Impact of Transjugular Intrahepatic Portosystemic Shunts on Liver Stiffness
Phase: NA
Conditions: Portal Hypertension, Liver Fibroses
Sponsor: University of Pennsylvania

Official Title: Impact of Transjugular Intrahepatic Portosystemic Shunts on Liver Stiffness 
NCT Number: 03352882 
Unique Protocol ID: 826196 
Date of Document: October 5, 2016 
 

  
CONFIDENTIAL 
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CLINICAL RESEARCH PROTOCOL 
 
 
 
 
Impact of Transjugular Intrahepatic Portosystemic Shunts on 
Liver Stiffness 
 
 
 
Regulatory Sponsor: 
Kimberly Forde, MD, MHS (PI) 
Funding Sponsor: 
NCI 
Study Product: 
None 
Protocol Number: 
TBD 
IND Number: 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial version: 10/05/2016 
Amended: 
[date] 
Amended: 
[date] 

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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................... 1 
1.1 
BACKGROUND ................................................................................................................................... 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................... 2 
1.3 
PRECLINICAL DATA ............................................................................................................................ 3 
1.4 
CLINICAL DATA TO DATE .................................................................................................................... 3 
2 
STUDY OBJECTIVES ............................................................................................................................ 3 
3 
STUDY DESIGN ..................................................................................................................................... 4 
3.1 
GENERAL DESIGN .............................................................................................................................. 4 
3.2 
PRIMARY STUDY ENDPOINTS .............................................................................................................. 4 
3.3 
SECONDARY STUDY ENDPOINTS ......................................................................................................... 4 
4 
SUBJECT SELECTION AND WITHDRAWAL ...................................................................................... 5 
4.1 
INCLUSION CRITERIA .......................................................................................................................... 5 
4.2 
EXCLUSION CRITERIA ......................................................................................................................... 5 
4.3 
SUBJECT RECRUITMENT AND SCREENING ........................................................................................... 5 
4.4 
EARLY WITHDRAWAL OF SUBJECTS .................................................................................................... 6 
4.4.1 
When and How to Withdraw Subjects...................................................................................... 6 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ........................................................... 6 
5 
STUDY DRUG ........................................................................................................................................ 6 
5.1 
DESCRIPTIONS .................................................................................................................................. 6 
5.2 
TREATMENT REGIMEN ........................................................................................................................ 6 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................................................. 7 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY INTERVENTIONS .......................................................... 8 
5.5 
SUBJECT COMPLIANCE MONITORING .................................................................................................. 8 
5.6 
PRIOR AND CONCOMITANT THERAPY .................................................................................................. 8 
5.7 
BLINDINGOFSTUDYINTERVENTIONS .................................................................................................... 8 
6 
STUDY PROCEDURES ......................................................................................................................... 8 
6.1 
VISIT 1 .............................................................................................................................................. 8 
6.2 
VISIT 2 .............................................................................................................................................. 8 
6.3 
ETC. .................................................................................................................................................. 8 
7 
STATISTICAL PLAN .............................................................................................................................. 8 
7.1 
STUDY OBJECTIVES, SAMPLE SIZE DETERMINATION, AND POWER CALCULATION .................................. 8 
7.2 
STATISTICAL METHODS ...................................................................................................................... 9 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS AND STUDY DURATION .......................................................... 9 
8 
SAFETY AND ADVERSE EVENTS ....................................................................................................... 9 
8.1 
DEFINITIONS ...................................................................................................................................... 9 
8.2 
RECORDING OF ADVERSE EVENTS .................................................................................................... 11 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ..................................... 11 
8.3.1 
Investigator reporting: notifying the study sponsor ................................................................ 12 
8.3.2 
Investigator reporting: notifying the Penn IRB ....................................................................... 12 
8.3.3 
Investigator reporting: Notifying a non-Penn IRB .................................................................. 13 
8.3.4 
Sponsor reporting: Notifying the FDA .................................................................................... 13 
8.3.5 
Sponsor reporting: Notifying participating investigators......................................................... 14 
8.4 
UNBLINDING PROCEDURES ............................................................................................................... 14 
8.5 
STOPPING RULES ............................................................................................................................ 14 

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8.6 
MEDICAL MONITORING ..................................................................................................................... 14 
8.6.1 
Auditing and Inspection .......................................................................................................... 14 
9 
DATA HANDLING AND RECORD KEEPING ..................................................................................... 14 
9.1 
CONFIDENTIALITY ............................................................................................................................ 14 
9.2 
SOURCE DOCUMENTS ...................................................................................................................... 14 
9.3 
CASE REPORT FORMS ..................................................................................................................... 14 
9.4 
RECORDS RETENTION ...................................................................................................................... 15 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................... 15 
10.1 
STUDY MONITORING PLAN ............................................................................................................. 15 
10.2 
AUDITING AND INSPECTING ............................................................................................................. 15 
11 
ETHICAL CONSIDERATIONS........................................................................................................... 15 
12 
STUDY FINANCES ............................................................................................................................ 15 
12.1 
FUNDING SOURCE ......................................................................................................................... 15 
12.2 
CONFLICT OF INTEREST.................................................................................................................. 15 
12.3 
SUBJECT STIPENDS OR PAYMENTS ................................................................................................. 16 
13 
PUBLICATION PLAN ........................................................................................................................ 16 
14 
REFERENCES ................................................................................................................................... 16 
15 
ATTACHMENTS ................................................................................................................................ 17 
 

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List of Abbreviations 
 
 
 
ESLD – end stage liver disease 
TIPS – transjugular portosystemic shunt 
PSG – portosystemic gradient 
ARFI - acoustic radiation force impulse 
 
 
 
 
 

TIPS and Stiffness 
 
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Study Summary 
Title 
Impact of Transjugular Intrahepatic Portosystemic Shunts on Liver 
Stiffness 
 
Short Title 
TIPS and Stiffness 
Protocol Number 
TBD 
Phase 
N/A 
Methodology 
Pilot study examining changes in liver stiffness measured by ultrasound 
before and after TIPS creation 
Study Duration 
12 months 
Study Center(s) 
Hospital of the University of Pennsylvania 
Objectives 
Primary:  
Liver stiffness as measured by ultrasound acoustic radiation force 
impulse (ARFI) before and after creation of TIPS 
 
Secondary: 
Change in portosystemic gradient 
Clinical success as measured by difference in frequency of repeat 
paracentesis post-TIPS or freedom from recurrence of variceal bleeding 
Rate of hepatic encephalopathy 
 
Exploratory: 
Serum biomarkers of liver stiffness 
 
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
≥18yo, undergoing TIPS creation for symptomatic portal hypertension 
Exclusions: 
BMI 
>35 
and/or 
cirrhosis 
due 
to 
non-alcoholic 
steatohepatitis, urgent or emergent TIPS for bleeding, revision of prior 
TIPS shunt, excessive alcohol use within the last 90 days 
 
Design 
Single arm pilot study 
Duration of 
participation 
30 days from TIPS creation 
Statistical 
Methodology 
Reduction in PSG below 12mm Hg will be associated with a 50% 
decrease in stiffness as measured by ultrasound 
Principal Investigator 
Kimberly Forde, MD (Medicine, Hepatology) 
Co-Investigators 
Marina Serper, MD (Medicine, Hepatology) 
David Kaplan, MD (Medicine, Hepatology) 
Rebecca Wells, MD (Medicine, Hepatology) 
Gregory Nadolski, MD (Interventional Radiology) 
Anil Chauhan, MD (Radiology) 
Key Personnel 
Kristi Lelionis CRC (Radiology Research Coordinator, UPenn) 
Biostatistician (TBD, UPenn) 
 
 
 
 

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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted according to US 
and international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference 
on Harmonization guidelines), applicable government regulations and Institutional research policies and 
procedures.  
1.1 Background 
End stage liver disease (ESLD), also known as cirrhosis or end-stage fibrosis, commonly presents with 
symptomatic portal hypertension. Two manifestations of symptomatic portal hypertension, ascites and 
variceal bleeding, can be treated by transjugular portosystemic shunt, or TIPS, creation. TIPS involves 
the percutaneous placement of a stent graft between the portal and hepatic veins to reduce the difference 
in blood pressure between the portal vein and the heart, also known as the portosystemic gradient, or 
PSG. Reduction of the PSG has been shown to decrease incidence of bleeding and reduce ascites. (1-3) 
 
Portal hypertension also causes liver stiffening, by ~5 fold or more, which increases myofibroblast 
differentiation and causes further fibrosis.(4) This increased liver stiffness is believed to play a role in the 
development of primary liver cancer called hepatocellular carcinoma (HCC) by creating a 
microenvironment that facilitates cancer development. HCC occurs overwhelmingly (>90%) in the cirrhotic 
liver (end-stage fibrosis), which is stiff. Thus, we hypothesize that rapidly reducing liver stiffness with TIPS 
could not only decrease liver stiffness but also limit hepatic fibrosis, and perhaps lower the incidence of 
HCC. 
 
About 1-2 weeks prior to and after TIPS placement, ultrasound is routinely performed to assess portal 
vein patency and obtain a baseline assessment of TIPS flow velocity.(5) During ultrasound, a non-
invasive measurement of liver stiffness can be obtained using a technique called ultrasound acoustic 
radiation force impulse (ARFI).(6) Acoustic radiation force is a phenomenon associated with the 
propagation of sound waves in a media that attenuates the movement of the sound wave by absorption or 
scatter. Attenuation depends on the frequency of the sound wave, but typically is dominated by 
absorption. With increasing frequency, the harmonic vibration of tissue in response to a sound wave 
becomes out of phase with the acoustic wave, and energy is deposited into the tissue. This energy 
generates a force that causes displacement of the tissue. This displacement (typically a few micrometers) 
can be used to derive additional information about the tissue beyond what is normally provided in an 
ultrasound image. The magnitude, location, spatial extent, and duration of acoustic radiation force can be 
controlled to interrogate the mechanical properties of the tissue. In the liver, the speed at which shear 
waves propagate in tissue can be used to quantify the shear modulus of the liver tissue allowing non-
invasive characterization the liver’s stiffness and fibrosis without the need for liver biopsy. 
  
1.2 Investigational Agent 
 
TIPS creations at the University of Pennsylvania are performed using Viatorr stent grafts, which are FDA 
approved devices for TIPS creation. ARFI at the University of Pennsylvania is available for clinical use on 
Phillips Epiq Ultrasound systems using ElastPQ ultrasound shear wave elastography. Both devices are 
considered standard of care for their respective purposes. Both devices will be used in accordance with 
their approved indication and manufacture’s instructions for use.  
1.3 Preclinical Data 
Preliminary data from laboratories in PSOC@Penn, an NCI-funded Physical Sciences in Oncology Center 
to study HCC, show that the liver undergoes significant compression stiffening, particularly with fibrosis 
and cirrhosis. Portal hypertension causes liver stiffening, by ~5 fold, which increases myofibroblast 
differentiation and further fibrosis.{Perepelyuk:2016hx} Tissues including liver stiffen and acquire more 
extracellular matrix with fibrosis. In our pre-clinical data, the relationship between matrix content and 
stiffness was found to be non-linear. A key feature of this model is that, while it assumes overall liver 

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incompressibility, it takes into account both tissue blood flow and solid phase compressibility. These 
findings suggest that both fibrosis and portal hypertension contribute to overall liver stiffness.   
1.4 Clinical Data to Date 
 
The present pilot study would serve as the initial data demonstrating that reductions in portosystemic 
gradient by TIPS will reduce liver stiffness as measured non-invasively by ARFI. 
2 Study Objectives 
 
Primary Objectives:  
To evaluate the relationship between portosystemic gradient (severity of portal hypertension) and liver 
stiffness as measured by ultrasound acoustic radiation force impulse (ARFI) before and after creation of 
TIPS 
 
Secondary: 
• 
Correlate change in portosystemic gradient with change in liver stiffness 
• 
Correlate baseline portosystemic gradient with baseline liver stiffness 
• 
Clinical success as measured by difference in frequency of repeat paracentesis post-TIPS or 
freedom from recurrence of variceal bleeding 
• 
Rate of hepatic encephalopathy 
 
Exploratory: 
• 
Correlation of serum biomarkers of liver stiffness with baseline ARFI measurements of liver 
stiffness 
 
3 Study Design 
3.1 General Design 
An open label, single arm trial investigating changes in liver stiffness as measured by ultrasound acoustic 
radiation force impulse (ARFI) before and after creation of TIPS. TIPS creation with Viatorr stent graft will 
be in accordance with its FDA-approved indication for symptomatic portal hypertension and per the 
manufacturer’s instructions for use. Liver stiffness will be measured on pre-TIPS and post-TIPS 
ultrasounds using Phillips Epiq Ultrasound systems equipped with ElastPQ ultrasound shear wave 
elastography. Both ultrasounds will be performed at times which are standard of care before and after 
TIPS creation. 
 
Trial Design 
 
Screening and Consent: Patients referred to Interventional Radiology for primary creation of TIPS for 
treatment of symptomatic portal hypertension will be screened for enrollment. Following recruitment of 
those meeting inclusion criteria, patients will be scheduled for liver ultrasound with shear wave 
elastography prior to the procedure (between 2 to 21 days prior to TIPS creation). In cases where ascites 
is present, which can interfere with the accuracy of elastography measurements, ultrasound will be 
scheduled on same day as an elective outpatient paracentesis or up to 2 days following paracentesis, 
which would be performed as part of routine clinical care to alleviate the patients symptoms of massive 
ascites and remove excess abdominal fluid prior to TIPS creation in order to allow TIPS procedure to be 
performed safely. 
 
By consenting to participate in this trial, patients will allow the researchers at the University of 
Pennsylvania health system to review parameters from their electronic medical record related to 
symptomatic portal hypertension including: 

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Etiology of cirrhosis 
Medical therapy for portal hypertension or its symptoms including dosage and duration of therapy 
Lab parameters: Platelet Count, Creatinine, Total Bilirubin, Sodium, INR, Albumin 
Childs-Pugh Score 
Model of end stage liver disease (MELD) score and Sodium MELD score 
History of frequency and severity hepatic encephalopathy as defined by West Haven criteria 
Frequency and volume of paracentesis 
Frequency and severity of variceal bleeding  
 
TIPS Creation: TIPS creation will be performed per current practice guidelines with the following 
modifications.(7) After initial access to the blood stream, 1 tablespoon (15mL) of blood will be obtained for 
analysis of direct measures of fibrinogenesis or fibrinolysis such as hyaluronic acid and tissue inhibitor of 
metalloproteinase-1.(8) At TIPS creation, pre- and post-TIPS PSG and absolute values of portal and right 
atrial blood pressures will be recorded. Following TIPS creation, patients will be admitted to the Hospital 
of the University of Pennsylvania for monitoring and pain control. 
 
Post-TIPS Creation Follow-up: Post-TIPS creation follow-up will occur according to standard clinical 
practice with the addition to ARFI at the time of initial post-TIPS ultrasound. Post-TIPS labs including 
complete blood count, coagulation studies, and comprehensive metabolic panel will be performed 
between 5 and 21 days following TIPS creation. Clinical visit for assessment of clinical success and 
complications including hepatic encephalopathy will be performed between 5 and 21 days following TIPS 
creation (typically scheduled for 1 week following procedure). Likewise, post-TIPS ultrasound including 
ARFI will be performed in the same time range (5 to 21 days post TIPS creation).  Data collected at Post-
TIPS Creation Follow-Up will include: 
Lab parameters: Platelet Count, Creatinine, Total Bilirubin, Sodium, INR, Albumin 
 
Childs-Pugh Score 
Model of end stage liver disease (MELD) score and Sodium MELD score 
Occurrence and severity of hepatic encephalopathy as defined by West Haven criteria 
Need for and volume of paracentesis since TIPS creation 
Incidence of variceal bleeding since TIPS creation  
 
Long-term Follow-up: Additional follow-up will occur as part of routine clinical care. Patient data up to 12 
months following TIPS insertion will be obtained from the electronic medical record or by direct patient 
contact via phone. Data collected in long-term follow-up will include 
Lab parameters: Platelet Count, Creatinine, Total Bilirubin, Sodium, INR, Albumin 
 
Childs-Pugh Score 
Model of end stage liver disease (MELD) score and Sodium MELD score 
Occurrence and severity of hepatic encephalopathy as defined by West Haven criteria 
Need for and volume of paracentesis since TIPS creation 
Incidence of variceal bleeding since TIPS creation  
Date of TIPS revision or TIPS flow reduction if performed 
 
3.2 Primary Study Endpoints 
 
The primary study endpoint will be decrease in liver stiffness following TIPS creation as measured by 
ARFI using mean propagation velocity values in meters per second. Mean normal values and mean 
values indicating severe fibrosis range about 0.8-1.7 m/s and about 1-3.4 m/s respectively. We 
hypothesize TIPS creation will reduce the liver stiffness by > 50%. Change in liver stiffness will be 
correlated to change in PSG.  
 
3.3 Secondary Study Endpoints 
1. Baseline PSG (mm Hg) correlation to baseline liver stiffness by ultrasound ARFI (m/s) 

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2. Clinical success as measured by difference in frequency of repeat paracentesis post-TIPS or 
freedom from recurrence of variceal bleeding at 12 months 
3. Correlation of serum biomarkers of liver stiffness (hyaluronic acid and tissue inhibitor of 
metalloproteinase-1) with baseline ARFI measurements of liver stiffness 
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1. Symptomatic portal hypertension secondary to cirrhosis undergoing elective outpatient TIPS 
2. Age >18, Age <80 
3. Capable of giving informed consent 
4.2 Exclusion Criteria 
1. Coagulopathy defined as international normalized ration (INR) >2 which cannot be corrected with fresh 
frozen plasma 
2. Platelet count <50,000/microliter, which cannot be corrected with platelet transfusion 
3. BMI >35 and/or cirrhosis due to non-alcoholic steatohepatitis (due to inaccurate elastography 
measurements in patients with fatty liver) 
4. Urgent or emergent TIPS for bleeding 
5. Portal vein thrombosis with in the main, 1st, or 2nd order branches of the portal vein 
6. Hepatic vein thrombosis (ie no Budd Chiari syndrome) 
7. Excessive alcohol use defined as more than 2 oz in 24 hours on any individual day within the last 30 
days 
8. Inability to provide informed consent 
9. Pregnant or nursing women 
10. Enrollment in concurrent therapeutic trial for symptomatic portal hypertension 
4.3 Subject Recruitment and Screening 
 
Currently, approximately 20-30 elective outpatient TIPS are created per year by the Interventional 
Radiology practice at Hospital of the University of Pennsylvania. These patients are referred from the 
Departments of Medicine Division of Gastroenterology.  
 
During the initial contact with the patient, potential candidates will be screened by research coordinator, 
PI, or co-PI for adequacy for the clinical trial. If the applicant meets inclusion criteria without any exclusion 
criteria, the patient will be approached by research coordinator to discuss enrollment. All patients who are 
identified as potential candidates 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. The potential subject will be given an opportunity to read the consent form thoroughly and ask and 
be provided answers to any questions that they may have regarding the study. The subject will be asked 
to sign the consent form only if they have indicated that they are willing to do so without reservation. The 
informed consent will be obtained before the subject undergoes any study procedure. The consent form 
must be signed by the subject or legally acceptable surrogate and the investigator or investigator-
designated research professional obtaining consent. The subjects will be informed that their participation 
is entirely voluntary, that if they chose not participate their care will not be affected and that they may 
withdraw consent at any time. 
 
Patients who experience a major complication from TIPS creation (eg hemobilia, ischemic liver failure) 
that likely affects the success of the TIPS to treat portal hypertension will be withdrawn at the discretion of 
the PI and study team and replaced with additional subjects. 

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4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
 
• 
PI Decision:  Subjects may be withdrawn at any time during the study if the PI believes it is in the 
subject’s best interest. In this event, the reasons for withdrawal will be documented. Patients who 
experience a major complication from TIPS creation (eg hemobilia, ischemic liver failure) that likely affects 
the success of the TIPS to treat portal hypertension will be withdrawn at the discretion of the PI and study 
team and replaced with additional subjects. 
• 
Subject Participation:  Refusal to continue with treatment, follow-up, comply with the protocol or 
withdrawal of consent. In this event, the reasons for withdrawal will be documented. 
 
Patients withdrawing from the study will be entitled to pursue all treatment options available for the 
treatment of end-stage liver disease without prejudice from the providing physicians. 
 
Once the subject has discontinued treatment, the primary reason for discontinuing treatment must be 
clearly documented in the subject’s records and on the eCRF. The investigator will assess each subject 
for response at the time of withdrawal.   
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
All data collected prior to subject withdraw will be retained in eCRFs and included for analysis. 
 
Even though subjects may be withdrawn prematurely from the study, attempts will be made to collect data 
on clinical success, TIPS complications and patency data for TIPS on such subjects throughout the 
protocol defined follow-up period for that subject.  Such data is important to the integrity of the final study 
analysis of secondary end-points.  If a subject withdraws consent to participate in the study, attempts will 
be made to obtain permission to record at least TIPS patency, complication, and clinical success data up 
to the protocol-described end of subject follow-up period. Methods that may be used to obtain primary 
patency data will include phone calls to the subject, phone calls to next-of-kin if possible, and certified 
letters to the subject or next-of-kin. If permission to collect or the specific patency data cannot be obtained 
after 4 phone calls and 4 letters to the subject and/or next-of-kin, the patient will be regarded as lost to 
follow up. 
5 Study Interventions  
5.1 Descriptions 
 
TIPS Creation  
TIPS creation will be in accordance with its FDA-approved indication under moderate sedation or general 
anesthesia with local anesthesia using Viatorr stent graft. In brief, using real time ultrasound guidance, 
access to the internal or external jugular vein will be achieved using a 21G needle and a guidewire 
advanced into the superior vena cava under fluoroscopic guidance. Using this access, a 10F vascular 
sheath will be placed and 15mL of blood obtained for analysis of hyaluronic acid and tissue inhibitor of 
metalloproteinase-1 (biomarkers of liver fibrosis). A catheter will be used to select a hepatic vein. Next, 
entry to the portal vein will be achieved using a portal access needle. Upon confirming portal entry with 
contrast injection, a guidewire will be advanced into the portal vein and the needle exchanged for flush 
marker catheter. PSG will be measured and portogram performed. After angioplasty of the parenchymal 
tract, an appropriate length Viatorr stent graft will be inserted to create TIPS. Repeat portogram and 
measurement of PSG will be performed using a flush catheter. The catheter and sheath will be removed 
and hemostasis achieved with manual compression.  
 
 
 

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Ultrasound with ARFI 
Pre-TIPS hepatic ultrasound will be performed between 2 and 21 days prior to TIPS creation using gray 
scale, color Doppler, and spectral Doppler imaging to evaluate hepatic vein and portal vein patency, 
direction and velocity of flow respectively. ARFI will be performed in the right hepatic lobe. Three 
measurements of stiffness (m/s) will be performed and the mean value recorded.  
 
Post-TIPS ultrasound will be performed between 5 and 21 days following TIPS creation using gray scale, 
color Doppler, and spectral Doppler imaging to evaluate TIPS, hepatic vein and portal vein patency, 
direction and velocity of flow respectively. ARFI will be performed in the right hepatic lobe. Three 
measurements of stiffness (m/s) will be performed and the mean value recorded. 
 
For patients with symptomatic ascites, ultrasound will be coordinated with subject’s elective paracentesis 
or up to two days following paracentesis to minimize interference with ARFI measurements from the 
presence of ascites. These paracenteses are considered standard clinical care to alleviate symptoms of 
massive ascites and remove excess abdominal fluid prior to TIPS creation to permit TIPS to be created 
safely.  
5.2 Treatment Regimen 
TIPS will be created using standard clinical techniques. All patients’ pre-TIPS and post-TIPS care will 
occur as part of standard of care with the exception of the addition of elastography at the time of 
ultrasound before and after TIPS creation. Patients will not be charged for the cost of the addition of ARFI 
to ultrasounds. Data related to cirrhosis, TIPS creation, follow-up TIPS performance and complications 
will be extracted from the electronic medical record at the University of Pennsylvania. Patients will be 
followed 12 months following TIPS creation. 
 
  
5.3 Method for Assigning Subjects to Treatment Groups 
The study is a non-randomized open label single arm pilot trial to provide preliminary clinical data on the 
change in liver stiffness in patients with symptomatic portal hypertension following TIPS creation. All 
procedures will be performed at times of routine clinical service. TIPS will be created using standard 
clinical techniques. All patient’s pre-TIPS and post-TIPS care will occur as part of standard of care with 
the exception of the addition of elastography at the time of ultrasound before and after TIPS creation. 
 
Monthly, the coordinators will provide documentation of the number of patients screened who chose not 
to enroll in the study. Otherwise, when a screened patient is recruited to the study, the coordinator will 
register the patient into the study database (RedCAP) and generate a study identification number, which 
will be recorded on the eCRF. 
5.4 Preparation and Administration of Study Interventions 
 
All procedures and imaging will be performed using FDA-approved devices/equipment for their intended 
FDA-approved indication using standard clinical practice as outlined in manufacturer’s instructions for 
use. Thus, no special preparation or administration of these interventions is necessary. 
 
Women who are able to become pregnant will be tested for pregnancy by urine pregnancy test.  The 
results of this test must be negative at the time of enrollment. At the time of enrollment, documentation of 
pregnancy status will be recorded on eCRF as one of the following: (a) reproductive age UPT negative, 
(b) unable to become by nature means and approximate date of menopause, or (c) unable to become 
pregnant by surgical means and approximate date of surgery. For patients of reproductive age, UPT will 
be retested on date of TIPS creation. 
 

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5.5 Subject Compliance Monitoring 
N/A 
5.6 Prior and Concomitant Therapy 
 
Patients may continue medical therapy for symptomatic portal hypertension. Enrollment in concurrent 
therapeutic clinical trial to treat portal hypertension is not allowed.  
 
5.7 Blinding of Study Intervention 
This protocol does not utilize blinding. Subjects and investigators will know the treatment being 
administered. 
6 Study Procedures 
6.1 Visit 1: Date of Enrollment and Clinical evaluation by Interventional 
Radiology 
Initial consult for TIPS creations. Patient will be evaluated for enrollment in the clinical trial at the time of 
IR consult visit after consenting to undergo TIPS creation and confirmation that patient meets all inclusion 
and no exclusion criteria. After enrollment, the patient will be entered into eCRF (RedCap) and assigned 
a subject number. At this time, baseline clinical data including etiology of cirrhosis, medical therapy for 
portal hypertension or its symptoms including dosage and duration of therapy, Lab parameters (Platelet 
Count, Creatinine, Total Bilirubin, Sodium, INR, Albumin), Childs-Pugh Score, Model of end stage liver 
disease (MELD) score and Sodium MELD scores, history of hepatic encephalopathy including frequency 
and severity of hepatic encephalopathy as defined by West Haven criteria, frequency and volume of 
paracentesis, and frequency and severity of variceal bleeding will be recorded from the electronic medical 
record. 
 
6.2 Visit 2: Pre-TIPS Ultrasound 
Pre-TIPS hepatic ultrasound will be performed between 2 and 21 days prior to TIPS creation using gray 
scale, color Doppler, and spectral Doppler imaging to evaluate hepatic vein and portal vein patency, 
direction and velocity of flow respectively. ARFI will be performed in the right hepatic lobe. Three 
measurements of stiffness (m/s) will be performed and the mean value recorded in eCRF. Patency of 
hepatic veins and portal veins as well as spectral Doppler velocity measurements will be recorded in 
eCRF. For patients with symptomatic ascites, ultrasound will be coordinated with subject’s elective 
paracentesis or up to two days following paracentesis to minimize interference with ARFI measurements 
from the presence of ascites. 
 
6.3 Visit 3: TIPS Creation 
TIPS creation will be in accordance with its FDA-approved indication under moderate sedation or general 
anesthesia with local anesthesia using Viatorr stent graft (FDA-approved for TIPS). In brief, using real 
time ultrasound guidance, access to the internal or external jugular vein will be achieved using a 21G 
needle and a guidewire advanced into the superior vena cava under fluoroscopic guidance. Using this 
access, a 10F vascular sheath will be placed and 15mL of blood obtained for analysis of hyaluronic acid 
and tissue inhibitor of metalloproteinase-1 (biomarkers of liver fibrosis). A catheter will be used to select a 
hepatic vein. Next, entry to the portal vein will be achieved using a portal access needle. Upon confirming 
portal entry with contrast injection, a guidewire will be advanced into the portal vein and the needle 
exchanged for flush marker catheter. PSG will be measured and portogram performed. After angioplasty 
of the parenchymal tract, an appropriate length Viatorr stent graft will be inserted to create TIPS. Repeat 
portogram and measurement of PSG will be performed using a flush catheter. The catheter and sheath 

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will be removed and hemostasis achieved with manual compression. After TIPS creation, patients will be 
admitted to the Hospital of the University of Pennsylvania for monitoring and pain control.  
 
At the time of TIPS creation, absolute mean right atrial and portal vein pressures before and after TIPS 
creation as well as PSG at both time points will be recorded. 
 
6.4 Visit 4: Post-TIPS Ultrasound and Clinical Follow-up Visit 
 
Follow-up clinic evaluation in interventional radiology will be performed by the treating physician or a 
member of the study team between 5 and 21 days following TIPS creation. During this same time period 
(5 to 21 days post-TIPS creation), routine post-TIPS laboratory studies will be performed including CBC, 
CMP, and coagulation factors. Ammonia levels will be ordered as clinically indicated for patients with 
history of encephalopathy or development of encephalopathy following TIPS.  
 
Post-TIPS ultrasound will be performed between 5 and 21 days following TIPS creation using gray scale, 
color Doppler, and spectral Doppler imaging to evaluate TIPS, hepatic vein and portal vein patency, 
direction and velocity of flow respectively. ARFI will be performed in the right hepatic lobe. Three 
measurements of stiffness (m/s) will be performed and the mean value recorded. 
 
For patients with symptomatic ascites, ultrasound will be coordinated with subject’s elective paracentesis 
or up to two days following paracentesis to minimize interference with ARFI measurements from the 
presence of ascites. 
 
At the time of this visit the following data will be collected: 
Lab parameters: Platelet Count, Creatinine, Total Bilirubin, Sodium, INR, Albumin 
Childs-Pugh Score 
Model of end stage liver disease (MELD) score and Sodium MELD score 
Occurrence and severity of hepatic encephalopathy as defined by West Haven criteria 
Need for and volume of paracentesis since TIPS creation 
Incidence of variceal bleeding since TIPS creation  
Patency of TIPS, hepatic veins and portal veins 
Spectral Doppler velocity measurements of TIPS, hepatic veins and portal veins 
Mean liver stiffness score from ARFI 
 
6.5 Visit 5, etc: On-going Clinical Follow-up 
Subsequent follow-up by interventional radiology or hepatology for TIPS complications or dysfunction and 
management of portal hypertension/cirrhosis will occur per routine clinical practice. Data related to the 
function and outcomes of TIPS will be extracted from the electronic medical record or by direct patient 
contact via the phone. Patients data will be recorded for up to 12 months following TIPS creation. Data 
collected in long-term follow-up will include 
Lab parameters: Platelet Count, Creatinine, Total Bilirubin, Sodium, INR, Albumin 
 
Childs-Pugh Score 
Model of end stage liver disease (MELD) score and Sodium MELD score 
Occurrence and severity of hepatic encephalopathy as defined by West Haven criteria 
Need for and volume of paracentesis since TIPS creation 
Incidence of variceal bleeding since TIPS creation  
TIPS, hepatic vein and portal vein flow and velocity measurements from repeat ultrasounds if 
performed 
Date of TIPS revision or TIPS flow reduction if performed 

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7 Statistical Plan 
7.1 Study Objectives, Sample Size Determination and Power Calculation 
 
Objectives 
This trial is designed to be the initial pilot trial evaluating the changes in liver stiffness following TIPS 
creation. The knowledge gained from this investigation will serve as the basis for clinical trials comparing 
the effect of decreasing liver stiffness on progression of cirrhosis and hepatocellular carcinoma. 
 
Primary Objective: To evaluate the relationship between portosystemic gradient (severity of portal 
hypertension) and liver stiffness as measured by ultrasound acoustic radiation force impulse (ARFI) 
before and after creation of TIPS 
 
Secondary: 
• 
Correlate change in portosystemic gradient with change in liver stiffness 
• 
Correlate baseline portosystemic gradient with baseline liver stiffness 
• 
Clinical success as measured by difference in frequency of repeat paracentesis post-TIPS or 
freedom from recurrence of variceal bleeding 
• 
Rate of hepatic encephalopathy 
 
Exploratory: 
• 
Correlation of serum biomarkers of liver stiffness with baseline ARFI measurements of liver 
stiffness  
 
Sample Size Determination and Power Calculation 
 
Sample size estimation is based on our hypothesis that TIPS creation will result in a > 50% reduction in 
the mean liver stiffness. Mean normal values and mean values indicating severe fibrosis range about 0.8-
1.7 m/s and about 1-3.4 m/s respectively. Prior investigations have demonstrated that ARFI can 
distinguish pathological grade F3 and F4 stage fibrosis. The optimal cut-off value to identify fibrosis stage 
F3 or higher was 1.54 m/s, with sensitivity and specificity of 97% and 100% respectively.(9). Thus, if we 
assume the mean pre-TIPS stiffness value will be 3.08 m/s or higher indicating advanced fibrosis and the 
standard deviation of ARFI will be set to 30%(10), the null hypothesis that the mean value of liver 
stiffness will not be different after TIPS creation will be tested against a two-sided alternative, the mean 
value of liver stiffness will decrease by an effect size of 50% or greater. A sample size of 18 patients will 
provide sufficient power to reject the null hypothesis if the effect size was a little as a 20% reduction in 
liver stiffness using a paired t-test with a type I error rate of 0.05 and power of 0.80.  
We anticipate 10% of subjects enrolled in this study will be removed from analysis due to major 
complication of TIPS creation interfering with accurate liver stiffness measurement. Thus, 20 patients will 
be enrolled in the trial.  If 30 elective outpatients are scheduled for TIPS creation each year at the 
Hospital of the University of Pennsylvania, then we expect 18 months will be needed to complete 
enrollment.  
 
7.2 Statistical Methods 
 
Primary Objective: Mean liver stiffness value by ARFI before and after TIPS creation will be compared 
using a paired t-test. 
 
Secondary Objectives: When comparing dichotomous variables before and after TIPS creation, a 2-sided 
χ2 test will be used. Fisher’s exact test will be used for contingency tables with fewer than 10 subjects in 
each category. When comparing continuous variables, a 2-sided t test will be used, provided that the 

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distributions are sufficiently close to the normal distribution. Otherwise, a 2-sided Mann-Whitney test will 
be used.  
 
7.3 Subject Population(s) for Analysis and Duration of Study 
Analysis of both primary and secondary end points will be performed on all subjects undergoing 
successful TIPS creation who complete follow up ultrasound and clinical evaluation. Approximately 20 
patients will be enrolled in this trial. Each patient will be followed for 1 year following TIPS creation.  
However, the primary end point will be recorded during visit 3 within 21 days of TIPS creation. Thus, we 
expect 18 months will be needed to complete enrollment and complete follow-up of all patients through 
the primary end-point. 
 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc.) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  

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Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from 
the initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 30 days following completion of the last survey.  
 
Preexisting Condition 
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. 
 
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.  
 
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 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.  The 
investigator should notify the study 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 investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has participated 
in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event 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 and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 
8.2 Recording of Adverse Events 
At each contact with the subject, the study team and investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on all adverse events 

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should be recorded immediately in the source document, and also in the appropriate adverse event 
module of the case report form (eCRF).  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results should recorded in the source document, though should be grouped under one 
diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study participation should 
be recorded and reported immediately. 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats 
and requirements of the various entities to which they are responsible, but at a minimum those events 
that must be reported are those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(see definitions, section 8.1).   
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of 
the initial report includes: 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator 
assessment 
of 
the 
association 
between the event and study treatment 
 
8.3.1 Investigator reporting: notifying the medical monitor 
 
N/A 
8.3.2 Investigator reporting: notifying the Penn IRB 
 
This section describes the requirements for safety reporting by investigators who are Penn faculty, 
affiliated with a Penn research site, or otherwise responsible for safety reporting to the Penn IRB. The 
University of Pennsylvania IRB (Penn IRB) requires expedited reporting of those events related to study 
participation that are unforeseen and indicate that participants or others are at increased risk of harm.  
The Penn IRB will not acknowledge safety reports or bulk adverse event submissions that do not meet 
the criteria outlined below.  The Penn IRB requires researchers to submit reports of the following 
problems within 10 working days from the time the investigator becomes aware of the event: 
• Any adverse event (regardless of whether the event is serious or non-serious, on-site or off-site) 
that occurs any time during or after the research study, which in the opinion of the principal 
investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately reflected 
in the protocol-related documents, such as the IRB-approved research protocol, any applicable 
investigator brochure, and the current IRB-approved informed consent document and other 
relevant sources of information, such as product labeling and package inserts.) 
AND 

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Related to the research procedures (An event is “related to the research procedures” if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be caused by 
the research procedures.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the Penn 
IRB using the form: “Unanticipated Problems Posing Risks to Subjects or Others Including Reportable 
Adverse Events” or as a written report of the event (including a description of the event with information 
regarding its fulfillment of the above criteria, follow-up/resolution and need for revision to consent form 
and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the Penn IRB: 
• Any adverse experience that, even without detailed analysis, represents a serious unexpected 
adverse event that is rare in the absence of drug exposure (such as agranulocytosis, hepatic 
necrosis, Stevens-Johnson syndrome). 
• Any adverse event that would cause the sponsor to modify the investigators brochure, protocol or 
informed consent form, or would prompt other action by the IRB to assure protection of human 
subjects. 
• Information that indicates a change to the risks or potential benefits of the research, in terms of 
severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of response to treatment than 
initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or more frequent than 
initially expected. 
– A paper is published from another study that shows that an arm of your research study is of no 
therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in 
a research protocol. 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a 
research participant. 
• Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
• Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot 
be resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB approved 
protocol) that in the opinion of the investigator placed one or more participants at increased risk, or 
affects the rights or welfare of subjects. 
8.3.3 Sponsor Reporting: NIH 
 
Investigators must report serious adverse events (SAE) attributed to study procedures to the NIH within 
the timelines described below.  
 
• 
Relevant follow-up information such as resolution and duration of the SAE attributed to study 
procedures should be submitted as soon as it becomes available. 
• 
Serious AE reports that are related to study procedures will be transmitted within fifteen (15) 
calendar days from the date investigators are made aware of the AE.  

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• 
Serious AE reports that are unrelated to study procedures will be transmitted within thirty (30) 
calendar days from the date investigators are made aware of the AE.  
• 
All Non-serious Adverse Events originating from the study will be forwarded in a semi-annual 
report  
 
8.3.4 Sponsor reporting: Notifying FDA 
 
Medical Device Reporting (MDR): In accordance with FDA regulation (21 CFR 803), the sponsor will 
report to the FDA when they learn that any of their devices may have caused or contributed to a death or 
serious injury. Manufacturers must also report to the FDA when they become aware that their device has 
malfunctioned and would be likely to cause or contribute to a death or serious injury if the malfunction 
were to recur. 
8.4 Unblinding Procedures 
N/A 
8.5 Stopping Rules  
The study will be terminated after completed follow up of the last patient enrolled (ie 1 year after this 
patient has TIPS created). 
8.6 Medical Monitoring 
It is the responsibility of the Principal 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 9 
Auditing, Monitoring and Inspecting).   
8.6.1 Auditing and Inspection 
This protocol will be audited and inspected in accordance with DSMP submitted separately. 
9 Data Handling and Record Keeping 
9.1 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 (i.e. that the subject is alive) at the end of their scheduled study 
period. 
9.2 Source Documents 
Source data is 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, 

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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. 
9.3 Case Report Forms 
The study case report form (eCRF) is the primary data collection instrument for the study. eCRFs will be 
created in the RedCap system to capture the data that the investigator wishes to collect for the purposes 
of research and for safety monitoring. Data will be entered into this system in a timely manner. Forms 
used in the source document should reflect the information needed for the completion of the eCRFs in 
RedCap.  
 
9.4 Records Retention 
 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last 
follow up visit with the last enrolled patient.  
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
The study PI is responsible for ensuring the ongoing quality and integrity of the research study. In 
addition, this study will be monitored or audited in accordance with Institutional Data and Safety 
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 above noted study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices.  
 
Certain studies, as identified by the ORA, will be monitored on an on-going basis by the DOCM. 
Each study will have an individualized monitoring plan developed by the DSMC and the study team. 
This plan must be approved by the DOCM Director. Once the ORA determines that a study 
needs prospective monitoring, the DSMC will work with the PI and study team to develop a 
monitoring plan that will cover 
 
• All of the Regulatory documentation 
• Informed Consents 
• Eligibility criteria 
• Treatment administration and accountability 
• Adverse/Serious Adverse Events and toxicities 
• Response assessment 
• Subject follow-up 
• Data completeness 

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• Source documentation to Case Report Form (CRF) 
• Manufacturing (where applicable) 
 
At the conclusion of the monitoring visit, the monitor will spend time with the PI and/or study team to  
discuss the findings and to provide guidance on resolving deficiencies. A formal letter will be sent to the 
PI within about five business days. The PI does not have to respond the monitoring letter unless 
specifically requested to do so by the monitor. Studies that are high risk protocols are audited 
approximately six months from their first subject accrual and approximately every six month thereafter for 
the duration of the study. However, this schedule may be changed at the discretion of the DSMC. High 
enrolling or quick enrolling studies will be audited more frequently as necessary. Investigators are notified 
in advance of the selection of their protocol for review and cases are randomly selected. Three subjects 
or 10% of the total accrual, whichever is higher, are audited. A formal report is provided to the PI within 
about five business days of the audit. The Committee may alter the frequency of re-monitoring based on 
the audit findings and degree of deficiencies. If an audit is unacceptable due to major deficiencies, 
representatives from the DOCM acting on behalf of the DSMC meet with the PI to discuss the findings of 
the audit and necessary corrective actions. If the deficiencies involve subject safety or serious regulatory 
violations, DSMC Chair, and DOCM Director will meet to discuss necessary actions concerning study 
status. 
 
10.3  Study Exceptions and Deviations  
In order to harmonize with the IRB, the DSMC has changed its designations from Deviations and 
Violations to Exceptions and Deviations 
Exception  
A one time, intentional action or process that departs from the IRB and CTSRMC approved study 
protocol, intended for one occurrence. If the action disrupts the study progress, such that the study design 
or outcome (endpoints) may be compromised, or the action compromises the safety and welfare of study 
subjects, advance documented IRB and DSMC approval is required.    
For in-house studies with a Medical Monitor or Safety Monitoring Committee (not DSMB), approval must 
be obtained from the Medical Monitor or Safety Monitoring Committee prior to submitting your exception 
request to the DSMC.  
Deviation 
A one time, unintentional action or process that departs from the IRB and DSMC approved study protocol, 
involving one incident and identified retrospectively, after the event occurred. If the impact on the protocol 
disrupts the study design, may affect the outcome (endpoints) or compromises the safety and welfare of 
the subjects, the deviation must be reported to the DSMC within 5 business days and the IRB within 10 
business days.  
11 Ethical Considerations 
This study is to be conducted accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor before 

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commencement of this study.  The investigator should provide a list of EC/IRB members and their affiliate 
to the sponsor. 
 
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.  See 
Attachment B for a copy of the Subject Informed Consent Form.  This consent form will be submitted with 
the protocol for review and approval by the EC/IRB for the study.  The formal consent of a subject, using 
the EC/IRB-approved consent form, must be obtained before that subject undergoes any study 
procedure.  The consent form must be signed by the subject or legally acceptable surrogate, and the 
investigator-designated research professional obtaining the consent.  
12 Study Finances 
12.1 Funding Source 
NIH 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that 
has been reviewed and approved by the study sponsor prior to participation in this study.  All University of 
Pennsylvania investigators will follow the applicable University conflict of interest policies. 
12.3 Subject Stipends or Payments 
None 
13 Publication Plan 
 
The Principal Investigator and Institution shall be free to publish and present the results and data from the 
Study. 
14 References 
 
15 Attachments 
 
eCRF 
Monitoring Plan  
ICF 
 
 
1. 
García-Pagán JC, Caca K, Bureau C, Laleman W, Appenrodt B, Luca A, et al. 
Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 
2010 Jun 24;362(25):2370–9.  
2. 
Narahara Y, Kanazawa H, Fukuda T, Matsushita Y, Harimoto H, Kidokoro H, et al. 
Transjugular intrahepatic portosystemic shunt versus paracentesis plus albumin in 

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patients with refractory ascites who have good hepatic and renal function: a 
prospective randomized trial. J Gastroenterol. 2010 Jul 15;46(1):78–85.  
3. 
Sanyal AJ, Genning C, Reddy KR, Wong F, Kowdley KV, Benner K, et al. The 
North American Study for the Treatment of Refractory Ascites. Gastroenterology. 
Elsevier; 2003 Mar 1;124(3):634–41.  
4. 
Perepelyuk M, Chin L, Cao X, van Oosten A, Shenoy VB, Janmey PA, et al. 
Normal and Fibrotic Rat Livers Demonstrate Shear Strain Softening and 
Compression Stiffening: A Model for Soft Tissue Mechanics. Kumar S, editor. 
PLoS ONE. Public Library of Science; 2016 Jan 6;11(1):e0146588.  
5. 
Kalva SP, Salazar GM, Walker TG. Transjugular Intrahepatic Portosystemic 
Shunt for Acute Variceal Hemorrhage. YTVIR. Elsevier Inc; 2009 Jun 1;12(2):92–
101.  
6. 
Cassinotto C, Lapuyade B, Mouries A, Hiriart J-B, Vergniol J, Gaye D, et al. Non-
invasive assessment of liver fibrosis with impulse elastography: Comparison of 
Supersonic Shear Imaging with ARFI and FibroScan®. Journal of Hepatology. 
2014 Sep;61(3):550–7.  
7. 
Clark TWI. Stepwise Placement of a Transjugular Intrahepatic Portosystemic 
Shunt Endograft. YTVIR. Elsevier Inc; 2008 Dec 1;11(4):208–11.  
8. 
Adams LA. Biomarkers of liver fibrosis. J Gastroenterol Hepatol. Blackwell 
Publishing Asia; 2011 May 1;26(5):802–9.  
9. 
Fierbinteanu-Braticevici C. Acoustic radiation force imaging sonoelastography for 
noninvasive staging of liver fibrosis. World journal of …. 2009.  
10. 
Goertz RS, Sturm J, Pfeifer L, Wildner D. ARFI cut-off values and significance of 
standard deviation for liver fibrosis staging in patients with chronic liver disease. 
Ann …. 2013.