Hepatorenal Syndrome-acute Kidney Injury (HRS-AKI) Treatment With Transjugular Intrahepatic Portosystemic Shunt in Patients With Cirrhosis. A Randomized Controlled Trial
Phase: NA
Conditions: Cirrhosis, Liver, Hepatorenal Syndrome, Acute Kidney Injury, Ascites Hepatic
Sponsor: Jena University Hospital

 
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Liver-HERO 
Identification No. DE-22-00013779 
Clinical Investigation Plan 
According § 47 MPDG in conjunction with Art. 82 MDR  
Title: 
Hepatorenal Syndrome-acute kidney injury (HRS-AKI) treatment 
with transjugular intrahepatic portosystemic shunt in patients with 
cirrhosis. A randomized controlled trial 
Acronym: 
Liver-HERO 
Identification No acc. to 
§ 48 (3) MPDG: 
DE-22-00013779 
Study code of ZKS Jena: ZKSJ0146 
Registration No.  
(public register): 
Clinicaltrials.gov: NCT05346393 
 
Protocol Version, Date: 
Final V01 of 03-AUG-2022 
Sponsor 
Friedrich-Schiller-University Jena  
07737 Jena  
Sponsor Representative 
and Study Lead / Princi-
pal Coordinating Investi-
gator 
Prof. Dr. Cristina Ripoll  
Jena University Hospital, Clinic for Internal Medicine IV (Gastro-
enterology, Hepatology, Infectiology, Interdisciplinary Endoscopy) 
Am Klinikum 1, 07747 Jena, Germany 
Tel: +49 3641 9 32 42 29 
Fax: +49 3641 9 32 42 22 
Cristina.Ripoll@med.uni-jena.de  
Confidential statement: 
The information in this trial protocol is strictly confidential. It is for the use of the sponsor, investigator, 
trial personnel, ethics committee, competent authorities and trial subjects only. This trial protocol may 
not be passed on to third parties without the express agreement of the sponsor or the Principal Coordi-
nating Investigator (PCI).  
Please note that in this study protocol a reference to a particular gender is a reference to all genders. 

 
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Table of Contents  
1 
General .................................................................................................................................................... 5 
1.1 
Synopsis ............................................................................................................................................. 5 
1.2 
Abbreviations .................................................................................................................................... 8 
1.3 
Flow Chart ......................................................................................................................................... 9 
1.4 
Visit Schedule .................................................................................................................................. 10 
2 
Medical Background .............................................................................................................................. 11 
3 
Medical Device ...................................................................................................................................... 14 
3.1 
Background & rationale for use ...................................................................................................... 14 
3.2 
Study Device .................................................................................................................................... 16 
4 
Risk-Benefit-Assessment ....................................................................................................................... 16 
5 
Study Rationale ..................................................................................................................................... 17 
5.1 
Study Rationale and Hypothesis ...................................................................................................... 17 
5.2 
Objectives ........................................................................................................................................ 18 
5.2.1 
Primary Objective ....................................................................................................................... 18 
5.2.2 
Secondary Objectives .................................................................................................................. 18 
5.3 
Endpoints ......................................................................................................................................... 18 
5.3.1 
Primary Endpoint ........................................................................................................................ 18 
5.3.2 
Secondary Endpoints .................................................................................................................. 18 
5.3.3 
Choice of endpoints and time points for data collection ............................................................ 19 
6 
Study Design .......................................................................................................................................... 19 
6.1 
General ............................................................................................................................................ 19 
6.2 
Study Population ............................................................................................................................. 20 
6.3 
Randomization ................................................................................................................................ 20 
6.4 
Feasibility of Recruitment ................................................................................................................ 20 
6.5 
Time Schedule.................................................................................................................................. 20 
7 
Participation .......................................................................................................................................... 20 
7.1 
Study subjects .................................................................................................................................. 20 
7.1.1 
Inclusion Criteria ......................................................................................................................... 20 
7.1.2 
Exclusion Criteria ........................................................................................................................ 21 
7.1.3 
Representativeness of the study population .............................................................................. 22 
7.2 
Participating sites ............................................................................................................................ 22 
8 
Study Conduct ....................................................................................................................................... 22 
8.1 
Subject Screening and routine assessments for diagnosis of HRS-AKI ............................................ 22 
8.2 
Informed Consent ............................................................................................................................ 23 
8.2.1 
Obtaining informed consent ....................................................................................................... 23 
8.2.2 
Withdrawing informed consent .................................................................................................. 24 
8.3 
Baseline Visit ................................................................................................................................... 24 
8.4 
Randomization ................................................................................................................................ 25 
8.5 
Standard Treatment of HRS-AKI / Control Group ............................................................................ 25 
8.6 
TIPS Procedure / Interventional Group ............................................................................................ 25 
8.6.1 
General aspects .......................................................................................................................... 25 
8.6.2 
TIPS procedure ............................................................................................................................ 26 
8.7 
Follow-up-Visits ............................................................................................................................... 27 
8.8 
Study Assessments .......................................................................................................................... 28 
8.8.1 
Physical examination .................................................................................................................. 28 
8.8.2 
Laboratory Assessments ............................................................................................................. 28 
8.8.3 
Abdominal ultrasound ................................................................................................................ 28 
8.8.4 
Health-related Quality of Life Assessment ................................................................................. 28 
8.8.5 
Renal replacement therapy ........................................................................................................ 29 
8.8.6 
Occurrence of HCC and need for liver transplantation ............................................................... 30 
8.9 
Indication for TIPS in the control group ........................................................................................... 30 
8.10 
Collection of biosamples .................................................................................................................. 30 
8.11 
End of Participation ......................................................................................................................... 30 
8.11.1 
Regular end of study ................................................................................................................... 30 
8.11.2 
Premature end of study / discontinuation of study participation .............................................. 31 
8.12 
End of the Clinical Trial .................................................................................................................... 32 
8.12.1 
Regular End of the Trial .............................................................................................................. 32 
8.12.2 
Premature Termination, suspension of the trial, closure of sites ............................................... 32 
9 
Safety .................................................................................................................................................... 33 
9.1 
Definitions ....................................................................................................................................... 33 
9.1.1 
Adverse Events (AE) .................................................................................................................... 33 

 
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9.1.2 
Adverse Events of Special Interest (AESI) ................................................................................... 34 
9.1.3 
Serious Adverse Events (SAE) ..................................................................................................... 34 
9.1.4 
(Serious) Adverse Device Effects ((S)ADE) .................................................................................. 34 
9.1.5 
Device Deficiencies ..................................................................................................................... 35 
9.1.6 
Incidents ..................................................................................................................................... 35 
9.1.7 
Relatedness ................................................................................................................................. 35 
9.1.8 
Intensity ...................................................................................................................................... 36 
9.2 
Reporting ......................................................................................................................................... 36 
9.2.1 
AE Reporting ............................................................................................................................... 36 
9.2.2 
SAE Reporting to sponsor ........................................................................................................... 36 
9.2.3 
Reporting to authorities by sponsor ........................................................................................... 37 
9.2.4 
Device complaints ....................................................................................................................... 37 
9.3 
Risks associated with the Investigational Medical Device and Procedure ...................................... 38 
9.4 
Evidence in the Occurrence of Pregnancy during the Study Period ................................................. 39 
9.5 
Radiation protection........................................................................................................................ 39 
10 
Data Management ................................................................................................................................. 39 
10.1 
List of responsibilities / Training ...................................................................................................... 39 
10.2 
Screening ......................................................................................................................................... 40 
10.3 
Patient identification list ................................................................................................................. 40 
10.4 
Medical Device Accounting Log ....................................................................................................... 40 
10.5 
Investigator Site File (ISF) ................................................................................................................ 40 
10.6 
Case Report Form (CRF) ................................................................................................................... 41 
10.7 
Source Documents ........................................................................................................................... 41 
10.8 
Data handling .................................................................................................................................. 42 
10.9 
Data protection ............................................................................................................................... 42 
11 
Quality Assurance .................................................................................................................................. 42 
11.1 
Standardization and Validation ....................................................................................................... 43 
11.2 
Monitoring ...................................................................................................................................... 43 
11.3 
Data and Safety Monitoring Board (DSMB) .................................................................................... 43 
11.4 
Protocol Deviations ......................................................................................................................... 43 
11.5 
Audits and Inspections .................................................................................................................... 43 
12 
Statistical methods ................................................................................................................................ 44 
12.1 
Sample Size Estimation .................................................................................................................... 44 
12.2 
Statistical Analysis ........................................................................................................................... 44 
12.2.1 
Populations for Analysis .............................................................................................................. 44 
12.2.2 
Methods of Analysis .................................................................................................................... 44 
12.2.3 
Subgroup Analysis ....................................................................................................................... 45 
12.3 
Definition of Screening Failures, Drop-outs and switchers .............................................................. 45 
12.4 
Missed visits .................................................................................................................................... 45 
13 
Regulatory and Administrative Issues .................................................................................................... 46 
13.1 
General remarks .............................................................................................................................. 46 
13.2 
Ethic committees ............................................................................................................................. 46 
13.3 
Regulatory Authority ....................................................................................................................... 46 
13.4 
Insurance ......................................................................................................................................... 46 
13.5 
Amendments ................................................................................................................................... 47 
13.6 
Study Reports .................................................................................................................................. 47 
13.7 
Registration ..................................................................................................................................... 47 
13.8 
Funding ............................................................................................................................................ 47 
13.9 
Contracts with sites ......................................................................................................................... 47 
13.10 
Study report ................................................................................................................................ 47 
13.11 
Publication Policy ........................................................................................................................ 48 
14 
Definitions ............................................................................................................................................. 48 
14.1 
Baseline Creatinine .......................................................................................................................... 48 
14.2 
Ascites ............................................................................................................................................. 48 
14.3 
AKI ................................................................................................................................................... 48 
14.4 
Refractory ascites ............................................................................................................................ 48 
14.5 
Recurrent ascites ............................................................................................................................. 48 
14.6 
Diuretic sensitive ascites ................................................................................................................. 49 
14.7 
Variceal bleeding ............................................................................................................................. 49 
14.8 
Hepatic encephalopathy .................................................................................................................. 49 
14.9 
ACLF ................................................................................................................................................. 49 
14.10 
AKI-HRS reversal.......................................................................................................................... 50 

 
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14.11 
AKI- HRS partial reversal ............................................................................................................. 50 
14.12 
HRS recurrence ............................................................................................................................ 50 
14.13 
Diastolic dysfunction ................................................................................................................... 50 
14.14 
Post contrast medium AKI ........................................................................................................... 50 
14.15 
NYHA Classification ..................................................................................................................... 50 
14.16 
Milan criteria............................................................................................................................... 51 
14.17 
ECOG ........................................................................................................................................... 51 
15 
Literature .............................................................................................................................................. 52 

 
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Identification No. DE-22-00013779 
1 
General  
1.1 
Synopsis  
Study Title 
 
Hepatorenal Syndrome-acute kidney injury (HRS-AKI) treatment with transjugular 
intrahepatic portosystemic shunt in patients with cirrhosis. A randomized con-
trolled trial.  
Short Title  
Liver-HERO  
Sponsor  
Friedrich-Schiller-University  
Represented by the Dean of the Medical Faculty 
Who is represented by the Principal Coordinating Investigator  
Prof. Dr. Cristina Ripoll  
University Hospital Jena, Clinic for Internal Medicine IV (Gastroenterology, Hepa-
tology, Infectiology, Interdisciplinary Endoscopy) 
Am Klinikum 1, 07747 Jena 
Indication 
Hepatorenal syndrome-acute kidney injury (HRS-AKI) in patients with cirrhosis 
Study Population 
Patients with cirrhosis with ascites and HRS-AKI 
Medical Device  
under Investigation  
Gore® Viatorr® Controlled Expansion® Endoprosthesis  
Transjugular intrahepatic portosystemic shunt, CE-certified 
Primary Objective 
To evaluate if a transjugular intrahepatic portosystemic shunt (TIPS) implantation 
in patients with HRS-AKI improves survival.  
Secondary  
Objectives 
To evaluate whether TIPS implantation in patients with HRS-AKI  
 
improves renal function 
 
improves Health-related Quality of Life (HrQoL) 
 
has an impact on development of liver cirrhosis complications 
Study Design 
Prospective, multicenter, randomized controlled parallel-group study 
Randomization: 1:1 
Blinding: open 
Stratification: site and AKI stage   
Study Treatment 
Experimental group: transjugular intrahepatic portosystemic shunt (TIPS) 
Control group: Standard of care (terlipressin and albumin) 
Further study spe-
cific measures  
 
Questionnaires (SF-36, CLDQ)  
 
Biosamples (Blood, urine; optional: stool)  
Primary Endpoint 
12-month Liver transplant-free survival  
Secondary  
Endpoints 
1. 3-month liver transplant-free survival  
2. Indication for TIPS placement or TIPS revision during follow-up 
3. Development of further decompensation during follow-up 
4. Reversal of HRS-AKI at 3 and 12 months (vs. baseline), defined as return of 
serum creatinine level to ≤ 0.3 mg/dl (26.5 µmol/L).  
5. Partial response to treatment at 3 and 12 months (vs. baseline), defined as 
reduction of at least one AKI stage with decrease of serum creatinine to ≥ 0.3 
mg/dl (26.5 µmol/L) above the baseline value.  
6. In-hospital, 28-day and 90-day survival.  
7. Length of in-hospital-stay  
8. Relative changes in HrQoL (as measured by SF-36 and CLDQ) at 3 and 12 
months (vs. baseline) 
9. Need for renal replacement therapy  
10. Recurrence of HRS-AKI after treatment at 3 and 12 months 
11. Development of acute-on-chronic liver failure during follow-up 
12. Impact of the presence of intrinsic nephropathy as assessed by cystatin C 
and UnGAL on outcomes 
13. Association of pathophysiological mechanisms of cirrhosis with outcomes (in 
further studies) 
14. Assessment of safety: Number of AEs and SAEs in each group with special 
attention on ischemic hepatitis, the development of acute on chronic liver fail-

 
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Liver-HERO 
Identification No. DE-22-00013779 
ure and signs of heart failure. Laboratory assessments include sodium, po-
tassium, ALAT, ASAT, GGT, AP, bilirubin, albumin and INR and will be ana-
lysed descriptively as safety parameters.   
Inclusion criteria 
1) Patients with cirrhosis confirmed by histology or liver stiffness or with unequiv-
ocal signs in ultrasound, endoscopy and/or blood tests 
2) Clinically evident ascites due to portal hypertension (SAAG > 1.1 g/dL)  
3) HRS-AKI stages 2 or 3  
4) Planned vasoactive treatment for the management of HRS, as defined by the 
administration of terlipressin + albumin 
5) Age: ≥ 18 to ≤ 75 years old at the time of consent 
6) ECOG < 4 prior to hospital admission 
7) Subject has been informed of the nature of the study, is willing to comply with 
all required follow-up evaluations within the defined follow-up visit windows 
and has signed an Ethics Committee (EC) approved consent form.  
8) Female subjects of childbearing potential have a negative pregnancy test ≤ 7 
days before the procedure and are willing to use a reliable method of birth 
control for the duration of study participation. Female subjects will be ex-
empted from this requirement in case they are sterile, infertile, or have been 
post-menopausal for at least 12 months (no menses). A contraceptive method 
with a pearl index below 1% is assumed to be effective. 
Exclusion criteria 
 
1) Patients with signs of intrinsic renal disease as defined by proteinuria 
(> 500 mg per day), microhematuria (> 50 RBC per high power field) or signs 
of chronic renal disease on ultrasound. 
2) Recent or current use of nephrotoxic drugs (NSAIDS, Aminoglycosides or io-
dinated contrast medium) in the previous 72 hours before AKI diagnosis  
3) Improvement of renal function after 2 days of diuretic removal and plasma 
volume expansion with albumin 1 gr/kg 
4) Uncontrolled shock 
5) Patients with uncontrolled infection (defined by a 20 % increase in inflamma-
tory parameters (CRP, leucocytes or insufficient decrease of PMN in ascitic 
fluid < 25 % from baseline in the case of a SBP) despite 48 hours of antibiotic 
treatment. 
6) Patients with cardiac cirrhosis as defined by the development of cirrhosis in a 
patient with chronic heart failure due to a primary cardiac disease (ischemic 
cardiomyopathy, hypertensive cardiomyopathy, etc.) 
7) Patients with contraindications to TIPS placement (Bilirubin > 5 mg/dL, recur-
rent hepatic encephalopathy) 
8) Patients with cavernous portal vein thrombosis, splenic vein thrombosis or 
mesenteric vein thrombosis 
9) Patients with clinically significant cardiac disease (NYHA ≥ II)  
10) Patients with diastolic dysfunction grade 3. 
11) Patients with a reduced systolic function with an ejection fraction ≤ 50 % 
12) Patients with an acute variceal bleeding at the time of screening who have 
indication for pre-emptive TIPS and/or terlipressin.  
13) Patients with refractory ascites as defined by the International Ascites Club (< 
800 gr weight loss over 4 days in patients on low salt diet and high dose diu-
retics (spironolactone 400 mg /day and furosemide * 160 mg /day), or lower 
dose of diuretics with complications secondary to the use of diuretics such as 
hyponatremia, renal failure, hepatic encephalopathy. *equivalent dose of 
torasemide 40 mg/day 
14) Patients with hepatocellular carcinoma outside of the Milan criteria 
15) Patients with hepatocellular carcinoma within the Milan criteria in whom the 
tumor is located in the puncture tract. 
16) Patients with benign liver tumors (except regenerative nodules) which are lo-
cated in the puncture tract. 
17) Patients with other comorbidities that lead to an estimated life expectancy 
under 1 year.  

 
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Liver-HERO 
Identification No. DE-22-00013779 
18) The subject is currently enrolled in another investigational device or drug trial. 
19) Patients with pregnancy or lactation 
Number of Sites  
Approximately 10-15 sites in Germany  
Number of Subjects To be assessed for eligibility:                       n = 230 
To be assigned to the trial, i.e. recruited:    n = 124 (62 per arm) 
To be analyzed:                                              n = 112 (56 per arm) 
Dropout rate of 10% expected. 
Schedule 
Study related: 
Planned Start date: Q3/2022 
Planned Duration of enrolment: 24 months 
Estimated end date: Q3/2026 
Duration of intervention per patient: The procedure of the TIPS implantation 
(interventional group only) takes approximately 2 hours. This device is then per-
manently implanted. 
Follow-up per patient: 12 months (13 on-site visits: days 1-5, 12, 19 and 1, 2, 3, 
6, 9 and 12 months)  
Statistical analysis  Statistical methods used to compare groups for primary and secondary out-
comes:  
The primary endpoint will be analyzed based on the intention-to-treat (ITT) princi-
ple using a Cox regression adjusted for AKI stage. Drop-outs will be dealt with as 
independent right censored in the primary analysis. All patients will be analyzed 
in their randomization-group. A per-protocol analysis will be performed as sensi-
tivity analysis of the primary outcome. Drop-outs and C-to-T-switcher will be dealt 
with as independent right censored in this analysis without T-to-C-switchers (T = 
TIPS group, C = control group).  
Additional both analyses will be performed with requirement of TIPS implanta-
tion/revision in the follow-up as third endpoint. 
A Competing-Risk-Analysis in addition to the primary endpoint with the competing 
events death and liver transplantation will be performed. Reversal of HRS-AKI (vs 
baseline), partial response to treatment (vs baseline), need of renal replacement 
therapy and recurrence of HRS-AKI at 3 and 12 months will be assessed by lo-
gistic regression adjusted for AKI stage. In-hospital, 28-day and 90-day survival 
will be assessed by logistic regression adjusted for AKI stage. Changes in HrQoL 
at 3 and 12 months with respect to study baseline will be compared between 
groups by linear regression adjusted for AKI stage. 3-month liver transplant free 
survival will be analyzed using a Cox regression adjusted for AKI stage. Develop-
ment of further decompensations and Length of in-hospital-stay will be analyzed 
descriptively. Results will be interpreted in an exploratory manner. 
Methods for additional analyses, such as subgroup analyses and adjusted 
analyses:  
Effects (centers, presence/absence of intrinsic renal damage as determined by 
plasma and urine biomarkers, etiology of the underlying liver disease (alcoholic 
versus non-alcoholic)) and impact of the presence of intrinsic nephropathy (as 
assessed by cystatin C and UnGAL) will be checked with BIC. In case of signifi-
cance, results will be interpreted in an exploratory manner.  
Funding  
German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)  
Funding number: 431667134 
Reference number: RI 3205/1-1 
 
 
 

 
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1.2 
Abbreviations
ACLF  
Acute-on-chronic liver failure  
ADE 
Adverse Device Effect  
AE 
Adverse event 
AESI 
Adverse events of special interest 
AKI 
Acute kidney injury  
ALAT 
alanine aminotransferase 
AP 
Alkaline phosphatase 
ASAP  
As soon as possible  
ASAT 
Aspartate aminotransferase 
BIC 
Bayesian information criterion 
BCLC 
Barcelona Clinic Liver Cancer classifica-
tion 
BfArM 
Bundesinstitut für Arzneimittel und Me-
dizinprodukte (German Federal Institute 
for Drugs and Medical Devices) 
BfS 
Bundesamt für Strahlenschutz (German 
Federal Office for Radiation Protection)  
C 
Control group  
CA 
Competent Authority  
CI 
Confidence interval  
CIP  
Clinical investigation plan  
CKD 
Chronic kidney disease  
CLDQ 
Chronic liver disease questionnaire  
CM 
Contrast medium  
CPG 
Clinical practice guidelines 
CRA 
Clinical research associate  
CRF 
case report forms 
CRP 
C-reactive protein  
CT 
Computer tomography  
CTCAE 
Common Terminology Criteria for Ad-
verse Events 
DFG 
Deutsche Forschungsgemeinschaft  
DMIDS 
Deutsches Medizinprodukte-Informa-
tions- und Datenbank-System  
DSMB 
Data Safety Monitoring Board 
EASL  
European Association for the Study of 
Liver Diseases 
EBL 
Endoscopic band ligation  
EC 
Ethic Committee  
ECG 
Electrocardiogram  
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture  
EOS  
End of study  
EOT 
End of Treatment 
ePTFE 
Expanded Polytetrafluorethylen 
FU 
Follow up 
GCP 
Good Clinical Practice 
GDPR 
General data protection regulation  
GGT 
Gamma-glutamyltransferase 
Gy 
Gray  
HCC 
Hepatocellular cancer  
HR 
Hazard ratio  
HrQoL  
Health-related Quality of Life  
HRS 
Hepatorenal syndrome  
IAC 
International Ascites Club  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmoniza-
tion  
ICMJE 
International Committee of Medical 
Journal Editors 
IFU 
Instructions for Use (Gebrauchsanlei-
tung) 
IMP 
Investigational Medicinal Product 
INR 
International normalized ratio  
ISF 
Investigator Site File  
ITT 
Intention to Treat 
KDIGO 
The Kidney Disease: Improving Global 
Out-comes 
KKS 
Koordinierungszentrum für Klinische 
Studien (Coordinating Center for Clinical 
Studies)  
LA 
Left atrium  
LtFU  
Lost to Follow up  
LTX  
Liver transplantation  
LV  
Left ventricle 
MAP 
Mean arterial pressure  
MDCG 
Medical Device Coordination Group 
MDR 
Medical Device Regulation (VO (EU) 
2014/745)  
MedDRA 
Medical Dictionary for Regulatory Activi-
ties 
MPDG 
Medizinprodukterecht-Durchfüh-
rungsgesetz  
NAKI  
Non Acute Kidney Injury 
NSAIDS 
Nonsteroidal anti-inflammatory drugs 
OR 
Odds ratio  
OS 
Overall survival  
PC 
Post-contrast 
PMN 
Polymorphonuclear leukocytes 
PP  
Per protocol  
PTFE  
Polytetrafluoroethylene 
RAAS 
renin-angiotensin-aldosterone system 
RBC 
Red blood cells  
RTC 
Randomized controlled trial  
SAAG 
Serum-Ascites-Albumin-Gradient 
SADE 
Serious Adverse Device Effect  
SAE 
Serious adverse event 
SBP 
Spontaneous bacterial Peritonitis 
sCr 
Serume creatinine  
SF36 
Short Form 36 (Health questionnaire)  
SoC 
Standard of Care 
Sv 
Sievert  
T 
TIPS group  
TIPS 
transjugular intrahepatic portosystemic 
shunt 
TMF  
Trial Master File  
TR 
tricuspid regurgitation 
UADE 
Unexpected ADE  
uETG 
urinary ethyl glucuronide 
uNGAL 
Urine neutrophil gelatinase-associated 
lipocalin 
USADE 
Unexpected serious ADE  
ZKS 
Zentrum für Klinische Studien (Center 
for Clinical Studies)  

 
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Identification No. DE-22-00013779 
1.3 
Flow Chart  
Patient with suspicion 
of HRS-AKI
HRS-AKI 
confirmed  
 Start treatment according to Standard of Care with Terlipressin i.v. in continuous perfusion + Albumin 40 gr/ 24 h 
 Evaluate study eligibility /  Check remaining inclusion & exclusion criteria 
Max. 2 days to 
rule out other 
causes of renal 
failure 
Patient meets inclusion/ none of 
exclusion criteria: 
Obtain informed consent 
Randomization
Control group: 
Standard of Care 
Interventional group: 
TIPS 
Baseline visit 
 Medical history & demographic data 
 Physical examination 
 Obligate blood & urine sampling 
 Optional stool sampling 
 HRQoL Questionnaires 
 Continue Terlipressin + Albumin
 In case of non-response increase Terlipressin 
dosis every 48 to 72 h until maximum dosis or 
complications 
 Prepare TIPS placement (max. 3 d after randomization) 
 Continue Terlipressin + Albumin until TIPS placement
 End treatment with Terlipressin and Albumin after TIPS 
placement according to clinical judgement
TIPS placement
(+ control angiography 
within 72 h)
After at least 6h without 
Terlipressin! 
Follow-up Visits 
 Day 1-5 /  Day 12+19 /  Day 30 (1 Month FU)
 2, 3, 6, 9 and 12 MFU 
Assessments 
 At every FU visit: Physical examination, routine laboratory values, anamnesis  
 FU visits 1, 3, 6, 9, 12 MFU: abdominal ultrasound 
 FU visits 3, 6, 9, 12 MFU: blood and urine samples (obligate), stool sample (optional) 
 FU visits 3, 12 MFU: HRQoL questionnaires 
 Pause diuretics
 Rule out other etiologies of AKI
 Collect 24 h urine 
 Administrate albumin 1 gr per kg  
body weigth, max. 100 gr
 Perform heart ultrasound
Check 
possible inclusion/ exclusion 
criteria 
EOS
Liver 
transplant during FU? 
(both groups)
After  HRS-AKI confirmed maximum 
two days to check inclusion /  
exclusion criteria and randomization
 
 
 

 
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1.4 
Visit Schedule  
 
Pre-Screening within 
SoC / confirmation of 
HRS-AKI diagnosis   
Screening / Baseline 
FU Day 1-5  
FU Day 12 and 19 
FU Day 30 (1 MFU)  
FU 2 Months (2 MFU) 
FU 3 Months (3 MFU) 
FU 6 and 9 months (6 
MFU, 9 MFU) 
FU 12 Months (12 
MFU) 
Medical history / Anamnesis1  
X  
X 
Demographic data  
 
X 
 
 
 
 
 
 
 
Physical examination2 
X  
X 
X 
X 
X 
X 
X 
X 
X 
Routine laboratory examination 3 
X 
 
X 
X 
X 
X 
X 
X 
X 
24h urine  
X 
 
 
 
X  
 
 
 
 
uETG / alcohol consumption 
 
X  
 
X  
X  
X 
X  
X  
X  
Echocardiography 
X 
 
 
 
 
 
 
 
 
Abdominal ultrasound  
X 
 
 
 
X 
 
X 
X 
X 
Diagnostic paracentesis 
X 
 
 
 
 
 
 
 
 
Chest-X-Ray 
X 
 
 
 
 
 
 
 
 
Inclusion / Exclusion criteria  
 
X 
 
 
 
 
 
 
 
ICF 
 
X 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
Blood and urine sampling  
 
X 
 
 
 
 
X 
X 
X 
Optional stool sampling 
 
X 
 
 
 
 
X 
X 
X 
Terlipressin / Albumin treatment4 
 
X 
# 
 
 
 
 
 
 
TIPS  
 
X 
An-
gio5 
 
 
 
 
 
 
HrQoL Questionnaires (SF-36, CLDQ) 
 
X 
 
 
 
 
X 
 
X 
AE/SAEs  
 
X 
Length of in hospital stay  
 
X 
Liver transplantation performed  
 
X 
Requirement of Renal replacement ther-
apy  
 
X 
 
Total: 13 follow-up visits, all conducted on-site.  
 
 
                                               
1 Medical history / Anamnesis includes questions on occurrence of HCC, medication intake, actual status 
of HRS-AKI/ascites (previous and actual therapies/measures, decompensation), intake of low-salt diet  
2 Physical examination includes: Evaluation of orientation (time, person, place) and presence of flapping 
tremor, Evaluation of skin, Heart and lung auscultation, abdominal physical examination, presence of 
lower limb edema  
3 Laboratory values (assessed by local lab): 1) in blood: creatinine, sodium, potassium, ALAT, ASAT, 
GGT, AP, Bilirubin, Albumin, CRP, INR, hemoglobin, hematocrit, leukocytes, platelets, 2) in asci-
tes/pleural effusion; albumin, leukocytes, neutrophils, glucose, LDH, bilirubin.  
4 For interventional arm until TIPS placement and then will be progressively discontinued according to 
the managing physician’s decision. For SoC arm the treatment will be given beyond baseline (#), and 
continued according to the Clinical Practice Guidelines and the managing physician’s decision.  
5 Control angiography within 72 hours after TIPS placement (measurement should be performed after 
pausing Terlipressin for at least 6 hours)  

 
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2 
Medical Background  
Liver cirrhosis is a major cause of global health burden with 31 million disability adjusted life 
years and 1 million deaths worldwide in 2010 (Mokdad et al. 2014). In the natural history of 
liver disease, there are two clearly distinct clinical phases (D'Amico, Garcia-Tsao, and Pagliaro 
2006; de Franchis et al. 2022). First, in the compensated phase, the patient is asymptomatic 
or oligosymptomatic. These patients have no symptoms of the disease although they may have 
signs of cirrhosis such as varices, spider naevi or blood test abnormalities. These patients 
have median survival of about 15 years (D'Amico, Garcia-Tsao, and Pagliaro 2006). During 
the course of the disease, the patients develop ascites, variceal bleeding or hepatic encepha-
lopathy, which marks the transition to the decompensated phase of the disease (de Franchis 
et al. 2021).Patients who transition to the decompensated phase have a marked reduction in 
estimated survival with a median of approximately 2 years (D'Amico, Garcia-Tsao, and 
Pagliaro 2006). One of the main drivers of the development of decompensation is the presence 
of clinically significant portal hypertension as estimated by the hepatic venous pressure gradi-
ent (Ripoll 2007). In the decompensated phase, one can differentiate between patients who 
have a sole event as decompensating event (normally ascites or variceal bleeding) and those 
who develop more than one decompensating event (further decompensation). These patients 
are at risk of dying due to their liver disease (de Franchis et al. 2022). 
Ascites is the most frequent complication, which marks the transition to the decompensated 
phase of the disease (D'Amico et al. 2014). The pathophysiology of the development of ascites 
follows the peripheral vasodilation and systemic inflammation hypothesis (Arroyo et al. 1996; 
Bernardi et al. 2015). In portal hypertension, patients have a marked splanchnic vasodilation, 
which leads to activation of vasoactive mechanisms such as the renin-angiotensin-aldosterone 
system (RAAS), the sympathetic nervous system and the non-osmotic release of antidiuretic 
hormone. This leads to sodium retention in the nephron (mainly due to the activation of the 
RAAS). Together with the sodium, patients retain water, which ultimately leads to the accumu-
lation of fluid in the abdomen. The diagnosis of ascites is established by clinical examination 
and ultrasound. Other common causes of ascites such as malignancy should be ruled out. 
Measurement of the serum ascites-albumin gradient (> 1.1 g/dL) allows the diagnosis of a 
portal hypertension associated ascites with an almost 97 % diagnostic accuracy (Runyon et 
al. 1992). Initially, the treatment of ascites includes administration of aldosterone antagonists 
with loop diuretics as well as the recommendation to a low salt diet (European Association for 
the Study of the Liver. Electronic address and European Association for the Study of the 2018). 
As the disease progresses or in the context of acute events such as spontaneous bacterial 
peritonitis (SBP), ascites can accumulate and may require large volume paracentesis for 
symptomatic treatment. If the liver disease continues its progression, ascites control can be-
come increasing challenging requiring increasing doses of diuretics or due to the development 
of complications secondary to the administration of diuretics such as renal failure or electrolyte 
disturbances (namely potassium and sodium). In this situation, the ascites is considered re-
fractory and repeat large volume paracentesis with albumin reposition are needed. Refractory 
ascites is considered as further decompensation (de Franchis et al. 2021) and is associated 
with even a greater reduction of life expectancy (D'Amico et al. 2014).  Refractory ascites is 
defined by the IAC (International Ascites Club) as the presence of ascites which cannot be 
mobilized or early recurrence of which, despite intensive diuretic therapy and intensive diuretic 
treatment (Arroyo et al. 1996). Although large volume paracentesis remains the first line treat-
ment of refractory ascites, an alternative to repeat large volume paracentesis is the use of a 
transjugular intrahepatic portosystemic shunt (see further description in Ch. 3 and 8.6), which 
leads to an improvement in control of ascites and possibly a reduction in mortality (European 
Association for the Study of the Liver. Electronic address and European Association for the 

 
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Study of the 2018). Besides refractory ascites, there are other ascites-associated complica-
tions which can mark the transition to further decompensation such as SBP, dilutional hypo-
natremia or hepatorenal syndrome (HRS) (European Association for the Study of the Liver. 
Electronic address and European Association for the Study of the 2018; de Franchis et al. 
2021). 
Hepatorenal syndrome refers to a “functional” renal dysfunction that occurs in patients with 
cirrhosis and ascites due to reduced renal perfusion secondary to hemodynamic alterations in 
the arterial circulation and activation of endogenous vasoactive system (Angeli et al. 2019). 
Traditionally (Arroyo et al. 1996; Salerno, Gerbes, et al. 2007), one distinguished between 
hepatorenal syndrome type 1, which was a rapidly progressive renal failure (increase of crea-
tinine to greater than 2.5 mg/dL within two weeks) or hepatorenal syndrome type 2, which has 
a less rapid course, with a progressive increase of creatinine to greater than 1.5 mg/dL. Typi-
cally, hepatorenal syndrome type 1 takes place in the context of an acute event, whereas 
hepatorenal syndrome type 2 takes place in end-stage refractory ascites.  
In 2015, the International Ascites Club (IAC) adopted a new classification of renal dysfunction 
in cirrhosis (Angeli, Gines, et al. 2015). This was motivated due to the fact that increasing 
evidence was available suggesting that serum creatinine could underestimate the real renal 
function in cirrhosis due to muscle wasting, increased tubular secretion of creatinine, increased 
volume of distribution which may dilute creatinine and interference with bilirubin. Furthermore, 
the use of thresholds, do not allow the flexibility that is required in order to confront a dynamic 
situation like hepatorenal syndrome type 1. For these reasons, the ICA proposed adopting the 
criteria proposed by The Kidney Disease: Improving Global Out-comes (KDIGO) guidelines, 
which define AKI as any of the following: 1) increase in sCr by ≥ 0.3 mg/dl (≥ 26.5 µmol/L) 
within 48 h; or 2) increase in sCr to ≥ 1.5x baseline, which is known or presumed to have 
occurred within the prior 7 days; or 3) urine volume < 0.5 ml/kg/h for 6 h. In the specific context 
of cirrhosis, the ICA proposed a modification of the KDIGO criteria by using only the first three 
criteria given the fact that urine output in cirrhosis can frequently not properly reflect the renal 
function as patients with cirrhosis are frequently oliguric due to avid sodium retention or have 
a falsely high urine output due to the use of diuretics. Furthermore, ICA proposed that if a 
baseline value within the previous 7 days is not available, a serum creatinine within the last 3 
months before admission can be used.  
According to the relative increase of creatinine, one can differentiate different AKI stages (See 
Table 1: AKI stages). Noticeably, one can have AKI despite the fact that the renal function is 
still within the given normal range. Inside AKI Stage I, one could distinguish between those 
who achieved a peak over sCr ≥ 1.5 mg/dL (Stage Ib) and those who achieved a peak below 
this threshold (Stage Ia), the latter of which may have a similar survival as those without AKI 
and in whom the AKI is more frequently reversible (Piano et al. 2013; Fagundes et al. 2013). 
Table 1: AKI stages  
AKI Stage 
Definition 
AKI Stage 1 
increase in sCr ≥ 0.3 mg/dL (26.5 μmol/L) within 48h or an increase in 
sCr ≥ 1.5-fold to 2-fold from baseline6 
AKI Stage 2 
increase in sCr > 2-fold to 3-fold from baseline 
AKI Stage 3 
increase of sCr > 3-fold from baseline or sCr ≥ 4.0 mg/dL (353.6 μmol/L) 
with an increase ≥ 0.3 mg/dL (26.5 μmol/L) or initiation of renal replace-
ment therapy 
                                               
6 Baseline means here the time before development of AKI  

 
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Acute kidney injury (AKI) occurs in approximately 20 % of hospitalized patients with cirrhosis 
(Belcher et al. 2013; Angeli, Gines, et al. 2015) and has been associated to mortality in patients 
with cirrhosis who have been hospitalized in regular wards (Belcher et al. 2013; Piano et al. 
2013; Fagundes et al. 2013; Tsien, Rabie, and Wong 2013; Wong et al. 2013; de Carvalho et 
al. 2012; Angeli, Rodriguez, et al. 2015). Approximately 2/3 of acute kidney injury are due to 
renal hypoperfusion, which in turn can be divided into prerenal AKI (responsive to the admin-
istration of volume overload) or hepatorenal AKI (HRS-AKI) (unresponsive to the administra-
tion of volume overload (Belcher et al. 2013). Hepatorenal syndrome (HRS) type 1 (now in-
cluded in hepatorenal AKI) has a high mortality of almost 100 % when left untreated (Gines et 
al. 1993) and is frequently part of multiorgan failure (acute on chronic liver failure). Among the 
etiologies of AKI in cirrhosis, hepatorenal AKI has the worst prognosis (Martin-Llahi et al. 
2011).  
The standard of care for the treatment of HRS is based on the use of terlipressin and albumin, 
which leads to an improvement in renal function (Martin-Llahi et al. 2008; Sanyal et al. 2008; 
Boyer et al. 2016; Wong et al. 2021) and a reduction in short-term mortality (Facciorusso et al. 
2017; Allegretti et al. 2017), especially in those who have HRS reversal (Sanyal et al. 2008; 
Boyer et al. 2016). Despite the response to treatment, patients remain at risk for new episodes 
of HRS-AKI and death, so that liver transplantation should be considered in these patients 
(Angeli and Gines 2012). However, due to the limited organ availability and that many patients 
have contraindications to liver transplantation, this ideal possibility is feasible only in few pa-
tients (Brensing et al. 2000).  
The transjugular intrahepatic portosystemic shunt (TIPS) is placed under radiological control 
and communicates the portal vein with a hepatic vein, leading to a reduction in portal pressure. 
Use of this shunt is part of the standard of care in patients with variceal bleeding and refractory 
ascites (Rossle and Gerbes 2010). The use of transjugular intrahepatic portosystemic shunt 
(TIPS) in the context of HRS is rationally plausible as it reverses portal hypertension, one of 
the main drivers of HRS, nevertheless this remains highly controversial (Rossle and Gerbes 
2010). Indirect data suggests that it could lead to an improvement in renal hemodynamics and 
renal function (Jalan et al. 1997; Stadlbauer et al. 2008; Guevara et al. 1998; Busk et al. 2018). 
However, patients with HRS-AKI have frequently liver dysfunction and cardiac dysfunction that 
preclude TIPS placement ('EASL clinical practice guidelines on the management of ascites, 
spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis'  2010). Both the Eu-
ropean Association for the Study of Liver Diseases (EASL) and American Association for the 
Study of Liver Diseases guidelines underline the lack of evidence to recommend TIPS place-
ment in patients with HRS ('EASL clinical practice guidelines on the management of ascites, 
spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis'  2010; European 
Association for the Study of the Liver. Electronic address and European Association for the 
Study of the 2018; Biggins et al. 2021). The German guidelines suggest that TIPS placement 
in these patients may be considered (Gerbes et al. 2019).  
The most recent guidelines for management of AKI in cirrhosis propose that in patients who 
have an initial AKI stage Ib or greater (increase of at least in 0.3 mg/dL or 1.5-2 fold baseline 
Creatinine to a final Creatinine greater than 1.5 mg/dL), initially causes of AKI should be eval-
uated (screening and treatment of infection, treatment of hypovolemia and removal of all ne-
phrotoxic drugs, tense ascites) and treated respectively (Angeli, Gines, et al. 2015). If no cause 
is identified, diuretics (+/- beta-blockers) should be removed and volume expansion should be 
undertaken with albumin 1 gr per kg of body weight for at least 2 days. After this time period, 
the patient should be re-evaluated. If the AKI resolves, the patient should undergo close follow-
up without further treatment. In the case that AKI remains, evaluation of the cause of AKI 
should be done including the evaluation of the HRS criteria. If other causes are ruled-out and 
therefore the patient fulfills the HRS criteria, treatment with vasoconstrictors and albumin 

 
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should be initiated. This proposal implies that therapy would be started earlier in the setting of 
HRS-AKI, before achieving the threshold for HRS Type 1. This approach has not yet been 
evaluated in clinical trials.  
This study would be the first randomized controlled trial to fill this gap of knowledge. If the trial 
were to confirm our hypothesis, TIPS placement would have a clear role in clinical practice for 
the management of HRS-AKI since it could reduce mortality and morbidity and increase quality 
of life in patients with cirrhosis and HRS-AKI compared to the actual Standard of Care. 
3 
Medical Device  
3.1 
Background & rationale for use   
The implantation of a transjugular intrahepatic portal systemic shunt (TIPS) is an interventional 
radiological procedure, which was developed in the 1980s. Initial attempts were hampered by 
the short-lived patency of the shunt (Gordon et al. 1987). However, technical improvements of 
the stent as well as of the procedure itself ameliorated the outcomes of the patients (Conn 
1993). Although initially used for the treatment of variceal bleeding (Conn 1997; Rossle et al. 
1997), an improvement of ascites was detected early on, so that randomized controlled trials 
were performed in this setting (Rossle 2013). The use of TIPS proved to be very effective in 
the management of complications of portal hypertension, although the initial positive effect was 
dampened by pseudointima hyperplasia in the stent, which led to stent dysfunction and recur-
rence of portal hypertension and its complications in the bare stents. In the first decade of the 
present century, a new stent coated with polytetrafluoroethylene was developed. This stent led 
to an improved stent patency and is now the standard of care (Bureau et al. 2004). In recent 
years, ePTFE covered stents in which the diameter can be controlled have been developed 
and associated to a decrease in complications after TIPS placement (Praktiknjo et al. 2021). 
Presently, the use of TIPS is approved for the management of complications of portal hyper-
tension namely variceal bleeding and refractory ascites. The main complications associated to 
TIPS implantation are the development of hepatic encephalopathy, heart failure and worsening 
of the liver function (Boike et al. 2021; Rossle 2013).   
In the setting of variceal bleeding, TIPS has been traditionally used in the context of an acute 
variceal bleeding refractory to endoscopical and pharmacological treatment or for patients who 
have a recurrent variceal bleeding despite an adequate secondary prophylaxis with endo-
scopic band ligation (EBL) and beta-blockers (de Franchis 2010). This approach had the dis-
advantage that by the time the refractoriness of the bleeding was determined or the recurrent 
bleeding occurred, patients were frequently too sick to benefit from a TIPS implantation. In 
2010, a landmark paper was published which evaluated a modification of the timing of TIPS 
implantation in the context of variceal bleeding (Garcia-Pagan et al. 2010) . This study included 
high-risk patients with cirrhosis (Child-Pugh B with active bleeding or Child-Pugh C 10-13 
points) and acute variceal bleeding. Patients were randomized within the first 72 hours after 
admission in the hospital for the bleeding episode to TIPS or standard of care. The primary 
end-point of the study was a composite outcome of failure to control acute bleeding or failure 
to prevent clinically significant variceal rebleeding within 1 year after enrollment. From the pa-
tients who were randomized to TIPS, 1/32 compared to 14/32 of the standard of care group 
reached this negative outcome. The patients who received TIPS had also a significantly higher 
survival rate at six weeks (97 % vs 67 %) and one year (86 % vs 61 %) (p=0.001). The inci-
dence of hepatic encephalopathy was lower among patients who received TIPS (28 % vs 
40 %) although this difference was not statistically significant. Since the publication of this trial, 
a number of trials have confirmed the beneficial effect of the early application of TIPS in the 
context of variceal bleeding and have been summarized in a meta-analysis (Zhou et al. 2021; 
Nicoara-Farcau et al. 2021). 

 
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As previously mentioned, although TIPS was initially applied in the context of variceal bleeding, 
it was noticed early on, that patients who had ascites before TIPS had no ascites thereafter. 
The use of TIPS for patients with refractory ascites was evaluated in a number of randomized 
controlled trials, which showed an improvement in ascites although no advantages in survival 
could be detected (Lebrec et al. 1996; Salerno et al. 2004; Rossle et al. 2000; Gines et al. 
2002; Sanyal et al. 2003). In 2007, a meta-analysis with individual patient data included in 4 
RCT was performed (Salerno, Camma, et al. 2007). In this analysis, an improvement in survival 
was observed, despite the fact that the trials were performed before the implementation of 
PTFE-covered stents, which have significantly lower dysfunction rate than the bare stents.  
A more recent study evaluated the use of PTFE-covered stents at an earlier stage in the natural 
history of ascites (Bureau et al. 2017). In this study, 62 patients with ascites and at least 2 
large volume paracenteses (but less than 6) were randomized to TIPS or standard of care. 
The primary end-point was one year survival. The patients who were randomized to TIPS had 
a significantly better survival rate than those who were randomized to standard of care (93 % 
vs 52 %, p =0.003), without an increase in the rate of hepatic encephalopathy. This study sug-
gests that the benefits of TIPS are maintained when PTFE covered TIPS are used, and that 
patients with ascites benefit from a TIPS implantation earlier on in the disease. 
In the setting of hepatorenal syndrome, the use of TIPS is highly controversial. On one hand it 
is well established that implantation of TIPS in patients with cirrhosis leads to beneficial effects 
for the kidney such as an improvement in renal blood flow (Jalan et al. 1997), an improvement 
in renal autoregulation in response to the perfusion pressure (Stadlbauer et al. 2008) , an 
improvement in the parameters of activation of vasoactive system (Guevara et al. 1998), an 
improvement in renal function (Brensing et al. 2000; Guevara et al. 1998; Busk et al. 2018) as 
well as a reduced incidence of HRS-AKI (Salerno, Camma, et al. 2007). On the other hand, 
patients with HRS-AKI (hepatorenal syndrome type 1) frequently have acute-on-chronic liver 
failure with increased bilirubin and hepatic encephalopathy, which may preclude TIPS implan-
tation in these patients, due to high mortality (Brensing et al. 2000; Rossle and Gerbes 2010). 
Furthermore, cardiac dysfunction due to cirrhotic cardiomyopathy is proposed to have a central 
role in the development of HRS-AKI (Wong et al. 2011; Bernardi et al. 2015). TIPS leads to an 
increase in cardiac preload, so that its placement should be evaluated on an individual basis, 
especially in the presence of diastolic dysfunction (Rabie et al. 2009). The data that is available 
in the context of hepatorenal syndrome refers to the classical definition with type 1 and type 2. 
Most of the studies have focused on the use of TIPS in HRS type 2, which is per definition not 
HRS-AKI (Testino et al. 2003; Guevara et al. 1998; Gines et al. 2002; Ponzo et al. 2021). In 
the setting of HRS type 2, now named HRS-NAKI or HRS-CKD, the use of TIPS is effective 
and leads to an improvement of renal function (Testino et al. 2003; Guevara et al. 1998; Gines 
et al. 2002; Ponzo et al. 2021). 
Two pilot studies have evaluated the use of TIPS in classical HRS type 1. One included only 
patients who had had a response to midodrine, octreotide and albumin. From the 14 patients 
with HRS type 1, only 10 had a response to treatment, of which 5 could receive TIPS. After 6-
30 months of follow-up, all patients with TIPS were alive (1 with liver transplantation), while in 
the other group 3 had died (and 2 were alive with liver transplantation) (Wong, Pantea, and 
Sniderman 2004). A phase II study, evaluating TIPS in HRS (type 1 and 2) (n=41) had a sub-
group of patients with HRS type 1 (n=21) (Brensing et al. 2000). Ten patients were excluded 
because of advanced liver failure, so 31 patients finally received TIPS (14 with HRS type 1). 
Survival improvement, both in the whole group and the subgroup with HRS type 1, was ob-
served in the TIPS patients compared to those who were excluded from TIPS implantation, 
however the groups were by definition not comparable. A retrospective administrative data-

 
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base analysis has shown that patients with HRS who received a TIPS had decreased in-hos-
pital mortality [adjusted OR 0.43 (95 % CI 0.30-0.62] (Charilaou et al. 2020). Distinction be-
tween type 1 and type 2 HRS is not possible due to the study design.  
3.2 
Study Device  
The medical device used within this study is the Gore® Viatorr® Controlled Expansion® En-
doprosthesis produced by 
W. L. GORE & ASSOCIATES, INC. 
1505 North Fourth Street 
Flagstaff, Arizona 86004, United States  
who is represented within the European Union by  
W. L. GORE & ASSOCIATES B.V. 
Ringbaan Oost 152A 
5013CE Tilburg, Netherlands  
The manufacturer is not involved in any way in the clinical trial. The devices will be purchased 
by the sites and compensated by case payments. No special labelling will be applied. No spe-
cial storage conditions apply (“avoid exposure to extreme temperatures and humidity. Store 
under ambient conditions”). Each site is required to keep a Medical Device Accounting Log to 
ensure traceability regarding use of a specific device. 
This TIPS is comprised of an implantable endoprosthesis and percutaneous delivery catheter. 
Each device is for single-use only as the endoprosthesis will be permanently implanted after 
the procedure. One device per patient within the interventional group will be used. The inner 
diameter of the shunt can be chosen between 8, 10 and 12 mm by the treating physician.  
The device is CE-marked (Notified Body No. 2797) and indicated for use in the treatment of 
portal hypertension and its complications such as: variceal bleeding refractory to, or intolerant 
of, conventional therapies, inaccessible varices, gastropathy, refractory ascites, and/or hepatic 
hydrothorax.  
In the context of this study, the device will be used to treat another portal hypertension asso-
ciated complication: hepatorenal syndrome AKI in patients with ascites. This indication is be-
yond the traditional indication established for TIPS use according the device’s Instructions for 
Use (IFU). Nevertheless, the effect that is aimed for, namely a reduction in portal hypertension 
is the same as is in the traditional indications. The procedure for TIPS implantation will take 
place the same way as described within the IFU.  
Contraindications and warnings for the use of the study device are adequately addressed in 
the inclusion and exclusion criteria. Possible adverse events related to the study device are 
listed in Ch. 9.3. The described precautions are covered by the study-specific requirements for 
study sites and personnel (refer also to Ch. 7.2). Please refer to the actual IFU for further 
information such as technical and functional characteristics of the device. Each site will receive 
the IFU with the Investigator Site File (ISF).  
4 
Risk-Benefit-Assessment  
The treatment in the control group is the standard medical care in Europe. TIPS placement is 
an invasive procedure with inherent risks. The main complications associated to TIPS place-
ment can be divided according to problems which are associated to the technique per se [i. e 
puncture of other structures (bile ducts, hepatic artery, extrahepatic); use of contrast medium 
in patients with AKI] and problems which are associated to the shunting that is aimed with the 
TIPS (such as hepatic encephalopathy, ischemic hepatitis, ACLF and heart failure). Neverthe-
less, it has become standard of care for different complications of cirrhosis including refractory 

 
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ascites. Furthermore, although direct evidence supporting this approach is lacking, TIPS place-
ment is occasionally used in Germany in the context of HRS-AKI in cirrhosis. In the specific 
situation of HRS-AKI, there are two conditions which require special attention. Firstly, HRS-
AKI is commonly part of an acute on chronic liver failure which is mainly associated with a 
worsening of liver function. Two recent studies have evaluated the use of TIPS, in this case 
early or pre-emptive TIPS, in ACLF in the context of variceal bleeding and have observed 
survival benefit for the patients who received TIPS, so that ACLF is not necessarily an absolute 
contraindication for TIPS placement in this context (Nicoara-Farcau et al. 2021; Trebicka et al. 
2020). This study will provide further data on this point. The second specific safety issue in the 
context of HRS-AKI is that the presence of cirrhotic cardiomyopathy has, according to the pre-
sent hypothesis (Wong et al. 2011; Bernardi et al. 2015), a central role in the development of 
hepatorenal syndrome type 1 (HRS-AKI). In order to overcome this issue, every patient will 
undergo a heart ultrasound to screen for any relevant cardiac disease. Patients with relevant 
cardiac disease will not be included in the study.  
Due to the nature of the study and the TIPS placement and control, the specific risks for study 
participants is higher in the interventional than in the control group. For possible risks, please 
refer to Ch. 3 and 9.3. 
The study specific risks regarding all study participants are very low compared to the overall 
risk of complications and death in patients with liver cirrhosis: 
 
study specific measures include only blood sampling as invasive measure; however, close 
routine laboratory examinations are necessary in patients with cirrhosis and AKI-HRS. 
 
the other study specific measures such as urine and stool sampling, abdominal ultrasound 
and questionnaires may be burdensome, but not invasive and not associated with any 
direct risk for the patient.  
Also, the high number of on-site Follow-up Visits may be burdensome to some patients, but is 
necessary for safety reasons and to assess the disease course. Regular on-site visits (at least 
every 3 months) would be also scheduled for non-study patients.    
Possible interactions of the study procedures with other medical treatments are either the same 
as in routine (for the control group with Standard of Care) or highly unlikely (TIPS group).  
The following measures will be taken to assure a continuous risk-benefit-assessment:  
 
An independent Data Safety Monitoring Board (DSMB) will closely review safety data on 
a regular basis and will make recommendations regarding further conduct of the trial.  
 
The risk-benefit-assessment will be re-assessed by the principal coordinating investigator 
with every quarterly safety report to the BfArM.  
 
The frequent on-site follow-up-visits, especially within the first month after the procedure, 
guarantee early detection and countermeasures if adverse events occur 
Despite the possible risk, the risk incurred by the individual participant is acceptable and ethi-
cally justifiable taking into account the potential benefit for patients with liver cirrhosis.  
5 
Study Rationale  
5.1 
Study Rationale and Hypothesis  
TIPS implantation in patients with cirrhosis and portal hypertension leads to a reduction in 
portal hypertension, which in turn leads to a number of beneficial effects which ultimately lead 
to an improvement in renal function (Brensing et al. 2000; Guevara et al. 1998; Busk et al. 

 
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2018) such as increase in renal blood flow (Jalan et al. 1997), an improvement in renal auto-
regulation in response to the perfusion pressure (Stadlbauer et al. 2008) and an improvement 
in the parameters of activation of vasoactive system (Guevara et al. 1998). Traditionally the 
use of TIPS in patients with HRS has not been recommended due to the frequent association 
of HRS to ACLF and cirrhotic cardiomyopathy (European Association for the Study of the Liver. 
Electronic address and European Association for the Study of the 2018; Biggins et al. 2021).  
However, it is possible that an earlier TIPS implantation in patients with HRS-AKI stage 2 or 3 
(instead of waiting that the patient fulfills the classical definition of HRS type 1) has a better 
outcome. Indeed, previous indirect data as well as small pilot studies have suggested that 
TIPS may be helpful in selected patients with HRS-AKI. Further information from an interven-
tional study will help fill gaps of evidence-based knowledge in this area. 
5.2 
Objectives  
5.2.1 Primary Objective  
The primary objective of the study will be to evaluate the effect of TIPS implantation in patients 
with cirrhosis and ascites and hepatorenal syndrome associated acute kidney injury on 12-
month liver transplant free survival.  
5.2.2 Secondary Objectives  
The secondary aims are directed at evaluating the effect of TIPS on renal function as well as 
transplant free survival at 3 and 12 months, as recommended in the recent position paper 
regarding end-points in studies in decompensated cirrhosis (Sola et al. 2021). Furthermore, 
the impact of TIPS implantation on the development of liver cirrhosis complications and the 
effect of TIPS on quality of life will be evaluated.  
5.3 
Endpoints  
5.3.1 Primary Endpoint 
The primary endpoint is the 12-month liver transplant free survival. This endpoint has been 
recently recommended as the primary endpoint to be reported in trials in decompensated cir-
rhosis (Sola et al. 2021). This endpoint is a hard clinical endpoint, which is evidently patient-
relevant. We hypothesize that the 12-month liver transplant free survival is higher in patients 
in the interventional group.  
5.3.2 Secondary Endpoints  
Secondary endpoints include:  
1. 3-month liver transplant free survival  
2. Requirement of TIPS implantation or TIPS revision during follow-up. The accepted indica-
tions for TIPS implantation/revision are 
a. Pre-emptive TIPS for variceal bleeding in patients with Child-Pugh C cirrhosis (≤13 
points) or Child-Pugh B cirrhosis with active bleeding at endoscopy 
b. Recurrence of variceal bleeding in Child-Pugh A patients or Child-Pugh B patients 
without active bleeding at endoscopy despite adequate secondary prophylaxis with 
beta-blockers and endoscopic band ligation 
c. Refractory ascites as previously defined (see above)7 
d. Recurrent ascites as previously defined (see above)Fehler! Textmarke nicht definiert. 
e. Additionally, TIPS revision can be undertaken if there is a clinical suspicion of TIPS 
dysfunction 
                                               
7 this diagnosis can only be established if the patient is in a stable situation without complications such 
as bleeding and infection; diagnosis should be discussed with PCI on a case by case basis  

 
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3. Development of cirrhosis associated complications (further decompensation) during follow-
up: overt hepatic encephalopathy, refractory or recurrent ascites, dilutional hyponatremia, 
new AKI-HRS, variceal bleeding 
4. Reversal of HRS-AKI at 3 and 12 months (vs baseline), defined as return of serum creati-
nine level within 0.3 mg/dl (26 µmol/L) of baseline value.  
5. Partial response to treatment at 3 and 12 months (vs baseline), defined as reduction of at 
least one AKI stage with decrease of serum creatinine to ≥ 0.3 mg/dl (26 µmol/L) above 
the baseline value.  
6. In-hospital, 28-day and 90-day survival.  
7. Length of in-hospital-stay  
8. Relative changes in HrQoL (as measured by SF36 and CLDQ) at 3 and 12 months (vs. 
baseline) 
9. Need for renal replacement therapy  
10. Recurrence of HRS-AKI after treatment at 3 and 12 months  
11. Development of acute-on-chronic liver failure during follow-up. 
12. Impact of the presence of intrinsic nephropathy as assessed by cystatin C and UnGAL on 
outcomes 
13. Association of pathophysiological mechanisms of cirrhosis with outcomes (in further stud-
ies)  
 
Safety assessment / Secondary endpoint regarding safety:  
14. The incidence of adverse events in the TIPS patients compared to standard of care (with 
specific focus on ischemic hepatitis, ACLF and heart failure) 
5.3.3 Choice of endpoints and time points for data collection  
The primary endpoint and secondary endpoints 1-11 as well as the safety assessment are 
directly related to the study aims. Most chosen variables are either hard clinical endpoints 
(such as survival and need for renal replacement therapy) or endpoints which can be clearly 
measured by given scores and definitions (e.g. reversal or recurrence of HRS-AKI; please see 
Ch. 14). Assessment of underlying laboratory values will be done by local laboratories which 
are subject to regular quality controls (Ch. 11.1). Changes in Quality of Life (assessed by ques-
tionnaires) are inevitably purely subjective but due to the use of standardized questionnaires 
a valid and meaningful endpoint.  
The endpoints for exploratory analyses (such as analysis of cystatin C and UnGAL) are not 
directly related to the study aims but may provide additional information on future treatment of 
patients with cirrhosis and HRS-AKI.   
The time points for data collection cover both short-term and long-term events and are chosen 
carefully to make a qualified statement about the course of the disease and the effects of the 
treatment. Endpoints such as Questionnaires are only collected at certain time points, whereas 
others need a continuous monitoring of the study participant for assessing the endpoint-rele-
vant event (e.g. recurrence of HRS-AKI).   
6 
Study Design  
6.1 
General  
This study is a prospective, 1:1-randomized, open, multicenter interventional trial. The control 
group will be a parallel group, which is managed according to the standard of care.  
Due to the TIPS placement in the intervention group, no blinding is possible. Potential cross-
overs are taken into account (please refer to Ch. 12.3).  

 
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6.2 
Study Population  
Eligible for the study are patients with cirrhosis and ascites and confirmed HRS-AKI. Only pa-
tients able to give informed consent themselves will be included, no especially vulnerable per-
sons will be included or patients who are directly dependent on the investigator.  
6.3 
Randomization  
Patients will be randomized in a 1:1 ratio to the TIPS or the SOC group. The randomization 
will be stratified according to AKI stage (II or III) and sites to adjust for site effects and potential 
effects caused by the severity of the underlying disease. For treatment with terlipressin, it is 
known that the response rate decreases with higher creatinine values at the start of treatment. 
Randomization of a patient will be done via an online tool of ZKS Jena (PaRANDies) to ensure 
that group assignment is unbiased and concealed from patients and investigator staff. A sep-
arate detailed description of the procedure will be provided by ZKS Jena. 
6.4 
Feasibility of Recruitment  
It is intended to include 124 patients at approximately 10-15 sites in Germany within 24 months 
(corresponding to less than 1 patient/month/site). There is no limit to the number of subjects 
randomized at any individual study site. Sample size calculation is described in Ch. 12.1.  
6.5 
Time Schedule  
The estimated study duration is approx. 50 months. All enrolled and randomized subjects will 
be followed through 12 months. The enrollment period is expected to take 24 months. Enrol-
ment will be continuously monitored during the recruitment phase to allow timely countermeas-
ures in case of lower recruitment rate as expected.    
After the baseline visit, 13 follow-up on-site visits will be performed (see Ch. 1.4 and 8.7). 
All study assessments are listed in Ch. 8.8.   
Start of recruitment is planned for Q3/2022, Last Patient In is planned for Q3/2024. Last Patient 
Out (= end of study) with completed 12-months-Follow-up is planned for Q3/2025.  
7 
Participation  
7.1 
Study subjects  
7.1.1 Inclusion Criteria  
1) Patients with cirrhosis confirmed by histology or liver stiffness or with unequivocal signs in 
ultrasound, endoscopy and/or blood tests 
2) Clinically evident ascites due to portal hypertension (SAAG > 1.1 g/dL) *Serum-ascites-albu-
min-gradient in case of ascites. The presence of hepatic hydrothorax is considered as an asci-
tes equivalent. In this case instead of SAAG, the serum-pleural effusion-albumin-gradient > 
1.1g/dL 
3) HRS-AKI stages 2 or 38  
4) Planned vasoactive treatment for the management of HRS, as defined by the administra-
tion of terlipressin + albumin 
5) Age: ≥ 18 to ≤ 75 years old at the time of consent 
                                               
8 HRS-AKI stage 2 and 3 are patients who have an at least two-fold increase in serum creatinine within 
7 days before baseline in whom other causes of AKI have been ruled out (see exclusion criteria). If a 
baseline value within the previous 7 days is not available, a serum creatinine within the last 3 months 
(in a stable situation) before admission can be used.   

 
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6) ECOG < 4 prior to hospital admission 
7) Subject has been informed of the nature of the study, is willing to comply with all required 
follow-up evaluations within the defined follow-up visit windows and has signed an Ethics 
Committee (EC) approved consent form.  
8) Female subjects of childbearing potential have a negative pregnancy test ≤ 7 days before 
the procedure and are willing to use a reliable method of birth control for the duration of 
study participation. Female subjects will be exempted from this requirement in case they 
are sterile, infertile, or have been post-menopausal for at least 12 months (no menses). A 
contraceptive method with a pearl index below 1 % is assumed to be effective. 
7.1.2 Exclusion Criteria  
1) Patients with signs of intrinsic renal disease as defined by proteinuria (>500 mg per day), 
microhematuria (>50 RBC per high power field) or signs of chronic renal disease on ultra-
sound. 
2) Recent or current use of nephrotoxic drugs (NSAIDS, Aminoglycosides or iodinated con-
trast medium) in the previous 72 hours 
3) Improvement of renal function after 2 days of diuretic removal and plasma volume expan-
sion with albumin 1 gr/kg 
4) Uncontrolled shock 
5) Patients with uncontrolled infection (defined by a 20% increase in inflammatory parameters 
(CRP, leucocytes or insufficient decrease of PMN in ascitic fluid < 25% from baseline in 
the case of a SBP) despite 48 hours of antibiotic treatment. 
6) Patients with cardiac cirrhosis as defined by the development of cirrhosis in a patient with 
chronic heart failure due to a primary cardiac disease (ischemic cardiomyopathy, hyper-
tensive cardiomyopathy, etc.) 
7) Patients with contraindications to TIPS placement (Bilirubin > 5 mg/dL, recurrent hepatic 
encephalopathy) 
8) Patients with cavernous portal vein thrombosis, splenic vein thrombosis or mesenteric vein 
thrombosis  
9) Patients with clinically significant cardiac disease (NYHA ≥ II)  
10) Patients with diastolic dysfunction grade 3. 
11) Patients with a reduced systolic function with an ejection fraction ≤ 50 %.  
12) Patients with an acute variceal bleeding at the time of screening who have indication for 
pre-emptive TIPS and/or terlipressin.  
13) Patients with refractory ascites as defined by the International Ascites Club (less than 800 
gr weight loss over 4 days in patients on low salt diet and high dose diuretics (spironolac-
tone 400 mg /day and furosemide * 160 mg /day), or lower dose of diuretics with complica-
tions secondary to the use of diuretics such as hyponatremia, renal failure, hepatic enceph-
alopathy. *equivalent dose of torasemide 40 mg/day 
14) Patients with hepatocellular carcinoma outside of the Milan criteria (1 lesion maximum of 
5 cm diameter or 3 lesions with a maximum of 3 cm of diameter)  
15) Patients with hepatocellular carcinoma within the Milan criteria in whom the tumor is lo-
cated in the puncture tract. 
16) Patients with benign liver tumors (except regenerative nodules) which are located in the 
puncture tract  
17) Patients with other comorbidities that lead to an estimated life expectancy under 1 year.  
18) The subject is currently enrolled in another investigational device or drug trial. 
19) Patients with pregnancy or lactation 

 
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7.1.3 Representativeness of the study population  
The study population represents the overall population in this indication very well. The chosen 
inclusion and exclusion criteria are necessary to secure the diagnosis of HRS-AKI, to insure 
patient safety (e.g. contraindications for TIPS) and/or significance and validity of the collected 
data (e.g. ECOG ≤ 4 to ensure on-site-FU-visits, life expectancy > 1 year).  
7.2 
Participating sites  
The clinical trial will be carried out multicentric in 10-15 trial sites in Germany.   
The participating site must be equipped with the appropriate resources to fulfill the clinical 
study requirements as described in this CIP. The site selection includes but is not limited to 
the following criteria:  
 
The site is experienced in the management of patients with end-stage liver disease and 
performance of TIPS with PTFE-covered controlled expansion stents  
 
The site is experienced in the conduct of clinical trials regarding the treatment of end-stage 
liver diseases and experienced in the conduct of clinical trials with medicinal products  
 
The site is willing to participate in the trial and to undergo a monitoring and audit by sponsor 
and all relevant regulatory authorities. This includes the willingness to provide sponsor’s 
representatives with an access to the hospital records, study files and subject files as they 
pertain to the study 
 
The site agrees to comply with the CIP and all regulatory requirements 
 
The site has a sufficient number of patients with cirrhosis with ascites and acute kidney 
injury. 
 
The site has the possibility to perform the described study assessments 
 
The leading investigator has to sign the Study Protocol Acceptance Form 
 
All investigators at the site have to sign the financial disclosure forms 
Furthermore, TIPS placement is an intervention which should only be done in centers with a 
multidisciplinary team (including hepatologists, interventional radiologists (in the case the TIPS 
are placed by them), intensive care and general surgery with expertise in liver surgery (and 
ideally liver transplantation) and experience in the treatment of patients with decompensated 
cirrhosis. Indeed, the adjusted mortality rate after TIPS placement decreased in centers which 
placed more than 20 TIPS per year (Sarwar et al. 2018). The median number of TIPS placed 
in German centers with expertise in TIPS placement was 28/year (Steib et al. 2020). The pro-
cedure should be done by an interventional radiologist or a gastroenterologist/hepatologist who 
has experience in this procedure having performed at least 5 TIPS under supervision before-
hand and at least 15 TIPS without supervision.  
The leading investigator is responsible for choosing adequately trained and experienced study 
personnel, oversight, quality control at his/her site and confirms the availability of the neces-
sary technical, personnel and time resources at his/her site on the site qualification form.  
8 
Study Conduct  
8.1 
Subject Screening and routine assessments for diagnosis of HRS-AKI  
Potential subjects with cirrhosis and suspicion of HRS-AKI, aged ≥ 18 and ≤ 75 years will be 
screened for eligibility.  All potential patients will be documented on the study-specific patient 
screening log. If inclusion is not possible, the reason should be given.  
Patients potentially eligible for the study will be informed by an authorized and delegated in-
vestigator about the study and will be asked for his/her written consent. It is imperative that 

 
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written consent is obtained prior to any study-specific procedures. Nevertheless, most of the 
screening visit procedures are done within routine clinical management and not exclu-
sively related to study participation so they may be performed prior to informed written 
consent (please see Visit Schedule Ch. 1.4). Particular attention should be paid to possible 
benefits and risks, possible side effects, voluntary participation and to the right of revocation 
without giving any reason. Patients should be given enough time for their decision (see Ch. 
8.2.1).  
Standard of care treatment for AKI will be started as recommended (Angeli, Gines, et al. 2015), 
namely diuretics will be paused and albumin will be given at 1 gr/kg per day (up to to a maxi-
mum of 100 gr per day) over two days. During this time period and prior to the inclusion in the 
study the patients will undergo anamnesis and physical examination, blood tests to evaluate 
the severity of the liver disease, the degree of renal function impairment and its possible con-
sequences and to evaluate possible causes of renal function impairment. A 24-hour urine sam-
ple will be obtained as part of the routine evaluation of causes of renal function impairment, 
specifically to rule out intrinsic renal disease. Exhaustive evaluation of possible infections will 
be done including diagnostic paracentesis with evaluation of the PMN and fluid culture, urine 
culture and chest X-ray. A heart ultrasound will be performed to rule out cardiac causes of AKI. 
The administration of albumin and the above-mentioned examinations are required to rule out 
other entities that may be the cause of AKI including prerenal AKI. Lack of response to volume 
overload is defined as improvement of serum creatinine < 25 % from peak value and is re-
quired for the diagnosis of HRS-AKI. The patient can be checked for the other inclusion and 
exclusion criteria during this time. The investigator will review all the inclusion/exclusion criteria 
and will decide about eligibility of the patient for the study. Verification of inclusion/exclusion 
criteria will be documented. Once the diagnosis of HRS-AKI is established, and all inclusion 
criteria and none of the exclusion criteria are fulfilled, informed consent for participation in the 
study will be obtained.  
8.2 
Informed Consent  
8.2.1 Obtaining informed consent  
The subject’s participation is voluntary. Only adult subjects capable of giving informed consent 
are included. It is the responsibility of the investigator to obtain written informed consent from 
each patient participating in this study after adequate face-to-face explanation of the aims, 
methods, objectives and potential risks of the study (see Ch. 4, 9.3 and 9.5). The investigator 
must advise male patients to inform their female partner of childbearing potential about safe 
contraceptive measures. The informed consent has to be signed prior to any study-related 
assessment or procedure. All subjects will be informed of the aims, nature and scope of the 
study, the possible adverse events, the anticipated benefits of the treatment, the procedures 
and possible hazards to which he/she will be exposed. The subjects also will be informed about 
their rights and duties as study participant and the (scientific) processing of the captured data. 
All subjects have to be informed verbally and in writing by a study investigator. A patient infor-
mation sheet in comprehensible/non-technical language will be handed out and the subject will 
have enough time to decide to participate in the study as well as for clarification of questions 
by a study investigator. The patient gives consent to the participation in the diagnostic and 
therapeutic procedures of the study as well as in the processing and storage of data. This 
includes consent to inspections where records may be reviewed by authorized individuals (e.g. 
Monitor, Auditor) of the sponsor or surveillance authorities. If the subject does not consent to 
the collection, processing and storage of his/her data, inclusion in the study is not possible. 
Before informed consent is obtained, the investigator has to provide the patient sufficient time 
and opportunity to inquire about details of the study and to decide whether or not to participate 

 
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in the study. All questions about the study have to be answered to the satisfaction of the pa-
tient. The patient´s written consent must be obtained before any study-specific activities. 
Therefore, the informed consent form must be dated and signed in duplicate by the subject 
and the investigator conducting the informed consent conversation. Only physicians who are 
authorized and delegated by the local PI may inform the patients and obtain the consent for 
the study. The signed original is archived by the investigator and a copy must be provided to 
the subject together with the patient insurance conditions. Provision of consent will be con-
firmed in the patient file by the investigator. It must be clear to study subjects that he or she 
can withdraw his or her consent at any time without giving reasons and without jeopardizing 
his / her further course of treatment. No special incentive for study participation exists, only 
reasonable reimbursement of the travel expenses to the on-site FU visits will be provided.  
If the patient is eligible after careful consideration of all inclusion and exclusion criteria and 
informed consent is obtained, he or she can be randomized in the clinical study (group assign-
ment). 
In case that changes during the course of the study are necessary which affect the safety of 
the study participants or the study conduct for the study participants, a new patient informed 
consent form will be provided and the participants ask to re-consent. As it may be possible 
during the course of the study that study participants lose their ability to give informed consent 
by themselves due to their age or diseases, the sponsor will provide also an informed consent 
form for their legal representative (not applicable for first consent for study inclusion!).   
8.2.2 Withdrawing informed consent  
Study participants can withdraw their declaration of consent at any time and without giving 
reasons and thus terminate their participation in the study. In case of withdrawal of the consent, 
the patient’s study participation is terminated, thus, no further study or follow-up visits will be 
conducted. The end of the study and the reasons (if known) must be documented. The decision 
to withdraw consent from the study treatment must be without any disadvantage for the patient. 
A final routine examination should be performed. Further treatment and follow-up outside the 
study should be ensured (see also Ch. 8.11.2). 
8.3 
Baseline Visit  
Randomization is seen as part of the baseline visit, in which the following evaluations have to 
be performed: 
 
Demography (Age, Sex, Weight, Height, Racial background) 
 
Relevant Medical History with special focus on the history of the cirrhosis (including etiol-
ogy, previous clinical decompensation (variceal bleeding, ascites, spontaneous bacterial 
peritonitis, hepatorenal syndrome, hepatic encephalopathy, acute on chronic liver failure; 
based on actual standards/guidelines), previous therapies including beta-blockers, lactu-
lose, rifaximin, endoscopic band ligation, alcohol consumption 
 
Previous serum creatinine in stable situation (before development of HRS-AKI; = baseline 
serum creatinine) 
 
Health-related Quality of Life Questionnaires  
 
Women of childbearing potential must have a negative pregnancy (serum and/or urine) test 
within 7 days prior to randomization in accordance with the institutional standard of care. 
Female subjects who are surgically sterile or post-menopausal or elder than 50 years are 
exempt from having a pregnancy test. As a chest X-ray is usually performed as per routine 
in the context of AKI to rule out pulmonary infection, the pregnancy test is also usually done 
within routine.  

 
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8.4 
Randomization  
Patients who have signed the informed consent form and are considered eligible according to 
inclusion and exclusion criteria by the investigator will be randomized to one of the two the 
study groups: TIPS placement or only standard of care (terlipressin and albumin). Randomi-
zation will be performed centrally via an internet-based automatic system at the ZKS Jena (see 
Ch. 6.3). Randomisation should be done as soon as the inclusion and exclusion criteria are 
checked independently to the changes in creatinine after initiation of terlipressin. AKI stage for 
stratification is the stage which has been determined with HRS-AKI diagnosis.  
8.5 
Standard Treatment of HRS-AKI / Control Group  
Once the diagnosis of HRS-AKI is established, the standard of care will be administered ac-
cording to actual clinical practice guidelines(European Association for the Study of the Liver. 
Electronic address and European Association for the Study of the 2018) following the judge-
ment of the attending physician (see below). 
To bridge the time gap until the TIPS placement (scheduling for radiological interven-
tion; no longer than 72h), patients in the interventional group will also receive standard 
of care until TIPS is placed. After TIPS placement the medication is to be weaned and 
discontinued. 
Terlipressin will be started in continuous perfusion (2-4 mg per day) and will be increased in a 
stepwise fashion every 2-3 days in the case of non-response of serum creatinine (decrease in 
serum creatinine < 25 % from peak value). The maximum dose of terlipressin is 12 mg/day. 
Albumin will be given at a dose between 20-40 mg per day and adjusted according to the 
volume status of the patient. Treatment will be maintained until achieving a full-response (de-
fined by regression of serum creatinine to within 26.5 µmol/L from baseline value) or a maxi-
mum of 14 days. Special attention will be given to volume overload. This will include daily 
physical examination including pulmonary auscultation and if considered necessary by the 
managing physician chest X-ray or measurement of central venous pressure or inferior vena 
cava diameter on ultrasound. If clinical suspicion of mild volume overload albumin will be re-
duced, if clinical suspicion of severe volume overload albumin will be temporarily suspended. 
Veno-venous hemodialysis will be initiated according to the decision of the managing physi-
cian. It is recommended that patients who require veno-venous hemodialysis do not receive 
further treatment with terlipressin +/- albumin, although this will be decided by the attending 
physician. The patient will remain in the study for the intention to treat analysis regarding the 
main end-point. 
8.6 
TIPS Procedure / Interventional Group  
8.6.1 General aspects  
Placement of TIPS is an interventional radiological procedure. A central access over the right 
jugular vein is obtained. Through this central access, the (right) hepatic vein is catheterized 
and then a needle is introduced in the hepatic vein. Under fluoroscopic and sonographic guid-
ance, the needle is introduced through the liver parenchyma to the (right) portal vein branch. 
Once in the portal vein, the puncture tract (between the hepatic vein and the portal vein) is 
dilated with a balloon and the stent-graft is placed.  
TIPS leads to a long-term reduction in portal pressure. Portal hypertension has a central role 
in the development of HRS-AKI, indeed the standard treatment leads to a temporary reduction 
in portal pressure. It is possible that long term portal pressure reduction with TIPS is helpful in 
this condition. 

 
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Placement of a transjugular intrahepatic portosystemic shunt is a routine procedure in patients 
with portal hypertension associated complications, namely refractory variceal bleeding, recur-
rent variceal bleeding despite appropriate secondary prophylaxis and refractory ascites.  
8.6.2 TIPS procedure  
Before the procedure, an evaluation of the patient to confirm the indication and to evaluate 
possible contraindications should be performed. Although in the recent Baveno Consensus 
Conference, performance of a CT before TIPS is recommended for vascular mapping and 
evaluation of the presence of splanchnic vein thrombosis, due to the characteristics of the 
study population (presence of AKI and therefore an increased risk of contrast-medium associ-
ated AKI (Danziger et al. 2015)) in the present study, the decision to perform a CT will be done 
on a case-by-case basis by the attending physician.  
For the procedure, one needs a high-resolution flat-panel detector X-ray C-arm with digital 
subtraction angiography. Vital sign monitoring should be performed including non-invasive 
blood pressure, heart frequency, ECG and peripheral oxygen saturation. Furthermore, possi-
bility to invasively measure and record intravascular pressure should be available. Ultrasound 
is frequently used to facilitate vascular punctures including both jugular vein as well as portal 
vein (Steib et al. 2020). For the TIPS placement, angiographic catheters and guidewires are 
required for accessing the hepatic veins. A TIPS-needle is required to puncture the portal vein. 
An 8-10 mm controlled-expansion ePTFE covered stent-graft is required and different angio-
plasty balloons in order to dilate the stent-graft to achieve the aimed reduction in the portal 
pressure gradient. Portosystemic collaterals may be embolized especially if these lead to a 
steal phenomenon.  
Ideally, the TIPS placement should be done through the right hepatic vein into the right branch 
of the portal vein, around two centimeters away from the portal trunk bifurcation. In liver trans-
plant candidates (or patients in whom liver transplantation may become a possibility in the 
future), special care should be taken to avoid a too proximal stent-graft position (i.e. until vena 
cava inferior or right atrium) or too distal stent-graft position in the portal vein (i.e. too close to 
the confluens) which could hinder future vascular anastomosis.  
The aim of the TIPS placement is to lead a reduction in portal pressure gradient. The portal 
pressure gradient is calculated by the difference in the pressure between the portal vein and 
the vena cava inferior. This requires the measurement of the pressure in these vessels before 
(once the portal vein is punctured) and after the stent-graft placement. The stent-graft should 
be expanded in order to achieve a sufficient reduction in pressure with special care to avoid 
an excessive reduction in pressure, which would lead to increase in shunting and increase in 
the incidence of post-TIPS hepatic encephalopathy. Only ePTFE covered stent-grafts are 
permitted in the present study. Before TIPS placement, measurement of the pressure in 
the hepatic vein (free hepatic venous pressure), in the main portal vein and in the vena 
cava at the juncture with the hepatic veins and in the right atrium is mandatory. Immedi-
ately after TIPS placement, measurement of the pressure in the main portal vein and in 
the vena cava at the juncture with the hepatic veins and in the right atrium should be meas-
ured again. The portosystemic gradient is calculated as the difference between the pres-
sure in the main portal vein and the vena cava  (de Franchis et al. 2021). The procedure 
should preferably be done in deep sedation. The TIPS should be placed initially with an 8 
mm diameter. A second measurement of the portal pressure gradient should be done after a 
maximum of 72 hours without deep sedation. Mild sedation with low dose midazolam is 
permitted if necessary, although not recommended. In this procedure, the pressure in the 
main portal vein and in the vena cava inferior at the junction with the hepatic veins should 
be measured.  

 
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Figure 1: Localization of pressure measurements: A) measurement in the vena cava, B) measurement in the main 
portal vein. The TIPS is shown as the gray tube.  
If terlipressin is still being administered by the second measurement, this medication 
should be paused at least for 6 hours before the measurement. The aim is to reduce the 
pressure to 8-10 mmHg, depending on the clinical characteristics of the patient. In the case of 
a very high (> 24 mmHg) or very low (< 15 mmHg) initial gradient, the aim would be to reduce 
the pressure from 25-50 % (de Franchis et al. 2021). All measurements of pressure must be 
registered in paper or digital format for at least 15 seconds. A routine TIPS requires approxi-
mately 15-20 minutes of X-ray fluoroscopy. Different measures (such as reducing the field of 
exposure, reducing the rate of fluoroscopy) are undertaken to reduce exposure. A second 
measurement of the portal pressure gradient requires on average approximately 2 minutes of 
X-ray fluoroscopy. During the procedure, use of contrast medium should be minimized and if 
possible CO2 angiography should be used. Management of patients after TIPS should be done 
according to local standards, anticoagulation or antiaggregation are not recommended 
taking into account the increased risk of these treatments in the context of AKI.  
8.7 
Follow-up-Visits  
All study subjects will be followed up for 12 months, until death or other defined end of study 
(EOS; see Ch. 8.11 for definitions for regular and premature EOS).  
After the study treatment, the patient will continue his/her treatment on an in-hospital or outpa-
tient basis according to the clinical situation. Initially daily visits are planned including anam-
nesis and physical examination and routine laboratory. Afterwards the visits will be done on a 
weekly basis the first month, on a monthly basis until month 3 and then every 3 months until 
the end of the participation in the study.  
The study site has to make all efforts to schedule the visit in the appropriate timeframe. If the 
follow up cannot be completed within the time range, it has to be documented as a protocol 
deviation.  
The follow-up visits have to be performed on-site and within the following time frames:  
 
day 1-5 (+/- 0 days)  
 
day 12 and 19 (+/-1 day) 
 
day 30 = 1 month FU and 2 MFU (-2/+ 7 days)  
 
3, 6, 9 and 12 MFU (+/- 15 days)  
 

 
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As the FU visits within the first month after study inclusion are very close, no additional study 
visit for hospital discharge will be scheduled.  
8.8 
Study Assessments  
8.8.1 Physical examination 
At every study visit, a physical examination including evaluation of orientation (time, person, 
place) and presence of flapping tremor, evaluation of skin and mucosa, heart and lung auscul-
tation, abdominal physical examination and presence of lower limb edema. Current alcohol 
consumption has to be elevated. Intake of low salt diet will be evaluated.  
8.8.2 Laboratory Assessments  
Blood tests are performed at every visit.  
At every study visit, approx. 20 ml blood is taken from the study participants and analyzed in 
the local lab. Laboratory assessments include sodium, potassium, creatinine, ALAT, ASAT, 
GGT, AP, bilirubin, Albumin, INR, pH. These laboratory values are usually routinely taken for 
assessment of liver and kidney diseases. Wherever possible, data from routine blood tests are 
taken for the study to keep the burden for the patients as low as possible. 
8.8.3 Abdominal ultrasound  
Abdominal ultrasound will be performed at month 1, 3, 6, 9 and 12 to assess TIPS permeability. 
The ultrasound should be done with a machine with doppler ultrasound. In the ultrasound eval-
uation the following information should be recorded: 
 
Presence of ascites (none/subclinical/clinically evident) 
 
Suspicion of HCC 
 
Color Doppler ultrasound of the main portal vein, left branch of the portal vein, right branch 
of the portal vein (hepatofugal or hepatopetal flow) as well as the TIPS (normal/abnormal 
flow). 
 
Pulse wave Doppler measurement of the flow velocity in the main portal vein, at the begin-
ning, middle and end of the TIPS.  
8.8.4 Health-related Quality of Life Assessment  
Health-related Quality of Life (HrQoL) will be assessed using the two questionnaires SF-36 
and CLDQ at baseline and FU visits at 3 and 12 months.   
8.8.4.1 SF-36  
The Short Form 36 (SF-36) questionnaire is a globally established, validated and most widely 
used instrument for recording Patient Reporting Outcomes (PROs) in clinical trials and its va-
lidity has already been proven in numerous studies also in the context of chronic liver disease 
(Ware and Sherbourne 1992; McHorney, Ware, and Raczek 1993; Ware et al. 1999; 
Bonkovsky and Woolley 1999; Bryan et al. 1998). It is one of the most sensitive standardized 
status instruments and is often used in combination with disease-specific measurement instru-
ments. 
The SF-36 consists of 36 questions and is a general health questionnaire that provides a profile 
of two summary health components by assessing the patient's health status along 8 different 
dimensions: 
 
vitality - 4 questions 
 
physical functioning – 10 questions 
 
physical pain – 2 questions 

 
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 
general health perception – 5 questions 
 
physical role function - 4 questions 
 
emotional role function - 3 questions 
 
social role function - 2 questions 
 
mental well-being – 5 questions 
To evaluate the SF-36 questionnaire in version 1.0, all answers are first converted into given 
points using a scoring key. Then the average value of all questions of the respective health 
dimension (e.g. physical health) is calculated, resulting in eight average values for the eight 
dimensions. These describe the patient's state of health in the respective dimensions, which 
can then be evaluated using comparison tables (Hays, Sherbourne, and Mazel 1993; Ware 
2000). 
The possible score ranges from 0 to 100 points, with 0 points representing the greatest possi-
ble impairment of health, while 100 points indicate no health impairment ('36-Item Short Form 
Survey (SF-36) Scoring Instructions [Internet]. Rand.org.  [cited 28 March 2021].'  2021). 
Analysis of the components of the SF-36 reveals two distinct concepts: a physical dimension 
represented by the Physical Component Summary (PCS) and a psychological dimension rep-
resented by the Mental Component Summary (MCS) (Lins and Carvalho 2016). 
Within this clinical trial, the Version 1.0 of the SF-36 is used, as there is no validated German 
version available for SF-36 Version 2.0. 
8.8.4.2 CLDQ  
The Chronic Liver Disease Questionnaire (CLDQ) is a disease-specific questionnaire and was 
developed and assessed as specific instrument for measuring health related quality of life in 
patients with chronic liver disease (Younossi et al. 1999). This questionnaire asks about symp-
toms related to their liver disease, how it affects their activities and how their mood has been. 
It has shown to better reflect the impairment of HRQoL that takes place as the liver disease 
progresses. The german translation of CLDQ has been validated in patients with liver disease 
in Germany (Hauser et al. 2004). 
The questionnaire consists of 29 questions in 6 domains with 7 answer options for each ques-
tion, ranging from the worst (1; “all the time”) to the best (7; “none of the time”) possible func-
tion.  
The questions can be assigned to the following domains:  
 
Abdominal symptoms (AS): 3 questions (Items 1, 5, 17) 
 
Fatigue (FA): 5 questions (Items 2, 4, 8, 11, 13) 
 
Systemic symptoms (SS): 5 questions (Items 3, 6, 21, 23, 27) 
 
Activity (AC): 3 questions (Items 7, 9, 14) 
 
Emotional function (EF): 8 questions (Items 10, 12, 15, 16, 19, 20, 24, 26) 
 
Worry (WO): 5 questions (Items 18, 22, 25, 28, 29) 
8.8.5 Renal replacement therapy  
At every FU visit, it has to be assessed if renal replacement therapy (RRT) has been neces-
sary. If yes, type and start date of RRT have to be documented.  
In case of necessary RRT in patients in the control group, it is recommended to end the med-
ication therapy with terlipressin and albumin, however this will be decided by the attending 
physician on a case-by-case basis. 

 
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8.8.6 Occurrence of HCC and need for liver transplantation  
At every FU visit, it has to be assessed if the patient developed a hepatocellular carcinoma 
(HCC) and if a liver transplantation is necessary or has already been performed.  
FU ends with liver transplant (both study arms), no further study related FU visits will be con-
ducted thereafter. Patients will be followed up according to routine at the respective sites.  
8.9 
Indication for TIPS in the control group  
One of the study end-points will be the development of a hard indication for TIPS placement 
(control group) or the need of TIPS revision (intervention group). TIPS placement and TIPS 
revision is indicated in the case of development of: 
 
massive bleeding requiring placement of an ELLA Danis stent or Sengstaken-Blakemore 
or Linton balloon (emergency TIPS)  
 
esophageal variceal bleeding (in patients with Child Pugh B 7-9 points and active bleeding 
at endoscopy or patients with Child Pugh C 10-13 points) (pre-emptive TIPS) 
 
recurrent esophageal bleeding despite adequate secondary prophylaxis with beta-blockers 
and endoscopic band ligation 
 
refractory ascites as defined by the IAC (see Ch. 14.4) (Arroyo et al. 1996) 
 
recurrent ascites as defined by the need of 3 large paracentesis within 3 months (in stable 
situation). Only paracentesis that take place in a stable situation, namely without concur-
rent infection, without AKI, without bleeding, etc. will be considered (European Asso-
ciation for the Study of the Liver. Electronic address and European Association for the 
Study of the 2018).  
If a patient randomized into the control group develops indication for TIPS (except emergency 
TIPS or pre-emptive TIPS) during Follow-up, the treating study physician should consult the 
Principal Coordinating Investigator to discuss the indication before TIPS implantation.  
8.10 Collection of biosamples  
Blood and urine and optional stool samples for the central laboratory will be obtained at base-
line, 3, 6, 9 and 12 months. These will be obtained in order to evaluate in further research the 
pathophysiological mechanisms involved in the development of HRS-AKI such as the activa-
tion of vasoactive parameters (Renin, Aldosterone, Noradrenalin) and bacterial translocation 
(IL-6, Endocab, LBP). An initial planned exploratory subanalysis will be performed according 
to blood and urine markers of functional or organic renal impairment (Cystatin C and uNGAL). 
Stool samples will be optionally collected for future exploratory analysis regarding the influence 
of the gut microbiome on outcomes. Embedded future substudies for research on HRS will 
have their specific protocol and will obtain specific approval from the ethic committee sepa-
rately.    
The samples will be stored at the sites at -80ºC until end of the study and shipped on dry ice 
to the central laboratory. For further sample processing, please refer to the separate manual.  
8.11 End of Participation  
8.11.1 Regular end of study  
The regular end of the study for the study participant is one of the following, whatever occurs 
first:  
 12 Month-FU  
 Death  
 Liver transplantation  

 
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After occurrence of EOS, no further FU visits are done. Once the patient finalizes the follow-
up in the study, he/she will return to routine clinical follow-up in the outpatient clinic every 3-6 
months depending on the clinical condition including screening ultrasound every 6 months 
when indicated. 
Please note that with liver transplantation the medical device in the interventional group is 
explanted. 
8.11.2 Premature end of study / discontinuation of study participation  
Premature end of the study / discontinuation of study participation is defined as:  
 Lost-to-Follow-up  
 Withdrawal of informed consent (see. Ch. 8.2.2)  
 Withdrawal at the investigator’s or sponsor’s discretion   
A subject will not be considered lost to follow-up unless all efforts to obtain compliance are 
unsuccessful. At a minimum, the effort to obtain follow-up information must include 3 attempts 
to make contact with the subject via telephone and if contact via telephone is not successful, 
a certified letter from the investigator must be sent to the subject’s last known address. Should 
both telephone and mail efforts to contact the subject be unsuccessful, the subject’s general 
practitioner should be contacted. All contact efforts to obtain follow-up information must be 
documented.  
If a patient permanently discontinues and is unwilling or unable to attend regular study visits 
at the study site, the investigator and patient must determine which of the follow-up options the 
patient is able and willing to comply with. The patient will be approached to provide consent 
for further follow-up at the time of withdrawal. Options for follow-up of these patients are listed 
below, in descending order of preference: 
1. Patient is unable or unwilling to attend this regular study visit, but will attend further study 
visits   
2. Patient will be contacted by phone at the regular study visit intervals. 
3. Patient allows his/her general practitioner (with a signed release of medical information) 
or a family relative to be contacted at the regular study visit intervals. 
4. Patient will be contacted once at the end of the study. 
5. No further contact. 
For patients who withdraw consent for any kind of follow-up, the patient’s vital status will be 
obtained at study end through applicable information sources according to local guidelines and 
as allowed by local regulations. Although a subject is not obliged to give his/her reason(s) for 
withdrawing prematurely from a study, the investigator should make a reasonable effort to 
ascertain the reason(s), while fully respecting the subject's rights. This information might be 
relevant for analysis in case of AE as reason. If provided, the reason for withdrawal has to be 
recorded in the eCRF and in the patient's medical records. 
The investigator may terminate the study participating for the patient in the case of lack of 
compliance or other circumstances, which make study-relevant follow-up impossible. The 
sponsor might also decide to withdraw a patient from study participation (reason has to be 
specified e.g. major protocol violation). If a patient decides to discontinue the study after ran-
domization (control or interventional group) but before respective start of treatment patients 
will be considered as drop-outs.  

 
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8.12 End of the Clinical Trial  
8.12.1 Regular End of the Trial  
The regular end of the trial is defined as the date when the last patient has completed the FU 
visit after 12 months (Last Patient Out (LPO)).  
The sponsor reports the completion of the trial to the relevant regulatory authority. The sponsor 
submits the final report to the regulatory authority within 12 months after completion or prem-
ature termination of the clinical trial. The sponsor will also submit the final report to the EC, if 
required. 
8.12.2 Premature Termination, suspension of the trial, closure of sites  
A premature discontinuation of a single study site or of the study as a whole must be docu-
mented adequately with reasons being stated and information must be conveyed according to 
national requirements (e.g., EC, CA and local regulatory authorities). The Sponsor/coordinat-
ing investigator, the Competent Authority (BfArM) and the Independent Ethics Committee have 
the right to discontinue this study at any time for reasonable medical or administrative reasons 
in any single study site, although this should occur only after consultation between the involved 
parties. Possible reasons for termination of the study at a study site could be but are not limited 
to: 
 
Unsatisfactory enrolment with respect to quantity or quality 
 
Inaccurate or incomplete data collection 
 
Unexpected accumulation of SAE/AE 
 
Major failure to adhere to the study protocol 
In addition, the investigator might terminate the study at their site prematurely, e.g. for unfore-
seeable circumstances which preclude the continuation of the clinical study at the site or the 
investigator considers that the resources for continuation, e.g. personnel or time, are no longer 
available. 
If the investigator terminates or suspends a trial site without prior agreement of the sponsor, 
the investigator will promptly inform the sponsor and the EC and will provide the sponsor and 
the EC with a detailed written explanation of the termination or suspension. Should a center 
be closed prematurely, all trial materials (except documentation that has to remain stored at 
center) must be returned to the sponsor. 
The Sponsor, the authorities and the EC have the right to terminate this clinical study as a 
whole prematurely at any time for reasonable medical or administrative reasons. For example: 
 
Unexpected accumulation of SAE/AE 
 
Change of risk-benefit considerations 
 
The reason for premature termination of the entire study could be also: 
 
A new finding concerning significant superiority or inferiority in one of the treatment arms, 
with regard to the primary endpoint data  
 
Coordinating investigator’s decision after unacceptable risks and toxicities have oc-
curred, upon recommendation of the Data Safety Monitoring Board (DSMB)  
 
The new scientific findings during the course of the study which either give the answer 
to the primary and secondary endpoints or indicate that the further continuation of the 
study is not meaningful any more.  
 
The study does not prove feasible any longer 
 
In case of contract termination by the financial sponsor    
 
If the DSMB raise concerns about the safety of the TIPS device in this indication/study 
population  

 
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Any premature termination or suspension of the trial must be discussed with the DSMB as 
appropriate.  
If the trial is prematurely terminated or suspended, the sponsor will promptly inform the inves-
tigators, the respective regulatory authority and the EC according to § 64 (2) MPDG within 15 
days, and provide the reason(s) for the premature termination or suspension. If the trial is 
prematurely terminated or suspended for any reason, the investigators will promptly inform the 
enrolled patients in agreement with the sponsor and ensures their appropriate treatment and 
follow-up.  
If the sponsor temporarily suspends or prematurely terminates the trial for safety reasons, the 
respective regulatory authority and EC have to be informed within 24 hours.  
The sponsor submits the final report to the regulatory authority in charge within 12 months after 
completion or premature termination of the clinical trial. The sponsor will also submit the final 
report to the EC, if required.  
9 
Safety  
9.1 
Definitions  
9.1.1 Adverse Events (AE)  
According to MDR an ‘adverse event’ means any untoward medical occurrence, unintended 
disease or injury or any untoward clinical signs, including an abnormal laboratory finding, in 
subjects, users or other persons, in the context of a clinical investigation, whether or not related 
to the investigational device.  
According to ISO 14155:2020(E), an adverse event is any untoward medical occurrence, un-
intended disease or injury or any untoward clinical signs (including an abnormal laboratory 
finding) in subjects, users or other persons whether or not related to the investigational medical 
device and whether anticipated or unanticipated. This definition includes events related to the 
investigational medical device or the comparator and includes events related to the procedures 
involved. For users or other persons, this definition is restricted to events related to the use of 
investigational medical devices or comparators. 
Added in MDCG 2020-10/1 with following note:  
a. This definition includes events that are anticipated as well as unanticipated events  
b. This definition includes events occurring in the context of a clinical investigation related to 
the investigational device, the comparator or the procedures involved. 
The disease or symptom that led to the necessary intervention should be documented as an 
AE (not the medical or surgical intervention). 
Disease signs, symptoms and/or laboratory abnormalities already existing prior to the use of 
the medical product are not considered adverse events after treatment unless they reoccur 
after the patient has recovered from the pre-existing condition or they represent an exacerba-
tion in intensity or frequency. 
A pre-existing concomitant disease is not considered as an AE. In the case of a worsening the 
concomitant disease has to be considered as AE. If the worsening comes to be serious it must 
be further reported as a SAE.  
Interventions, to treat a pre-existing condition that were already planned before consenting to 
the clinical trial, have not to be documented as AEs. 
Daily fluctuations in the clinical picture are not considered as AEs. 

 
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9.1.2 Adverse Events of Special Interest (AESI)  
The adverse event of special interest (AESI) are  
 
ischemic hepatitis defined by a threefold increase in transaminases (ASAT/ALAT) com-
pared to baseline value 
 
ACLF as defined by the CLIF criteria (Arroyo, Moreau, and Jalan 2020)  
 
heart failure defined by the development of lower limb edema (without significant asci-
tes) and/or pulmonary edema  
 
hepatic encephalopathy as evaluated clinically and graded using the West-Haven cri-
teria (Bajaj et al. 2011)  
 
development of PC (post contrast)-AKI as defined by an increase of serum creatinine 
PC-AKI and of ≥ 0.3 mg/dl, or of ≥ 1.5-1.9 times baseline (KDIGO definition of AKI) in 
the 48-72 h following CM administration (van der Molen et al. 2018).  
9.1.3 Serious Adverse Events (SAE)  
According to MDR Art. 2 (58), a serious adverse event’ means any adverse event that led to 
any of the following: 
(a) death, 
(b) serious deterioration in the health of the subject, that resulted in any of the following: 
(i) 
life-threatening illness or injury, 
(ii) permanent impairment of a body structure or a body function, 
(iii) hospitalisation or prolongation of patient hospitalisation, 
(iv) medical or surgical intervention to prevent life-threatening illness or injury or per-
manent impairment to a body structure or a body function, 
(v) chronic disease, 
(c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect 
In accordance with ISO 14155:2020 (E); 3.45 serious adverse event means an adverse event 
that led to any of the following  
a) death, 
b) serious deterioration in the health of the subject, users, or other persons as defined by 
one or more of the following:  
1) life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function including chronic 
diseases, or 
3) in-patient or prolonged hospitalization, or 
4) medical or surgical intervention to prevent life-threatening illness or injury or per-
manent impairment to a body structure or a body function, 
c) foetal distress, foetal death, a congenital abnormality or birth defect including physical 
or mental impairment 
9.1.4  (Serious) Adverse Device Effects ((S)ADE)  
An adverse device effect is an adverse event related to the use of a medical device. This 
includes any adverse event resulting from insufficiencies or inadequacies in the instructions 
for use, the deployment, the implantation, the installation, the operation, or any malfunction of 
the used medical device. This also includes any event that is a result of a use error or from 
intentional abnormal use of the investigational medical device (in accordance with ISO 
14155.2020(E)). A serious adverse device effect is an adverse device effect that has resulted 
in any of the consequence characteristics of a serious adverse event (MDCG 2020-10/1 and 
ISO 14155.2020(E)). 

 
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According to BfArM an adverse device effect is a (serious) adverse event that has a causal 
relationship with the investigation procedure or where such causal relationship is reasonably 
possible (Article 80(5) and (6) MDR). 
9.1.5 Device Deficiencies  
According to MDR Art. 2 and ISO 14155:2020 (E) ‘device deficiency’ means any inadequacy 
in the identity, quality, durability, reliability, usability, safety or performance of an investigational 
device, including malfunction, use errors or inadequacy in information and labelling supplied 
by the manufacturer. This definition includes device deficiencies related to the investigational 
medical device or the comparator. As the comparator in the Liver-HERO study is the standard 
medication, device deficiencies can only occur in with the TIPS device.  
Special observation is required for any device deficiency that might have led to a serious ad-
verse event if appropriate action had not been taken, intervention had not occurred or circum-
stances had been less fortunate (MDR) Article 80(2). 
9.1.6 Incidents  
Independent from participating in clinical studies every user of a medical device has an obli-
gation to report suspected serious incidents to the competent authority. In Germany these 
reporting obligation is regulated in MPAMIV §§ 2 and 3 additional to Article 2 (64) and (65) 
MDR: 
Article 2 (64) MDR 
‘incident’ means any malfunction or deterioration in the characteristics or performance of a 
device made available on the market, including use-error due to ergonomic features, as well 
as any inadequacy in the information supplied by the manufacturer and any undesirable side-
effect; 
Article 2 (65) MDR 
‘serious incident’ means any incident that directly or indirectly led, might have led or might lead 
to any of the following: 
a. the death of a patient, user or other person, 
b. the temporary or permanent serious deterioration of a patient's, user's or other person's 
state of health, 
c. a serious public health threat; 
This means that all those who professionally or commercially operate or use medical devices 
(also health professionals like physicians) are obliged to report suspected serious incidents. A 
suspected serious incident  
is defined by the MPAMIV as an incident where a serious incident cannot be ruled out accord-
ing to MDR 2017/745. For persons who use medical devices professionally or commercially, 
the notification must be made immediately to the BfArM as the competent higher federal au-
thority. 
9.1.7 Relatedness  
Each AE will be assessed by investigator whether a causal relationship with the medical device 
or study procedure may be possible or not. Each SAE submitted by the trial centres, will also 
undergo a secondary assessment by an experienced medical specialist delegated by the spon-
sor with regard to the criteria "serious", "causal relationship" and "expectedness".  
Definitions of causal relationship to medical device are as follows: 

 
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Not related:  bears no relation to timing of device and is similar to symptoms or signs 
expected in the disease process 
Possible: 
bears relation to timing of device and is similar to symptoms or signs 
expected in the disease process 
Yes:  
clear relation to timing of device and is distinct from symptoms or signs 
expected in the disease process 
Definitions of causal relationship to study procedure (TIPS implantation and control an-
giography) are as follows: 
Not related:  bears no relation to timing of TIPS implantation. 
Possible:  
bears relation to timing of TIPS implantation  
Yes:  
clear relation to timing of TIPS implantation independent from whether 
or not it requires re-intervention or disappears on its own 
9.1.8 Intensity  
The intensity of adverse events will be classified according to the following 3-point scale. 
Mild: 
a clinical symptom or sign that is well/easily tolerated and usually re-
quires no intervention  
Moderate: 
clinical symptom or sign sufficient to interfere with normal/daily activity, 
intervention may be required 
Severe: 
a clinical symptom or sign that results in severe disability, inability to 
work or inability to perform everyday activities = daily activities/work not 
possible, treatment or intervention usually required 
9.2 
Reporting  
(S)AE and AESI recording and documentation start for all subjects with randomization and 
ends with the 12-month follow up visit or with the prematurely end of study for the subject 
(death, liver transplantation), whichever event occurs earlier.  
All SAE that are still ongoing at the 12-month FU or other regular or prematurely end of the 
study for the subject should be followed up until they are resolved or the investigator confirms 
that no further improvement or deterioration is expected. 
9.2.1 AE Reporting  
Any AE (or AESI) must be documented in the eCRF as soon as possible by the investigator or 
study center staff. In addition to other information, it must also be documented in the eCRF 
whether it is an SAE as stated in the definition in chapter 9.1.3.  
9.2.2 SAE Reporting to sponsor  
The (principal) investigator reports to the sponsor of this study according to § 63 MPDG  
1) Without delay  
a. 
every serious adverse event within the meaning of Art. 2 No. 58 MDR and  
b. 
every device deficiency within the meaning of Art. 2 No. 59 MDR which, in the 
absence of appropriate measures or intervention or under less favorable cir-
cumstances, could have led to serious adverse events. 
According to § 62(2) MPDG, (principal) investigators ensure that the investigational product 
suspected of having caused a serious adverse event (SAEs) is not discarded before the as-
sessment of the competent federal authority has been completed. This does not preclude them 

 
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from making the investigational product available to the manufacturer or sponsor for the pur-
pose of the investigation.  
In the event of a SAE (included AESI), the investigational site must report by fax (+49 (0) 3641 
9 39 99 46) immediately (without undue delay) after knowledge of the event.  
In order to transfer all significant information, the SAE Report Form (filed in the ISF) provided 
by ZKS Jena must be used. Every available follow-up information must be provided as soon 
as possible. Please refer to the Working Instructions filed in the ISF for further information. 
9.2.3 Reporting to authorities by sponsor  
Serious adverse events related to a CE marked device which is part of the investigation pro-
cedure are reportable per MDR Article 80(2) if there is a causal, (or reasonably possible) rela-
tionship to the device, the comparator or the investigation procedure. The reporting procedures 
described in the guide MDCG 2020-10/1 should then be followed in addition to the normal 
vigilance reporting procedures for CE marked devices. 
The reporting and notification obligations of the sponsor in other clinical trials result from § 64 
MPDG: 
1) The sponsor reports immediately to the competent higher federal authority via the German 
medical product information and database system in accordance with Section 86 
a. 
any serious adverse event (SAEs) within the meaning of Art. 2 No. 58 MDR which has 
a causal connection with the investigational device, the comparator or the investiga-
tional procedure or for which a causal connection appears entirely possible, 
b. 
any product defect within the meaning of Art. 2 No. 59 MDR which could have led to 
serious adverse events (SAEs) in the absence of appropriate measures or interven-
tion or under less favorable circumstances. 
2) If the sponsor temporarily suspends another clinical trial (German “sonstige Klinische 
Prüfung”) or breaks off the clinical trial, he/she shall notify the competent ethics committee, 
the competent higher federal authority and the authority responsible for him/her as well as 
the authorities responsible for the trial sites via the German medical product information 
and database system according to § 86 within 15 days, stating the reasons. The notification 
pursuant to sentence 1 is made within 24 hours if the sponsor temporarily suspends or 
terminates the clinical trial for safety reasons (see also Ch. 8.12.2). 
The sponsor reports SADEs to BfArM immediately by SADE-Form.  
The sponsor reports all occurred SAEs quarterly via MDCG SAE report table to the German 
BfArM and to all sites. The ECs receive the MDCG SAE report table as requested.  
Additionally, the sponsor sends with the quarterly report a cumulative SAE Assessment to 
BfArM and to the ECs as required.  
9.2.4 Device complaints  
The site must report each incident to the competent authority according to the MPAMIV.  
Participating in the study does not release the physician from his/her obligation to report inci-
dents according to the respective local regulations to the competent authority!  
Incidents of any medical device with CE sign that have occurred in Germany irrespective of a 
clinical study have to be reported to the competent authority by the device user following the 
instructions on the homepage:  
https://www.bfarm.de/EN/Service/Forms/medDev/mp-forms-startseite_en.html (future reports 
via DMIDS (formerly: DIMDI))  

 
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9.3 
Risks associated with the Investigational Medical Device and Procedure  
TIPS placement is an interventional procedure, which in experienced hands has low risk, but 
is not absent of all risk. The rate of major complications after TIPS implantation should remain 
under 5 % and the mortality rate under 1 %. The main complications associated to TIPS place-
ment may be associated to a) the procedure itself such as puncture of other structures such 
as the biliary tract, the hepatic artery or an extrahepatic puncture. In order to avoid an inade-
quate position of the stent, injection of contrast medium should be performed before the place-
ment of the stent-graft. Extrahepatic punctures can be minimized by real-time ultrasound guid-
ance for the placement of the stent. Further complications may develop after TIPS placement 
due to the shunting of the blood from the splanchnic circulation directly into the systemic cir-
culation namely heart failure and hepatic ischemia. In order to foresee complications and be 
able to react swiftly, blood test evaluation including transaminases, liver function (mainly bili-
rubin and INR) as well as blood cell count should be performed the day following the proce-
dure. Due to the shunting, patients with TIPS may develop hepatic encephalopathy, which 
may be avoided with prophylaxis. In the case a hepatic encephalopathy develops, it will be 
treated according to the standard of care. A very infrequent complication is an infection of the 
stent-graft also known as “Endotipsitis”, which can ultimately require liver transplantation for 
its treatment. Prophylactic antibiotics may be considered depending on patient and local risk 
factors.  
The following risks are associated with the study device and potential adverse events include, 
but are not limited to, the following (Bettinger et al. 2016; Billey et al. 2019). 
 
Allergic reaction (contrast medium, medications) 
 
Arrhythmias 
 
Cervical hematoma  
 
Puncture of the carotid artery 
 
Pneumothorax 
 
Extrahepatic puncture 
 
Liver hematoma 
 
Puncture of the hepatic artery or bile ducts 
 
Vascular thrombosis 
 
Vessel injury (e.g., dissection, perforation, rupture) 
 
Ischemic hepatitis 
 
Heart failure 
 
Hepatic encephalopathy 
 
Contrast-medium induced acute kidney injury 
 
Infections 
 
Death 
There may be other potential adverse events that are unforeseen at this time. 
The IFU of the investigational device gives explicit warning for patients with biliary obstruction, 
pneumonia, adult respiratory distress syndrome, pulmonary hypertension, non-cavernoma-
tous complete obstruction of the portal vein, cholangitis, or bacteremia. For these patients the 
risk and possible side effects of a TIPS must be weighed against the potential benefit of this 
procedure. These patients are not included in the present clinical study.  

 
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9.4 
Evidence in the Occurrence of Pregnancy during the Study Period  
Due to the nature of the underlying disease and therapy, no pregnancies are expected. Women 
with decompensated liver cirrhosis usually cannot get pregnant due to lack of ovulation / amen-
orrhea. Terlipressin as standard of care must not be given to pregnant women due to its side 
effects. Nevertheless, the following precautions should be taken:  
Appropriate precautions must be taken by women of childbearing potential. Patients (women 
of childbearing potential as well as men with the desire to have children) should use appropri-
ate methods of contraception within three months after the index procedure. Reliable methods 
of contraception are described in the patient’s information.  
Pregnancy occurring during the clinical study, although not considered a serious adverse 
event, must be reported to the sponsor. The outcome of a pregnancy should be followed up 
carefully and any abnormal outcome of the mother or the child should be reported. 
9.5 
Radiation protection  
At the moment only limited data are available regarding the radiation exposure of the patient 
and the surgeon during the application of a TIPS. The German radiation protection office (Bun-
desamt für Strahlenschutz, BfS) also currently does not provide any reference values for this 
intervention. Miraglia et al. were able to show in a small collective that the mean dose area 
product is 235 ± 198 Gy cm2 and the mean effective dose for the operator as 1.40 ± 2.68 μSv 
(Miraglia et al. 2016). In addition, this team and David et al. provided evidence for a significant 
reduction in radiation exposure through ultrasound-guided puncture of the portal vein system 
in contrast to a fluoroscopically guided approach (David et al. 2019; Miraglia et al. 2017).  
The investigators are free in the choice of method they use for the TIPS application.  
10 Data Management  
10.1 List of responsibilities / Training  
The list of responsibilities (Signature and Delegation Log) identifies all study site staff members 
involved in the clinical trial with their names, signatures and abbreviations, as well as their 
responsibilities and authority. This list must be filed in the ISF and in the TMF. All staff has to 
be trained sufficiently for the delegated responsibilities and re-trained when aspects of the 
study are changed. The training has to be recorded in writing (Training Log). 
The principal Investigator at site has adequate experience in the field of the study specific 
indication and designates a deputy with comparable qualification before the start of the study. 
He/she has to lead and supervise his study team which consists of qualified persons in the 
field of the study specific indication. The principal investigator is also obliged to forward any 
study specific information (e.g. study protocol, product information) or updates of these docu-
ments to the study team. He/she is responsible for conducting the clinical study in accordance 
with the protocol, the ethical principles that have their origin in the Declaration of Helsinki (cur-
rent version) as well as with the International Council on Harmonization of Technical Require-
ments of Pharmaceuticals for Humans Use (ICH) especially Guideline for Good Clinical Prac-
tice (ICH, E6,) and the relevant national laws and applicable regulatory requirements. The 
principal investigator is responsible for the treatment of the patients, for the SAE declaration 
to the sponsor and the CRF documentation. 

 
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10.2 Screening  
For all patients potentially eligible to participate in the clinical trial, inclusion and exclusion cri-
teria will be reviewed. Documentation of these patients is required in a “screening and enrol-
ment log”. All eligible patients must be documented, regardless of the later participation in the 
clinical trial (pseudonymized data). Reasons for non-participation of an eligible patient must be 
indicated.  
10.3 Patient identification list  
A confidential log of the names of all study patients with the identification code assigned to 
each patient at the time of enrolment in the clinical study. With this list, the identity of each 
patient can be revealed (key list for pseudonymization). The list must be kept confidential and 
must be maintained and stored exclusively at the study site in the investigator site file (ISF). It 
must not be copied or otherwise be passed on; no duplicates of this list may be made. The 
personal data collected and generated in the course of the study are processed and stored at 
the sponsor site solely based on the patient identification number in order to maintain the pseu-
donymization. However, sponsor representatives, clinical research associates (CRA), auditors 
and representatives of competent authorities (CA) must be allowed to inspect the list on re-
quest. 
10.4 Medical Device Accounting Log  
The sites have to keep a record over the used medical product under investigation that trace-
ability in case of recall from the market is possible. Other regulatory recording requirements 
may apply which is in the site’s responsibility.  
10.5 Investigator Site File (ISF)  
The ISF will keep the documents required for the clinical trial, and will provide an overview on 
the clinical trial at the respective trial center. The ISF contains the essential documents, such 
as the trial protocol, patient information and consent form, approval of the competent authori-
ties, approval of the responsible ethics committee (s), notification to the competent state au-
thorities, investigators' CVs, list of responsibilities, trial-related correspondence, and other rel-
evant documents.  
As part of the monitoring process, the ISF will be checked to ensure it is up-to-date and com-
plete in accordance with the regulations.  
The investigator will be provided with an investigator site file (ISF) containing all necessary 
essential and relevant study documents for the initiation of the study at his/her site. The es-
sential documents include a list on which the investigator will enter all appropriately qualified 
persons to whom he/she has delegated important study-related tasks. The investigator, or an 
individual who is designated by the investigator, will be responsible for the maintenance and 
completeness of the study documents during the clinical study. At the request of the CRA, 
auditor, EC or CA(s), the investigator shall make available all the requested study-related rec-
ords for direct access. This file and associated study-related documents must be safely ar-
chived after termination of the study for at least 10 years. The investigator is responsible to 
ensure that the patient identification list is stored for at least 15 years beyond the end of the 
clinical study. All original patient files must be stored for the longest possible time permitted by 
the regulations at the hospital, research institute, or practice in question. The investigator will 
be responsible for the storage. 

 
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10.6 Case Report Form (CRF)  
Data capture takes place via a web application on the servers of Center for Clinical Studies at 
Jena University Hospital with a study management software that meets all regulatory require-
ments (GCP, 21CFRPart11). Data is recorded via an encrypted data link (HTTPS) by use of 
data entry masks. In order to ensure a pseudonymized data analysis, a unique patient identi-
fication number is assigned to each patient. 
The CRF consists of individual sections, including inclusion and randomization, visits during 
the study, AE/SAE, end of intervention and termination of the clinical trial. All appropriate sec-
tions of the eCRFs must be completed. For each patient, an own eCRF will be completed. It is 
the investigators' responsibility to ensure that all data collected during the trial are entered 
correctly and completely into the database specifically created for this trial. The eCRFs will be 
reviewed and signed by the site’s Principal Investigator or his designees.  
Data management is done by using a study management software, which enables checking 
of data plausibility by range-, validity- and consistency-checks during and after data entry. 
Missing or obviously erroneous values produce query messages. Any modification of the data 
is documented in the database by an audit trail. The study database will also be reviewed for 
missing data, data consistency, and reasonableness of responses. Discrepancies will be re-
solved through a formal query process involving direct contact with investigators or research 
coordinators. Corrections in the eCRF may only be made by authorized persons or by the 
investigator-in-charge/head of unit/medical director of the trial group and must be justified.  
A paper based CRF as a "copy" is provided to the trial sites as part of the ISF.  
The data collection serves a scientific purpose.  
The electronic data will be backed up regularly. The data storage is located in a locked room 
that should only be accessible to system administrators. 
Data to be collected on screening failures and dropouts: Screening failures are defined as 
patients who signed an ICF but failed to be randomized in the study for any reason. These 
patients are to be documented on the subject screening log (see Ch. 10.2), no further docu-
mentation in the eCRF is required. Drop outs as defined according to Ch. 12.2.1 have to be 
documented on the subject screening log as well as on the patient identification log (see Ch. 
10.3), for further data see notes for documentation (separate document in ISF). 
10.7 Source Documents  
The investigator is responsible for the filing of the relevant medical documentation for each 
study subject in the patient’s/subject’s medical records. The investigator has to keep a written 
or electronic subject/patient file for every subject participating in the clinical study. In this file 
study participation, date and process of informed consent, study visit dates, examinations and 
clinical findings, relevant medical history and relevant concomitant treatment, observed AEs 
and reason for withdrawal from the study if applicable of each study patient will be recorded. lt 
should be possible to verify the inclusion and exclusion criteria for the study from the available 
data in this file. Additionally, any other documents with source data, especially original printouts 
of data that were generated by technical equipment have to be filed. The medical evaluation 
of such records should be documented as necessary. 
For the current study, documents considered to be source data include original documents, 
data and records such as (but are not limited to): 
 
Subject’s record (subject’s medical file). 
 
Signed Patient Informed Consent Form 
 
Evaluation check lists 

 
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 
Device printouts  
 
Any other records maintained to conduct and evaluate the clinical study 
 
Documentation of results and findings 
10.8 Data handling  
The data collection serves a scientific purpose. The data is generated in the participating study 
centers and collected via a web application on the servers of the organization responsible for 
data management. The software meets the regulatory requirements. The data is entered via 
an encrypted data connection (HTTPS) in input masks using a web browser.  
The accuracy of the data is verified by validity and consistency checks. Implausible or missing 
data are requested from the study center. Every change to the data, e.g. by recording an-
swered questions, is documented in the database via an automatic change tracking (audit 
trail). A hierarchical, role-based access concept prevents unauthorized access to the data. 
The electronic data will be backed up regularly. The data storage is located in a locked room 
that should only be accessible to system administrators. 
10.9 Data protection  
Records and documents related to the clinical trial e.g., patient identification list, informed con-
sent forms, correspondence with the Ethics Committee, competent authorities, sponsor, and 
other relevant documents must be kept for at least 10 years (or longer, if required by law). The 
investigator must take precautions to prevent the accidental or premature destruction of these 
documents. 
During the clinical trial, it is necessary to collect and process medical data from individual pa-
tients. Data collection will take place in the involved trial centers. All collected medical data will 
be entered in the trial centers with the aid of a computer-aided online data collection system 
and transmitted directly to the Data Management. Name-related identification of individual pa-
tients by the Data Management is not required at any time during the clinical trial, as the trans-
fer of patient-related medical data will be carried out using a pseudonym. No features will be 
transferred that enable immediate identification of specific patients by the Data Management. 
However, to conduct queries within the framework of the ongoing monitoring of the quality of 
documentation, it is necessary for the documentation center to assign pseudonyms to specific 
trial centers.  
The data entry, processing and evaluation comply with the provisions of the Data Protection 
Act. The data managers of the ZKS Jena will have access to all clinical trial data. These per-
sons are sworn to secrecy. The data will be protected against unauthorized access. The mon-
itor, safety-manager and trial statistician will also have access to several clinical trial data.  
Privacy statement: 
The concerned persons, in whom transmission of their pseudonymized data is necessary, 
should be informed about the nature of the transmitted data. Persons who disagree with the 
disclosure of their pseudonymized data will not be included in the clinical trial.  
The relevant data protection provisions are complied with. 
11 Quality Assurance  
The study will be managed by the Sponsor and monitored by Sponsor and its designee in 
compliance with the Declaration of Helsinki, ICH-GCP, the protocol and all applying local reg-
ulations.  

 
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11.1 Standardization and Validation  
The responsible local laboratories of the trial sites must have a QM system and appropriate 
internal and external quality assurance measures. Successful participation in external quality 
assurance measures must be demonstrated by the submission of appropriate proficiency test 
/ accreditation certificates or similar documents. The laboratory tests required for the clinical 
trial must be GCLP-compliant and follow procedures established in the study manual. 
11.2 Monitoring  
The monitoring will be done in cooperation with the KKS Halle according to ICH-GCP E6 and 
standard operating procedures (SOP). Patient recruitment will begin after the initiation visit and 
all essential documents are available. The monitoring will be done centrally (check of the data 
entered into the eCRFs by KKS Halle and by means of on-site visits at the respective study 
center. The frequency of on-site visits depends on the patient recruitment. The monitor’s ac-
cess to the study documents and medical records is ensured by the investigator’s agreement 
and the cooperation agreement between the sponsor and KKS Halle. The KKS Halle guaran-
tees that patient confidentiality will be respected at all times. Participation in this study will be 
taken as agreement to permit direct source data verification (refer also to section 8.2). Initially 
a formal check of captured information for completeness and plausibility will be done. There-
after, a check of the correct transfer of data from the source data will be done. The informed 
consent forms, the inclusion and exclusion criteria and the data related to the primary target 
variables should be checked completely (100% source data verification). The specific extent 
of the monitoring and the source data verification will be specified in the monitoring manual. 
11.3 Data and Safety Monitoring Board (DSMB) 
The data and safety monitoring board (DSMB) is an independent committee composed of a 
group of individuals (independent physicians/scientists, statistician) with relevant experience 
in the field of the study. A DSMB will be established to monitor safety data during the course 
of the clinical study. The composition and responsibilities of the DSMB, and the structure and 
procedures of its meetings will be laid down in a DSMB manual before inclusion of the first 
patient. The DSMB will give recommendations to the coordinating investigator for continuation, 
discontinuation, modification or termination of the study.  
11.4 Protocol Deviations  
Investigators are not allowed to deviate from the study protocol except under emergency situ-
ations when necessary to preserve the rights, safety and well-being of human subjects. Devi-
ations (failures to follow requirements of the study protocol) will be recorded together with an 
explanation within the eCRF. Investigators should additionally inform the sponsor by mail as 
in case of serious protocol deviations regarding the safety of the participant. Deviations that 
impact the rights, welfare, or safety of patients shall be reported to the reviewing Ethics Com-
mittees (ECs) as required by local regulations. 
11.5 Audits and Inspections  
The investigator will permit study-related monitoring and audits, Ethics Committee review and 
regulatory inspections, providing direct access to source data/documents as ensured by the 
investigator’s agreement and the cooperation agreement between the sponsor and ZKS Jena. 
To ensure quality of data and study performance the sponsor may conduct site visits by an 
independent auditor. An audit will only be performed after notification and arrangement with 
the investigator. An audit certificate will be issued as quality proof and has to be filed in the 
study master file and as a copy in the investigator site file. There is a possibility of inspections 
by the responsible supervisory authority for the purpose of supervision of the ongoing or the 

 
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completed clinical study. If an inspection of the study site is announced by the authority, the 
investigator must inform the sponsor immediately. The investigator ensures immediate access 
to any study related documents including the original data if requested by a representative of 
the sponsor (monitor and auditor), the ethics committee or the responsible authorities (regional 
authority, BfArM). 
12 Statistical methods  
12.1 Sample Size Estimation  
The sample size estimation is based on the primary outcome transplant-free survival (LTX-
OS) and two-sided log-rank test. Previous data suggest that type 1 HRS who received TIPS 
had a 64 % survival at 3 months, with a 20 % one-year survival (Angeli and Gines 2012). In 
the treatment arms of the RCT in HRS evaluating the combination of terlipressin and albumin, 
the 3-month transplant free survival rate was 26 % (Martin-Llahi et al. 2008; Sanyal et al. 2008; 
Boyer et al. 2016; Wong et al. 2021).  
Because of the change in the definition of HRS the patients in the present study will be in a 
slightly better shape, so that an estimated 3-month survival rate of 50 % (exponential param-
eter 0.231) in the control and 70 % (exponential parameter 0.1189) in the experimental group 
(resulting in a hazard ratio HR=0.51) are expected. With significance level of 5 %, power of 
90 %, recruitment period of 24 months, individual follow-up of 12 months and dropout rate of 
10 % (exponential parameter 0.0088) 56 patients are needed in each group. Because of ex-
pected additional T-to-C-switcher (patients, randomized in the TIPS-group, but who develop 
contraindications and therefore are not in constitution for this procedure) between randomiza-
tion and TIPS procedure 62 patients will be randomized to each group. Although there are no 
data regarding this, from clinical experience we believe that this will happen in approximately 
10 % of patients. As the adjusted Cox regression analysis is more powerful than the log-rank 
test, this sample size calculation is considered to be conservative. Furthermore, patients who 
are initially assigned to the C group, may develop during follow-up complications of cirrhosis 
in which TIPS placement is indicated. There is no clear-cut data about the number of patients 
in whom this will occur and hence drop in TIPS treatment (C-to-T-switcher). Assuming, that 
this number will be low, a relatively high power of 90 % was chosen to account for possible 
switchers, the sample size is calculated without this information. 
12.2 Statistical Analysis  
12.2.1 Populations for Analysis 
The primary analysis data set is the intention-to-treat population. This data set contains all the 
patients who have been enrolled in the clinical trial and randomized.  
The secondary analysis data set is derived from the per-protocol population. This data set 
includes all patients who have been treated according to the protocol during the whole duration 
of the study and reached a defined endpoint. 
The tertiary analysis data set (safety-population) contains all the patients who have received 
the trial procedure. 
12.2.2 Methods of Analysis 
All compiled data will be analyzed at least in a descriptive manner. Including count of compiled 
data and missings, mean, standard deviation, minimum, quartiles, maximum for metric and 
frequency analysis for ordinal and categorical data. 
Demography: age, sex, size, weight, racial background. 
We hypothesize that the 12-month liver transplant free survival is higher in patients in the in-
terventional group. We will test the hypothesis  

 
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H0: HR = 1.0 vs. HA: HR ≠ 1.0. 
 
The primary endpoint will be analyzed based on the intention to treat principle using a Cox 
regression adjusted for AKI stage. Drop-outs will be dealt with as independent right censored 
in the primary analysis. All patients will be analyzed in their randomization-group. Because 
both switcher groups are not random inside their groups a per protocol analysis will be per-
formed as sensitivity analysis of the primary outcome. Drop-outs and C-to-T-switcher will be 
dealt with as independent right censored in this analysis without T-to-C-switchers.  
Additional both analyses will be performed with requirement of TIPS implantation/revision in 
the Follow-Up as third endpoint. 
We will perform a competing-risk-analysis in addition to the primary endpoint with the compet-
ing events death and Liver-transplantation. As secondary outcomes reversal of HRS-AKI (vs 
baseline), partial response to treatment (vs baseline), need of renal replacement therapy and 
recurrence of HRS-AKI at 3 and 12 months will be assessed by logistic regression adjusted 
for AKI stage. In-hospital, 28-day and 90-day survival will be assessed by logistic regression 
adjusted for AKI stage. Changes in HrQoL at 3 and 12 months with respect to study baseline 
will be compared between groups by linear regression adjusted for AKI stage. 3-month liver 
transplant free survival will be analyzed using a Cox regression adjusted for AKI stage. Devel-
opment of further decompensations and length of in-hospital-stay will be analyzed descrip-
tively. Results will be interpreted in an exploratory manner. 
The Number of AEs and SAEs in each group with special attention on the development of 
ischemic hepatitis, acute on chronic liver failure, hepatic encephalopathy and signs of heart 
failure will be analyzed. Laboratory assessments include sodium, potassium, ALAT, ASAT, 
GGT, AP, Bilirubin, Albumin, INR will be analyzed descriptively as safety parameters.   
12.2.3 Subgroup Analysis  
The primary endpoint will be analyzed in a secondary analysis based on the intention to treat 
principle using a Cox regression (with centers, presence/absence of intrinsic renal damage as 
determined by plasma and urine biomarkers, etiology of the underlying liver disease (alcoholic 
versus non-alcoholic) and impact of the presence of intrinsic nephropathy as assessed by cys-
tatin C and UnGAL as fixed effects) adjusted for AKI stage. These effects will be checked with 
BIC (Bayesian information criterion). In case of significance, results will be interpreted in an 
exploratory manner.  
12.3 Definition of Screening Failures, Drop-outs and switchers  
Patients who do not meet all inclusion criteria or meet any exclusion criterion are not eligible 
for randomization and will be considered as screening failures. Patients who for any reason 
fail to continue in the trial until the last visit are considered as dropouts. 
C-to-T-switcher: patients, who are initially assigned to standard of care (Control, C) but develop 
complications of cirrhosis in which TIPS placement is indicated during follow-up and hence 
drop in TIPS treatment (T).  
T-to-C-switcher: patients, randomized in the TIPS group (T), but who are not in constitution for 
this procedure or develop contraindications for TIPS procedure between randomization and 
day of planned TIPS placement, respectively and drop into standard of care treatment.  
12.4 Missed visits  
It is possible that patients miss to attend one or more visits but can be followed up until the 
regular end of the study at the 12-months FU. The number of missed visits at the respective 
time points will be given in the CONSORT 2010 flow diagram.  

 
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13 Regulatory and Administrative Issues  
13.1 General remarks  
This clinical study was designed, will be conducted and reported in compliance with Good 
Clinical Practice (GCP), and the applicable national laws and regulations and with the ethical 
principles laid down in the Declaration of Helsinki to assure that the rights, safety, and well-
being of the participating subjects are protected. 
The Liver-HERO trial is a clinical trial of a medical device that serves to answer scientific ques-
tions. Therefore, this study is conducted as a “sonstige klinische Prüfung“ according to 
§ 3 Abs. 4 MPDG in accordance with Article 82 of the European Medical Device Regulation 
(MDR) and § 47 of the German Medical Device Implementation Act (MPDG) and requires a 
sponsor (§ 25 MPDG). 
13.2 Ethic committees  
The study protocol and other associated documents will be submitted to the responsible ethics 
committee before initiation of the study. In each study site, the clinical study must not be started 
until the competent local ethics committee has approved the suitability of the study site and 
the qualifications of the investigators. Additional requirements issued by the EC must be met. 
Recommendations should be considered and implemented if necessary.    
13.3 Regulatory Authority  
Before study start the sponsor has to submit a notification (“Anzeige”) to the German Compe-
tent Authority (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) via DMIDS and the 
Federal Office for Radiation Protection (Bundesamt für Strahlenschutz, BfS) by electronic/pa-
per mail.  
13.4 Insurance  
All patients participating in the trial will have insurance coverage by the sponsor which is in line 
with the applicable law and regulations, covering in its terms and provisions, its legal liability 
for injuries caused to participating persons arising out of this research performed strictly in 
accordance with scientific protocol as well as applicable law and professional standards.  
The insurance was taken out at  
Newline Europe Versicherung AG, Schanzenstraße 28a, D-51063 Köln Germany (Insurance 
policy number: NEV050158A  
Each patient will get a copy of the conditions of insurance (including coverage of accidents on 
the way from the patient’s home to the study site and back). Investigators will find the respec-
tive conditions and confirmation of insurance in the ISF. 
Any impairment of the health which might occur as a consequence of trial participation must 
be notified to the insurance company. The patient is responsible for notification. The insured 
person will agree with the appropriate measures serving for clarification of the cause and the 
extent of damage as well as the reduction of damage. During the conduct of the trial, the patient 
must not undergo other clinical treatment except for cases of emergency. The patient is bound 
to inform the investigator immediately about any AE and additionally drugs taken. The terms 
and conditions of the insurance will be delivered to the patient. The insurance company has to 
be informed about all amendments that could affect patient’s safety. 

 
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13.5 Amendments  
After the commencement of the clinical study, the sponsor may make amendments to the pro-
tocol. All changes in documentation will be advertised to the respective competent authorities 
according the current valid legislation at the respective time point. All planned substantial 
changes have to be approved by the ethic committee (EC) and the regulatory authority. The 
implementation of a substantial amendment can only occur after formal approval of EC and 
the regulatory authority and must be signed by the investigators 
Study conduction has to be done according to the study protocol unless it is necessary to take 
immediate action required for the safety of any patient included in this study. In such cases, 
the sponsor has to be notified as soon as possible of this action. Protocol violations have to be 
documented and if applicable explained (see Ch. 11.4). Study conduction has to be done ac-
cording to the study protocol. In exceptional cases, however, modifications of the study proto-
col may be necessary. Such changes can only be made if agreed by the sponsor, coordinating 
investigator, study coordinator and biometrician. Any changes to the study procedures have to 
be done in writing and must be documented with reasons signed by all authors of the original 
study protocol. Amendments that require approval have to be submitted to the ethics commit-
tee and the competent federal authority and will not be implemented until approval. Not in-
cluded are protocol deviations to avoid immediate dangers. Any changes of examination and 
treatment procedures or points of time which are justifiable according to the investigator have 
to be documented (e.g. as emergency measure on the Case Report Form) giving the reasons 
and reported to the sponsor immediately. 
13.6 Study Reports  
The Coordinating Investigator supported by ZKS Jena is responsible for the preparation of the 
report and submission to the EC and CA. 
13.7 Registration  
Prior to the beginning of the study, the Coordinating Investigator has registered the trial in a 
public register which is a prerequisite for publication in a peer-review journal. The study is 
registered at clinicaltrials.gov (NCT identifier: NCT05346393). 
13.8 Funding  
The study is entirely funded by the Deutsche Forschungsgemeinschaft (DFG project number 
431667134). There is no direct or indirect funding by the manufacturer / distributor of the me-
dicinal product. 
13.9 Contracts with sites     
Agreements between sponsor and sites cover description of the contractual object, legal 
frameworks, required approvals & unfeasibility, responsibilities and obligations of both partners 
regarding all parts of the clinical trial, intellectual property rights, publications, confidentiality 
statement, warranty coverage and remuneration. Remuneration include a set-up fee inde-
pendently from patient inclusion and a case-by-case fee, depending on the occurred FU visits. 
The agreement has to be signed prior to site initiation.   
13.10  Study report  
The sponsor is responsible for preparation and submission of the final study report which is 
due within 12 months of study completion (LPLV). No interim analyses and reports are 
planned. The study report is to be written in compliance with the relevant regulations and 
guidelines.  

 
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13.11 Publication Policy  
Publication policy, rights and obligations for this study have been negotiated, detailed and de-
fined in the Investigation Contractual Documents and Agreements with the Investigation Site 
and Investigators. All publications will ensure privacy rules are met for all patients.  
14 Definitions  
14.1 Baseline Creatinine 
In order to evaluate the presence of AKI, one needs to evaluate the difference with the baseline 
creatinine. Baseline creatinine is a value of serum creatinine obtained in the previous 3 months, 
in a stable situation. In patients in whom more than one value in the last 3 months is available, 
the value closest to the admission time to the hospital should be used. In patients without a 
previous serum creatinine value, the serum creatinine on admission should be used as base-
line (Angeli, Rodriguez, et al. 2015).  
14.2 Ascites  
Grading of ascites should be done as follows:   
 
no ascites (in the physical examination) 
 
ascites  
 
tense ascites 
14.3 AKI 
AKI is an increase in serum creatinine from at least 0.3 mg/dL (26.5 μmol/L) or greater within 
48 hours or a 50 % increase of serum creatinine from its baseline value which is known, or 
presumed to have occurred in the prior 7 days (Angeli, Gines, et al. 2015).   
AKI Stage 
Definition 
AKI Stage 1 
increase in sCr ≥ 0.3 mg/dL (26.5 μmol/L) within 48h or an increase in sCr ≥ 1.5-fold 
to 2-fold from baseline9 
AKI Stage 2 
increase in sCr > 2-fold to 3-fold from baseline 
AKI Stage 3 
increase of sCr > 3-fold from baseline or sCr ≥ 4.0 mg/dL (353.6 μmol/L) with an in-
crease ≥ 0.3 mg/dL (26.5 μmol/L) or initiation of renal replacement therapy 
14.4 Refractory ascites 
Refractory ascites is defined according to the International Ascites Club criteria, when there is 
less than 800 gr weight loss over 4 days in patients on low salt diet and high dose diuretics 
(spironolactone 400 mg/day and furosemide* 160 mg/day), or lower dose of diuretics with com-
plications secondary to the use of diuretics such as hyponatremia, renal failure, hepatic en-
cephalopathy. *equivalent dose of torasemide 40 mg/day. This diagnosis can only be ascer-
tained in a stable patient without complications such as infection or bleeding (European 
Association for the Study of the Liver. Electronic address and European Association for the 
Study of the 2018; Gerbes et al. 2019). 
14.5 Recurrent ascites 
Patients with recurrent ascites despite low salt diet and adequate dose of diuretics defined by 
the need of more than 3 paracenteses in three months. This diagnosis can only be ascertained 
                                               
9 Baseline means here the time before development of AKI  

 
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in a stable patient without complications such as infection or bleeding at the time of paracen-
tesis (European Association for the Study of the Liver. Electronic address and European 
Association for the Study of the 2018; Gerbes et al. 2019). 
14.6 Diuretic sensitive ascites  
Patients with ascites with a high SAAG in whom administration of loop diuretics and mineralo-
corticoid receptor antagonist (with or without low salt diet) leads to a reduction in body weight 
have a diuretic sensitive ascites. In these patients less than 3 large volume paracentesis per 
year are required (European Association for the Study of the Liver. Electronic address and 
European Association for the Study of the 2018).  
14.7 Variceal bleeding 
Suspicion of variceal bleeding is defined by the occurrence of acute upper gastrointestinal 
bleeding with hematemesis or melena or gastric aspirate with blood in patients with cirrhosis. 
The diagnosis of variceal bleeding is if bleeding signs are seen on a varix (jet, oozing, white 
nipple) or if blood is seen in the stomach in the first 24 hours after time zero (time of admission) 
and no other source of upper gastrointestinal bleeding is identified. Clinically significant vari-
ceal bleeding is defined by variceal bleeding with at least transfusion requirement of 2 units of 
blood or more within 24 hour of time zero (time of admission) together with a systolic blood 
pressure < 100 mmHg and/or a pulse rate > 100 bpm (de Franchis et al. 1992; de Franchis 
2005).  
14.8 Hepatic encephalopathy 
Overt hepatic encephalopathy is defined by the presence of clinically evident altered mental 
status with disorientation and with or without asterixis. This applies to patients with hepatic 
encephalopathy grad II-IV in the West Haven Classification. Covert hepatic encephalopathy 
refers to patients with neuropsychometric and/or neurophysiological disorders without disori-
entation or asterixis (Bajaj et al. 2011). 
West Haven Criteria for grading mental state in patients with cirrhosis 
Grade 
Features 
0 
No abnormalities detected 
I 
Trivial lack of awareness 
Euphoria or anxiety 
Shortened attention span 
Impaired addition or subtraction 
II 
Lethargy or apathy 
Disorientation for time 
Obvious personality changes 
Inappropriate behavior 
Asterixis 
III 
Somnolence to semi-stupor 
Responsive to stimuli 
Confused 
Bizarre behavior 
IV 
Coma, unable to test mental state 
14.9 ACLF 
Acute on chronic liver failure is a distinct entity with acute decompensation and organ failure 
(Arroyo, Moreau, and Jalan 2020). Its evaluation is done by means of the EASL-CLIF Consor-
tium organ failure score (European Foundation for the study of chronic liver failure; 

 
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https://www.efclif.com/scientific-activity/score-calculators/clif-c-aclf). Each organ system func-
tion receives a score ranging from 1 point (close to normal) to 3 points (abnormal). The pres-
ence of organ failure (in grey on the table) is defined by a score of 3 points and in the case of 
kidney by the presence of a creatinine greater than 2 mg/dL.  
Organ system 
1 point 
2 points 
3 points 
Liver 
Bilirubin < 6 mg/dL 
Bilirubin 6-11.9 mg/dL 
Bilirubin ≥ 12 mg/dL 
Kidney 
Creatinine < 1.9 mg/dL 
Creatinine 2-3.4 mg/dL 
Creatinine ≥ 3.5 mg/dL 
Brain (West Haven Criteria)  Grade 0 
Grade 1-2 
Grade 3-4 
Coagulation 
INR < 2.0 
INR 2.0-2.4 
INR ≥ 2.5 
Circulation 
MAP ≥ 70 mmHg 
MAP < 70 mmHg 
Vasopressor requirement 
Respiration 
PaO2/FiO2 > 300 
SpO2/FiO2 > 357 
PaO2/FiO2 201-300 
SpO2/FiO2 215-357 
PaO2/FiO2 ≤ 200 
SpO2/FiO2 ≤ 214 
PaO2 = oxygen partial pressure; SpO2 = peripheral capillary oxygen saturation; FiO2 = fraction of inspired oxygen  
14.10 AKI-HRS reversal 
A full response or HRS-AKI reversal is a return of serum creatinine to a value within 0.3 mg/dL 
(26.5 μmol/L) of the baseline value (Angeli, Gines, et al. 2015; Sola et al. 2021). 
14.11 AKI- HRS partial reversal 
A partial response or partial reversal is the regression of the AKI to a serum creatinine 
≥ 0.3 mg/dL (26.5 μmol/L) above the baseline value (Angeli, Gines, et al. 2015; Sola et al. 
2021).  
14.12 HRS recurrence 
An AKI-HRS recurrence is defined by a new episode of HRS-AKI in a patient in whom a rever-
sal or partial reversal took place and in whom treatment for HRS was successfully discontinued 
(at least 48 hours). 
14.13 Diastolic dysfunction 
Diastolic dysfunction is defined by the presence of at least three abnormal values from the 
following four parameters (Nagueh et al. 2016):  
 
annular e′ velocity: septal e′ < 7 cm/ sec or lateral e′ < 10 cm/sec  
 
average E/e′ ratio > 14 
 
LA volume index > 34 mL/m2 and  
 
peak TR velocity > 2.8 m/sec 
Patients who have abnormal diastolic function can be further graded according to the E/A Ra-
tio: Grade I diastolic dysfunction is defined by a mitral E/A ratio ≤ 0.8, Grade II > 0.8 to < 2 and 
grade III by a mitral E/A ratio > 2 (Nagueh et al. 2016). 
14.14 Post contrast medium AKI 
Development of PC (post contrast)-AKI as defined by an increase of serum creatinine PC-AKI 
and of ≥ 0.3mg/dl, or of ≥ 1.5–1.9 times baseline (KDIGO definition of AKI) in the 48–72 h 
following CM administration (van der Molen et al. 2018). 
14.15 NYHA Classification  
Class New York Heart Association functional classification 

 
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I  
Patients have cardiac disease but without the resulting limitations of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnoea or anginal pain 
II 
Patients have cardiac disease resulting in slight limitation of physical activity. They are com-
fortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea or anginal 
pain 
III  
Patients have cardiac disease resulting in marked limitation of physical activity. They are com-
fortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnoea or 
anginal pain 
IV  
Patients have cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present 
even at rest. If any physical activity is undertaken, discomfort is increased 
14.16 Milan criteria  
The threshold Milan criteria (“Milan in”) are as follows:  
 
one lesion smaller than 5 cm; alternatively, up to three lesions, each smaller than 3 cm 
 
no extrahepatic manifestations 
 
no evidence of gross vascular invasion 
If at least one of the criteria is not fulfilled, it is considered as “Milan out”.   
14.17 ECOG  
Grade ECOG Performance Status   
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about 
more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 

 
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