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

This study has been completed.
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Ned Sacktor, Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT01354314
First received: May 13, 2011
Last updated: May 11, 2017
Last verified: May 2017
  Purpose
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.

Condition Intervention Phase
HIV Associated Neurocognitive Disorder Drug: Fluconazole Drug: Paroxetine Drug: Paroxetine and Fluconazole Drug: Placebo Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Participant, Care Provider, Investigator
Primary Purpose: Treatment
Official Title: Pilot Study of Paroxetine and Fluconazole for the Treatment of HIV Associated Neurocognitive Disorder (HAND)

Resource links provided by NLM:


Further study details as provided by Ned Sacktor, Johns Hopkins University:

Primary Outcome Measures:
  • Change in CSF Ceramide Between Baseline and Week 24 (C18:0 Levels) - Intent to Treat [ Time Frame: 24 Weeks ]
    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).

  • Change in CSF Ceramide Between Baseline and Week 24 (C18:0 Levels) - Per Protocol [ Time Frame: 24 Weeks ]
    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).

  • Change in CSF 3-nitrosylated Protein Levels Between Baseline and Week 24 - Intent to Treat [ Time Frame: 24 Weeks ]
    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).

  • Change in CSF 3-nitrosylated Protein Levels Between Baseline and Week 24 - Per Protocol [ Time Frame: 24 Weeks ]
    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).


Secondary Outcome Measures:
  • Change in CSF sCD14 Between Baseline and Week 24 - Intent to Treat [ Time Frame: 24 Weeks ]
    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).

  • Change in CSF sCD14 Between Baseline and Week 24 - Per Protocol [ Time Frame: 24 Weeks ]
    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).

  • Change in CSF CD163 Between Baseline and Week 24 - Intent to Treat [ Time Frame: 24 Weeks ]
    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).

  • Change in CSF CD163 Between Baseline and Week 24 - Per Protocol [ Time Frame: 24 Weeks ]
    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).

  • Change in CSF Neurofilament Protein Light Chain (NFL) Between Baseline and Week 24 - Intent to Treat [ Time Frame: 24 Weeks ]
    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).

  • Change in CSF Neurofilament Protein Light Chain (NFL) Between Baseline and Week 24 - Per Protocol [ Time Frame: 24 Weeks ]
    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).

  • Change in CSF Neurofilament Protein Heavy Chain (pNFL) Between Baseline and Week 24 - Intent to Treat [ Time Frame: 24 Weeks ]
    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).

  • Change in CSF Neurofilament Protein Heavy Chain (pNFH) Between Baseline and Week 24 - Per Protocol [ Time Frame: 24 Weeks ]
    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).

  • Neurocognitive Performance: Trail Making A - Intent to Treat [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by the Trail-making test, part A speed of completion (Z scores).

  • Neurocognitive Performance: Trail Making A - Per Protocol [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by the Trail-making test, part A speed of completion (Z scores).

  • Neurocognitive Performance: Trail Making B - Intent to Treat [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by the Trail-making test, part B speed of completion (Z scores).

  • Neurocognitive Performance: Trail Making B - Per Protocol [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by the Trail-making test, part B speed of completion (Z scores).

  • Neurocognitive Performance: Grooved Pegboard, Dominant - Intent to Treat [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by the Grooved Pegboard test, dominant hand speed of completion (Z scores).

  • Neurocognitive Performance: Grooved Pegboard, Dominant - Per Protocol [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by the Grooved Pegboard test, dominant hand speed of completion (Z scores).

  • Neurocognitive Performance: Grooved Pegboard, Non-Dominant - Intent to Treat [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by the Grooved Pegboard test, non-dominant hand speed of completion (Z scores).

  • Neurocognitive Performance: Grooved Pegboard, Non-Dominant - Per Protocol [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by the Grooved Pegboard test, non-dominant hand speed of completion (Z scores).

  • Neurocognitive Performance: CalCAP, Choice - Intent to Treat [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by the CalCAP Choice test, mean reaction time (Z scores).

  • Neurocognitive Performance: CalCAP, Choice - Per Protocol [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by the CalCAP Choice test, mean reaction time (Z scores).

  • Neurocognitive Performance: CalCAP, Sequential - Intent to Treat [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by the CalCAP Sequential test, mean reaction time (Z scores).

  • Neurocognitive Performance: CalCAP, Sequential - Per Protocol [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by the CalCAP Sequential test, mean reaction time (Z scores).

  • Neurocognitive Performance: Symbol-Digit Test - Intent to Treat [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by Symbol-Digit Test score, number correct in 120 seconds (Z scores).

  • Neurocognitive Performance: Symbol-Digit Test - Per Protocol [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by Symbol-Digit Test score, number correct in 120 seconds (Z scores).

  • Neurocognitive Performance: Timed Gait - Intent to Treat [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by Timed Gait, three-trial average time (Z scores).

  • Neurocognitive Performance: Timed Gait - Per Protocol [ Time Frame: 24 Weeks ]
    Baseline to Week 24 change in neurocognitive performance as measured by Timed Gait, three-trial average time (Z scores).

  • Neurocognitive Performance: NPZ-8 - Intent to Treat [ Time Frame: 24 Weeks ]
    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.

  • Neurocognitive Performance: NPZ-8 - Per Protocol [ Time Frame: 24 Weeks ]
    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.

  • Change in CES-D Score - Intent to Treat [ Time Frame: 24 Weeks ]
    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).

  • Change in CES-D Score - Per Protocol [ Time Frame: 24 Weeks ]
    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).


Enrollment: 45
Study Start Date: November 2010
Study Completion Date: March 2016
Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01354314

Locations
United States, Maryland
The Johns Hopkins Institute for Clinical and Translational Research, Adult Outpatient Clinical Research Unit
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
Johns Hopkins University
National Institute of Mental Health (NIMH)
Investigators
Principal Investigator: Ned Sacktor, MD Johns Hopkins University
  More Information

Responsible Party: Ned Sacktor, Professor of Neurology, Johns Hopkins University
ClinicalTrials.gov Identifier: NCT01354314     History of Changes
Other Study ID Numbers: NA_00037283
P30MH075673-05 ( U.S. NIH Grant/Contract )
Study First Received: May 13, 2011
Results First Received: April 3, 2017
Last Updated: May 11, 2017

Keywords provided by Ned Sacktor, Johns Hopkins University:
HIV
Neurocognitive impairment
Memory
Dementia
CSF marker
Functional assessment
MRS
Magnetic resonance spectroscopy
Arterial spin labeling
SSRI

Additional relevant MeSH terms:
Disease
Neurocognitive Disorders
Pathologic Processes
Mental Disorders
Paroxetine
Fluconazole
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors

ClinicalTrials.gov processed this record on June 29, 2017