A Study Of Different Doses Of UK-453, 061 Plus Truvada Compared To Efavirenz Plus Truvada In Patients Who Have Not Been Previously Treated For HIV-1

Study Overview
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Brief Summary
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This is a 96 week study to determine if UK- 453,061 in combination with Truvada is as efficacious, safe and tolerable as efavirenz in combination with Truvada in HIV-1 infected patients who have not been previously treated with antiretroviral drugs.

Official Title
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A Phase 2B Multicenter, Randomized, Double-Blind, Comparative Trial Of UK-453,061, In Combination With Tenofovir Df And Emtricitabine Versus Efavirenz In Combination With Tenofovir DF And Emtricitabine For The Treatment Of Antiretroviral-Naive HIV-1 Infected Subjects

Conditions
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HIV-1

Intervention / Treatment
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* Drug: UK-453, 061
* Drug: UK-453, 061
* Drug: EFV +TVA


Participation Criteria
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Eligibility Criteria
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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 1,000 copies/mL Negative urine pregnancy test. Exclusion Criteria: Suspected or documented active, untreated HIV-1 related opportunist 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. Absolute CD4 count <200 cells/mm3.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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>UK 453,061 Dose One plus Truvada | Drug: UK-453, 061<br>* UK-453,061 500 mg tablets PO QD + Tenofovir DF 300 mg/Emtricitabine 200 mg tablets PO QD.<br>|
| Experimental: UK-453,061 Dose Two<br>UK 453,061 Dose Two plus Truvada | Drug: UK-453, 061<br>* UK-453,061 750 mg tablets PO QD + Tenofovir DF 300 mg/Emtricitabine 200 mg tablets PO QD.<br>|
| Active Comparator: Efavirenz + Truvada<br>Efavirenz + Truvada | Drug: EFV +TVA<br>* Efavirenz 600 mg tablets PO QD + Tenofovir DF 300 mg/Emtricitabine 200 tablets mg PO QD.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Less Than 50 Copies Per Milliliter (Copies/mL) of Human Immunodeficiency Virus Type 1 Ribonucleic Acid (HIV-1 RNA) at Week 48 | Plasma HIV-1 RNA level was determined by validated Roche Amplicor HIV-1 Monitor standard assay. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Less Than 50 Copies/mL of HIV-1 RNA at Week 24 and 96 | Plasma HIV-1 RNA level was determined by validated Roche Amplicor HIV-1 Monitor standard assay. | Week 24, 96 | 
| Percentage of Participants With Less Than 400 Copies/mL of HIV-1 RNA at Week 24, 48 and 96 | Plasma HIV-1 RNA level was determined by validated Roche Amplicor HIV-1 Monitor standard assay. | Week 24, 48, 96 | 
| Change From Baseline in Log 10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96 | For the log 10 scale, all the HIV-1 RNA levels were log 10 transformed prior to the average calculations. Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose. | Baseline, Week 24, 48, 96 | 
| Time-Averaged Difference (TAD) in Log 10 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 was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose. | Baseline up to Week 24, 48, 96 | 
| Percentage of Participants With Response as Determined Using the Time-to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96 | TLOVR50 response is 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; met treatment failure [TF] criteria). TF: an increase to at least 3 times 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). TF criteria's defined above were confirmed by second measurement at least 14 days after first. In 'TLOVR50', '50' denotes the lower limit of quantification (LLOQ) of assay (which is 50 copies/mL). Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose. | Week 24, 48, 96 | 
| Change From Baseline in Cluster of Differentiation (CD4+) Absolute Cell Count at Week 24, 48 and 96 | Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose. | Baseline, Week 24, 48, 96 | 
| Change From Baseline in Cluster of Differentiation (CD4+) Percentage Cell Count at Week 24, 48 and 96 | Baseline value was calculated as the average of all the measurements collected prior to and including Day 1 pre-dose. | Baseline, Week 24, 48, 96 | 
| Number of Participants With NRTI and NNRTI Resistance-Associated Mutations (RAMs) at Time of Treatment Failure Through Week 24, 48 and 96 | Phenotypic resistance and genotypic resistance was assessed for all participants at Day 1 predose, and was evaluated for nucleotide reverse transcriptase inhibitors (NRTIs), and non-NRTIs (NNRTIs) resistance-associated mutations at time of treatment failure using Monogram GenoSeq and/or PhenoSenseGT assays. This was then repeated for all participants with HIV-1 viral load more than 500 copies/mL at treatment failure, up to Week 96. | Day 1 (pre-dose) through Week 24, 48, 96 | 
| Number of Participants With Laboratory Test Abnormalities | Laboratory analysis included hematology, blood chemistry, serum and urine pregnancy test, hepatitis testing and urinalysis. Laboratory values that met the criteria of the Division of Acquired Immuno Deficiency Syndrome (DAIDS) grade 1 (mild, symptoms causing no or minimal interference with usual social and functional activities) or greater were considered as abnormal. | Baseline up to Week 96 or early termination | 
| Population Pharmacokinetic (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. | Week 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. | Week 2, 4, 8, 12, 16, 24, 32, 40, 48 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) of Lersivirine | AUC (0-24)= Area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0-24). Only participants from Lersivirine treatment arms were planned to be analyzed for Pharmacokinetic (PK) sub-study. | 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 24 hours (hrs) post-dose on Week 4 | 
| Maximum Observed Plasma Concentration (Cmax) of Lersivirine |  | 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 24 hrs post-dose on Week 4 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Lersivirine |  | 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 24 hrs post-dose on Week 4 | 
| Plasma Concentration of Lersivirine at 24 Hour | The observed plasma concentration at 24 hours post-dose (C 24h). | 24 hrs post-dose on Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1. Treatment Naive, HIV Infections, treatment naive