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TMC278-TiDP6-C209: A Clinical Trial in Treatment Naive HIV-1 Patients Comparing TMC278 to Efavirenz in Combination With Tenofovir + Emtricitabine.

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Tibotec Pharmaceuticals, Ireland
ClinicalTrials.gov Identifier:
NCT00540449
First received: October 4, 2007
Last updated: March 1, 2016
Last verified: February 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
Human Immunodeficiency Virus Type 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
One hundred and twelve sites in 21 countries randomized participants. In total, 694 participants were randomized: four participants did not start treatment and 690 participants started treatment (346 in the TMC278 group and 344 in the efavirenz [control ] group).

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Participant Flow:   Overall Study
    TMC278   Efavirenz
STARTED   346   344 
COMPLETED   262   266 
NOT COMPLETED   84   78 
Adverse Event                12                32 
Sponsor's Decision                1                1 
Subject Ineligible To Continue The Trial                2                1 
Lost to Follow-up                19                17 
Subject Non-Compliant                7                5 
Subject Reached A Virologic Endpoint                32                8 
Withdrawal by Subject                10                10 
Not specified                1                4 



  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.
The analysis population included intent to treat (ITT) population defined as all randomized participants who received at least one dose of the study medication.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.
Total Total of all reporting groups

Baseline Measures
   TMC278   Efavirenz   Total 
Overall Participants Analyzed 
[Units: Participants]
 346   344   690 
Age 
[Units: Participants]
     
<=18 years   1   0   1 
Between 18 and 65 years   343   343   686 
>=65 years   2   1   3 
Age 
[Units: Years]
Mean (Standard Deviation)
 37  (9.68)   36.7  (9.51)   36.8  (9.59) 
Gender 
[Units: Participants]
     
Female   78   69   147 
Male   268   275   543 
Region Enroll 
[Units: Participants]
     
Africa   32   31   63 
Asia   47   51   98 
Latin America   60   69   129 
USA, Canada, Europe, Australia   207   193   400 


  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/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/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 ITT analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 346   344 
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/ml) at Week 48 
[Units: Participants]
   
Responder   287   285 
Virologic failure   38   15 
Discontinued due to Adverse Event (AE)   6   25 
Discontinued due to other reason than AE   15   19 


Statistical Analysis 1 for Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/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] -0.4
95% Confidence Interval -5.9 to 5.2
[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 as factor 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:   The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 48   [ Time Frame: Week 48 ]

Measure Type Secondary
Measure Title The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/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 Wk48 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 ITT analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 346   344 
The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 48 
[Units: Participants]
   
Virologic Response HIV RNA <50 copies/mL at Wk 48   285   281 
Virologic Failure   47   24 
No Viral Load Data in 48 week window   14   39 


Statistical Analysis 1 for The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/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] 0.3
95% Confidence Interval -5.4 to 5.9
[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 as factor 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/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/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 ITT analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 346   344 
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/ml) at Week 96 
[Units: Participants]
   
Responder   263   271 
Virologic failure   45   16 
Death   0   3 
Discontinued due to AE   10   29 
Discontinued due to other reason than AE   28   25 


Statistical Analysis 1 for Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/ml) at Week 96
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Regression, Logistic
P Value [4] 0.0055
Difference in proportion of response [5] -3.2
95% Confidence Interval -9.4 to 3.1
[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:
  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 as factor 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.



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

Measure Type Secondary
Measure Title The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/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 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 346   344 
The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 96 
[Units: Participants]
   
Virologic Response, <50 copies/ml   265   268 
Virologic failure   54   27 
No viral load data in the 96 week window   27   49 


Statistical Analysis 1 for The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 96
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Regression, Logistic
P Value [4] 0.0013
Difference in proportion of response [5] -1.7
95% Confidence Interval -8.0 to 4.5
[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:
  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 as factor 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:
  No text entered.



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 15 months for TMC278 and 12 months for Efavirenz after the 96-week visit ]

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 visit (post-Week 96).
Time Frame Variable, ranging from 3 months up to maximum 15 months for TMC278 and 12 months for Efavirenz after the 96-week visit  
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 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 258   271 
Number of Participants With Virological Response (Observed, <50 Copies/ml) at Last On-Treatment Visit (Post-Week 96). 
[Units: Participants]
 245   261 

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/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/ml) at Week 48
Measure Description No text entered.
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 ITT analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 346   344 
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/ml) at Week 48 
[Units: Participants]
 297   293 

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



7.  Secondary:   Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/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/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 ITT analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 346   344 
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/ml) at Week 96 
[Units: Participants]
 273   278 

No statistical analysis provided for Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/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 ITT analysis set was considered the primary efficacy analysis set.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 346   344 
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 (Standard Deviation)
   
Absolute cell count, Week 48   195.5  (151.7)   181.6  (156.9) 
Absolute cell count, Week 96   220.7  (167.1)   226.7  (188.9) 
Relative cell count, Week 48   8.6  (5.8)   8.7  (6.0) 
Relative cell count, Week 96   10.1  (7.5)   10.2  (7.2) 

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 Determination by Emerging Resistance Associated 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 Determination by Emerging Resistance Associated 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 ITT 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 measure.

Reporting Groups
  Description
TMC278 25 milligram (mg) tablet once daily for 96 weeks.
Efavirenz 600 mg once daily for 96 weeks.

Measured Values
   TMC278   Efavirenz 
Participants Analyzed 
[Units: Participants]
 52   18 
Number of Participants With Virologic Failure for the Resistance Determination by Emerging Resistance Associated Mutations: First Available On-Treatment Genotypic Data After Failure 
[Units: Participants]
   
Any RAM from Extended NNRTI RAMs list   29   9 
NNRTI RAM: E138K   18   0 
NNRTI RAM: K101E   5   0 
NNRTI RAM: Y181C   5   0 
NNRTI RAM: V90I   4   0 
NNRTI RAM: V189I   4   0 
NNRTI RAM: H221Y   4   0 
NNRTI RAM: E138Q   3   0 
NNRTI RAM: K103N   1   8 
Any RAM from IAS-USA N(t)RTI RAMs list   31   5 
N(t)RTI RAM: M184I   24   3 
N(t)RTI RAM: M184V   7   3 
N(t)RTI RAM: K065R   3   0 
N(t)RTI RAM: K219E   3   0 
N(t)RTI RAM: Y115F   2   0 

No statistical analysis provided for Number of Participants With Virologic Failure for the Resistance Determination by Emerging Resistance Associated 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