Endothelin Receptor Antagonism With Ambrisentan to Treat Hepatorenal Syndrome

Launched by NOORIK BIOPHARMACEUTICALS AG · Feb 5, 2024

Keywords

ClinConnect Summary

This clinical trial is studying a medication called ambrisentan, which may help improve kidney function in patients with a serious condition known as Hepatorenal Syndrome. This condition occurs in people with advanced liver cirrhosis, where their kidneys start to fail, leading to hospitalization and increased risk of death. The trial aims to find out if low doses of ambrisentan can be safe and effective for these patients, especially compared to another medication commonly used for this condition called terlipressin.

To participate in the trial, you need to be between 18 and 60 years old and have liver cirrhosis along with kidney problems identified by specific blood tests. While in the hospital, participants will receive either ambrisentan or terlipressin for the first few days. If ambrisentan is not working after that, they may switch to terlipressin. If you receive ambrisentan, you will continue taking it at home for up to 60 days after leaving the hospital. It’s important to know that the trial is currently looking for volunteers, and participants must be able to provide informed consent and follow the study guidelines.

Gender

ALL

Eligibility criteria

• Inclusion Criteria:
• • 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.
• Exclusion Criteria:
• • 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).
• • Severe cardiovascular disease, including, but not limited to, unstable angina, pulmonary oedema, congestive heart failure (NYHA ≥ II), or persisting symptomatic peripheral vascular disease, myocardial infarction or stable chronic angina within the past 12 months, or any other cardiovascular disease judged by the Investigator to be severe.
• • Subject has a history of Transjugular Intrahepatic Portosystemic shunt (TIPS).
• • Subject with acute variceal bleeding at the time of screening who may undergo pre-emptive TIPS or is anticipated to be treated with terlipressin.
• • Current or recent Renal Replacement Therapy (RRT) within 30 days of enrolment, or anticipation of RRT in the next 3 days after screening.
• • Hepatocellular Carcinoma (HCC) beyond the Milan criteria or other malignancy affecting survival beyond 6 months.
• • Participation in a study of an investigational medical product or device within the last 30 days preceding screening.
• • Hepatic Encephalopathy with West Haven Grade III or IV.
• • Current or recent (30 days prior to enrolment) treatment with endothelin receptor antagonists, including ambrisentan.
• • Estimated life expectancy of less than 3 days.
• • Known allergy or sensitivity to ambrisentan or propylene glycol.
• • History of Idiopathic Pulmonary Fibrosis.
• • Subject is unable or unwilling to follow instructions or comply with study procedures.