Back to resultsRefractory Ascites in Patients With Liver Cirrhosis, and the Potential Treatment With 48 Hours Infusion of Ularitide. (ULA04)
Primary Purpose
Cirrhosis, Liver, Ascites Hepatic
Status
Terminated
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
Ularitide
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Cirrhosis, Liver focused on measuring Cirrhosis, Ascites, Refractory ascites, Natriuresis, Diuresis, Urodilatin, Ularitide, natriuretic peptide
Eligibility Criteria
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
Sites / Locations
- Department of Hepatology and Gastroenterology, Aarhus University Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Ularitide
Placebo
Arm Description
Test product. Continuous intravenous infusion with 30 ng/kg/min for 48 hours.
Matching placebo. Continuous IV infusion for 48 hours.
Outcomes
Primary Outcome Measures
Absolute and relative change in sodium excretion rate.
Absolute and relative change in urine volume.
Change of absolute body weight.
Secondary Outcome Measures
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.
Absolute and relative change in sodium excretion rate.
Absolute and relative change in urine volume.
Absolute and relative change in plasma cyclic guanosine monophosphate (cGMP) concentration.
Absolute and relative change in waist circumference.
Absolute and relative change in serum creatinine.
Absolute and relative change in estimated glomerular filtration rate (eGFR).
Absolute and relative change in plasma and urine osmolalities.
Absolute and relative change in GFR-24h-Crea (Glomerular filtration rate based on 24-hour creatinine clearance).
Absolute and relative change in hematocrit.
Absolute and relative change in plasma copeptin concentration.
Absolute and relative change in plasma renin concentration.
Absolute and relative change in plasma angiotensin concentration.
Absolute and relative change in plasma aldosterone concentration.
Full Information
NCT ID
NCT04311489
First Posted
March 12, 2020
Last Updated
May 16, 2023
Sponsor
University of Aarhus
Collaborators
Aarhus University Hospital, ADS AIPHIA Development Services AG
1. Study Identification
Unique Protocol Identification Number
NCT04311489
Brief Title
Refractory Ascites in Patients With Liver Cirrhosis, and the Potential Treatment With 48 Hours Infusion of Ularitide.
Acronym
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.
Study Type
Interventional
2. Study Status
Record Verification Date
May 2022
Overall Recruitment Status
Terminated
Why Stopped
Interim analysis showing safety concerns
Study Start Date
August 1, 2020 (Actual)
Primary Completion Date
November 30, 2022 (Actual)
Study Completion Date
November 30, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Aarhus
Collaborators
Aarhus University Hospital, ADS AIPHIA Development Services AG
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cirrhosis, Liver, Ascites Hepatic
Keywords
Cirrhosis, Ascites, Refractory ascites, Natriuresis, Diuresis, Urodilatin, Ularitide, natriuretic peptide
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Randomized, double-blind, placebo-controlled clinical trial
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
17 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Ularitide
Arm Type
Experimental
Arm Description
Test product. Continuous intravenous infusion with 30 ng/kg/min for 48 hours.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Matching placebo. Continuous IV infusion for 48 hours.
Intervention Type
Drug
Intervention Name(s)
Ularitide
Other Intervention Name(s)
Urodilatin
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Continuous intravenous infusion for 48 hours at a bodyweight-adjusted infusion rate.
Primary Outcome Measure Information:
Title
Absolute and relative change in sodium excretion rate.
Time Frame
After 24 hours and at termination of treatment (up to 48 hours)
Title
Absolute and relative change in urine volume.
Time Frame
After 24 hours and at termination of treatment (up to 48 hours)
Title
Change of absolute body weight.
Time Frame
At termination of treatment (up to 48 hours)
Secondary Outcome Measure Information:
Title
Number of responders in the ularitide group versus the placebo group, defined by:
Description
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.
Time Frame
Throughout the treatment period. Latest measure at termination of treatment (up to 48 hours)
Title
Absolute and relative change in sodium excretion rate.
Time Frame
After 2 hours and 4 hours of treatment and at 6 hours post-treatment follow-up
Title
Absolute and relative change in urine volume.
Time Frame
After 2 hours and 4 hours of treatment and at 6 hours post-treatment follow-up
Title
Absolute and relative change in plasma cyclic guanosine monophosphate (cGMP) concentration.
Time Frame
Throughout the treatment period. Latest measure at 6 hours post-treatment follow-up
Title
Absolute and relative change in waist circumference.
Time Frame
After 24 hours and at termination of treatment (up to 48 hours)
Title
Absolute and relative change in serum creatinine.
Time Frame
After 24 hours and at termination of treatment (up to 48 hours)
Title
Absolute and relative change in estimated glomerular filtration rate (eGFR).
Time Frame
After 24 hours and at termination of treatment (up to 48 hours)
Title
Absolute and relative change in plasma and urine osmolalities.
Time Frame
Throughout the treatment period. Latest measure at 6 hours post-treatment follow-up
Title
Absolute and relative change in GFR-24h-Crea (Glomerular filtration rate based on 24-hour creatinine clearance).
Time Frame
After 24 hours and 48 hours of treatment
Title
Absolute and relative change in hematocrit.
Time Frame
After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up
Title
Absolute and relative change in plasma copeptin concentration.
Time Frame
After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up
Title
Absolute and relative change in plasma renin concentration.
Time Frame
After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up
Title
Absolute and relative change in plasma angiotensin concentration.
Time Frame
After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up
Title
Absolute and relative change in plasma aldosterone concentration.
Time Frame
After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up
Other Pre-specified Outcome Measures:
Title
Incidence of adverse events/reactions.
Time Frame
Throughout the treatment period and until 6 hours post-treatment follow-up
Title
Incidence of serious adverse events/reactions.
Time Frame
Throughout the treatment period and until 30 days post-treatment follow-up
Title
Incidence of stopping criteria leading to a dose reduction.
Time Frame
Throughout the treatment period (up to 48 hours)
Title
Incidence of stopping criteria leading to early termination of treatment.
Time Frame
Throughout the treatment period (up to 48 hours)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Henning Grønbæk, Prof,MD,PhD
Organizational Affiliation
Department of Hepatology and Gastroenterology, Aarhus University Hospital,
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Hepatology and Gastroenterology, Aarhus University Hospital
City
Aarhus
State/Province
Central Denmark Region
ZIP/Postal Code
8200
Country
Denmark
12. IPD Sharing Statement
Citations:
PubMed Identifier
9697672
Citation
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.
Results Reference
background
PubMed Identifier
17257428
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.
Results Reference
background
PubMed Identifier
34851251
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.
Results Reference
background
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Refractory Ascites in Patients With Liver Cirrhosis, and the Potential Treatment With 48 Hours Infusion of Ularitide.
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