Clinical trial NCT04426591: Red Blood Cell Survival in Sickle Cell Disease
Official title: Kinetics of Donor Red Blood Cell Survival in Sickle Cell Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Sickle Cell Disease
Keywords: Chronic transfusion therapy
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Cerus Corporation
First posted: 2020-06-11
Enrollment: 22
Sex: ALL
Minimum age (years): 2
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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. An optional sub-study using INTERCEPT RBCs will mirror the main study but will use INTERCEPT RBCs that have biotinylated for 1 RBC unit.

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 supplying normal, non-sickle RBC to circulation, thereby reducing the percentage of endogenous sickle RBC in circulation, and 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.

Aim 3 will compare the in vivo survival and clearance rate of phenotype-matched RBCs prepared with an investigational pathogen-reduction system (INTERCEPT Blood System) vs. the in vivo survival and clearance rate of conventional, phenotype-matched RBCs (not treated with INTERCEPT). Biotin labeling of donor RBC will be used to measure RBC survival. This is an optional study activity for study participants.

Eligibility criteria: Inclusion Criteria:

* Hemoglobinopathy:

  * Any sickle cell disease genotype, or
  * Transfusion-dependent thalassemia (TDT)
* Receiving CTT for ≥3 months prior to enrollment.
* For participants with past BioRBC transfusion exposure, BioRBC antibody screens must have been conducted through at least 6 months post exposure, with negative results.

Exclusion Criteria:

* Anticipated cessation of CTT in the next ≤2 months
* Ongoing consumption of biotin or raw egg dietary supplements
* Antibody specific of INTERCEPT RBCs at baseline (for subjects consenting to the optional arm)
* BioRBC-specific antibodies ever detected in the past, or detected on post-enrollment screening prior to first infusion of Bio-RBC.

Primary outcomes:
measure: Change in Number of Biotin Labeled RBCs
timeFrame: Day 1, Weeks 1-12
measure: Half-life of Biotinylated RBCs
timeFrame: Up to Day 70
measure: Mean Potential Lifespan (MPL) of Biotinylated RBCs
timeFrame: Up to Day 70
Secondary outcomes:
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Hughes Spalding Children's Hospital
state: Georgia
city: Atlanta
country: United States
facility: Childrens Healthcare of Atlanta
state: Georgia
city: Atlanta
country: United States
facility: Grady Health System
state: Georgia
Study officials:
affiliation: Emory University
name: Marianne Yee, MD
role: PRINCIPAL_INVESTIGATOR
References: