Evaluation of Ionized Calcium Target Adjustment on Regional Citrate Anticoagulation Efficacy in Continuous Renal Replacement Therapy Using Sodium Chloride and Sodium Citrate

The primary objective of this study is to demonstrate that a post-filter **Ca2+** target between 0.35-0.45 mmol/l provides anticoagulation of the circuit with efficiency comparable to a post-filter Ca2+ target between 0.25-0.35 mmol/l during continuous extra-renal purification with regional citrate anticoagulation (ARC) in intensive care. This is clinically relevant as it may optimize the management of anticoagulation in critically ill patients, potentially improving outcomes and reducing complications associated with inadequate anticoagulation.

Secondary objectives include:

• Comparing the lifespan of hemofilters between the two groups, up to filter thrombosis and considering all causes of stoppage combined.
• Evaluating the last post-filter Ca2+ value before thrombosis and the proportion of post-filter Ca2+ within the objectives.
• Assessing the total dose of citrate infused and the incidence of suspected citrate accumulation syndrome.
• Investigating the incidence of metabolic events such as hypocalcemia, metabolic acidosis, metabolic alkalosis, hypernatremia, and hypomagnesemia.
• Comparing the financial costs of filter changes and citrate, as well as evaluating blood theft between the two groups.

The clinical trial involves **adult patients** who are hospitalized in intensive care units and have an indication for **extracorporeal renal replacement therapy (EER)** with augmented renal clearance (ARC) during their stay. The study population includes both male and female participants aged 18 years and older. Participants are required to be affiliated with a social security scheme or entitled to it, excluding those with state medical aid. Written consent is necessary, although in emergency situations, inclusion can occur based on the investigator's decision, with subsequent consent required to continue. The sponsor has not provided information regarding the total number of participants. The trial does not specifically target a vulnerable population, and no particular lifestyle considerations such as diet or physical activity are highlighted for this study.

The clinical trial is designed as a **randomized**, controlled, non-inferiority study to evaluate the effectiveness of regional citrate anticoagulation during continuous extra-renal purification in intensive care. The trial will involve adult patients hospitalized in intensive care with an indication for extra-renal replacement therapy (EER) with anticoagulation using regional citrate (ARC). The primary objective is to demonstrate that a post-filter calcium ion (Ca2+) target between 0.35-0.45 mmol/l provides anticoagulation efficiency comparable to a target between 0.25-0.35 mmol/l. The primary endpoint is the incidence of filter thrombosis, while secondary endpoints include the lifespan of each hemofilter, post-filter Ca2+ levels, citrate infusion rates, and the incidence of metabolic complications such as hypocalcemia and metabolic acidosis.

The trial is expected to commence recruitment on July 1, 2023, and conclude by July 1, 2025. Participants will be involved in the study for a maximum treatment period of three days. The study will include an initial screening visit to confirm eligibility based on criteria such as age (18 years or older), hospitalization in intensive care, and the need for EER with ARC. Written consent is required, although in emergency situations, inclusion may proceed with subsequent consent. Follow-up visits will monitor the primary and secondary endpoints, with data collection on filter lifespan, metabolic parameters, and citrate infusion rates. The end-of-study visit will assess the overall outcomes and any adverse events.

Participants may be withdrawn from the study if they experience severe adverse events, withdraw consent, or if the investigator deems it necessary for safety reasons. The trial will utilize **Regiocit solution**, containing **sodium chloride** and **sodium citrate**, administered intravenously as the investigational product. The study is categorized as a low-intervention trial, with the investigational product being a solution for hemofiltration. The trial is conducted under the sponsorship of Baxter Holding B.V., with adherence to ethical guidelines and regulatory requirements.

The clinical trial involves the use of **Regiocit solution for haemofiltration**, an experimental medication formulated as a solution specifically designed for haemofiltration. This pharmaceutical product contains the active substances **sodium chloride** and **sodium citrate**, both of which are of chemical origin. The solution is administered intravenously, and its primary role in the trial is to facilitate regional citrate anticoagulation during continuous extra-renal purification in intensive care settings. The maximum treatment period for the administration of this solution is three days. The dosage is determined as quantity sufficient (QS), with no specified maximum daily or total dose amount, allowing for flexibility in administration based on clinical needs.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the efficacy of the Regiocit solution in achieving the desired post-filter ionized calcium target levels. Participant compliance with the dosing schedule is monitored to ensure adherence to the intravenous administration protocol. The trial aims to demonstrate that a post-filter calcium target between 0.35-0.45 mmol/l provides anticoagulation efficiency comparable to a target between 0.25-0.35 mmol/l.

Efficacy in this clinical trial will be assessed primarily through the incidence of filter thrombosis, expressed as a percentage. This serves as the primary endpoint to evaluate the effectiveness of regional citrate anticoagulation during continuous extra-renal purification in intensive care settings. Secondary endpoints include the lifespan of each hemofilter, measured in hours, and the cause of cessation of the extra-renal replacement (EER) procedure, categorized into predefined methods such as filter thrombosis, catheter dysfunction, and others.

Additional secondary endpoints involve measuring post-filter **Ca2+** levels in mmol/l during the EER session, citrate infusion rates, and the incidence of suspected citrate accumulation syndrome, defined by hypocalcemia with a total calcium/ionized calcium ratio greater than 2.5. The trial will also monitor the occurrence of specific metabolic complications, including hypocalcemia, metabolic acidosis, metabolic alkalosis, hypernatremia, and hypomagnesemia. Furthermore, the costs associated with each hemofilter change and the quantities of citrate infused will be evaluated, along with the inability to restore the EER circuit at the end of the session.