A Phase 2B Multicenter, Randomized, Comparative Trial Of UK-453,061 Versus Etravirine In Combination With Darunavir/Ritonavir And A Nucleos(t)Ide Reverse Transcriptase Inhibitor For The Treatment Of Antiretroviral Experienced HIV-1 Infected Subjects With Evidence Of NNRTI Resistant HIV-1

Study Overview
=================
Brief Summary
-----------------
This is a 96 week study to determine if UK- 453,061 in combination with Darunavir /ritonavir and a Nucleos(t)ide Reverse Transcriptase inhibitor is as efficacious, safe and tolerable as etravirine in combination with Darunavir /ritonavir and a Nucleos(t)ide Reverse Transcriptase inhibitor in HIV-1 infected patients who have been previously treated with antiretroviral drugs and have NNRTI resistance mutations.

Detailed Description
-----------------
The trial was terminated on 12 April, 2012 due to lack of efficacy at the Week 24 analysis. The decision to terminate the trial was not based on any safety concerns.

Official Title
-----------------
A Phase 2b Multicenter, Randomized, Comparative Trial Of Uk-453,061 Versus Etravirine In Combination With Darunavir/Ritonavir And A Nucleotide/Nucleoside Reverse Transcriptase Inhibitor For The Treatment Of Antiretroviral Experienced Hiv-1 Infected Subjects With Evidence Of Nnrti Resistant Hiv-1

Conditions
-----------------
HIV-1

Intervention / Treatment
-----------------
* Drug: UK-453,061 Dose 1
* Drug: UK-453,061 Dose 2
* Drug: Etravirine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female at least 18 years of age available for a follow-up period of at least 96 weeks. HIV 1 RNA viral load of greater then 500 copies/mL. Negative urine pregnancy test. Exclusion Criteria: Suspected or documented active, untreated HIV-1 related opportunistic infection or other condition requiring acute therapy at the time of randomization. Subjects with acute Hepatitis B and/or C within 30 days of randomization. Previous use of Darunavir or etravirine

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UK- 453,061 Dose One<br> | Drug: UK-453,061 Dose 1<br>* UK 453,061 750 mg QD + one optimized NRTI + darunavir/ritonavir.<br>|
| Experimental: UK- 453,061 Dose Two<br> | Drug: UK-453,061 Dose 2<br>* UK 453,061 1000 mg QD + one optimized NRTI + darunavir/ritonavir.<br>|
| Active Comparator: Comparator<br> | Drug: Etravirine<br>* Etravirine 200 mg BID + one optimized NRTI + darunavir/ritonavir.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Human Immunodeficiency Virus Type 1 Ribonucleic Acid (HIV-1 RNA) Levels Less Than (<) 50 Copies/Milliliter (mL) at Week 24 | Plasma HIV-1 RNA level was determined by the Roche Amplicor HIV-1 Monitor standard assay (version 1.5). | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HIV-1 RNA Levels <50 Copies/mL at Week 48 and 96 | Plasma HIV-1 RNA level was determined by the Roche Amplicor HIV-1 Monitor standard assay (version 1.5). | Weeks 48, 96 | 
| Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL at Week 24, 48 and 96 | Plasma HIV-1 RNA level was determined by the Roche Amplicor HIV-1 Monitor standard assay (version 1.5). | Week 24, 48, 96 | 
| Change From Baseline in log10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | Plasma HIV-1 RNA level was determined by the Roche Amplicor HIV-1 Monitor standard assay (version 1.5). For the log10 scale, all the HIV-1 RNA levels were log10 transformed prior to the average calculations. Baseline value calculated as average of measurements collected prior to and including Day 1 pre-dose. | Baseline, Week 24, 48, 96 | 
| Time-Averaged Difference (TAD) in log10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | TAD was calculated as (area under the curve of HIV-1 RNA levels [log10 copies/mL] from baseline to the time point of interest divided by time period in weeks) minus baseline HIV-1 RNA level (log10 copies/mL). Baseline value calculated as average of measurements collected at prior to and including Day 1 pre-dose. Due to early termination of the study decision was made not to derive TAD results for Week 96. | Week 24, 48, 96 | 
| Percentage of Participants With Response as Determined by the Time to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96 | TLOVR50 response (50 denotes lower limit of quantification [LLOQ] of assay=50 copies/mL): compliment to TLOVR50 failure. TLOVR50 failure based on observed HIV-1 RNA levels and failure events (death; permanent discontinuation of drug; lost to follow-up; new ARV drug; met treatment failure [TF] criteria). TF: an increase of at least (>=)3 times the baseline plasma HIV-1 RNA level at Week 2 or thereafter; failure to achieve HIV-1 RNA level <50 copies/mL at Week 24; starting at Week 2, an increase in HIV-1 RNA level to detectable levels (>50 copies/mL); HIV-1 RNA <1 log10 decrease from baseline at Week 4 or thereafter. TF were confirmed by second measurement >=14 days after first. Baseline value was calculated as the average of the measurements collected prior to and including Day 1 pre-dose. | Week 24, 48, 96 | 
| Change From Baseline in Cluster of Differentiation 4 (CD4+) Absolute Lymphocyte Counts at Week 24, 48 and 96 | Blood samples for immunological status assessed by CD4+ lymphocyte count. Baseline value was calculated as the average of the measurements collected prior to and including Day 1 pre-dose. | Baseline, Week 24, 48, 96 | 
| Change From Baseline in Cluster of Differentiation 4 (CD4+) Percentage Lymphocyte Counts at Week 24, 48, 96 | Blood samples for immunological status assessed by CD4+ lymphocyte count. Baseline value was calculated as the average of the measurements collected prior to and including Day 1 pre-dose. | Baseline, Week 24, 48, 96 | 
| Number of Participants With Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) Resistance-Associated Mutations (RAMs) and/or Phenotypic Susceptibility at Time of Treatment Failure Through Week 48 | Genotypic and phenotypic resistance to NNRTIs based on International Acquired Immunodeficiency Syndrome (AIDS) Society, United States of America (IAS-USA) RAM guidelines were evaluated using Monogram Biosciences PhenoSenseGT Assay at Baseline. This was then repeated for all participants with HIV-1 viral load >500 copies/mL at treatment failure, up to Week 48. | Baseline through Week 48 | 
| Number of Participants With Laboratory Test Abnormalities | Laboratory analysis included blood chemistry, hematology and urinalysis. | Baseline up to Week 48 or early termination | 
| Population Pharmacokinetics (PK) of Lersivirine | Data for this Outcome Measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules. | Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48 | 
| Lersivirine Success Percentage With Reference to Median Minimum Observed Plasma Concentration (Cmin) | Simple quartile exposure analysis of success rate (viral load <50 copies/mL) versus median Cmin assesses the exposure response relationship. Percentage of participants with HIV-1 RNA level <50 copies/mL at median Cmin quartile were planned to be reported. | Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV-1 NNRTI Treatment Experienced, may have Protease inhibitor experience