Transfusion Efficacy and Safety of Amustaline/Glutathione Pathogen-Reduced Red Blood Cells: Results of a Randomized, Controlled Phase III Trial

Field: Medicine (Health Sciences)

Introduction: Red blood cell (RBC) transfusion is a lifesaving intervention with a low but persistent risk of transfusion-transmitted infection. Amustaline/glutathione RBC pathogen-reduction (PR) technology is designed to proactively inactivate a broad spectrum of viruses, bacteria, protozoa and leukocytes by chemically crosslinking nucleic acids and preventing replication and transcription. The Red Cell Pathogen Inactivation (ReCePI) trial was a Phase III, double-blinded, randomized non-inferiority study comparing PR and conventional RBCs for the support of acute anemia. Methods/Study Design: Complex cardiac or thoracic-aorta surgery patients received conventional (Control) or PR RBCs (Test) during and for 7 days after surgery. The protocol was conducted with ethics committee approval at all participating centers and written informed consent from all participants. Hemoglobin levels, blood utilization and serum creatinine were assessed as indicators of efficacy and oxygenation of tissues (Karkouti et al. Br J Anaesth. 2012; 109 Suppl 1: i29-i38). The primary endpoint was the incidence of acute kidney injury (AKI) measured as change in serum creatinine from baseline within 48 hours of surgery, a predictor of adverse postoperative outcomes including mortality by Day 30 post-surgery (Lassnig et al. Am Soc Nephrol 2004; 1597-1605). Secondary endpoints included AKI occurring up to 7 days post-surgery (KDIGO Clinical Practice Guideline for AKI, Kidney Inter, Suppl. 2012;2:1-138); death or the need for renal replacement therapy by 30 days post-surgery; PR RBC-specific antibodies; and death by day 75 post-surgery. With &gt;292 subjects enrolled, the study had 80% power to demonstrate non-inferiority, assuming an AKI incidence of 30% with conventional RBCs and a non-inferiority margin of half the conventional RBC rate. Under these circumstances, an absolute treatment increase of 5% in the AKI rate in the PR RBC arm would fail the non-inferiority test. This work was supported by a contract with the US Biomedical Advanced Research and Development Authority (HHS010020160009c) with Cerus Corporation. Results: Five-hundred and eighty-one subjects were randomized and 321 (55%) transfused in 18 US hospitals. In the modified intent-to-treat analysis subjects receiving Test and Control RBCs had similar median [IQR] total blood loss (1500 [940-2475] mL Test, 1733 [1060-2880] mL Control, p=0.310) and comparable median hemoglobin levels at baseline and immediately post-surgery (9.8 [8.9-10.9] g/dL Test, 9.6 [8.6-10.6] g/dL Control, p=0.157) and for 7 days after surgery, The PR RBC arm was transfused with fewer RBCs, measured as total RBC Hb transfused over 7-days (169.0 [102.0-240.0] g Hb PR arm, 188.0 [126.0-295.0] g Hb, conventional RBC arm, p=0.008). The incidence of AKI was 29.3% (46/157) for Test and 28.0% (45/161) for Control. The treatment difference was 0.74% (95% CI -8.9, 10.4%, non-inferiority margin 14.0%, p=0.001 for non-inferiority). Non-inferiority was also achieved by the per protocol analysis. Average mean change in serum creatinine within 48 hours of surgery was comparable (Test 0.020, Control 0.23 mg/dL, P=0.515). Adverse events, serious adverse events and deaths on study were not different. Five of 159 (3.1%) PR RBC recipients developed low titer PR RBC-specific antibodies without clinical signs of hemolysis. Flow cytometry analysis revealed persistent circulating PR RBCs with uniform antigen loss (modulation). Low level human IgG antibody binding was demonstrated in 3 of 5 subjects. Conclusions: PR RBCs showed equivalent hemoglobin support for acute bleeding patients undergoing cardiac or thoracic-aorta surgery while using less transfused total RBC Hb over 7 days. The incidence of AKI in patients transfused with PR RBCs was non-inferior to that observed with conventional RBCs, indicative of effective tissue oxygenation. Treatment-related antibodies to PR-RBC were observed only in Test subjects, the antibodies were low titer, transient, without clinical hemolysis, and persistent circulating PR RBCs were detected with modulated low level acridine antigen expression (www.clinicaltrials.gov #NCT03459287).