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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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Janssen R&D Ireland
ClinicalTrials.gov Identifier:
NCT00896051
First received: May 7, 2009
Last updated: September 27, 2013
Last verified: September 2013
Results First Received: April 10, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Pharmacokinetics/Dynamics Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Conditions: HIV Infections
Acquired Immunodeficiency Syndrome
Interventions: 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

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Etravirine coadministered with 2 doses of atazanavir/low-dose ritonavir each combined with 1 nucleoside reverse transcriptase inhibitor was evaluated in human immunodeficiency virus – type 1 infected participants. The study was conducted between 25 June 2009 and 10 April 2012 and participants were recruited by 17 investigators in 4 countries.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Fifty (50) participants were enrolled in the study and received treatment with study drug during a 2-week Pre-treatment Period (Week -2 to Day -1) and a 48-week Treatment Period (Day 1 to Week 48). Efficacy data are reported for the 48-week Treatment Period.

Reporting Groups
  Description
ATV/Rtv 300/100 mg (Treatment A) Treatment-experienced human immunodeficiency virus – type 1 (HIV-1) infected participants took by mouth atazanavir (ATV)/low-dose ritonavir (rtv) 300/100 mg once daily + 2 nucleoside reverse transcriptase inhibitors (NRTIs) for pre-treatment for 2 weeks followed by ATV/rtv 300/100 mg once daily + etravirine (ETR) 200 mg twice daily + 1 NRTI for 48 weeks.
ATV/Rtv 400/100 mg (Treatment B) Treatment-experienced human immunodeficiency virus – type 1 (HIV-1) infected participants took by mouth atazanavir (ATV)/low-dose ritonavir (rtv) 300/100 mg once daily + 2 nucleoside reverse transcriptase inhibitors (NRTIs) pretreatment for 2 weeks followed by ATV/rtv 400/100 mg once daily + etravirine (ETR) 200 mg twice daily + 1 NRTI for 48 weeks.

Participant Flow:   Overall Study
    ATV/Rtv 300/100 mg (Treatment A)     ATV/Rtv 400/100 mg (Treatment B)  
STARTED     25     25  
COMPLETED     15     16  
NOT COMPLETED     10     9  
Adverse Event                 2                 1  
Lost to Follow-up                 3                 2  
Withdrawal by Subject                 3                 2  
Subject noncompliant                 1                 3  
Not specified                 1                 1  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
ATV/Rtv 300/100 mg (Treatment A) Treatment-experienced human immunodeficiency virus – type 1 (HIV-1) infected participants took by mouth atazanavir (ATV)/low-dose ritonavir (rtv) 300/100 mg once daily + 2 nucleoside reverse transcriptase inhibitors (NRTIs) for pre-treatment for 2 weeks followed by ATV/rtv 300/100 mg once daily + etravirine (ETR) 200 mg twice daily + 1 NRTI for 48 weeks.
ATV/Rtv 400/100 mg (Treatment B) Treatment-experienced human immunodeficiency virus – type 1 (HIV-1) infected participants took by mouth atazanavir (ATV)/low-dose ritonavir (rtv) 300/100 mg once daily + 2 nucleoside reverse transcriptase inhibitors (NRTIs) pretreatment for 2 weeks followed by ATV/rtv 400/100 mg once daily + etravirine (ETR) 200 mg twice daily + 1 NRTI for 48 weeks.
Total Total of all reporting groups

Baseline Measures
    ATV/Rtv 300/100 mg (Treatment A)     ATV/Rtv 400/100 mg (Treatment B)     Total  
Number of Participants  
[units: participants]
  25     25     50  
Age  
[units: participants]
     
<=18 years     0     1     1  
Between 18 and 65 years     25     24     49  
>=65 years     0     0     0  
Age  
[units: years]
Mean ± Standard Deviation
  41.2  ± 10.44     39.8  ± 9.37     40.5  ± 9.85  
Gender  
[units: participants]
     
Female     12     13     25  
Male     13     12     25  



  Outcome Measures
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1.  Primary:   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) ]

2.  Primary:   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) ]

3.  Primary:   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) ]

4.  Primary:   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) ]

5.  Primary:   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) ]

6.  Primary:   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) ]

7.  Primary:   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) ]

8.  Primary:   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) ]

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

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

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

12.  Secondary:   Change From Prebaseline in CD4+ Cell Count Over Time   [ Time Frame: Prebaseline, Baseline, Weeks 4, 12, 24, 48 ]
  Hide Outcome Measure 12

Measure Type Secondary
Measure Title Change From Prebaseline in CD4+ Cell Count Over Time
Measure Description The table below shows the mean change from prebaseline over time in CD4+ cell count using the Non-Completing = Failure (NC=F) imputation method.
Time Frame Prebaseline, Baseline, Weeks 4, 12, 24, 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The population analyzed included all randomized participants with at least 1 etravirine (ETR) intake regardless of their compliance with the protocol (ie, the efficacy ITT population).

Reporting Groups
  Description
ATV/Rtv 300/100 mg (Treatment A) Treatment-experienced HIV-1 infected participants took by mouth atazanavir (ATV)/low-dose ritonavir (rtv) 300/100 mg once daily + 2 nucleoside reverse transcriptase inhibitors (NRTIs) for 2 weeks (Pre-treatment Period) followed by ATV/rtv 300/100 mg once daily + etravirine (ETR) 200 mg twice daily + 1 NRTI for 48 weeks (Treatment A).
ATV/Rtv 400/100 mg (Treatment B) Treatment-experienced HIV-1 infected participants took by mouth atazanavir (ATV)/low-dose ritonavir (rtv) 300/100 mg once daily + 2 nucleoside reverse transcriptase inhibitors (NRTIs) for 2 weeks (Pre-treatment Period) followed by ATV/rtv 400/100 mg once daily + etravirine (ETR) 200 mg twice daily + 1 NRTI for 48 weeks (Treatment B).

Measured Values
    ATV/Rtv 300/100 mg (Treatment A)     ATV/Rtv 400/100 mg (Treatment B)  
Number of Participants Analyzed  
[units: participants]
  22     22  
Change From Prebaseline in CD4+ Cell Count Over Time  
[units: CD4+┬ácell┬ácount]
Mean ± Standard Error
   
Baseline     16  ± 11.8     8  ± 18  
Week 4     55  ± 15.4     46  ± 27.4  
Week 12     31  ± 15.0     72  ± 23.5  
Week 24     54  ± 22.0     83  ± 23.2  
Week 48     105  ± 31.1     132  ± 32.6  

No statistical analysis provided for Change From Prebaseline in CD4+ Cell Count Over Time



13.  Secondary:   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 ]

14.  Secondary:   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 ]

15.  Secondary:   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 ]

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

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

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


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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