Study of Paroxetine and Fluconazole for the Treatment of HIV Associated Neurocognitive Disorder

Johns Hopkins University45 enrolled

Overview

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.

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

HIV Associated Neurocognitive Disorder

Interventions

FluconazoleDRUG

One 100 MG capsule taken twice daily, 12 hour dosing

ParoxetineDRUG

Two 10 MG capsules paroxetine once daily in the evening

Paroxetine and FluconazoleDRUG

One capsule 100 MG fluconazole every 12 hours orally per day; Two 10 MG capsules paroxetine orally once daily in the evening

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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)

Locations (1)

The Johns Hopkins Institute for Clinical and Translational Research, Adult Outpatient Clinical Research Unit

Baltimore, Maryland, United States

Outcomes

Primary Outcomes

Change in CSF Ceramide Between Baseline and Week 24 (C18:0 Levels) - Intent to Treat

CSF lipid and protein markers of oxidative stress: Change in CSF ceramide (C18:0 levels) between baseline and week 24 for all participants for whom baseline and follow-up CSF data are available (intent to treat analysis).

Time frame: 24 Weeks

Change in CSF Ceramide Between Baseline and Week 24 (C18:0 Levels) - Per Protocol

CSF lipid and protein markers of oxidative stress: Change in CSF ceramide (C18:0 levels) between baseline and week 24 for participants with 90% or greater study drug adherence and for whom baseline and follow-up CSF data are available (per protocol analysis).

Time frame: 24 Weeks

Change in CSF 3-nitrosylated Protein Levels Between Baseline and Week 24 - Intent to Treat

CSF lipid and protein markers of oxidative stress: Change in 3-nitrosylated protein levels between baseline and week 24 for all participants for whom CSF data are available (intent to treat analysis).

Time frame: 24 Weeks

Change in CSF 3-nitrosylated Protein Levels Between Baseline and Week 24 - Per Protocol

CSF lipid and protein markers of oxidative stress: Change in 3-nitrosylated protein levels between baseline and week 24 for participants with 90% or greater adherence to study drug and for whom CSF data are available (per protocol analysis).

Time frame: 24 Weeks

Secondary Outcomes

Change in CSF sCD14 Between Baseline and Week 24 - Intent to Treat

CSF immune and neuronal injury markers: Change in CSF sCD14 between baseline and week 24 for all participants for whom baseline and follow-up CSF data are available (intent to treat analysis).

Time frame: 24 Weeks

Data from ClinicalTrials.gov

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One capsule in the morning, three capsules in the evening

Change in CSF sCD14 Between Baseline and Week 24 - Per Protocol

CSF immune and neuronal injury markers: Change in CSF sCD14 between baseline and week 24 for participants with 90% or greater study drug adherence and for whom baseline and follow-up CSF data are available (per protocol analysis).

Time frame: 24 Weeks

Change in CSF CD163 Between Baseline and Week 24 - Intent to Treat

CSF immune and neuronal injury markers: Change in CSF CD163 between baseline and week 24 for all participants for whom baseline and follow-up CSF data are available (intent to treat analysis).

Time frame: 24 Weeks

Change in CSF CD163 Between Baseline and Week 24 - Per Protocol

CSF immune and neuronal injury markers: Change in CSF CD163 between baseline and week 24 for participants with 90% or greater study drug adherence and for whom baseline and follow-up CSF data are available (per protocol analysis).

Time frame: 24 Weeks

Change in CSF Neurofilament Protein Light Chain (NFL) Between Baseline and Week 24 - Intent to Treat

CSF immune and neuronal injury markers: Change in CSF neurofilament protein light chain (NFL) between baseline and week 24 for all participants for whom baseline and follow-up CSF data are available (intent to treat analysis).

Time frame: 24 Weeks

Change in CSF Neurofilament Protein Light Chain (NFL) Between Baseline and Week 24 - Per Protocol

CSF immune and neuronal injury markers: Change in CSF neurofilament protein light chain (NFL) between baseline and week 24 for participants with 90% or greater study drug adherence and for whom baseline and follow-up CSF data are available (per protocol analysis).

Time frame: 24 Weeks

Change in CSF Neurofilament Protein Heavy Chain (pNFL) Between Baseline and Week 24 - Intent to Treat

CSF immune and neuronal injury markers: Change in CSF neurofilament protein heavy chain (pNFL) between baseline and week 24 for all participants for whom baseline and follow-up CSF data are available (intent to treat analysis).

Time frame: 24 Weeks

Change in CSF Neurofilament Protein Heavy Chain (pNFH) Between Baseline and Week 24 - Per Protocol

CSF immune and neuronal injury markers: Change in CSF neurofilament protein heavy chain (pNFH) between baseline and week 24 for participants with 90% or greater study drug adherence and for whom baseline and follow-up CSF data are available (per protocol analysis).

Time frame: 24 Weeks

Neurocognitive Performance: Trail Making A - Intent to Treat

Baseline to Week 24 change in neurocognitive performance as measured by the Trail-making test, part A speed of completion (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: Trail Making A - Per Protocol

Baseline to Week 24 change in neurocognitive performance as measured by the Trail-making test, part A speed of completion (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: Trail Making B - Intent to Treat

Baseline to Week 24 change in neurocognitive performance as measured by the Trail-making test, part B speed of completion (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: Trail Making B - Per Protocol

Baseline to Week 24 change in neurocognitive performance as measured by the Trail-making test, part B speed of completion (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: Grooved Pegboard, Dominant - Intent to Treat

Baseline to Week 24 change in neurocognitive performance as measured by the Grooved Pegboard test, dominant hand speed of completion (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: Grooved Pegboard, Dominant - Per Protocol

Baseline to Week 24 change in neurocognitive performance as measured by the Grooved Pegboard test, dominant hand speed of completion (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: Grooved Pegboard, Non-Dominant - Intent to Treat

Baseline to Week 24 change in neurocognitive performance as measured by the Grooved Pegboard test, non-dominant hand speed of completion (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: Grooved Pegboard, Non-Dominant - Per Protocol

Baseline to Week 24 change in neurocognitive performance as measured by the Grooved Pegboard test, non-dominant hand speed of completion (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: CalCAP, Choice - Intent to Treat

Baseline to Week 24 change in neurocognitive performance as measured by the CalCAP Choice test, mean reaction time (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: CalCAP, Choice - Per Protocol

Baseline to Week 24 change in neurocognitive performance as measured by the CalCAP Choice test, mean reaction time (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: CalCAP, Sequential - Intent to Treat

Baseline to Week 24 change in neurocognitive performance as measured by the CalCAP Sequential test, mean reaction time (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: CalCAP, Sequential - Per Protocol

Baseline to Week 24 change in neurocognitive performance as measured by the CalCAP Sequential test, mean reaction time (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: Symbol-Digit Test - Intent to Treat

Baseline to Week 24 change in neurocognitive performance as measured by Symbol-Digit Test score, number correct in 120 seconds (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: Symbol-Digit Test - Per Protocol

Baseline to Week 24 change in neurocognitive performance as measured by Symbol-Digit Test score, number correct in 120 seconds (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: Timed Gait - Intent to Treat

Baseline to Week 24 change in neurocognitive performance as measured by Timed Gait, three-trial average time (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: Timed Gait - Per Protocol

Baseline to Week 24 change in neurocognitive performance as measured by Timed Gait, three-trial average time (Z scores).

Time frame: 24 Weeks

Neurocognitive Performance: NPZ-8 - Intent to Treat

Baseline to Week 24 change in neurocognitive performance as measured by NPZ-8 scores calculated for all participants who completed the trial with measurable Baseline and Week 24 data for at least 6 of the 8 data points. The data points that comprise the NPZ-8 include timed gait, symbol-digit, grooved pegboard dominant and non-dominant, CalCAP Choice reaction time and Sequential reaction time, Trail-making Test A and B. The baseline to week 24 changes for each test were averaged to get each change in NPZ-8 score.

Time frame: 24 Weeks

Neurocognitive Performance: NPZ-8 - Per Protocol

Time frame: 24 Weeks

Change in CES-D Score - Intent to Treat

Functional assessment: Change in Center for Epidemiologic Studies Depression Scale (CES-D) score between baseline and week 24 for all participants for whom baseline and follow-up CES-D data are available (intent to treat analysis).

Time frame: 24 Weeks

Change in CES-D Score - Per Protocol

Time frame: 24 Weeks