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

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ClinicalTrials.gov Identifier: NCT04311489
Recruitment Status : Not yet recruiting
First Posted : March 17, 2020
Last Update Posted : March 17, 2020
Sponsor:
Collaborators:
Aarhus University Hospital
ADS AIPHIA Development Services AG
Information provided by (Responsible Party):
University of Aarhus

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.

Condition or disease Intervention/treatment Phase
Cirrhosis, Liver Ascites Hepatic Drug: Ularitide Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, double-blind, placebo-controlled clinical trial
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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.
Estimated Study Start Date : June 1, 2020
Estimated Primary Completion Date : May 31, 2022
Estimated Study Completion Date : May 31, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cirrhosis

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 Name: 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.




Primary Outcome Measures :
  1. Absolute and relative change in sodium excretion rate. [ Time Frame: After 24 hours and at termination of treatment (up to 48 hours) ]
  2. Absolute and relative change in urine volume. [ Time Frame: After 24 hours and at termination of treatment (up to 48 hours) ]
  3. Change of absolute body weight. [ Time Frame: At termination of treatment (up to 48 hours) ]

Secondary Outcome Measures :
  1. Number of responders in the ularitide group versus the placebo group, defined by: [ Time Frame: Throughout the treatment period. Latest measure at termination of treatment (up to 48 hours) ]
    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.

  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. Absolute and relative change in waist circumference. [ Time Frame: After 24 hours and at termination of treatment (up to 48 hours) ]
  6. Absolute and relative change in serum creatinine. [ Time Frame: After 24 hours and at termination of treatment (up to 48 hours) ]
  7. Absolute and relative change in estimated glomerular filtration rate (eGFR). [ Time Frame: After 24 hours and at termination of treatment (up to 48 hours) ]
  8. Absolute and relative change in plasma and urine osmolalities. [ Time Frame: Throughout the treatment period. Latest measure at 6 hours post-treatment follow-up ]
  9. 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 ]
  10. Absolute and relative change in hematocrit. [ Time Frame: After 24 hours and 48 hours of treatment and at 6 hours post-treatment follow-up ]
  11. 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 ]
  12. 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 ]
  13. 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 ]
  14. 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 Outcome Measures:
  1. Incidence of adverse events/reactions. [ Time Frame: Throughout the treatment period and until 6 hours post-treatment follow-up ]
  2. Incidence of serious adverse events/reactions. [ Time Frame: Throughout the treatment period and until 30 days post-treatment follow-up ]
  3. Incidence of stopping criteria leading to a dose reduction. [ Time Frame: Throughout the treatment period (up to 48 hours) ]
  4. Incidence of stopping criteria leading to early termination of treatment. [ Time Frame: Throughout the treatment period (up to 48 hours) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04311489


Contacts
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Contact: Henning Grønbæk, Prof,MD,PhD +45 21 67 92 81 henngroe@rm.dk
Contact: Rasmus H Gantzel, MD +45 40 87 92 22 ragant@rm.dk

Locations
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Denmark
Department of Hepatology and Gastroenterology, Aarhus University Hospital
Aarhus, Central Denmark Region, Denmark, 8200
Contact: Henning Grønbæk, Prof,MD,PhD    +45 21 67 92 81    henngroe@rm.dk   
Contact: Rasmus H Gantzel, MD    +45 40 87 92 22    ragant@rm.dk   
Sponsors and Collaborators
University of Aarhus
Aarhus University Hospital
ADS AIPHIA Development Services AG
Investigators
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Principal Investigator: Henning Grønbæk, Prof,MD,PhD Department of Hepatology and Gastroenterology, Aarhus University Hospital,

Publications:
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Responsible Party: University of Aarhus
ClinicalTrials.gov Identifier: NCT04311489    
Other Study ID Numbers: ULA04
2019-002268-28 ( EudraCT Number )
First Posted: March 17, 2020    Key Record Dates
Last Update Posted: March 17, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Aarhus:
Cirrhosis
Ascites
Refractory ascites
Natriuresis
Diuresis
Urodilatin
Ularitide
natriuretic peptide
Additional relevant MeSH terms:
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Liver Cirrhosis
Fibrosis
Ascites
Pathologic Processes
Liver Diseases
Digestive System Diseases
Ularitide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Diuretics
Natriuretic Agents