A Dose Ranging Study Of GW640385 Boosted With Ritonavir (Rtv) In Comparison To A RTV-Boosted Protease Inhibitor (PI) In HIV-1 Infected PI-Experienced Adults

Study Overview
=================
Brief Summary
-----------------
This is a two phase study (randomised and non-randomised phase). The randomised phase will initially examine 4 blinded doses of GW640385 boosted with rtv (with continuation of current background therapy) in comparison to an ongoing, open-labeled rtv-boosted protease inhibitor (PI) regimen for 15 days. At the Day 15 visit, all subjects will optimize background therapy. Additionally, subjects receiving the lowest dose of GW640385 will be re-randomised to one of the higher doses and subjects in the control arm will receive a new rtv-boosted PI based on resistance testing at screening. Subjects will remain in the randomized phase on one of these 4 continuing treatment arms for at least 48 weeks. An interim analysis will occur during the randomised phase to select for a dose of GW640385 to evaluate further in Phase III studies. After dose selection subjects will move to the non-randomised phase of the study. In the non-randomised phase subjects who are receiving GW640385 will be assigned to final selected dose for assessment of long term safety, tolerability, pharmacokinetics, and antiviral activity.

Detailed Description
-----------------
A Phase IIB, Randomized, Multicenter, Parallel Group Study to Evaluate the Short-Term Safety, PK and Antiviral Activity of Four Dosing Regimens of GW640385/rtv Therapy Compared to Open-label Current Protease Inhibitor (PI) Therapy in HIV-1, PI-Experienced Adults for 2 wks with Long-Term Evaluation (>48 wks) of Safety, PK and Antiviral Activity of Selected GW640385/rtv Dosing Regimen(s) vs. a RTV-boosted, PI Containing Regimen

Official Title
-----------------
Phase IIB, Randomized, Multicenter, Parallel Group, Study to Evaluate the Safety, Pharmacokinetics and Antiviral Effect of Four Blinded Dosing Regimens of GW640385X/Ritonavir Compared to Open-label Current PI Therapy in HIV-1 Infected, Protease Inhibitor Experienced Adults for 2 Weeks With Long-term Assessment (>48 Weeks) of Safety, Pharmacokinetic and Antiviral Activity of Selected 385/RTV Dosing Regimen(s) vs. a Ritonavir-boosted, Protease Inhibitor Containing Regimen

Conditions
-----------------
Infection, Human Immunodeficiency Virus I, HIV-1 Infection

Intervention / Treatment
-----------------
* Drug: Physician determined comparator PI + ritonavir
* Drug: GW640385 + ritonavir


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: 18+ years of age (or =16 years of age for non-EU countries, according to local requirements). HIV-1 infected subjects. Females must be of either non-childbearing potential or have a negative pregnancy test at Screening and agree to use a protocol approved method of contraception. Plasma HIV-1 RNA (viral load) =1,000 copies/mL at Screening. Evidence of at least 2 multi-PI resistant mutations at Screening or within 3 months of Screening. Subjects must have been receiving the same anti-HIV medicines that they are on currently for at least 8 weeks prior to Screening; these anti-HIV medicines will include a single protease inhibitor (PI) in combination with a low dose of ritonavir (i.e., a ritonavir-boosted PI). However, the current PI cannot be tipranavir. Able to understand and follow protocol requirements, instructions and protocol-stated restrictions. Be willing and able to provide signed and dated written informed consent prior to study entry. Exclusion criteria: Subjects cannot change their anti-HIV medicines between Screening and Day 1 Visit. Subjects can not be receiving dual ritonavir-boosted PIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs) or Tipranavir at Screening. Active CDC Class C disease at screening. Pregnant or breastfeeding women. Protocol-specified laboratory abnormalities at Screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Physician determined comparator PI + ritonavir|nan|
|Drug: GW640385 + ritonavir|nan|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time averaged change in plasma HIV-1 RNA over 16 wks |  |  | 
| Proportion of subjects achieving the target pharmacokinetic (PK) GW640385 drug levels |  |  | 
| Change in laboratory parameters |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessments of HIV viral load changes |  |  | 
| GW640385 and RTV pharmacokinetic measurements |  |  | 
| The incidence of adverse events |  |  | 
| Changes in laboratory measurements |  |  | 
| ECG measurements |  |  | 
| HIV viral resistance assessment |  |  | 
| Immunologic measures |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
treatment-experienced, RTV, protease inhibitor, ritonavir, GW640385, HIV-1