A Single-blind, Phase 2, Multi-center, Randomized Study to Assess Safety, Tolerability, Efficacy and Pharmacokinetics of the R2R01 Plus Terlipressin Versus Terlipressin Alone in Patients With Hepatorenal Syndrome - Acute Kidney Injury

R2R01-HRS-201

This study aims to evaluate the safety, tolerability and efficacy of R2R01 combined with terlipressin as compared to terlipressin alone in the treatment of patients with HRS-AKI

2023-06-30

2024-12-01

2024-12-01

Recruiting

Early phase I

95

Inclusion Criteria: 1. Patient is able to communicate well with the Investigator, understands and is willing to comply with all requirements of the study, and understands and signs the written informed consent form (ICF). 2. At least 18 years of age. 3. Cirrhosis and ascites. 4. AKI stage 2 or 3. AKI defined by any of the following: 1) increase in SCr (SCr) ≥ 0.3 mg/dl (or ≥ 26.5 micromolar/L) within 48 h, or 2) increase ≥ 50% in baseline SCr, which is known or presumed to have occurred within the prior seven days. 5. QLY SCr ≥ to 1.5 mg/dl. 6. No sustained improvement in renal function (less than 20% decrease in SCr and SCr =\> 1.5 mg/dL) after 48 h of diuretic withdrawal and the beginning of plasma volume expansion with albumin. 7. Female patients as well as female partners of male patients must be willing to avoid pregnancy for the duration of the study (\>90 days). Exclusion Criteria: 1. Significant co-morbidities that in the opinion of the Investigator would preclude study participation. 2. QLY SCr level \> 5 mg/dL. 3. AKI stage 1. 4. ACLF stage 3. 5. Model for End-Stage Liver Disease (MELD) score \>35. 6. At least one event of large volume paracentesis (LVP) \> 4 Liters in the last 4 days before enrollment. 7. Current or recent (within 4 weeks) treatment with nephrotoxic drugs (e.g., aminoglycosides, amphotericin, cyclosporine, NSAIDS (e.g., ibuprofen, naproxen, celecoxib), significant exposure to radiographic contrast agents (large doses or multiple injections of iodinated contrast media). 8. Shock (hypovolemic-, cardiogenic-, or vasodilatory/distributive shock) with mean arterial blood pressure (MAP) ≤70 mmHg or systolic blood pressure ≤90 mmHg along with hypoperfusion. 9. Sepsis or uncontrolled bacterial infection (e.g., persisting bacteremia, persisting ascitic fluid leucocytosis, fever, increasing leucocytosis with vasomotor instability) as measured with the quick sepsis-related organ dysfunction assessment (qSOFA) score. 10. Fewer than two days of anti-infective therapy for documented or suspected infection. 11. Superimposed acute liver injury induced by drugs, herbal preparation or dietary supplements, with the exception of alcoholic hepatitis. 12. Estimated life expectancy less than 5 days. 13. Hypoxia (\<90%) or worsening respiratory symptoms. 14. Proteinuria \> 500 mg/day. 15. Tubular epithelial casts, heme granular casts. 16. Haematuria or microhaematuria (more than 50 red blood cells per high power field). 17. Abnormal renal ultra-sonography unless there is a known chronic structural disease (e.g., diabetic or hypertensive nephropathy). 18. Current or recent (within 4 weeks) renal replacement therapy (RRT). 19. Severe cardiovascular and pulmonary diseases including, but not limited to, unstable angina, pulmonary edema, congestive heart failure requiring increasing doses of drug therapy, persisting symptomatic peripheral vascular disease, or any other cardiovascular disease judged by the Investigator to be severe. 20. Transjugular intra-hepatic systemic shunt (TIPS) unless it is known to be non-functioning or occluded. 21. Ongoing use of vasopressors, unless used for only 48 h before screening; in this case a wash-out period of 8 h before enrollment will be necessary. Patients receiving midodrine and octreotide may be enrolled but treatment must be discontinued prior to enrollment. 22. Known allergy or hypersensitivity to terlipressin or other component of the study treatment. 23. Subject is not suitable to participate in the study for any reason (including, but not limited to co-morbidities, history of non-compliance with study visits, procedures, or drug administration) in the opinion of the Investigator. 24. Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at least 1 year) are excluded from participation in the study unless they agree to use highly effective contraception. 25. Males who have no sterilization history and whose female partners have child-bearing potential must agree to use a highly effective method of contraception during the period from the time of signing the informed consent form (ICF) through 90 days after the last dose of study drug. A male patient must agree to immediately inform the Investigator if his partner becomes pregnant during the study.

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE2'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'SEQUENTIAL', 'interventionModelDescription': 'A. An Open-Label Safety Run-In Part with 3 Cohorts of patients, followed by\n\nB. A Single-Blind Placebo-Controlled Randomized Part with two Cohorts of patients treated in parallel, and\n\nC. An Open-Label Terlipressin Non-Responder Cohort.', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'SINGLE', 'maskingDescription': 'Patients in Cohorts 4 and 5 will be blinded to study treatment. Patients randomized to Cohort 4 will receive terlipressin and R2R01. Patients randomized to Cohort 5 will receive terlipressin and R2R01-matching placebo in the same schedule as Cohort 4. Study staff and Investigators will not be blinded', 'whoMasked': ['PARTICIPANT']}}, 'enrollmentInfo': {'count': 95, 'type': 'ESTIMATED'}}

2023-10-03