<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/NCT01665846</url>
  </required_header>
  <id_info>
    <org_study_id>H015</org_study_id>
    <nct_id>NCT01665846</nct_id>
  </id_info>
  <brief_title>Ferumoxytol-enhanced Brain MRI in HIV-associated Neurocognitive Disorders</brief_title>
  <official_title>Neuroimaging Correlates of Monocyte/Macrophage Infiltration in HIV-infected Individuals: A Cross-sectional Pilot Study Using IV Ferumoxytol</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Hawaii</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Oregon Health and Science University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Hawaii</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to describe the radiologic findings on brain MRI after&#xD;
      ferumoxytol administration in HIV-infected patients with cognitive impairment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The continued existence of cognitive dysfunction in HIV infected individuals in the era of&#xD;
      effective antiretroviral therapy may be, in part, secondary to the failure of current&#xD;
      antiretroviral regimens to eradicate the pool of HIV-infected and activated monocytes within&#xD;
      the bloodstream. Trafficking of such HIV infected and activated blood monocytes into the&#xD;
      brain parenchyma is believed to introduce HIV into the brain and precipitate immune&#xD;
      activation and inflammation, ultimately leading to neuronal degeneration.&#xD;
&#xD;
      Ferumoxytol is an ultrasmall superparamagnetic iron-oxide (USPIO), which is FDA-approved for&#xD;
      intravenous iron-replacement therapy in anemic patients with chronic kidney disease. The&#xD;
      paramagnetic properties of ferumoxytol also allow it to be used as a MRI contrast agent.&#xD;
      Ferumoxytol is avidly taken up by circulating monocytes and reactive astrocytes, microglia,&#xD;
      and dendritic cells within the brain, making it potentially a novel biomarker for&#xD;
      HIV-associated cognitive impairment given the role of monocytes in its pathogenesis.&#xD;
&#xD;
      This proposal intends to investigate the possible use of ferumoxytol (a new MRI contrast&#xD;
      agent) as a biomarker for HIV-associated cognitive impairment and to assess the safety and&#xD;
      tolerability of ferumoxytol in HIV-infected individuals.&#xD;
&#xD;
      Hypotheses to be tested:&#xD;
&#xD;
        -  HIV-infected subjects with undetectable plasma HIV RNA levels and detectable levels of&#xD;
           HIV DNA in CD14+ peripheral blood mononuclear cells (PBMCs) and impairment on&#xD;
           neurocognitive testing will demonstrate ferumoxytol contrast enhancement in the&#xD;
           perivascular regions of the brain consistent with monocyte/macrophage infiltration in&#xD;
           these regions.&#xD;
&#xD;
        -  Ferumoxytol can be safely administered to HIV-infected subjects.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>July 2011</start_date>
  <completion_date type="Actual">June 2012</completion_date>
  <primary_completion_date type="Actual">June 2012</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>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Post-ferumoxytol enhancement on Brain MRI</measure>
    <time_frame>48 hour following administration of a dose of 4 mg/kg of feruomoxytol up to a maximum of 510 mg of elemental iron</time_frame>
    <description>The location and extent of ferumoxytol enhancement within the brain will be described.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety</measure>
    <time_frame>1 hour and 1 month following administration of a dose of 4 mg/kg of ferumxotyol up to a maximum of 510 mg of elemental iron</time_frame>
    <description>The rate of overall grade &gt; 2 toxicities (categorized by the NIAID Division of AIDS adverse events table) during ferumoxytol infusion and 1 month post-ferumoxytol infusion will be assessed.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">4</enrollment>
  <condition>HIV Dementia</condition>
  <arm_group>
    <arm_group_label>Ferumoxotyol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Brain MRI will be performed before and 48 +/- 8 hours after ferumoxytol administration.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ferumoxytol</intervention_name>
    <description>A dose of 4 mg/kg of ferumoxytol up to a maximum of 510 mg of elemental iron will be administered.</description>
    <arm_group_label>Ferumoxotyol</arm_group_label>
    <other_name>FERAHEME</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HIV-1 infection as documented by ELISA and confirmed by Western blot, HIV-1 culture,&#xD;
             HIV-1 antigen, plasma HIV-1 RNA by RT-PCR or DNA at any time prior to study entry.&#xD;
&#xD;
          -  Receipt of antiretroviral (ARV) medication uninterrupted for at least 6 months leading&#xD;
             up to the screening period with demonstrated plasma HIV RNA &lt; 48 copies/ml within the&#xD;
             last 6 months.&#xD;
&#xD;
          -  Willingness for both males and females of childbearing potential to utilize 2&#xD;
             effective contraception methods (2 separate forms, one of which must be an effective&#xD;
             barrier method), be non-heterosexually active or have a an exclusive vasectomized&#xD;
             partner from screening throughout the duration of the study treatment and for 30 days&#xD;
             following the last dose of study drugs.&#xD;
&#xD;
          -  Age &gt;18 years.&#xD;
&#xD;
          -  Ability and willingness to provide written informed consent&#xD;
&#xD;
          -  HIV DNA &gt; 10 copies/106 CD14+ PBMCs&#xD;
&#xD;
          -  Mild or greater cognitive impairment as indicated by global NPZ8 z-score &lt; -0.5 with a&#xD;
             neurocognitive abnormality (defined as a z-score &lt; -0.5) in at least one cognitive&#xD;
             domain characteristic of HAD (i.e., executive function, psychomotor speed, memory).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Requirement for acute therapy for other AIDS-defining illness or other serious medical&#xD;
             illnesses (in the opinion of the site investigator) within 14 days prior to study&#xD;
             entry.&#xD;
&#xD;
          -  Known allergic or hypersensitivity reaction to FERAHEME, parental iron, parental&#xD;
             dextran, parental iron-dextran, or parental iron-polysaccharide preparations&#xD;
&#xD;
          -  Known history of an iron overload syndrome (e.g., hereditary hemochromatosis,&#xD;
             porphyria cutanea tarda)&#xD;
&#xD;
          -  Medical conditions (e.g., chronic hemolytic anemia) which requires frequent blood&#xD;
             transfusions&#xD;
&#xD;
          -  Taking oral iron supplementation&#xD;
&#xD;
          -  Any factor that precludes MRI scan including presence of metal or exposure to metal&#xD;
             work (e.g. metal grinder/worker) and claustrophobia&#xD;
&#xD;
          -  Past or present HIV opportunistic infection of the brain, learning disability, head&#xD;
             injury with prolonged loss of consciousness or cognitive sequelae, or other non-HIV&#xD;
             risk factor that in the opinion of the principal investigator (PI) may impact&#xD;
             cognitive performance.&#xD;
&#xD;
          -  History of epilepsy requiring treatment with an antiepileptic&#xD;
&#xD;
          -  Other chronic illnesses including insulin-dependent diabetes, autoimmune diseases, and&#xD;
             endocrinopathies, except subjects on stable physiologic replacement therapy for low&#xD;
             testosterone or thyroid levels&#xD;
&#xD;
          -  Current active substance or alcohol dependence or positive urine toxicology screen.&#xD;
&#xD;
          -  Pregnancy or breast-feeding, intent to become pregnant during the course of the study.&#xD;
&#xD;
          -  Any condition which, in the opinion of the investigator, would compromise the&#xD;
             subject's ability to participate in the study&#xD;
&#xD;
          -  Aspartate aminotransferase (AST), alanine aminotransferase (ALT) greater than 2x upper&#xD;
             limits of normal on pre-entry baseline laboratory safety assessment prior to study&#xD;
             enrollment.&#xD;
&#xD;
          -  Elevated iron levels on pre-entry baseline laboratory safety assessment prior to study&#xD;
             enrollment.&#xD;
&#xD;
          -  Hematocrit &gt; 52% or Hemoglobin &gt; 18 g/dL on pre-entry baseline laboratory safety&#xD;
             assessment prior to study enrollment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Beau K Nakamoto, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Hawaii, Hawaii Center for AIDS, John A Burns School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hawaii Center for AIDS</name>
      <address>
        <city>Honolulu</city>
        <state>Hawaii</state>
        <zip>96816</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.amagpharma.com/products/ferumoxytol.php</url>
    <description>AMAG Pharmaceuticals</description>
  </link>
  <reference>
    <citation>Neuwelt EA, Hamilton BE, Varallyay CG, Rooney WR, Edelman RD, Jacobs PM, Watnick SG. Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)? Kidney Int. 2009 Mar;75(5):465-74. doi: 10.1038/ki.2008.496. Epub 2008 Oct 8.</citation>
    <PMID>18843256</PMID>
  </reference>
  <verification_date>May 2018</verification_date>
  <study_first_submitted>August 13, 2012</study_first_submitted>
  <study_first_submitted_qc>August 13, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 15, 2012</study_first_posted>
  <last_update_submitted>May 30, 2018</last_update_submitted>
  <last_update_submitted_qc>May 30, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 1, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Hawaii</investigator_affiliation>
    <investigator_full_name>Beau Nakamoto</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>HIV associated neurocognitive disorders</keyword>
  <keyword>MRI</keyword>
  <keyword>Ferumoxytol</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>AIDS Dementia Complex</mesh_term>
    <mesh_term>Neurocognitive Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ferrosoferric Oxide</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/NCT01665846
org study id: H015
nct id: NCT01665846
lead sponsor: 
collaborator: 
has dmc: No
The purpose of this study is to describe the radiologic findings on brain MRI after
      ferumoxytol administration in HIV-infected patients with cognitive impairment.
The continued existence of cognitive dysfunction in HIV infected individuals in the era of
      effective antiretroviral therapy may be, in part, secondary to the failure of current
      antiretroviral regimens to eradicate the pool of HIV-infected and activated monocytes within
      the bloodstream. Trafficking of such HIV infected and activated blood monocytes into the
      brain parenchyma is believed to introduce HIV into the brain and precipitate immune
      activation and inflammation, ultimately leading to neuronal degeneration.

      Ferumoxytol is an ultrasmall superparamagnetic iron-oxide (USPIO), which is FDA-approved for
      intravenous iron-replacement therapy in anemic patients with chronic kidney disease. The
      paramagnetic properties of ferumoxytol also allow it to be used as a MRI contrast agent.
      Ferumoxytol is avidly taken up by circulating monocytes and reactive astrocytes, microglia,
      and dendritic cells within the brain, making it potentially a novel biomarker for
      HIV-associated cognitive impairment given the role of monocytes in its pathogenesis.

      This proposal intends to investigate the possible use of ferumoxytol (a new MRI contrast
      agent) as a biomarker for HIV-associated cognitive impairment and to assess the safety and
      tolerability of ferumoxytol in HIV-infected individuals.

      Hypotheses to be tested:

        -  HIV-infected subjects with undetectable plasma HIV RNA levels and detectable levels of
           HIV DNA in CD14+ peripheral blood mononuclear cells (PBMCs) and impairment on
           neurocognitive testing will demonstrate ferumoxytol contrast enhancement in the
           perivascular regions of the brain consistent with monocyte/macrophage infiltration in
           these regions.

        -  Ferumoxytol can be safely administered to HIV-infected subjects.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Post-ferumoxytol enhancement on Brain MRI
time frame: 48 hour following administration of a dose of 4 mg/kg of feruomoxytol up to a maximum of 510 mg of elemental iron
description: The location and extent of ferumoxytol enhancement within the brain will be described.
measure: Safety
time frame: 1 hour and 1 month following administration of a dose of 4 mg/kg of ferumxotyol up to a maximum of 510 mg of elemental iron
description: The rate of overall grade > 2 toxicities (categorized by the NIAID Division of AIDS adverse events table) during ferumoxytol infusion and 1 month post-ferumoxytol infusion will be assessed.
arm group label: Ferumoxotyol
arm group type: Experimental
description: Brain MRI will be performed before and 48 +/- 8 hours after ferumoxytol administration.
intervention type: Drug
intervention name: Ferumoxytol
description: A dose of 4 mg/kg of ferumoxytol up to a maximum of 510 mg of elemental iron will be administered.
arm group label: Ferumoxotyol
other name: FERAHEME
criteria: 
gender: All
minimum age: 19 Years
maximum age: N/A
healthy volunteers: No
last name: Beau K Nakamoto, MD, PhD
role: Principal Investigator
affiliation: University of Hawaii, Hawaii Center for AIDS, John A Burns School of Medicine
facility: 
country: United States
url: http://www.amagpharma.com/products/ferumoxytol.php
description: AMAG Pharmaceuticals
citation: Neuwelt EA, Hamilton BE, Varallyay CG, Rooney WR, Edelman RD, Jacobs PM, Watnick SG. Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)? Kidney Int. 2009 Mar;75(5):465-74. doi: 10.1038/ki.2008.496. Epub 2008 Oct 8.
PMID: 18843256
responsible party type: Principal Investigator
investigator affiliation: University of Hawaii
investigator full name: Beau Nakamoto
investigator title: Assistant Professor
mesh term: AIDS Dementia Complex
mesh term: Neurocognitive Disorders
mesh term: Ferrosoferric Oxide