Clinical trial NCT01354314: Study of Paroxetine and Fluconazole for the Treatment of HIV Associated Neurocognitive Disorder
Official title: Pilot Study of Paroxetine and Fluconazole for the Treatment of HIV Associated Neurocognitive Disorder (HAND)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Associated Neurocognitive Disorder
Keywords: HIV
Neurocognitive impairment
Memory
Dementia
CSF marker
Functional assessment
MRS
Magnetic resonance spectroscopy
Arterial spin labeling
SSRI
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2011-05-16
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to see if paroxetine and fluconazole are safe and effective as a treatment for problems with memory, concentration, thinking, and judgment in people who are infected with HIV. Paroxetine is an antidepressant approved by the FDA to treat major depression. Fluconazole is an antifungal medication approved by the FDA to treat fungal infections.

Detailed description: The study will be a 24 week double-blind, placebo-controlled 2x2 factorial design pilot Phase I/II study in 60 HIV+ individuals with HAND. Participants will be randomly assigned to one of four groups: 1) fluconazole 100 mg every 12 hours orally per day, 2) paroxetine 20mg every evening orally per day, 3) fluconazole 100mg every 12 hours orally per day and paroxetine 20mg every evening orally per day and 4) placebo.

Primary Aim: To obtain preliminary data to evaluate the efficacy of fluconazole and/or paroxetine to decrease CSF lipid and protein markers of oxidative stress \[CSF ceramide and (C18:0 levels) and 3-nitrosylated proteins\].

Secondary Aims:

i) To evaluate the safety and tolerability of fluconazole and/or paroxetine in HIV+ individuals with HAND ii) To evaluate the effect of fluconazole and/or paroxetine on neurocognitive performance in HIV+ individuals with HAND iii) To evaluate the effect of fluconazole and/or paroxetine on functional performance in HIV+ individuals with HAND iv) To evaluate the CNS penetration of fluconazole and paroxetine after 24 weeks of treatment v) To obtain preliminary data to evaluate the efficacy of fluconazole and/or paroxetine to improve abnormal imaging markers as measured by magnetic resonance spectroscopy (MRS) and arterial spin labeling

Eligibility criteria: Inclusion Criteria:

* HIV+ based on ELISA and confirmed by either Western blot or plasma HIV RNA
* capable of providing informed consent
* age range: 18-65 years
* presence of neuropsychological testing impairment as defined by performance at least 1.0 standard deviation below age-matched and education-matched controls on three or more independent neuropsychological tests at the screening visit, or performance at least 2.0 standard deviations below age-matched and education-matched controls on one independent neuropsychological test and at least 1.0 standard deviation below age-matched and education-matched controls on a second independent neuropsychological test at the screening visit
* a stable HAART regimen for 3 months with no plans to change the antiretroviral regimen over the study period (confirmed by discussion with a patient's primary provider)
* the following lab values within 2 weeks prior to entry: hemoglobin \> 8.9 g/dl, absolute neutrophil count \> 500 cells/mm3, platelet count \> 50,000 cells/mm3, ALT \< 2.5 X upper limit of normal, alkaline phosphatase \< 3 X upper limit of normal, serum creatinine \>= 2 X upper limit of normal
* a negative serum or urine beta-HCG pregnancy test for all women of reproductive potential (have not reached menopause or undergone hysterectomy, oophorectomy, or tubal ligation)
* neurological examination by a physician revealing no contraindication to a lumbar puncture. If an examination suggests a possible space-occupying brain mass lesion, neuroimaging with CT or MRI must confirm the absence of a mass lesion.

Exclusion Criteria:

* current or past opportunistic CNS infection (fungal or non-fungal) at study entry
* current systemic fungal infection
* current or past use of fluconazole within 30 days of the screening visit
* history or current clinical evidence of schizophrenia
* history of chronic neurological disorder such as multiple sclerosis or uncontrolled epilepsy
* active symptomatic AIDS defining opportunistic infection within 30 days prior to study entry
* history of abnormal medical illness or current severe affective disorder (e.g., depression with suicidal intention) which in the opinion of the investigators would constitute a safety risk for patients or interfere with the ability of a patient to complete the study
* treatment with anticoagulants including coumadin, heparin, or low molecular weight heparin which would be a contraindication for the lumbar puncture
* HIV+ individuals with moderate or severe confounding illnesses
* prior use of SSRI's within 1 month of screening
* active substance abuse (illicit drugs and/or controlled medications) or active severe alcohol abuse, evidenced by history intake or urine toxicology at any visit prior to study entry (starting study medication)

Primary outcomes:
measure: Change in CSF Ceramide Between Baseline and Week 24 (C18:0 Levels) - Intent to Treat
timeFrame: 24 Weeks
measure: Change in CSF Ceramide Between Baseline and Week 24 (C18:0 Levels) - Per Protocol
timeFrame: 24 Weeks
measure: Change in CSF 3-nitrosylated Protein Levels Between Baseline and Week 24 - Intent to Treat
timeFrame: 24 Weeks
measure: Change in CSF 3-nitrosylated Protein Levels Between Baseline and Week 24 - Per Protocol
timeFrame: 24 Weeks
Secondary outcomes:
measure: Change in CSF sCD14 Between Baseline and Week 24 - Intent to Treat
timeFrame: 24 Weeks
measure: Change in CSF sCD14 Between Baseline and Week 24 - Per Protocol
timeFrame: 24 Weeks
measure: Change in CSF CD163 Between Baseline and Week 24 - Intent to Treat
timeFrame: 24 Weeks
measure: Change in CSF CD163 Between Baseline and Week 24 - Per Protocol
timeFrame: 24 Weeks
measure: Change in CSF Neurofilament Protein Light Chain (NFL) Between Baseline and Week 24 - Intent to Treat
timeFrame: 24 Weeks
measure: Change in CSF Neurofilament Protein Light Chain (NFL) Between Baseline and Week 24 - Per Protocol
timeFrame: 24 Weeks
measure: Change in CSF Neurofilament Protein Heavy Chain (pNFL) Between Baseline and Week 24 - Intent to Treat
timeFrame: 24 Weeks
measure: Change in CSF Neurofilament Protein Heavy Chain (pNFH) Between Baseline and Week 24 - Per Protocol
timeFrame: 24 Weeks
measure: Neurocognitive Performance: Trail Making A - Intent to Treat
timeFrame: 24 Weeks
measure: Neurocognitive Performance: Trail Making A - Per Protocol
timeFrame: 24 Weeks
measure: Neurocognitive Performance: Trail Making B - Intent to Treat
timeFrame: 24 Weeks
measure: Neurocognitive Performance: Trail Making B - Per Protocol
timeFrame: 24 Weeks
measure: Neurocognitive Performance: Grooved Pegboard, Dominant - Intent to Treat
timeFrame: 24 Weeks
measure: Neurocognitive Performance: Grooved Pegboard, Dominant - Per Protocol
timeFrame: 24 Weeks
measure: Neurocognitive Performance: Grooved Pegboard, Non-Dominant - Intent to Treat
timeFrame: 24 Weeks
measure: Neurocognitive Performance: Grooved Pegboard, Non-Dominant - Per Protocol
timeFrame: 24 Weeks
measure: Neurocognitive Performance: CalCAP, Choice - Intent to Treat
timeFrame: 24 Weeks
measure: Neurocognitive Performance: CalCAP, Choice - Per Protocol
timeFrame: 24 Weeks
measure: Neurocognitive Performance: CalCAP, Sequential - Intent to Treat
timeFrame: 24 Weeks
measure: Neurocognitive Performance: CalCAP, Sequential - Per Protocol
timeFrame: 24 Weeks
measure: Neurocognitive Performance: Symbol-Digit Test - Intent to Treat
timeFrame: 24 Weeks
measure: Neurocognitive Performance: Symbol-Digit Test - Per Protocol
timeFrame: 24 Weeks
measure: Neurocognitive Performance: Timed Gait - Intent to Treat
timeFrame: 24 Weeks
measure: Neurocognitive Performance: Timed Gait - Per Protocol
timeFrame: 24 Weeks
measure: Neurocognitive Performance: NPZ-8 - Intent to Treat
timeFrame: 24 Weeks
measure: Neurocognitive Performance: NPZ-8 - Per Protocol
timeFrame: 24 Weeks
measure: Change in CES-D Score - Intent to Treat
timeFrame: 24 Weeks
measure: Change in CES-D Score - Per Protocol
timeFrame: 24 Weeks
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: The Johns Hopkins Institute for Clinical and Translational Research, Adult Outpatient Clinical Research Unit
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Ned Sacktor, MD
role: PRINCIPAL_INVESTIGATOR
References: