Title
Refractory Ascites in Patients With Liver Cirrhosis, and the Potential Treatment With 48 Hours Infusion of Ularitide.
Single-center, Randomized, Double-blind, Placebo-controlled Clinical Trial for the Safety, Tolerability and Efficacy of Ularitide in Cirrhosis Patients With Refractory Ascites.
Phase
Phase 2Lead Sponsor
Aarhus UniversityStudy Type
InterventionalStatus
TerminatedIndication/Condition
Cirrhosis, Liver Ascites HepaticIntervention/Treatment
Ularitide ...Study Participants
17This 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.
Continuous intravenous infusion for 48 hours at a dose of 30 ng/kg/min. Depending on effect and/or side effects dose can be adjusted to 15 ng/kg/min or 45 ng/kg/min.
Continuous intravenous infusion for 48 hours at a bodyweight-adjusted infusion rate.
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
