<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/NCT02258997</url>
  </required_header>
  <id_info>
    <org_study_id>13-2811</org_study_id>
    <nct_id>NCT02258997</nct_id>
  </id_info>
  <brief_title>Hepcidin Levels in Sickle Cell Disease (SCD)</brief_title>
  <official_title>Hepcidin Levels in Sickle Cell Disease (SCD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kenneth Ataga, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Augusta University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of North Carolina, Chapel Hill</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators propose that patients with HbSβ-thalassemia have lower levels of hepcidin&#xD;
      and higher levels of GDF-15 than HbSS patients during the non-crisis, &quot;steady states.&quot; In&#xD;
      addition, the investigators propose that when controlled for RBC transfusion, patients with&#xD;
      HbSβ-thalassemia will have higher levels of storage iron (based on serum ferritin).&#xD;
&#xD;
      Participants: Total number of subjects is 42 - 21 subjects with HbSS, and 21 subjects with&#xD;
      HbSβ-thalassemia ).&#xD;
&#xD;
      Procedures (methods): Eligible subjects with documented SCD (HbSS, HbS-β 0-thalassemia or&#xD;
      HbS-β+-thalassemia) followed at the University of North Carolina (UNC) Comprehensive Sickle&#xD;
      Cell Program will be evaluated in this single-center, prospective, cross-sectional study. The&#xD;
      patients will be screened for eligibility at the time of a routine sickle cell clinic visit.&#xD;
      Patients' data will be obtained in person at the time of evaluation and through review of&#xD;
      their medical records. Investigators will obtain information on SCD-related clinical&#xD;
      complications and obtain an estimate of the number of lifetime RBC transfusions. Blood&#xD;
      samples will be obtained for laboratory tests. Plasma samples for hepcidin, growth&#xD;
      differentiation factor 15 (GDF -15), and high-sensitivity CRP will be stored at -80 degrees&#xD;
      Celsius until analysis. Other routine laboratory studies including complete blood count (CBC)&#xD;
      with differential and reticulocyte count, serum iron profile and ferritin, and liver function&#xD;
      tests will be performed at the clinical laboratories of UNC Hospitals.The subjects will have&#xD;
      30 ml. of blood drawn for this research study. Females of child bearing potential will have a&#xD;
      urine pregnancy test at the time of the study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Sickle cell disease (SCD) refers to a group of inherited disorders characterized by the&#xD;
      presence of sickle hemoglobin (HbS) that are associated with episodes of acute illness and&#xD;
      progressive organ damage. The most common variant of SCD, sickle cell anemia (HbSS), refers&#xD;
      to homozygosity for the β S allele, with most of the remaining patients having sickle&#xD;
      hemoglobin C disease (HbSC) and sickle beta thalassemia (HbSβ-thalassemia).&#xD;
&#xD;
      SCD may be associated with iron overload that occurs following repeated red blood cell (RBC)&#xD;
      transfusions. However, in patients with beta thalassemia major, iron overload occurs due to&#xD;
      both repeated RBC transfusions and hyperabsorption of iron. The hyperabsorption of iron in&#xD;
      beta thalassemia occurs due to ineffective erythropoiesis and subsequent downregulation of&#xD;
      hepcidin. Thalassemia intermedia and major are the most studied human models of hepcidin&#xD;
      modulation by ineffective erythropoiesis alone and the combined and opposite effect of both&#xD;
      ineffective erythropoiesis and transfusion dependent iron overload, accordingly. Regular&#xD;
      transfusions induce massive iron loading but inhibit erythropoietic drive. Accordingly,&#xD;
      hepcidin production is higher in thalassemia major than in thalassemia intermedia although&#xD;
      still inappropriate to the massive transfusional iron loading that partially counteracts the&#xD;
      erythropoietic-dependent hepcidin down-regulation (Origa R et al, 2007; Kattamis A et al,&#xD;
      2006; Camberlein E et al, 2008). No differences in the steady-state levels of hepcidin was&#xD;
      observed when HbSS patients (N = 40) were compared with healthy hemoglobin AA (HbAA)controls&#xD;
      (N = 30) (85.3 ± 30 l μg/L vs. 83.5 ± 40 l μg/L) (Ezeh C et al, 2005).&#xD;
&#xD;
      Hepcidin is a 25-amino acid peptide produced mainly in the liver and is the major&#xD;
      physiological regulator of body iron stores and serum iron. It negatively regulates egress of&#xD;
      iron from cells, such as intestinal epithelial cells and macrophages. Growth differentiation&#xD;
      factor-15 (GDF-15) and twisted gastrulation protein homolog 1(TWSG1), two transforming growth&#xD;
      factor-β (TGF-β) superfamily members released from erythroid precursors, have been proposed&#xD;
      to contribute to hepcidin suppression in thalassemia, although it remains unresolved whether&#xD;
      GDF-15 and TWSG1 are markers of ineffective erythropoiesis or mediators of hepcidin&#xD;
      suppression in vivo.&#xD;
&#xD;
      With the presence of a thalassemia gene, patients with HbSβ-thalassemia (HbSβ0-thalassemia&#xD;
      and HbSβ+-thalassemia) may have an increased tendency to absorb excess iron compared to&#xD;
      patients with HbSS.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>March 2014</start_date>
  <completion_date type="Actual">September 2015</completion_date>
  <primary_completion_date type="Actual">September 2015</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Hepcidin levels in HbSS and HbSβ-thalassemia SCD patients</measure>
    <time_frame>Assessed at time of enrollment</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Levels of GDF-15 in HbSS and HbSβ-thalassemia SCD patients</measure>
    <time_frame>Assessed at time of enrollment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ferritin and C-reactive protein (CRP) levels in SCD patients in the non-crisis state</measure>
    <time_frame>Assessed at time of enrollment</time_frame>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">42</enrollment>
  <condition>Sickle Cell Anemia</condition>
  <condition>Sickle - Beta Thalassemia</condition>
  <arm_group>
    <arm_group_label>HbSS</arm_group_label>
    <description>Subjects are homozygous for the sickle hemoglobin mutation (HbS).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HbS-beta thalassemia</arm_group_label>
    <description>Subjects are heterozygous for the HbS mutation and beta thalassemia</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Subjects will be recruited from the population followed in the Adult Sickle Cell Clinic&#xD;
        with either HbSS or HbS-βthalassemia who meet the eligibility criteria for the study.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  age 18 - 70 years&#xD;
&#xD;
          -  confirmed diagnosis of HbSS or HbS-β thalassemia&#xD;
&#xD;
          -  no history of acute vaso-occlusive event (acute pain crisis or acute chest syndrome)&#xD;
             requiring emergency room visit or hospitalization over the preceding 4 weeks&#xD;
&#xD;
          -  clinically acceptable physical examination and vital signs&#xD;
&#xD;
          -  ability of patient or legal representative to understand the requirements of the study&#xD;
             and willingness to sign the Informed Consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  pregnancy or breastfeeding&#xD;
&#xD;
          -  current acute illness, including a painful crisis&#xD;
&#xD;
          -  iron deficiency anemia&#xD;
&#xD;
          -  history of liver disease with alanine aminotransferase (ALT) ≥ 3 X upper limit of&#xD;
             normal (ULN)&#xD;
&#xD;
          -  history of hereditary hemochromatosis, connective tissues disease, chronic&#xD;
             inflammatory, disorder, or malignancy&#xD;
&#xD;
          -  chronic transfusion program or any transfusion within the previous 3 months&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kenneth I Ataga, MBBS</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of North Carolina, Chapel Hill</affiliation>
  </overall_official>
  <reference>
    <citation>Origa R, Galanello R, Ganz T, Giagu N, Maccioni L, Faa G, Nemeth E. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica. 2007 May;92(5):583-8. doi: 10.3324/haematol.10842.</citation>
    <PMID>17488680</PMID>
  </reference>
  <reference>
    <citation>Kattamis A, Papassotiriou I, Palaiologou D, Apostolakou F, Galani A, Ladis V, Sakellaropoulos N, Papanikolaou G. The effects of erythropoetic activity and iron burden on hepcidin expression in patients with thalassemia major. Haematologica. 2006 Jun;91(6):809-12.</citation>
    <PMID>16769583</PMID>
  </reference>
  <reference>
    <citation>Camberlein E, Zanninelli G, Detivaud L, Lizzi AR, Sorrentino F, Vacquer S, Troadec MB, Angelucci E, Abgueguen E, Loreal O, Cianciulli P, Lai ME, Brissot P. Anemia in beta-thalassemia patients targets hepatic hepcidin transcript levels independently of iron metabolism genes controlling hepcidin expression. Haematologica. 2008 Jan;93(1):111-5. doi: 10.3324/haematol.11656.</citation>
    <PMID>18166793</PMID>
  </reference>
  <reference>
    <citation>Ezeh C, Ugochukwu CC, Weinstein J, Okpala I. Hepcidin, haemoglobin and ferritin levels in sickle cell anaemia. Eur J Haematol. 2005 Jan;74(1):86-8. doi: 10.1111/j.1600-0609.2004.00337.x. No abstract available.</citation>
    <PMID>15613115</PMID>
  </reference>
  <verification_date>October 2014</verification_date>
  <study_first_submitted>September 27, 2014</study_first_submitted>
  <study_first_submitted_qc>October 3, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 8, 2014</study_first_posted>
  <last_update_submitted>October 7, 2015</last_update_submitted>
  <last_update_submitted_qc>October 7, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 8, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of North Carolina, Chapel Hill</investigator_affiliation>
    <investigator_full_name>Kenneth Ataga, MD</investigator_full_name>
    <investigator_title>Associate Professor of Medicine, Director, University of North Carolina (UNC) Comprehensive Sickle Cell Program</investigator_title>
  </responsible_party>
  <keyword>sickle cell disease</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Sickle Cell</mesh_term>
    <mesh_term>Thalassemia</mesh_term>
    <mesh_term>beta-Thalassemia</mesh_term>
  </condition_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/NCT02258997
org study id: 13-2811
nct id: NCT02258997
lead sponsor: 
collaborator: 
has dmc: No
The investigators propose that patients with HbSβ-thalassemia have lower levels of hepcidin
      and higher levels of GDF-15 than HbSS patients during the non-crisis, "steady states." In
      addition, the investigators propose that when controlled for RBC transfusion, patients with
      HbSβ-thalassemia will have higher levels of storage iron (based on serum ferritin).

      Participants: Total number of subjects is 42 - 21 subjects with HbSS, and 21 subjects with
      HbSβ-thalassemia ).

      Procedures (methods): Eligible subjects with documented SCD (HbSS, HbS-β 0-thalassemia or
      HbS-β+-thalassemia) followed at the University of North Carolina (UNC) Comprehensive Sickle
      Cell Program will be evaluated in this single-center, prospective, cross-sectional study. The
      patients will be screened for eligibility at the time of a routine sickle cell clinic visit.
      Patients' data will be obtained in person at the time of evaluation and through review of
      their medical records. Investigators will obtain information on SCD-related clinical
      complications and obtain an estimate of the number of lifetime RBC transfusions. Blood
      samples will be obtained for laboratory tests. Plasma samples for hepcidin, growth
      differentiation factor 15 (GDF -15), and high-sensitivity CRP will be stored at -80 degrees
      Celsius until analysis. Other routine laboratory studies including complete blood count (CBC)
      with differential and reticulocyte count, serum iron profile and ferritin, and liver function
      tests will be performed at the clinical laboratories of UNC Hospitals.The subjects will have
      30 ml. of blood drawn for this research study. Females of child bearing potential will have a
      urine pregnancy test at the time of the study.
Sickle cell disease (SCD) refers to a group of inherited disorders characterized by the
      presence of sickle hemoglobin (HbS) that are associated with episodes of acute illness and
      progressive organ damage. The most common variant of SCD, sickle cell anemia (HbSS), refers
      to homozygosity for the β S allele, with most of the remaining patients having sickle
      hemoglobin C disease (HbSC) and sickle beta thalassemia (HbSβ-thalassemia).

      SCD may be associated with iron overload that occurs following repeated red blood cell (RBC)
      transfusions. However, in patients with beta thalassemia major, iron overload occurs due to
      both repeated RBC transfusions and hyperabsorption of iron. The hyperabsorption of iron in
      beta thalassemia occurs due to ineffective erythropoiesis and subsequent downregulation of
      hepcidin. Thalassemia intermedia and major are the most studied human models of hepcidin
      modulation by ineffective erythropoiesis alone and the combined and opposite effect of both
      ineffective erythropoiesis and transfusion dependent iron overload, accordingly. Regular
      transfusions induce massive iron loading but inhibit erythropoietic drive. Accordingly,
      hepcidin production is higher in thalassemia major than in thalassemia intermedia although
      still inappropriate to the massive transfusional iron loading that partially counteracts the
      erythropoietic-dependent hepcidin down-regulation (Origa R et al, 2007; Kattamis A et al,
      2006; Camberlein E et al, 2008). No differences in the steady-state levels of hepcidin was
      observed when HbSS patients (N = 40) were compared with healthy hemoglobin AA (HbAA)controls
      (N = 30) (85.3 ± 30 l μg/L vs. 83.5 ± 40 l μg/L) (Ezeh C et al, 2005).

      Hepcidin is a 25-amino acid peptide produced mainly in the liver and is the major
      physiological regulator of body iron stores and serum iron. It negatively regulates egress of
      iron from cells, such as intestinal epithelial cells and macrophages. Growth differentiation
      factor-15 (GDF-15) and twisted gastrulation protein homolog 1(TWSG1), two transforming growth
      factor-β (TGF-β) superfamily members released from erythroid precursors, have been proposed
      to contribute to hepcidin suppression in thalassemia, although it remains unresolved whether
      GDF-15 and TWSG1 are markers of ineffective erythropoiesis or mediators of hepcidin
      suppression in vivo.

      With the presence of a thalassemia gene, patients with HbSβ-thalassemia (HbSβ0-thalassemia
      and HbSβ+-thalassemia) may have an increased tendency to absorb excess iron compared to
      patients with HbSS.
observational model: Cohort
time perspective: Cross-Sectional
measure: Hepcidin levels in HbSS and HbSβ-thalassemia SCD patients
time frame: Assessed at time of enrollment
measure: Levels of GDF-15 in HbSS and HbSβ-thalassemia SCD patients
time frame: Assessed at time of enrollment
measure: Ferritin and C-reactive protein (CRP) levels in SCD patients in the non-crisis state
time frame: Assessed at time of enrollment
arm group label: HbSS
description: Subjects are homozygous for the sickle hemoglobin mutation (HbS).
arm group label: HbS-beta thalassemia
description: Subjects are heterozygous for the HbS mutation and beta thalassemia
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Kenneth I Ataga, MBBS
role: Principal Investigator
affiliation: University of North Carolina, Chapel Hill
citation: Origa R, Galanello R, Ganz T, Giagu N, Maccioni L, Faa G, Nemeth E. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica. 2007 May;92(5):583-8. doi: 10.3324/haematol.10842.
PMID: 17488680
citation: Kattamis A, Papassotiriou I, Palaiologou D, Apostolakou F, Galani A, Ladis V, Sakellaropoulos N, Papanikolaou G. The effects of erythropoetic activity and iron burden on hepcidin expression in patients with thalassemia major. Haematologica. 2006 Jun;91(6):809-12.
PMID: 16769583
citation: Camberlein E, Zanninelli G, Detivaud L, Lizzi AR, Sorrentino F, Vacquer S, Troadec MB, Angelucci E, Abgueguen E, Loreal O, Cianciulli P, Lai ME, Brissot P. Anemia in beta-thalassemia patients targets hepatic hepcidin transcript levels independently of iron metabolism genes controlling hepcidin expression. Haematologica. 2008 Jan;93(1):111-5. doi: 10.3324/haematol.11656.
PMID: 18166793
citation: Ezeh C, Ugochukwu CC, Weinstein J, Okpala I. Hepcidin, haemoglobin and ferritin levels in sickle cell anaemia. Eur J Haematol. 2005 Jan;74(1):86-8. doi: 10.1111/j.1600-0609.2004.00337.x. No abstract available.
PMID: 15613115
responsible party type: Sponsor-Investigator
investigator affiliation: University of North Carolina, Chapel Hill
investigator full name: Kenneth Ataga, MD
investigator title: Associate Professor of Medicine, Director, University of North Carolina (UNC) Comprehensive Sickle Cell Program
mesh term: Anemia, Sickle Cell
mesh term: Thalassemia
mesh term: beta-Thalassemia