Clinical trial NCT01665846: Ferumoxytol-enhanced Brain MRI in HIV-associated Neurocognitive Disorders
Official title: Neuroimaging Correlates of Monocyte/Macrophage Infiltration in HIV-infected Individuals: A Cross-sectional Pilot Study Using IV Ferumoxytol
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Dementia
Keywords: HIV associated neurocognitive disorders
MRI
Ferumoxytol
Lead sponsor: University of Hawaii
Sponsor class: OTHER
Collaborators: name: Oregon Health and Science University
First posted: 2012-08-15
Enrollment: 4
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Post-ferumoxytol enhancement on Brain MRI
timeFrame: 48 hour following administration of a dose of 4 mg/kg of feruomoxytol up to a maximum of 510 mg of elemental iron
Secondary outcomes:
measure: Safety
timeFrame: 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
Other outcomes:
Locations:
city: Honolulu
country: United States
facility: Hawaii Center for AIDS
state: Hawaii
Study officials:
affiliation: University of Hawaii, Hawaii Center for AIDS, John A Burns School of Medicine
name: Beau K Nakamoto, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.