A Randomized Controlled Trial of Angiotensin II Versus Noradrenaline for Prevention of Cardiac Surgery-Associated Acute Kidney Injury

The primary objective of this study is to evaluate the effect of **angiotensin II** as the primary vasopressor on the occurrence of moderate or severe **acute kidney injury** within 72 hours following cardiac surgery. This is clinically relevant as acute kidney injury is a common complication after cardiac surgery, and its prevention could significantly improve patient outcomes and reduce healthcare costs.

Secondary objectives include:

• Investigating the effect of angiotensin II as the primary vasopressor on long-term Major Adverse Kidney Events (MAKE) at day 90 (MAKE90).
• Assessing the impact of angiotensin II on the development or progression of chronic kidney injury.

The clinical trial focuses on **acute kidney injury** in patients undergoing cardiac surgery. The study population includes both male and female adults aged 18 years and older. Participants are selected based on their elevated risk of developing acute kidney injury, as predicted by a specific scoring system that considers factors such as hemoglobin levels, creatinine levels, age, New York Heart Association (NYHA) classification, and body mass index (BMI). The trial does not involve a vulnerable population. Participants must have undergone cardiac surgery using cardiopulmonary bypass, including procedures like coronary artery bypass grafting (CABG), valve surgery, or combined CABG/valve surgery. Written informed consent is required for participation. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **angiotensin II** compared to **noradrenaline tartrate** in managing hypotension to reduce the incidence of cardiac-surgery associated **acute kidney injury** (AKI). This study is a prospective, randomized, double-blind, controlled trial. The trial is expected to commence on January 6, 2025, and conclude by April 30, 2027. Participants will be randomly assigned to receive either angiotensin II or noradrenaline tartrate, both administered via intravenous infusion. The maximum treatment period for each participant is three days.

The trial includes several key visits: an initial screening visit, follow-up visits, and an end-of-study visit. During the **screening visit**, eligibility will be assessed based on criteria such as undergoing cardiac surgery with cardiopulmonary bypass, an elevated risk of AKI, being an adult aged 18 years or older, and providing written informed consent. Follow-up visits will occur within 72 hours post-surgery to monitor the primary endpoint, which is the rate of AKI KDIGO stage 2 or 3 or death. Secondary endpoints include MAKE90, which encompasses mortality, any dialysis within 90 days, and persistent renal dysfunction, as well as the development or progression of chronic kidney disease.

Participants are expected to be involved in the study for a duration of up to 120 days, with the primary focus on the first 72 hours post-surgery. Conditions that may lead to early termination from the study include withdrawal of consent or any adverse events that compromise participant safety. The trial aims to provide insights into the comparative effectiveness of these vasopressors in reducing AKI incidence following cardiac surgery.

The clinical trial involves the administration of two experimental medications for the management of **hypotension** to reduce cardiac-surgery associated acute kidney injury. The first experimental medication is **Noradrenaline Tartrate**, also known by synonyms such as Norepinephrine Bitartrate and Levaterenol Acid Tartrate. It is classified under the ATC code C01CA03 and is used as a vasopressor. The pharmaceutical form of Noradrenaline Tartrate is identified as PHF00230MIG, and it is administered via **intravenous perfusion**. The dosing regimen includes a maximum daily dose of 4.3 mg/kg and a maximum total dose of 13 mg/kg over a treatment period of up to 3 days. Compliance with the dosing schedule is monitored to ensure adherence to the protocol.

The second experimental medication is **Giapreza**, which contains the active substance **Angiotensin II**. This medication is provided as a 2.5 mg/ml concentrate for solution for infusion and is administered through **intravenous use**. The maximum daily dose for Giapreza is 64.8 µg/kg, with a maximum total dose of 180 µg/kg, also over a treatment period of up to 3 days. Angiotensin II is categorized under the ATC code C01CX09 and is produced by PAION PHARMA GMBH. The administration and dosing of Giapreza are carefully monitored to ensure participant safety and protocol compliance.

The efficacy of the clinical trial titled "A Prospective Angiotensin II versus Noradrenaline trial for Hypotension management to reduce cardiac-surgery associated Acute Kidney Injury (PAN-AKI)" will be assessed using specific primary and secondary endpoints. The primary endpoint is the rate of **Acute Kidney Injury (AKI)** KDIGO stage 2 or 3 or death within 72 hours after cardiac surgery. This will be measured to determine the immediate impact of the intervention on kidney function and patient survival post-surgery.

Secondary endpoints include the MAKE90 composite outcome, which consists of mortality, any dialysis within 90 days, and persistent renal dysfunction, defined as more than a 25% reduction in estimated glomerular filtration rate (eGFR) from baseline at day 90. Additionally, the development or progression of chronic kidney disease will be evaluated based on albuminuria and two serum creatinine measurements between day 90 and 120. These secondary endpoints will provide a broader understanding of the long-term renal outcomes and overall patient health following the intervention.