Clinical trial NCT05346393: HRS-AKI Treatment With TIPS in Patients With Cirrhosis
Official title: Hepatorenal Syndrome-acute Kidney Injury (HRS-AKI) Treatment With Transjugular Intrahepatic Portosystemic Shunt in Patients With Cirrhosis. A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Cirrhosis, Liver
Hepatorenal Syndrome
Acute Kidney Injury
Ascites Hepatic
Keywords: Ascites
Acute Kidney Injury
Cirrhosis
Hepatorenal Syndrome
TIPS
transjugular intrahepatic portosystemic shunt
Terlipressin
Lead sponsor: Jena University Hospital
Sponsor class: OTHER
Collaborators: name: German Research Foundation
name: University Hospital Halle (Saale)
First posted: 2022-04-26
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel Assignment 1:1-randomization, parallel design, stratified by center and AKI stage.
Primary purpose: TREATMENT

Brief summary: The study compares the effectiveness and safety of TIPS implantation in patients with HRS-AKI (stage1, 2 and 3) and liver cirrhosis with standard therapy (drug therapy with terlipressin + albumin).

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 (14 centers), prospective, randomized controlled trial which evaluates use of TIPS in patients with HRS-AKI (stage 1, 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.

Eligibility 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
3. HRS-AKI
4. Age: ≥ 18 to ≤ 80 years old at the time of consent
5. ECOG \< 4 prior to hospital admission
6. 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.
7. 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. Recent or current use of nephrotoxic drugs (NSAIDS, Aminoglycosides or high-dosed iodinated contrast medium) in the previous 72 hours before AKI diagnosis
2. Improvement of renal function after 1 day of diuretic removal and plasma volume expansion with albumin 1-1.5 gr/kg
3. Uncontrolled shock within the last 48 hours prior to randomization
4. 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.
5. 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.)
6. Patients with contraindications to TIPS placement (e.g. Bilirubin \> 85.5 µmol/L (≙ 5 mg/dL), recurrent hepatic encephalopathy, clinically relevant pulmonary hypertension, aortic stenosis)
7. Patients with cavernous portal vein thrombosis, splenic vein thrombosis or mesenteric vein thrombosis
8. Patients with clinically significant cardiac disease (NYHA ≥ II)
9. Patients with diastolic dysfunction grade 3.
10. Patients with a reduced systolic function with an ejection fraction ≤ 50 %
11. Patients with ACLF grade 3
12. Patients with creatinine value \> 442 µmol/L (≙ 5 mg/dL)
13. Patients with an acute variceal bleeding at the time of screening who have indication for pre-emptive TIPS and/or terlipressin.
14. 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
15. Patients with hepatocellular carcinoma outside of the Milan criteria
16. Patients with hepatocellular carcinoma within the Milan criteria in whom the tumor is located in the puncture tract.
17. Patients with benign liver tumors (except regenerative nodules) which are located in the puncture tract.
18. Patients who already have a TIPS placed
19. Patients who already had a liver transplantation
20. Patients with other comorbidities that lead to an estimated life expectancy under 1 year.
21. Patients with respiratory insufficiency which requires mechanical ventila-tion
22. Patients with circulatory failure which requires administration of other vas-opressors (catecholamines)
23. Patients receiving renal replacement therapy
24. The subject is currently enrolled in another investigational device or drug trial.
25. Patients with pregnancy or lactation
26. Patients which are suspected to be incompliant for study participation.

Primary outcomes:
measure: 12 month Liver transplant-free survival
timeFrame: 12 months after Baseline
Secondary outcomes:
measure: 3-month liver transplant free survival
timeFrame: 3 months after Baseline
measure: 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
timeFrame: within 12 months after Baseline
measure: Development of further decompensation of HRS-AKI during follow-up
timeFrame: within 12 months after Baseline
measure: Reversal of HRS-AKI-AKI 3 MFU
timeFrame: 3 months after Baseline
measure: Reversal of HRS-AKI-AKI 12 MFU
timeFrame: 12 months after Baseline
measure: Partial response to treatment 3 MFU
timeFrame: 3 months after Baseline
measure: Partial response to treatment 12 MFU
timeFrame: 12 months after Baseline
measure: In-hospital survival
timeFrame: baseline until 12 months
measure: 28-day survival
timeFrame: baseline until day 28 after baseline
measure: 90-day survival
timeFrame: baseline until day 90 after baseline
measure: Length of in-hospital-stay
timeFrame: baseline until 12 months
measure: Changes in HrQoL as measured by SF36 3 MFU
timeFrame: 3 months after Baseline
measure: Changes in HrQoL as measured by SF36 12 MFU
timeFrame: 12 months after Baseline
measure: Changes in HrQoL as measured by CLDQ 3 MFU
timeFrame: 3 months after Baseline
measure: Changes in HrQoL as measured by CLDQ 12 MFU
timeFrame: 12 months after Baseline
measure: Need for renal replacement therapy
timeFrame: 12 months after Baseline
measure: recurrence of HRS-AKI after treatment at 3 months
timeFrame: 3 months after Baseline
measure: recurrence of HRS-AKI after treatment at 12 months
timeFrame: 12 months after Baseline
measure: Safety Assessment
timeFrame: 12 months after Baseline
measure: Development of acute-on-chronic liver failure during follow-up
timeFrame: 12 months after Baseline
measure: Impact of the presence of intrinsic nephropathy as assessed by cystatin C and UnGAL on outcomes (survival and reversal of AKI)
timeFrame: 12 months after Baseline
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: University Hospital RWTH Aachen
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin CVK
city: Dresden
country: Germany
facility: University Hospital Dresden, Medical Clinic I, Gastroenterology
city: Essen
country: Germany
facility: Universitätsklinikum Essen (AöR)
city: Freiburg im Breisgau
country: Germany
facility: University Hospital Freiburg
city: Halle (Saale)
country: Germany
facility: University Hospital Halle
city: Hamburg
country: Germany
facility: University Hospital Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Medical University Hannover
city: Jena
country: Germany
facility: Jena University Hospital, Clinic for Inner Medicine IV
city: Landshut
country: Germany
facility: Klinikum Landshut AdöR der Stadt Landshut
city: Leipzig
country: Germany
facility: University Hospital Leipzig
city: Ludwigsburg
country: Germany
facility: RKH Clinic Ludwigsburg
city: Munich
country: Germany
facility: Ludwig-Maximilians-University, Klinikum Großhadern
city: Münster
country: Germany
facility: University Hospital Münster, Medical Clinic B
Study officials:
affiliation: Jena University Hospital
name: Cristina Ripoll, Prof. Dr.
role: STUDY_DIRECTOR
References: