Evaluation of Bovine Alkaline Phosphatase in Reducing Systemic Inflammation and Acute Kidney Injury Post-Cardiac Surgery with Cardiopulmonary Bypass

The primary objective of this study is to evaluate the efficacy of **RESCAP®** intervention in reducing the time to reach stability in patients during their stay in the Intensive Care Unit (ICU) following invasive cardiac surgery. This is assessed using the **Sequential Organ Failure Assessment (SOFA)** score over a 12-day period, with a specific comparison made after 72 hours in the ICU. Additionally, the study aims to demonstrate that **alkaline phosphatase** reduces the incidence and extent of acute kidney injury post-cardiopulmonary bypass, as defined by the **Acute Kidney Injury Network (AKIN)** criteria. This includes monitoring for a rise in serum creatinine or a drop in urine output, with occurrences checked within 30 and 90 days post-surgery. These objectives are clinically relevant as they address the reduction of systemic inflammation and ischemic injury, which are significant complications associated with cardiac surgery.

Secondary objectives include: - Measuring cost-related outcomes associated with cardiopulmonary bypass (CPB) and alkaline phosphatase (AP) intervention, such as the incidence and duration of renal replacement therapy, the influence of prolonged treatment duration on primary endpoints, days spent in the ICU and hospital, and the incidence of arrhythmias in the two groups. - Comparing plasma levels of inflammatory markers (IL-6, IL-8, IL-10, IL-17, IL-18, TNF-alpha) and kidney function markers (IL18, NGAL, TIMP-1, GFR) between the control and AP-treated groups.

The clinical trial involves participants who are undergoing cardiac surgery with planned cardiopulmonary bypass, focusing on addressing **systemic inflammation** as a side-effect of the heart-lung machine. The study population includes both male and female subjects, aged 21 years and older, who are considered legal adults in Singapore. Participants are required to have a EuroSCORE II of 3 or higher, indicating a certain level of risk associated with cardiac surgery. All participants must be capable of providing informed consent and have agreed to comply with the trial protocol. The trial does not include vulnerable populations. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. Key inclusion criteria emphasize the ability to provide informed consent and the requirement for written consent prior to participation. The trial aims to evaluate the effectiveness of the RESCAP® intervention in reducing the time to reach stability in the ICU and the role of alkaline phosphatase in mitigating acute kidney injury post-surgery.

The clinical trial is designed to evaluate the efficacy of **alkaline phosphatase, bovine** in reducing systemic inflammation and acute kidney injury associated with cardiac surgery involving cardiopulmonary bypass. This is a randomized, double-blind, controlled trial with a placebo group. The trial is expected to run from December 2017 to March 2026, with participants involved for a maximum of 30 days. The study will include adult patients over 21 years of age undergoing cardiac surgery with a EuroSCORE II of 3 or higher, who are capable of providing informed consent.

Participants will be randomly assigned to receive either the investigational product, **RESCAP iv**, or a placebo, both administered as a solution for injection/infusion. The primary endpoints include assessing the time to reach stability in the ICU using the SOFA score and evaluating the incidence and extent of acute kidney injury as per the AKIN criteria. The trial will monitor outcomes over a 12-day period in the ICU and check for acute kidney injury within 30 and 90 days post-surgery.

The sequence of study visits begins with a screening visit to confirm eligibility based on the inclusion criteria. Follow-up visits will occur during the ICU stay to assess the primary endpoints. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any adverse events are documented. Participants may be withdrawn from the study if significant adverse reactions occur, if mortality rates are higher in the experimental group, or if the primary outcomes are not met. The trial will cease administration of the placebo if the experimental drug shows significantly better outcomes in reducing acute kidney injury or mortality.

The clinical trial involves the administration of **RESCAP iv**, an investigational medicinal product containing **alkaline phosphatase, bovine** as the active substance. This product is formulated as a **solution for injection/infusion** and is manufactured by ALLOKSYS LIFE SCIENCES B.V. The administration route for RESCAP iv is via **intravenous bolus injection/IV infusion**. The maximum daily dose is set at 13,300 IU per kilogram, with a total maximum dose of 190 IU per kilogram over the treatment period. The treatment duration is limited to a maximum of 30 days. The trial aims to assess the efficacy of RESCAP iv in reducing oxidative stress-induced ischemic injury and systemic inflammation complications during and after invasive cardiac surgery.

The study also includes a **placebo** group, where participants receive a solution identical in appearance to the investigational medicinal product but devoid of the active substance. The placebo is used to ensure the blinding of the study and to serve as a comparator to evaluate the true efficacy of RESCAP iv. The placebo is administered following the same route and schedule as the investigational product to maintain consistency across treatment groups. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

Efficacy in the clinical trial titled "Preventing oxidative stress-induced ischemic injury and systemic inflammation complications during and after invasive cardiac surgery with alkaline phosphatase (APPIRED III)" will be assessed using two primary endpoints. The first primary endpoint aims to demonstrate that the intervention with RESCAP® reduces the time to reach stability while the patient is in the Intensive Care Unit (ICU). This will be evaluated by assessing the severity of illness using the **SOFA (Sequential Organ Failure Assessment)** score over a period of 12 days, with outcomes compared after 72 hours in the ICU.

The second primary composite endpoint focuses on demonstrating that **alkaline phosphatase** reduces the incidence and extent of acute kidney injury (AKI) following cardiopulmonary bypass, as defined by the **AKIN criteria**. This includes a rise in serum creatinine by 0.3 mg/dl or 26 μmol/L within 48 hours, or a percentage increase in serum creatinine concentration of ≥50%, or a drop in urine output to 0.5 ml/kg/hour for 6 hours. The occurrence of acute kidney injury will be monitored within 30 days and additionally after 90 days post-surgery.