Interim analysis showing safety concerns

This clinical trial intends to investigate the safety, tolerability and efficacy of ularitide on the renal response in patients with liver cirrhosis and refractory ascites for a maximum exposure duration of 48 hours, through a randomized, placebo-controlled, double-blind, single-center trial.

The investigators hypothesize that ularitide infusion is more effective than placebo to induce and maintain clinically meaningful natriuresis and diuresis in patients with liver cirrhosis and refractory ascites.

Participants will be given ularitide or placebo intravenously while hospitalized at Department of Hepatology and Gastroenterology at Aarhus University Hospital. During the hospitalization blood and urine samples are frequently collected.

30 ng/kg/min is the starting dosage for all participants. Depending on effects and/or side effects, ULA04 is designed to individualize treatment doses by up- and/or downtitration of the infusion dose within a predefined dose range. Relevant safety precautions are incorporated in the study design and treatment will be prematurely discontinued if a pre-defined stopping criteria presents.

Patients will be followed up for the appearance of serious adverse events 30 days after the treatment.

If a separate written consent is given by the participants, additional blood and urine samples will be collected and stored in a biobank for future research.

Inclusion Criteria:

• Men and women >18 years
• Liver cirrhosis confirmed by fibroscan (>20 kPa), or by imaging with signs of an irregular liver surface with collaterals, or clinically by cirrhosis stigmata
• Refractory ascites Definition: failure to respond to or intolerance to high dose diuretics (spironolactone up to 400mg/day and furosemide up to 160mg/day) and early ascites recurrence (reappearance of grade 2 or 3 ascites within 4 weeks of initial mobilization or ≥2 paracentesis within last 3 months)
• Urine sodium excretion <60 mmol/24 hour
• Serum creatinine <150 µmol/L
• Child-Turcotte-Pugh score of B or C (<13)
• Bilirubin <150 µmol/L
• Prothrombin time (PP) 0.20-0.60 (INR 1.3-2.5)
• Systolic blood pressure ≥95 mmHg
• Written informed consent to participate in the clinical trial

Exclusion Criteria:

• Gastrointestinal bleeding within 2 weeks prior to inclusion
• Proteinuria >500 mg/day
• Hemoglobin <5.5 mmol/L
• Spontaneous bacterial peritonitis within 2 weeks prior to inclusion
• Loculated ascites
• Hepatic encephalopathy grade 2-4 (West-Haven classification)
• Obstructive uropathy
• Primary kidney disease
• Known diagnosis of congestive heart failure
• Known diagnosis of acute-on-chronic liver failure
• Known diagnosis of systemic inflammatory response syndrome
• Acute infections by known diagnosis and/or antibiotic treatment
• Known HIV infection
• Known allergy to the investigational drug or other natriuretic peptides
• Treatment with dobutamine, levosimendan, milrinone, any phosphodiesterase inhibitor, octreotide, midodrine, vasopressin, dopamine or other vasopressors within 2 weeks prior to inclusion
• Nephrotoxic drugs within 1 month prior to inclusion
• Fertile women not using contraception, either an intrauterine device or hormonal contraception
• Positive pregnancy test in pre-menopausal women or in breast-feeding women
• Participation in an interventional clinical drug trial within 1 month prior to inclusion
• Legal incapacity or limited legal capacity
• Patients who are employees or relatives of the investigator