<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/NCT03277547</url>
  </required_header>
  <id_info>
    <org_study_id>17-0936</org_study_id>
    <secondary_id>1R01FD006030-01</secondary_id>
    <nct_id>NCT03277547</nct_id>
  </id_info>
  <brief_title>Kidney Function in Sickle Cell Anemia</brief_title>
  <official_title>The Association of Biomarkers of Endothelial Function With Prospective Changes in Kidney Function in Sickle Cell Anemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kenneth Ataga MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ohio State University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of North Carolina</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Tennessee</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a prospective clinical cohort study that involves a baseline study visit followed by&#xD;
      up to 3 annual follow-up study visits for a total follow-up of 36-48 months to evaluate the&#xD;
      age- and sex-adjusted rate of change in kidney function, and to identify biomarkers of&#xD;
      endothelial function, metabolomic profiles and clinical characteristics for the worsening of&#xD;
      kidney function and for a rapid decline in kidney function.&#xD;
&#xD;
      &quot;Funding Source - FDA OOPD&quot;&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Sickle cell disease is a severe monogenic disorder which affects approximately 80,000&#xD;
      patients in the US. It is characterized by a vasculopathy with involvement of multiple organs&#xD;
      and resulting in complications such as ischemic stroke, pulmonary hypertension,&#xD;
      autosplenectomy, priapism, as well as chronic kidney disease (CKD). Despite the high&#xD;
      prevalence of CKD and its known association with increased mortality, the natural history of&#xD;
      CKD and the factors associated with changes in kidney function in patients with SCD remain&#xD;
      incompletely defined. Furthermore, the available treatment options for albuminuria, an early&#xD;
      manifestation of CKD, in patients with SCD are limited. In fact, no controlled studies have&#xD;
      confirmed the long-term efficacy of angiotensin-converting enzyme (ACE) inhibitors, the&#xD;
      current &quot;standard of care.&quot; There is increasing evidence for a contribution of endothelial&#xD;
      dysfunction to the pathophysiology of albuminuria in SCD. The association of biomarkers of&#xD;
      endothelial function with albuminuria provides opportunities, not only to assess the effect&#xD;
      of therapies which improve endothelial function, but also to evaluate the predictive value of&#xD;
      these biomarkers for a decline in kidney function. The long-range goal is to develop a model&#xD;
      to identify patients at particularly high risk for a decline in kidney function.&#xD;
&#xD;
      In this study, the investigators will evaluate rate of change in kidney function (decline in&#xD;
      estimated glomerular filtration rates and increase in albuminuria) and identify biomarkers of&#xD;
      endothelial function, metabolomic profiles and clinical characteristics for the worsening of&#xD;
      kidney function and for a rapid decline in kidney function. At the conclusion of this&#xD;
      proposed work, the investigators will have an improved understanding of the natural history&#xD;
      of CKD in sickle cell anemia. With the limited available therapies for the treatment of&#xD;
      albuminuria in SCD and the paucity of data on the long-term efficacy of available&#xD;
      pharmacotherapies, identification of biomarkers for the progression of CKD will facilitate&#xD;
      the development of treatments which may be more effective than the current &quot;standard of&#xD;
      care.&quot;&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 17, 2017</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">June 2023</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>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Age- and sex-adjusted rate of change, over 36 - 48 months, in estimated glomerular filtration rate in patients with sickle cell anemia</measure>
    <time_frame>36-48 months</time_frame>
    <description>Estimated glomerular filtration rate will be ascertained using the CKD EPI equation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Age- and sex-adjusted rate of change, over 36 - 48 months, in albuminuria in patients with sickle cell anemia</measure>
    <time_frame>36-48 months</time_frame>
    <description>Evaluate the rate of change in albuminuria by spot urine measurements of albumin-creatinine ratio during designated study visits</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cross-sectional association of biomarkers of endothelial function with kidney function (estimated glomerular filtration rate and albuminuria) in patients with sickle cell anemia</measure>
    <time_frame>36-48 months</time_frame>
    <description>Plasma levels of ET-1, VEGF and soluble VCAM-1 from samples obtained at designated study visits will serve as measures of endothelial function</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cross-sectional association of urine and plasma metabolomics profiles with kidney function (estimated glomerular filtration rates and albuminuria) in patients with sickle cell anemia</measure>
    <time_frame>36-48 months</time_frame>
    <description>Untargeted metabolic profiling of plasma and urine will be performed using high-resonance nuclear magnetic resonance spectrometry. Plasma and urine analytes which are significantly associated with estimated glomerular filtration rate and albumin-creatinine ratio will be ascertained.</description>
  </primary_outcome>
  <enrollment type="Anticipated">300</enrollment>
  <condition>Sickle Cell Disease</condition>
  <condition>Kidney Failure, Chronic</condition>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Plasma samples will be collected to measure biomarkers of endothelial function. Plasma and&#xD;
      urine samples will be collected for measurement of metabolic profiles.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with HbSS or HbSB0 thalassemia between the ages of 18 and 65 years who meet the&#xD;
        eligibility criteria and provide consent to participate in the study&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. age of 18 to 65 years;&#xD;
&#xD;
          2. confirmed diagnosis of sickle cell anemia (HbSS and SB0 thalassemia);&#xD;
&#xD;
          3. non-crisis, &quot;steady state&quot; with no severe pain episodes requiring medical contact&#xD;
             during the preceding 4 weeks;&#xD;
&#xD;
          4. ability to understand the requirements of the study and be willing to give informed&#xD;
             consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. bone marrow transplantation;&#xD;
&#xD;
          2. history of long-standing diabetes mellitus with suspicion for diabetic nephropathy as&#xD;
             determined by a nephrologist;&#xD;
&#xD;
          3. known diagnosis of hepatitis B or C infection (patients will not be screened&#xD;
             specifically for this during the study);&#xD;
&#xD;
          4. known HIV positive (patients will not be screened specifically for this);&#xD;
&#xD;
          5. history of cancer, except non-melanoma skin cancer;&#xD;
&#xD;
          6. pregnant or breastfeeding;&#xD;
&#xD;
          7. connective tissue disease such as SLE;&#xD;
&#xD;
          8. known glomerular disease unrelated to SCD;&#xD;
&#xD;
          9. patients with ESRD on chronic dialysis.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kenneth Ataga, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UTHSC Center for Sickle Cell Disease</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of North Carolina-Chapel Hill</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio State Adult Sickle Cell Program</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UTHSC Center for Sickle Cell Disease</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38163</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Ataga KI, Brittain JE, Moore D, Jones SK, Hulkower B, Strayhorn D, Adam S, Redding-Lallinger R, Nachman P, Orringer EP. Urinary albumin excretion is associated with pulmonary hypertension in sickle cell disease: potential role of soluble fms-like tyrosine kinase-1. Eur J Haematol. 2010 Sep;85(3):257-63. doi: 10.1111/j.1600-0609.2010.01471.x. Epub 2010 Jun 3.</citation>
    <PMID>20491879</PMID>
  </reference>
  <reference>
    <citation>Ataga KI, Derebail VK, Archer DR. The glomerulopathy of sickle cell disease. Am J Hematol. 2014 Sep;89(9):907-14. doi: 10.1002/ajh.23762. Epub 2014 Jun 19.</citation>
    <PMID>24840607</PMID>
  </reference>
  <reference>
    <citation>Ataga KI, Brittain JE, Jones SK, May R, Delaney J, Strayhorn D, Desai P, Redding-Lallinger R, Key NS, Orringer EP. Association of soluble fms-like tyrosine kinase-1 with pulmonary hypertension and haemolysis in sickle cell disease. Br J Haematol. 2011 Feb;152(4):485-91. doi: 10.1111/j.1365-2141.2010.08410.x. Epub 2011 Jan 11.</citation>
    <PMID>21223248</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>September 1, 2017</study_first_submitted>
  <study_first_submitted_qc>September 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 11, 2017</study_first_posted>
  <last_update_submitted>March 2, 2023</last_update_submitted>
  <last_update_submitted_qc>March 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Tennessee</investigator_affiliation>
    <investigator_full_name>Kenneth Ataga MD</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>Renal Insufficiency</mesh_term>
    <mesh_term>Kidney Failure, Chronic</mesh_term>
    <mesh_term>Anemia, Sickle Cell</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03277547
org study id: 17-0936
secondary id: 1R01FD006030-01
nct id: NCT03277547
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a prospective clinical cohort study that involves a baseline study visit followed by
      up to 3 annual follow-up study visits for a total follow-up of 36-48 months to evaluate the
      age- and sex-adjusted rate of change in kidney function, and to identify biomarkers of
      endothelial function, metabolomic profiles and clinical characteristics for the worsening of
      kidney function and for a rapid decline in kidney function.

      "Funding Source - FDA OOPD"
Sickle cell disease is a severe monogenic disorder which affects approximately 80,000
      patients in the US. It is characterized by a vasculopathy with involvement of multiple organs
      and resulting in complications such as ischemic stroke, pulmonary hypertension,
      autosplenectomy, priapism, as well as chronic kidney disease (CKD). Despite the high
      prevalence of CKD and its known association with increased mortality, the natural history of
      CKD and the factors associated with changes in kidney function in patients with SCD remain
      incompletely defined. Furthermore, the available treatment options for albuminuria, an early
      manifestation of CKD, in patients with SCD are limited. In fact, no controlled studies have
      confirmed the long-term efficacy of angiotensin-converting enzyme (ACE) inhibitors, the
      current "standard of care." There is increasing evidence for a contribution of endothelial
      dysfunction to the pathophysiology of albuminuria in SCD. The association of biomarkers of
      endothelial function with albuminuria provides opportunities, not only to assess the effect
      of therapies which improve endothelial function, but also to evaluate the predictive value of
      these biomarkers for a decline in kidney function. The long-range goal is to develop a model
      to identify patients at particularly high risk for a decline in kidney function.

      In this study, the investigators will evaluate rate of change in kidney function (decline in
      estimated glomerular filtration rates and increase in albuminuria) and identify biomarkers of
      endothelial function, metabolomic profiles and clinical characteristics for the worsening of
      kidney function and for a rapid decline in kidney function. At the conclusion of this
      proposed work, the investigators will have an improved understanding of the natural history
      of CKD in sickle cell anemia. With the limited available therapies for the treatment of
      albuminuria in SCD and the paucity of data on the long-term efficacy of available
      pharmacotherapies, identification of biomarkers for the progression of CKD will facilitate
      the development of treatments which may be more effective than the current "standard of
      care."
observational model: Cohort
time perspective: Prospective
measure: Age- and sex-adjusted rate of change, over 36 - 48 months, in estimated glomerular filtration rate in patients with sickle cell anemia
time frame: 36-48 months
description: Estimated glomerular filtration rate will be ascertained using the CKD EPI equation
measure: Age- and sex-adjusted rate of change, over 36 - 48 months, in albuminuria in patients with sickle cell anemia
time frame: 36-48 months
description: Evaluate the rate of change in albuminuria by spot urine measurements of albumin-creatinine ratio during designated study visits
measure: Cross-sectional association of biomarkers of endothelial function with kidney function (estimated glomerular filtration rate and albuminuria) in patients with sickle cell anemia
time frame: 36-48 months
description: Plasma levels of ET-1, VEGF and soluble VCAM-1 from samples obtained at designated study visits will serve as measures of endothelial function
measure: Cross-sectional association of urine and plasma metabolomics profiles with kidney function (estimated glomerular filtration rates and albuminuria) in patients with sickle cell anemia
time frame: 36-48 months
description: Untargeted metabolic profiling of plasma and urine will be performed using high-resonance nuclear magnetic resonance spectrometry. Plasma and urine analytes which are significantly associated with estimated glomerular filtration rate and albumin-creatinine ratio will be ascertained.
Plasma samples will be collected to measure biomarkers of endothelial function. Plasma and
      urine samples will be collected for measurement of metabolic profiles.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Kenneth Ataga, MD
role: Principal Investigator
affiliation: UTHSC Center for Sickle Cell Disease
facility: 
facility: 
facility: 
country: United States
citation: Ataga KI, Brittain JE, Moore D, Jones SK, Hulkower B, Strayhorn D, Adam S, Redding-Lallinger R, Nachman P, Orringer EP. Urinary albumin excretion is associated with pulmonary hypertension in sickle cell disease: potential role of soluble fms-like tyrosine kinase-1. Eur J Haematol. 2010 Sep;85(3):257-63. doi: 10.1111/j.1600-0609.2010.01471.x. Epub 2010 Jun 3.
PMID: 20491879
citation: Ataga KI, Derebail VK, Archer DR. The glomerulopathy of sickle cell disease. Am J Hematol. 2014 Sep;89(9):907-14. doi: 10.1002/ajh.23762. Epub 2014 Jun 19.
PMID: 24840607
citation: Ataga KI, Brittain JE, Jones SK, May R, Delaney J, Strayhorn D, Desai P, Redding-Lallinger R, Key NS, Orringer EP. Association of soluble fms-like tyrosine kinase-1 with pulmonary hypertension and haemolysis in sickle cell disease. Br J Haematol. 2011 Feb;152(4):485-91. doi: 10.1111/j.1365-2141.2010.08410.x. Epub 2011 Jan 11.
PMID: 21223248
responsible party type: Sponsor-Investigator
investigator affiliation: University of Tennessee
investigator full name: Kenneth Ataga MD
investigator title: Professor
mesh term: Renal Insufficiency
mesh term: Kidney Failure, Chronic
mesh term: Anemia, Sickle Cell
sharing ipd: No