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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05346393
Recruitment Status : Not yet recruiting
First Posted : April 26, 2022
Last Update Posted : November 29, 2022
Sponsor:
Collaborators:
German Research Foundation
Center for Clinical Studies, Jena University Hospital
KKS Halle, University Hospital Halle (Saale)
Information provided by (Responsible Party):
Cristina Ripoll, Jena University Hospital

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Cirrhosis, Liver Hepatorenal Syndrome Acute Kidney Injury Ascites Hepatic Procedure: TIPS Drug: Standard of Care Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 124 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel Assignment 1:1-randomization, parallel design, stratified by center and AKI stage.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Hepatorenal Syndrome-acute Kidney Injury (HRS-AKI) Treatment With Transjugular Intrahepatic Portosystemic Shunt in Patients With Cirrhosis. A Randomized Controlled Trial
Estimated Study Start Date : December 2022
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : June 2026


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
Drug: Standard of Care
Administration of Terlipressin and Albumin according to Standard of Care
Other Name: Terlipressin + Albumin




Primary Outcome Measures :
  1. 12 month Liver transplant-free survival [ Time Frame: 12 months after Baseline ]
    12 month Liver transplant-free survival


Secondary Outcome Measures :
  1. 3-month liver transplant free survival [ Time Frame: 3 months after Baseline ]
    3-month liver transplant free survival

  2. 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 [ Time Frame: within 12 months after Baseline ]
    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

  3. Development of further decompensation of HRS-AKI during follow-up [ Time Frame: within 12 months after Baseline ]
    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

  4. Reversal of HRS-AKI-AKI 3 MFU [ Time Frame: 3 months after Baseline ]
    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).

  5. Reversal of HRS-AKI-AKI 12 MFU [ Time Frame: 12 months after Baseline ]
    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).

  6. Partial response to treatment 3 MFU [ Time Frame: 3 months after Baseline ]
    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.

  7. Partial response to treatment 12 MFU [ Time Frame: 12 months after Baseline ]
    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.

  8. In-hospital survival [ Time Frame: baseline until 12 months ]
    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)

  9. 28-day survival [ Time Frame: baseline until day 28 after baseline ]
    28-day survival

  10. 90-day survival [ Time Frame: baseline until day 90 after baseline ]
    90-day survival

  11. Length of in-hospital-stay [ Time Frame: baseline until 12 months ]
    Length of in-hospital-stay of the patients (patients are hospitalized for diagnosis of HRS-AKI and start of treatment)

  12. Changes in HrQoL as measured by SF36 3 MFU [ Time Frame: 3 months after Baseline ]
    Relative changes in Health-related Quality of Life as measured by SF36 at 3 months (vs. baseline)

  13. Changes in HrQoL as measured by SF36 12 MFU [ Time Frame: 12 months after Baseline ]
    Relative changes in Health-related Quality of Life as measured by SF36 at 12 months (vs. baseline)

  14. Changes in HrQoL as measured by CLDQ 3 MFU [ Time Frame: 3 months after Baseline ]
    Relative changes in Health-related Quality of Life as measured by CLDQ (Chronic Liver Disease Questionnaire) at 3 months (vs. baseline)

  15. Changes in HrQoL as measured by CLDQ 12 MFU [ Time Frame: 12 months after Baseline ]
    Relative changes in Health-related Quality of Life as measured by CLDQ (Chronic Liver Disease Questionnaire) at 12 months (vs. baseline)

  16. Need for renal replacement therapy [ Time Frame: 12 months after Baseline ]
    Need for renal replacement therapy within Follow-up

  17. recurrence of HRS-AKI after treatment at 3 months [ Time Frame: 3 months after Baseline ]
    recurrence of HRS-AKI after treatment at 3 months

  18. recurrence of HRS-AKI after treatment at 12 months [ Time Frame: 12 months after Baseline ]
    recurrence of HRS-AKI after treatment at 12 months

  19. Safety Assessment [ Time Frame: 12 months after Baseline ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)
  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 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 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
  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, hypertensive 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 (< 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
  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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05346393


Contacts
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Contact: Cristina Ripoll, Prof. Dr. +4936419 ext 32 44 01 cristina.ripoll@med.uni-jena.de
Contact: Alexander Zipprich, Prof. Dr. +4936419 ext 32 44 01 alexander.zipprich@med.uni-jena.de

Locations
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Germany
University Hospital RWTH Aachen
Aachen, Germany, 52074
Contact: Tony Bruns, Prof. Dr.       tbruns@ukaachen.de   
University Hospital Dresden, Medical Clinic I, Gastroenterology
Dresden, Germany, 01307
Contact: Marco Berning, Dr.    +49 351 458 ext 5643    Marco.Berning@uniklinikum-dresden.de   
University Hospital Freiburg
Freiburg im Breisgau, Germany, 79106
Contact: Dominik Bettinger, PD Dr.       dominik.bettinger@uniklinik-freiburg.de   
University Hospital Halle
Halle (Saale), Germany, 06120
Contact: Robin Greinert, Dr.    +49345557 ext 2665    robin.greinert@uk-halle.de   
Medical University Hannover
Hannover, Germany, 30625
Contact: Benjamin Maasoumy, PD Dr.    +49 511532 ext 6814    Maasoumy.Benjamin@mh-hannover.de   
Jena University Hospital, Clinic for Inner Medicine IV
Jena, Germany, 07747
Contact: Cristina Ripoll, Prof. Dr.    +4936419 ext 324401    cristina.ripoll@med.uni-jena.de   
RKH Clinic Ludwigsburg
Ludwigsburg, Germany, 71640
Contact: Karel Caca, Prof. Dr.    +49 7141 99 ext 67201    karel.caca@rkh-kliniken.de   
Ludwig-Maximilians-University, Klinikum Großhadern
Munich, Germany, 81377
Contact: Christian Lange, Prof. Dr.       Christian.Lange@med.uni-muenchen.de   
University Hospital Münster, Medical Clinic B
Münster, Germany, 48149
Contact: Jonel Trebicka, Prof. Dr.    +49 251 83 ext 57562    jonel.trebicka@ukmuenster.de   
Sponsors and Collaborators
Jena University Hospital
German Research Foundation
Center for Clinical Studies, Jena University Hospital
KKS Halle, University Hospital Halle (Saale)
Investigators
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Study Director: Cristina Ripoll, Prof. Dr. Jena University Hospital
  Study Documents (Full-Text)

Documents provided by Cristina Ripoll, Jena University Hospital:
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Responsible Party: Cristina Ripoll, Prof. Dr., Jena University Hospital
ClinicalTrials.gov Identifier: NCT05346393    
Other Study ID Numbers: ZKSJ0146
DE-22-00013779 ( Other Identifier: BfArM )
431667134 ( Other Grant/Funding Number: DFG )
First Posted: April 26, 2022    Key Record Dates
Last Update Posted: November 29, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Liver Cirrhosis
Hepatorenal Syndrome
Acute Kidney Injury
Syndrome
Fibrosis
Ascites
Disease
Pathologic Processes
Liver Diseases
Digestive System Diseases
Renal Insufficiency
Kidney Diseases
Urologic Diseases
Terlipressin
Antihypertensive Agents
Vasoconstrictor Agents