Cornelius Engelmann 1, Oana Brosteanu 2, Hannelore Tenckhoff 1, Jana Babatz 3, Frank Lammert 4, Michael Manns 5, Ingolf Schiefke 6, Tony Bruns 7, Christian Trautwein 8, Stefan Zeuzem 9, Ulrich Treichel 10, Rajiv Jalan 11, Thomas Berg 1 1 University Hospital Leipzig, Division of Gastroenterology and Hepatology, Leipzig, Germany; 2 University Leipzig, Clinical trials centre, Leipzig, Germany; 3 University Hospital Dresden, Division of Gastroenterology, Dresden, Germany; 4University Hospital Homburg, Devision of Gastroenterology and Endocrinology, Homburg, Germany; 5 Hannover Medical School, Division of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany; 6 St. Georg Hospital, Division of Gastroenterology and Hepatology, Leipzig, Germany; 7 University Hospital Jena, Division of Gastroenterology, Hepatology and Infectiology, Jena, Germany; 8 University Hospital Aachen, Division of Gastroenterology, Metabolism and Intensive care, Aachen, Germany; 9 University Hospital Frankfurt, Division of Gastroenterology and Hepatology, Frankfurt, Germany; 10 General Hospital Hagenow; Division of Internal Medicine, Hagenow, Germany; 11 Royal Free Hospital, UCL Institute for Liver and Digestive Health, London, Great Britain BACKGROUND Ascites represents a complication of liver cirrhosis that becomes refractory to medical treatment in 5-10% of patients. The treatment of choice is repeated paracentesis or if applicable the implantation of a transjugular intrahepatic portosystemic shunt (TIPS). However, complications such as bleedings, hepatic encephalopathy and liver failure limit applicability of TIPS. The alfapump® system from Sequana Medical is a device implanted at subcutaneous level, which is able to move the ascitic fluid from the peritoneal cavity to the urinary bladder. Usually the device is implanted in patients with advanced stages of liver cirrhosis if TIPS is contraindicated. However, complications like renal insufficiency and infections largely result from this late disease stage. AIM The purpose of the Agua-Trial is to evaluate the efficacy of the alfapump in patients with cirrhosis presenting with recurrent or refractory ascites. Two patient populations are studied with different aims: 1.patients with indication to TIPS - the aim is to show that alfapump is non-inferior to TIPS in reducing the need for paracenteses. 2.patients with contraindication to TIPS - the aim is to show that alfapump is superior to repeated paracenteses, reducing the need for paracenteses. PERSPECTIVE REFERENCES Agua-Trial is the first large-sale clinical trial to evaluate the efficacy as well as the complications of alfapump in comparison with TIPS in patients with recurrent or refractory ascites qualifying for both treatments. Agua-Trial will provide important information about the clinical course of this condition and may have significant impact on treatment strategies in these patients. Arroyo V, Colmenero J. J Hepatol 2003; 38: S69–89. Ginès P et al;. J Hepatol 2010;53: Planas R et al. Clin Gastroenterol Hepatol 2006; 4: 1385–94. Arroyo V et al. Hepatology 1996; 23: 164–76. Pache I, Bilodeau M. Aliment Pharmacol Ther 2005;21:525–9. Ginès P et al. Gastroenterology 1988;94:1493–502. Lebrec D et al. J Hepatol 1996;25:135–44. Bellot J et al. J Hepatol 2013;58:922-7 Alfapump system versus transjugular intrahepatic portosystemic shunt and paracentesis in the treatment of ascites. A multicentre randomised controlled study (Agua-Trial) Contact Information Cornelius Engelmann Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Germany Liebigstraße 20, Leipzig Phone number: Fax number: Patients will be randomised using centralised randomisation stratified by site and frequency of paracentesis to ensure an approximate 1:1 ratio between both treatment groups overall and at all sites ENROLLMENT 1. Key Inclusion Criteria Males and non-pregnant females ≥ 18 years of age. Cirrhosis of the liver defined by histological and/or clinical, and/or radiological criteria Presenting recurrent and refractory ascites Capable of giving written informed consent and ability to operate the device Alcohol abstinence > 3 month No active chronic hepatitis C 2. Key Exclusion Criteria General contraindications indicating an advanced stage of liver cirrhosis: Bilirubin >5 mg/dl, INR > 1.5, Serum-Sodium <130 mmol/l ECOG >1 (Perfomance status) Renal failure defined as serum creatinine higher than or equal to 1,5 mg/dl recurring bacterial peritonitis and/or urinary infections hepatic or extra hepatic malignancy, unless adequately treated or in complete remission for ≥ 3 years. 3. Contraindication for TIPS-Implantation defining arm A (TIPS-Indication) and arm B (TIPS- Contraindication): left ventricular ejection fraction (EF) <40% pulmonary hypertension Hepatic encephalopathy Bilirubin > 3mg/dl Age >70 years Hepatocellular Carcinoma Primary Objective Is to evaluate the efficacy of the alfapump in comparison with TIPS and standard care for refractory/recurrent ascites Primary Endpoint: Average number of paracenteses per quarter (three month) documented over 4 quarters (1 year) Secondary Objective Is to evaluate the influence on life quality as well as safety of the alfapump in comparison with TIPS and standard medical care for refractory/recurrent ascites Secondary endpoints: Transplant-free survival Treatment related complications Cumulative Incidence of device failure Number of paracenteses within a quarter (3 month) with and without device failure Rate of therapeutic paracentesis and ascites volume that has been removed (starting four weeks after study inclusion) Rate of cirrhosis-related complications including infections Patients Quality of Life (chronic liver disease specific) Frequency and duration of hospital stays Nutrition: upper arm girth Amount (per patient) of albumin substitution OBJECTIVE/ENDPOINTS Two hundred sixty male and female patients ≥18 years with recurrent/refractory ascites with underlying cirrhosis at up to 20 European centres (Germany, Great Britain) TRIAL TREATMENTS After pump implantation prophylaxis against spontaneous bacterial peritonitis (SBP) with Ciprofloxacin 750mg/once weekly or norfloxacin 400mg/day. The alfapump System will be implanted using general anaesthesia or conscious sedation. The parameters of the device will be modified according to each patient’s individual requirements, setting the daily loss of ascitic fluid needed to maintain a stable body weight. TIPS will be implanted using standardized interventional radiological techniques. Albumin substitution is recommended according to the recommendation of the German as well as European guideline for the treatment of ascites: Renal insufficiency (according to AKIN; at least increase in serum creatinine ≥0.3 mg/dl or increase to ≥150% to 200% from baseline urine output 0.5 ml/kg/h for > 6 h) Large-volume paracentesis Spontaneous bacterial peritonitis RANDOMIZATIONDESIGN