Red Cell Half Life Determination in Patients With and Without Sickle Cell Disease

Background:

Sickle cell disease (SCD) is an inherited blood disorder. It results from a single genetic change (mutation) in red blood cells (RBCs). RBCs are the cells that carry oxygen to the body. In people with SCD, some RBCs are abnormal and die early. This leaves a shortage of healthy RBCs. Researchers want to learn more about how long RBCs live in the human body.

Objective:

To study how long RBCs live in people with and without SCD.

Eligibility:

People age 18 and older who either have SCD, had SCD but were cured with a bone marrow transplant, have the sickle cell trait (SCT), or are a healthy volunteer without SCD or SCT

Design:

Participants will be screened with a medical history and physical exam. They will give a blood sample.

Participants will have a small amount of blood drawn from a vein. In the laboratory, the blood will be mixed with a vitamin called biotin. Biotin sticks to the outside of RBCs without changing their function, shape, or overall lifetime. This process is known as biotin labeling of RBCs. The biotin labeled RBCs will be returned to the participant via vein injection.

Participants will give frequent blood samples. Their RBCs will be studied to see how many biotin labeled RBCs remain over time. This shows how long the RBCs live. Participants will give blood samples until no biotin labeled RBCs can be detected.

During the study visits, participants will report any major changes to their health.

Participation lasts for up to 6 months.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease; Sickle Cell Anemia
• Intervention / Treatment: Drug: Biotin label

Detailed Description

Study Description:

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) compared to patients who have successfully undergone curative bone marrow transplantation (BMT, allogeneic or autologous), participants with sickle cell trait, and healthy donors without SCD. Previous studies have corroborated the MPL of healthy donor RBCs to be approximately 115 days while RBCs from patients with SCD have a much more variable but consistently shorter MPL of approximately 32 days. Allogeneic BMT is a curative therapy for the treatment of severe SCD with stable, mixed donor recipient chimerism after BMT sufficient to reverse the sickle cell phenotype by virtue of improved donor red cell survival compared to the ineffective erythropoiesis of SCD. We predict that the hematologic variables associated with red cell survival among patients with SCD vs. participants with SCT and healthy donors can be used to determine the necessary amount of corrected hemoglobin required to overcome the red cell pathology of SCD. Data generated will be used to determine the utility of performing a population study of RBC lifespan in gene therapy treated patients to ultimately target the percentage of transferred globin gene needed to reverse SCD. The data generated will refine our understanding of the degree of correction necessary to reverse the phenotype of SCD.

Objectives:

Primary Objective: To determine and compare red blood cell survival in patients with SCD, patients with SCD who have undergone BMT, participants with SCT, and healthy donors, and validate the association of red cell survival with known markers of increased red cell survival.

Secondary Objectives: To evaluate correlation of markers of hemolysis (reticulocyte count), number of alpha globin genes, and fetal hemoglobin with RBC survival.

Endpoints:

Primary Endpoint: Red blood cell survival

Secondary Endpoints: Relationship of red blood cell survival to hematologic parameters. Antibody detection to biotin.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

INCLUSION CRITERIA:

• Age 18 or greater with a confirmed diagnosis of homozygous SCD (HbSS, HbSC, HbSB0), sickle cell trait (HbAS), or healthy volunteer (HbA)
• Normal renal function: creatinine <1.5 mg/dL
• Negative direct antiglobulin test (DAT)
• Ability to give informed consent to participate in the protocol

EXCLUSION CRITERIA:

• Any uncontrolled chronic illness other than sickle cell disease
• Active viral, bacterial, fungal, or parasitic infection
• Consumption of biotin supplements or raw eggs within 30 days
• Blood loss within the previous 8 weeks >540mL
• Pregnancy
• Pre-existing, naturally occurring antibodies against biotin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sickle Cell Disease Pre-Transplantation; Autologous cells will be collected in participants with Sickle Cell Disease Pre-Transplantation and biotin-labeled ex vivo and reinfused to measure red cell survival	Drug: Biotin label; Autologous cells will be collected and biotin-labeled ex vivo and reinfused to measure red cell survival
Experimental: Sickle Cell Disease Post-Transplantation; Autologous cells will be collected in participants with Sickle Cell Disease Post-Transplantation and biotin-labeled ex vivo and reinfused to measure red cell survival	Drug: Biotin label; Autologous cells will be collected and biotin-labeled ex vivo and reinfused to measure red cell survival
Experimental: Sickle Cell Trait (HbAS); Autologous cells will be collected in participants with Sickle Cell Trait (HbAS) and biotin-labeled ex vivo and reinfused to measure red cell survival	Drug: Biotin label; Autologous cells will be collected and biotin-labeled ex vivo and reinfused to measure red cell survival
Experimental: HbAA (Healthy volunteers); Autologous cells will be collected in participants with HbAA (Healthy volunteers) and biotin-labeled ex vivo and reinfused to measure red cell survival	Drug: Biotin label; Autologous cells will be collected and biotin-labeled ex vivo and reinfused to measure red cell survival

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Red Blood Cells Lifespan in Participants	Mean Days of Red Blood Cells (RBC) survival in participants with Sickle Cell Disease (SCD), participants with SCD who have undergone stem cell transplant, participants with Sickle Cell Trait, and healthy volunteers. Peripheral blood samples were analyzed by flow cytometry until biotin was not detectable on RBC.	Sickle Cell Disease Pre-Transplantation cohort time frame is as follows: baseline, twice weekly up to week 3 then weekly up to week 22. All other cohorts, time frame is as follows: baseline, weekly up to week 4, then every other week up to week 22.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Antibody Detection	Number of participants with Antibody detection to biotin	Baseline, 3 months, 6 months
Mean White Blood Cell Count	Mean White Blood Cell (WBC) count between Sickle Cell Disease Pre-transplantation and Sickle Cell Disease Post-Transplantation	Sickle Cell Disease Pre-Transplantation cohort time frame is as follows: baseline, twice weekly up to week 3 then weekly up to week 22. All other cohorts, time frame is as follows: baseline, weekly up to week 4, then every other week up to week 22.
Mean Red Blood Cell Count	Mean Red Blood Cell (RBC) Count between Sickle Cell Disease Pre-transplantation and Sickle Cell Disease Post-Transplantation	Sickle Cell Disease Pre-Transplantation cohort time frame is as follows: baseline, twice weekly up to week 3 then weekly up to week 22. All other cohorts, time frame is as follows: baseline, weekly up to week 4, then every other week up to week 22.
Mean Hemoglobin Value	Mean Hemoglobin (Hb) Value between Sickle Cell Disease Pre-transplantation and Sickle Cell Disease Post-Transplantation	Sickle Cell Disease Pre-Transplantation cohort time frame is as follows: baseline, twice weekly up to week 3 then weekly up to week 22. All other cohorts, time frame is as follows: baseline, weekly up to week 4, then every other week up to week 22.
Mean Hematocrit Value	Mean Hematocrit (Hct) value between Sickle Cell Disease Pre-transplantation and Sickle Cell Disease Post-Transplantation	Sickle Cell Disease Pre-Transplantation cohort time frame is as follows: baseline, twice weekly up to week 3 then weekly up to week 22. All other cohorts, time frame is as follows: baseline, weekly up to week 4, then every other week up to week 22.
Mean Value of Mean Corpuscular Volume	Mean Value of Mean Corpuscular Volume (MCV) between Sickle Cell Disease Pre-transplantation and Sickle Cell Disease Post-Transplantation	Sickle Cell Disease Pre-Transplantation cohort time frame is as follows: baseline, twice weekly up to week 3 then weekly up to week 22. All other cohorts, time frame is as follows: baseline, weekly up to week 4, then every other week up to week 22.
Mean Absolute Reticulocyte Count	Mean Absolute Reticulocyte Count (ARC) between Sickle Cell Disease Pre-transplantation and Sickle Cell Disease Post-Transplantation	Sickle Cell Disease Pre-Transplantation cohort time frame is as follows: baseline, twice weekly up to week 3 then weekly up to week 22. All other cohorts, time frame is as follows: baseline, weekly up to week 4, then every other week up to week 22.
Mean Aspartate Aminotransferase Value	Mean Aspartate Aminotransferase (AST) value between Sickle Cell Disease Pre-transplantation and Sickle Cell Disease Post-Transplantation	Sickle Cell Disease Pre-Transplantation cohort time frame is as follows: baseline, twice weekly up to week 3 then weekly up to week 22. All other cohorts, time frame is as follows: baseline, weekly up to week 4, then every other week up to week 22.
Mean Total Bilirubin Value	Mean Total Bilirubin value between Sickle Cell Disease Pre-transplantation and Sickle Cell Disease Post-Transplantation	Sickle Cell Disease Pre-Transplantation cohort time frame is as follows: baseline, twice weekly up to week 3 then weekly up to week 22. All other cohorts, time frame is as follows: baseline, weekly up to week 4, then every other week up to week 22.
Mean Lactate Dehydrogenase Value	Mean Lactate Dehydrogenase (LDH) value between Sickle Cell Disease Pre-transplantation and Sickle Cell Disease Post-Transplantation	Sickle Cell Disease Pre-Transplantation cohort time frame is as follows: baseline, twice weekly up to week 3 then weekly up to week 22. All other cohorts, time frame is as follows: baseline, weekly up to week 4, then every other week up to week 22.
Mean Adult Hemoglobin Percentage	Mean Adult Hemoglobin (HbA) percentage between Sickle Cell Disease Pre-transplantation and Sickle Cell Disease Post-Transplantation	Sickle Cell Disease Pre-Transplantation cohort time frame is as follows: baseline, twice weekly up to week 3 then weekly up to week 22. All other cohorts, time frame is as follows: baseline, weekly up to week 4, then every other week up to week 22.
Mean Sickle Hemoglobin Percentage	Mean Sickle Hemoglobin (HbS) Percentage between Sickle Cell Disease Pre-transplantation and Sickle Cell Disease Post-Transplantation	Sickle Cell Disease Pre-Transplantation cohort time frame is as follows: baseline, twice weekly up to week 3 then weekly up to week 22. All other cohorts, time frame is as follows: baseline, weekly up to week 4, then every other week up to week 22.
Mean Fetal Hemoglobin Percentage	Mean Fetal Hemoglobin (HbF) Percentage between Sickle Cell Disease Pre-transplantation and Sickle Cell Disease Post-Transplantation	Sickle Cell Disease Pre-Transplantation cohort time frame is as follows: baseline, twice weekly up to week 3 then weekly up to week 22. All other cohorts, time frame is as follows: baseline, weekly up to week 4, then every other week up to week 22.

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: John F Tisdale, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2021
• Primary Completion (Actual): December 20, 2022
• Study Completion (Actual): February 14, 2023

Study Registration Dates

• First Submitted: July 17, 2020
• First Submitted That Met QC Criteria: July 17, 2020
• First Posted (Actual): July 20, 2020

Study Record Updates

• Last Update Posted (Actual): February 13, 2024
• Last Update Submitted That Met QC Criteria: January 17, 2024
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Sickle Cell Disease; Sickle Cell Anemia; Biotin; Red Cell Survival; Sickle Cell Trait
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Biotin
• Other Study ID Numbers: 200080; 20-H-0080

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No