19-Gauge Fine Needle Aspirate (FNA) Versus 19-Gauge Fine Needle Biopsy (FNB) Needles for Endoscopic Ultrasound Guided Liver Biopsy (EUS-LB): A Randomized Prospective Trial
Phase: NA
Conditions: Abnormal Liver Function
Sponsor: Geisinger Clinic

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
1
19-Gauge Fine Needle Aspirate (FNA) Versus 19-Gauge Fine Needle Biopsy (FNB) Needles 
for Endoscopic Ultrasound Guided Liver Biopsy (EUS-LB):  A Randomized Prospective 
Trial
Principal Investigator:
David L. Diehl
100 N. Academy Ave.    
Danville, PA  17822-2111  
Phone: 570.271.6856
Fax: 570.271.6852
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
2
TABLE OF CONTENTS 
1
ABBREVIATIONS USED IN THE PROTOCOL
................................................................................................................................................4
2
ABSTRACT
................................................................................................................................................5
3
BACKGROUND AND SIGNIFICANCE
................................................................................................................................................6
4
HYPOTHESIS AND SPECIFIC AIMS
................................................................................................................................................7
4.1
Hypothesis ....................................................................................................................7
4.2
Specific Aim 1 ..............................................................................................................7
4.3
Specific Aim 2 ..............................................................................................................7
5
PRELIMINARY DATA
................................................................................................................................................7
6
STUDY DESIGN
................................................................................................................................................7
6.1
Description....................................................................................................................7
6.2
Study Population...........................................................................................................7
6.2.1
Approximate Number of Subjects..................................................................7
6.2.2
Inclusion Criteria............................................................................................7
6.2.3
Exclusion Criteria...........................................................................................8
6.3
Recruitment...................................................................................................................8
6.4
Study Duration..............................................................................................................8
6.4.1
Approximate Duration of Subject Participation.............................................8
6.4.2
Approximate Duration of Study.....................................................................8
6.5
Procedures.....................................................................................................................8
6.5.1
Study Time and Events Table ......................................................................11
All activities are standard of care, except for the selection of needle type. ...............11
6.6
Primary Endpoints ......................................................................................................11
6.7
Secondary Endpoints ..................................................................................................12
6.8
Statistics......................................................................................................................12
6.8.1
Statistical Analysis Plan...............................................................................12
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
3
6.8.2
Statistical Power and Sample Size Considerations ......................................12
6.9
Data Management.......................................................................................................13
6.9.1
Data Collection and Storage.........................................................................13
6.9.2
Records Retention ........................................................................................13
7
SAFETY MONITORING
..............................................................................................................................................13
7.1
Adverse Event Reporting............................................................................................13
7.2
Definitions ..................................................................................................................13
7.3
Recording and Reporting............................................................................................15
7.4
Serious Adverse Event Reporting...............................................................................16
8
PROTECTION OF HUMAN SUBJECTS
..............................................................................................................................................16
8.1
Informed Consent .......................................................................................................16
8.2
Protection of Human Subjects Against Risks.............................................................16
8.3
Data Monitoring Plan .................................................................................................17
9
REFERENCES
..............................................................................................................................................18
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
4
1
 ABBREVIATIONS USED IN THE PROTOCOL
Abbreviation
Term
AE
Adverse event
ASGE
American Society of Gastrointestinal Endoscopy
ALS
Aggregate specimen length
BMI
Body mass index
CA
California
CLD
Chronic liver disease
Cm
Centimeter
Co-I
Co-Investigator
CPT
Complete portal tracts
CRNA
Certified Registered Nurse Anesthetist
EUS
Endoscopic ultrasound
EUS-LB
Endoscopic ultrasound guided-liver biopsy
EGD
Esophagogastroduodenoscopy
FNA
Fine needle aspirate
FNB
Fine needle biopsy
g
Gauge
GIRB
Geisinger IRB
HRPO
Human Research Protection Office
In
Inches
Inc
Incorporated
IRB
Institutional Review Board
Lb
Pounds
LB
Liver biopsy
mm
Millimeters 
PA
Pennsylvania
PI
Principle investigator
PLB
Percutaneous liver biopsy
PPT
Partial portal tracts
QASM
Quality and Safety Monitoring 
SA
Specimen adequacy
SAE
Serious adverse event
SLB
Surgical liver biopsy
TLB
Transjugular liver biopsy
US
United States
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
5
2
ABSTRACT
Chronic liver disorders (CLD) are a major cause of morbidity and mortality for individuals in the 
US.  Though serologic analysis will often lead to a conclusive diagnosis, liver biopsy remains an 
important method for helping to determine the etiology and stage of LD.  Percutaneous liver 
biopsy (PLB), transjugular liver biopsy (TLB) and surgical liver biopsy (SLB) are alternative 
methods for obtaining hepatic tissue.  In recent years endoscopic ultrasound guided-liver biopsy 
(EUS-LB) has come to the forefront as a safe and effective method for obtaining tissue in CLD.  
There are several studies of the safety of EUS-LB as well as the adequacy of specimens obtained 
in this fashion.  Most studies involve a 19-g needle, therefore in this study we hope to compare 
the tissue yields of a 19-g FNB needle, in comparison to conventional 19-g FNA needle.  We 
predict that 19-g FNA and 19-g FNB needle will demonstrate similar diagnostic accuracy, with 
less visible blood artifact.  Similarly, we predict the safety to be equal.
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
6
3
BACKGROUND AND SIGNIFICANCE
Chronic liver disease has a number of causes, and leads to significant mortality and morbidity in 
the United States.  It has been estimated that roughly 36,000 individuals die annually from the 
burden of chronic liver disease, thus early diagnosis and intervention are paramount to 
preventing such complications [1].  Though serologic markers and non-invasive diagnostic 
imaging modalities are used as a method for determining the underlying disease process, these 
methods lack the specificity of determining etiology of a patient’s chronic liver disease [2-5].  
Therefore, liver biopsy remains the “gold standard” for obtaining valuable diagnostic and 
prognostic information. 
At present there exist several methods for liver tissue acquisition.  The most widely accepted 
method remains percutaneous route (PLB), which utilizes percussion or imaging to localization 
the biopsy site [6-8].  The issue with this approach is its potential complication of post-
procedural pain in up to 84%, bleeding in 1/2500-10,000 procedures, with under 1/10,000 of 
these cases being fatal [7-17].  Another means for obtaining tissue samples is the transjugular 
route (TLB), which also allows for portal pressure measurement, and is usually reserved for 
patients with coagulopathy[18,19].  
More recently, endoscopic ultrasound guided liver biopsy (EUS-LB) has been developed as a 
newer LB technique [23, 24].  The feasibility of EUS-LB for liver lesions has been validated 
yielding excellent diagnostic results in several studies [25-27].  This technique has also been 
evaluated for hepatic parenchymal disease with up to 90% diagnostic yield.  Subsequently, EUS-
LB using a 19-g needle was compared to percutaneous/transjugular routes showing at least 
comparative, and in some instances improved sample acquisition, versus other methods [28].  
Different 19-g needles have been utilized in this setting yielding variable diagnostic specimens 
[29-33].  However, there has yet to be comparison of 19-g FNA versus a 19-g core biopsy needle 
for EUS-LB.  
Primary End Points
1. Proportion of cases for which a histologic diagnosis could be made based upon the 
amount of tissue obtained with the needle.
2. Number of portal tracts (PT) in the specimen. [34-36]
3. Aggregate specimen length (ASL), length of the longest piece (LLP), and degree of 
fragmentation. 
Secondary End Points
1. Presence of a visible core specimen.
2. Presence of visible clots in specimen.
3. Adverse events (AE) and serious adverse events (SAE).
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
7
4
HYPOTHESIS AND SPECIFIC AIMS
4.1
Hypothesis 
We predict that the 19-g FNA needle and 19-g FNB needle will have similar ability to obtain 
adequate EUS-LB specimens
4.2
Specific Aim 1
To determine the adequacy of EUS-LB using a 19-g FNB needle as compared with 19-g FNA 
needle.
4.3
Specific Aim 2
To determine if the 19-g FNB needle will demonstrate less blood artifact during the time of 
EUS-LB as compared with 19-g FNA needle.
5
PRELIMINARY DATA 
Our EUS group has used the 19-g EUS FNB needle in several patients undergoing EUS-guided 
liver biopsy, and cores of liver tissue can be obtained.  We have found that special tissue 
handling after biopsy is required to prevent fragmenting the tissue. We have improved the 
technique of tissue handling, and can minimize post-biopsy fragmentation.  This can allow a 
better comparison of different needle gauges.
6
STUDY DESIGN
6.1
Description
This is a prospective randomized trial comparing the biopsy specimen adequacy (SA) of 19-g 
FNA versus 19-g FNB needle for EUS-LB.
6.2
Study Population
6.2.1
Approximate Number of Subjects
Approximately 32 subjects will participate in this study.  
6.2.2
Inclusion Criteria
1. Patients undergoing EUS-LB
2. Platelet count > 50,000
3. International normalized ratio (INR) < 1.5 
4. Age > 18 years
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
8
5. Non-pregnant patients
6.2.3
Exclusion Criteria
1. Age < 18 years
2. Pregnant patients
3. Inability to obtain consent
4. Anticoagulants or anti-platelet agents use (excluding aspirin) within the last 7-10 days
5. Platelet count < 50,000
6. INR > 1.5
7. Presence of ascites
8. Known liver cirrhosis
9. Hemophilia
6.3
Recruitment
Patients shall be recruited in the pre-procedural endoscopy area.  After identifying subjects, a 
study investigator shall discuss the study in detail in person.  The patient will be given time to 
read the consent form and ask questions. 
6.4
Study Duration
6.4.1
Approximate Duration of Subject Participation
Participation is just for the duration of the EUS-LB.
6.4.2
Approximate Duration of Study
The duration of the study shall last until 6 months from enrollment of the last study participant.  
This shall allow for analysis of final data points and construction of a manuscript.
6.5
Procedures
EPIC electronic health records database will allow for availability of demographic data and 
office-based follow-up records.  ProVation MD software information will provide details 
regarding endoscopic parameters and intervention performed.  
Electronic records gathered for study purposes will only be available to study investigators and 
will be stored on an encrypted hard drive on a computer. Data will initially be entered with PHI 
attached so that all information can be obtained. Once all data collection is complete identifiers 
will be removed and random number assigned to the patients.   
Upon initial encounter, the study shall be described to the patient in detail by one of the study 
investigators and informed consent obtained.  
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
9
Once the patient has agreed to participate, demographic data will be obtained from the medical 
record including; age, gender, height [inches (in)], weight [pounds (lb)], body mass index (BMI) 
(lb/in2), past medical history [in particular diagnosis of liver disease, biliary or pancreatic 
disease, ascites, encephalopathy, portal hypertension, portal hypertension-related bleeding (i.e. 
varices), liver cancer or masses].  Past surgical history shall be obtained regarding prior 
cholecystectomy, hepatobiliary or pancreatic surgery (i.e. pancreatojejunostomy) or bariatric 
surgery (i.e. Roux-en-Y gastric bypass).  Medication and social history shall be performed 
regarding alcohol intake per week and hepatotoxic medications (i.e. acetaminophen).  A baseline 
INR and platelet count shall be performed on all individuals prior to EUS-LB, as is the standard 
of care.
EUS-LB Protocol
Patients undergoing EUS-LB receive anesthesia during the procedure, as per normal practice.  
This is provided by a certified registered nurse anesthetist (CRNA). The endosonographic study 
will be conducted with a linear array echoendoscope (GF-UC140-AL5; Olympus America, 
Center Valley, PA). Before needle puncture of the desired lobe, color Doppler imaging will be 
used to ensure the lack of vascular structures in the trajectory of the needle. The EUS-LB will be 
performed in widely separated regions of the liver using a 19-g EUS-FNA needle (Expect 
Flexible 19g, Boston Scientific, Marlborough, MA) or a 19-g FNB needle (Acquire 19g, Boston 
Scientific, Marlborough, MA). A computer-generated randomized schema shall determine needle 
type selection.  
The left lobe is described as liver parenchyma identified a few centimeters below the 
gastroesophageal junction with the echoendoscope torqued clockwise. The right lobe is 
considered the large area of liver tissue can be seen through the duodenal bulb, near the 
gallbladder [37]. The stylet is removed, heparin flushed through the needle lumen, and the 
suction device set and attached to the needle hub. The prepared needle is then inserted into the 
echoendoscope. A transgastric approach will be used to obtain samples from the left lobe of the 
liver; a transduodenal approach, with the linear echoendoscope positioned in the duodenal bulb, 
will be used to obtain samples from the large amount of liver parenchyma seen in that location. 
Once adequate liver parenchymal penetration will be achieved with the needle (∼2-6 cm), full 
suction will be applied with a 20-mL vacuum syringe. One pass consists of a total of 7 to 10 to-
and-fro needle motions with the fanning technique applied under direct and continuous 
endosonographic visualization of the tip of the needle.
The needle will then be removed from the echoendoscope. The specimen will be pushed from the 
needle with the stylet directly into a microseive, and blood washed from the specimen with a 
gentle saline rinse.  The endosonographer looks for multiple pieces of light brown tissue 
approximately 5 to 15 mm in length.  The tissue cores are then “floated” off the microseive into 
formalin solution.  Heparin is flushed through the needle lumen prior to the next pass. The 
biopsy process is then repeated on the opposite liver lobe. A pass per liver lobe will be 
performed in each patient; using the standard 19-g EUS-FNA needle or the 19-g EUS FNB 
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
10
needle. All patients are closely observed in the recovery area for 1 hour after the procedure, as 
per our standard policy. Patients will be followed-up with by a phone call the next day and at 1 
week after the procedure, as per standard of care.
Sample Processing
The surgical pathology department, per a specific protocol for clinical practice, will process the 
EUS-LB samples. Tissue samples are left in formalin for at least 1 hour before processing. The 
contents of the formalin jar will be poured into a petri dish, and visible cores of liver tissue 
picked out with small forceps by the surgical pathology technician. These pieces are arranged in 
a linear fashion on lens paper, then the specimen photographed alongside a ruler to estimates pre-
processing tissue lengths. Samples from both lobes and the different needles will be submitted 
for evaluation separately. The tissue will be processed in standard fashion, and slide blanks made 
(5-μm tissue thickness). These blanks are stained with hematoxylin and eosin, trichrome, and 
reticulin, with other special stains done as needed. The slides are digitized using a whole slide 
scanner (ScanScope CS; Aperio Technologies, Inc, Vista, CA), and the digitized images used for 
quantitative analysis (eSlide Manager; Aperio Technologies, Inc). Quantification of sample 
length (mm) and portal triads is performed by 2 of the investigators, annotating the digital 
images with the software.  Fellowship-trained GI pathologists then perform histologic 
interpretation for clinical use.
Post-Procedural Follow-up
After undergoing the procedure, patients will receive a 1week follow-up phone call to monitor 
for adverse events (i.e. bleeding), as per standard of care. 
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
11
6.5.1
Study Time and Events Table  
Study Procedures
Study Interval
Pre-
Endoscopy 
Procedure
Day of 
Proce
dure
Follow-
up
Informed consent
X
Demographics
X
Medical history
X
Surgical history
X
Medication History
X
X
INR
X
Platelet Count
X
Height (in)
X
Weight (lb)
X
BMI
X
Urine Pregnancy test, when 
applicable
X
Randomization regarding 
needle type
X
EUS-LB
X
Adverse eventsa
X---------------------------------X
aFrom the signing of the informed consent form to 1 week post-
EUS-LB 
INR = international normalized ratio, BMI = Body Mass Index 
(lb/in2), EUS-LB = Endoscopic Ultrasound Guided Liver Biopsy
All activities are standard of care, except for the selection of needle type.
Follow-up will be conducted via phone call.
6.6
Primary Endpoints
1. Proportion of cases for which a histologic diagnosis could be made based upon the 
amount of tissue obtained with the needle.
2. Number of portal tracts (PT) in the specimen [34-36]
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
12
3. Aggregate specimen length (ASL), length of the longest piece (LLP), and degree of 
fragmentation 
6.7
Secondary Endpoints
1. Presence of a visible core specimen
2. Presence of visible clots in specimen
3. Adverse events (AE) and serious adverse events (SAE)
6.8
Statistics
A representative from the Biostatistics & Research Data Core will be doing the statistical 
analysis. 
6.8.1
Statistical Analysis Plan
Assuming the 19-g FNB needle has a success percentage of 98% (ie,>= 5 portal triads), and 
margin over FNA needle of 5% (98% vs. 93%), the study needs to evaluate 32 patients to 
achieve 80% power for a 1-sided non-inferiority test. This also assumes each patient provides 2 
specimens.  If the margin is increased to 10% (98% vs. 88%), then the study needs to evaluate 18 
patients to achieve 80% power.
Descriptive statistics will be utilized to represent continuous and categorical variables, with 
results expressed as medians with ranges. Multiple comparisons between the aggregate tissue 
length and CPT yield from bilobar, left lobe only, and right lobe only biopsies will be carried out 
using the Mann-Whitney-Wilcoxon test. A P-value of < 0.05 will be considered statistically 
significant.
6.8.2
Statistical Power and Sample Size Considerations
The purpose of this study to determine if the 19-g FNB EUS needle provides liver cores equal or 
superior to 19-g FNA needle for histologic interpretation.  A few preliminary cases utilizing the 
19g core needle have been found to provide adequate cores. It is felt that 32 cases collected 
prospectively should be adequate to learn how the 19g FNB needle compares to the 19g FNA 
needle in different patients with different liver conditions.
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
13
6.9
Data Management
6.9.1
Data Collection and Storage
EPIC electronic health records database will allow for availability of demographic data and 
office-based follow-up records.  ProVation MD software information will provide details 
regarding endoscopic parameters and intervention performed.  
Electronic records gathered for study purposes will only be available to study investigators and 
will be stored on an encrypted hard drive on a computer. Data will initially be entered with PHI 
attached so that all information can be obtained. Once all data collection is complete identifiers 
will be removed and random number assigned to the patients.   
 
6.9.2
Records Retention
Records shall be retained for a total of 6 years as per Geisinger policy
7
SAFETY MONITORING 
7.1
Adverse Event Reporting
Clinical adverse events (AEs) will be monitored throughout the study.  All AEs will be reported 
to the institutional review board (IRB) regardless of whether they are considered study related.  
The date and time of onset and outcome, course, intensity, action taken, and causality to study 
treatment will be assessed by the study PI.  In the event of a serious AE (SAE), this will be 
reported to the Geisinger IRB (GIRB) according to the GIRB guidelines.   All other AEs will be 
summarized and submitted to GIRB during continuing review.
7.2
Definitions
An adverse event (AE) is any untoward, undesired, or unplanned event in the form of signs, 
symptoms, disease, or laboratory or physiologic observations occurring in a person given a test 
article or in a clinical study. The event does not need to be causally related to the test article or 
clinical study. 
[Include as applicable to study]
An AE includes, but is not limited to, the following:

Any clinically significant worsening of a preexisting condition.

An AE occurring from overdose of a test article, whether accidental or intentional.  Define 
overdose for each test article here or in the Overdose section.  Overdose is a dose greater than 
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
14
that specified in the protocol. OR Overdose is a dose greater than that specified in the 
investigator’s brochure/label.  OR define overdose

An AE occurring from abuse (e.g., use for nonclinical reasons) of a test article.

An AE that has been associated with the discontinuation of the use of a test article.

For reports from post marketing studies, any failure of expected pharmacologic action of a 
test article.  For over-the-counter products, the recommended daily dose must be 
administered before failure of expected pharmacologic action can be attributed.
A serious adverse event (SAE) is an AE that:

Results in death.

Is life-threatening (see below).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see below).

Results in a persistent or significant disability or incapacity (see below).

Results in cancer.

Results in a congenital anomaly or birth defect.

Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
Life-threatening refers to immediate risk of death as the event occurred per the reporter. A 
life-threatening experience does not include an experience, had it occurred in a more severe 
form, might have caused death, but as it actually occurred, did not create an immediate risk of 
death. For example, hepatitis that resolved without evidence of hepatic failure would not be 
considered life-threatening, even though hepatitis of a more severe nature can be fatal. Similarly, 
an allergic reaction resulting in angioedema of the face would not be life-threatening, even 
though angioedema of the larynx, allergic bronchospasm, or anaphylaxis can be fatal. 
Hospitalization is official admission to a hospital. Hospitalization or prolongation of a 
hospitalization constitutes criteria for an AE to be serious; however, it is not in itself considered 
an SAE. In absence of an AE, a hospitalization or prolongation of a hospitalization should not be 
reported as an SAE by the participating investigator. 
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
15
In addition, a hospitalization for a preexisting condition that has not worsened does not constitute 
an SAE.
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions.
If there is any doubt about whether the information constitutes an SAE, the information is treated 
as an SAE.
A protocol-related adverse event is an AE occurring during a clinical study that is not related 
to the test article, but is considered by the investigator or the medical monitor (or designee) to be 
related to the research conditions, i.e., related to the fact that a subject is participating in the 
study. For example, a protocol-related AE may be an untoward event occurring during a washout 
period or an event related to a medical procedure required by the protocol.
Other Reportable Information.  Certain information, although not considered an SAE, must be 
recorded, reported, and followed up as indicated for an SAE.  This includes: 

Pregnancy exposure to a test article, except for exposure to prenatal vitamins.  If a pregnancy 
is confirmed, use of the test article must be discontinued immediately.  Information about 
pregnancy exposure includes the entire course of pregnancy and delivery, and perinatal and 
neonatal outcomes, even if there are no abnormal findings.  Both maternal and paternal 
exposure are considered other reportable information.  For exposure involving the female 
partner of a male subject, the necessary information must be collected from the subject, while 
respecting the confidentiality of the partner.

Lactation exposure to a test article with or without an AE.   

Overdose of a test article as specified in this protocol with or without an AE.  Baby formula 
overdoses without any AEs are excluded.

Inadvertent or accidental exposure to a test article with or without an AE.
7.3
Recording and Reporting
A subject’s AEs and SAEs will be recorded and reported from the signing of the informed 
consent form to 1 week from EUS-LB Procedure.
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
16
7.4
Serious Adverse Event Reporting
David L. Diehl will notify GIRB of all study SAEs in accordance with policy guidelines.    If an 
SAE has not resolved at the time of the initial report, a follow-up report including all relevant 
new or reassessed information (e.g., concomitant medication, medical history) will be submitted 
to GIRB.  An SAE will be followed until either resolved or stabilized.  
8
PROTECTION OF HUMAN SUBJECTS
8.1
Informed Consent
The investigator will provide for the protection of the subjects by following all applicable 
regulations.  The informed consent form will be submitted to the IRB for review and approval.  
Before any procedures specified in this protocol are performed, a subject must:

Be informed of all pertinent aspects of the study and all elements of informed consent. 

Be given time to ask questions and time to consider the decision to participate.

Voluntarily agree to participate in the study. 

Sign and date an IRB-approved informed consent form.
8.2
Protection of Human Subjects Against Risks
Potential Risks due to Study participation -  
A potential risk is loss of the patients’ privacy and loss of the confidentiality of their data.  
Upper endoscopy possesses a 0.0004-0.00009% risk of perforation, and less than 0.5% risk of 
bleeding [38].  Adverse events described with the EUS and fine needle aspirate possess a 
complication rate of 1.72% in prospective studies and 0.64% in retrospective studies.  The risk of 
perforation for EUS is roughly 0.06% and bleeding 0.13%.  There have not been established 
increased risks of complication in patients who undergo EUS with different biopsy needles. 
However, the 19g needle is the standard needle size in use for EUS-LB, and has been found to be 
very safe.  
Potential Benefits
Included patients are already undergoing the procedure to make a clinical diagnosis of the liver 
abnormality, and also have the benefit of requiring only one endoscopic procedure to evaluate 
digestive system problems while at the same time obtaining liver biopsy.  As the potential 
complications with EUS-LB seem to be lower than other means of liver biopsy, a potential 
benefit is sparing patients from the complications caused by other methods of liver biopsy.  This 
study shall also benefit future patients by providing data regarding prediction of success for 
EUS-LB with 19-g FNA versus 19-g FNB needles.
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
17
Risk: Benefit Ratio 
A potential risk in this study involves loss of confidentiality.  The use of password protected data 
storage, removal of PHI and assignment of randomly generated patient number and limitation of 
data to the study investigators shall limit this risk.  Additionally, there is a small risk of 
perforation or bleeding in diagnostic endoscopy and EUS-LB.  These risks are outweighed by the 
benefit of procuring a diagnosis behind their liver-related abnormality.  
Procedures to Maintain Privacy and Confidentiality 
As exposure of confidential information is a potential risk, subject identifiers shall not be 
recorded and subjects shall be given a randomly generated number.  The project investigators 
shall be the only ones with access to the study data, which shall be kept on a password 
protected/locked Geisinger computer.  All data will be destroyed at the completion of this 
study’s manuscript completion.
Vulnerable Subjects
It is possible that terminally ill patients may be involved in this study.  This study will however 
not involve direct intervention and not impact/delay the procedure for which they are 
undergoing.  The observational nature of the study and the subject’s ability to exclude them from 
the study at any time shall be reinforced by the PI/Co-I.
No individuals who require substituted consent shall be involved in this study, nor any children.
Compensation to Subjects
No compensation shall be granted to subjects as this is an observational study and does not 
deviate from the standard of care.
Treatment of Research-Related Injuries
Potential procedure-related injuries would include perforation or bleeding, which would be 
managed in a standard fashion.  There are no additional “research-related” injuries.  Any injuries 
in the study cohort will be a result of risks inherent to the procedure.  This is always explained 
during the consent process for the procedure and is the standard of care.
8.3
Data Monitoring Plan 
Procedures to Maintain Privacy and Confidentiality 
As exposure of confidential information is a potential risk, subject identifiers shall not be 
maintained and subjects shall be given a randomly generated number.  The project investigators 
shall be the only ones with access to the study data, which shall be kept on a password-protected 
Geisinger computer. All physical forms will remain in a locked storage device. All data will be 
destroyed at the completion of this study’s manuscript completion. 
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
18
9
REFERENCES
1. Deaths: Final Data for 2013, Centers for Disease Control and Prevention, Division of 
Vital Statistics. Available at: http://www.cdc.gov/nchs/data_access/Vitalstatsonline.htm. 
Accessed May 14, 2016.
2. Rockey DC, Caldwell SH, Goodman ZD, et al. American Association for the Study of 
Liver Diseases. Liver biopsy. Hepatology 2009;49:1017-44. 
3. Rockey DC, Bissell DM. Noninvasive measures of liver fibrosis. Hepatology 
2006;43:S113-S120. 
4. Rockey DC. Non-invasive assessment of liver fibrosis and portal hypertension with 
transient elastography. Gastroenterology 2008;134:8-14. 
5. Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by 
measurement of stiffness in patients with chronic hepatitis C. Hepatology.  2005;41: 48-
54.
6. Sherlock S, Dick R, Van Leeuwen DJ. Liver biopsy today. The Royal Free Hospital 
experience. J Hepatol 1985;1:75-85.
7. Eisenberg E, Konopniki M, Veitsman E, et al. Prevalence and characteristics of pain 
induced by percutaneous liver biopsy. Anesth Analg 2003;96:1392-1396. 
8. Perrault J, McGill DB, Ott BJ, et al. Liver biopsy: complications in 1000 inpatients and 
outpatients. Gastroenterology 1978;74:103-106. 
9. Firpi RJ, Soldevila-Pico C, Abdelmalek MF, et al. Short recovery time after percutaneous 
liver biopsy: should we change our current practices? Clin Gastroenterol Hepatol 
2005;3:926- 929.
10. Stone MA, Mayberry JF. An audit of ultrasound guided liver biopsies: a need for 
evidence-based practice. Hepatogastroenterology 1996;43:432- 434. 
11. McGill DB, Rakela J, Zinsmeister AR, Ott BJ. A 21-year experience with major 
hemorrhage after percutaneous liver biopsy. Gastroenterology 1990;99:1396-1400. 
12. Janes CH, Lindor KD. Outcome of patients hospitalized for complications after 
outpatient liver biopsy. Ann Intern Med 1993;118:96- 98. 
13. Piccinino F, Sagnelli E, Pasquale G, et al. Complications following percutaneous liver 
biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol 1986;2:165-173. 
14. Huang JF, Hsieh MY, Dai CY, et al. The incidence and risks of liver biopsy in non-
cirrhotic patients: An evaluation of 3806 biopsies. Gut 2007;56:736-737. 
15. Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a 
prospective nationwide survey. For the Group of Epidemiology of the French Association 
for the Study of the Liver (AFEF). Hepatology 2000;32:477-481. 
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
19
16. Myers RP, Fong A, Shaheen AA. Utilization rates, complications and costs of 
percutaneous liver biopsy: a population-based study including 4275 biopsies. Liver Int 
2008;28:705-712. 
17. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001;344: 495-500.
18. Lebrec D, Goldfarb G, Degott C, et al.. Transvenous liver biopsy: an experience based on 
1000 hepatic tissue samplings with this procedure. Gastroenterology 1982;83:338-340. 
19. Bull HJ, Gilmore IT, Bradley RD, et al. Experience with transjugular liver biopsy. Gut 
1983;24:1057-1060.
20. Orlando R, Lirussi F, Okolicsanyi L. Laparoscopy and liver biopsy: further evidence that 
the two procedures improve the diagnosis of liver cirrhosis. A retrospective study of 
1,003 consecutive examinations. J Clin Gastroenterol 1990;12:47-52. 
21. Poniachik J, Bernstein DE, Reddy KR, et al. The role of laparoscopy in the diagnosis of 
cirrhosis. Gastrointest Endosc 1996;43:568-571. 
22. Denzer U, Arnoldy A, Kanzler S, et al.  Prospective randomized comparison of 
minilaparoscopy and percutaneous liver biopsy: diagnosis of cirrhosis and complications. 
J Clin Gastroenterol 2007;41:103-110.
23. Stavropoulos SN, Im GY, Jlayer Z, et al. High yield of same-session EUS-guided liver 
biopsy by 19-gauge FNA needle in patients undergoing EUS to exclude biliary 
obstruction. Gastrointest Endosc 2012;75:310-8. 
24. Diehl DL, Johal AS, Khara KS, et al. Endoscopic ultrasound-guided liver biopsy: a 
multicenter experience. Endosc Int Open 2015;3:E1-6.
25. DeWitt J, LeBlanc J, McHenry L, et al. Endoscopic ultrasound-guided fine needle 
aspiration cytology of solid liver lesions: a large singlecenter experience. Am J 
Gastroenterol. 2003;98:1976-81. 
26. Hollerbach S, Willert J, Topalidis T, et al. Endoscopic ultrasound-guided fine-needle 
aspiration biopsy of liver lesions: histological and cytological assessment. Endoscopy.  
2003;35:743-9.
27. tenBerge J, Hoffman BJ, Hawes RH, et al. EUS-guided fine needle aspiration of the liver: 
indications, yield, and safety based on an international survey of 167 cases. Gastrointest 
Endosc.  2002;55:859-62.
28. Pineda JJ, Diehl DL, Miao CL, et al.  EUS-guided liver biopsy provides diagnostic 
samples comparable with those via the percutaneous or transjugular route.  
Gastrointestinal Endosc 2016; 83(2):360-5.
29. Sey MSL, Al-Haddad M, Imperiale TF, et al.  EUS-guided liver biopsy for parenchymal 
disease: a comparison of diagnostic yield between two core biopsy needles.  Gastrointest 
Endosc.  2016;83(2):347-52.
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017

Date Last Modified: 10/2/2017
IRB # 2017-0391
CONFIDENTIAL AND PROPRIETARY
20
30. Gleeson FC, Clayton AC, Zhang L, et al. Adequacy of endoscopic ultrasound core needle 
biopsy specimen of nonmalignant hepatic parenchymal disease. Clin Gastroenterol 
Hepatol 2008;6:1437-40. 
31. Dewitt J, McGreevy K, Cummings O, et al. Initial experience with EUSguided Tru-cut 
biopsy of benign liver disease. Gastrointest Endosc 2009;69(3 Pt 1):535-42. 
32. Gor N, Salem SB, Jakate S, et al. Histological adequacy of EUS-guided liver biopsy 
when using a 19-gauge non-Tru-Cut FNA needle. Gastrointest Endosc 2014;79:170-2. 
33. Stavropoulos SN, Im GY, Jlayer Z, et al. High yield of same-session EUS-guided liver 
biopsy by 19-gauge FNA needle in patients undergoing EUS to exclude biliary 
obstruction. Gastrointest Endosc 2012;75:310-8.
34. Colloredo G, Guido M, Sonzogni A, et al. Impact of liver biopsy size on histological 
evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. J 
Hepatol 2003;39:239-44. 
35. Crawford AR, Lin XZ, Crawford JM. The normal adult human liver biopsy: a 
quantitative reference standard. Hepatology 1998;28:323-31. 
36. Rocken C, Meier H, Klauck S, et al. Large-needle biopsy versus thin-needle biopsy in 
diagnostic pathology of liver diseases. Liver 2001;21:391-7.
37. V. Bhatia, S. Hijoka, K. Hara, et al.  Endoscopic ultrasound description of liver 
segmentation and anatomy.  Dig Endosc 2014;26:482–90.
38. Early DS, Acosta RD, Chandrasekhara V, et al. Adverse events associated with EUS and 
EUS with FNA.  Gastrointest Endosc 2013;77960;839-43.
39. Cotton PB, Eisen GM, Aabakken L, et al.  A lexicon for endoscopic adverse events: 
report of an ASGE workshop.  Gastrointest Endosc.  2010;71(3):446-54.
IRB NUMBER: 2017-0391
IRB Approved:  10/09/2017