Phase III Study to Evaluate the Efficacy and Safety of the INTERCEPT Blood System for Red Blood Cells in Patients Undergoing Complex Cardiac Surgery Procedures

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 will be identified through pre-operative scheduling procedures in advance of their
operations.

All potentially eligible patients will be approached for study consent prior to their
surgical procedure. Subjects who consent to the study will be assigned a study ID number and
undergo screening. Screening data collection and procedures will include:

Demographics (age, sex), vital signs, height, weight, EKG, type of scheduled surgery, need
for irradiated blood products, medical and surgical history, transfusion history, physical
examination, concomitant medications, complete blood count, blood type, blood chemistry,
coagulation panel, troponin, DAT test, immune reactivity to IBS RBCs, and pregnancy test
(when applicable). All TRUST components will be collected on the CRF.

Randomization and Blinding Potentially eligible subjects will be screened and will be
considered for randomization. If a subject is screened and receives a red cell transfusion
prior to randomization, that subject will no longer be considered for randomization, and
their participation in the study will end. An Interactive Web Response System 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 ≥1.2mg/dL), and
cardiac surgery type will be employed. Randomized subjects who do not receive any study RBC
transfusions during surgery or within the first 48 hours after completion of surgery,
hospital discharge, or death, whichever occurs first, will be replaced.

Screening will include documentation of the patients' pre-surgical exposure to radiographic
contrast media, number of prior pregnancies (females), complete blood count, blood
chemistries, blood type, DAT, IAT, RBC antibody screen, and the presence of antibodies to
INTERCEPT RBC. Data may be derived from the medical record where performed within 7 days of
screening.

At screening, the subject's eligibility status will be entered into the electronic data
capture system (EDC). On the day before or day of scheduled surgery, eligible subjects will
be enrolled and randomized with a 1:1 ratio for Test: Control within each randomization
stratum. Only appropriate blood bank staff will be able to access the treatment arm
assignment. RBC unit labels will be identical for Test and Control products. Operating room
staff, surgical staff, ICU staff, and others caring for participating patients, as well as
the sponsor (and delegates) will be blinded to treatment assignment. Unblinded monitors will
monitor the production of the RBC components.

Treatment Randomized subjects will be transfused with Test or Control RBCs during surgery
(Day 0) through Day 7 post surgery, hospital discharge, or death, whichever is first, as
clinically indicated and determined by the treating physician. Treatment assessments will be
divided into an acute surgical care period starting the day of surgery until Day 7, hospital
discharge, or death, whichever is first, 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, clinical assessment at day 30 and day 75 (±15)
after the last study transfusion for mortality and RRT status, and collection of samples for
serological screening for antibodies specific to IBS at end of study (75 (±15) days).

In all patients anesthesia and surgical procedures will be performed according to the local
standards of the institution. Study RBC components will be ordered and administered to study
subjects by their treating physicians, also according to the local standards of care.
Following the study treatment period, subjects may receive conventional RBC components if
additional transfusions are needed, as indicated by their treating physician.

Study Assessments: Monitoring and Follow-up Acute Surgical Care Period (Pre-operative to
Post-operative Day 7) Hemodynamic and laboratory measures will be assessed pre-operatively
(Day -1) and daily from post-operative Day 1 through post-operative 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 standard care on Day 7, attempts will be made to perform phlebotomy on
that day for a complete blood count and sCr determination. Randomized subjects who do not
receive an RBC transfusion either during surgery or within the first 48 hours after surgery,
hospital discharge, or death, whichever occurs first, will not be followed any longer and
will be replaced.

Hemodynamic parameters that will be monitored include heart rate, blood pressure, mean
arterial pressure, central venous pressure (CVP), peripheral oxygen saturation via pulse
oximetry probe, arterial PO2, FiO2 and arterial oxygen saturation (as available in the
medical records).

Laboratory parameters that will be monitored include BUN, creatinine, ALT, fibrinogen,
bilirubin, troponin-I, lactic acid, hemoglobin and platelet counts. A blood sample for sCR
will be taken at 48 (±4 hours) after completion of surgery, and sCr will be determined on a
daily basis during the acute surgical care period up to 7 days post-surgery. Other parameters
will be collected on a daily basis as available in the medical record. Laboratory parameters
will be measured by a CLIA accredited local laboratory.

The use of radiographic contrast media will be documented starting 7 days prior to surgery,
as will details related to the specific surgical procedure (type of procedure, start and end
times, RBC components transfused, all other blood components transfused, estimated blood loss
from the surgical procedure, concomitant medications, intraoperative cell recovery and
reinfusion, hemodilution procedures, and nadir temperature. Additionally, daily estimated
blood loss from chest tube(s) and from other sources, and day of chest tube removal will be
recorded.

Transfusion reactions, AEs and SAEs will be documented on a daily basis from the time of
randomization through post-operative and as available through day 28 after the last study
transfusion.

Blood samples for detection of antibody to IBS RBC will be collected at Day 28 (± 3 days
window) and Day 75 (±15 day window) following the last study transfusion.

Post-operative Day 8 to 28 Days After Last Study Transfusion Subjects will be monitored for
transfusion reactions, AEs and SAEs as available following the 7-day treatment 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 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 studies including sCr ,DAT/ IAT and RBC allo-antibodies; a sample for HLA
antibodies and antibodies specific to IBS RBC will be obtained, either in hospital or at
clinic visit. 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.
Mortality and the need for RRT through Day 30 post-surgery will also be documented.

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.

End of Study (75±15 Days After last Study Transfusion) On 75±15 days after the last study
transfusion (End of Study), serum samples for antibodies specific for IBS RBC 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, intensive care and/or cardiac surgery
experts, and a statistician. DSMB members will be independent of the Sponsor.

Interim Analysis and Early Stopping Rule Aside from the interim sample size re-estimation, no
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.

Inclusion Criteria:

1. Age ≥ 11 years of age

2. Weight ≥ 40 kg

3. Scheduled complex cardiac surgery with planned use of median sternotomy. The procedure
may be performed either on-pump or off-pump. For the purposes of this protocol "Repeat
procedure" means that the subject had a previous cardiac surgery with median
sternotomy. Procedures that qualify as complex cardiac surgery include the following:

- Single Vessel Coronary Artery Bypass Graft, repeat procedure

- Multiple Coronary Artery Bypass Grafts, first or repeat procedure

- Single Valve Repair or Replacement, 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 defect repair, and

- aortic root procedures

4. TRUST probability score (Alghamdi, Davis et al. 2006) ≥ 3, or currently on a regimen
of aspirin, clopidogrel (or analogs) and/or GPIIb/IIIa inhibitors.

5. Female subjects of child-bearing potential must meet the 2 criteria below:

- Have negative serum or urine pregnancy tests prior to study treatment to rule out
pregnancy

- 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. Confirmed negative anti-human globulin (AHG) crossmatch with IBS RBCs to detect
antibodies to IBS-treated RBCs prior to receiving first study transfusion

7. Signed and dated informed consent form

Exclusion Criteria:

1. Pregnant or breast feeding.

2. Refusal of blood products or other inability to comply with the protocol in the
opinion of the Investigator or the treating physician.

3. Treatment with any medication that is known to adversely affect RBC viability, such
as, dapsone, levodopa, methyldopa, nitrofurantoin, and its derivatives,
phenazopyridine and quinidine.

4. Planned surgery is minimally invasive.

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) (IABP done for unstable angina or prophylactically for low ejection fraction is
not excluded).

9. Planned deep hypothermic circulatory arrest (DHCA).

10. Planned use of autologous or directed donations.

11. RBC transfusion during current hospitalization prior to enrollment and randomization
(within 14 days).

12. Participation in any one of the following types of clinical studies either
concurrently or within the previous 28 days: investigational blood products,
pharmacologic agents or imaging materials, including dyes, investigational surgical
techniques, or devices. Studies of nutrition, psychology, or socioeconomic issues are
not grounds for exclusion.

13. Current diagnosis of either chronic kidney disease or acute kidney injury with sCr ≥
1.8 mg/dL at screening or requiring RRT.

14. Current diagnosis of either chronic or acute hepatic insufficiency or a total serum
bilirubin greater than or equal to 2.0 mg/dL (≥34.2 µmol/L) at screening.

15. Pre-existing antibody to RBC antigens that may make the provision of compatible study
RBC components difficult.

16. History of transfusion reactions requiring washed RBCs, volume reduced RBC, or RBCs
with additive solution removed.

17. Patients with documented IgA deficiency or a history of severe allergic reactions to
blood products.

18. Patients who require gamma-irradiated RBC blood components