<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/NCT04476277</url>
  </required_header>
  <id_info>
    <org_study_id>200080</org_study_id>
    <secondary_id>20-H-0080</secondary_id>
    <nct_id>NCT04476277</nct_id>
  </id_info>
  <brief_title>Red Cell Half Life Determination in Patients With and Without Sickle Cell Disease</brief_title>
  <official_title>Red Cell Half Life Determination in Patients With and Without Sickle Cell Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      Sickle cell disease (SCD) is an inherited blood disorder. It results from a single genetic&#xD;
      change (mutation) in red blood cells (RBCs). RBCs are the cells that carry oxygen to the&#xD;
      body. In people with SCD, some RBCs are abnormal and die early. This leaves a shortage of&#xD;
      healthy RBCs. Researchers want to learn more about how long RBCs live in the human body.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To study how long RBCs live in people with and without SCD.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      People age 18 and older who either have SCD, had SCD but were cured with a bone marrow&#xD;
      transplant, have the sickle cell trait (SCT), or are a healthy volunteer without SCD or SCT&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened with a medical history and physical exam. They will give a&#xD;
      blood sample.&#xD;
&#xD;
      Participants will have a small amount of blood drawn from a vein. In the laboratory, the&#xD;
      blood will be mixed with a vitamin called biotin. Biotin sticks to the outside of RBCs&#xD;
      without changing their function, shape, or overall lifetime. This process is known as biotin&#xD;
      labeling of RBCs. The biotin labeled RBCs will be returned to the participant via vein&#xD;
      injection.&#xD;
&#xD;
      Participants will give frequent blood samples. Their RBCs will be studied to see how many&#xD;
      biotin labeled RBCs remain over time. This shows how long the RBCs live. Participants will&#xD;
      give blood samples until no biotin labeled RBCs can be detected.&#xD;
&#xD;
      During the study visits, participants will report any major changes to their health.&#xD;
&#xD;
      Participation lasts for up to 6 months.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Description:&#xD;
&#xD;
      This study will use biotin-labeling of red blood cells (RBCs) to determine the mean potential&#xD;
      lifespan (MPL) of RBCs in patients with sickle cell disease (SCD) compared to patients who&#xD;
      have successfully undergone curative bone marrow transplantation (BMT, allogeneic or&#xD;
      autologous), participants with sickle cell trait, and healthy donors without SCD. Previous&#xD;
      studies have corroborated the MPL of healthy donor RBCs to be approximately 115 days while&#xD;
      RBCs from patients with SCD have a much more variable but consistently shorter MPL of&#xD;
      approximately 32 days. Allogeneic BMT is a curative therapy for the treatment of severe SCD&#xD;
      with stable, mixed donor recipient chimerism after BMT sufficient to reverse the sickle cell&#xD;
      phenotype by virtue of improved donor red cell survival compared to the ineffective&#xD;
      erythropoiesis of SCD. We predict that the hematologic variables associated with red cell&#xD;
      survival among patients with SCD vs. participants with SCT and healthy donors can be used to&#xD;
      determine the necessary amount of corrected hemoglobin required to overcome the red cell&#xD;
      pathology of SCD. Data generated will be used to determine the utility of performing a&#xD;
      population study of RBC lifespan in gene therapy treated patients to ultimately target the&#xD;
      percentage of transferred globin gene needed to reverse SCD. The data generated will refine&#xD;
      our understanding of the degree of correction necessary to reverse the phenotype of SCD.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      Primary Objective: To determine and compare red blood cell survival in patients with SCD,&#xD;
      patients with SCD who have undergone BMT, participants with SCT, and healthy donors, and&#xD;
      validate the association of red cell survival with known markers of increased red cell&#xD;
      survival.&#xD;
&#xD;
      Secondary Objectives: To create a mathematical model incorporating RBC survival and&#xD;
      reticulocyte count to determine the necessary amount of normal hemoglobin, and therefore&#xD;
      vector copy number or amount of transferred globin, required for gene therapy protocols.&#xD;
&#xD;
      Endpoints:&#xD;
&#xD;
      Primary Endpoint: Red blood cell survival&#xD;
&#xD;
      Secondary Endpoints: Relationship of red blood cell survival to hematologic parameters.&#xD;
      Antibody detection to biotin.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 19, 2021</start_date>
  <completion_date type="Actual">February 14, 2023</completion_date>
  <primary_completion_date type="Actual">December 20, 2022</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</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>To determine and compare red blood cell survival in patients with SCD (HbSS genotype), patients with SCD who have undergone BMT, subjects with SCT, and healthy donors</measure>
    <time_frame>6 months</time_frame>
    <description>Percentage of red blood cells at specific time points as measured by flow cytometry.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To create a mathematical model incorporating RBC survival and reticulocyte count to determine the necessary amount of normal hemoglobin, and therefore VCN, required for gene therapy protocols</measure>
    <time_frame>18 months</time_frame>
    <description>Design completion of mathematical model</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Sickle Cell Disease</condition>
  <condition>Sickle Cell Anemia</condition>
  <arm_group>
    <arm_group_label>Sickle Cell Disease Pre-Transplantation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sickle Cell Disease Post-Transplantation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sickle Cell Trait (HbAS)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Autologous cells will be collected in participants with Sickle Cell Trait (HbAS) and biotin-labeled ex vivo and reinfused to measure red cell survival</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HbAA (Healthy volunteers)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Autologous cells will be collected in participants with HbAA (Healthy volunteers) and biotin-labeled ex vivo and reinfused to measure red cell survival</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Biotin label</intervention_name>
    <description>Autologous cells will be collected and biotin-labeled ex vivo and reinfused to measure red cell survival</description>
    <arm_group_label>HbAA (Healthy volunteers)</arm_group_label>
    <arm_group_label>Sickle Cell Disease Post-Transplantation</arm_group_label>
    <arm_group_label>Sickle Cell Disease Pre-Transplantation</arm_group_label>
    <arm_group_label>Sickle Cell Trait (HbAS)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Age 18 or greater with a confirmed diagnosis of homozygous SCD (HbSS, HbSC, HbSB0),&#xD;
             sickle cell trait (HbAS), or healthy volunteer (HbA)&#xD;
&#xD;
          -  Normal renal function: creatinine &lt;1.5 mg/dL&#xD;
&#xD;
          -  Negative direct antiglobulin test (DAT)&#xD;
&#xD;
          -  Ability to give informed consent to participate in the protocol&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Any uncontrolled chronic illness other than sickle cell disease&#xD;
&#xD;
          -  Active viral, bacterial, fungal, or parasitic infection&#xD;
&#xD;
          -  Consumption of biotin supplements or raw eggs within 30 days&#xD;
&#xD;
          -  Blood loss within the previous 8 weeks &gt;540mL&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Pre-existing, naturally occurring antibodies against biotin&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>John F Tisdale, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Heart, Lung, and Blood Institute (NHLBI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2020-H-0080.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>July 17, 2020</study_first_submitted>
  <study_first_submitted_qc>July 17, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 20, 2020</study_first_posted>
  <last_update_submitted>March 31, 2023</last_update_submitted>
  <last_update_submitted_qc>March 31, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 4, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Red Cell Survival</keyword>
  <keyword>Biotin</keyword>
  <keyword>Sickle Cell Anemia</keyword>
  <keyword>Sickle Cell Disease</keyword>
  <keyword>Sickle Cell Trait</keyword>
  <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>
  <!-- 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/NCT04476277
org study id: 200080
secondary id: 20-H-0080
nct id: NCT04476277
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
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 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 create a mathematical model incorporating RBC survival and
      reticulocyte count to determine the necessary amount of normal hemoglobin, and therefore
      vector copy number or amount of transferred globin, required for gene therapy protocols.

      Endpoints:

      Primary Endpoint: Red blood cell survival

      Secondary Endpoints: Relationship of red blood cell survival to hematologic parameters.
      Antibody detection to biotin.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: To determine and compare red blood cell survival in patients with SCD (HbSS genotype), patients with SCD who have undergone BMT, subjects with SCT, and healthy donors
time frame: 6 months
description: Percentage of red blood cells at specific time points as measured by flow cytometry.
measure: To create a mathematical model incorporating RBC survival and reticulocyte count to determine the necessary amount of normal hemoglobin, and therefore VCN, required for gene therapy protocols
time frame: 18 months
description: Design completion of mathematical model
arm group label: Sickle Cell Disease Pre-Transplantation
arm group type: Experimental
description: 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
arm group label: Sickle Cell Disease Post-Transplantation
arm group type: Experimental
description: 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
arm group label: Sickle Cell Trait (HbAS)
arm group type: Experimental
description: Autologous cells will be collected in participants with Sickle Cell Trait (HbAS) and biotin-labeled ex vivo and reinfused to measure red cell survival
arm group label: HbAA (Healthy volunteers)
arm group type: Experimental
description: Autologous cells will be collected in participants with HbAA (Healthy volunteers) and biotin-labeled ex vivo and reinfused to measure red cell survival
intervention type: Drug
intervention name: Biotin label
description: Autologous cells will be collected and biotin-labeled ex vivo and reinfused to measure red cell survival
arm group label: HbAA (Healthy volunteers)
arm group label: Sickle Cell Disease Post-Transplantation
arm group label: Sickle Cell Disease Pre-Transplantation
arm group label: Sickle Cell Trait (HbAS)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: John F Tisdale, M.D.
role: Principal Investigator
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2020-H-0080.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Anemia, Sickle Cell
mesh term: Biotin