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TMC278-TiDP6-C215: A Clinical Trial in Treatment Naive HIV-subjects Patients Comparing TMC278 to Efavirenz in Combination With 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Tibotec Pharmaceuticals, Ireland
ClinicalTrials.gov Identifier:
NCT00543725
First received: October 11, 2007
Last updated: March 3, 2016
Last verified: March 2016
Results First Received: June 14, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions: HIV Infections
HIV-1
Interventions: Drug: TMC278
Drug: efavirenz

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
A phase III, randomized, double-blind trial of TMC278 25 mg q.d. versus efavirenz 600mg q.d. in combination with a background regimen containing 2 nucleoside/nucleotide reverse transcriptase inhibitors in antiretroviral-naïve HIV-1 infected subjects

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
680 participants were randomized (340 in TMC 278 and 340 in efavirenz) but only 338 participants were treated with efavirenz (2 were randomized but not treated).

Reporting Groups
  Description
TMC278 25 mg tablet once daily
Efavirenz 600 mg once daily

Participant Flow:   Overall Study
    TMC278   Efavirenz
STARTED   340   338 
COMPLETED   272   264 
NOT COMPLETED   68   74 
Adverse Event                18                27 
Sponsor's Decision                0                1 
Subject Non-Compliant                4                4 
Subject Ineligible To Continue The Trial                2                0 
Subject Reached A Virologic Endpoint                22                14 
Protocol Violation                0                1 
Withdrawal by Subject                4                13 
Lost to Follow-up                15                11 
Not specified                3                3 



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

Reporting Groups
  Description
TMC278 25 mg tablet once daily
Efavirenz 600 mg once daily
Total Total of all reporting groups

Baseline Measures
   TMC278   Efavirenz   Total 
Overall Participants Analyzed 
[Units: Participants]
 340   338   678 
Age 
[Units: Participants]
     
<=18 years   0   0   0 
Between 18 and 65 years   339   337   676 
>=65 years   1   1   2 
Age 
[Units: Years]
Mean (Standard Deviation)
 36.7  (9.39)   36.4  (8.92)   36.5  (9.15) 
Gender 
[Units: Participants]
     
Female   90   94   184 
Male   250   244   494 
Region Enroll 
[Units: Participants]
     
Africa   19   38   57 
Asia   59   61   120 
Latin America   90   85   175 
USA, Canada, Europe, Australia   172   154   326 


  Outcome Measures
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1.  Primary:   Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies Per mL) at Week 48   [ Time Frame: Week 48 ]

Measure Type Primary
Measure Title Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies Per mL) at Week 48
Measure Description Virological response is defined as confirmed plasma viral load less than (<) 50 human immunodeficiency virus-1 (HIV-1) (ribonucleic acid [RNA]) copies/milliliter (ml) at Week 48. The TLOVR algorithm was used to derive response. Response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders after discontinuation. Resuppression after confirmed virologic failure was considered as failure. Virologic Failure includes participants who were rebounder (confirmed viral load >= 50 copies/ml after being responder) or who were never suppressed (no confirmed viral load <50 copies/ml).
Time Frame Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Intent-to-Treat analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 mg tablet once daily
Efavirenz 600 mg once daily

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 340   338 
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies Per mL) at Week 48 
[Units: Participants]
   
Responder   291   276 
Virologic failure   24   18 
Death   1   3 
Discontinued due to AE   8   21 
Discontinued due to other reason than AE   16   20 


Statistical Analysis 1 for Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies Per mL) at Week 48
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Regression, Logistic
P Value [4] <0.0001
Difference in proportion of response [5] 3.7
95% Confidence Interval -1.6 to 9.0
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Assuming a response rate of 75% at 48 weeks for both treatment groups, 340 subjects were needed per treatment (TMC278 or EFV) to establish non-inferiority of TMC278 versus EFV with a maximum allowable difference of 12% and a 1-sided significance level of 2.5%, to yield 95% power.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  If the lower limit of the 95% 2-sided confidence interval of the difference in proportions (TMC278 – EFV) exceeds -12%, non-inferiority of TMC278 versus EFV can be concluded.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Logistic regression model included treatment arm and background NRTI regimen as factors, and baseline (log10) 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:
  Significance level was set at 2.5% (one-sided). No adjustment of p-value for multiple comparisons, since there was only single comparison for the primary endpoint.
[5] Other relevant estimation information:
  Difference in proportion responders was estimated through the logistic regression model.



2.  Secondary:   Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies Per mL) at Week 48   [ Time Frame: Week 48 ]

Measure Type Secondary
Measure Title Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies Per mL) at Week 48
Measure Description The analysis is based on the last observed viral load (VL) data within the Week 48 window. Virologic response is defined as a VL<50 copies/mL (observed case). Missing VL was considered as non-response. Virologic Failure includes subjects who had VL>=50 copies/mL in the Wk 48 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a VL>=50 copies/mL and subjects who had a switch in background regimen that was not permitted by the protocol.
Time Frame Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Intent-to-Treat analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 mg tablet once daily
Efavirenz 600 mg once daily

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 340   338 
Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies Per mL) at Week 48 
[Units: Participants]
   
Virologic Response (<50 copies/mL)   281   265 
Virologic failure   41   38 
No plasma viral load data in 48-week window   18   35 


Statistical Analysis 1 for Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies Per mL) at Week 48
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Regression, Logistic
P Value [4] <0.0001
Difference in proportion of response [5] 3.9
95% Confidence Interval -1.9 to 9.6
[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:
  If the lower limit of the 95% 2-sided confidence interval of the difference in proportions (TMC278 – EFV) exceeds -12%, non-inferiority of TMC278 versus EFV can be concluded.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Logistic regression model included treatment arm and background NRTI regimen as factors, and baseline (log10) 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:
  No text entered.
[5] Other relevant estimation information:
  Difference in proportion responders was estimated through the logistic regression model.



3.  Secondary:   Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies Per mL) at Week 96   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies Per mL) at Week 96
Measure Description No text entered.
Time Frame Week 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Intent-to-Treat analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 mg tablet once daily
Efavirenz 600 mg once daily

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 340   338 
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies Per mL) at Week 96 
[Units: Participants]
   
Responder   269   258 
Virologic failure   34   24 
Death   1   3 
Discontinued due to AE   16   23 
Discontinued due to other reason than AE   20   30 


Statistical Analysis 1 for Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies Per mL) at Week 96
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Regression, Logistic
P Value [4] <0.0001
Difference in proportion of response [5] 2.4
95% Confidence Interval -3.6 to 8.4
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Assuming a response rate of 75% at 48 weeks for both treatment groups, 340 subjects were needed per treatment (TMC278 or EFV) to establish non-inferiority of TMC278 versus EFV with a maximum allowable difference of 12% and a 1-sided significance level of 2.5%, to yield 95% power.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  If the lower limit of the 95% 2-sided confidence interval of the difference in proportions (TMC278 – EFV) exceeds -12%, non-inferiority of TMC278 versus EFV can be concluded.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Logistic regression model included treatment arm and background NRTI regimen as factors, and baseline (log10) 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:
  Significance level was set at 2.5% (one-sided). No adjustment of p-value for multiple comparisons, since there was only single comparison for the primary endpoint.
[5] Other relevant estimation information:
  Difference in proportion responders was estimated through the logistic regression model.



4.  Secondary:   Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies Per mL) at Week 96   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies Per mL) at Week 96
Measure Description No text entered.
Time Frame Week 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Intent-to-Treat analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 mg tablet once daily
Efavirenz 600 mg once daily

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 340   338 
Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies Per mL) at Week 96 
[Units: Participants]
   
Virologic response (<50 copies/mL)   259   254 
Virologic failure   53   38 
No plasma viral load data in 96-Week window   28   46 


Statistical Analysis 1 for Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies Per mL) at Week 96
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Regression, Logistic
P Value [4] <0.0001
Difference in proportion of response [5] 0.7
95% Confidence Interval -5.6 to 7.0
[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:
  If the lower limit of the 95% 2-sided confidence interval of the difference in proportions (TMC278 – EFV) exceeds -12%, non-inferiority of TMC278 versus EFV can be concluded.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Logistic regression model included treatment arm and background NRTI regimen as factors, and baseline (log10) 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:
  No text entered.
[5] Other relevant estimation information:
  Difference in proportion responders was estimated through the logistic regression model.



5.  Secondary:   Number of Participants With Virological Response (Observed, <50 Copies/mL) at Last On-Treatment Visit (Post-Week 96).   [ Time Frame: Variable, ranging from 3 months up to maximum 18 months for TMC278 and 12 months for Efavirenz ]

Measure Type Secondary
Measure Title Number of Participants With Virological Response (Observed, <50 Copies/mL) at Last On-Treatment Visit (Post-Week 96).
Measure Description Virological response is defined as (observed) plasma viral load less than 50 human immunodeficiency virus-type 1 (HIV-1) ribonucleic acid (RNA) copies per mL at the last on-treatment post-Week 96 visit.
Time Frame Variable, ranging from 3 months up to maximum 18 months for TMC278 and 12 months for Efavirenz  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants with at least 1 Post-Week 96 visit were included in the analysis.

Reporting Groups
  Description
TMC278 25 mg tablet once daily
Efavirenz 600 mg once daily

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 269   257 
Number of Participants With Virological Response (Observed, <50 Copies/mL) at Last On-Treatment Visit (Post-Week 96). 
[Units: Participants]
 260   246 

No statistical analysis provided for Number of Participants With Virological Response (Observed, <50 Copies/mL) at Last On-Treatment Visit (Post-Week 96).



6.  Secondary:   Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies Per mL) at Week 48   [ Time Frame: Week 48 ]

Measure Type Secondary
Measure Title Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies Per mL) at Week 48
Measure Description Virological response is defined as confirmed plasma viral load < 400 HIV-1 (RNA) copies/mL at Week 48. The TLOVR algorithm was used to derive response. Response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders after discontinuation. Resuppression after confirmed virologic failure was considered as failure. Virologic Failure includes participants who were rebounder (confirmed viral load >= 400 copies/mL after being responder) or who were never suppressed (no confirmed viral load <400 copies/mL).
Time Frame Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Intent-to-Treat analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 mg tablet once daily
Efavirenz 600 mg once daily

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 340   338 
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies Per mL) at Week 48 
[Units: Participants]
 300   286 

No statistical analysis provided for Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies Per mL) at Week 48



7.  Secondary:   Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies Per mL) at Week 96   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies Per mL) at Week 96
Measure Description Virological response is defined as confirmed plasma viral load < 400 HIV-1 (RNA) copies/mL at Week 96. The TLOVR algorithm was used to derive response. Response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders after discontinuation. Resuppression after confirmed virologic failure was considered as failure. Virologic Failure includes participants who were rebounder (confirmed viral load >= 400 copies/mL after being responder) or who were never suppressed (no confirmed viral load <400 copies/mL).
Time Frame Week 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Intent-to-Treat analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 mg tablet once daily
Efavirenz 600 mg once daily

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 340   338 
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies Per mL) at Week 96 
[Units: Participants]
 283   270 

No statistical analysis provided for Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies Per mL) at Week 96



8.  Secondary:   Mean Change From Baseline to Week 48 and Week 96 in Absolute and Relative CD4+ Cell Counts (Using Imputed Data)   [ Time Frame: Baseline, Week 48, and Week 96 ]

Measure Type Secondary
Measure Title Mean Change From Baseline to Week 48 and Week 96 in Absolute and Relative CD4+ Cell Counts (Using Imputed Data)
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, Week 48, and Week 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Intent-to-Treat analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 mg tablet once daily
Efavirenz 600 mg once daily

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 339   338 
Mean Change From Baseline to Week 48 and Week 96 in Absolute and Relative CD4+ Cell Counts (Using Imputed Data) 
[Units: Cells per microliter]
Mean (95% Confidence Interval)
   
Absolute cell count, Week 48   188.6 
 (173.98 to 203.15) 
 170.7 
 (154.55 to 186.77) 
Absolute cell count, Week 96   234.5 
 (217.40 to 251.55) 
 212.0 
 (193.70 to 230.34) 
Relative cell count, Week 48   8.3 
 (7.68 to 8.85) 
 8.0 
 (7.39 to 8.60) 
Relative cell count, Week 96   10.1 
 (9.35 to 10.75) 
 9.7 
 (8.95 to 10.40) 

No statistical analysis provided for Mean Change From Baseline to Week 48 and Week 96 in Absolute and Relative CD4+ Cell Counts (Using Imputed Data)



9.  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 96 ]

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 lack of virologic response (never having had 2 consecutive plasma viral load <50 copies/mL) and plasma viral load increase of >=0.5 log 10 copies/mL above nadir (i.e., never suppressed), or confirmed loss of virologic response (2 consecutive plasma viral load >=50 copies/mL after having had 2 consecutive plasma viral load <50 copies/mL; i.e., rebounder), or discontinued with a last observed on-treatment plasma viral load >=50 copies/mL after having had 2 consecutive plasma viral load <50 copies/mL. For this study, treatment-emergent reverse transcriptase (RT) resistance associated mutations (RAMs) occurring in at least 2 virologic failures (for at least one treatment group) for the following lists are presented: i) Extended list of Non-nucleoside reverse transcriptase inhibitor (NNRTI RAMs) ii) IAS-USA list of Nucleoside/tide reverse transcriptase inhibitor (N[t]RTI RAMs).
Time Frame Week 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Intent-to-Treat analysis set was considered the primary efficacy analysis set. Here "N" (Number of Participants Analyzed) signifies number of Participants who were evaluable (had data) for this outcome.

Reporting Groups
  Description
TMC278 25 mg tablet once daily
Efavirenz 600 mg once daily

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 34   24 
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   11 
E138K   13   1 
H221Y   3   0 
K101E   3   2 
K103N   0   6 
V90I   2   1 
V106M   0   2 
V189I   2   0 
Y188C   0   2 
Treatment-emergent N(t)RTI RAM   17   6 
K65R   0   2 
K219E   2   0 
M184I   8   1 
M184V   10   3 

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




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide 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
No text entered.


  More Information