Phase 2 Randomized Study of R2R01 for the Prevention of Cardiac Surgery-Associated Acute Kidney Injury in High-Risk Patients

Trial ID: 2025-523037-25-00
Protocol: R2R01-CSA-AKI-201
Sponsor: River 2 Renal Corp.

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Diseases & Conditions

Cardiac function disturbance postoperative Acute kidney injury

Objectives

The primary objective is to evaluate the safety and efficacy of R2R01 for the prophylaxis of acute kidney injury, as defined by the KDIGO criteria, in patients undergoing cardiac surgery involving cardiopulmonary bypass who possess additional risk factors for cardiac surgery associated acute kidney injury. Secondary objectives include the assessment of:

Reduction in the severity and duration of postoperative acute kidney injury;
Impact on renal function;
Reduction of major adverse kidney events, comprising all-cause mortality, renal replacement therapy, or a sustained reduction in kidney function of at least 25% from baseline at postoperative day 7 and day 30;
Changes in the duration of intensive care unit stay and total hospitalization time;
Rate of hospital readmissions at postoperative day 30.

Participants

The sponsor did not provide information regarding the total number of participants. The study population consists of male and female patients aged 18 to 75 years who are at high risk for Cardiac Surgery Associated – Acute Kidney Injury (CSA-AKI). Participants are scheduled for non-emergent coronary artery bypass graft, valve surgery, aortic surgery, or a combination of these procedures involving cardiopulmonary bypass. Selection is based on the presence of specific risk factors, which include diabetes mellitus, hypertension, chronic heart failure, left ventricular ejection fraction of ≤40%, peripheral vascular disease, stroke, transient ischemic attack, atrial fibrillation, anemia, body mass index ≥30 kg/m², or age ≥70 years. Included subjects must have stable renal function and be able to communicate with the investigator.

Plans and Procedures

This Phase 2, multicenter, randomized, dose-ranging, placebo-controlled, double-blind study is designed to evaluate the safety and efficacy of the relaxin agonist R2R01 in preventing acute kidney injury (AKI) in patients at high risk following cardiac surgery involving cardiopulmonary bypass. Participants undergo a screening visit to confirm eligibility based on age, surgical requirements, and specific risk factors such as diabetes mellitus, hypertension, or atrial fibrillation. Following screening, subjects are randomized to receive either R2R01 via subcutaneous use or a placebo consisting of sodium chloride via subcutaneous injection. The clinical assessment includes monitoring serum creatinine and cystatin C levels at various postoperative intervals to determine the incidence and severity of AKI according to KDIGO criteria. The study involves follow-up observations through postoperative day 30 to evaluate major adverse kidney events and hospital resource utilization. The total trial period is estimated to conclude by June 30, 2027. Early termination from the study may occur if a subject fails to meet the requirements of the protocol or participates in another interventional study.

Treatment

The experimental treatment consists of R2R01, a relaxin agonist provided in a liquid pharmaceutical form. The administration involves a subcutaneous route at a dosage of 5 mg.

The placebo group receives sodium chloride 0.9% solution for infusion. This substance is administered via subcutaneous injection at a volume of 0.75 ml.

Efficacy

The primary efficacy endpoint is the proportion of subjects developing acute kidney injury (AKI) within 7 days after the commencement of on-pump cardiac surgery, as determined by serum creatinine (SCr) levels according to KDIGO criteria. Secondary efficacy assessments include the severity grade of AKI within 7 days post-surgery, the duration of AKI, and the changes in SCr and cystatin C, including corresponding estimated glomerular filtration rate (eGFR) values, compared to baseline at postoperative hours 12, 24, 48, 72, and postoperative days 7 and 30. Additionally, the proportion of subjects experiencing a major adverse kidney event (MAKE)—defined as all-cause mortality, renal replacement therapy (RRT), or a sustained reduction in kidney function of ≥ 25% based on CKD-EPI equations at postoperative day 7 and day 30—will be evaluated.

Other secondary parameters include the length of intensive care unit (ICU) stay in hours, length of hospital stay in days, total ICU-free days, and hospital-free days. The proportion of subjects requiring hospital readmission at postoperative day 30 will also be assessed.

Inclusion and Exclusion Criteria

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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
Subject is scheduled for non-emergent CABG (single or multiple vessels), valve surgery (single or multiple valves), surgery of the ascending part of the aorta, or a combination of the above, involving cardiopulmonary bypass (CPB), AND risk factors for acute kidney injury (AKI) are present (at screening) as specified below: a. If only one type of surgery is scheduled, at least two AKI risk factors should be present b. If any combined surgery is scheduled, at least one AKI risk factor should be present. Risk factors for AKI: • Diabetes mellitus on pharmacological treatment • Confirmed diagnosis of hypertension • Documented history of Chronic Heart Failure with New York Heart Association (NYHA) class III or higher (see section 11.5 in Appendix) • Left ventricular ejection fraction (LVEF) ≤40% • Peripheral vascular disease defined as one or more of the following: claudication, carotid occlusion or >50% stenosis, amputation for arterial disease, previous or planned intervention on the abdominal aorta, limb arteries or carotids • Stroke/transient ischemic attack (TIA) defined as sudden onset of focal or global brain, spinal cord, or retinal vascular damage, resulting in symptoms and signs of acute nervous system defects, associated with cerebral circulation disorders • Documented atrial fibrillation (AF) on the ECG performed at the screening visit • Anemia with hemoglobin ≤11 g/dL at any time during the 3-month period before or at the time of screening • Body Mass Index (BMI) ≥ 30 kg/m2 • Age ≥70 years at the time of screening
Have stable renal function per Investigator assessment
Subject agrees not to participate in another interventional study after signing the ICF and until the end of study (EoS) visit has been completed

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Exclusion Criteria

Patient currently enrolled into another interventional clinical trial
Subject is scheduled for emergent surgery
Cardiac surgery planned to be performed "off-pump" without CPB
Expected CPB duration < 60 minutes
Body weight <50 kg; >120 kg
Presence of AKI (KDIGO criteria) at the time of randomization
Current, recent (within 4 weeks), or scheduled renal replacement therapy
Patients who are post-nephrectomy
Patients with CKD of equal or more than stage IV (GFR≤30 ml/min/1.73 m2)
Patient with a kidney transplant
Subject has a known or suspected glomerulonephritis at the time of randomization
Cardiogenic shock, hemodynamic instability, mechanical ventilation, intra-aortic balloon pump (IABP), left ventricular assist device (LVAD) or other forms of mechanical circulatory support (MCS), within 7 days prior to surgery
Patient received inotropes or vasopressors within 48 hours prior to the day of surgery
Known or suspected sepsis
Confirmed or suspected endocarditis
Other current active infection requiring antibiotic treatment
Patient has severe liver disease (Child-Pugh score >7 points)
Recently received (within the last 4 weeks) or is anticipated to receive before the end of the study chemotherapy which can interfere with kidney function (e.g. Platinum agents)
Patient previously enrolled and randomized into this study
Pregnant or nursing (lactating) women, where pregnancy was defined as the state of a female after conception and until the termination of gestate, confirmed by a positive human chorionic gonadotropin laboratory
Known hypersensitivity to the study drug or any of its excipients
Any medical or social condition deemed by the investigator to be likely to interfere with a patient’s ability to give informed consent, cooperate, and participate in the study or to be likely to interfere with the interpretation of the results