Challenge Transfusion of INTERCEPT Pathogen Reduced Red Blood Cells (RBCs) in Subjects With or Without Pre-existing Antibodies to INTERCEPT RBCs

An Open-label, Controlled Phase 2 Study Assessing a Challenge Transfusion of INTERCEPT Pathogen Reduced Red Blood Cells (RBCs) in Subjects With or Without Pre-existing Antibodies to INTERCEPT RBCs

This study aims to determine whether transfusion of INTERCEPT RBCs into patients with pre-existing antibodies to INTERCEPT RBCs will result in increased antibody titer indicative of a secondary immune response, and whether these immune responses would be associated with clinical adverse events, increased RBC clearance, and/or evidence of hemolysis. Because the recovery and survival of fresh allogeneic INTERCEPT RBCs in patients with a diverse group of diseases is poorly characterized, a Control group of subjects without a history or evidence of antibodies to INTERCEPT RBCs may be evaluated as a comparator (Control group subjects may or may not have previously been transfused with INTERCEPT RBCs).

The study will also compare and correlate results from anti-human globulin (AHG) crossmatch using INTERCEPT RBCs prepared for transfusion, with results from indirect antiglobulin testing (IAT) with S 303 treated reagent RBCs (i.e., INTERCEPT RBC screening assay, as used in previous studies) to assess the utility of the AHG crossmatch to define the compatibility of transfused INTERCEPT RBCs

This is a prospective, open-label, controlled Phase 2 study. Consented subjects will be screened for currently detectable or previously documented allogeneic, autologous, and INTERCEPT RBC-specific antibodies, assigned to a study arm, then receive a small volume transfusion of fresh (≤14 days old) allogeneic INTERCEPT RBCs under careful clinical oversight for adverse events including evidence of hemolysis.

Subjects will have blood samples drawn pre-transfusion and over 90 days after transfusion (Days 0, 1, 7, 14, 30, 60, and 90) to detect evidence of primary or secondary immune responses to INTERCEPT RBCs (see Section 8.4.2), and to assess the in vivo post transfusion 24-hour recovery (PTR24) and survival assessed as the half-life [T50], predicted mean/median lifespan, and area-under-the-survival curve (AUC) of the transfused cells.

RBCs and plasma will be collected and stored frozen for further analysis. Specific studies will include gel card-based INTERCEPT RBC antibody screen assay and titer, AHG crossmatch using cells from INTERCEPT RBC units prepared for transfusion, as well as RBC flow cytometric analysis using an antibody specific for acridine to quantitate the proportion of circulating INTERCEPT RBCs and the acridine adduct surface density.

Clinical evidence of hemolysis will be evaluated using routine laboratory tests, including complete blood counts (CBC), chemistry tests and urinalysis.

Test and Control subjects may be recruited from other INTERCEPT RBC studies. Control subjects may be recruited from specific age groups (e.g., children, adults) with specific medical conditions that are known to impact RBC survival in vivo, particularly conditions that are shown to be present in Test subjects (e.g., sickle cell disease, thalassemia).

After an initial challenge dose of 30-40 ml total volume (appx 20 ml RBCs at 50-70% hematocrit), subjects may be consented and enrolled for second and third challenge doses after completion of all study requirements for the subject's prior dose as well as a 120-day minimum wash-out period since the previous study transfusion.

If a subject requires a therapeutic RBC transfusion, had no evidence of hemolysis with the previous challenge dose(s) and remains eligible for a subsequent challenge dose, they may be administered a challenge dose of one full unit volume. Prior to administering each full unit challenge dose, a Data Safety Monitoring Board (DSMB) must perform an interim safety analysis considering all available study data.

Subjects may receive up to three challenge doses of INTERCEPT RBCs.

Inclusion Criteria:

• Age ≥4 years in children who meet the requirement of US Code of Federal Regulation (CFR) Title 21, §50.53 as determined by the local Institutional Review Board (IRB).
• Control subjects shall have no current or previously documented antibodies to INTERCEPT RBC.
• Test subjects shall have current or previously documented natural or treatment-emergent antibodies to INTERCEPT RBCs.
• History of prior transfusion with allogeneic blood products (INTERCEPT or non-INTERCEPT treated).
• >120 days from the subjects most recent exposure to Study RBCs (pathogen reduced or non-pathogen reduced - if any) prior to the planned study transfusion.
• Signed and dated informed consent form

Exclusion Criteria:

• Foreseeable active blood loss due to trauma, surgery, or pathologic condition during the study period.
• Exposure to another interventional drug or device in a clinical study within 28 days prior to enrollment or concurrently during the study.
• Positive Direct Antiglobulin Test (≥2+) at the time of screening, prior to the first study transfusion.
• Current or historical medical conditions judged by the Investigator to significantly increase the risk of morbidity/mortality due to hemolysis or the medical management of acute hemolysis.
• Treatment with any medication known to affect RBC viability at the time of enrollment (e.g., ribavirin, sulfa drugs, chemotherapy medications, methylene blue, dapsone, levodopa, methyldopa, nitrofurantoin and its derivatives, phenazopyridine, quinidine, and hydantoins)
• History of or development of a drug-associated RBC antibody not associated with INTERCEPT RBCs.
• Congenital or acquired immunodeficiency judged by the Investigator to potentially impact the humoral immune response.
• Immunosuppressive therapy within 1 month prior to enrollment or during the study period, including steroids and intravenous immunoglobulin.
• Current or historical RBC alloantibodies that are judged by the Investigator to prevent selection of antigen-negative RBCs for transfusion.
• History of immunoglobulin A (IgA) deficiency, severe allergic reaction to blood product(s), or clinical requirement to receive washed cellular products.
• History of warm autoantibody with hemolysis.
• Subjects who are pregnant, or biologically able to become pregnant and unwilling to remain on medically accepted contraception during this study.