Advancing Liver Therapeutic Approaches (ALTA). The ALTA Consortium Study Group for the Management of Portal Hypertension - A 5-year Longitudinal Observational Study of Patients Undergoing Transjugular Intrahepatic Portosystemic Shunt (TIPS) Placement
Conditions: Cirrhosis, Liver, Transjugular Intrahepatic Portosystemic Shunt (TIPS)
Sponsor: University of Texas Southwestern Medical Center

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Advancing Liver Therapeutic Approaches (ALTA). The ALTA Consortium Study Group in the use of 
TIPS for the management of Portal Hypertension 
Short Name: ALTA TIPS 
 
 
Version 1.2 
Amendment 1 
Amendment 2 
 
 
 
 
 
 
Sponsor Name: W. L. Gore & Associates, Inc., Northwestern University  
 
 
 
 
 
 
 

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PROTOCOL SUMMARY 
 
Study Title 
Advancing Liver Therapeutic Approaches (ALTA). The 
ALTA Consortium Study Group in the use of TIPS for the 
management of Portal Hypertension 
Amendment 
Version 1.2 
Sponsor 
W. L. Gore & Associates, Inc., Northwestern University  
Study Design 
Multi-center, prospective registry of patient characteristics 
and clinical outcomes of patients undergoing Transjugular 
Intraheptic Portosystemic Shunt (TIPS) placement. 
Study Objective 
To assess contemporary patterns of use of TIPS stents and 
associated patient related outcomes. To utilize knowledge 
gained to serve as a foundation for future prospective 
randomized controlled trials. 
Study Endpoint(s) 
1. Patient survival / liver transplantation 
2. TIPS related complications: stenosis/need for 
revision 
3. Worsening or new onset hepatic encephalopathy 
4. Recurrent portal hypertensive complications (e.g. 
ascites, variceal bleeding) 
5. Cardiovascular outcomes (new onset heart failure) 
6. Renal outcomes 
Subject Population 
All patients undergoing TIPS placement. 
Number of Sites 
Lead site: Northwestern University. Additional 11 tertiary 
academic sites throughout the U.S. (Columbia University, 
Scripps Clinic, Stanford University, Mayo Clinic Rochester, 
University of California San Francisco, University of 
Chicago, University of Florida, University of Wisconsin 
Madison, Weil Cornell, University of Texas Baylor-Dallas, 
University of Arizona-College of Medicine Phoenix Banner 
Health) 
Expected 1,000 patient cases over 3 years. 
Expected Time to 
Complete Enrollment  
Three years of enrollment and up to 5 years of clinical 
follow-up. 
Schedule of Events 
 
Month 0: TIPS placement (medical history, baseline 
quality of life assessments)  
 
Months 1, 3, 6, 12, 24, 36, 48, 60: Follow up 
assessments (survival, transplantation status, TIPS 
ultrasound, quality of life assessments, impact on 
cardiovascular/renal function) 
Clinical Sites / Sub-PIs 
Northwestern University – Dr. Lisa VanWagner 
University of California San Francisco – Dr. Jennifer Lai 
Scripps Health – Dr. Catherine Frenette 
University of Wisconsin Madison – Dr. Erin Spengler 
University of Florida – Dr. Giuseppe Morelli 
University of Arizona – Dr. Michael Fallon 
Stanford University – Dr. Aparna Goel 
Columbia University – Dr. Elizabeth Verna 

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University of Chicago – Dr. Sonali Paul 
Mayo Clinic Rochester – Dr. Doug Simonetto 
Weill Cornell – Dr. Brett Fortune 
Baylor Scott & White Liver Consultants of Texas – Dr. 
Sumeet Asrani 
 
 
 
Amendment 1 – Summary of Changes: 
 
Removal of references to study “sponsor” and replaced with “lead site". 
 
 
Amendment 2 – Summary of Changes: 
 
Removal of the Hepatic Encephalopathy Staging Algorithm (HESA) and addition of the Clinical 
Hepatic Encephalopathy Staging Scale (CHESS). 

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LIST OF ABBREVIATIONS 
 
TIPS – Transjugular Intrahepatic Portosystemic Shunt 
HE – Hepatic Encephalopathy  
eGFR - estimated glomerular filtration rate 
MELD – Model for Endstage Liver Disease 
MELD-Na – Model for Endstage Liver Disease incorporating serum sodium

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PROTOCOL SUMMARY ........................................................................................................................................... ii 
LIST OF ABBREVIATIONS ..................................................................................................................................... iv 
1. Introduction ........................................................................................................................................................ 1 
1.1. 
Historical Treatments: ............................................................................................................................ 1 
1.2. 
Study Device Description: ...................................................................................................................... 1 
2. Study Objectives ............................................................................................................................................... 1 
2.1. 
Primary Objective(s) ............................................................................................................................... 1 
2.2. 
Secondary Objective(s) .......................................................................................................................... 2 
3. Study Design ...................................................................................................................................................... 2 
3.1. 
Study Design Schema ............................................................................................................................ 2 
3.2. 
Description of Study Design: .................................................................................................................. 2 
3.3. 
Study Endpoint(s) ................................................................................................................................... 3 
3.3.1. 
Primary Endpoint(s) ................................................................................................................ 3 
3.3.2. 
Secondary Endpoint(s) ............................................................................................................ 3 
4. Study Population ............................................................................................................................................... 3 
4.1. 
Description of Population: ...................................................................................................................... 3 
4.2. 
Inclusion Criteria: .................................................................................................................................... 3 
4.3. 
Exclusion Criteria.................................................................................................................................... 4 
5. Study Procedures/Evaluations ........................................................................................................................ 4 
5.1. 
Schedule of Events ................................................................................................................................ 4 
5.2. 
Informed Consent Process ..................................................................................................................... 4 
5.3. 
Pre-Screening / Screening ..................................................................................................................... 5 
5.4. 
Enrollment .............................................................................................................................................. 5 
5.5. 
Procedure ............................................................................................................................................... 5 
5.6. 
Repeat Interventions .............................................................................................................................. 5 
5.7. 
Follow-Up: .............................................................................................................................................. 5 
5.8. 
Subject Withdrawal from the Study ........................................................................................................ 6 
5.9. 
Subject Lost to Follow-Up ...................................................................................................................... 6 
5.10. 
Subject Study Completion ...................................................................................................................... 6 
6. Study Administration ........................................................................................................................................ 6 
6.1. 
Monitoring ............................................................................................................................................... 6 
6.2. 
Protocol Deviations ................................................................................................................................ 6 
6.3. 
Protocol Amendments ............................................................................................................................ 7 
6.4. 
Access to Source Data/Documents........................................................................................................ 7 
6.5. 
Study Records Retention ....................................................................................................................... 7 
6.6. 
Publication Plan ...................................................................................................................................... 7 
7. Data Collection and Submission ..................................................................................................................... 7 
7.1. 
Data Collection Methods ........................................................................................................................ 7 
Data will be abstracted from the subjects’ medical records and uploaded directly to REDCap.  Questionnaire 
and hepatic encephalopathy assessments will be collected on paper case report forms stored in the subjects’ 
paper chart and uploaded to REDCap. ............................................................................................................... 7 
7.2. 
Data Clarification and Correction ........................................................................................................... 7 
Data verification and queries will be processed every 14 days.  Sites will have 14 days to respond to queries. 7 
7.3. 
CRF Completion Schedule ..................................................................................................................... 7 
8. Risk Assessment ............................................................................................................................................... 8 
9. Adverse Events and Safety Monitoring .......................................................................................................... 8 

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9.1. 
Anticipated Adverse Events ................................................................................................................... 8 
9.1.1. 
Subject Death .......................................................................................................................... 8 
10. Statistical Analysis ............................................................................................................................................ 8 
10.1. 
Study Hypotheses .................................................................................................................................. 8 
10.2. 
Sample Size Assumptions ...................................................................................................................... 8 
10.3. 
Sample Size Determination .................................................................................................................... 8 
10.4. 
Data Analysis.......................................................................................................................................... 9 
10.4.1. 
Timing of Analyses .................................................................................................................. 9 
10.4.2. 
Analysis Populations ............................................................................................................... 9 
10.4.3. 
Statistical Analysis of Primary/Secondary Endpoint(s) ........................................................... 9 
11. Ethical and Regulatory Considerations .......................................................................................................... 9 
11.1. 
Statement of Compliance ....................................................................................................................... 9 
 
Compliance Responsibilities .................................................................................................................. 9 
11.2. 
9 
11.3. 
Informed Consent ................................................................................................................................. 10 
11.4. 
Independent Ethical Review ................................................................................................................. 10 
11.5. 
Conflict of Interest ................................................................................................................................ 10 
11.6. 
Confidentiality ....................................................................................................................................... 10 
11.7. 
Study Discontinuation or Suspension .................................................................................................. 11 
12. References ....................................................................................................................................................... 11 
13. Study-Specific Appendices ............................................................................................................................ 11 
 

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1. 
Introduction 
Portal hypertension is the primary physiologic complication in patients with cirrhosis or other 
forms of chronic liver disease. Advanced fibrosis or cirrhosis of the liver or chronic portal vein 
thrombosis can lead to elevated pressures in the portal venous system.  This will manifest as 
abdominal ascites, hepatic hydrothorax, hepatorenal syndrome, portal hypertensive 
gastropathy and gastro-esophageal varices with or without bleeding. These complications are 
markers of decompensation and associated with significant morbidity and mortality.  
Approximately 50% of patients will die from liver related disease at 1 year after development of 
ascites. These complications often prompt referral for liver transplantation however many 
patients are not suitable candidate for liver transplant either due to advanced age, 
comorbidities such as recent malignancy or comorbid psychosocial issues such as ongoing 
alcohol use.   
 
1.1. Historical Treatments: 
Management of portal hypertensive complications has historically focused at controlling the 
specific complication. This has included diuretics for ascites or volume overload states and 
endoscopic band ligation of large or bleeding gastro-esophageal varices. Transjugular 
Intrahepatic Portosystemic Shunt (TIPS), an artificial shunt placed within the liver, is a method 
to control the complications of liver advanced liver disease by directly reducing the portal blood 
pressure. This has been demonstrated to be a critical tool in the management of ascites that is 
refractory to diuretic therapy or when gastro-esophageal variceal bleeding continues despite 
ongoing band ligation. TIPS has been shown to be highly effective at controlling these 
complications and has even demonstrated improved transplant free survival compared to 
standard medical management. Contemporary covered TIPS stents have also resulted in 
lower rates of stent occlusion and more recent controlled expansion stents have allowed 
operators to control the degree of portal pressure reduction at the time of placement. 
Complications have however been associated with TIPS placement. Patients with significant 
hepatic decompensation can develop worsening liver function resulting in rapid deterioration 
and death. Hepatic encephalopathy (HE) has been the major comorbidity associated with 
TIPS and has historically occurred at rates as high as 40-50%. Hepatic encephalopathy can 
have detrimental consequences on a patient’s quality of life and in some cases requires 
constraint or complete occlusion of the TIPS. Despite these complications, the overall use of 
TIPS has increased, and the indications have expanded. For example, elective TIPS can be 
used in patients with portal hypertension to permit safe abdominal surgery.  It has also been 
used in conjunction with portal vein thrombectomy in efforts to restore portal vein flow and 
permit liver transplantation. Data on the use of contemporary covered stents with controlled 
expansion has been limited however and patterns of use vary among centers.   
 
1.2. Study Device Description: 
All TIPS stents including VIATORR CX, regular VIATORR and bare metal stents placed during 
a TIPS procedure.   
 
2. 
Study Objectives 
2.1. Primary Objective(s) 

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The primary objective of the ALTA TIPS is to evaluate the current practice pattern of TIPS 
stents, the impact on patient outcomes and characterize the peri-procedural complications as 
well as the long-terms complications such as hepatic encephalopathy among all patients 
receiving a TIPS in a multi-center prospective registry.  
 
2.2. Secondary Objective(s) 
The secondary objectives of ALTA TIPS are: 
 
To assess patient overall survival and rates of liver transplantation 
 
To evaluate immediate TIPS related complications 
 
To quantify the rates of hepatic encephalopathy, characterize the severity and identify 
predictive risk factors 
 
To evaluate rates of recurrent portal hypertensive complications and need for revision 
of TIPS 
 
To evaluate the impact of TIPS on change in quality of life responses 
 
To assess the rates of cardiovascular outcomes after TIPS 
 
To assess the rates renal dysfunction or renal recovery after TIPS 
 
To assess differences in TIPS approaches on clinical outcomes in order to establish 
best practices for TIPS placement 
 
3. 
Study Design 
3.1. Study Design Schema 
Month 0 – TIPS insertion and registry enrollment 
Months 1, 3, 6, 12, 24 (minimal follow up) 
Months 36, 48, 60 (maximal follow up) 
 
 
3.2. Description of Study Design: 
This study is a prospective, multicenter, non-randomized single-arm study to evaluate the 
clinical outcomes and complications of TIPS stent use for the treatment of portal hypertension 
in patients all patients receiving TIPS. 
 
A maximum of 12 Clinical Sites (referred to as “Sites” in the remainder of this document) in the 
U.S. will participate in this study. Approximately 1000 patients will be enrolled in this study 
without a limit of number of subjects enrolled per Site. The anticipated accrual rate is 
approximately 33 subjects per month for a total accrual period of approximately 0 – 36 months 
and followed for at least 24 months after enrollment. 
 
Patients may be enrolled into the study provided all inclusion and no exclusion criteria are met 
as specified in Section 4. Subjects will be evaluated at the time of TIPS placement and at 
routine standard of care follow-up visits at months 1, 3, 6, 12, 24 and up through months 36, 
48, 60 if applicable. Total estimated duration of the study is 36 months of enrollment followed 
by 24 months of clinical follow up. 

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3.3. Study Endpoint(s) 
3.3.1. 
Primary Endpoint(s) 
Death or liver transplantation 
Cause of death defined as: 
 
direct procedural complication of TIPS placement (as determined by site 
PI) 
 
death from decompensation of underlying liver disease exacerbated by 
TIPS (as determined by site PI)  
 
death from other cause unrelated to TIPS or underlying liver disease (as 
determined by site PI) 
 
liver transplant, expected (listed or anticipated listing prior to TIPS) 
 
liver transplant, unexpected (not previously listed or anticipated listing prior 
to TIPS) 
3.3.2. 
Secondary Endpoint(s) 
 
Incidence and grade of hepatic encephalopathy 0-7 days after TIPS 
 
Incidence and grade of hepatic encephalopathy at all follow up visits 
 
Number of hospital admissions for hepatic encephalopathy 
 
Change in quality of life assessment after TIPS  
 
Number of paracentesis after TIPS 
 
Number of thoracentesis after TIPS 
 
Change in renal function as measured by serum creatinine and estimated 
glomerular filtration rate (eGFR)  
 
Change in platelet count after TIPS at follow up visits 
 
Change in traditional MELD and MELD-Na scores 
 
Change in protocol serial comprehensive echocardiogram parameters (e.g., 
markers of cardiac mechanics including myocardial strain, chamber size, left 
ventricular systolic function, diastolic function, right ventricular systolic 
pressure and right atrial pressure) at 0, 3, 6, 12 months 
 
Rate of TIPS revision requiring dilation of initial TIPS stent diameter 
 
Rate of TIPS revision to address stent occlusion 
 
Rate of TIPS constraint or complete occlusion 
 
4. 
Study Population 
4.1. Description of Population: 
Patients who are over the age of 18 who undergo a TIPS for any reason are eligible for 
screening for participation in the study. 
 
4.2. Inclusion Criteria: 
The patient is / has: 

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1. Age ≥18 at the time of informed consent signature. 
1. Capable of complying with Protocol requirements, including follow-up. 
2. An Informed Consent Form signed by Subject or legal representative. 
4.3. Exclusion Criteria 
The patient is / has: 
1. Prisoner 
2. Pregnant female at the time of informed consent signature. 
3. Undergoing TIPS placement as part of an investigational study outside usual clinical care 
 
5. 
Study Procedures/Evaluations 
5.1. Schedule of Events 
 
 
Screening/
TIPS 
(Month 0) 
Month 1 
(Routine 
Clinical Visit) 
Month 3 
(Phone Call 
if no Visit) 
Months 6, 
12 
Months 24, 
36, 48, 60 
(Routine 
Clinical 
Visits)X 
Informed Consent 
X 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
Physical Exam 
X 
X 
 
X 
X 
TIPS procedural 
assessment 
X 
 
 
 
 
Update Medical 
History 
 
X 
X 
X 
X 
Quality of Life 
Assessments* 
X 
X 
X 
X 
X 
Hepatic 
Encephalopathy 
Assessments* 
X 
X 
 
X 
X 
Duplex Ultrasound 
X 
X 
 
X 
X 
Standard of care 
comprehensive 
echocardiography# 
X 
X 
X 
X 
 
Outcome 
Assessment 
 
X 
X 
X 
X 
*study-related interventions 
#All echocardiogram images will be transferred to the coordinating center (Northwestern 
University) for future standardized analysis as part of the impact of TIPS on cardiac function 
ancillary study 
xVisit to be marked as “not complete” if no visit occurred; a telephone call will be made by the 
study team to review questionnaires and confirm outcomes. 
5.2. Informed Consent Process 

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All patients must provide informed consent prior to any study related procedures being 
performed. The case history (i.e., source documents/Subject chart) for each Subject shall 
document that such informed consent was obtained. The site-specific IRB approved consent 
form will be signed and personally dated by the Subject and the person who conducted the 
informed consent discussion. The original signed informed consent form will be retained in the 
Subject records. A copy of the informed consent document will be given to the Subject for their 
records. 
 
5.3. Pre-Screening / Screening 
All patients being referred for TIPS will be screened for enrollment.  Patients may be 
approached for before the scheduled TIPS procedure, at the time of TIPS or within 14 days 
after TIPS placement.   
 
5.4. Enrollment   
Patients will be considered enrolled after signing informed consent and provided 
inclusion/exclusion criteria at met. If consent is signed (either by the patient or surrogate) after 
the TIPS procedures (such as in the event of emergent TIPS) then the patient will be 
considered enrolled at the time of TIPS. Patients may not be enrolled however if 14 days have 
passed from time of TIPS before informed consent. 
 
5.5. Procedure 
There are no investigational procedures or interventions as part of this study. 
 
5.6. Repeat Interventions 
The treating physicians may decide a repeat TIPS or intervention is required as part of routine 
medical care. This is not considered investigational however this information will be captured 
are part of the registry.  
 
5.7. Follow-Up: 
Routine follow up visits with the treating physician are considered standard of care after TIPS 
placement.   
 
Month 1 (Day 14-45 post-TIPS) – As per standard of care, the treating physician will see the 
patient within one month after TIPS placement, obtain routine laboratory assessments 
(complete blood counts, complete metabolic panel and INR/Prothrombin Time) as well as 
obtain a liver ultrasound with doppler assessment to evaluate patency of the TIPS stent and a 
transthoracic echocardiogram to assess cardiac function. As part of the study, patients will be 
asked to complete quality of life assessments and be assessed for hepatic encephalopathy 
with grading.    
 
Month 31 month – A routine clinical visit may or may not occur depending on the treating 
physicians’ preference.  If it occurs, data similar to Month 1 will be collected as applicable.  If 
no visit occurs, then the study coordinators will contact the patient by phone to complete 
quality of life assessments and schedule standard of care comprehensive echocardiography.  

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Months 6, 12, 24, 36, 48, 60 - A routine clinical visit may or may not occur depending on the 
treating physicians’ preference.  If it occurs, data similar to Month 1 will be collected as 
applicable.  If no visit occurs, then the study coordinators will contact the patient by phone to 
complete quality of life assessments and schedule standard of care comprehensive 
echocardiography (Months 3, 6, 12) 
 
If a subject undergoes repeat TIPS or further intervention to the porto-venous system, then 
this information will be captured in an ad-hoc procedure visit.  Only details from the procedure 
note will be collected for study related purposes. The subject will continue following I the 
original study schedule based on the index TIPS date. 
 
If a subject dies or receives a liver transplant, then the subject will be considered having met 
the primary endpoint and study participation will be complete.  
 
5.8. Subject Withdrawal from the Study 
A Subject may withdraw from the study at any time and should notify the Investigator in this 
event. The Investigator may also withdraw the Subject from the study at any time based on his 
/ her medical judgment. 
5.9. Subject Lost to Follow-Up 
A Subject will be considered lost to follow-up and withdrawn from the study once they have 
missed two consecutive follow-up visits and three documented attempts have been made by 
the Investigator or designee to contact the Subject and emergency contact by phone. 
5.10. Subject Study Completion 
A Subject has completed the study when the primary endpoint of death or liver transplantation 
occurs, the subject completes Month 60 visit or if the study period of 5 years with a minimum 
of 2 years of post-TIPS follow up. Any Subject that does not complete these requirements due 
to voluntary withdrawal, physician withdrawal, or any other reason will be considered a 
withdrawal.  
 
6. 
Study Administration 
6.1. Monitoring 
Onsite site monitoring for this study will not be provided. Uploaded registry data will be 
reviewed centrally by the coordinating center (Northwestern University) and issues with data 
validation will be sent to individual sites to address any missing or aberrant data.  
 
6.2. Protocol Deviations 
A Protocol deviation is defined as any change, divergence, or departure from the study design 
or procedures of a research protocol. The Investigator is responsible for promptly recording 
and reporting Protocol Deviations to the lead site and the reviewing IRB per IRB policy. The 
lead site will determine the effect of the protocol deviation on the scientific soundness of the 
study and Subject safety and determine if additional reports or actions are required. Additional 
action may include Site retraining or Site termination. 

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The Investigator will not implement any changes to the protocol without first obtaining written 
agreement documented approval from the IRB sites, except in the event of an immediate 
hazard(s) to a Subject. The Investigator will report the Protocol Deviation in accordance with 
the applicable regulations.  
6.3. Protocol Amendments 
The Investigator will obtain IRB approval on all amendments in a timely manner.  
 
6.4. Access to Source Data/Documents 
Source data are defined as all information necessary for the reconstruction and evaluation of 
the Clinical Investigation. 
The Investigator will keep all study records, source data available for inspection by the IRB 
and regulatory authorities. 
6.5. Study Records Retention 
The Investigator will maintain complete, accurate and current study records as required by 
applicable regulatory requirements. Electronic records will be maintained during the study and 
for a minimum of 10 years after completion of the study.  
 
6.6. Publication Plan  
It is the intent of the lead site that the multicenter results of this study will be submitted for 
publication (in a peer reviewed journal). A publications and presentations committee will be 
established to review the multicenter results, develop and review all publications and 
presentations at the completion of the study. 
 
7. 
Data Collection and Submission 
 
The electronic data capture system (EDC system) for this study will be a REDCap database hosted 
and maintained by Northwestern University.  
7.1. Data Collection Methods  
Data will be abstracted from the subjects’ medical records and uploaded directly to REDCap.  
Questionnaire and hepatic encephalopathy assessments will be collected on paper case 
report forms stored in the subjects’ paper chart and uploaded to REDCap.  
7.2. Data Clarification and Correction 
Data verification and queries will be processed every 14 days.  Sites will have 14 days to 
respond to queries.  
7.3. CRF Completion Schedule 
Sites will be expected to upload data within 14 days of completion of the clinical visit.  
 

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8. 
Risk Assessment  
The Risk Assessment section must be consistent with the Risk-Benefit Analysis section of the 
Clinical Evaluation Plan, the Instructions for Use (see Hazards and Adverse Events section in IFU) 
and align with the Informed Consent Form. 
 
Describe possible interactions with concomitant medical treatments, any prohibited and restricted 
therapies during the study, or, any precautions which should be taken during the study for any 
therapies, if applicable. 
 
There are no anticipated Adverse Events with participation in this registry study.  There are no drug 
or device interventions that are investigational.  The TIPS procedure has been associated with 
complications that include bleeding, infection, heart failure, hepatic encephalopathy and/or death.  
All data collected will be abstracted from the subjects’ routine medical chart with additional phone 
call assessments for vital status and hospitalization outcomes.   
 
9. 
Adverse Events and Safety Monitoring 
9.1. Anticipated Adverse Events 
 
Anticipated Adverse Events are complications that are known to be associated with 
patients undergoing TIPS. See Section 8, Risk Assessment. No assessment of 
Adverse Events will be performed as this is an observational registry study. 
9.1.1. 
Subject Death 
Subject death is considered a primary endpoint in this study.  
 
10. Statistical Analysis 
10.1. Study Hypotheses 
This prospective, registry study will characterize the current patient population receiving TIPS, 
the primary and secondary indications, the role of TIPS either as a bridge to transplant or as 
definitive therapy, procedural complication rates, rates of hepatic encephalopathy after TIPS, 
and the degree of change of quality of life survey responses.  
 
10.2. Sample Size Assumptions 
Based on prior retrospective data, a sample size of approximately 1000 patients will be 
required in order to draw meaningful conclusions regarding different indications for TIPS.   
 
10.3. Sample Size Determination 
A sample size of 1000 patients will provide an acceptable range of indications for TIPS 
(approximately 400 for refractory ascites, 300 for variceal bleeding, 100 for both ascites and 
variceal bleeding 50 for hepatic hydrothorax, 50 for treatment of portal vein thrombosis and 
100 for treatment of portal hypertension management prior to elective invasive procedure such 
as abdominal surgery.  
 

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10.4. Data Analysis 
10.4.1. Timing of Analyses 
No a priori interim analysis will be planned as this is a registry study, however, 
ongoing data analysis will be performed for quality control and for generating 
preliminary data for abstract submissions and future grant proposals.  
10.4.2. Analysis Populations 
The data set will be analyzed based on etiology for liver disease, primary/secondary 
indications for TIPS, MELD sore before TIPS, intentions for liver transplant 
(listed/evaluated before TIPS vs not formally listed/evaluated for transplant). 
10.4.3. Statistical Analysis of Primary/Secondary Endpoint(s) 
Analyses of the registry cohort will involve estimation of primary/secondary outcome 
incidence event rates.  These event rates will be calculated for all subjects as well as 
stratified among the indications for TIPS, MELD sore before TIPS, intentions for liver 
transplant (listed/evaluated before TIPS vs not formally listed/evaluated for 
transplant). 
 
Risk factors for primary and secondary endpoints will be assessed. These risk factors 
will include medical history (including severity and etiology of underlying liver 
disease), laboratory results, technical factors associated with the TIPS procedure. 
The longitudinal analyses will utilize established methods of statistical models for 
longitudinal interval-scale responses, longitudinal categorical responses, and 
survivorship.  
 
Relative risk estimates will be calculated for the entire cohort as well as subgroups 
outlined above. 
 
 
11. Ethical and Regulatory Considerations 
11.1. Statement of Compliance 
The study will be conducted in compliance with this protocol, International Conference on 
Harmonization Good Clinical Practice E6 (ICH-GCP), ISO 14155:2011 and in accordance with 
Good Clinical Practice (GCP) requirements described in the current revision of ICH Guidelines 
and all applicable regulations, including current United States Code of Federal Regulations 
(CFR), Title 21, Parts 50, 54, 56, and 312 and Title 45, Part 164. Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in 
the current revision of the Declaration of Helsinki. This study will also be carried out in 
accordance with local legal requirements.  
 
 
11.2. Compliance Responsibilities 

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The Investigator will conduct the study in accordance with all applicable regulations and laws, 
any relevant agreements, the study protocol, and all approval conditions of the reviewing IRB. 
The Investigator will verify IRB approval is obtained prior to enrollment, maintained throughout 
the course of the study, and that all IRB reporting requirements are met. The Investigator is 
responsible for protecting the rights, safety, and welfare of Subjects under the Investigator’s 
care and for the control of devices under investigation. The Investigator is also responsible for 
ensuring that informed consent is properly obtained. 
 
The study shall be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki. 
11.3. Informed Consent 
The Investigator shall verify that all potential Subjects for this study are provided with a 
consent form describing this study and sufficient information to make an informed decision 
about their participation. 
The formal consent of a Subject, using the IRB approved consent form, must be obtained by 
the Investigator before that Subject undergoes any study-related procedure. The consent form 
will be signed and personally dated by the Subject and the person who conducted the 
informed consent discussion. The original signed informed consent form will be retained in the 
Subject records. A copy of the informed consent document will be given to the Subject for his 
or her records. Any significant, new information which emerges while the study is in progress 
that may influence a Subject’s willingness to continue to take part in the study will be provided 
to the Subject. 
 
The Investigator shall verify that documentation of the acquisition of informed consent is 
recorded in each Subject’s records in accordance with applicable regulations. 
11.4. Independent Ethical Review 
The Investigator shall not enroll any Subjects prior to obtaining approval for the study from a 
properly constituted independent IRB. 
 
The Investigator will submit the protocol, informed consent forms, other information to be 
provided to Subjects such as survey instruments or questionnaires, and any proposed 
advertising / recruitment materials, to the IRB for written approval. 
11.5. Conflict of Interest 
All Investigators will follow applicable laws and regulations as well as the conflict of interest 
policies of their Site and the reviewing IRB. 
 
11.6. Confidentiality 
All Subject records will be kept confidential to the extent provided by applicable laws and 
regulations. The study monitors and other authorized representatives of the Sponsor may 
inspect all documents and records required to be maintained by the Investigator, including but 
not limited to medical records. 
 
Such records may also be reviewed by the Site’s IRB as applicable. 
 

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The Investigator will inform the Subjects that their records will be reviewed. 
11.7. Study Discontinuation or Suspension 
There are no anticipated study related events that would result in study discontinuation or 
suspension given this is a registry study.  In the event the study sponsor withdrawals funding, 
then all new subject enrollment and subject follow up will cease.   
12. References 
1. Ascha, M., Hanouneh, M., Ascha, M. S., Zein, N. N., Sands, M., Lopez, R., & Hanouneh, I. A. 
(2016). Transjugular Intrahepatic Porto-Systemic Shunt in Patients with Liver Cirrhosis and Model 
for End-Stage Liver Disease ≥15. Digestive Diseases and Sciences, 1–9. 
http://doi.org/10.1007/s10620-016-4185-3 
2. Lerrigo, R., Beste, L. A., Leipertz, S. L., Green, P. K., Lok, A. S. F., Kogut, M. J., & Ioannou, G. N. 
(2016). Characteristics and outcomes of transjugular intrahepatic portosystemic shunt recipients 
in the VA Healthcare System. European Journal of Gastroenterology & Hepatology, 28(6), 667–
675. http://doi.org/10.1097/MEG.0000000000000604 
3. Boike, J., Ge, J., German, M., Jest, N., Morelli, G., Spengler, E., ... & Lai, J. (2018). 
Contemporary practice patterns and outcomes after transjugular intrahepatic portosystemic shunt 
placement: A multicenter US experience of 1146 patients. Journal of Hepatology, 68, S78. 
4. Casadaban LC, Parvinian A, Minocha J, et al. Clearing the confusion over hepatic 
encephalopathy after TIPS creation: incidence, prog- nostic factors, and clinical outcomes. Dig 
Dis Sci 2015;60(04): 1059–1066 
5. Srinivasa RN, Srinivasa RN, Chick JFB, Hage A, Saad WA. Transju- gular intrahepatic 
portosystemic shunt reduction using the GORE VIATORR controlled expansion endoprosthesis: 
hemodynamics of reducing an established 10-mm TIPS to 8-mm in diameter. Cardiovasc 
Intervent Radiol 2018;41(03):518-521  
6. RiChard, J., & Thornburg, B. New Techniques and Devices in Transjugular Intrahepatic 
Portosystemic Shunt Placement. Seminars in interventional radiology 2018;35(03):206-214. 
 
 
13. Study-Specific Appendices 
 
 
 

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Appendix 1. Schedule of Events 
 
 
Screening/
Enrollment 
(-2 
Months)1 
 
TIPS 
(Month 0) 
Month 1 
(Routine 
Clinical Visit) 
Month 3 
(Phone Call 
if no Visit) 
Months 6, 
12 
Months 24, 
36, 48, 60 
(Routine 
Clinical 
Visits) 
Informed Consent 
X 
 
 
 
 
 
Demographics 
and Medical 
History 
X 
 
 
 
 
 
Update Medical 
History 
X 
 
X 
X 
X 
X 
Physical Exam 
X 
 
X 
 
X 
X 
TIPS procedural 
assessment 
 
X 
 
 
 
 
Blood Tests2 
X 
X 
X 
X 
X 
X 
Global Health 
Questionnaire - 
PROMIS® Scale 
v1.2 – Global 
Health 
X 
X1 
X 
X 
X 
X 
PROMIS Item 
Bank v1.0 – 
Fatigue – Short 
Form 8a 
X 
X1 
X 
X 
X 
X 
Short Form 36 – 
Version 2 
X 
X1 
X 
X 
X 
X 
Chronic Liver 
Disease 
Questionnaire 
X 
X1 
X 
X 
X 
X 
Hepatic 
Encephalopathy 
Staging Tool 
X 
X1 
X 
 
X 
X 
Clinical Hepatic 
Encephalopathy 
Staging Scale 
X 
X1 
X 
 
X 
X 
Liver Duplex 
Ultrasound 
X3 
 
X 
 
X 
X 
Comprehensive 
echocardiogram 
X 
 
X 
X 
X 
 
Outcome 
assessment 
 
 
X 
X 
X 
X 
 
1. Screening and enrollment visit may occur up to 2 months prior to the TIPS procedure. This visit 
can also include quality of life and hepatic encephalopathy assessments. These assessments 
should be repeated at the time of TIPS if there is a significant change in medical history such as a 
hospitalization for any reason or an unplanned visit to a healthcare professional (office visit, 
urgent care, etc.). 

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2. Standard of care blood work should ideally include complete blood counts, complete metabolic 
profile (including hepatic panel) and coagulation panel (prothrombin time and INR). 
3. Liver duplex ultrasound should include the most recent ultrasound available – standard practice 
would suggest within 6 months of TIPS. 
4. Standard of care serial echocardiography will be assessed for change in cardiac function over 
time. All images will be transmitted to the coordinating center (Northwestern University) for central 
review as part of an ancillary study on cardiac function after TIPS. 
 
 

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Appendix 2. PROMIS® Scale v1.2 – Global Health 
 

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Appendix 3. PROMIS Item Bank v1.0 – Fatigue – Short Form 8a 
 
 

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Appendix 4. Short Form 36 – Version 2
 
Medical Outcomes Study Questionnaire Short Form 36 Health Survey 
 
This survey asks for your views about your health. This information will help keep 
track of how you feel and how well you are able to do your usual activities. Thank 
you for completing this survey! For each of the following questions, please circle 
the number that best describes your answer. 
 
1. In general, would you say your health 
is: 
 
Excellent 
1 
Very good 
2 
Good 
3 
Fair 
4 
Poor 
5 
2. Compared to one year ago, 
 
Much better now than one year ago 
1 
Somewhat better now than one year ago 
2 
About the same 
3 
Somewhat worse now than one year ago 
4 
Much worse now than one year ago 
5 
 
3. The following items are about activities you might do during a typical day. Does 
your health now limit you in these activities? If so, how much? 
(Circle One Number on Each Line) 
 
 
Yes, 
Limited 
a 
Lot (1) 
Yes, 
Limited 
a 
Little 
(2)  
No, Not 
limited 
at 
All (3) 
a. Vigorous activities, such as running, lifting 
heavy objects, participating in strenuous sports 
1 
2 
3 
b. Moderate activities, such as moving a table, 
pushing a vacuum cleaner, bowling, or playing 
golf 
1 
2 
3 
c. Lifting or carrying groceries 
1 
2 
3 
d. Climbing several flights of stairs 
1 
2 
3 
e. Climbing one flight of stairs 
1 
2 
3 
f. Bending, kneeling, or stooping 
1 
2 
3 

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g. Walking more than a mile 
1 
2 
3 
h. Walking several blocks 
1 
2 
3 
i. Walking one block 
1 
2 
3 
j. Bathing or dressing yourself 
1 
2 
3 
 
4. During the past 4 weeks, have you had any of the following problems with your 
work or other regular daily activities as a result of your physical health? 
(Circle One Number on Each Line) 
 
Yes 
(1) 
No 
(2)  
a. Cut down the amount of time you spent on work or other 
activities 
1 
2 
b. Accomplished less than you would like 
1 
2 
c. Were limited in the kind of work or other activities 
1 
2 
d. Had difficulty performing the work or other activities (for 
example, it took extra effort) 
1 
2 
 
5. During the past 4 weeks, have you had any of the following problems with your 
work or other regular daily activities as a result of any emotional problems (such 
as feeling depressed or anxious)? 
(Circle One Number on Each Line) 
 
Yes  
No  
a. Cut down the amount of time you spent on work or other 
activities 
1 
2 
b. Accomplished less than you would like 
1 
2 
c. Didn't do work or other activities as carefully as usual 
1 
2 
 
6. During the past 4 weeks, to what extent has your physical 
health or emotional problems interfered with your normal 
social activities with family, friends, neighbors, or groups? 
 
Not at all 
1 
Slightly 
2 
Moderately 
3 
Quite a bit 
4 
Extremely 
5 
 

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7. How much bodily pain have you had during the past 4 
weeks? 
 
None 
1 
Very mild 
2 
Mild 
3 
Moderate 
4 
Severe 
5 
Very severe 
6 
8. During the past 4 weeks, how much did pain interfere with 
your normal work (including both work outside the home and 
housework)? 
 
Not at all 
1 
A little bit 
2 
Moderately 
3 
Quite a bit 
4 
Extremely 
5 
 
These questions are about how you feel and how things have been with you during 
the past 4 weeks. For each question, please give the one answer that comes closest 
to the way you have been feeling. (Circle One Number on Each Line) 
 
9. How much of the time during the past 4 weeks . . . 
 
All of 
the 
Time 
Most 
of 
the 
Time 
A 
Good 
Bit of 
the 
Time 
Some 
of 
the 
Time 
 
A 
Little 
of the 
Time 
 
None 
of 
the 
Time 
a. Did you feel full of pep? 
1 
2 
3 
4 
5 
6 
b. Have you been a very 
nervous person? 
1 
2 
3 
4 
5 
6 
c. Have you felt so down in 
the dumps that nothing 
could cheer you up? 
1 
2 
3 
4 
5 
6 
d. Have you felt calm and 
peaceful? 
1 
2 
3 
4 
5 
6 
e. Did you have a lot of 
energy? 
1 
2 
3 
4 
5 
6 
 

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All 
of 
the 
Time 
Most 
of 
the 
Time 
A 
Good 
Bit of 
the 
Time 
Some 
of 
the 
Time 
 
A 
Little 
of the 
Time 
 
None 
of 
the 
Time 
f. Have you felt 
downhearted and blue? 
1 
2 
3 
4 
5 
6 
g. Did you feel worn out? 
1 
2 
3 
4 
5 
6 
h. Have you been a happy 
person? 
1 
2 
3 
4 
5 
6 
i. Did you feel tired? 
1 
2 
3 
4 
5 
6 
 
10. During the past 4 weeks, how much of the time has your 
physical health or emotional problems interfered with your 
social activities (like visiting with friends, relatives, etc.)? 
(Circle One Number) 
 
All of the time 
1 
Most of the time 
2 
Some of the time 
3 
A little of the time 
4 
None of the time 
5 
 
11. How TRUE or FALSE is each of the following statements for you.          
(Circle One Number on Each Line) 
 
Definitely 
True 
Mostly 
True 
Don't 
Know 
Mostly 
False 
Definitely 
False 
a. I seem to get sick a little 
easier than other people 
1 
2 
3 
4 
5 
b. I am as healthy as 
anybody I know 
1 
2 
3 
4 
5 
c. I expect my health to get 
worse 
1 
2 
3 
4 
5 
d. My health is excellent 
1 
2 
3 
4 
5 
 

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Appendix 5. Chronic Liver Disease Questionnaire 
 
THE CHRONIC LIVER DISEASE QUESTIONNAIRE (CLDQ)—QUALITY OF LIFE INDEX FOR 
PATIENTS WITH CHRONIC LIVER DISEASE 
 
This questionnaire is designed to find out how you have been feeling during the last two weeks. You will 
be asked about your symptoms related to your liver disease, how you have been affected in doing 
activities, and how your mood has been. Please complete all of the questions and select only one 
response for each question. 
 
QUESTIONS 
 
All of 
the 
time 
Most 
of the 
time 
A good 
bit of 
the 
time 
Some 
of the 
time 
A little 
of the 
time 
Hardly 
any of 
the 
time 
None 
of the 
time 
1. How much of the time during the 
last two weeks have you been 
troubled by a feeling of abdominal 
bloating? 
 
 
 
 
 
 
 
2. How much of the time have you 
been tired or fatigued during the 
last two weeks? 
 
 
 
 
 
 
 
3. How much of the time during the 
last two weeks have you 
experienced bodily pain? 
 
 
 
 
 
 
 
4. How often during the last two 
weeks have you felt sleepy during 
the day? 
 
 
 
 
 
 
 
5. How much of the time during the 
last two weeks have you 
experienced abdominal pain? 
 
 
 
 
 
 
 
6. How much of the time during the 
last two weeks has shortness of 
breath been a problem for you in 
your daily activities? 
 
 
 
 
 
 
 
7. How much of the time during the 
last two weeks have you not been 
able to eat as much as you would 
like? 
 
 
 
 
 
 
 
8. How much of the time in the last 
two weeks have you been 
bothered by having decreased 
strength?  
 
 
 
 
 
 
 
9. How often during the last two 
weeks have you had trouble lifting 
or carrying heavy objects? 
 
 
 
 
 
 
 
10. How often during the last two 
weeks have you felt anxious? 
 
 
 
 
 
 
 

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11. How often during the last two 
weeks have you felt a decreased 
level of energy? 
 
 
 
 
 
 
 
12. How much of the time during 
the last two weeks have you felt 
unhappy? 
 
 
 
 
 
 
 
13. How often during the last two 
weeks have you felt drowsy? 
 
 
 
 
 
 
 
14. How much of the time during 
the last two weeks have you been 
bothered by a limitation of your 
diet?  
 
 
 
 
 
 
 
15. How often during the last two 
weeks have you been irritable? 
 
 
 
 
 
 
 
16. How much of the time during 
the last two weeks have you had 
difficulty sleeping at night? 
 
 
 
 
 
 
 
17. How much of the time during 
the last two weeks have you been 
troubled by a feeling of abdominal 
discomfort? 
 
 
 
 
 
 
 
18. How much of the time during 
the last two weeks have you been 
worried about the impact your liver 
disease has on your family? 
 
 
 
 
 
 
 
19. How much of the time during 
the last two weeks have you had 
mood swings? 
 
 
 
 
 
 
 
20. How much of the time during 
the last two weeks have you been 
unable to fall asleep at night? 
 
 
 
 
 
 
 
21. How often during the last two 
weeks have you had muscle 
cramps? 
 
 
 
 
 
 
 
22. How much of the time during 
the last two weeks have you been 
worried that your symptoms will 
develop into major problems? 
 
 
 
 
 
 
 
23. How much of the time during 
the last two weeks have you had a 
dry mouth? 
 
 
 
 
 
 
 
24. How much of the time during 
the last two weeks have you felt 
depressed? 
 
 
 
 
 
 
 
25. How much of the time during 
the last two weeks have you been 
worried about your condition 
getting worse? 
 
 
 
 
 
 
 

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26. How much of the time during 
the last two weeks have you had 
problems concentrating? 
 
 
 
 
 
 
 
27. How much of the time have 
you been troubled by itching 
during the last two weeks? 
 
 
 
 
 
 
 
28. How much of the time during 
the last two weeks have you been 
worried about never feeling any 
better? 
 
 
 
 
 
 
 
29. How much of the time during 
the last two weeks have you been 
concerned about the availability of 
a liver if you need a liver 
transplant? 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 6. Hepatic Encephalopathy Staging Tool 
 
 
 
 

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Appendix 7. Clinical Hepatic Encephalopathy Staging Scale 

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