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

Study Overview
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Brief Summary
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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
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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

Official Title
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Pilot Study of Paroxetine and Fluconazole for the Treatment of HIV Associated Neurocognitive Disorder (HAND)

Conditions
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HIV Associated Neurocognitive Disorder

Intervention / Treatment
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* Drug: Fluconazole
* Drug: Paroxetine
* Drug: Paroxetine and Fluconazole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fluconazole<br>Fluconazole 100 mg every 12 hours orally per day; placebo in place of paroxetine | Drug: Fluconazole<br>* One 100 MG capsule taken twice daily, 12 hour dosing<br>|
| Experimental: Paroxetine<br>Paroxetine 20 mg orally once per day; placebo in place of fluconazole | Drug: Paroxetine<br>* Two 10 MG capsules paroxetine once daily in the evening<br>|
| Experimental: Paroxetine and Fluconazole<br>Fluconazole 100 mg every 12 hours orally per day and paroxetine 20 mg every evening orally per day | Drug: Paroxetine and Fluconazole<br>* One capsule 100 MG fluconazole every 12 hours orally per day; Two 10 MG capsules paroxetine orally once daily in the evening<br>|
| Placebo Comparator: Placebo<br>Placebo in place of both fluconazole and paroxetine | Drug: Placebo<br>* One capsule in the morning, three capsules in the evening<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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). | 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). | 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). | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 24 Weeks | 
| 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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. | 24 Weeks | 
| Neurocognitive Performance: NPZ-8 - Per Protocol | 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. | 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). | 24 Weeks | 
| Change in CES-D Score - Per Protocol | 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 (per protocol). | 24 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Neurocognitive impairment, Memory, Dementia, CSF marker, Functional assessment, MRS, Magnetic resonance spectroscopy, Arterial spin labeling, SSRI