Study of INTERCEPT Blood System for Red Blood Cells in Regions at Potential Risk for Zika Virus Transfusion-Transmitted Infections (RedeS)

Stage A

Eligible patients will be randomized and transfused with study RBCs (Test or Control with 1:1
ratio) according to local practices for up to 28 days of transfusion support. Following the
28-day transfusion support period, patients will be transfused with conventional RBC
components as indicated by their treating physician. Patients will attend post-transfusion
follow up visits at 5-7 and 28 days after the last study transfusion for routine safety labs,
immune reactivity test to IBS RBC and to obtain samples for CHIKV, DENV and ZIKV viremia
(blood and urine by RT-PCR), DENV/ZIKV/CHIKV serology (IgM/IgG and confirmation with the
plaque reduction neutralization test [PRNT] or Reporter Virus Particles [RVP] when antibodies
are detected/increasing) and antibody assessment. A final blood sample for immune reactivity
test to IBS RBC will be collected 75 days after the last study transfusion. Study procedures
are summarized as follows:

Screening/Recruitment

All potentially eligible patients at participating institutions will be approached for study
consent prior to RBC transfusion. Patients 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, indication for anticipated transfusion,
type of scheduled surgery (if applicable), medical and surgical history, transfusion history,
physical examination, comorbid conditions, concomitant medications, hematology panel
(including complete blood count, blood type, blood chemistry, coagulation panel, DAT test,
immune reactivity to IBS RBCs, pregnancy test [when applicable]), Blood and urine samples
will also be taken and archived for future testing for viral RNA and/or antibodies for ZIKV,
CHIKV and DENV. Positive ZIKV/CHIKV/DENV serology will be further investigated for IgG and
IgM, as well as confirmation with PRNT or RVP when antibodies are detected).

Randomization and Blinding Eligible patients will be enrolled in the study and will be
considered for randomization. If a patient is enrolled and receives a RBC transfusion prior
to randomization, that patient will no longer be considered for randomization, and their
participation in the study will end. An Interactive Web Response System (IWRS) will be used
for electronic randomization of eligible patients.

Randomization will be at a 1:1 ratio of Test: Control and stratified by site and baseline
bleeding status [indication for RBC transfusion due to active bleeding (WHO grade 3 or 4,
Appendix 5) or for anemia without active bleeding]. Randomized patients who do not receive
any study RBC transfusions through 28 days after randomization will be discontinued/withdrawn
from the study and replaced. Additional data will not be collected for these patients.

At enrollment, the patient's eligibility status will be entered into the electronic data
capture system (EDC). If eligible, the patient will be randomized. Only appropriate blood
bank staff will be able to access the treatment arm assignment. Study RBC unit labels will be
indistinguishable for Test and Control products. Medical staff, and others caring for
participating patients, as well as the sponsor (and delegates) will be blinded to treatment
assignment.

Unblinded delegates will monitor the production of the RBC components.

Treatment Patients will be transfused with Test or Control RBC components for up to 28 days.
An RBC transfusion episode will be defined as all RBC units transfused within 4 hours. A
confirmed negative immune reaction to IBS RBC is required prior to the first study
transfusion. Compatibility for RBC antigens will be confirmed using site's SOPs prior to
transfusion of IBS RBCs. In case of confirmed physiologically active antibodies to IBS RBC or
any presumed or documented antibodies to IBS RBC that preclude further transfusion with IBS
RBCs, patients will be discontinued/withdrawn from the study and supported with locally
sourced and ZIKV-screened RBC components; if not available locally, components may be
imported from ZIKV non-epidemic regions.

Study Assessments: Monitoring and Follow-up Acute Transfusion Support Period (First study
transfusion through Day 28 or death) The acute transfusion support period will comprise 28
days from the day of the first study transfusion through Day 28, or death of a patient.
During this period, patients will receive as many study RBCs as deemed appropriate by the
treating physician. All AEs, SAEs, TRs and unanticipated adverse device effects will be
collected starting from the initiation of the first study transfusion through the entire
transfusion support period (and through 28 days after the last study transfusion). The
Investigators will assess each AE/SAE/TR and unanticipated adverse device effects for
relation to the transfusion study RBCs. Transfusion reactions will be classified by the
definitions in the CDC NHSN Hemovigilance Module Surveillance Protocol (Appendix 1) and will
be captured in the eCRF and in the CDC NHSN Biovigilance Component/Hemovigilance Module
(www.cdc.gov/nhsn).

Most proximate vital signs in the medical record will be collected prior to and following
each study transfusion. All concomitant medications taken during the study and blood products
transfused will be recorded on the EDC system with indication, total daily dose, and dates of
drug administration.

During the acute transfusion support period, patients will undergo the following assessments
prior to transfusion, at any time that 5 days have elapsed since the last study transfusion
or at death: vital signs, AEs, TRs, SAEs and unanticipated adverse device effects, comorbid
conditions, blood samples for safety labs (complete blood count, blood chemistry panel,
coagulation panel), DAT test, ZIKV/DENV/CHIKV viremia (blood and urine by RT-PCR) and
DENV/ZIKV/CHIKV serology (IgM/IgG and confirmation with PRNT/RVP when antibodies are
detected/increasing), and immune reactivity to IBS RBCs.. Samples may be used for additional
in vitro research tests as required to confirm suspected ZIKV, CHIKV and DENV or other
transfusion-transmitted pathogen mediated infections.

Follow-Up Period (5, 28 and 75 days after last study transfusion) For the purposes of the Day
5-7, Day 28 (± 7 days) and Day 75 (± 15 days) follow-up visits, Day 1 of the follow-up period
is the first day after the last study transfusion Day 5-7 and Day 28 After the Last Study
Transfusion (± 7 days) Five to seven (5-7) and 28 (± 7) days after the last study
transfusion, blood samples will be collected for routine safety labs, for assessment of
ZIKV/DENV/CHIKV viremia and ZIKV/DENV/CHIKV serology and for immune reactivity test for IBS
RBC; a blood and urine sample will also be collected for ZIKV/DENV/CHIKV viremia assessment.

All AEs, SAEs, TRs and unanticipated adverse device effects will be reviewed and recorded for
the period from the first study transfusion through Day 28 after the last study transfusion.

End of Study Visit (Day 75 ±15 days) At Day 75 (± 15 days) after the last study transfusion,
a blood sample will be collected for immune reactivity test for IBS RBC.

Stage B Upon review and approval by FDA, all eligible patients who provide consent at
participating sites will be transfused with IBS RBCs according to local practices for as long
as needed during the duration of the study. A confirmed negative crossmatch with IBS RBC is
required prior to every study transfusion. Compatibility for RBC antigens will be confirmed
according to site's SOPs prior to transfusion of IBS RBCs. In case of confirmed
physiologically active antibodies to IBS RBC, patients will be discontinued from the study
and supported with conventional RBCs, locally sourced and ZIKV-screened. Transfusion
reactions and SAEs occurring through 28 days post transfusion will be documented. A serum
sample for antibodies specific for IBS RBC associated antigens and a blood sample for
archival testing for viral RNA and/or antibodies for CHIKV, DENV and ZIKV will be taken
before and 28 days after the first study transfusion (±7 days) until data are available for
at least 1000 participants.

Stage A: Inclusion Criteria:

1. Age ≥ 18 years

2. Patients who are required or expected to require a transfusion of RBC component(s).

3. Signed and dated informed consent

4. Female patients of child-bearing potential must:

1. Have negative serum or urine pregnancy tests prior to study treatment to rule out
pregnancy, and

2. Agree to use at least one medically accepted 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, sexual abstinence or vasectomized partner for the duration
of study participation and for an additional 28 days.

Stage A: Exclusion Criteria:

1. Confirmed positive baseline serum/plasma antibody specific to IBS RBC as determined by
INTERCEPT antibody screening panel prior to receiving their first study transfusion

2. Pregnant or breast feeding.

3. Patients who require neonatal transfusions and intrauterine transfusions.

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

5. Presence of a RBC warm autoantibody or positive DAT with a panreactive eluate.

6. Have had an RBC transfusion during current hospitalization prior to enrollment (within
28 days)

7. Have received investigational products, including investigational blood products,
pharmacologic agents or imaging materials, within the prior 28 days. Prior receipt of
conventional blood products tested with an investigational ZIKV NAT test are not
considered grounds for exclusion despite the investigational nature of the NAT test.

8. Patients presenting with or expected to have massive hemorrhage (≥10 RBC units within
24 hours) or expected to require massive transfusion protocols

Stage B: Inclusion Criteria

1. Age ≥ 18 years

2. Patients who are require or expected to require a transfusion of RBC component(s).

3. Signed and dated informed consent

Stage B: Exclusion Criteria

1. Confirmed positive baseline serum/plasma antibody specific to IBS RBC as determined by
INTERCEPT antibody screening panel prior to receiving their first study transfusion

2. Pregnant or breast feeding.

3. Patients who require neonatal transfusions and intrauterine transfusions.

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