Refractory Ascites in Patients With Liver Cirrhosis, and the Potential Treatment With 48 Hours Infusion of Ularitide.

Cirrhosis, Liver Clinical Trial

— ULA04  

Official title:

Single-center, Randomized, Double-blind, Placebo-controlled Clinical Trial for the Safety, Tolerability and Efficacy of Ularitide in Cirrhosis Patients With Refractory Ascites.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04311489
• Other study ID #: ULA04
• Secondary ID: 2019-002268-28
• Status: Terminated
• Phase: Phase 2
• Start date: August 1, 2020
• Est. completion date: November 30, 2022

Study information

• Verified date: May 2022
• Source: University of Aarhus
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 17
• Est. completion date: November 30, 2022
• Est. primary completion date: November 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Ascites
• Ascites Hepatic
• Cirrhosis, Liver
• Fibrosis
• Liver Cirrhosis

Intervention

Drug:
• Ularitide
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.
• Placebo
Continuous intravenous infusion for 48 hours at a bodyweight-adjusted infusion rate.

Locations

Country	Name	City	State
Denmark	Department of Hepatology and Gastroenterology, Aarhus University Hospital	Aarhus	Central Denmark Region

Sponsors (3)

Lead Sponsor	Collaborator
University of Aarhus	Aarhus University Hospital, ADS AIPHIA Development Services AG

Country where clinical trial is conducted

Denmark, 

References & Publications (3)

Carstens J, Greisen J, Jensen KT, Vilstrup H, Pedersen EB. Renal effects of a urodilatin infusion in patients with liver cirrhosis, with and without ascites. J Am Soc Nephrol. 1998 Aug;9(8):1489-98. doi: 10.1681/ASN.V981489. — View Citation

Carstens J, Gronbaek H, Larsen HK, Pedersen EB, Vilstrup H. Effects of urodilatin on natriuresis in cirrhosis patients with sodium retention. BMC Gastroenterol. 2007 Jan 26;7:1. doi: 10.1186/1471-230X-7-1. — View Citation

Gantzel RH, Meyer M, Mazgareanu S, Aagaard NK, Jepsen P, Holzmeister J, Watson H, Gronbaek H. Ularitide as treatment of refractory ascites in cirrhosis- a study protocol for a randomised trial. Dan Med J. 2021 Nov 12;68(12):A07210610. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of adverse events/reactions.		Throughout the treatment period and until 6 hours post-treatment follow-up
Other	Incidence of serious adverse events/reactions.		Throughout the treatment period and until 30 days post-treatment follow-up
Other	Incidence of stopping criteria leading to a dose reduction.		Throughout the treatment period (up to 48 hours)
Other	Incidence of stopping criteria leading to early termination of treatment.		Throughout the treatment period (up to 48 hours)
Primary	Absolute and relative change in sodium excretion rate.		After 24 hours and at termination of treatment (up to 48 hours)
Primary	Absolute and relative change in urine volume.		After 24 hours and at termination of treatment (up to 48 hours)
Primary	Change of absolute body weight.		At termination of treatment (up to 48 hours)
Secondary	Number of responders in the ularitide group versus the placebo group, defined by:	Urine volume increase of =100 % versus baseline, urine volume increase =50 % versus baseline, natriuresis increase by =100 % versus baseline and/or body weight reduction by =2 kg versus baseline.	Throughout the treatment period. Latest measure at termination of treatment (up to 48 hours)
Secondary	Absolute and relative change in sodium excretion rate.		After 2 hours and 4 hours of treatment and at 6 hours post-treatment follow-up
Secondary	Absolute and relative change in urine volume.		After 2 hours and 4 hours of treatment and at 6 hours post-treatment follow-up
Secondary	Absolute and relative change in plasma cyclic guanosine monophosphate (cGMP) concentration.		Throughout the treatment period. Latest measure at 6 hours post-treatment follow-up
Secondary	Absolute and relative change in waist circumference.		After 24 hours and at termination of treatment (up to 48 hours)
Secondary	Absolute and relative change in serum creatinine.		After 24 hours and at termination of treatment (up to 48 hours)
Secondary	Absolute and relative change in estimated glomerular filtration rate (eGFR).		After 24 hours and at termination of treatment (up to 48 hours)
Secondary	Absolute and relative change in plasma and urine osmolalities.		Throughout the treatment period. Latest measure at 6 hours post-treatment follow-up
Secondary	Absolute and relative change in GFR-24h-Crea (Glomerular filtration rate based on 24-hour creatinine clearance).		After 24 hours and 48 hours of treatment
Secondary	Absolute and relative change in hematocrit.		After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up
Secondary	Absolute and relative change in plasma copeptin concentration.		After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up
Secondary	Absolute and relative change in plasma renin concentration.		After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up
Secondary	Absolute and relative change in plasma angiotensin concentration.		After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up
Secondary	Absolute and relative change in plasma aldosterone concentration.		After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up