HRS-AKI Treatment With TIPS in Patients With Cirrhosis (Liver-HERO)

Hepatorenal Syndrome-acute Kidney Injury (HRS-AKI) Treatment With Transjugular Intrahepatic Portosystemic Shunt in Patients With Cirrhosis. A Randomized Controlled Trial

The study compares the effectiveness and safety of TIPS implantation in patients with HRS-AKI (stage 2 and 3) and liver cirrhosis with standard therapy (drug therapy with terlipressin + albumin).

Study Overview

• Status: Recruiting
• Conditions: Acute Kidney Injury; Cirrhosis, Liver; Hepatorenal Syndrome; Ascites Hepatic
• Intervention / Treatment: Procedure: TIPS; Drug: Standard of Care

Detailed Description

Cirrhosis is a major cause of global health burden worldwide. Acute kidney injury (AKI) occurs in 20% of hospitalized patients with cirrhosis. Acute kidney injury is a relatively new definition of renal failure which takes into account the dynamic changes in serum creatinine. Among the causes of AKI, hepatorenal syndrome-AKI has the worst prognosis. HRS-AKI is an acute condition which occurs in patients with ascites, mainly refractory ascites. HRS-AKI includes the traditional hepatorenal syndrome type 1, which was defined by a serum creatinine cutoff and which has an ominous prognosis when left untreated, nevertheless HRS-AKI also includes milder forms of renal failure.

The standard treatment of HRS-AKI is with the infusion of albumin and terlipressin. Although this treatment improves renal function, patients remain at risk for new episodes of HRS-AKI and liver transplantation should be considered. Nevertheless, this optimal solution is only a reality for a privileged few given the shortage of organs and the common presence of contraindications.

Development of HRS-AKI is caused by increased pressure in the portal vein (the vein which brings the blood from the intestines to the liver), among other factors. Increased pressure in the portal vein, also called portal hypertension, is one of the main pathophysiological mechanisms that lead to the different complications of cirrhosis. Transjugular intrahepatic portosystemic shunt (TIPS) is an interventional radiological procedure which reduces the pressure in the portal vein by creating a short-cut between the portal vein and the hepatic vein, the vein which brings the blood from the liver towards the heart. TIPS placement has become the mainstay of treatment of some complications of cirrhosis, namely variceal bleeding and refractory ascites. Although rationally plausible, the use of TIPS in HRS-AKI has not been evaluated in the context of randomized controlled trials. Indirect data suggest that it could be helpful, since patients who become TIPS have an improvement in renal hemodynamics and renal function as well as less episodes of HRS-AKI in the follow-up. On the other hand, traditional HRS type 1 can be associated to liver failure and cardiac alterations which contraindicate TIPS placement. HRS-AKI includes not only traditional HRS type 1, but also milder forms of the disease, so that it is reasonable to consider that TIPS placement may have a role in this condition.

This study is a multicenter (9 centers), prospective, randomized controlled trial which evaluates use of TIPS in patients with HRS-AKI (stage 2 and 3) versus standard of care (albumin and terlipressin). Patients with cirrhosis and HRS-AKI who fulfill the inclusion criteria and do not have any exclusion criteria will be randomized to standard of care or standard of care and TIPS. Patients will be followed for a minimum of 12 months until the end of the trial. The main end-point is to compare the survival at the end of follow-up among the two groups.

• Study Type: Interventional
• Enrollment (Estimated): 124
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Cristina Ripoll, Prof. Dr.; Phone Number: 32 44 01 +4936419; Email: cristina.ripoll@med.uni-jena.de
• Study Contact Backup: Name: Alexander Zipprich, Prof. Dr.; Phone Number: 32 44 01 +4936419; Email: alexander.zipprich@med.uni-jena.de

Study Locations

• Germany
  • Aachen, Germany, 52074
    • Recruiting
    • University Hospital RWTH Aachen
    • Contact: Tony Bruns, Prof. Dr.; Email: tbruns@ukaachen.de
  • Dresden, Germany, 01307
    • Recruiting
    • University Hospital Dresden, Medical Clinic I, Gastroenterology
    • Contact: Marco Berning, Dr.; Phone Number: 5643 +49 351 458; Email: Marco.Berning@uniklinikum-dresden.de
  • Freiburg im Breisgau, Germany, 79106
    • Recruiting
    • University Hospital Freiburg
    • Contact: Dominik Bettinger, PD Dr.; Email: dominik.bettinger@uniklinik-freiburg.de
  • Halle (Saale), Germany, 06120
    • Recruiting
    • University Hospital Halle
    • Contact: Robin Greinert, Dr.; Phone Number: 2665 +49345557; Email: robin.greinert@uk-halle.de
  • Hamburg, Germany, 20246
    • Not yet recruiting
    • University Hospital Hamburg-Eppendorf
    • Contact: Andreas Drolz, Dr.; Phone Number: 53910 +49 40 7410; Email: a.drolz@uke.de
  • Hannover, Germany, 30625
    • Not yet recruiting
    • Medical University Hannover
    • Contact: Benjamin Maasoumy, PD Dr.; Phone Number: 6814 +49 511532; Email: Maasoumy.Benjamin@mh-hannover.de
  • Jena, Germany, 07747
    • Recruiting
    • Jena University Hospital, Clinic for Inner Medicine IV
    • Contact: Cristina Ripoll, Prof. Dr.; Phone Number: 324401 +4936419; Email: cristina.ripoll@med.uni-jena.de
  • Leipzig, Germany, 04103
    • Not yet recruiting
    • University Hospital Leipzig
    • Contact: Thomas Berg, Prof. Dr.; Phone Number: 24831 +49 0341 97; Email: studien-hepatologie@medizin.uni-leipzig.de
  • Ludwigsburg, Germany, 71640
    • Recruiting
    • RKH Clinic Ludwigsburg
    • Contact: Karel Caca, Prof. Dr.; Phone Number: 67201 +49 7141 99; Email: karel.caca@rkh-kliniken.de
  • Munich, Germany, 81377
    • Recruiting
    • Ludwig-Maximilians-University, Klinikum Großhadern
    • Contact: Christian Lange, Prof. Dr.; Email: Christian.Lange@med.uni-muenchen.de
  • Münster, Germany, 48149
    • Recruiting
    • University Hospital Münster, Medical Clinic B
    • Contact: Jonel Trebicka, Prof. Dr.; Phone Number: 57562 +49 251 83; Email: jonel.trebicka@ukmuenster.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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
3. HRS-AKI stages 2 or 3
4. Planned vasoactive treatment for the management of HRS
5. Age: ≥ 18 to ≤ 80 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 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.

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 > 200 erythrocytes per µl) or signs of chronic renal disease on ultrasound.
2. Recent or current use of nephrotoxic drugs (NSAIDS, Aminoglycosides or iodinated 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 within the last 48 hours prior to randomization
5. Patients with uncontrolled infection (defined by a 20 % increase in inflam-matory 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 (is-chemic cardiomyopathy, hypertensive cardiomyopathy, etc.)
7. Patients with contraindications to TIPS placement (e.g. Bilirubin > 85.5 µmol/L (≙ 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 ACLF grade 3
13. Patients with creatinine value > 442 µmol/L (≙ 5 mg/dL)
14. Patients with an acute variceal bleeding at the time of screening who have indication for pre-emptive TIPS and/or terlipressin.
15. 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 diuretics (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
16. Patients with hepatocellular carcinoma outside of the Milan criteria
17. Patients with hepatocellular carcinoma within the Milan criteria in whom the tumor is located in the puncture tract.
18. Patients with benign liver tumors (except regenerative nodules) which are located in the puncture tract.
19. Patients who already have a TIPS placed
20. Patients who already had a liver transplantation
21. Patients with other comorbidities that lead to an estimated life expectancy under 1 year.
22. Patients with respiratory insufficiency which requires mechanical ventila-tion
23. Patients with circulatory failure which requires administration of other vas-opressors (catecholamines)
24. Patients receiving renal replacement therapy
25. The subject is currently enrolled in another investigational device or drug trial.
26. Patients with pregnancy or lactation
27. Patients which are suspected to be incompliant for study participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TIPS group; TIPS implant (transjugular intrahepatic portosystemic shunt)	Procedure: TIPS; A transjugular intrahepatic portosystemic shunt (TIPS) is implanted into the cirrhotic liver
Active Comparator: Control group; Standard medication therapy with terlipressin and albumin. In the case Terlipressin is not tolerated treatment with Noradrenaline may be considered following actual guidelines.	Drug: Standard of Care; Terlipressin/Albumin treatment is the preferred standard of care treatment. In the case Terlipressin is not tolerated treatment with Noradrenaline may be considered following actual guidelines.; Other Names: Terlipressin + Albumin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
12 month Liver transplant-free survival	12 month Liver transplant-free survival	12 months after Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-month liver transplant free survival	3-month liver transplant free survival	3 months after Baseline
Number of patient which develop an indication for TIPS placement (variceal bleeding or refractory ascites) or TIPS revision (variceal bleeding or development of ascites) during follow-up	Number of patient which develop an indication for TIPS placement according to clinical guidelines (such as variceal bleeding or refractory ascites) in the control group or indication for a TIPS revision (variceal bleeding, development of ascites) in the intervention group will be assessed during the 12 months follow-up	within 12 months after Baseline
Development of further decompensation of HRS-AKI during follow-up	Development of further decompensation as defined in the Baveno VII Consensus Workshop (e.g. overt hepatic encephalopathy, refractory or recurrent ascites, dilutional hyponatremia, new AKI-HRS, variceal bleeding) during follow-up	within 12 months after Baseline
Reversal of HRS-AKI-AKI 3 MFU	Reversal of HRS-AKI-AKI at 3 months (vs. baseline), defined as return of serum creatinine level within 0.3 mg/dl (26 mmol/L).	3 months after Baseline
Reversal of HRS-AKI-AKI 12 MFU	Reversal of HRS-AKI-AKI at 12 months (vs. baseline), defined as return of serum creatinine level within 0.3 mg/dl (26 mmol/L).	12 months after Baseline
Partial response to treatment 3 MFU	Partial response to treatment at 3 months (vs. baseline) defined as reduction of at least one AKI stage with decrease of serum creatinine to ≥ 0.3 mg/dl (26 mmol/L) above the baseline value.	3 months after Baseline
Partial response to treatment 12 MFU	Partial response to treatment at 12 months (vs. baseline) defined as reduction of at least one AKI stage with decrease of serum creatinine to ≥ 0.3 mg/dl (26 mmol/L) above the baseline value.	12 months after Baseline
In-hospital survival	In-hospital survival of the patients (patients are hospitalized for diagnosis of HRS-AKI and start of treatment - due to poor diagnosis, patients may die during hospital stay)	baseline until 12 months
28-day survival	28-day survival	baseline until day 28 after baseline
90-day survival	90-day survival	baseline until day 90 after baseline
Length of in-hospital-stay	Length of in-hospital-stay of the patients (patients are hospitalized for diagnosis of HRS-AKI and start of treatment)	baseline until 12 months
Changes in HrQoL as measured by SF36 3 MFU	Relative changes in Health-related Quality of Life as measured by SF36 at 3 months (vs. baseline)	3 months after Baseline
Changes in HrQoL as measured by SF36 12 MFU	Relative changes in Health-related Quality of Life as measured by SF36 at 12 months (vs. baseline)	12 months after Baseline
Changes in HrQoL as measured by CLDQ 3 MFU	Relative changes in Health-related Quality of Life as measured by CLDQ (Chronic Liver Disease Questionnaire) at 3 months (vs. baseline)	3 months after Baseline
Changes in HrQoL as measured by CLDQ 12 MFU	Relative changes in Health-related Quality of Life as measured by CLDQ (Chronic Liver Disease Questionnaire) at 12 months (vs. baseline)	12 months after Baseline
Need for renal replacement therapy	Need for renal replacement therapy within Follow-up	12 months after Baseline
recurrence of HRS-AKI after treatment at 3 months	recurrence of HRS-AKI after treatment at 3 months	3 months after Baseline
recurrence of HRS-AKI after treatment at 12 months	recurrence of HRS-AKI after treatment at 12 months	12 months after Baseline
Safety Assessment	Number of AEs and SAEs in each group with special attention on the development of acute on chronic liver failure and signs of heart failure.	12 months after Baseline
Development of acute-on-chronic liver failure during follow-up	Development of acute-on-chronic liver failure during follow-up	12 months after Baseline
Impact of the presence of intrinsic nephropathy as assessed by cystatin C and UnGAL on outcomes (survival and reversal of AKI)	Patients with clear intrinsic nephropathy will be excluded from the study, as the diagnosis of hepatorenal syndrome requires exclusion of intrinsic nephropathy. Nevertheless, patients with HRS may also have other conditions that may lead to a subclinical chronic nephropathy. This will be assessed with cystitis C and/or UnGAL and its association with survival and reversal of AKI. This is a secondary exploratory end-point	12 months after Baseline

Collaborators and Investigators

• Sponsor: Jena University Hospital
• Collaborators: German Research Foundation; Center for Clinical Studies, Jena University Hospital; KKS Halle, University Hospital Halle (Saale)
• Investigators: Study Director: Cristina Ripoll, Prof. Dr., Jena University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2022
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: April 1, 2022
• First Submitted That Met QC Criteria: April 20, 2022
• First Posted (Actual): April 26, 2022

Study Record Updates

• Last Update Posted (Estimated): January 11, 2024
• Last Update Submitted That Met QC Criteria: January 8, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Cirrhosis; Ascites; Acute Kidney Injury; Terlipressin; transjugular intrahepatic portosystemic shunt; TIPS; Hepatorenal Syndrome
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Liver Diseases; Renal Insufficiency; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Fibrosis; Syndrome; Liver Cirrhosis; Ascites; Acute Kidney Injury; Hepatorenal Syndrome; Antihypertensive Agents; Vasoconstrictor Agents; Terlipressin
• Other Study ID Numbers: ZKSJ0146; DE-22-00013779 (Other Identifier: BfArM); 431667134 (Other Grant/Funding Number: DFG)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No