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

Johns Hopkins University

Status and phase: Completed; Phase 2; Phase 1

Conditions: HIV Associated Neurocognitive Disorder

Treatments: Drug: Fluconazole; Drug: Paroxetine; Drug: Placebo; Drug: Paroxetine and Fluconazole

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01354314

P30MH075673-05 (U.S. NIH Grant/Contract)

NA_00037283

Details and patient eligibility

About

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.

Full 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

Enrollment: 45 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Triple Blind

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45 participants in 4 patient groups, including a placebo group

Fluconazole

Experimental group

Description:

Fluconazole 100 mg every 12 hours orally per day; placebo in place of paroxetine

Treatment:

Drug: Fluconazole

Paroxetine

Experimental group

Description:

Paroxetine 20 mg orally once per day; placebo in place of fluconazole

Treatment:

Drug: Paroxetine

Paroxetine and Fluconazole

Experimental group

Description:

Fluconazole 100 mg every 12 hours orally per day and paroxetine 20 mg every evening orally per day

Treatment:

Drug: Paroxetine and Fluconazole

Placebo

Placebo Comparator group

Description:

Placebo in place of both fluconazole and paroxetine

Treatment:

Drug: Placebo