The purpose of this study is to evaluate the dose-response relationship of antiviral activity after 48 weeks treatment with 3 different dose regimens of TMC278.
This is a randomized (the study medication is assigned by chance), active controlled (participants are assigned to either a recognized effective treatment or the study medication) study. This study consists of 3 phases: screening phase (4 weeks), treatment phase (96 weeks), and follow up phase (4 weeks). In the treatment phase, participants will be randomly assigned to 1 of the 4 treatment groups: (1) TMC278 25 mg, (2) TMC278 75 mg, (3) TMC278 150 mg, or (4) efavirnez (control group); along with investigator selected 2 non-nucleoside reverse transcriptase inhibitor (NRTIs) until Week 96. TMC278 will be assigned by double-blinded fashion (participant and investigator are not aware of the TMC278 dose what participants will receive) and efavirnez will be assigned by open-label fashion (all people know what treatment participants will receive). After Week 96, 3 optional open-label (all people know the identity of the intervention) extension periods will be conducted to collect long term safety and effectiveness data of TMC278. 3 optional extension periods are: first optional extension period (all participants will receive TMC278 75 mg + 2 NRTIs from Week 96 to Week144); second optional extension period (all participants will receive TMC278 25 mg + 2 NRTIs from Week 144 to Week 240); and third optional extension period (all participants will receive TMC278 25 mg + 2 NRTIs from Week 240 until TMC278 is commercially available). Participants on efavirenz group will have the option to continue on efavirenz + 2 NRTIs until the total treatment duration of 240 weeks. Safety evaluations will include assessment of adverse events, clinical laboratory tests, electrocardiogram, physical examination, and vital signs which will be monitored throughout the study. The maximum duration of the study will be 104, 152, or 248 weeks, plus the optional third extension period.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
368
TMC278 25 mg tablet will be administered once daily.
TMC278 75 mg (1 X 25 mg + 1 X 50 mg) tablets will be administered once daily.
TMC278 150 mg (1 X 50 mg + 1 X 100 mg) tablets will be administered once daily.
Unnamed facility
Beverly Hills, California, United States
Number of Participants With Virologic Response at Week 48 (Viral Load Less Than 50 Copies Per mL) - as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm
The TLOVR algorithm was used to derive response, ie, response and loss of response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders. Participants with intermittent missing viral load values were considered responders if the preceeding and succeeding visits indicated response. In all other cases, intermittent values were imputed with nonresponse. Resuppression after confirmed virologic failure was considered as failure in this algorithm.
Time frame: Week 48
Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm
The TLOVR algorithm was used to derive response, ie, response and loss of response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders. Participants with intermittent missing viral load values were considered responders if the preceeding and succeeding visits indicated response. In all other cases, intermittent values were imputed with nonresponse. Resuppression after confirmed virologic failure was considered as failure in this algorithm.
Time frame: Week 96
Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis
The analysis is based on the last observed viral load data within the Week 96 window. Virologic response is defined as a viral load less than 50 copies/mL. Missing viral load was considered as non-response.
Time frame: Week 96
Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 50 Copies Per mL) - as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm
The TLOVR algorithm was used to derive response, ie, response and loss of response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders. Participants with intermittent missing viral load values were considered responders if the preceeding and succeeding visits indicated response. In all other cases, intermittent values were imputed with nonresponse. Resuppression after confirmed virologic failure was considered as failure in this algorithm.
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Efavirenz 600 mg (1 x 600 mg tablet or 3 x 200 mg capsules, depending on formulation locally available) will be administered once daily.
Investigator selected 2 NRTIs: (1) Zidovudine and lamivudine (Combivir) and (2) tenofovir disoproxil fumarate and emtricitabine (Truvada) will be administered as per the package inserts, along with the TMC278 during the study period.
Unnamed facility
Washington D.C., District of Columbia, United States
Unnamed facility
Orlando, Florida, United States
Unnamed facility
Tampa, Florida, United States
Unnamed facility
Atlanta, Georgia, United States
Unnamed facility
Stony Brook, New York, United States
Unnamed facility
Winston-Salem, North Carolina, United States
Unnamed facility
Addison, Texas, United States
Unnamed facility
Seattle, Washington, United States
Unnamed facility
Buenos Aires, Argentina
...and 30 more locations
Time frame: Week 240
Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis
The analysis is based on the last observed viral load data within the Week 240 window. Virologic response is defined as a viral load less than 50 copies/mL. Missing viral load was considered as non-response.
Time frame: Week 240
Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 400 Copies/mL) - as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm
The TLOVR algorithm was used to derive response, ie, response and loss of response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders. Participants with intermittent missing viral load values were considered responders if the preceeding and succeeding visits indicated response. In all other cases, intermittent values were imputed with nonresponse. Resuppression after confirmed virologic failure was considered as failure in this algorithm.
Time frame: Week 240
Change From Baseline in CD4+ Cell Count (Absolute) at Week 96
Change from baseline in CD4+ cell count was imputed in case of missing values: in case of premature discontinuation, data were imputed with the baseline value after discontinuation (i.e. change=0, Non-Completer \[NC\] = Failure); otherwise last observation carried forward was applied.
Time frame: Baseline (Day 1 of Week 0) to Week 96
Change From Baseline in CD4+ Cell Count (Relative) at Week 96
Change from baseline in CD4+ cell count was imputed in case of missing values: in case of premature discontinuation, data were imputed with the baseline value after discontinuation (i.e. change=0, Non-Completer \[NC\] = Failure); otherwise last observation carried forward was applied.
Time frame: Baseline (Day 1 of Week 0) to Week 96
Change From Baseline in CD4+ Cell Count (Absolute) at Week 240
Change from baseline in CD4+ cell count was imputed in case of missing values: in case of premature discontinuation, data were imputed with the baseline value after discontinuation (i.e. change=0, Non-Completer \[NC\] = Failure); otherwise last observation carried forward was applied.
Time frame: Baseline (Day 1 of Week 0) to Week 240
Change From Baseline in CD4+ Cell Count (Relative) at Week 240
Change from baseline in CD4+ cell count was imputed in case of missing values: in case of premature discontinuation, data were imputed with the baseline value after discontinuation (i.e. change=0, Non-Completer \[NC\] = Failure); otherwise last observation carried forward was applied.
Time frame: Baseline (Day 1 of week 0) to Week 240
Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure
Virologic failure for the resistance determinations was defined as a viral load greater than 0.5 log10 copies /mL above the nadir with a minimum of 500 copies/mL. For this study, treatment-emergent mutations (for at least one treatment) are presented as Resistance associated mutation (RAMs): i) Non-nucleotide reverse transcriptase inhibitor (NNRTI) RAMs, ii) Nucleoside/tide reverse transcriptase inhibitor (N\[t\]RTI RAMs).
Time frame: Week 240
Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) for TMC278
For each participant, a single value for area under the plasma concentration-time curve from time of administration up to 24 hours post dosing (AUC24h) of TMC278 was estimated from a population pharmacokinetic model, based on all samples collected throughout the trial up to Week 96.
Time frame: Up to Week 96
Trough Plasma Concentration (Ctrough) for TMC278
For each participant, a single value for trough (i.e. predose) plasma concentration (Ctrough) of TMC278 was estimated from a population pharmacokinetic model, based on samples collected throughout the trial up to Week 96.
Time frame: Up to Week 96
Number of Participants With Virologic Response (Viral Load Less Than 50 Copies Per mL) - as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm, by Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) Quartiles
Quartile 1, 2, 3 and 4 of AUC24h means the quartile with the lowest 25%, 26-50%, 51-75% and the highest 25% of AUC24h values, respectively, irrespective of the different doses of TMC278. For each participant, a single value for area under the plasma concentration-time curve from time of administration up to 24 hours post dosing (AUC24h) of TMC278 was estimated from a population pharmacokinetic model, based on all samples collected throughout the trial up to Week 96. Virologic response was calculated by time to loss of virologic response (TLOVR) algorithm.
Time frame: Up to Week 96