Biotin Labeling for Sickle Cell Anemia

Overseen By John F Tisdale, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Disqualifiers: Biotin supplements, Chronic transfusion therapy, Hemodialysis, Malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the lifespan of red blood cells (RBCs) in individuals with sickle cell disease (SCD) and other inherited blood disorders. Researchers will compare RBC survival in those with SCD before and after treatment to those who have undergone a bone marrow transplant. Participants will have a small amount of their blood labeled with biotin (a type of vitamin) to track RBC survival over several weeks. Suitable candidates for this trial are adults with SCD or similar blood disorders who have not recently received a blood transfusion or bone marrow transplant. As an Early Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, you cannot participate if you are on chronic transfusion therapy or have consumed biotin supplements or raw eggs in the last 30 days.

What prior data suggests that biotin labeling of RBCs is safe for patients with sickle cell disease?

Research shows that labeling red blood cells (RBCs) with biotin is a safe method to study their lifespan in the body. In studies involving individuals with sickle cell disease (SCD), this method proved safe and practical. By attaching biotin, a vitamin, to RBCs, researchers can track how long the cells remain in the bloodstream.

Previous studies have shown minimal immediate loss of RBCs labeled with biotin, indicating that the process does not harm the cells initially. This method has successfully measured RBC survival in people with SCD and holds promise for understanding blood disorders. Overall, evidence suggests that biotin labeling is well-tolerated and does not cause significant side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about biotin-labeled red blood cells for sickle cell anemia because this approach offers a unique way to study red blood cell lifespan. Unlike traditional treatments that focus on alleviating symptoms or modifying the disease, this technique aims to provide precise information on how red blood cells behave over time, especially before and after starting other therapies like bone marrow transplants. By labeling red blood cells with biotin, scientists can track their survival in the bloodstream, which could lead to better understanding and management of sickle cell disease.

What evidence suggests that biotin labeling is effective for studying RBC survival in sickle cell anemia?

Research has shown that marking red blood cells (RBCs) with biotin effectively tracks their lifespan in people with sickle cell disease (SCD). In this trial, participants will receive biotin-labeled RBCs to monitor their lifespan. Studies have found that using biotin to track RBCs over time is safe and involves no radiation. This method helps researchers understand how treatments like bone marrow transplants affect RBC lifespan. Early results suggest that biotin-marked RBCs provide a clear view of RBC health before and after treatment. Knowing RBC lifespan is crucial for effectively managing SCD. ^{1 3 6 7 8}

Who Is on the Research Team?

John F Tisdale, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

This trial is for individuals with sickle cell disease or other hemoglobin disorders like thalassemia. It's open to those who are on disease-modifying treatments or have had a stem cell transplant. The study aims to understand how long their red blood cells live using biotin labeling.

Inclusion Criteria

Provision of signed and dated informed consent form

I can have blood samples taken.

Agreement to adhere to Lifestyle Considerations (Refrain from consumption of raw eggs or biotin supplements until after the study completion) throughout study duration

Exclusion Criteria

Consumption of biotin supplements or raw eggs within the last 30 days

Pregnancy, lactation or absence of adequate contraception for fertile subjects

I am not on hemodialysis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Biotin Labeling

Participants have blood drawn and mixed with biotin, then returned to their bloodstream

1 day

1 visit (in-person)

Monitoring

Participants return regularly for blood samples to detect biotin-labeled RBCs

Up to 20 weeks

Every 2-4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Biotin-labeled red blood cells

Trial Overview The trial tests the lifespan of red blood cells in patients with sickle cell and related disorders by marking them with biotin, a vitamin. Researchers will compare this before and after treatments like transplants, looking at how different therapies affect red cell survival.

How Is the Trial Designed?

Group I: RBC survival in patients with SCD Experimental Treatment 1 Intervention

RBC lifespan, determined by the mean number of days from biotin-labeled RBC infusion until biotin-labeled RBCs are below limit of detection, in patients with inherited hemoglobinopathies prior to and post initiation of disease modifying therapy or HSCT

Biotin-labeled red blood cells is already approved in United States for the following indications:

Approved in United States as Biotin-labeled RBCs for:

• Research use in sickle cell disease and other hemoglobinopathies

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Children's National Research Institute

Collaborator

Trials

227

Recruited

258,000+

Published Research Related to This Trial

Biotinylation of red blood cells (B-RBCs) does not appear to make them immunogenic, as none of the 20 healthy subjects developed antibodies before transfusion, and only 3 showed transient antibody production after receiving autologous B-RBCs.

While the antibodies produced were not linked to any changes in red blood cell kinetics, their presence suggests that monitoring for these antibodies is advisable during multiple B-RBC transfusions to ensure safety and understand potential biological effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibodies provoked by the transfusion of biotin-labeled red cells. Cordle, DG., Strauss, RG., Lankford, G., et al.[2019]

Biotin labeling using BxNHS allows for the detection of red blood cells for nearly 100 days post-infusion, making it a reliable method for studying cell survival compared to water-soluble biotin compounds, which lose effectiveness after about 4 weeks.

The study found that BxNHS labeling provides a nonradioactive and nontoxic alternative for red cell survival studies, with survival times comparable to traditional 51Cr labeling, indicating its potential for safe and effective use in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of biotin labeling for red cell survival testing. Hoffmann-Fezer, G., Trastl, C., Beisker, W., et al.[2019]

A new method using biotin-labeled red blood cells (BioRBCs) allows for safe and accurate measurement of red blood cell survival in vivo, which is particularly beneficial for infants, children, and pregnant women who cannot use traditional chromium-51 methods.

This biotin labeling technique enables multiple independent measurements of red blood cell survival without exposing subjects to radiation and requires only small blood volumes, making it a significant advancement in studying anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Red blood cell (RBC) survival determined in humans using RBCs labeled at multiple biotin densities. Mock, DM., Matthews, NI., Zhu, S., et al.[2021]

A standardized method for labeling red blood cell concentrates (RCCs) with biotin was developed, allowing for accurate tracking of donor RBCs in recipients without compromising the biological activity of the cells.

This biotin labeling process can be completed in under 2 hours in a sterile, closed system, making it suitable for clinical research and compliant with Good Practice Guidelines for blood establishments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A method for red blood cell biotinylation in a closed system. de Back, DZ., Vlaar, R., Beuger, B., et al.[2018]

A new closed-system procedure for biotinylating red blood cells (RBCs) has been developed, ensuring safety and compliance with current good manufacturing practices (cGMP), which is crucial for clinical applications.

Biotinylated RBCs can be reliably tracked in the bloodstream using flow cytometry, demonstrating stability for up to 50 days, which is important for optimizing RBC storage and understanding factors affecting transfusion outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current good manufacturing practices-compliant manufacture and measurement of biotin-labeled red blood cells. Donnenberg, AD., Kanias, T., Triulzi, DJ., et al.[2023]

Re-exposure to biotin-labeled red blood cells (BioRBC) in previously immunized adults led to an increase in specific antibodies, which can affect the accuracy of red cell survival measurements.

No adverse clinical events were reported during the study, but to reduce the risk of antibody induction and ensure accurate red cell survival assessments, it is recommended to limit the initial BioRBC exposure volume to ≤10 mL and use label densities of ≤18 μg/mL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibodies against biotin-labeled red blood cells can shorten posttransfusion survival. Mock, DM., Stowell, SR., Franco, RS., et al.[2022]

In vivo biotin labeling of erythrocytes using biotin-N-hydroxysuccinimide ester (BNHS) and caproylamidobiotin-N-hydroxysuccinimide ester (C-BNHS) allows for accurate estimation of red blood cell survival without damaging the cells or affecting their production.

This method demonstrated a consistent daily disappearance rate of biotin-labeled red cells (2.5%-3.3%), making it a reliable technique for studying red cell lifespan in small animal models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct in vivo biotinylation of erythrocytes as an assay for red cell survival studies. Hoffmann-Fezer, G., Maschke, H., Zeitler, HJ., et al.[2019]

Sickle red blood cells (RBC) have a significantly shorter lifespan compared to normal RBC, with biotin labeling showing that sickle RBC without fetal hemoglobin (HbF) survive for about 2 weeks, while those with HbF can last 6-8 weeks.

The study validated a biotin RBC label against the standard 51Cr label, confirming that both methods yield equivalent results, and revealed that sickle RBCs experience rapid loss from circulation shortly after reinfusion, particularly in reticulocytes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Time-dependent changes in the density and hemoglobin F content of biotin-labeled sickle cells. Franco, RS., Lohmann, J., Silberstein, EB., et al.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06313398

Determination of Red Cell Survival in Sickle Cell Disease ... This study will use biotin-labeling of red blood cells (RBCs) to determine the mean potential lifespan (MPL) of RBCs in patients with sickle cell disease (SCD) ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11088511/

Post-transfusion biotin-labeled red blood cell survival ... Biotin-labeling provides a direct measurement of red cell survival (RCS) over time, thus can be used to assess the clinical significance of RBC antibodies.

3. ashpublications.org ashpublications.org/bloodadvances/article/8/7/1806/506967/In-vivo-measurement-of-RBC-survival-in-patients

In vivo measurement of RBC survival in patients with sickle ... Biotin labeling of RBCs is a safe and feasible methodology to evaluate RBC survival in patients with SCD before and after HSCT.

4. sciencedirect.com sciencedirect.com/science/article/pii/S2473952924000193

In vivo measurement of RBC survival in patients with sickle ... This study used biotin labeling of RBCs to determine the lifespan of RBCs in patients with SCD compared with patients who have successfully undergone curative ...

5. withpower.com withpower.com/trial/early-phase-1-sickle-cell-disease-scd-2-2024-3cd00

Biotin Labeling for Sickle Cell Anemia Biotin-labeled red blood cells are unique because they allow for tracking the survival and lifespan of red blood cells without using radiation, which is ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04476277

Red Cell Half Life Determination in Patients With and ... This study will use biotin-labeling of red blood cells (RBCs) to determine the mean potential lifespan (MPL) of RBCs in patients with sickle cell disease ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4122272/

Measurement of Post-Transfusion Red Cell Survival with ... At least three lines of evidence indicate that immediate loss of biotin labeled RBC is negligible: a) In normal individuals and sickle cell disease patients, ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT06313398

Determination of Red Cell Survival in Sickle Cell Disease ... This study will use biotin-labeling of red blood cells (RBCs) to determine the mean potential lifespan (MPL) of RBCs in patients with sickle cell disease (SCD) ...