<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04426591</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00117580</org_study_id>
    <secondary_id>1K23HL146904</secondary_id>
    <nct_id>NCT04426591</nct_id>
  </id_info>
  <brief_title>Red Blood Cell Survival in Sickle Cell Disease</brief_title>
  <official_title>Kinetics of Donor Red Blood Cell Survival in Sickle Cell Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Emory University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Emory University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a single-arm, mechanistic clinical trial to measure predictors of senescence and the&#xD;
      in vivo survival of transfused red blood cells (RBCs) in individuals with sickle cell disease&#xD;
      (SCD) receiving chronic transfusion therapy (CTT). Chronic transfusion in patients with SCD&#xD;
      is a common treatment. The efficacy of RBC transfusion therapy to treat or prevent&#xD;
      complications of SCD may be hampered by variable survival of the transfused donor RBC. The&#xD;
      overall aim is to see how long RBC survive in SCD patients who are chronically transfused.&#xD;
      When a study participant has a regular blood transfusion the researchers will label a small&#xD;
      portion of the RBCs that are transfused with biotin. The participant will return at Day 1,&#xD;
      weekly for 3 months and monthly for 3 months to measure how long those RBCs survive.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Sickle cell disease (SCD) carries significant morbidity as a result of red blood cell (RBC)&#xD;
      sickling and hemolysis. Stroke is one of the most devastating sequelae of SCD. Chronic&#xD;
      transfusion therapy (CTT) reduces stroke risk by (1) supplying normal, non-sickle RBC to&#xD;
      circulation, thereby reducing the percentage of endogenous sickle RBC in circulation, and (2)&#xD;
      maintaining a higher hemoglobin (Hb), thereby suppressing erythropoiesis of new sickle RBC.&#xD;
      While the efficacy of CTT in stroke prophylaxis is well-established, nearly 45% of children&#xD;
      continue to have silent or overt strokes despite CTT. The failure of CTT to prevent stroke&#xD;
      events may be related to inadequate reduction of circulating sickle RBC and erythropoiesis.&#xD;
      The amount of circulating sickle-RBC is related to the survival kinetics of both transfused&#xD;
      RBC and endogenous sickle RBC.&#xD;
&#xD;
      In a large, longitudinal analysis of CTT in SCD, the researchers found wide variation in the&#xD;
      survival of donor RBC following transfusion, with faster clearance associated with patient&#xD;
      immune features (historical RBC alloimmunization and spleen presence) and with donor RBC&#xD;
      glucose-6-phosphate-dehydrogenase (G6PD) deficiency. To better understand the roles of&#xD;
      patient and donor factors in the survival and clearance of transfused RBC, the researchers&#xD;
      propose a mechanistic, clinical trial during chronic transfusion episodes in patients with&#xD;
      SCD, in which a small aliquot of each transfused unit is labeled with biotin conjugated to&#xD;
      RBC surface proteins, to safely identify and measure the in vivo survival of donor RBC.&#xD;
&#xD;
      Aim 1 will examine the relationships of the recipient's immune system (past alloimmunization,&#xD;
      splenic volume, and markers of reticuloendothelial system function) on the post-transfusion&#xD;
      survival of biotin-labeled donor RBC.&#xD;
&#xD;
      Aim 2 will examine the relationships of donor RBC G6PD levels and donor RBC metabolomics with&#xD;
      the in vivo survival and changes in donor RBC senescence markers. Completion of these aims&#xD;
      will increase the understanding of mechanisms for the variability in RBC survival during CTT,&#xD;
      identifying donor and recipient risk factors for decreased RBC survival. Ultimately this&#xD;
      knowledge will inform the management of CTT to improve the prevention of strokes in SCD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 29, 2021</start_date>
  <completion_date type="Anticipated">May 2025</completion_date>
  <primary_completion_date type="Anticipated">May 2025</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Number of Biotin Labeled RBCs</measure>
    <time_frame>Day 1, Weeks 1-12</time_frame>
    <description>Survival of the transfused biotin labeled RBCs will be assessed as the count of biotinylated RBCs per sample.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Sickle Cell Disease</condition>
  <arm_group>
    <arm_group_label>Biotin labeled Red Blood Cells</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Biotin Labeled Red Blood Cells</intervention_name>
    <description>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.</description>
    <arm_group_label>Biotin labeled Red Blood Cells</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HbSS or HbSβ0 thalassemia SCD&#xD;
&#xD;
          -  receiving CTT for ≥3 months prior to enrollment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  anticipated cessation of CTT in the next ≤2 months&#xD;
&#xD;
          -  concurrent hydroxyurea therapy&#xD;
&#xD;
          -  automated RBC exchange therapy within 3 months prior to enrollment or anticipated&#xD;
             within the next 3 months&#xD;
&#xD;
          -  delayed hemolytic transfusion reaction in the past 3 months&#xD;
&#xD;
          -  consuming high-dose biotin or raw egg supplements&#xD;
&#xD;
          -  current pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Marianne Yee, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Emory University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Marianne Yee, MD</last_name>
    <phone>404-785-6190</phone>
    <email>Marianne.Yee@choa.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>Hughes Spalding Children's Hospital</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30303</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Childrens Healthcare of Atlanta</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Grady Health System</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>May 29, 2020</study_first_submitted>
  <study_first_submitted_qc>June 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>November 1, 2021</last_update_submitted>
  <last_update_submitted_qc>November 1, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 3, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Emory University</investigator_affiliation>
    <investigator_full_name>John D Roback</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Sickle Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Biotin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>All of the individual participant data collected during the trial will be made available for sharing with other researchers, after deidentification.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>Individual participant data will be made available for sharing immediately following publication, with no end date.</ipd_time_frame>
    <ipd_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.</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04426591
org study id: IRB00117580
secondary id: 1K23HL146904
nct id: NCT04426591
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Change in Number of Biotin Labeled RBCs
time frame: Day 1, Weeks 1-12
description: Survival of the transfused biotin labeled RBCs will be assessed as the count of biotinylated RBCs per sample.
arm group label: Biotin labeled Red Blood Cells
arm group type: Experimental
description: 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 type: Drug
intervention name: Biotin Labeled Red Blood Cells
description: 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.
arm group label: Biotin labeled Red Blood Cells
criteria: 
gender: All
minimum age: 6 Years
maximum age: N/A
healthy volunteers: No
last name: Marianne Yee, MD
role: Principal Investigator
affiliation: Emory University
last name: Marianne Yee, MD
phone: 404-785-6190
email: Marianne.Yee@choa.org
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
country: United States
responsible party type: Principal Investigator
investigator affiliation: Emory University
investigator full name: John D Roback
investigator title: Professor
mesh term: Anemia, Sickle Cell
mesh term: Biotin
sharing ipd: Yes
ipd description: All of the individual participant data collected during the trial will be made available for sharing with other researchers, after deidentification.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: Individual participant data will be made available for sharing immediately following publication, with no end date.
ipd 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.