The Efavirenz (EFV) Central Nervous System Exposure Sub-study of Encore1

HIV Infection Clinical Trial

— ENCORE1-CNS  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01451333
• Other study ID #: NCHECR-ENCORE1-CNS
• Status: Completed
• Phase: Phase 3
• First received: January 5, 2011
• Last updated: May 10, 2013
• Start date: September 2011
• Est. completion date: February 2013

Study information

• Verified date: May 2013
• Source: Kirby Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: Australia: Therapeutic Goods AdministrationUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: February 2013
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV Infection

Intervention

Drug:
• Efavirenz
600mg qd; 3 x 200mg qd
• Efavirenz
400mg qd; 2 x 200mg

Locations

Country	Name	City	State
Germany	Medical Group Practice	Berlin
Thailand	Khon Kaen University	Khon Kaen
Thailand	HIVNAT Research Collaboration	Patumwan	Bangkok
United Kingdom	Imperial College, St. Mary's Hospital	Clinical Trials Centre, Winston Churchil Wing	London
United Kingdom	Chelsea and Westminster Hospital	HIV/GUM laboratory 5th floor St. Stephen Centre	London

Sponsors (2)

Lead Sponsor	Collaborator
Kirby Institute	Imperial College London

Countries where clinical trial is conducted

Germany,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	comparison of mean CSF concentration of EFV from both doses after week 24.	measure the CSF exposure of EFV when dosed at 400mg and 600mg daily. Efavirenz plasma and CSF concentrations will be analysed and CSF:plasma ratios will be compared. Associations between plasma and CSF concentrations and relationship to study clinical parameters will be assessed.	24 weeks	Yes
Secondary	CSF EFV exposure and plasma exposure (CSF:plasma ratio) using statistical analysis	The relationship between CSF EFV exposure and plasma exposure (CSF:plasma ratio), both for protein bound and free plasma EFV exposure.	24 weeks	Yes
Secondary	The relationship between CSF EFV exposure and neuropsychiatric side effects using questionnaires and medical assessments		24 weeks	Yes
Secondary	The relationship between CSF EFV exposure and other study parameters such as race and sex.		24 weeks	Yes
Secondary	The number of subjects with EFV CSF exposure greater than the postulated CSF IC50 for wild type virus (0.51ng/mL)		24 weeks	Yes
Secondary	CSF HIV RNA measurement after 12 - 24 weeks of study therapy		24 weeks	Yes
Secondary	Relationship between plasma HIV RNA and CSF HIV RNA		24 weeks	Yes
Secondary	CSF biomarker analysis after 12 - 24 weeks of study therapy		24 weeks	Yes
Secondary	comparison between magnetic resonance (MR) spectroscopy findings and CSF HIV RNA and EFV concentration		24 weeks	Yes