(P-BC-43) Manufacturing Amustaline/Glutathione Pathogen-Reduced Red Cells to Support the ReCePI Phase III Clinical Study

The ReCePI Phase III randomized, double blinded clinical study compared  amustaline (S-303)/glutathione (GSH) pathogen-reduced (PR) RBCs (Test) with conventional RBCs (Control) in subjects undergoing complex cardiac surgery. Study RBCs were provided from 2018 to 2023 by four US blood centers that manufactured sufficient Test and Control RBCs units with storage to 35 days to maintain an inventory at 18 hospital sites despite blood shortages related to the COVID pandemic.

Study

Design/Methods:

Test units were leukoreduced PRRBCs in SAG-M additive solution manufactured from packed RBCs in AS-5 storage solution that were treated with the S-303/GSH process and then resuspended in SAG-M storage solution after a final exchange step. Control units were leukoreduced RBCs in AS-1 or AS-5 storage solution. Blood centers validated bespoke manufacturing and whole blood collection processes to produce both Test and Control components that were labeled with a common ISBT-compatible label to maintain the blind. A computerized ordering system facilitated communication between the transfusion services and blood centers.

Results/Findings:

4,755 Test and 4,856 Control RBC components were manufactured and 456 Test and 524 Control (P=0.049) were transfused to 321 subjects at 18 clinical sites (Overall 10.2% transfused). RBC units were ~33% ABO group A and ~67% group O and ~21% Rh negative, but this varied by blood center. On average, Test units were older than Control at the time of transfusion (Test 23.2 ±7.6 vs. Control 21.4 ±8.1 days, P=0.003). Test and Control RBCs (Figure) contained a range of total hemoglobin (40-85 g Hb/concentrate). On average, 2.7 g Hb (4.4%) was lost during the PR process, however, Test RBCs remained well within the Hb content range of Control RBCs. Despite the manufacturing losses, the ReCePI study showed that Test subjects received fewer total study RBCs within 48 hours of surgery (median 2 (range 1-16) Test versus 3, (range 1-21) Control, P=0.048) despite similar baseline Hb (11.7 ±1.9 g/dL Test, 11.5 ±2.1 g/dL Control) and surgical blood losses, and maintained comparable hemoglobin levels post-surgery for 7 days (Day 1 post surgery Hb 9.1 ±1.3 g/dL in both Test and Control).

Conclusions:

Four US Blood Centers demonstrated the capacity to validate and implement a dedicated manufacturing process for S-303/GSH PRRBCS despite the COVID pandemic.  The ~10.2% overall transfusion rate speaks to the difficulty in maintaining sufficient hospital inventories of both Test and Control RBCs, and the extraordinary effort of the blood center staff to minimize non-study RBC transfusions in this randomized, double-blinded study. (funded by the Biomedical Advanced Research Development Authority, DHHS; ClinicalTrials.gov, NCT03459287).