INTERCEPT Blood System for RBCs Study in Regions at Potential Risk for Zika Virus Transfusion-Transmitted Infections

A Randomized, Double-Blind, Controlled, Parallel Group Study With the INTERCEPT Blood System for Red Blood Cells in Regions at Potential Risk for Zika Virus Transfusion-Transmitted Infections (RedeS)

To evaluate the safety and efficacy of red blood cells (RBCs) prepared with the INTERCEPT Blood System for Red Blood Cells Pathogen Reduction Treatment (PRT) in comparison to conventional RBCs in patients who require RBC transfusion support.

Patients will be approached, consented, screened for eligibility and randomized to receive either Test or Control RBCs in one of the three arms at the beginning of the study:

• Bleeding or non-bleeding patients at baseline may be enrolled into the acute 28-day transfusion period.
• Non-bleeding patients at baseline with chronic anemia requiring repeated simple transfusion may be enrolled into the 28-day +6-month extension period.
• SCD on a regular repeated RCE program at baseline may be enrolled into 28-day +6-month extension period to receive a total of 3 consecutive RCE procedures.

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 acute transfusion support period, patients will be transfused with conventional RBC components as indicated by their treating physician unless they were enrolled at baseline in the optional 6-month extension period.

Non-bleeding patients at baseline requiring repeated RBC transfusion for congenital or acquired chronic anemia (e.g., sickle anemia, thalassemia, other hemoglobinopathies, myelodysplastic syndrome, aplastic anemia, chemotherapy or stem cell transplant etc.) will be eligible to participate in an extension option for up to 6 months or up to 10 transfusion episodes, whichever occurs first, to evaluate patients requiring repeated transfusion for chronic anemia.

In addition, SCD patients on a regular RCE program at 2 or more clinical sites may be enrolled at baseline into the 6-month extension period to receive up to a total of 3 consecutive RCE procedures.

Screening/Recruitment

All potentially eligible patients at participating institutions will be approached for study consent. Subjects <18 years of age will require subject assent and parental consent. For subjects eligible for enrollment into the 6-month extension period option, consent/assent for the extension period should be obtained at initial enrollment.

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, blood type and Rh, Indirect Antiglobulin Test (IAT), blood chemistry, coagulation panel, Direct Antiglobulin Test (DAT), immune reactivity to IBS RBCs (if available), pregnancy test (when applicable). Once all screening assessments are completed and eligibility is confirmed, the subject may be randomized.

For SCD patients on a regular RCE program, if available in the medical record, the pre- and post- RCE total Hemoglobin, HbA, HbS and HbF concentrations should be recorded for up to 6 months prior to the first study transfusion.

If results from the Screening assessments are available in the medical record within 30 days prior to randomization, those data may serve as the screening data and the assessments do not need to be repeated unless the subject has an RBC transfusion in the 30-day period.

If an RBC transfusion occurs after determined eligibility but prior to randomization, the subject may be randomized and those Screening assessments should be repeated prior to the first study transfusion.

A pregnancy test (when applicable) must be performed at the Screening visit within 30 days of randomization.

Randomization and Blinding

Potential patients will be consented and begin screening in the study in order to determine eligibility for inclusion in one of the three study arms. An Interactive Web Response System (IWRS) will be used for electronic randomization of eligible patients to receive Test or Control RBCs.

Randomization will be at a 1:1 ratio of Test: Control and stratified by site, baseline bleeding status [indication for RBC transfusion due to active bleeding or for anemia without active bleeding], patients' participation in the optional extension period (yes/no) and patients' need for RCE. Anticipated surgical bleeding and planned blood loss/replacement through RCE at baseline should be included as active bleeding (Grade ≥3) by definition. Randomized patients who do not receive any study RBC transfusions through 28 days after randomization will be withdrawn from the study and replaced. Additional data will not be collected for these patients. These subjects may be reassessed for eligibility and re-enrollment after withdrawal.

At the end of screening, 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 at designated blood centers.

Treatment

Repeated Simple Transfusion Arm In the initial acute transfusion period, randomized patients will be transfused with Test or Control RBC components for up to 28 days. If the patient is entered into the optional extension period, randomized patients will be transfused with Test or Control RBC components for an additional 6 months, or up to 10 transfusion episodes, whichever occurs first. Subjects participating in optional extended study will continue to receive the same study RBCs (Test or Control) as in their initial 28-day study period for up to 10 transfusion episodes. Patients will be transfused with conventional RBC components as indicated by their treating physician once the 10 transfusion episodes or 6 months has been completed.

An RBC transfusion episode is defined to include consecutive RBC units transfused until the next post-transfusion Hb determination with ≤12 hours between transfusions (from the end of a prior component transfused to the start of a subsequent component transfused).

RCE Arm SCD patients on a regular RCE program enrolled into the 6-month extension period will receive 3 consecutive RCE procedures with study RBC with an interval of 3-8 weeks between RCE procedures, as determined by their physician.

A confirmed negative immune reaction to IBS RBC is required prior to the first study transfusion/RCE and at every time point a Type and Screen (IAT) is performed for a patient within the 28-day acute transfusion period or during the extension period. Compatibility for RBC antigens will be confirmed using site's SOPs prior to transfusion of study 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 study RBCs, patients will be withdrawn from the study treatment and supported with conventional RBC components and followed for safety. Patients with antibodies to IBS RBC will be investigated for evidence of hemolysis and continue with all planned visits and safety monitoring.

Study Assessments: Monitoring and Follow-up

The acute transfusion support period will comprise 28 days from the day of the first study transfusion (Day 1) through Day 28, or death. For subjects enrolled in the optional extension period, they will receive transfusion support for an additional 6-months.

During these periods, patients enrolled into the 6-month repeated simple transfusion arm will receive as many study RBCs as deemed appropriate by the treating physician for up to 10 transfusion episodes. Patients enrolled into the 6-month RCE arm will receive 3 consecutive RCE. All adverse events (AE), serious AE (SAE), transfusion reactions (TR) and unanticipated adverse device effects (UADE) will be collected starting from the initiation of the first study transfusion through exactly 28 days after the last study transfusion or death, whichever occurs first. The Investigators will assess each AE/SAE/TR/UADE for relation to the transfused study RBCs. TR will be classified by the definitions in the CDC NHSN Hemovigilance Module Surveillance Protocol and will be captured in the eCRF and in the CDC NHSN Biovigilance Component/Hemovigilance Module, if in routine use by the site (www.cdc.gov/nhsn).

Most proximate vital signs in the medical record will be collected prior to and following each study transfusion. The subject's hemoglobin value will be collected from the medical record, or if not available, a study sample will be submitted for testing, prior to and following each study transfusion episode/RCE within 15 minutes to 24 hours after the end of the transfusion episode and before the next RBC transfusion.

Relevant concomitant medications taken during the study and blood products transfused will be recorded with indication, total daily dose, and dates of drug administration.

During the acute transfusion period, patients will undergo the following assessments prior to each transfusion episode: vital signs, AEs, TRs, SAEs and UADEs, comorbid conditions, blood samples for safety labs (hematology panel, blood chemistry panel), IAT and immune reactivity to IBS RBCs. Samples may be used for additional in vitro research tests as required to confirm transfusion-transmitted infections.

An immune reactivity to IBS RBCs test will be performed and resulted each time an IAT is performed within the 28-day acute and 6-month extension transfusion support period.

RCE Arm

The following parameters should be assessed before and 15 mins to 4 hours after each RCE procedure:

• Hematology panel
• Reticulocytes
• % of HbS, HbA, and HbF
• Coagulation panel
• Plasma frozen sample for determination of S-300 and GSH concentrations

Day 14 (±7 days) after each RCE procedure for SCD patients undergoing regular RCE:

• Hematology panel
• Reticulocytes
• % of HbS, HbA, and HbF

Follow-Up Period for all transfused patients For the purposes of the Day 28 (± 7 days) and Day 75 (± 15 days) follow-up visits, Day 1 of the follow-up period is the day after the last study transfusion, either in the initial 28-day acute transfusion period or, if the subject is entered, in the optional extension period.

Day 28 (± 7 days) after the last study transfusion or before first post-study RCE with conventional RBCs in patients on a regular RCE program

Vital signs will be collected, and blood samples will be collected for:

• Hematology panel

• Blood chemistry panel

• Coagulation panel

• DAT and IAT

• Immune reactivity test for IBS RBC

• In addition for SCD patients undergoing regular RCE:

  • Reticulocytes
  • % of HbS, HbA, and HbF
  • Plasma frozen sample for determination of S-300 and GSH concentrations.

All AEs, SAEs, TRs and UADEs will be reviewed and recorded for the period from the first study transfusion through exactly 28 days after the last study transfusion.

End of Study Visit Day 75 (±15 days) after the last study transfusion) for all transfused patients

Blood samples will be collected for:

• DAT
• Immune reactivity test for IBS RBC

Inclusion Criteria:

• Age ≥ 4 years.

• Patients who require or are expected to require a transfusion of RBC component(s), including red cell exchange transfusion

• Signed and dated informed consent form.

• Female patients of child-bearing potential must:

  • Have negative serum or urine pregnancy tests performed at the Screening visit within 30 days of randomization to rule out pregnancy, and
  • Agree to use to 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 for the duration of study participation and an additional 28 days.

For 28-day +6-month extension study in patients requiring repeated simple transfusions:

• A diagnosis of a bone marrow failure syndrome requiring repeated RBC transfusion for congenital or acquired chronic anemia (e.g., sickle cell anemia, thalassemia, other hemoglobinopathies, myelodysplastic syndrome, aplastic anemia, chemotherapy or stem cell transplant etc.)

For 28-day +6-month extension study in SCD patients requiring regular repeated RCE.

• Diagnosis of SCD, either HbSS, HbSC or HbSB0 thalassemia, confirmed by Hb electrophoresis, deoxyribonucleic acid (DNA) analysis or high-performance liquid chromatography (HPLC)
• Currently participating in an automated RCE transfusion program (for at least 3 months prior to enrollment) with 3-to-8 week intervals between RCE episodes

Exclusion Criteria

• Confirmed positive baseline serum/plasma antibody specific to IBS RBC (S- 303 treated RBC) as determined by INTERCEPT S 303 antibody screening panel prior to receiving the first study transfusion

• Pregnant or breast feeding.

• Presence of an RBC warm autoantibody with evidence of active hemolysis.

• 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.

• Have received investigational products, including investigational blood products, pharmacologic agents or imaging materials, within 28 days prior to randomization. Prior receipt of conventional blood products tested with an investigational NAT test is not considered ground for exclusion.

• Patients presenting with or expected to have massive hemorrhage (≥10 RBC units within 24 hours) or expected to require massive transfusion protocols. Planned RCE does not apply.

• Patients who require neonatal transfusions and intrauterine transfusions.

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

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

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

• For SCD patients to be enrolled into the 28-day +6-month repeated RCE arm of the study:

  • A history of acute chest syndrome in the last 6 months, or hyperhemolysis syndrome at any time.
  • Clinical evidence of splenic hyperfunction or splenic enlargement: ≥18 cm in longitudinal diameter (diagnosed at the Investigator's discretion according to the data available, with ultrasound data being preferable).
  • Currently receiving chemotherapy for treatment of cancer. Hydroxyurea for SCD is acceptable if subject has been on stable therapy for 3 months and no changes to dosage are planned.
  • Subject is in active treatment with renal dialysis.
  • Any subject for whom a substantial change in the number of RBC components transfused is anticipated due to anticipated splenectomy, bone marrow transplant, surgery or other change in clinical status.
  • Subject with known G6PD deficiency or requiring treatment with medications that are known to adversely affect RBC viability or bone marrow function.