TMC125-TiDP2-C238: An Exploratory Pharmacokinetics, Safety and Anti-HIV Activity Study of Etravirine (ETR) When Given With Boosted Atazanavir (ATV/Rtv) at Two Different Doses and 1 Nucleoside Reverse Transcriptase Inhibitor (NRTI) in Treatment Experienced HIV Patients

Study Overview
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Brief Summary
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The purpose of this study is to determine the pharmacokinetics (how the body absorbs, distributes, metabolizes and eliminates a drug) (PK) of ETR when given with ATV/rtv and 1 NRTI in treatment experienced HIV-1 infected patients. In addition, safety, tolerability and anti-HIV effect of this regimen will also be studied. A total of 46 patients will be enrolled.

Detailed Description
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This is a randomized (study drug assigned by chance), exploratory, open-label (all involved people know the identity of the intervention) trial to evaluate the pharmacokinetics (PK), safety, tolerability and anti-HIV (anti Human Immunodeficiency Virus) activity of etravirine (ETR ) when given with atazanavir/ritonavir (ATV/rtv) and 1 nucleoside reverse transcriptase inhibitor (NRTI) in 46 treatment experienced HIV-1 infected patients. The trial will consist of : 4 weeks of Screening Period, 2 weeks Pre-Treatment Phase, 48-week Treatment Period, and a Final Visit followed by a 4-week Follow-up Period (only for patients not continuing treatment with ETR in another trial or program). Safety evaluations (AE reporting, labs, vital signs, etc.) will be monitored at each study visit. A PK substudy (included in the protocol, with optional participation) with tenofovir (TDF) added to the antiretroviral regimen for 7 days will be conducted in patients with > 24 weeks of treatment with suppressed HIV-1 viral load. In Pre-Treatment Phase, all patients will receive ATV/rtv 300/100 mg once daily to be taken following a meal each morning + 2 NRTIs (dose as specified in the labels) for 14 days. In Treatment Phase, patients will receive ETR 200 mg twice daily in addition to ATV/rtv (300/100 mg or 400/100 mg) once daily with meals + 1 investigator-selected NRTI for 48 weeks. In substudy TDF 300 mg once daily will be added to the treatment regimen x 7 days.

Official Title
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TMC125-TiDP2-C238: A Randomized, Exploratory, Open-label 48-week Trial to Investigate the Pharmacokinetics, Safety, Tolerability and Antiviral Activity of Etravirine (ETR) in Combination With Ritonavir-boosted Atazanavir (ATV/Rtv) and 1 NRTI in Treatment-experienced HIV-1 Infected Subjects

Conditions
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HIV Infections, Acquired Immunodeficiency Syndrome

Intervention / Treatment
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* Drug: Atazanavir (ATV) 300 mg
* Drug: Atazanavir (ATV) 400 mg
* Drug: Ritonavir (rtv) 100 mg
* Drug: Nucleo(side)/(tide) reverse transcriptase inhibitors (NRTIs)
* Drug: Etravirine (ETR) 200 mg
* Drug: Tenofovir disoproxil fumarate (TDF) 300 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Documented HIV-1 infection Failing on a stable ART (anti retroviral therapy) with HIV-1 plasma viral load above 500 HIV-1 RNA copies/ml Presence of at least 1 documented NNRTI mutation Demonstrated sensitivity to ATV, ETR and at least one of the selected NRTIs based on the resistance test at screening General medical condition, in the investigator's opinion, does not interfere with the assessments and completion of the trial Substudy: patients who have been treated in C238 for more than 24 weeks and are currently suppressed (defined as patients with at least 2 most recent and consecutive viral loads less than 50 cp/mL) will be considered eligible for the substudy Exclusion Criteria: Primary HIV-1 infection Previously documented HIV-2 infection Previously failed 2 or more HIV PI-containing regimens Previous diagnosis of hereditary hyperbilirubinemia (eg. Gilbert's syndrome, Crigler-Najjar syndrome). Grade 3 or 4 toxicities (according to DAIDS grading) Acute and chronic viral hepatitis Receipt of an investigational drug or investigational vaccine within 30 days prior to the trial drug administration Pregnant or breastfeeding female

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATV/rtv 300/100 mg (Treatment A)<br>Treatment-experienced human immunodeficiency virus - type 1 (HIV-1) infected participants will take by mouth atazanavir (ATV)/low-dose ritonavir (rtv) 300/100 mg once daily + 2 nucleoside reverse transcriptase inhibitors (NRTIs) for 2 weeks pre-treatment followed by ATV/rtv 300/100 mg once daily + etravirine (ETR) 200 mg twice daily + 1 NRTI for 48 weeks. If particpating in an optional substudy to assess the effect of adding tenofovir disoproxil fumarate (TDF) for 7 days on ATV and ETR pharmacokinetics, participants will receive TDF 300 mg once daily for 7 days in addition to their antiretroviral regimen (ETR+ATV/rtv+NRTI). | Drug: Atazanavir (ATV) 300 mg<br>* Atazanavir (ATV) 300 mg taken by mouth following a meal each morning for 2 weeks during the Pre-Treatment Period and for 48 weeks during the Treatment Period. If participating in the optional substudy, participants will take ATV 300 mg by mouth following a meal each morning on Substudy Days -1 to 7.<br>Drug: Ritonavir (rtv) 100 mg<br>* Ritonavir (rtv) 100 mg taken by mouth following a meal each morning for 2 weeks during the Pre-Treatment Period and for 48 weeks during the Treatment Period. If participating in the optional substudy, participants will take rtv 100 mg by mouth following a meal each morning on Substudy Days -1 to 7.<br>Drug: Nucleo(side)/(tide) reverse transcriptase inhibitors (NRTIs)<br>* 2 investigator-selected NRTIs taken as specified in the individual product labels for 2 weeks during the Pre-Treatment Period followed by 1 investigator-selected NRTI (of the 2 NRTIs in the Pre-Treatment Phase) taken as specified in the individual product label for 48 weeks during the Treatment Period. If participating in the optional substudy, participants will take 1 investigator-selected NRTI (of the 2 NRTIs in the Pre-Treatment Phase) mg taken as specified in the individual product label during the Substudy.<br>Drug: Etravirine (ETR) 200 mg<br>* Etravirine (ETR) 200 mg taken twice daily as two 100-mg tablets following a meal (morning and evening) for at least the first two weeks of the 48-week Treatment Period. If participating in the optional substudy, participants will take ETR 200 mg twice daily as two 100-mg tablets following a meal each morning and evening on Substudy Days -1 to 7.<br>Drug: Tenofovir disoproxil fumarate (TDF) 300 mg<br>* Tenofovir disoproxil fumarate (TDF) 300 mg taken by mouth following a meal each morning on Substudy Days 1 to 7.<br>|
| Experimental: ATV/rtv 400/100 mg (Treatment B)<br>Treatment-experienced human immunodeficiency virus - type 1 (HIV-1) infected participants will take by mouth atazanavir (ATV)/low-dose ritonavir (rtv) 300/100 mg once daily + 2 nucleoside reverse transcriptase inhibitors (NRTIs) for 2 weeks pretreatment followed by ATV/rtv 400/100 mg once daily + etravirine (ETR) 200 mg twice daily + 1 NRTI for 48 weeks. If particpating in an optional substudy to assess the effect of adding tenofovir disoproxil fumarate (TDF) for 7 days on ATV and ETR pharmacokinetics, participants will take TDF 300 mg once daily for 7 days in addition to their antiretroviral regimen (ETR+ATV/rtv+NRTI). | Drug: Atazanavir (ATV) 400 mg<br>* Atazanavir (ATV) 400 mg taken by mouth following a meal each morning for 2 weeks during the Pre-Treatment Period and for 48 weeks during the Treatment Period. If participating in the optional substudy, participants will take ATV 400 mg by mouth following a meal each morning on Substudy Days -1 to 7.<br>Drug: Ritonavir (rtv) 100 mg<br>* Ritonavir (rtv) 100 mg taken by mouth following a meal each morning for 2 weeks during the Pre-Treatment Period and for 48 weeks during the Treatment Period. If participating in the optional substudy, participants will take rtv 100 mg by mouth following a meal each morning on Substudy Days -1 to 7.<br>Drug: Nucleo(side)/(tide) reverse transcriptase inhibitors (NRTIs)<br>* 2 investigator-selected NRTIs taken as specified in the individual product labels for 2 weeks during the Pre-Treatment Period followed by 1 investigator-selected NRTI (of the 2 NRTIs in the Pre-Treatment Phase) taken as specified in the individual product label for 48 weeks during the Treatment Period. If participating in the optional substudy, participants will take 1 investigator-selected NRTI (of the 2 NRTIs in the Pre-Treatment Phase) mg taken as specified in the individual product label during the Substudy.<br>Drug: Etravirine (ETR) 200 mg<br>* Etravirine (ETR) 200 mg taken twice daily as two 100-mg tablets following a meal (morning and evening) for at least the first two weeks of the 48-week Treatment Period. If participating in the optional substudy, participants will take ETR 200 mg twice daily as two 100-mg tablets following a meal each morning and evening on Substudy Days -1 to 7.<br>Drug: Tenofovir disoproxil fumarate (TDF) 300 mg<br>* Tenofovir disoproxil fumarate (TDF) 300 mg taken by mouth following a meal each morning on Substudy Days 1 to 7.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Results of Atazanavir (ATV): Treatment A: ATV/Low-Dose Ritonavir (Rtv) 300/100 mg (Results for C0h, Cmin, and Cmax) | The table below shows pharmacokinetic (PK) results of atazanavir (ATZ) when administered as ATV/rtv 300/100 mg pretreatment (Reference) and at Week 2 after treatment (Test). Results are expressed as the predose plasma concentration (C0h), minimum plasma concentration (Cmin), and maximum plasma concentration (Cmax). | Day -1 (Pretreatment); Week 2 (Test) | 
| Pharmacokinetic Results of Atazanavir (ATV): Treatment A: ATV/Low-Dose Ritonavir (Rtv) 300/100 mg (Results for AUC24hr) | The table below shows pharmacokinetic (PK) results of atazanavir (ATZ) when administered as ATV/rtv 300/100 mg pretreatment (Reference) and at Week 2 after treatment (Test). Results are expressed as the area under the plasma concentration-time curve from time of intake to 24 hours after dosing (AUC24hr). | Day -1 (Pretreatment); Week 2 (Test) | 
| Pharmacokinetic Results of Atazanavir (ATV): Treatment B: ATV/Low-Dose Ritonavir (Rtv) 400/100 mg (Results for C0h, Cmin, and Cmax) | The table below shows pharmacokinetic (PK) results of atazanavir (ATV) when administered as ATV/ritonavir (rtv) 300/100 mg pretreatment (Reference) and when administered as ATV/rtv 400/100 mg at Week 2 after treatment (Test). Results are expressed as the predose plasma concentration (C0h), minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), and area under the plasma concentration-time curve from time of intake to 24 hours after dosing (AUC24hr). | Day -1 (Reference); Week 2 (Test) | 
| Pharmacokinetic Results of Atazanavir (ATV): Treatment B: ATV/Low-Dose Ritonavir (Rtv) 400/100 mg (Results for AUC24hr) | The table below shows pharmacokinetic (PK) results of atazanavir (ATV) when administered as ATV/ritonavir (rtv) 300/100 mg pretreatment (Reference) and when administered as ATV/rtv 400/100 mg at Week 2 after treatment (Test). Results are expressed as the area under the plasma concentration-time curve from time of intake to 24 hours after dosing (AUC24hr). | Day -1 (Reference); Week 2 (Test) | 
| Pharmacokinetic Results of Low-Dose Ritonavir (Rtv): Treatment A: Atazanavir (ATV)/Rtv 300/100 mg (Results for C0h, Cmin, and Cmax) | The table below shows the pharmacokinetic (PK) results of low-dose ritonavir (rtv) when administered as atazanavir (ATV)/rtv 300/100 mg pretreatment (Reference) and at Week 2 after treatment (Test). Results are expressed as the predose plasma concentration (C0h), minimum plasma concentration (Cmin), and maximum plasma concentration (Cmax). | Day -1 (Reference); Week 2 (Test) | 
| Pharmacokinetic Results of Low-Dose Ritonavir (Rtv): Treatment A: Atazanavir (ATV)/Rtv 300/100 mg (Results for AUC24hr) | The table below shows the pharmacokinetic (PK) results of low-dose ritonavir (rtv) when administered as atazanavir (ATV)/rtv 300/100 mg pretreatment (Reference) and at Week 2 after treatment (Test). Results are expressed as the area under the plasma concentration-time curve from time of intake to 24 hours after dosing (AUC24hr). | Day -1 (Reference); Week 2 (Test) | 
| Pharmacokinetic Results of Low-Dose Ritonavir (Rtv): Treatment B: Atazanavir (ATV)/Rtv 400/100 mg (Results for C0h, Cmin, and Cmax) | The table below shows pharmacokinetic (PK) results of low-dose ritonavir (rtv) when administered as atazanavir (ATV)/ritonavir (rtv) 300/100 mg pretreatment (Reference) and when administered as ATV/rtv 400/100 mg at Week 2 after treatment (Test). Results are expressed as the predose plasma concentration (C0h), minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), and area under the plasma concentration-time curve from time of intake to 24 hours after dosing (AUC24hr). | Day -1 (Reference); Week 2 (Test) | 
| Pharmacokinetic Results of Low-Dose Ritonavir (Rtv): Treatment B: Atazanavir (ATV)/Rtv 400/100 mg (Results for AUC24hr) | The table below shows pharmacokinetic (PK) results of low-dose ritonavir (rtv) when administered as atazanavir (ATV)/ritonavir (rtv) 300/100 mg pretreatment (Reference) and when administered as ATV/rtv 400/100 mg at Week 2 after treatment (Test). Results are expressed as the area under the plasma concentration-time curve from time of intake to 24 hours after dosing (AUC24hr). | Day -1 (Reference); Week 2 (Test) | 
| Pharmacokinetic Results of Etravirine (ETR) (Results for C0h, Cmin, and Cmax) | The table below shows pharmacokinetic (PK) results of ETR in the current study expressed as the predose plasma concentration (C0h), minimum plasma concentration (Cmin) and maximum plasma concentration (Cmax). | Week 2 | 
| Pharmacokinetic Results of Etravirine (ETR) (Results for AUC12hr) | The table below shows pharmacokinetic (PK) results of ETR in the current study expressed as the area under the plasma concentration-time curve from time of intake to 12 hours after dosing (AUC12hr). | Week 2 | 
| Percentage of Participants With Undetectable Plasma Viral Load (VL) Values (<50 Copies/mL) at Week 48 | The table below shows the percentage of participants wih undetectable plasma viral load (VL) values (<50 copies/mL) at Week 48 using the Non-Completing = Failure (NC=F) imputation method (ie, participants who discontinued early were counted as nonresponders by having their VL values after discontinuation imputed with their baseline value, thus resulting in a 0 change). | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Prebaseline in CD4+ Cell Count Over Time | The table below shows the mean change from prebaseline over time in CD4+ cell count using the Non-Completing = Failure (NC=F) imputation method. | Prebaseline, Baseline, Weeks 4, 12, 24, 48 | 
| The Percentage of Participants With a Virologic Response Using the Non-Completing = Failure (NC=F) Imputation Method | The table below shows the percentage of participants per time point with a virologic response defined as having a plasma viral load (VL) <50 copies/mL, and with plasma VL <400 copies/mL using the Non-Completing = Failure (NC=F) imputation method (ie, participants who discontinued early were counted as nonresponders by having their VL values after discontinuation imputed with their Baseline value, thus resulting in a 0 change). | Baseline, Weeks 4, 12, 24, 48 | 
| The Percentage of Participants With a Virologic Response Using the Time to Loss of Virologic Response (TLOVR) Imputation Method | The table below shows the percentage of participants with a virologic response defined as a viral load <50 Copies/mL and <400 Copies/mL per time point calculated using the time to loss of virologic response (TLOVR) imputation method. | Baseline, Weeks 4, 12, 24, 48 | 
| The Percentage of Participants With a Virologic Response (Plasma Viral Load < 50 Copies/mL) at Week 48 Using the Snapshot Analysis Method | The table below provides the results from the snapshot analysis method that includes the percentage of participants with virologic response (<50 copies/mL), the percentage of participants who were virologic failures (VF) (>50 copies/mL, discontinued prior to time X for reasons of VF or for other reasons, except for VF or adverse event, with a last viral load >50 copies/mL), and the percentage of participants with no viral load (VL) data available at Week 48. | Week 48 | 
| Change From Pre-Baseline in Log10 Viral Load Over Time | The table below shows the mean change from prebaseline over time in log10 (Copies/mL) plasma viral load using the Non-Completing = Failure (NC=F) imputation method. | Pre-Baseline, Baseline, Weeks 4, 12, 24, 48 | 
| Time to Confirmed Virologic Response | The table below provides the time in days it took participants to reach a confirmed virologic response defined as a plasma viral load (VL) <50 copies/mL, and plasma VL <400 copies/mL analyzed according to the Time to Loss of Virologic Response (TLOVR) imputation method. | Prebaseline to Week 48 | 
| Time to Virologic Failure | The table below shows the number of days to virologic failure defined as a plasma viral load (VL) > 50 copies/mL for participants who had been virologic responders (ie, having a plasma VL <50, and <400 copies/mL according to the time to loss of virologic response [TLOVR] imputation method). Time to virologic failure was the time to subsequent loss of virologic response, and the time was calculated from Prebaseline (Week -2). Participants who never achieved a virologic response were defined as nonresponders and counted as virologic failures on Day 1. | Prebaseline to Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV Infections, Acquired Immunodeficiency Syndrome, TMC125-TiDP2-C238, TMC125-C238, Etravirine, Intelence, HIV, HIV-1, Pharmacokinetics