Clinical trial NCT01451333: The Efavirenz (EFV) Central Nervous System Exposure Sub-study of Encore1
Official title: The EFV Central Nervous System Exposure Sub-study of Encore1: A Randomised, Double-blind, Placebo-controlled, Clinical Trial to Compare the Safety and Efficacy of Reduced Dose Efavirenz (EFV) With Standard Dose EFV Plus Two Nucleotide Reverse Transcriptase Inhibitors (N(t)RTI) in Antiretroviral-naïve HIV-infected Individuals Over 96 Weeks
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infection
Keywords: HIV
Efavirenz
Central Nervous System (CNS)
Lumbar puncture
Dose reduction
Lead sponsor: Kirby Institute
Sponsor class: OTHER_GOV
Collaborators: name: Imperial College London
First posted: 2011-10-13
Enrollment: 32
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Persistent HIV infection in the central nervous system (CNS) compartment may put subjects at risk of developing HIV-related brain disease. Important factors associated with the development of HIV-related brain disease include therapeutic concentrations of antiretroviral drugs in the CNS. Conflicting evidence regarding the CNS exposure of the antiretroviral drug used for the encore1 study, efavirenz (EFV) have been described in related studies. There were recent study of two small series assessment of EFV exposure in the cerebral spinal fluid (CSF); one group reported small detectable EFV concentrations, while another observed undetectable EFV exposure in the CSF. Also, in a larger reported series comprising of 80 subjects on EFV-containing antiretroviral therapy, a CSF to plasma concentration suggested that there is limited movement of EFV out of the CSF. In HIV-1 infected subjects at steady state, EFV plasma level parameters are dose proportional following 200mg, 400mg, and 600mg daily doses. The CNS exposure of EFV at different daily dosing has not been described.


Eligibility criteria: Inclusion Criteria:

* All subjects entering into the main study protocol at participating centres will be eligible to enter this sub-study.

Exclusion Criteria:

* Existing neurological disease which in the opinion of the investigator would be a contra-indication to lumbar puncture examination
* CNS opportunistic infections in the past 12 weeks of randomisation
* Bacterial or viral meningitis in the past 12 weeks of randomisation
* Head injury requiring medical assessment in the past 12 weeks of randomisation

Primary outcomes:
measure: comparison of mean CSF concentration of EFV from both doses after week 24.
timeFrame: 24 weeks
Secondary outcomes:
measure: CSF EFV exposure and plasma exposure (CSF:plasma ratio) using statistical analysis
timeFrame: 24 weeks
measure: The relationship between CSF EFV exposure and neuropsychiatric side effects using questionnaires and medical assessments
timeFrame: 24 weeks
measure: The relationship between CSF EFV exposure and other study parameters such as race and sex.
timeFrame: 24 weeks
measure: The number of subjects with EFV CSF exposure greater than the postulated CSF IC50 for wild type virus (0.51ng/mL)
timeFrame: 24 weeks
measure: CSF HIV RNA measurement after 12 - 24 weeks of study therapy
timeFrame: 24 weeks
measure: Relationship between plasma HIV RNA and CSF HIV RNA
timeFrame: 24 weeks
measure: CSF biomarker analysis after 12 - 24 weeks of study therapy
timeFrame: 24 weeks
measure: comparison between magnetic resonance (MR) spectroscopy findings and CSF HIV RNA and EFV concentration
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Medical Group Practice
city: Patumwan
country: Thailand
facility: HIVNAT Research Collaboration
state: Bangkok
city: Khon Kaen
country: Thailand
facility: Khon Kaen University
city: Clinical Trials Centre, Winston Churchil Wing
country: United Kingdom
facility: Imperial College, St. Mary's Hospital
state: London
city: HIV/GUM laboratory 5th floor St. Stephen Centre
country: United Kingdom
facility: Chelsea and Westminster Hospital
state: London
Study officials:
affiliation: Imperial College London
name: Alan Winston, Dr.
role: PRINCIPAL_INVESTIGATOR
References: