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A Study of TMC278 in Human Immunodeficiency Virus Type 1 Infected Patients, Who Are Not Treated With Antiretroviral Medicines

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ClinicalTrials.gov Identifier: NCT00110305
Recruitment Status : Completed
First Posted : May 6, 2005
Results First Posted : October 28, 2013
Last Update Posted : June 25, 2014
Sponsor:
Information provided by (Responsible Party):
Tibotec Pharmaceuticals, Ireland

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Human Immunodeficiency Virus Type 1
Interventions: Drug: TMC278 25 mg
Drug: TMC278 75 mg
Drug: TMC278 150 mg
Drug: Efavirenz
Drug: Non-nucleoside reverse transcriptase inhibitor (NRTIs)

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
368 participants were enrolled at multiple centers in different countries.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups
  Description
All TMC278 TMC278 25 mg, 75 mg, and 150 mg once daily
Efavirenz Efavirenz 600 mg once daily

Participant Flow:   Overall Study
    All TMC278   Efavirenz
STARTED   279   89 
COMPLETED   165   57 
NOT COMPLETED   114   32 
Adverse Event                46                13 
Sponsors Decision                1                0 
Subject Non-Compliant                9                2 
Subject Ineligible To Continue The Trial                2                1 
Subject Reached A Virologic Endpoint                21                3 
Protocol Violation                0                1 
Withdrawal by Subject                7                7 
Lost to Follow-up                20                3 
Other                8                2 



  Baseline Characteristics

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
TMC278 25 mg TMC278 25 mg once daily
TMC278 75 mg TMC278 75 mg once daily
TMC 150 mg TMC278 150 mg once daily
Efavirenz Efavirenz 600 mg once daily
Total Total of all reporting groups

Baseline Measures
   TMC278 25 mg   TMC278 75 mg   TMC 150 mg   Efavirenz   Total 
Overall Participants Analyzed 
[Units: Participants]
 93   95   91   89   368 
Age 
[Units: Participants]
         
<=18 years   0   0   0   0   0 
Between 18 and 65 years   92   95   89   89   365 
>=65 years   1   0   2   0   3 
Age 
[Units: Years]
Mean (Standard Deviation)
 36.7  (8.9)   36.3  (8.3)   35.9  (9.7)   35.4  (8.1)   36.1  (8.75) 
Gender 
[Units: Participants]
         
Female   28   31   33   29   121 
Male   65   64   58   60   247 
Region Enroll 
[Units: Participants]
         
Asia, South Africa and Uganda   32   32   31   29   124 
Europe, USA and Russia   33   33   32   32   130 
Latin America   28   30   28   28   114 


  Outcome Measures

1.  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   [ Time Frame: Week 48 ]

Measure Type Primary
Measure Title 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
Measure Description 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 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.
Intent to treat population: Participants who received at least 1 dose of study medication.

Reporting Groups
  Description
TMC278 25 mg TMC278 25 mg once daily
TMC278 75 mg TMC278 75 mg once daily
TMC278 150 mg TMC278 150 mg once daily
All TMC278 TMC278 25 mg, 75 mg, and 150 mg once daily
Efavirenz Efaviren 600 mg once daily

Measured Values
   TMC278 25 mg   TMC278 75 mg   TMC278 150 mg   All TMC278   Efavirenz 
Participants Analyzed   93   95   91   279   89 
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 
[Units: Participants]
 74   76   70   220   72 


Statistical Analysis 1 for 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
Groups [1] TMC278 25 mg vs. TMC278 75 mg
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.92
Differences in response rate [5] 0.5
95% Confidence Interval -10.4 to 11.3
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  This model with factors treatment, region, and Nucleoside/tide reverse transcriptase inhibitors (N[t]RTIs) used, and baseline viral load as covariate.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for 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
Groups [1] TMC278 25 mg vs. TMC278 150 mg
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.56
Difference in response rate [5] -2.3
95% Confidence Interval -13.6 to 9.0
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  This model with factors treatment, region, and N(t)RTIs used, and baseline viral load as covariate.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for 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
Groups [1] TMC278 75 mg vs. TMC278 150 mg
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.62
Difference in response rate [5] -2.8
95% Confidence Interval -14.0 to 8.4
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  This model with factors treatment, region, and N(t)RTIs used, and baseline viral load as covariate.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for 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
Groups [1] All TMC278 vs. Efavirenz
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.80
Difference in response rate [5] -1.5
95% Confidence Interval -10.5 to 7.5
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  This model with factors treatment, region, and N(t)RTIs used, and baseline viral load as covariate.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
[5] Other relevant estimation information:
  No text entered.



2.  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   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title 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
Measure Description 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 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.
Intent to treat population: Participants who received at least 1 dose of study medication.

Reporting Groups
  Description
TMC278 25 mg TMC278 25 mg once daily
TMC278 75 mg TMC278 75 mg once daily
TMC278 150 mg TMC278 150 mg once daily
All TMC278 TMC278 25 mg, 75 mg, and 150 mg once daily
Efavirenz Efavirenz 600 mg once daily

Measured Values
   TMC278 25 mg   TMC278 75 mg   TMC278 150 mg   All TMC278   Efavirenz 
Participants Analyzed   93   95   91   279   89 
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 
[Units: Participants]
 71   68   65   204   63 


Statistical Analysis 1 for 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
Groups [1] TMC278 25 mg vs. TMC278 75 mg
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.45
Difference in response rate [5] -4.8
95% Confidence Interval -17.1 to 7.6
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  This model with factors treatment, region, and Nucleoside/tide reverse transcriptase inhibitors (N[t]RTIs) used, and baseline viral load as covariate.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for 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
Groups [1] TMC278 25 mg vs. TMC278 150 mg
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.45
Difference in response rate [5] -4.8
95% Confidence Interval -17.3 to 7.7
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  This model with factors treatment, region, and N(t)RTIs used, and baseline viral load as covariate.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for 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
Groups [1] TMC278 75 mg vs. TMC278 150 mg
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.99
Difference in response rate [5] 0.0
95% Confidence Interval -12.9 to 12.8
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  This model with factors treatment, region, and N(t)RTIs used, and baseline viral load as covariate.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for 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
Groups [1] All TMC278 vs. Efavirenz
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.63
Differences in response [5] 2.6
95% Confidence Interval -8.1 to 13.3
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  This model with factors treatment, region, and N(t)RTIs used, and baseline viral load as covariate.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
[5] Other relevant estimation information:
  No text entered.



3.  Secondary:   Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis
Measure Description 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 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.
Intent to treat population: Participants who received at least 1 dose of study medication.

Reporting Groups
  Description
TMC278 25 mg TMC278 25 mg once daily
TMC278 75 mg TMC278 75 mg once daily
TMC278 150 mg TMC278 150 mg once daily
All TMC278 TMC278 25 mg, 75 mg, and 150 mg once daily
Efavirenz Efavirenz 600 mg once daily

Measured Values
   TMC278 25 mg   TMC278 75 mg   TMC278 150 mg   All TMC278   Efavirenz 
Participants Analyzed   93   95   91   279   89 
Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis 
[Units: Participants]
 71   70   66   207   64 

No statistical analysis provided for Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis



4.  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   [ Time Frame: Week 240 ]

Measure Type Secondary
Measure Title 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
Measure Description 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 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.
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.

Reporting Groups
  Description
All TMC278 TMC278 25 mg, 75 mg, and 150 mg once daily
Efavirenz Efavirenz 600 mg once daily

Measured Values
   All TMC278   Efavirenz 
Participants Analyzed   279   89 
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 
[Units: Participants]
 152   51 


Statistical Analysis 1 for 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
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Difference in response rate [3] -2.8
95% Confidence Interval -14.7 to 9.1
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



5.  Secondary:   Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis   [ Time Frame: Week 240 ]

Measure Type Secondary
Measure Title Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis
Measure Description 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 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.
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.

Reporting Groups
  Description
All TMC278 TMC278 25 mg, 75 mg, and 150 mg once daily
Efavirenz Efavirenz 600 mg once daily

Measured Values
   All TMC278   Efavirenz 
Participants Analyzed   279   89 
Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis 
[Units: Participants]
 150   51 

No statistical analysis provided for Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis



6.  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   [ Time Frame: Week 240 ]

Measure Type Secondary
Measure Title 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
Measure Description 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 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.
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.

Reporting Groups
  Description
All TMC278 TMC278 25 mg, 75 mg, and 150 mg once daily
Efavirenz Efavirenz 600 mg once daily

Measured Values
   All TMC278   Efavirenz 
Participants Analyzed   279   89 
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 
[Units: Participants]
 166   54 

No statistical analysis provided for 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



7.  Secondary:   Change From Baseline in CD4+ Cell Count (Absolute) at Week 96   [ Time Frame: Baseline (Day 1 of Week 0) to Week 96 ]

Measure Type Secondary
Measure Title Change From Baseline in CD4+ Cell Count (Absolute) at Week 96
Measure Description 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 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.
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.

Reporting Groups
  Description
TMC278 25mg TMC278 25 mg once daily
TMC278 75 mg TMC278 75 mg once daily
TMC278 150 mg TMC278 150 mg once daily
All TMC278 TMC278 25 mg, 75 mg, and 150 mg once daily
Efavirenz Efavirenz 600 mg once daily

Measured Values
   TMC278 25mg   TMC278 75 mg   TMC278 150 mg   All TMC278   Efavirenz 
Participants Analyzed   93   95   91   279   88 
Change From Baseline in CD4+ Cell Count (Absolute) at Week 96 
[Units: Cells per microliter]
Mean (Standard Deviation)
 145.9  (117.0)   172.0  (156.5)   158.9  (156.5)   159.0  (144.4)   159.8  (125.7) 

No statistical analysis provided for Change From Baseline in CD4+ Cell Count (Absolute) at Week 96



8.  Secondary:   Change From Baseline in CD4+ Cell Count (Relative) at Week 96   [ Time Frame: Baseline (Day 1 of Week 0) to Week 96 ]

Measure Type Secondary
Measure Title Change From Baseline in CD4+ Cell Count (Relative) at Week 96
Measure Description 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 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.
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.

Reporting Groups
  Description
TMC278 25mg TMC278 25 mg once daily
TMC278 75 mg TMC278 75 mg once daily
TMC278 150 mg TMC278 150 mg once daily
All TMC278 TMC278 25 mg, 75 mg, and 150 mg once daily
Efavirenz Efavirenz 600 mg once daily

Measured Values
   TMC278 25mg   TMC278 75 mg   TMC278 150 mg   All TMC278   Efavirenz 
Participants Analyzed   93   95   91   279   88 
Change From Baseline in CD4+ Cell Count (Relative) at Week 96 
[Units: Percentage of CD4+ Cells]
Mean (Standard Deviation)
 8.6  (6.9)   9.9  (7.3)   9.3  (7.1)   9.3  (7.1)   9.6  (7.0) 

No statistical analysis provided for Change From Baseline in CD4+ Cell Count (Relative) at Week 96



9.  Secondary:   Change From Baseline in CD4+ Cell Count (Absolute) at Week 240   [ Time Frame: Baseline (Day 1 of Week 0) to Week 240 ]

Measure Type Secondary
Measure Title Change From Baseline in CD4+ Cell Count (Absolute) at Week 240
Measure Description 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 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.
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.

Reporting Groups
  Description
All TMC278 TMC278 25 mg, 75 mg, and 150 mg once daily
Efavirenz Efavirenz 600 mg once daily

Measured Values
   All TMC278   Efavirenz 
Participants Analyzed   279   88 
Change From Baseline in CD4+ Cell Count (Absolute) at Week 240 
[Units: Cells per microliter]
Mean (Standard Deviation)
 221.0  (227.2)   217.9  (213.7) 

No statistical analysis provided for Change From Baseline in CD4+ Cell Count (Absolute) at Week 240



10.  Secondary:   Change From Baseline in CD4+ Cell Count (Relative) at Week 240   [ Time Frame: Baseline (Day 1 of week 0) to Week 240 ]

Measure Type Secondary
Measure Title Change From Baseline in CD4+ Cell Count (Relative) at Week 240
Measure Description 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 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.
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.

Reporting Groups
  Description
All TMC278 TMC278 25 mg, 75 mg, and 150 mg once daily
Efavirenz Efavirenz 600 mg once daily

Measured Values
   All TMC278   Efavirenz 
Participants Analyzed   279   88 
Change From Baseline in CD4+ Cell Count (Relative) at Week 240 
[Units: Percentage of CD4+ cells]
Mean (Standard Deviation)
 8.7  (8.7)   9.7  (9.1) 

No statistical analysis provided for Change From Baseline in CD4+ Cell Count (Relative) at Week 240



11.  Secondary:   Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure   [ Time Frame: Week 240 ]

Measure Type Secondary
Measure Title Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure
Measure Description 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 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.
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.

Reporting Groups
  Description
All TMC278 TMC278 25 mg, 75 mg, and 150 mg once daily
Efavirenz Efavirenz 600 mg once daily

Measured Values
   All TMC278   Efavirenz 
Participants Analyzed   279   89 
Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure 
[Units: Participants]
   
Treatment-emergent NNRTI RAM   17   4 
E138K   7   0 
K101E   6   0 
K103N   1   3 
Treatment-emergent N(t)RTI RAM   13   0 
M184V   10   0 

No statistical analysis provided for Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure



12.  Secondary:   Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) for TMC278   [ Time Frame: Up to Week 96 ]

Measure Type Secondary
Measure Title Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) for TMC278
Measure Description 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 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.
Analysis included participants with sufficient number of pharmacokinetic samples in order to derive population pharmacokinetic parameter.

Reporting Groups
  Description
TMC278 25 mg TMC278 25 mg once daily
TMC278 75 mg TMC278 75 mg once daily
TMC278 150 mg TMC278 150 mg once daily

Measured Values
   TMC278 25 mg   TMC278 75 mg   TMC278 150 mg 
Participants Analyzed   89   93   87 
Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) for TMC278 
[Units: ng*h/mL]
Mean (Standard Deviation)
 2767  (1166)   5906  (2419)   10281  (4208) 

No statistical analysis provided for Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) for TMC278



13.  Secondary:   Trough Plasma Concentration (Ctrough) for TMC278   [ Time Frame: Up to Week 96 ]

Measure Type Secondary
Measure Title Trough Plasma Concentration (Ctrough) for TMC278
Measure Description 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 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.
Analysis included participants with sufficient number of pharnacokintetic samples in order to derive population pharmacokinetic parameter.

Reporting Groups
  Description
TMC278 25 mg TMC278 25 mg once daily
TMC278 75 mg TMC278 75 mg once daily
TMC278 150 mg TMC278 150 mg once daily

Measured Values
   TMC278 25 mg   TMC278 75 mg   TMC278 150 mg 
Participants Analyzed   89   93   87 
Trough Plasma Concentration (Ctrough) for TMC278 
[Units: ng/mL]
Mean (Standard Deviation)
 92.7  (45.2)   196.0  (90.1)   342.0  (154.0) 

No statistical analysis provided for Trough Plasma Concentration (Ctrough) for TMC278



14.  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   [ Time Frame: Up to Week 96 ]

Measure Type Secondary
Measure Title 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
Measure Description 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 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.
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.

Reporting Groups
  Description
AUC24h Quartile 1 TMC278 25 mg, 75 mg, and 150 mg once daily
AUC24h Quartile 2 TMC278 25 mg, 75 mg, and 150 mg once daily
AUC24h Quartile 3 TMC278 25 mg, 75 mg, and 150 mg once daily
AUC24h Quartile 4 TMC278 25 mg, 75 mg, and 150 mg once daily

Measured Values
   AUC24h Quartile 1   AUC24h Quartile 2   AUC24h Quartile 3   AUC24h Quartile 4 
Participants Analyzed   58   54   59   56 
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 
[Units: Participants]
 48   50   55   51 

No statistical analysis provided for 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




  Serious Adverse Events

Time Frame Up to 336 weeks for participants in the TMC278 treatment group and up to 260 weeks for participants in the efavirenz treatment group.
Additional Description Adverse events were reported 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.

Reporting Groups
  Description
All TMC278 TMC278 25 mg, 75 mg, and 150 mg once daily
Efavirenz Efavirenz 600 mg once daily

Serious Adverse Events
    All TMC278   Efavirenz
Total, Serious Adverse Events     
# participants affected / at risk   49/279 (17.56%)   17/89 (19.10%) 
Blood and lymphatic system disorders     
Anaemia † 1     
# participants affected / at risk   5/279 (1.79%)   0/89 (0.00%) 
Leukopenia † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Neutropenia † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Cardiac disorders     
Acute myocardial infarction † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Angina unstable † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Supraventricular tachycardia † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Gastrointestinal disorders     
Abdominal pain † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Anal fissure † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Anal fistula † 1     
# participants affected / at risk   2/279 (0.72%)   0/89 (0.00%) 
Appendicitis perforated † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Colitis † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Constipation † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Diarrhoea haemorrhagic † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Intestinal infarction † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Intestinal obstruction † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Pancreatitis † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Pancreatitis acute † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Peritonitis † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Rectal haemorrhage † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
General disorders     
Chest pain † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Death † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Pyrexia † 1     
# participants affected / at risk   2/279 (0.72%)   0/89 (0.00%) 
Hepatobiliary disorders     
Bile duct stone † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Cholecystitis acute † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Cholelithiasis † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Cytolytic hepatitis † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Hepatitis † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Hepatitis acute † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Hydrocholecystis † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Infections and infestations     
Abscess neck † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Appendicitis † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Arthritis bacterial † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Cellulitis † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Clostridial infection † 1     
# participants affected / at risk   1/279 (0.36%)   1/89 (1.12%) 
Cytomegalovirus colitis † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Hepatitis C † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Implant site infection † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Lobar pneumonia † 1     
# participants affected / at risk   1/279 (0.36%)   1/89 (1.12%) 
Lung infection † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Malaria † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Meningitis tuberculous † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Oral candidiasis † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Osteomyelitis † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Perianal abscess † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Pneumonia † 1     
# participants affected / at risk   3/279 (1.08%)   0/89 (0.00%) 
Pneumonia streptococcal † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Respiratory tract infection † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Sepsis syndrome † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Septic shock † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Subcutaneous abscess † 1     
# participants affected / at risk   0/279 (0.00%)   2/89 (2.25%) 
Injury, poisoning and procedural complications     
Ankle fracture † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Brain contusion † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Drug toxicity † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Humerus fracture † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Muscle injury † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Road traffic accident † 1     
# participants affected / at risk   1/279 (0.36%)   1/89 (1.12%) 
Investigations     
Alanine aminotransferase increased † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Aspartate aminotransferase increased † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Blood amylase increased † 1     
# participants affected / at risk   1/279 (0.36%)   1/89 (1.12%) 
Metabolism and nutrition disorders     
Anorexia † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Dehydration † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Diabetes mellitus † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Metabolic acidosis † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Back pain † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Costochondritis † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Lumbar spinal stenosis † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Burkitt's lymphoma † 1     
# participants affected / at risk   2/279 (0.72%)   0/89 (0.00%) 
Cervix cancer metastatic † 1     
# participants affected / at risk   1/279 (0.36%)   1/89 (1.12%) 
Chondrosarcoma metastatic † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Kaposi's sarcoma † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Lymphoma † 1     
# participants affected / at risk   2/279 (0.72%)   0/89 (0.00%) 
Squamous cell carcinoma † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Uterine leiomyoma † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Nervous system disorders     
Epilepsy † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Headache † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Pregnancy, puerperium and perinatal conditions     
Pregnancy † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Psychiatric disorders     
Depression † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Intentional self-injury † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Major depression † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Suicide attempt † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Renal and urinary disorders     
Renal failure † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Renal impairment † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Reproductive system and breast disorders     
Ovarian cyst † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Prostatitis † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Respiratory, thoracic and mediastinal disorders     
Alveolitis allergic † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Skin and subcutaneous tissue disorders     
Rash maculo-papular † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Surgical and medical procedures     
Ovarian cystectomy † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Penile prosthesis insertion † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Vascular disorders     
Arterial occlusive disease † 1     
# participants affected / at risk   1/279 (0.36%)   0/89 (0.00%) 
Deep vein thrombosis † 1     
# participants affected / at risk   0/279 (0.00%)   1/89 (1.12%) 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 11.0




  Other Adverse Events


  Limitations and Caveats

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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