Human Immunodeficiency Virus Type 1
Conditions
Keywords
Human Immunodeficiency Virus Type 1, Human immunodeficiency virus (HIV), Antiretroviral, Antiviral, ARV, TMC278, Efavirenz, Combivir, Truvada, Zidovudine, Lamivudine, Tenofovir disoproxil fumarate, Emtricitabine
Brief summary
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.
Detailed description
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.
Interventions
DRUGTMC278 25 mg
TMC278 25 mg tablet will be administered once daily.
DRUGTMC278 75 mg
TMC278 75 mg (1 X 25 mg + 1 X 50 mg) tablets will be administered once daily.
DRUGTMC278 150 mg
TMC278 150 mg (1 X 50 mg + 1 X 100 mg) tablets will be administered once daily.
DRUGEfavirenz
Efavirenz 600 mg (1 x 600 mg tablet or 3 x 200 mg capsules, depending on formulation locally available) will be administered once daily.
DRUGNon-nucleoside reverse transcriptase inhibitor (NRTIs)
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.
Sponsors
Tibotec Pharmaceuticals, Ireland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented human immunodeficiency virus type 1 (HIV-1) infection * Never been treated with an antiretroviral (ARV) treatment or therapeutic HIV vaccine, or received less than or equal to 2 weeks treatment prior to screening with an nucleoside reverse transcriptase inhibitors * HIV-1 plasma viral load above 5000 HIV-1 RNA copies per milliliter, at screening * Cortisol of at least 550 nano moles per liter (19.9 microgram per deciliter) at screening * Sensitivity to investigator selected nucleosides, at screening
Exclusion criteria
* Currently having active Acquired Immunodeficiency Syndrome (AIDS) defining illness * Known or suspected acute (primary) HIV-1 infection * Any current or history of adrenal disorder, and an acute hepatitis A, B, or C infection * Documented genotypic evidence of Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) resistance at screening * Pregnant or breastfeeding females * Not agree to protocol-defined effective use of contraception
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Week 48 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis | Week 96 | 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. |
| 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 | Week 240 | 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. |
| Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis | Week 240 | 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. |
| 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 | Week 240 | 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. |
| Change From Baseline in CD4+ Cell Count (Absolute) at Week 96 | Baseline (Day 1 of Week 0) to 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. |
| Change From Baseline in CD4+ Cell Count (Relative) at Week 96 | Baseline (Day 1 of Week 0) to 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. |
| 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 | Week 96 | 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. |
| Change From Baseline in CD4+ Cell Count (Relative) at Week 240 | Baseline (Day 1 of week 0) to 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. |
| Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure | Week 240 | 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). |
| Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) for TMC278 | Up to Week 96 | 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. |
| Trough Plasma Concentration (Ctrough) for TMC278 | Up to Week 96 | 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. |
| 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 | Up to Week 96 | 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. |
| Change From Baseline in CD4+ Cell Count (Absolute) at Week 240 | Baseline (Day 1 of Week 0) to 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. |
Countries
Argentina, Austria, Brazil, China, France, Germany, Mexico, Puerto Rico, Russia, South Africa, Thailand, Uganda, United Kingdom, United States
Participant flow
Recruitment details
368 participants were enrolled at multiple centers in different countries.
Pre-assignment details
368 participants were randomly assigned to 4 treatment groups (TMC278 25 mg: 93; TMC278 75 mg: 95; TMC278 150 mg: 91; and Efavirenz: 89). Participant flow through Week 240 was reported for the combined TMC278 and Efavirenz groups, as all TMC278 participants were switched after Week 96 initially to 75 mg and subsequently to 25 mg dose.
Participants by arm
| Arm | Count |
|---|---|
| TMC278 25 mg TMC278 25 mg once daily | 93 |
| TMC278 75 mg TMC278 75 mg once daily | 95 |
| TMC 150 mg TMC278 150 mg once daily | 91 |
| Efavirenz Efavirenz 600 mg once daily | 89 |
| Total | 368 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 46 | 13 |
| Overall Study | Lost to Follow-up | 20 | 3 |
| Overall Study | Other | 8 | 2 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Sponsors Decision | 1 | 0 |
| Overall Study | Subject Ineligible To Continue The Trial | 2 | 1 |
| Overall Study | Subject Non-Compliant | 9 | 2 |
| Overall Study | Subject Reached A Virologic Endpoint | 21 | 3 |
| Overall Study | Withdrawal by Subject | 7 | 7 |
Baseline characteristics
| Characteristic | TMC278 25 mg | TMC278 75 mg | TMC 150 mg | Efavirenz | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 92 Participants | 95 Participants | 89 Participants | 89 Participants | 365 Participants |
| Age, Continuous | 36.7 years STANDARD_DEVIATION 8.9 | 36.3 years STANDARD_DEVIATION 8.3 | 35.9 years STANDARD_DEVIATION 9.7 | 35.4 years STANDARD_DEVIATION 8.1 | 36.1 years STANDARD_DEVIATION 8.75 |
| Region Enroll Asia, South Africa and Uganda | 32 participants | 32 participants | 31 participants | 29 participants | 124 participants |
| Region Enroll Europe, USA and Russia | 33 participants | 33 participants | 32 participants | 32 participants | 130 participants |
| Region Enroll Latin America | 28 participants | 30 participants | 28 participants | 28 participants | 114 participants |
| Sex: Female, Male Female | 28 Participants | 31 Participants | 33 Participants | 29 Participants | 121 Participants |
| Sex: Female, Male Male | 65 Participants | 64 Participants | 58 Participants | 60 Participants | 247 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 241 / 279 | 82 / 89 |
| serious Total, serious adverse events | 49 / 279 | 17 / 89 |
Outcome results
Primary
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
Population: Intent to treat population: Participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TMC278 25 mg | 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 | 74 Participants |
| TMC278 75 mg | 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 | 76 Participants |
| TMC278 150 mg | 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 | 70 Participants |
| All TMC278 | 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 | 220 Participants |
| Efavirenz | 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 | 72 Participants |
p-value: 0.9295% CI: [-10.4, 11.3]Regression, Logistic
p-value: 0.5695% CI: [-13.6, 9]Regression, Logistic
p-value: 0.6295% CI: [-14, 8.4]Regression, Logistic
p-value: 0.895% CI: [-10.5, 7.5]Regression, Logistic
Secondary
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
Population: Analysis included participants with sufficient number of pharmacokinetic samples in order to derive population pharmacokinetic parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC278 25 mg | Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) for TMC278 | 2767 ng*h/mL | Standard Deviation 1166 |
| TMC278 75 mg | Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) for TMC278 | 5906 ng*h/mL | Standard Deviation 2419 |
| TMC278 150 mg | Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) for TMC278 | 10281 ng*h/mL | Standard Deviation 4208 |
Secondary
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
Population: ITT population: Participants who received at least 1 dose of study medication. Efavirenz group, 1 participant was excluded due to missing baseline CD4+ cell count. This was measured at Week 240 for the combined TMC278 and Efavirenz groups, as all TMC278 participants were switched after Week 96 initially to 75 mg and subsequently to 25 mg dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC278 25 mg | Change From Baseline in CD4+ Cell Count (Absolute) at Week 240 | 221.0 Cells per microliter | Standard Deviation 227.2 |
| TMC278 75 mg | Change From Baseline in CD4+ Cell Count (Absolute) at Week 240 | 217.9 Cells per microliter | Standard Deviation 213.7 |
Secondary
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
Population: Intent to treat population: Participants who received at least 1 dose of study medication.Efavirenz group, 1 participant was excluded due to missing baseline CD4+ cell count.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC278 25 mg | Change From Baseline in CD4+ Cell Count (Absolute) at Week 96 | 145.9 Cells per microliter | Standard Deviation 117 |
| TMC278 75 mg | Change From Baseline in CD4+ Cell Count (Absolute) at Week 96 | 172.0 Cells per microliter | Standard Deviation 156.5 |
| TMC278 150 mg | Change From Baseline in CD4+ Cell Count (Absolute) at Week 96 | 158.9 Cells per microliter | Standard Deviation 156.5 |
| All TMC278 | Change From Baseline in CD4+ Cell Count (Absolute) at Week 96 | 159.0 Cells per microliter | Standard Deviation 144.4 |
| Efavirenz | Change From Baseline in CD4+ Cell Count (Absolute) at Week 96 | 159.8 Cells per microliter | Standard Deviation 125.7 |
Secondary
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
Population: ITT population: Participants who received at least 1 dose of study medication. Efavirenz group, 1 participant was excluded due to missing baseline CD4+ cell count. This was measured at Week 240 for the combined TMC278 and Efavirenz groups, as all TMC278 participants were switched after Week 96 initially to 75 mg and subsequently to 25 mg dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC278 25 mg | Change From Baseline in CD4+ Cell Count (Relative) at Week 240 | 8.7 Percentage of CD4+ cells | Standard Deviation 8.7 |
| TMC278 75 mg | Change From Baseline in CD4+ Cell Count (Relative) at Week 240 | 9.7 Percentage of CD4+ cells | Standard Deviation 9.1 |
Secondary
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
Population: Intent to treat (ITT) population: Participants who received at least 1 dose of study medication. Efavirenz group, 1 participant was excluded due to missing baseline CD4+ cell count.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC278 25 mg | Change From Baseline in CD4+ Cell Count (Relative) at Week 96 | 8.6 Percentage of CD4+ Cells | Standard Deviation 6.9 |
| TMC278 75 mg | Change From Baseline in CD4+ Cell Count (Relative) at Week 96 | 9.9 Percentage of CD4+ Cells | Standard Deviation 7.3 |
| TMC278 150 mg | Change From Baseline in CD4+ Cell Count (Relative) at Week 96 | 9.3 Percentage of CD4+ Cells | Standard Deviation 7.1 |
| All TMC278 | Change From Baseline in CD4+ Cell Count (Relative) at Week 96 | 9.3 Percentage of CD4+ Cells | Standard Deviation 7.1 |
| Efavirenz | Change From Baseline in CD4+ Cell Count (Relative) at Week 96 | 9.6 Percentage of CD4+ Cells | Standard Deviation 7 |
Secondary
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
Population: Intent to treat population: Participants who received at least 1 dose of study medication. This was measured at Week 240 for the combined TMC278 and Efavirenz groups, as all TMC278 participants were switched after Week 96 initially to 75 mg and subsequently to 25 mg dose.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TMC278 25 mg | Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure | Treatment-emergent NNRTI RAM | 17 Participants |
| TMC278 25 mg | Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure | E138K | 7 Participants |
| TMC278 25 mg | Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure | K101E | 6 Participants |
| TMC278 25 mg | Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure | K103N | 1 Participants |
| TMC278 25 mg | Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure | Treatment-emergent N(t)RTI RAM | 13 Participants |
| TMC278 25 mg | Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure | M184V | 10 Participants |
| TMC278 75 mg | Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure | Treatment-emergent N(t)RTI RAM | 0 Participants |
| TMC278 75 mg | Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure | Treatment-emergent NNRTI RAM | 4 Participants |
| TMC278 75 mg | Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure | K103N | 3 Participants |
| TMC278 75 mg | Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure | E138K | 0 Participants |
| TMC278 75 mg | Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure | M184V | 0 Participants |
| TMC278 75 mg | Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure | K101E | 0 Participants |
Secondary
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
Population: Intent to treat population: Participants who received at least 1 dose of study medication. This was measured at Week 240 for the combined TMC278 and Efavirenz groups, as all TMC278 participants were switched after Week 96 initially to 75 mg and subsequently to 25 mg dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TMC278 25 mg | 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 | 166 Participants |
| TMC278 75 mg | 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 | 54 Participants |
Secondary
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.
Time frame: Week 240
Population: Intent to treat population: Participants who received at least 1 dose of study medication. This was measured at Week 240 for the combined TMC278 and Efavirenz groups, as all TMC278 participants were switched after Week 96 initially to 75 mg and subsequently to 25 mg dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TMC278 25 mg | 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 | 152 Participants |
| TMC278 75 mg | 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 | 51 Participants |
95% CI: [-14.7, 9.1]
Secondary
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
Population: Intent to treat population: Participants who received at least 1 dose of study medication. This was measured at Week 240 for the combined TMC278 and Efavirenz groups, as all TMC278 participants were switched after Week 96 initially to 75 mg and subsequently to 25 mg dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TMC278 25 mg | Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis | 150 Participants |
| TMC278 75 mg | Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis | 51 Participants |
Secondary
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
Population: Intent to treat population: Participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TMC278 25 mg | 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 | 71 Participants |
| TMC278 75 mg | 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 | 68 Participants |
| TMC278 150 mg | 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 | 65 Participants |
| All TMC278 | 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 | 204 Participants |
| Efavirenz | 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 | 63 Participants |
p-value: 0.4595% CI: [-17.1, 7.6]Regression, Logistic
p-value: 0.4595% CI: [-17.3, 7.7]Regression, Logistic
p-value: 0.9995% CI: [-12.9, 12.8]Regression, Logistic
p-value: 0.6395% CI: [-8.1, 13.3]Regression, Logistic
Secondary
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
Population: Intent to treat population: Participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TMC278 25 mg | Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis | 71 Participants |
| TMC278 75 mg | Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis | 70 Participants |
| TMC278 150 mg | Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis | 66 Participants |
| All TMC278 | Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis | 207 Participants |
| Efavirenz | Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis | 64 Participants |
Secondary
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
Population: Analysis included participants who received TMC278 with sufficient number of pharnacokintetic samples in order to derive population pharmacokinetic parameter. Participants who discontinued treatment for reasons other than virological failure were excluded from this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TMC278 25 mg | 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 | 48 Participants |
| TMC278 75 mg | 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 | 50 Participants |
| TMC278 150 mg | 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 | 55 Participants |
| All TMC278 | 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 | 51 Participants |
Secondary
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
Population: Analysis included participants with sufficient number of pharnacokintetic samples in order to derive population pharmacokinetic parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC278 25 mg | Trough Plasma Concentration (Ctrough) for TMC278 | 92.7 ng/mL | Standard Deviation 45.2 |
| TMC278 75 mg | Trough Plasma Concentration (Ctrough) for TMC278 | 196.0 ng/mL | Standard Deviation 90.1 |
| TMC278 150 mg | Trough Plasma Concentration (Ctrough) for TMC278 | 342.0 ng/mL | Standard Deviation 154 |