The Intensive Pharmacokinetics Sub-study of Encore1 (ENCORE1-PK)

Study Overview
=================
Brief Summary
-----------------
Safety and efficacy are key issues in antiretroviral therapy (ART) selection. Efavirenz (EFV) is an important component of combination ART in treatment naive individuals. Like many drugs, there are inter-individual differences in the efficacy and tolerability of EFV. The Encore1 study provides an opportunity to examine the pharmacokinetics (PK)(processes by which a drug is absorbed, distributed, metabolized, and eliminated by the body) of EFV in blood samples collected over a 24-hour dosing interval in participants receiving either standard 600 mg or reduced 400 mg dose EFV once daily.

Detailed Description
-----------------
This sub-study will investigate the relationships between dosage, EFV plasma concentrations, toxicity and virological efficacy. EFV concentrations in dried blood spots and matched plasma and will be evaluated to determine the utility of dried blood spot measurements in measuring EFV plasma concentrations. Measurements dried blood spots could potentially be a cheap and easy alternative to measurements in plasma. Dried blood spots can be easily collected from venous blood or fingerprick, do not need plasma separation and potentially need less stringent storage conditions during shipment.

Official Title
-----------------
The Intensive Pharmacokinetics 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

Conditions
-----------------
HIV Infection

Intervention / Treatment
-----------------
* Drug: Efavirenz
* Drug: Efavirenz


Participation Criteria
=================
Eligibility Criteria
-----------------
All participants enrolled into the main Encore1 study at participating sub-study sites will be eligible to participate. Participants must meet the following additional inclusion criteria prior to intensive pharmacokinetic assessment. Inclusion Criteria: provide written sub-study consent at or before week 0 taken randomized study drugs for at least 4 weeks but less than 8 weeks taken EFV in the evening for at least 7 days taken all EFV doses over the 3 preceding days.

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reduced dose Efavirenz arm<br>Participants randomized in main study to receive EFV (400 mg once daily; 2 x 200 mg + 1 x placebo once daily) plus tenofovir/emtricitabine (300/200 mg) fixed-dose combination once daily | Drug: Efavirenz<br>* 400 mg once daily; given as 2 x 200 mg + 1 x placebo<br>|
| Active Comparator: Normal Efavirenz dose arm<br>Patients randomized in the main study to receive EFV (600 mg once daily; 3 x 200 mg once daily) plus tenofovir/emtricitabine (300/200 mg) fixed-dose combination once daily | Drug: Efavirenz<br>* 600 mg once daily; given as 3 x 200 mg once<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the pharmacokinetic parameters of EFV determined from blood collected over a 24-hour dosing interval in blinded samples from participants taking either 600 mg or 400 mg once daily in combination with Truvada. |  | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the safety and tolerability of EFV 400 mg versus 600 mg given once daily. |  | 48 weeks | 
| To investigate the correlation between EFV concentration measurements from dried blood spots and concentration measured in matched plasma samples. |  | 48 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV, efavirenz, pharmacokinetic