Evaluation of Safety, Tolerability, and Efficacy of Relaxin Agonist R2R01 with Terlipressin in Hepatorenal Syndrome-Acute Kidney Injury
- Trial ID
- 2023-503504-88-00
- Protocol
- R2R01-HRS-201
- Sponsor
- River 2 Renal Corp.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **tolerability** and safety of the relaxin agonist R2R01 in combination with **terlipressin** compared to terlipressin alone in patients with **Hepatorenal Syndrome – Acute Kidney Injury**. The study aims to evaluate the efficacy of this combination by determining the number of responding patients, defined as those achieving a full or partial reversal of Hepatorenal Syndrome (HRS) based on serum creatinine (SCr) and acute kidney injury (AKI) stage, and who remain alive without the need for renal replacement therapy (RRT) for at least 30 days post-treatment initiation. Additionally, the study seeks to evaluate the efficacy of adding R2R01 to terlipressin in patients who do not initially respond to terlipressin alone. This is clinically relevant as it may offer a new therapeutic option for improving outcomes in this patient population.
Secondary objectives include evaluating the efficacy of R2R01 in combination with terlipressin versus terlipressin alone on several clinical outcomes: mortality, liver transplant rates, RRT rates, durability of HRS reversal, HRS recurrence, progression to stage 3 acute on chronic liver failure (ACLF), and changes in the Model for End-Stage Liver Disease (MELD) score at 30, 60, and 90 days after treatment initiation. These measures are crucial for understanding the broader impact of the treatment on patient health and disease progression.
Participants
The clinical trial involves a total of **77 participants** diagnosed with **Hepatorenal Syndrome – Acute Kidney Injury**. The study population includes both male and female subjects, aged 18 years and older, who are considered a vulnerable population due to their medical condition. Participants were selected based on their ability to communicate effectively with the investigator and their willingness to comply with study requirements, as well as their consent to participate. All participants have cirrhosis and ascites, and are in **Acute Kidney Injury (AKI)** stage 2 or 3, characterized by specific increases in serum creatinine (SCr) levels. The trial does not specify particular lifestyle considerations such as diet or physical activity. However, female participants and female partners of male participants are required to avoid pregnancy during the study period. The selection criteria ensure that participants have not shown sustained improvement in renal function after diuretic withdrawal and plasma volume expansion with albumin.
Plans and Procedures
The clinical trial is a **single-blind**, **Phase 2**, multi-center, randomized study designed to evaluate the safety, tolerability, efficacy, and pharmacokinetics of the relaxin agonist R2R01 in combination with **terlipressin** versus terlipressin alone in patients with **Hepatorenal Syndrome – Acute Kidney Injury**. The trial will involve a comparison between the combination therapy and monotherapy to assess the number of responding patients, defined as those with a full or partial HRS response based on serum creatinine (SCr) and acute kidney injury (AKI) stage, who are alive without renal replacement therapy (RRT) for at least 30 days after the first dose of study medication. The trial is expected to run from September 1, 2023, to September 30, 2024.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as age, presence of cirrhosis and ascites, and specific AKI stages. Following the screening, eligible participants will be randomized to receive either the combination therapy or monotherapy. The treatment period will last up to 14 days, with follow-up visits scheduled at day 30, 60, and 90 to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur at day 90, marking the conclusion of participant involvement.
The expected length of participant involvement is approximately 90 days, encompassing the treatment and follow-up periods. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or the need for liver transplantation within the first 30 days after treatment initiation. The primary endpoints include the assessment of safety and tolerability through the occurrence of adverse events, changes in physical examinations, vital signs, ECGs, and clinical laboratory parameters. Secondary endpoints will evaluate mortality rates, transplant occurrences, and the number of patients with durable HRS reversal, among other measures.
Treatment
The clinical trial involves the administration of **Terlipressin Acetate**, an experimental medication, which is provided in the form of a **solution for injection**. The active substance, terlipressin acetate, is classified as a protein of other origin. The medication is administered via **intravenous bolus injection or IV infusion**. The maximum daily dose is 8 mg, with a total maximum dose of 104 mg over a treatment period of up to 14 days. This medication is not a pediatric formulation and is used as a comparator in the study.
Another component of the trial is the investigational drug **R2R01**, which is provided in a **liquid** pharmaceutical form. The active substance, R2R01, is also a protein of other origin. This medication can be administered either **intravenously (IV) or subcutaneously (SC)**. The maximum daily dose is 19 mg, with a total maximum dose of 149 mg over a 14-day treatment period. R2R01 is the test product in this study and is not formulated for pediatric use.
The trial also includes the use of a non-experimental treatment, classified under the ATC code **V07AB**, which pertains to solvents and diluting agents, including irrigating solutions. This auxiliary treatment is administered via **intravenous bolus injection or IV infusion**. The maximum daily dose is 1.9 ml, with a total maximum dose of 14.9 ml over the same 14-day period. This component is not a pediatric formulation and serves as an auxiliary treatment in the study.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed administration routes and dosages. The study aims to evaluate the safety, tolerability, and efficacy of the combination of R2R01 with terlipressin compared to terlipressin alone in patients with **Hepatorenal Syndrome – Acute Kidney Injury**.
Efficacy
The efficacy of the investigational treatment in the clinical trial will be assessed through several primary and secondary endpoints. The primary efficacy endpoint is the incidence of responders, defined as patients achieving an **Established Hepatorenal Syndrome (HRS) reversal**. This is characterized by a Full or Partial HRS response based on serum creatinine (SCr) and Acute Kidney Injury (AKI) stage, with patients being alive and without Renal Replacement Therapy (RRT) for at least 30 days after the first dose of study medication. Patients undergoing liver transplant within the first 30 days will have their SCr and AKI stage evaluated prior to the transplant and will be considered responders if they meet the criteria for HRS response before the transplant and remain alive without RRT at day 30 post-treatment initiation.
Secondary efficacy endpoints include the number of patients who die at day 30, 60, and 90, the number of patients with renal and/or liver transplant at these timepoints, and the number of patients with RRT. Additionally, the trial will assess the number of patients with durable Established HRS reversal by day 45, 60, and 90, the number of patients with HRS recurrence, and the number of patients with an HRS response based on SCr/AKI stage as Full, Partial, and Combined. Other secondary endpoints include the number of patients with worsening or improvement of Acute-on-Chronic Liver Failure (ACLF) stages, mean change from baseline in Model for End-Stage Liver Disease (MELD) score, and mean change from baseline in serum and urine biomarkers such as Cystatin C, Endothelin-1, vWF, NGAL, and KIM 1. Population pharmacokinetic (PK) analysis will also be conducted to derive primary and secondary PK parameters.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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).
- At least 18 years of age.
- Cirrhosis and ascites.
- AKI stage 2 or 3. AKI defined by any of the following: 1) increase in SCr (SCr) ≥ 0.3 mg/dl (or ≥ 26.5 μmol/L) within 48 h, or 2) increase ≥ 50% in BL SCr, which is known or presumed to have occurred within the prior seven days. - Stage 2 is defined as an increase in sCr > 2 fold to 3 fold from baseline. - Stage 3 is defined as increase of sCr > 3 fold from baseline or sCr ≥ 4.0 mg/dl (353.6 μmol/L) with an or initiation acute increase ≥ 0.3 mg/dl (26.5 μmol/L)
- QLY SCr ≥ to 1.5 mg/dl.
- 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.
- 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
- Significant co-morbidities that in the opinion of the Investigator would preclude study participation.
- QLY SCr level > 5 mg/dL.
- AKI stage 1 (see Table 13).
- ACLF stage 3.
- Model for End-Stage Liver Disease (MELD) score >35.
- At least one event of large volume paracentesis (LVP) > 4 Liters in the last 4 days before enrollment.
- 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).
- Shock (hypovolemic-, cardiogenic-, or vasodilatory/distributive shock) with mean arterial blood pressure (MAP) ≤70 mmHg or systolic blood pressure ≤90 mmHg along with hypoperfusion.
- 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.
- Fewer than two days of anti-infective therapy for documented or suspected infection.
- Superimposed acute liver injury induced by drugs, herbal preparation or dietary supplements, with the exception of alcoholic hepatitis.
- Estimated life expectancy less than 5 days.
- Hypoxia (<90%) or worsening respiratory symptoms
- Proteinuria > 500 mg/day.
- Tubular epithelial casts, heme granular casts.
- Haematuria or microhaematuria (more than 50 red blood cells per high power field).
- Abnormal renal ultra-sonography unless there is a known chronic structural disease (e.g., diabetic or hypertensive nephropathy).
- Current or recent (within 4 weeks) renal replacement therapy (RRT).
- 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.
- Transjugular intra-hepatic systemic shunt (TIPS) unless it is known to be non-functioning or occluded.
- 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.
- Known allergy or hypersensitivity to terlipressin or other component of the study treatment.
- 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.
- 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 as described in Section 11.3.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 01 Sept 2023 | 10 |
 Italy | Not Recruiting | 01 Sept 2023 | 8 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TERLIPRESSIN ACETATE | Other | — | INTRAVENOUS BOLUS INJECTION/IV INFUSION | 8 | 14 | SUB04727MIG |
- | Comparator | PHF00017MIG | INTRAVENOUS BOLUS INJECTION/IV INFUSION | 1.9 | 14 | V07AB |