Comparison of Anticoagulant Effects of Different Doses of Nafamostat in Continuous Renal Replacement Therapy (CRRT) in the Intensive Care Unit (ICU)

Investigational drug: Nafamostat Mesilate for Injection Study title: Comparison of Anticoagulation Efficacy of Different Doses of Nafamostat Mesilate during Continuous Renal Replacement Therapy in ICU: A Single-Center, Randomized, Open-Label, Parallel-Controlled Clinical Trial Principal Investigator: Zhanguo Liu, Professor, Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University Study subjects: Patients aged 18-80 years admitted to the ICU requiring Continuous Renal Replacement Therapy (CRRT) for ≥24 hours, with normal coagulation function (INR ≤1.5, Fibrinogen ≥1.5 g/L, APTT ≤45 s), platelet count ≥50 G/L, and BMI between 18.5 and 25 kg/m². Patients with known allergy to Nafamostat, active bleeding, pregnancy, or those using other systemic anticoagulants or extracorporeal devices (e.g., ECMO, IABP) are excluded.

Study objectives: The primary objective is to determine whether a high initial dose (50 mg/h) of Nafamostat Mesilate, compared to a low initial dose (20 mg/h), prolongs the filter lifespan in ICU patients undergoing CRRT. Secondary objectives include evaluating differences in transmembrane pressure, clotting events, CRRT duration, blood flow rates, delivered dose, and safety outcomes such as bleeding complications and adverse drug reactions.

Study design: A single-center, randomized, open-label, parallel-controlled clinical trial.

Method: Eligible patients will be randomized into two groups:Low-Dose Group (Group A): Receives Nafamostat Mesilate at an initial continuous infusion dose of 20 mg/h pre-filter.High-Dose Group (Group B): Receives Nafamostat Mesilate at an initial continuous infusion dose of 50 mg/h pre-filter.

In both groups, the dosage will be titrated in increments of 5 or 10 mg/h based on activated clotting time (ACT) and activated partial thromboplastin time (APTT) measured post-filter. The target is to maintain post-filter ACT at 150-250 s (or 2.5 times baseline) and APTT at 50-70 s, while ensuring pre-filter values do not exceed 1.5 times baseline. The intervention continues until CRRT discontinuation due to filter clotting, recovery, transfer, death, or bleeding. Standardized CRRT protocols (CVVH mode, blood flow 150-200 mL/min) and routine critical care treatments are applied to all patients.

Course: Up to 72 hours per filter session, or until CRRT discontinuation. Sample size: 92 patients (46 per group). The number of study centers: 1 Study center:Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China Primary endpoint:Filter Lifespan: Defined as the duration (in hours) from the initiation of Nafamostat anticoagulation to filter change or discontinuation of CRRT due to clotting, extended downtime, renal recovery, patient transfer/death, or bleeding events necessitating a change in anticoagulation strategy.

Secondary endpoints:Filter Performance: Changes in Transmembrane Pressure (TMP) at specified intervals (2h, 8h, 16h, 24h, etc.); Number of filter clotting events (defined as TMP >250 mmHg or visible clotting).

Treatment Metrics: Total CRRT duration; Average daily blood flow rate; Daily delivered CRRT dose.

Coagulation Parameters: Maintenance levels of ACT and APTT; Changes in hemoglobin and platelet counts.

Safety Outcomes: Incidence of bleeding complications (e.g., gingival bleeding, epistaxis, GI bleeding); Incidence of adverse drug reactions related to Nafamostat (e.g., rash, hyperkalemia, elevated liver enzymes, gastrointestinal symptoms); Total blood product transfusion volume during CRRT.

Safety endpoints:Adverse Events: Monitoring for specific adverse reactions including drug allergy (rash), hyperkalemia, elevated AST/ALT, bleeding, thrombocytopenia, and gastrointestinal symptoms (nausea, vomiting, diarrhea).

Serious Adverse Events (SAE): Recording any event leading to death, life-threatening conditions, prolonged hospitalization, or significant disability, assessed for causality with the study drug.

Inclusion criteria

• Age & Gender: Aged 18 to 80 years, regardless of gender.
• Clinical Indication: Admitted to the Intensive Care Unit (ICU) with a confirmed indication for Continuous Renal Replacement Therapy (CRRT) and an expected treatment duration of greater than 24 hours.
• Coagulation Status: Normal coagulation function prior to CRRT initiation, defined as:International Normalized Ratio (INR) ≤ 1.5,Fibrinogen (FIB) ≥ 1.5 g/L,Activated Partial Thromboplastin Time (APTT) ≤ 45 seconds
• Platelet Count: Platelet count (PLT) ≥ 50 × 10⁹/L.
• Body Mass Index (BMI): 18.5 kg/m² ≤ BMI ≤ 25 kg/m².
• Informed Consent: Written informed consent obtained from the patient or their legally authorized representative.

Exclusion criteria

• Hypersensitivity: Known allergy or hypersensitivity to Nafamostat Mesilate or any component of the formulation.
• Active Bleeding: Presence of active bleeding or a high risk of bleeding that contraindicates anticoagulation (e.g., active gastrointestinal bleeding, intracranial hemorrhage, or recent major surgery with a high bleeding risk).
• Pregnancy/Lactation: Pregnant or breastfeeding women.
• Concurrent Anticoagulation: Current use of other systemic anticoagulants (e.g., unfractionated heparin, low molecular weight heparin, warfarin, or direct oral anticoagulants) that cannot be discontinued.
• Concurrent Extracorporeal Support: Concurrent use of other extracorporeal life support or blood purification therapies that may interfere with coagulation assessment, such as Extracorporeal Membrane Oxygenation (ECMO), Intra-Aortic Balloon Pump (IABP), or Plasma Exchange (PE).
• Severe Liver Dysfunction: Severe hepatic impairment (Child-Pugh Class C) or baseline total bilirubin levels exceeding 5 times the upper limit of normal.
• Limited Life Expectancy: Expected survival time of less than 24 hours due to the progression of underlying disease.
• Conflicting Trials: Current participation in another interventional clinical trial that may influence the outcomes of this study.