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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Associated Neurocognitive Disorder
• Intervention / Treatment: Drug: Fluconazole; Drug: Paroxetine; Drug: Paroxetine and Fluconazole; Drug: Placebo

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

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Johns Hopkins Institute for Clinical and Translational Research, Adult Outpatient Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Ned Sacktor, MD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: May 13, 2011
• First Submitted That Met QC Criteria: May 13, 2011
• First Posted (Estimate): May 16, 2011

Study Record Updates

• Last Update Posted (Actual): June 9, 2017
• Last Update Submitted That Met QC Criteria: May 11, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: HIV; Dementia; Memory; Magnetic resonance spectroscopy; MRS; SSRI; Functional assessment; Neurocognitive impairment; CSF marker; Arterial spin labeling
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Paroxetine; Fluconazole
• Other Study ID Numbers: NA_00037283; P30MH075673-05 (U.S. NIH Grant/Contract)