case report form data.  
 
Data Clarification Process 
N/A 
8.11 Records Retention 
The sponsor-investigator will maintain records and essential documents related to the 
conduct of the study.  These will include subject case histories and regulatory documents. 
 
The sponsor-investigator will retain the specified records and reports for: 
1. Up to 2 years after the marketing application is approved for the drug; or, if a 
marketing application is not submitted or approved for the drug, until 2 years after 
shipment and delivery of the drug for investigational use is discontinued and the FDA 
has been so notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717,  
whichever is longer. 
9 Study Monitoring, Auditing, and Inspecting 
9.1 
Study Monitoring Plan 
The investigator will allocate adequate time for such monitoring activities.  The 
Investigator will also ensure that the monitor or other compliance or quality assurance 
reviewer is given access to all the study-related documents and study related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the monitoring 
visit. 
 
This study will be monitored during the conduct of the trial by staff from the Mayo Clinic 
Office of Research Regulatory Support.  Clinical trial monitoring may include review of the 
study documents and data generated throughout the duration of the study to help ensure the 
validity and integrity of the data along with the protection of human research subjects.  This 
will assist sponsor-investigators in complying with Food and Drug Administration 
regulations. 

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9.2 
Auditing and Inspecting 
The sponsor-investigator will permit study-related monitoring, audits, and inspections by 
the IRB, the monitor, and government regulatory agencies, of all study related documents 
(e.g., source documents, regulatory documents, data collection instruments, study data etc.).  
The sponsor-investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
 
Participation as a sponsor-investigator in this study implies acceptance of potential 
inspection by government regulatory authorities and applicable compliance offices. 
10 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. 
11 Study Finances 
11.1 Funding Source 
This study will be sponsored by an internal Mayo Clinic development grant and an 
endoscopic research grant from the American Society for Gastrointestinal Endoscopy. 
11.2 Subject Stipends or Payments 
None  
12 Publication Plan 
This is an investigator initiated and funded study. The investigator holds the primary 
responsibility for publication. The trial will be registered on ClinicalTrials.gov prior to 
subject recruitment and enrollment. The results will also be posted to ClinicalTrials.gov 
within 12 months of final data collection for the primary outcome.   
 
 

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