BioRBC Survival in Adults With Prior Antibody Response to BioRBCs
Condition: Anemia
Study type: Interventional
Phase: Phase 1

Summary: 
      Objective: To gather safety and efficacy BioRBC data from adult subjects who previously
      developed transient BioRBC antibody responses by redosing them and observing for adverse
      clinical or laboratory (i.e., a positive BioRBC antibody titer) outcomes to determine if RBC
      kinetic study results differ from the previous study.

      Hypothesis: BioRBC survival studies performed in adult subjects who previously developed a
      transient BioRBC antibody response will: 1) be associated with no adverse clinical or
      laboratory events; 2) experience a second transient, BioRBC antibody response; and 3) display
      a pattern of RBC survival that is identical to their prior dosing with BioRBCs at the same
      dose.
    

Detailed description: 
      Summary. Subjects eligible for study include adult study subjects older than 18 years who had
      a positive antibody response to BioRBCs in previous BioRBC studies at the University of Iowa,
      Adult BioRBC Redosing Safety Protocol Page 3 of 6 but who are now BioRBC antibody
      sero-negative. The study will begin after IRB approval. The information summaries and IRB
      consent forms used in prior studies did not include a statement indicating that subjects
      would not be re-contacted for future research. Written informed consent will be obtained
      prior to study. The total number of subjects available for study is 4, i.e., all subjects who
      we previously identified as having formed antibodies to BioRBC following autologous BioRBC
      transfusion.

      Removal of subjects. Subjects will be free to withdraw from the study at their discretion.
      The investigators will also be free to withdraw study subjects from the study for reasons of
      non-compliance, inability to conduct the required study assessments or if the Investigators
      determined it was in the best interest of the subject. The reasons for subject withdrawal
      will be documented. The Investigators will attempt to collect safety data on withdrawn
      subjects.

      Study design. This is an open Phase 1 study in which the only 4 subjects we identified as
      having developed antibodies to BioRBCs - and who are now negative for these antibodies - will
      be re-dosed with BioRBCs. This will be conducted at a single study site at the University of
      Iowa.

      As illustrated in the protocol diagram figure below, following screening and enrolment, each
      subject will donate 100 mL of whole blood collected in CPD preservative from which RBC
      concentrates will be prepared according to the standard methodology and procedures included
      in our original 2006 FDA IND application with only minor modification of study sample times.

      Specific Aims. Using a dose of biotin labeled autologous RBCs that is ~30% of our previous
      dose we will determine during a 20 wk post-transfusion study period whether study subjects:

        1. Develop a second BioRBC antibody response that is greater than, less than, or equal to
           each subject's previous response.

        2. Experience a fall in Hb/Hct, rise in reticulocyte count, and/or a decrease in RBC
           survival following the appearance of BioRBC antibodies;

        3. Experience clinical signs or symptoms following the appearance of BioRBC antibodies.

        4. Have detectable BioRBC enrichment throughout the entire study period (as was possible
           previously with a larger BioRBC dose).

      Dose and duration. A single dose of BioRBCs that will include the same densities of biotin
      labeled RBCs as studied previously in survival studies. On the first day of study, a fresh
      ~100 mL aliquot of autologous RBC will be collected and labeled with biotin at densities 6,
      18, 54 and 128 μg/mL RBC. Immediately after preparing the four populations of BioRBC
      densities, the four densities will be combined, mixed, and a gravimetrically determined
      weight of the blood infused intravenously. An aliquot of the infusate will be saved and
      analyzed to determine the dose of each density administered.

      All labeling will be conducted using approved sterile instruments and materials in a
      certified laminar flow containment hood to minimize the potential for bacterial
      contamination. Two aliquots of the BioRBC infusate will be saved: 1) one for endotoxin
      testing should the subject Adult BioRBC Redosing Safety Protocol Page 5 of 6 develop a
      transfusion reaction (we have not encountered this in the ~35 adult subjects we have studied
      to date); and 2) the other for aerobic bacteria cultured for any potential contamination
      during the labeling process. Although the culture results will not be available prior to the
      infusion, they will be available in the event the subject develops symptoms of bacterial
      infection, e.g., fever.
    

Intervention name(s): biotin labelled RBCs
Intervention type(s): Drug
Intervention description(s): Autologous red blood cells are biotin labelled and transfused to the subject. Survival of these red blood cells is tracked through examination of blood samples until no biotin labelled red blood cells remain.
Other intervention name(s): biotinylated RBCs
Intervention MeSH terms: Biotin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic