Refractory Ascites in Patients With Liver Cirrhosis, and the Potential Treatment With 48 Hours Infusion of Ularitide. (ULA04)

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

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.

Study Overview

• Status: Terminated
• Conditions: Cirrhosis, Liver; Ascites Hepatic
• Intervention / Treatment: Drug: Ularitide; Drug: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Henning Grønbæk, Prof,MD,PhD; Phone Number: +45 21 67 92 81; Email: henngroe@rm.dk
• Study Contact Backup: Name: Rasmus H Gantzel, MD; Phone Number: +45 40 87 92 22; Email: ragant@rm.dk

Study Locations

• Denmark
  • Central Denmark Region
    • Aarhus, Central Denmark Region, Denmark, 8200
      • Department of Hepatology and Gastroenterology, Aarhus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ularitide; Test product. Continuous intravenous infusion with 30 ng/kg/min for 48 hours.	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.; Other Names: Urodilatin
Placebo Comparator: Placebo; Matching placebo. Continuous IV infusion for 48 hours.	Drug: Placebo; Continuous intravenous infusion for 48 hours at a bodyweight-adjusted infusion rate.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Absolute and relative change in sodium excretion rate.	After 24 hours and at termination of treatment (up to 48 hours)
Absolute and relative change in urine volume.	After 24 hours and at termination of treatment (up to 48 hours)
Change of absolute body weight.	At termination of treatment (up to 48 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
Absolute and relative change in sodium excretion rate.		After 2 hours and 4 hours of treatment and at 6 hours post-treatment follow-up
Absolute and relative change in urine volume.		After 2 hours and 4 hours of treatment and at 6 hours post-treatment follow-up
Absolute and relative change in plasma cyclic guanosine monophosphate (cGMP) concentration.		Throughout the treatment period. Latest measure at 6 hours post-treatment follow-up
Absolute and relative change in waist circumference.		After 24 hours and at termination of treatment (up to 48 hours)
Absolute and relative change in serum creatinine.		After 24 hours and at termination of treatment (up to 48 hours)
Absolute and relative change in estimated glomerular filtration rate (eGFR).		After 24 hours and at termination of treatment (up to 48 hours)
Absolute and relative change in plasma and urine osmolalities.		Throughout the treatment period. Latest measure at 6 hours post-treatment follow-up
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
Absolute and relative change in hematocrit.		After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up
Absolute and relative change in plasma copeptin concentration.		After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up
Absolute and relative change in plasma renin concentration.		After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up
Absolute and relative change in plasma angiotensin concentration.		After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up
Absolute and relative change in plasma aldosterone concentration.		After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up

Other Outcome Measures

Outcome Measure	Time Frame
Incidence of adverse events/reactions.	Throughout the treatment period and until 6 hours post-treatment follow-up
Incidence of serious adverse events/reactions.	Throughout the treatment period and until 30 days post-treatment follow-up
Incidence of stopping criteria leading to a dose reduction.	Throughout the treatment period (up to 48 hours)
Incidence of stopping criteria leading to early termination of treatment.	Throughout the treatment period (up to 48 hours)

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Aarhus University Hospital; ADS AIPHIA Development Services AG
• Investigators: Principal Investigator: Henning Grønbæk, Prof,MD,PhD, Department of Hepatology and Gastroenterology, Aarhus University Hospital,

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2020
• Primary Completion (Actual): November 30, 2022
• Study Completion (Actual): November 30, 2022

Study Registration Dates

• First Submitted: March 12, 2020
• First Submitted That Met QC Criteria: March 16, 2020
• First Posted (Actual): March 17, 2020

Study Record Updates

• Last Update Posted (Actual): May 18, 2023
• Last Update Submitted That Met QC Criteria: May 16, 2023
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Cirrhosis; Ascites; Diuresis; Natriuresis; Refractory ascites; natriuretic peptide; Urodilatin; Ularitide
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis; Ascites; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Natriuretic Agents; Diuretics; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Ularitide
• Other Study ID Numbers: ULA04; 2019-002268-28 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No