Endothelin Receptor Antagonism With Ambrisentan to Treat Hepatorenal Syndrome

NCT06256432 | Active Not Recruiting Phase 2

• 1 other identifier: N-003-CRD005
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 6

Brief Summary

Patients with advanced cirrhosis of the liver develop kidney problems occasionally. This condition is called Hepatorenal Syndrome, requires hospitalization and frequently results in death. The goal of this clinical trial is to test whether the administration of low doses of ambrisentan can help patients with Hepatorenal Syndrome and to determine if it is safe. Ambrisentan is a drug that is approved for the treatment of high blood pressure in the lungs at higher doses. This clinical trial will compare the safety and effects of ambrisentan to another drug called terlipressin, which is commonly used to treat patients with hepatorenal syndrome. The main questions the clinical trial aims to answer are:

• Does ambrisentan help the kidney function of the patient?
• Does ambrisentan help prevent death in patients with Hepatorenal Syndrome?
• Does ambrisentan prevent Hepatorenal Syndrome from reappearing? While in the hospital, trial participants will receive either one of two doses of ambrisentan or terlipressin. If in the first 4 days, ambrisentan is not helpful, the patient may be eligible to receive terlipressin. Patients assigned to receive ambrisentan will continue taking this medication at home after leaving the hospitals and until they complete 60 days of treatment.

Conditions

Ascites Hepatic; Hepatorenal Syndrome; Liver Cirrhosis; Acute Kidney Injury

Outcome Measures

Primary Outcomes (1)

• Change in estimated GFR (eGFR) from baseline

  As determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula

  4 days

Secondary Outcomes (3)

• Proportion of patients achieving Hepatorenal Syndrome reversal

  14 days

• Proportion of subjects experiencing Hepatorenal Syndrome recurrence

  60 days

• Overall survival

  60 days

Study Arms (3)

Ambrisentan - Low Dose 1

EXPERIMENTAL

Liquid solution for oral administration, dose \< 250 µg/day, up to 60 days

Drug: Ambrisentan

Ambrisentan - Low Dose 2

EXPERIMENTAL

Liquid solution for oral administration, dose \< 250 µg/day, up to 60 days

Drug: Ambrisentan

Terlipressin

ACTIVE COMPARATOR

Sterile lyophilized powder, to be reconstituted for intravenous administration, at a dose indicated by the study investigator and administered for up to 14 days, considering the following recommendation: 1 mg terlipressin administered in 2-minute bolus every 6 hours for 3 days, and dose of terlipressin increased to 2 mg every 6 hours in the absence of a decrease of at least 30% in serum creatinine by day 4

Drug: Terlipressin

Interventions

Ambrisentan DRUG

Endothelin receptor antagonist

Ambrisentan - Low Dose 1; Ambrisentan - Low Dose 2

Terlipressin DRUG

Terlipressin

Terlipressin

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written Informed consent prior to any study-related procedures.
• Age ≥ 18 years and ≤ 70 years.
• Male or non-pregnant, non-lactating female. Women of child-bearing potential must have a confirmed negative serum pregnancy test at the time of screening and must use a highly effective contraceptive method throughout the study such as combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tube occlusion, vasectomised partner, and sexual abstinence and until one month after completing treatment with the study medication. In the case of hormonal contraception, women should have been on a stable regimen for a minimum of three months before study enrolment. Women not of child-bearing potential include post-menopausal females (defined as having a history of amenorrhea for at least one year) or a documented status as being surgically sterile (hysterectomy, bilateral oophorectomy, tubal ligation/salpingectomy). Men must use an effective contraception method (i.e., condom + diaphragm/spermicidal gel or foam, or vasectomy), and should not donate semen during the study. Men are considered to be fertile from the time of puberty, except for those men with permanent sterility secondary to bilateral orchiectomy.
• Cirrhosis of the liver by laboratory examination, clinical history or biopsy.
• History of ascites.
• Increase in serum creatinine ≥ 0.3 mg/dl (26.5 µmol/L) from a value obtained in the 7 days prior to admission, OR a serum creatinine ≥ 1.5 mg/dl (132.6 µmol/L) and is ≥ 1.5-fold above the most recent and lowest value obtained in the last 3 months.
• The subject has no clinical and/or haemodynamic evidence of intravascular volume depletion; or has undergone at least 12 hours of diuretic withdrawal and fluid resuscitation to discard or treat intravascular volume depletion (such as difficulty in establishing volume status, volume status is assessed as equivocal, or there is clinical and/or haemodynamic evidence of intravascular volume depletion), and no significant improvement in serum creatinine has been observed.

You may not qualify if:

• Serum creatinine \> 5 mg/dL (442 µmol/L).
• Mean arterial pressure (MAP) \< 60 mmHg.
• Large Volume Paracentesis (LVP) in the 3 days prior to screening.
• Sepsis, uncontrolled bacterial infection or less than 2 days anti-infective therapy for documented or suspected bacterial infection.
• Total bilirubin \> 8 mg/dL (137 µmol/L).
• Serum sodium \< 125 mmol/L.
• International Normalised Ratio (INR) ≥ 3.5.
• Proteinuria ≥ 1000 mg/dL.
• Microhaematuria \> 50 red blood cells per high power field.
• Clinically significant casts on urinalysis, including granular casts.
• History or evidence of obstructive uropathy or parenchymal renal disease on ultrasound or other imaging.
• Subject with a recent history of circulatory shock defined as MAP \< 60 mmHg within 5 days prior to screening requiring vasopressors or subjects requires circulatory support with vasopressors during screening.
• Subject requiring oxygen supplementation or mechanical ventilation.
• Recent exposure to nephrotoxic agents or exposure to radiographic contrast agents within 72 hrs prior to screening.
• Superimposed acute liver failure/injury due to factors other than alcohol, including acute viral hepatitis, drugs, medications (e.g., acetaminophen), or other toxins (e.g., mushroom \[Amanita\] poisoning).

Sponsors & Collaborators

• Noorik Biopharmaceuticals AG: lead

Study Sites (6)

Aster CMI Hospital

Bangalore, Karnataka, 560092, India

Location

Sir HN Reliance Hospital Foundation

Mumbai, Maharashtra, 400004, India

Location

All India Institute of Medical Sciences

New Delhi, National Capital Territory of Delhi, 110029, India

Location

Asian Institute of Gastroenterology (AIG)

Hyderabad, Telangana, 500082, India

Location

Ganesh Shankar Vidyarthi Memorial (GSVM) Medical College

Kanpur, Uttar Pradesh, 208002, India

Location

Medanta Multi Super Specialty Hospital

Lucknow, Uttar Pradesh, 226030, India

Location

Related Publications (9)

• Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, Moreau R, Jalan R, Sarin SK, Piano S, Moore K, Lee SS, Durand F, Salerno F, Caraceni P, Kim WR, Arroyo V, Garcia-Tsao G; International Club of Ascites. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut. 2015 Apr;64(4):531-7. doi: 10.1136/gutjnl-2014-308874. Epub 2015 Jan 28. No abstract available.

  PMID: 25631669 BACKGROUND

• Soper CP, Latif AB, Bending MR. Amelioration of hepatorenal syndrome with selective endothelin-A antagonist. Lancet. 1996 Jun 29;347(9018):1842-3. No abstract available.

  PMID: 8667963 BACKGROUND

• Mindikoglu AL, Weir MR. Current concepts in the diagnosis and classification of renal dysfunction in cirrhosis. Am J Nephrol. 2013;38(4):345-54. doi: 10.1159/000355540. Epub 2013 Oct 5.

  PMID: 24107793 BACKGROUND

• Ring-Larsen H. Renal blood flow in cirrhosis: relation to systemic and portal haemodynamics and liver function. Scand J Clin Lab Invest. 1977 Nov;37(7):635-42. doi: 10.3109/00365517709100657.

  PMID: 594643 BACKGROUND

• Moore K. Endothelin and vascular function in liver disease. Gut. 2004 Feb;53(2):159-61. doi: 10.1136/gut.2003.024703.

  PMID: 14724140 BACKGROUND

• Moore K, Wendon J, Frazer M, Karani J, Williams R, Badr K. Plasma endothelin immunoreactivity in liver disease and the hepatorenal syndrome. N Engl J Med. 1992 Dec 17;327(25):1774-8. doi: 10.1056/NEJM199212173272502.

  PMID: 1435931 BACKGROUND

• Zipprich A, Gittinger F, Winkler M, Dollinger MM, Ripoll C. Effect of ET-A blockade on portal pressure and hepatic arterial perfusion in patients with cirrhosis: A proof of concept study. Liver Int. 2021 Mar;41(3):554-561. doi: 10.1111/liv.14757. Epub 2021 Jan 5.

  PMID: 33295121 BACKGROUND

• Dhaun N, Macintyre IM, Melville V, Lilitkarntakul P, Johnston NR, Goddard J, Webb DJ. Blood pressure-independent reduction in proteinuria and arterial stiffness after acute endothelin-a receptor antagonism in chronic kidney disease. Hypertension. 2009 Jul;54(1):113-9. doi: 10.1161/HYPERTENSIONAHA.109.132670. Epub 2009 Jun 8.

  PMID: 19506099 BACKGROUND

• Wong F, Moore K, Dingemanse J, Jalan R. Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome. Hepatology. 2008 Jan;47(1):160-8. doi: 10.1002/hep.21940.

  PMID: 17886336 BACKGROUND

MeSH Terms

Conditions

Hepatorenal Syndrome; Liver Cirrhosis; Acute Kidney Injury

Interventions

ambrisentan; Terlipressin

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Renal Insufficiency

Intervention Hierarchy (Ancestors)

Lypressin; Vasopressins; Pituitary Hormones, Posterior; Pituitary Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Study Officials

• Iker Navarro, MD

  Noorik Biopharmaceuticals AG

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 5, 2024
• First Posted: February 13, 2024
• Study Start: April 17, 2024
• Primary Completion: May 1, 2026
• Study Completion (Estimated): June 1, 2026
• Last Updated: April 13, 2026

Record last verified: 2026-04

Locations

IN (6)