Red Blood Cell Survival in Sickle Cell Disease

• ClinicalTrials.gov Identifier: NCT04426591
• Recruitment Status: Recruiting
• First Posted: June 11, 2020
• Last Update Posted: November 3, 2021
• Sponsor: Emory University
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): John D Roback, Emory University

Tracking Information

• First Submitted Date: May 29, 2020
• First Posted Date: June 11, 2020
• Last Update Posted Date: November 3, 2021
• Actual Study Start Date: October 29, 2021
• Estimated Primary Completion Date: May 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 8, 2020)

Change in Number of Biotin Labeled RBCs [ Time Frame: Day 1, Weeks 1-12 ]

Survival of the transfused biotin labeled RBCs will be assessed as the count of biotinylated RBCs per sample.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Red Blood Cell Survival in Sickle Cell Disease
• Official Title: Kinetics of Donor Red Blood Cell Survival in Sickle Cell Disease
• Brief Summary: This is a single-arm, mechanistic clinical trial to measure predictors of senescence and the in vivo survival of transfused red blood cells (RBCs) in individuals with sickle cell disease (SCD) receiving chronic transfusion therapy (CTT). Chronic transfusion in patients with SCD is a common treatment. The efficacy of RBC transfusion therapy to treat or prevent complications of SCD may be hampered by variable survival of the transfused donor RBC. The overall aim is to see how long RBC survive in SCD patients who are chronically transfused. When a study participant has a regular blood transfusion the researchers will label a small portion of the RBCs that are transfused with biotin. The participant will return at Day 1, weekly for 3 months and monthly for 3 months to measure how long those RBCs survive.

Detailed Description

Sickle cell disease (SCD) carries significant morbidity as a result of red blood cell (RBC) sickling and hemolysis. Stroke is one of the most devastating sequelae of SCD. Chronic transfusion therapy (CTT) reduces stroke risk by (1) supplying normal, non-sickle RBC to circulation, thereby reducing the percentage of endogenous sickle RBC in circulation, and (2) maintaining a higher hemoglobin (Hb), thereby suppressing erythropoiesis of new sickle RBC. While the efficacy of CTT in stroke prophylaxis is well-established, nearly 45% of children continue to have silent or overt strokes despite CTT. The failure of CTT to prevent stroke events may be related to inadequate reduction of circulating sickle RBC and erythropoiesis. The amount of circulating sickle-RBC is related to the survival kinetics of both transfused RBC and endogenous sickle RBC.

In a large, longitudinal analysis of CTT in SCD, the researchers found wide variation in the survival of donor RBC following transfusion, with faster clearance associated with patient immune features (historical RBC alloimmunization and spleen presence) and with donor RBC glucose-6-phosphate-dehydrogenase (G6PD) deficiency. To better understand the roles of patient and donor factors in the survival and clearance of transfused RBC, the researchers propose a mechanistic, clinical trial during chronic transfusion episodes in patients with SCD, in which a small aliquot of each transfused unit is labeled with biotin conjugated to RBC surface proteins, to safely identify and measure the in vivo survival of donor RBC.

Aim 1 will examine the relationships of the recipient's immune system (past alloimmunization, splenic volume, and markers of reticuloendothelial system function) on the post-transfusion survival of biotin-labeled donor RBC.

Aim 2 will examine the relationships of donor RBC G6PD levels and donor RBC metabolomics with the in vivo survival and changes in donor RBC senescence markers. Completion of these aims will increase the understanding of mechanisms for the variability in RBC survival during CTT, identifying donor and recipient risk factors for decreased RBC survival. Ultimately this knowledge will inform the management of CTT to improve the prevention of strokes in SCD.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Basic Science
• Condition: Sickle Cell Disease

Intervention

Drug: Biotin Labeled Red Blood Cells

On the day of transfusion, a 20 mL aliquot will be sterilely withdrawn from each RBC unit, washed and labeled with sulfo-NHS-biotin for 30 minutes, washed to stop the labeling reaction, then resuspended in plasma to a hematocrit of ~60%. The biotin-labeled RBC (BioRBC) will be transfused along with the remainder of the RBC unit (unlabeled volume). Standard blood bank and CTT protocols and minor antigen matching for SCD patients will be followed. Exact transfusion volume will be determined based on pre-transfusion Hb, HbS, and body weight, per clinical protocol.

Study Arms

Experimental: Biotin labeled Red Blood Cells

Participants receiving a transfusion with biotin labeled RBCs. Samples will be taken for 12 weeks after the biotinylated transfusion. During this time participants will continue to receive regular monthly transfusions (non-biotinylated) as part of CTT.

Intervention: Drug: Biotin Labeled Red Blood Cells

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 8, 2020): 40
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 2025
• Estimated Primary Completion Date: May 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• HbSS or HbSβ0 thalassemia SCD
• receiving CTT for ≥3 months prior to enrollment

Exclusion Criteria:

• anticipated cessation of CTT in the next ≤2 months
• concurrent hydroxyurea therapy
• automated RBC exchange therapy within 3 months prior to enrollment or anticipated within the next 3 months
• delayed hemolytic transfusion reaction in the past 3 months
• consuming high-dose biotin or raw egg supplements
• current pregnancy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Marianne Yee, MD; 404-785-6190; Marianne.Yee@choa.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04426591
• Other Study ID Numbers: IRB00117580; 1K23HL146904 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: All of the individual participant data collected during the trial will be made available for sharing with other researchers, after deidentification.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: Analytic Code
• Time Frame: Individual participant data will be made available for sharing immediately following publication, with no end date.
• Access Criteria: Data will be available for sharing with researchers who provide a methodologically sound proposal, for the purpose of achieving the aims in the approved proposal. Proposals should be directed to Marianne.Yee@choa.org. To gain access, data requestors will need to sign a data access agreement.

• Current Responsible Party: John D Roback, Emory University
• Original Responsible Party: Same as current
• Current Study Sponsor: Emory University
• Original Study Sponsor: Same as current
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Marianne Yee, MD; Emory University

• PRS Account: Emory University
• Verification Date: November 2021