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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

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ClinicalTrials.gov Identifier: NCT00896051
Recruitment Status : Completed
First Posted : May 11, 2009
Results First Posted : September 30, 2013
Last Update Posted : September 30, 2013
Sponsor:
Information provided by (Responsible Party):
Janssen R&D Ireland

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
HIV Infections Acquired Immunodeficiency Syndrome 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 Phase 2

Detailed Description:
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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : August 2009
Actual Primary Completion Date : April 2012
Actual Study Completion Date : April 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
U.S. FDA Resources

Arms and Interventions
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Arm Intervention/treatment
Experimental: ATV/rtv 300/100 mg (Treatment A)
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
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.
Drug: Ritonavir (rtv) 100 mg
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.
Drug: Nucleo(side)/(tide) reverse transcriptase inhibitors (NRTIs)
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.
Drug: Etravirine (ETR) 200 mg
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.
Drug: Tenofovir disoproxil fumarate (TDF) 300 mg
Tenofovir disoproxil fumarate (TDF) 300 mg taken by mouth following a meal each morning on Substudy Days 1 to 7.
Experimental: ATV/rtv 400/100 mg (Treatment B)
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
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.
Drug: Ritonavir (rtv) 100 mg
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.
Drug: Nucleo(side)/(tide) reverse transcriptase inhibitors (NRTIs)
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.
Drug: Etravirine (ETR) 200 mg
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.
Drug: Tenofovir disoproxil fumarate (TDF) 300 mg
Tenofovir disoproxil fumarate (TDF) 300 mg taken by mouth following a meal each morning on Substudy Days 1 to 7.


Outcome Measures
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Primary Outcome Measures :
  1. Pharmacokinetic Results of Atazanavir (ATV): Treatment A: ATV/Low-Dose Ritonavir (Rtv) 300/100 mg (Results for C0h, Cmin, and Cmax) [ Time Frame: Day -1 (Pretreatment); Week 2 (Test) ]
    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).

  2. Pharmacokinetic Results of Atazanavir (ATV): Treatment A: ATV/Low-Dose Ritonavir (Rtv) 300/100 mg (Results for AUC24hr) [ Time Frame: Day -1 (Pretreatment); Week 2 (Test) ]
    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).

  3. Pharmacokinetic Results of Atazanavir (ATV): Treatment B: ATV/Low-Dose Ritonavir (Rtv) 400/100 mg (Results for C0h, Cmin, and Cmax) [ Time Frame: Day -1 (Reference); Week 2 (Test) ]
    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).

  4. Pharmacokinetic Results of Atazanavir (ATV): Treatment B: ATV/Low-Dose Ritonavir (Rtv) 400/100 mg (Results for AUC24hr) [ Time Frame: Day -1 (Reference); Week 2 (Test) ]
    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).

  5. Pharmacokinetic Results of Low-Dose Ritonavir (Rtv): Treatment A: Atazanavir (ATV)/Rtv 300/100 mg (Results for C0h, Cmin, and Cmax) [ Time Frame: Day -1 (Reference); Week 2 (Test) ]
    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).

  6. Pharmacokinetic Results of Low-Dose Ritonavir (Rtv): Treatment A: Atazanavir (ATV)/Rtv 300/100 mg (Results for AUC24hr) [ Time Frame: Day -1 (Reference); Week 2 (Test) ]
    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).

  7. Pharmacokinetic Results of Low-Dose Ritonavir (Rtv): Treatment B: Atazanavir (ATV)/Rtv 400/100 mg (Results for C0h, Cmin, and Cmax) [ Time Frame: Day -1 (Reference); Week 2 (Test) ]
    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).

  8. Pharmacokinetic Results of Low-Dose Ritonavir (Rtv): Treatment B: Atazanavir (ATV)/Rtv 400/100 mg (Results for AUC24hr) [ Time Frame: Day -1 (Reference); Week 2 (Test) ]
    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).

  9. Pharmacokinetic Results of Etravirine (ETR) (Results for C0h, Cmin, and Cmax) [ Time Frame: Week 2 ]
    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).

  10. Pharmacokinetic Results of Etravirine (ETR) (Results for AUC12hr) [ Time Frame: Week 2 ]
    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).

  11. Percentage of Participants With Undetectable Plasma Viral Load (VL) Values (<50 Copies/mL) at Week 48 [ Time Frame: 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).


Secondary Outcome Measures :
  1. Change From Prebaseline in CD4+ Cell Count Over Time [ Time Frame: Prebaseline, Baseline, Weeks 4, 12, 24, 48 ]
    The table below shows the mean change from prebaseline over time in CD4+ cell count using the Non-Completing = Failure (NC=F) imputation method.

  2. The Percentage of Participants With a Virologic Response Using the Non-Completing = Failure (NC=F) Imputation Method [ Time Frame: Baseline, Weeks 4, 12, 24, 48 ]
    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).

  3. The Percentage of Participants With a Virologic Response Using the Time to Loss of Virologic Response (TLOVR) Imputation Method [ Time Frame: Baseline, Weeks 4, 12, 24, 48 ]
    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.

  4. The Percentage of Participants With a Virologic Response (Plasma Viral Load < 50 Copies/mL) at Week 48 Using the Snapshot Analysis Method [ Time Frame: Week 48 ]
    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.

  5. Change From Pre-Baseline in Log10 Viral Load Over Time [ Time Frame: Pre-Baseline, Baseline, Weeks 4, 12, 24, 48 ]
    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.

  6. Time to Confirmed Virologic Response [ Time Frame: Prebaseline to Week 48 ]
    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.

  7. Time to Virologic Failure [ Time Frame: Prebaseline to Week 48 ]
    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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00896051


Locations
United States, Arkansas
Little Rock, Arkansas, United States
United States, California
Bakersfield, California, United States
Beverly Hills, California, United States
United States, Florida
Orlando, Florida, United States
Tampa, Florida, United States
Vero Beach, Florida, United States
West Palm Beach, Florida, United States
United States, Georgia
Macon, Georgia, United States
United States, Texas
Dallas, Texas, United States
Houston, Texas, United States
Argentina
Buenos Aires, Argentina
Cordoba, Argentina
France
Paris Cedex 10, France
Paris, France
Tourcoing, France
South Africa
Bloemfontein, South Africa
Cape Town, South Africa
George, South Africa
Thailand
Bangkok, Thailand
Sponsors and Collaborators
Janssen R&D Ireland
Investigators
Study Director: Janssen R&D Ireland Clinical Trial Janssen R&D Ireland
More Information
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Responsible Party: Janssen R&D Ireland
ClinicalTrials.gov Identifier: NCT00896051     History of Changes
Other Study ID Numbers: CR016045
TMC125-TiDP2-C238 ( Other Identifier: Janssen R&D Ireland )
First Posted: May 11, 2009    Key Record Dates
Results First Posted: September 30, 2013
Last Update Posted: September 30, 2013
Last Verified: September 2013

Keywords provided by Janssen R&D Ireland:
HIV Infections
Acquired Immunodeficiency Syndrome
TMC125-TiDP2-C238
TMC125-C238
Etravirine
 Intelence
HIV
HIV-1
Pharmacokinetics

Additional relevant MeSH terms:
HIV Infections
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immune System Diseases
Slow Virus Diseases
Ritonavir
Atazanavir Sulfate
Tenofovir
 Etravirine
Reverse Transcriptase Inhibitors
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Nucleic Acid Synthesis Inhibitors