Study to Evaluate the Efficacy & Safety of the INTERCEPT Blood System for RBCs in Complex Cardiac Surgery Patients

The objective of this study is to evaluate the efficacy and safety of RBC transfusion for support of acute anemia in cardiovascular surgery patients based on the clinical outcome of renal impairment following transfusion of red blood cells (RBCs) treated with the INTERCEPT Blood System (IBS) for Red Blood Cells compared to patients transfused with conventional RBCs.

This is a prospective, multicenter, randomized, double-blinded, active controlled, parallel-design, non-inferiority study.

Screening/Recruitment

In order to minimize the number of patients who enroll in the study but do not require RBC transfusion, only patients with a relatively high likelihood to receive a RBC transfusion as determined by the Investigator (e.g., patients receiving aspirin, clopidogrel (or analogs) and/or GPIIb/IIIa inhibitors), or patients with a TRUST Score of ≥3 will be eligible for enrollment. Patients ≥11 years of age undergoing complex cardiac surgery may be identified through pre-operative scheduling procedures in advance of their surgery.

Patients undergoing urgent or emergent cardiac surgery are eligible for the study, subject to institutional review board (IRB) approval of an appropriate informed consent process.

All potentially eligible patients will be approached for study consent/assent within 30 days prior to their surgical procedure. Subjects who consent/assent to the study will be assigned a subject ID number and undergo screening.

Screening will include documentation of the patient's pre-surgical exposure to radiographic contrast media and number of prior pregnancies (females). Screening data may be derived from the medical record when performed within 30 days prior to their surgical procedure. Eligibility status and other study data including all TRUST components will be entered into the clinical database via an electronic data capture (EDC) system using electronic case report forms (eCRFs). Patients who fail eligibility for any or multiple inclusion/exclusion criteria may be rescreened for eligibility closer to the time of surgery.

Randomization and Blinding

Eligible subjects will be randomized up to 7 days before or on the day of scheduled surgery (Day 0). An Interactive Web Response System (IWRS) will be used for electronic randomization of eligible patients. Randomization (in 1:1 ratio for Test:Control) stratified by site, pre-existing renal impairment (baseline sCr ≥1.2 mg/dL vs. \< 1.2 mg/dL), and cardiac surgery group (more at risk for renal complications vs. less at risk) will be employed. Screened subjects who receive a red cell transfusion prior to randomization will no longer be considered for randomization, and their participation in the study will end. Patients may be rescreened for eligibility closer to the time of surgery.

Treatment

Once a subject is randomized, only study RBCs (Test or Control, per the subject's randomization) should be dispensed and transfused during the acute transfusion support period (Day 0 to Day 7 post surgery, hospital discharge, or death, whichever is first), as clinically indicated and determined by the treating physician.

In rare exceptions where study RBCs are unavailable or patient's need for RBC transfusions exceeds the quantity of study RBCs in inventory at the hospital blood bank (e.g., during a Massive Transfusion Protocol), a transfusion using non-study RBC (conventional) may be given to provide the patient with an appropriate and necessary treatment. In this case, a protocol deviation should be documented. If a study RBC transfusion is given after randomization before surgery commences, a protocol deviation should also be documented.

Treatment assessments will be divided into an acute transfusion support period starting the day of surgery (Day 0 up to Day 7) during which study RBC (Test or Control) are administered, a post-surgical follow-up period of a minimum of 28 days after the last study transfusion to collect additional safety data, a clinical assessment at day 30 after surgery specifically for mortality and RRT status, and a visit at day 75 (±15) after the last study transfusion to assess mortality and RRT status, and collect samples for serological screening for antibodies specific to INTERCEPT RBCs.

In all patients, anesthesia and surgical procedures will be performed according to the local standards of care. Following the acute transfusion support period, subjects may receive conventional RBC components if additional transfusions are needed, as indicated by their treating physician.

Study Assessments: Monitoring and Follow-up

Baseline through Acute Transfusion Support Period (Pre-Op Day -1 up to Post-Op Day 7):

A screen for antibodies specific for INTERCEPT RBCs should be performed every time that a routine IAT is performed during the acute 7-day study transfusion period.

A blood sample for sCr will be taken at 48 ±4 hours after completion of surgery for both transfused and non-transfused subjects., A sCr will be determined on a daily basis during the acute transfusion support period up to 7 days post-surgery. Other parameters including additional sCr will be collected on eCRFs only when available in the medical record.

Randomized subjects who do not receive an RBC transfusion following randomization within the first 48 hours after surgery will be discontinued from the study and replaced.

Daily sCr assessments will be recorded up to and including 48 ±4 hours for transfused and non-transfused subjects. Other post baseline laboratory parameters and adverse events (AEs) will not be collected for non-transfused subjects. Vital status will be reported for randomized and non-transfused subjects at the time of discontinuation.

Hemodynamic and laboratory measures will be assessed pre-operatively (Day -1, Baseline) and daily as available in the medical record from post operative Day 1 through Day 7, hospital discharge or death, whichever occurs first. If a subject is discharged prior to Day 7 but returns to the study site for a standard of care visit on Day 7, blood samples should be obtained on that day for a complete blood count and sCr determination.

Hemodynamic parameters that will be collected if available, include heart rate, blood pressure, mean arterial pressure, central venous pressure (CVP), and peripheral oxygen saturation via pulse oximetry probe.

Laboratory parameters that will be captured on eCRFs include BUN, creatinine (sCr), AST, ALT, fibrinogen, bilirubin, troponin, hemoglobin, and platelet counts.

Transfusion reactions (TRs), adverse events (AEs) and serious adverse events (SAEs) will be assessed on a daily basis and documented in the eCRF from the start of surgery or the start of the first study transfusion (whichever is first) through post-operative Day 7 and as available through day 28 after the last study transfusion. Vital status will be reported for randomized and non-transfused subjects at the time of discontinuation.

NOTE: The following applies to randomized transfused subjects only.

Post-operative Day 8 (or Post-discharge, if earlier) through 28 Days After Last Study Transfusion:

Subjects will be monitored for TRs, AEs and SAEs following the 7-day acute transfusion support period, through 28 days after the last study transfusion or death, whichever occurs first, according to the local standard of care. In an outpatient setting, weekly telephone surveillance calls to the subject will be performed in order to collect safety events until the next follow-up visit.

28 (±3) Days After Last Study Transfusion or Premature Discontinuation from study:

Subjects who have been discharged should be scheduled for the follow up visit 28 (±3) days after the last study transfusion to obtain additional safety information, including patient-reported AEs/ SAEs; laboratory results including sCr, DAT/ IAT; a sample for HLA antibodies and antibodies specific to INTERCEPT RBCs will be obtained. All randomized subjects who receive any study RBC transfusion must have their vital status documented at this visit, or earlier, if the subject dies prior to the visit. If a subject has been discharged, other safety information (e.g., AEs and SAEs) may be obtained through medical records, the subject's physician, or a telephone interview with either the subject or a family member.

30 Days After Surgery:

All randomized subjects who receive a study RBC transfusion must have their vital status and need for RRT (defined as hemodialysis or peritoneal dialysis) documented at Day 30 after surgery. RRT that is provided prophylactically during surgery while patient is on a bypass machine (the pump), does not meet this endpoint. The vital status and RRT assessment on Day 30 can be performed either from the medical records, from a phone call to the subject or family, or during the visit 28±3 days after the last study transfusion (only if the last study transfusion was given at day 2 or later in the acute transfusion support period).

End of Study: 75 (±15 Days) After last Study Transfusion:

75 (±15) days after the last study transfusion (End of Study), serum samples for antibodies specific for INTERCEPT RBCs will be obtained, either in hospital, at a clinic visitor or offsite. Mortality and the need for RRT will be assessed

Data and Safety Monitoring Board (DSMB)

The study data and safety will be monitored by an independent Data and Safety Monitoring Board (DSMB). The primary mission of the DSMB is to ensure patient safety and protocol compliance for data collection. The DSMB will be assembled by the Sponsor and composed of transfusion medicine and other experts as per the DSMB charter. DSMB members will be independent of the Sponsor.

Interim Analysis and Early Stopping Rule

Aside from the blinded interim analysis for sample size re-estimation performed in October 2021, no other interim analysis is planned for this study to compare treatment differences with respect to efficacy or safety at any time prior to the completion of the study. Specific stopping rules, defined for safety considerations, are defined in Section 4.6 of the protocol.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥ 11 years of age
2. Weight ≥ 40 kg
3. Scheduled complex cardiac surgery or thoracic aorta surgery. The procedure may be performed either on or off cardiopulmonary bypass machine (CBP or "pump"). For the purposes of this protocol "Repeat procedure" means that the subject had a previous cardiac surgery. Procedures that qualify as complex cardiac surgery include but are not limited to, the following:

   * Single Vessel Coronary Artery Bypass Graft, first or repeat procedure
   * Multiple Coronary Artery Bypass Grafts, first or repeat procedure
   * Single Valve Repair or Replacement, first or repeat procedure
   * Multiple Valve Repair or Replacement, first or repeat procedure
   * Surgery involving both Coronary Artery Bypass Graft(s) and Valve Repair(s), first or repeat procedure
   * One or more of the following procedures, with or without Coronary Bypass Graft(s):

     * left ventricular aneurysm repair
     * ventricular and/or atrial septal defect repairs
     * Batista procedure (surgical ventricular remodeling)
     * surgical ventricular restoration
     * congenital cardiac defect repair
     * aortic procedures
     * other cardiac surgery or thoracic aorta surgery types with a high probability of bleeding
4. TRUST probability score (Alghamdi, Davis et al. 2006) ≥ 3, or currently on a regimen of aspirin (any dose), clopidogrel (or analogs) and/or GPIIb/IIIa inhibitors or at a high probability for need of a transfusion during or after surgery at the discretion of the Investigator
5. Female subjects of child-bearing potential must meet the 2 criteria below at screening:

   * Negative serum or urine pregnancy test
   * Use at least one method of birth control that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized partner
6. Signed and dated informed consent/assent form

Exclusion Criteria:

1. Confirmed positive baseline serum/plasma antibody specific to INTERCEPT RBCs (S-303 specific antibody) screening panel prior to randomization.
2. Pregnant or breast feeding
3. Refusal of blood products or other inability to comply with the protocol in the opinion of the Investigator or the treating physician
4. Treatment with any medication that is known to adversely affect RBC viability, such as, but not limited to dapsone, levodopa, methyldopa, nitrofurantoin, and its derivatives, phenazopyridine and quinidine.
5. Planned cardiac transplantation
6. Active autoimmune hemolytic anemia
7. Left ventricular assist device (LVAD) or extracorporeal membrane oxygenation (ECMO) support pre operatively or planned need post-operatively
8. Cardiogenic shock requiring pre-operative placement of an intra-aortic balloon pump (IABP) (NOTE: IABP done for unstable angina or prophylactically for low ejection fraction is not excluded).
9. Planned use of autologous or directed donations.
10. RBC transfusion during current hospitalization prior to enrollment and randomization (within 7 days).
11. Participation in an interventional clinical study concurrently or within the previous 28 days. This includes investigational blood products, pharmacologic agents, imaging materials (including dyes), surgical techniques, or devices. Observational studies of FDA cleared or approved products or nutrition, psychology, or socioeconomic issues are not grounds for exclusion
12. Patients with a current diagnosis of either chronic kidney disease or acute kidney injury and with sCr ≥1.8 mg/dL at screening and patients requiring RRT. (NOTE: If sCr at screening is \<1.8 mg/dL, a patient with a diagnosis of chronic or acute kidney injury alone is not excluded).
13. Patients with a current diagnosis of either chronic or acute hepatic insufficiency and with a total serum bilirubin ≥ 2.0 mg/dL (≥34.2 µmol/L). (NOTE: If total serum bilirubin at screening is \<2.0 mg/dL, a patient with a diagnosis of chronic or acute hepatic failure alone is not excluded).
14. Pre-existing antibody(ies) to RBC antigens that may make the provision of compatible study RBC components difficult.
15. History of TRs requiring washed RBCs, volume reduced RBC, or RBCs with additive solution removed.
16. Patients with documented IgA deficiency or a history of severe allergic reactions to blood products.
17. Patients who require gamma-irradiated RBC blood components.
18. Positive DAT as defined below:

A polyspecific DAT reaction strength \> 2+, or

A polyspecific DAT (any strength) in conjunction with pan-reactivity with a commercial IAT antibody screening panel that precludes the identification of underlying alloantibodies or indicates the presence of autoantibody