Ferumoxytol-enhanced Brain MRI in HIV-associated Neurocognitive Disorders

May 30, 2018 updated by: Beau Nakamoto, University of Hawaii

Neuroimaging Correlates of Monocyte/Macrophage Infiltration in HIV-infected Individuals: A Cross-sectional Pilot Study Using IV Ferumoxytol

The purpose of this study is to describe the radiologic findings on brain MRI after ferumoxytol administration in HIV-infected patients with cognitive impairment.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

4

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Hawaii
      • Honolulu, Hawaii, United States, 96816
        • Hawaii Center for AIDS

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • HIV-1 infection as documented by ELISA and confirmed by Western blot, HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA by RT-PCR or DNA at any time prior to study entry.
  • Receipt of antiretroviral (ARV) medication uninterrupted for at least 6 months leading up to the screening period with demonstrated plasma HIV RNA < 48 copies/ml within the last 6 months.
  • Willingness for both males and females of childbearing potential to utilize 2 effective contraception methods (2 separate forms, one of which must be an effective barrier method), be non-heterosexually active or have a an exclusive vasectomized partner from screening throughout the duration of the study treatment and for 30 days following the last dose of study drugs.
  • Age >18 years.
  • Ability and willingness to provide written informed consent
  • HIV DNA > 10 copies/106 CD14+ PBMCs
  • Mild or greater cognitive impairment as indicated by global NPZ8 z-score < -0.5 with a neurocognitive abnormality (defined as a z-score < -0.5) in at least one cognitive domain characteristic of HAD (i.e., executive function, psychomotor speed, memory).

Exclusion Criteria:

  • Requirement for acute therapy for other AIDS-defining illness or other serious medical illnesses (in the opinion of the site investigator) within 14 days prior to study entry.
  • Known allergic or hypersensitivity reaction to FERAHEME, parental iron, parental dextran, parental iron-dextran, or parental iron-polysaccharide preparations
  • Known history of an iron overload syndrome (e.g., hereditary hemochromatosis, porphyria cutanea tarda)
  • Medical conditions (e.g., chronic hemolytic anemia) which requires frequent blood transfusions
  • Taking oral iron supplementation
  • Any factor that precludes MRI scan including presence of metal or exposure to metal work (e.g. metal grinder/worker) and claustrophobia
  • Past or present HIV opportunistic infection of the brain, learning disability, head injury with prolonged loss of consciousness or cognitive sequelae, or other non-HIV risk factor that in the opinion of the principal investigator (PI) may impact cognitive performance.
  • History of epilepsy requiring treatment with an antiepileptic
  • Other chronic illnesses including insulin-dependent diabetes, autoimmune diseases, and endocrinopathies, except subjects on stable physiologic replacement therapy for low testosterone or thyroid levels
  • Current active substance or alcohol dependence or positive urine toxicology screen.
  • Pregnancy or breast-feeding, intent to become pregnant during the course of the study.
  • Any condition which, in the opinion of the investigator, would compromise the subject's ability to participate in the study
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) greater than 2x upper limits of normal on pre-entry baseline laboratory safety assessment prior to study enrollment.
  • Elevated iron levels on pre-entry baseline laboratory safety assessment prior to study enrollment.
  • Hematocrit > 52% or Hemoglobin > 18 g/dL on pre-entry baseline laboratory safety assessment prior to study enrollment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ferumoxotyol
Brain MRI will be performed before and 48 +/- 8 hours after ferumoxytol administration.
Drug: Ferumoxytol
A dose of 4 mg/kg of ferumoxytol up to a maximum of 510 mg of elemental iron will be administered.
Other Names:
  • FERAHEME

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
The location and extent of ferumoxytol enhancement within the brain will be described.
48 hour following administration of a dose of 4 mg/kg of feruomoxytol up to a maximum of 510 mg of elemental iron

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
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.
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Hawaii

Collaborators

Oregon Health and Science University

Investigators

  • Principal Investigator: Beau K Nakamoto, MD, PhD, University of Hawaii, Hawaii Center for AIDS, John A Burns School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2011

Primary Completion (Actual)

June 1, 2012

Study Completion (Actual)

June 1, 2012

Study Registration Dates

First Submitted

August 13, 2012

First Submitted That Met QC Criteria

August 13, 2012

First Posted (Estimate)

August 15, 2012

Study Record Updates

Last Update Posted (Actual)

June 1, 2018

Last Update Submitted That Met QC Criteria

May 30, 2018

Last Verified

May 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H015

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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