HRS-AKI Treatment With TIPS in Patients With Cirrhosis

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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Cirrhosis, Liver, Hepatorenal Syndrome, Acute Kidney Injury, Ascites Hepatic

Intervention / Treatment
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* Procedure: TIPS
* Drug: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with cirrhosis confirmed by histology or liver stiffness or with unequivocal signs in ultrasound, endoscopy and/or blood tests Clinically evident ascites due to portal hypertension (SAAG > 11 g/L) HRS-AKI stages 2 or 3 Planned vasoactive treatment for the management of HRS, as defined by the administration of terlipressin + albumin Age: ≥ 18 to ≤ 75 years old at the time of consent ECOG < 4 prior to hospital admission 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. 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: 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. Recent or current use of nephrotoxic drugs (NSAIDS, Aminoglycosides or iodinated contrast medium) in the previous 72 hours before AKI diagnosis Improvement of renal function after 2 days of diuretic removal and plasma volume expansion with albumin 1 gr/kg Uncontrolled shock within the last 48 hours prior to randomization 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. 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.) Patients with contraindications to TIPS placement (e.g. Bilirubin > 85.5 µmol/L (≙ 5 mg/dL), recurrent hepatic encephalopathy) Patients with cavernous portal vein thrombosis, splenic vein thrombosis or mesenteric vein thrombosis Patients with clinically significant cardiac disease (NYHA ≥ II) Patients with diastolic dysfunction grade 3. Patients with a reduced systolic function with an ejection fraction ≤ 50 % Patients with ACLF grade 3 Patients with creatinine value > 442 µmol/L (≙ 5 mg/dL) Patients with an acute variceal bleeding at the time of screening who have indication for pre-emptive TIPS and/or terlipressin. 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 Patients with hepatocellular carcinoma outside of the Milan criteria Patients with hepatocellular carcinoma within the Milan criteria in whom the tumor is located in the puncture tract. Patients with benign liver tumors (except regenerative nodules) which are located in the puncture tract. Patients who already have a TIPS placed Patients who already had a liver transplantation Patients with other comorbidities that lead to an estimated life expectancy under 1 year. Patients with respiratory insufficiency which requires mechanical ventila-tion Patients with circulatory failure which requires administration of other vas-opressors (catecholamines) Patients receiving renal replacement therapy The subject is currently enrolled in another investigational device or drug trial. Patients with pregnancy or lactation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel Assignment 1:1-randomization, parallel design, stratified by center and AKI stage.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TIPS group<br>TIPS implant (transjugular intrahepatic portosystemic shunt) | Procedure: TIPS<br>* A transjugular intrahepatic portosystemic shunt (TIPS) is implanted into the cirrhotic liver<br>|
| Active Comparator: Control group<br>Standard medication therapy with terlipressin and albumin | Drug: Standard of Care<br>* Administration of Terlipressin and Albumin according to Standard of Care<br>* Other names: Terlipressin + Albumin;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ascites, Cirrhosis, Acute Kidney Injury, Hepatorenal Syndrome, TIPS, transjugular intrahepatic portosystemic shunt, Terlipressin