The Efavirenz (EFV) Central Nervous System Exposure Sub-study of Encore1 (ENCORE1-CNS)

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infection
• Intervention / Treatment: Drug: Efavirenz; Drug: Efavirenz

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10777
    • Medical Group Practice
• Thailand
  • Khon Kaen, Thailand, 40002
    • Khon Kaen University
  • Bangkok
    • Patumwan, Bangkok, Thailand, 10330
      • HIVNAT Research Collaboration
• United Kingdom
  • London
    • Clinical Trials Centre, Winston Churchil Wing, London, United Kingdom, W2 1NY
      • Imperial College, St. Mary's Hospital
    • HIV/GUM laboratory 5th floor St. Stephen Centre, London, United Kingdom, SW10 9NH
      • Chelsea and Westminster Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Reduced dose Efavirenz arm; Patient's on main study that was randomised to receive TDF (300mg qd)/FTC (200mg qd) + EFV (400mg qd; 2 x 200mg + 1 x 200mg placebo qd).	Drug: Efavirenz; 600mg qd; 3 x 200mg qd; Drug: Efavirenz; 400mg qd; 2 x 200mg
Active Comparator: Normal Efavirenz dose arm; Patient's on main study randomised to receive tenofovir (TDF) (300mg qd)/emtricitabine (FTC) (200mg qd) + EFV (600mg qd; 3 x 200mg qd)	Drug: Efavirenz; 600mg qd; 3 x 200mg qd; Drug: Efavirenz; 400mg qd; 2 x 200mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
The relationship between CSF EFV exposure and neuropsychiatric side effects using questionnaires and medical assessments		24 weeks
The relationship between CSF EFV exposure and other study parameters such as race and sex.		24 weeks
The number of subjects with EFV CSF exposure greater than the postulated CSF IC50 for wild type virus (0.51ng/mL)		24 weeks
CSF HIV RNA measurement after 12 - 24 weeks of study therapy		24 weeks
Relationship between plasma HIV RNA and CSF HIV RNA		24 weeks
CSF biomarker analysis after 12 - 24 weeks of study therapy		24 weeks
comparison between magnetic resonance (MR) spectroscopy findings and CSF HIV RNA and EFV concentration		24 weeks

Collaborators and Investigators

• Sponsor: Kirby Institute
• Collaborators: Imperial College London
• Investigators: Principal Investigator: Alan Winston, Dr., Imperial College London

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): February 1, 2013

Study Registration Dates

• First Submitted: January 5, 2011
• First Submitted That Met QC Criteria: October 12, 2011
• First Posted (Estimate): October 13, 2011

Study Record Updates

• Last Update Posted (Estimate): May 13, 2013
• Last Update Submitted That Met QC Criteria: May 10, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: HIV; Efavirenz; Lumbar puncture; Dose reduction; Central Nervous System (CNS)
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Efavirenz
• Other Study ID Numbers: NCHECR-ENCORE1-CNS