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

View this study on Beta.ClinicalTrials.gov

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)
Enrollment	368

Participant Flow

Recruitment Details	368 participants were enrolled at multiple centers in different countries.
Pre-assignment Details	368 participants were randomly assigned to 4 treatment groups (TMC278 25 mg: 93; TMC278 75 mg: 95; TMC278 150 mg: 91; and Efavirenz: 89). Participant flow through Week 240 was reported for the combined TMC278 and Efavirenz groups, as all TMC278 participants were switched after Week 96 initially to 75 mg and subsequently to 25 mg dose.


Arm/Group Title	All TMC278	Efavirenz
Arm/Group Description	TMC278 25 mg, 75 mg, and 150 mg onc...	Efavirenz 600 mg once daily
Arm/Group Description	TMC278 25 mg, 75 mg, and 150 mg once daily	Efavirenz 600 mg once daily
Period Title: Overall Study
Started	279	89
Completed	165	57
Not Completed	114	32
Reason Not Completed
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

Arm/Group Title		TMC278 25 mg	TMC278 75 mg	TMC 150 mg	Efavirenz	Total
Arm/Group Description		TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily	Efavirenz 600 mg once daily	Total of all reporting groups
Arm/Group Description		TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily	Efavirenz 600 mg once daily	Total of all reporting groups
Overall Number of Baseline Participants		93	95	91	89	368
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	93 participants	95 participants	91 participants	89 participants	368 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	92 98.9%	95 100.0%	89 97.8%	89 100.0%	365 99.2%
	>=65 years	1 1.1%	0 0.0%	2 2.2%	0 0.0%	3 0.8%
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	93 participants	95 participants	91 participants	89 participants	368 participants
		36.7 (8.9)	36.3 (8.3)	35.9 (9.7)	35.4 (8.1)	36.1 (8.75)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	93 participants	95 participants	91 participants	89 participants	368 participants
	Female	28 30.1%	31 32.6%	33 36.3%	29 32.6%	121 32.9%
	Male	65 69.9%	64 67.4%	58 63.7%	60 67.4%	247 67.1%
Region Enroll Measure Type: Number Unit of measure: Participants	Number Analyzed	93 participants	95 participants	91 participants	89 participants	368 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 Outcome


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
Description	The TLOVR algorithm was used to derive response, ie, response and loss...
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

Outcome Measure Data

Analysis Population Description

Intent to treat population: Participants who received at least 1 dose of study medication.


Arm/Group Title	TMC278 25 mg	TMC278 75 mg	TMC278 150 mg	All TMC278	Efavirenz
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily	TMC278 25 mg, 75 mg, and 150 mg onc...	Efaviren 600 mg once daily
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily	TMC278 25 mg, 75 mg, and 150 mg once daily	Efaviren 600 mg once daily
Overall Number of Participants Analyzed	93	95	91	279	89
Measure Type: Number Unit of Measure: Participants
	74	76	70	220	72

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TMC278 25 mg, TMC278 75 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.92
	Comments	The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
	Method	Regression, Logistic
	Comments	This model with factors treatment, region, and Nucleoside/tide reverse transcriptase inhibitors (N[t]RTIs) used, and baseline viral load as covariate.

Method of Estimation	Estimation Parameter	Differences in response rate
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95% -10.4 to 11.3
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TMC278 25 mg, TMC278 150 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.56
	Comments	The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
	Method	Regression, Logistic
	Comments	This model with factors treatment, region, and N(t)RTIs used, and baseline viral load as covariate.

Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	-2.3
	Confidence Interval	(2-Sided) 95% -13.6 to 9.0
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	TMC278 75 mg, TMC278 150 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.62
	Comments	The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
	Method	Regression, Logistic
	Comments	This model with factors treatment, region, and N(t)RTIs used, and baseline viral load as covariate.

Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	-2.8
	Confidence Interval	(2-Sided) 95% -14.0 to 8.4
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	All TMC278, Efavirenz
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.80
	Comments	The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
	Method	Regression, Logistic
	Comments	This model with factors treatment, region, and N(t)RTIs used, and baseline viral load as covariate.

Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95% -10.5 to 7.5
	Estimation Comments	[Not Specified]

2.Secondary Outcome


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
Description	The TLOVR algorithm was used to derive response, ie, response and loss...
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

Outcome Measure Data

Analysis Population Description

Intent to treat population: Participants who received at least 1 dose of study medication.


Arm/Group Title	TMC278 25 mg	TMC278 75 mg	TMC278 150 mg	All TMC278	Efavirenz
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily	TMC278 25 mg, 75 mg, and 150 mg onc...	Efavirenz 600 mg once daily
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily	TMC278 25 mg, 75 mg, and 150 mg once daily	Efavirenz 600 mg once daily
Overall Number of Participants Analyzed	93	95	91	279	89
Measure Type: Number Unit of Measure: Participants
	71	68	65	204	63

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TMC278 25 mg, TMC278 75 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.45
	Comments	The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
	Method	Regression, Logistic
	Comments	This model with factors treatment, region, and Nucleoside/tide reverse transcriptase inhibitors (N[t]RTIs) used, and baseline viral load as covariate.

Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	-4.8
	Confidence Interval	(2-Sided) 95% -17.1 to 7.6
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TMC278 25 mg, TMC278 150 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.45
	Comments	The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
	Method	Regression, Logistic
	Comments	This model with factors treatment, region, and N(t)RTIs used, and baseline viral load as covariate.

Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	-4.8
	Confidence Interval	(2-Sided) 95% -17.3 to 7.7
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	TMC278 75 mg, TMC278 150 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.99
	Comments	The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
	Method	Regression, Logistic
	Comments	This model with factors treatment, region, and N(t)RTIs used, and baseline viral load as covariate.

Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95% -12.9 to 12.8
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	All TMC278, Efavirenz
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.63
	Comments	The significance level for each comparison was 5% (two-sided). No further adjustment of this significance level was applied.
	Method	Regression, Logistic
	Comments	This model with factors treatment, region, and N(t)RTIs used, and baseline viral load as covariate.

Method of Estimation	Estimation Parameter	Differences in response
	Estimated Value	2.6
	Confidence Interval	(2-Sided) 95% -8.1 to 13.3
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis
Description	The analysis is based on the last observed viral load data within the ...
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

Outcome Measure Data

Analysis Population Description

Intent to treat population: Participants who received at least 1 dose of study medication.


Arm/Group Title	TMC278 25 mg	TMC278 75 mg	TMC278 150 mg	All TMC278	Efavirenz
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily	TMC278 25 mg, 75 mg, and 150 mg onc...	Efavirenz 600 mg once daily
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily	TMC278 25 mg, 75 mg, and 150 mg once daily	Efavirenz 600 mg once daily
Overall Number of Participants Analyzed	93	95	91	279	89
Measure Type: Number Unit of Measure: Participants
	71	70	66	207	64

4.Secondary Outcome


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
Description	The TLOVR algorithm was used to derive response, ie, response and loss...
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

Outcome Measure Data

Analysis Population Description

Intent to treat population: Participants who received at least 1 dose of study medication. This was measured at Week 240 for the combined TMC278 and Efavirenz groups, as all TMC278 participants were switched after Week 96 initially to 75 mg and subsequently to 25 mg dose.


Arm/Group Title	All TMC278	Efavirenz
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg onc...	Efavirenz 600 mg once daily
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg once daily	Efavirenz 600 mg once daily
Overall Number of Participants Analyzed	279	89
Measure Type: Number Unit of Measure: Participants
	152	51

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All TMC278, Efavirenz
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	-2.8
	Confidence Interval	95% -14.7 to 9.1
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis
Description	The analysis is based on the last observed viral load data within the ...
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

Outcome Measure Data

Analysis Population Description


Arm/Group Title	All TMC278	Efavirenz
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg onc...	Efavirenz 600 mg once daily
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg once daily	Efavirenz 600 mg once daily
Overall Number of Participants Analyzed	279	89
Measure Type: Number Unit of Measure: Participants
	150	51

6.Secondary Outcome


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
Description	The TLOVR algorithm was used to derive response, ie, response and loss...
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

Outcome Measure Data

Analysis Population Description


Arm/Group Title	All TMC278	Efavirenz
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg onc...	Efavirenz 600 mg once daily
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg once daily	Efavirenz 600 mg once daily
Overall Number of Participants Analyzed	279	89
Measure Type: Number Unit of Measure: Participants
	166	54

7.Secondary Outcome


Title	Change From Baseline in CD4+ Cell Count (Absolute) at Week 96
Description	Change from baseline in CD4+ cell count was imputed in case of missing...
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

Outcome Measure Data

Analysis Population Description

Intent to treat population: Participants who received at least 1 dose of study medication.Efavirenz group, 1 participant was excluded due to missing baseline CD4+ cell count.


Arm/Group Title	TMC278 25mg	TMC278 75 mg	TMC278 150 mg	All TMC278	Efavirenz
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily	TMC278 25 mg, 75 mg, and 150 mg onc...	Efavirenz 600 mg once daily
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily	TMC278 25 mg, 75 mg, and 150 mg once daily	Efavirenz 600 mg once daily
Overall Number of Participants Analyzed	93	95	91	279	88
Mean (Standard Deviation) Unit of Measure: Cells per microliter
	145.9 (117.0)	172.0 (156.5)	158.9 (156.5)	159.0 (144.4)	159.8 (125.7)

8.Secondary Outcome


Title	Change From Baseline in CD4+ Cell Count (Relative) at Week 96
Description	Change from baseline in CD4+ cell count was imputed in case of missing...
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

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) population: Participants who received at least 1 dose of study medication. Efavirenz group, 1 participant was excluded due to missing baseline CD4+ cell count.


Arm/Group Title	TMC278 25mg	TMC278 75 mg	TMC278 150 mg	All TMC278	Efavirenz
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily	TMC278 25 mg, 75 mg, and 150 mg onc...	Efavirenz 600 mg once daily
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily	TMC278 25 mg, 75 mg, and 150 mg once daily	Efavirenz 600 mg once daily
Overall Number of Participants Analyzed	93	95	91	279	88
Mean (Standard Deviation) Unit of Measure: Percentage of CD4+ Cells
	8.6 (6.9)	9.9 (7.3)	9.3 (7.1)	9.3 (7.1)	9.6 (7.0)

9.Secondary Outcome


Title	Change From Baseline in CD4+ Cell Count (Absolute) at Week 240
Description	Change from baseline in CD4+ cell count was imputed in case of missing...
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

Outcome Measure Data

Analysis Population Description

ITT population: Participants who received at least 1 dose of study medication. Efavirenz group, 1 participant was excluded due to missing baseline CD4+ cell count. This was measured at Week 240 for the combined TMC278 and Efavirenz groups, as all TMC278 participants were switched after Week 96 initially to 75 mg and subsequently to 25 mg dose.


Arm/Group Title	All TMC278	Efavirenz
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg onc...	Efavirenz 600 mg once daily
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg once daily	Efavirenz 600 mg once daily
Overall Number of Participants Analyzed	279	88
Mean (Standard Deviation) Unit of Measure: Cells per microliter
	221.0 (227.2)	217.9 (213.7)

10.Secondary Outcome


Title	Change From Baseline in CD4+ Cell Count (Relative) at Week 240
Description	Change from baseline in CD4+ cell count was imputed in case of missing...
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

Outcome Measure Data

Analysis Population Description


Arm/Group Title	All TMC278	Efavirenz
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg onc...	Efavirenz 600 mg once daily
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg once daily	Efavirenz 600 mg once daily
Overall Number of Participants Analyzed	279	88
Mean (Standard Deviation) Unit of Measure: Percentage of CD4+ cells
	8.7 (8.7)	9.7 (9.1)

11.Secondary Outcome


Title	Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure
Description	Virologic failure for the resistance determinations was defined as a v...
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

Outcome Measure Data

Analysis Population Description


Arm/Group Title	All TMC278	Efavirenz
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg onc...	Efavirenz 600 mg once daily
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg once daily	Efavirenz 600 mg once daily
Overall Number of Participants Analyzed	279	89
Measure Type: Number Unit of Measure: 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

12.Secondary Outcome


Title	Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) for TMC278
Description	For each participant, a single value for area under the plasma concent...
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

Outcome Measure Data

Analysis Population Description

Analysis included participants with sufficient number of pharmacokinetic samples in order to derive population pharmacokinetic parameter.


Arm/Group Title	TMC278 25 mg	TMC278 75 mg	TMC278 150 mg
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily
Overall Number of Participants Analyzed	89	93	87
Mean (Standard Deviation) Unit of Measure: ng*h/mL
	2767 (1166)	5906 (2419)	10281 (4208)

13.Secondary Outcome


Title	Trough Plasma Concentration (Ctrough) for TMC278
Description	For each participant, a single value for trough (i.e. predose) plasma ...
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

Outcome Measure Data

Analysis Population Description

Analysis included participants with sufficient number of pharnacokintetic samples in order to derive population pharmacokinetic parameter.


Arm/Group Title	TMC278 25 mg	TMC278 75 mg	TMC278 150 mg
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily
Arm/Group Description:	TMC278 25 mg once daily	TMC278 75 mg once daily	TMC278 150 mg once daily
Overall Number of Participants Analyzed	89	93	87
Mean (Standard Deviation) Unit of Measure: ng/mL
	92.7 (45.2)	196.0 (90.1)	342.0 (154.0)

14.Secondary Outcome


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
Description	Quartile 1, 2, 3 and 4 of AUC24h means the quartile with the lowest 25...
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

Outcome Measure Data

Analysis Population Description

Analysis included participants who received TMC278 with sufficient number of pharnacokintetic samples in order to derive population pharmacokinetic parameter. Participants who discontinued treatment for reasons other than virological failure were excluded from this analysis.


Arm/Group Title	AUC24h Quartile 1	AUC24h Quartile 2	AUC24h Quartile 3	AUC24h Quartile 4
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg onc...	TMC278 25 mg, 75 mg, and 150 mg onc...	TMC278 25 mg, 75 mg, and 150 mg onc...	TMC278 25 mg, 75 mg, and 150 mg onc...
Arm/Group Description:	TMC278 25 mg, 75 mg, and 150 mg once daily	TMC278 25 mg, 75 mg, and 150 mg once daily	TMC278 25 mg, 75 mg, and 150 mg once daily	TMC278 25 mg, 75 mg, and 150 mg once daily
Overall Number of Participants Analyzed	58	54	59	56
Measure Type: Number Unit of Measure: Participants
	48	50	55	51

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.
Adverse Event Reporting 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.

Arm/Group Title	All TMC278	Efavirenz
Arm/Group Description	TMC278 25 mg, 75 mg, and 150 mg onc...	Efavirenz 600 mg once daily
Arm/Group Description	TMC278 25 mg, 75 mg, and 150 mg once daily	Efavirenz 600 mg once daily
All-Cause Mortality
	All TMC278	Efavirenz
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events Serious Adverse Events
	All TMC278	Efavirenz
	Affected / at Risk (%)	Affected / at Risk (%)
Total	49/279 (17.56%)	17/89 (19.10%)
Blood and lymphatic system disorders
Anaemia ^† 1	5/279 (1.79%)	0/89 (0.00%)
Leukopenia ^† 1	1/279 (0.36%)	0/89 (0.00%)
Neutropenia ^† 1	1/279 (0.36%)	0/89 (0.00%)
Cardiac disorders
Acute myocardial infarction ^† 1	1/279 (0.36%)	0/89 (0.00%)
Angina unstable ^† 1	1/279 (0.36%)	0/89 (0.00%)
Supraventricular tachycardia ^† 1	1/279 (0.36%)	0/89 (0.00%)
Gastrointestinal disorders
Abdominal pain ^† 1	1/279 (0.36%)	0/89 (0.00%)
Anal fissure ^† 1	1/279 (0.36%)	0/89 (0.00%)
Anal fistula ^† 1	2/279 (0.72%)	0/89 (0.00%)
Appendicitis perforated ^† 1	1/279 (0.36%)	0/89 (0.00%)
Colitis ^† 1	0/279 (0.00%)	1/89 (1.12%)
Constipation ^† 1	1/279 (0.36%)	0/89 (0.00%)
Diarrhoea haemorrhagic ^† 1	0/279 (0.00%)	1/89 (1.12%)
Intestinal infarction ^† 1	1/279 (0.36%)	0/89 (0.00%)
Intestinal obstruction ^† 1	1/279 (0.36%)	0/89 (0.00%)
Pancreatitis ^† 1	1/279 (0.36%)	0/89 (0.00%)
Pancreatitis acute ^† 1	1/279 (0.36%)	0/89 (0.00%)
Peritonitis ^† 1	0/279 (0.00%)	1/89 (1.12%)
Rectal haemorrhage ^† 1	1/279 (0.36%)	0/89 (0.00%)
General disorders
Chest pain ^† 1	1/279 (0.36%)	0/89 (0.00%)
Death ^† 1	1/279 (0.36%)	0/89 (0.00%)
Pyrexia ^† 1	2/279 (0.72%)	0/89 (0.00%)
Hepatobiliary disorders
Bile duct stone ^† 1	1/279 (0.36%)	0/89 (0.00%)
Cholecystitis acute ^† 1	1/279 (0.36%)	0/89 (0.00%)
Cholelithiasis ^† 1	1/279 (0.36%)	0/89 (0.00%)
Cytolytic hepatitis ^† 1	1/279 (0.36%)	0/89 (0.00%)
Hepatitis ^† 1	1/279 (0.36%)	0/89 (0.00%)
Hepatitis acute ^† 1	0/279 (0.00%)	1/89 (1.12%)
Hydrocholecystis ^† 1	1/279 (0.36%)	0/89 (0.00%)
Infections and infestations
Abscess neck ^† 1	1/279 (0.36%)	0/89 (0.00%)
Appendicitis ^† 1	0/279 (0.00%)	1/89 (1.12%)
Arthritis bacterial ^† 1	1/279 (0.36%)	0/89 (0.00%)
Cellulitis ^† 1	0/279 (0.00%)	1/89 (1.12%)
Clostridial infection ^† 1	1/279 (0.36%)	1/89 (1.12%)
Cytomegalovirus colitis ^† 1	1/279 (0.36%)	0/89 (0.00%)
Hepatitis C ^† 1	0/279 (0.00%)	1/89 (1.12%)
Implant site infection ^† 1	1/279 (0.36%)	0/89 (0.00%)
Lobar pneumonia ^† 1	1/279 (0.36%)	1/89 (1.12%)
Lung infection ^† 1	1/279 (0.36%)	0/89 (0.00%)
Malaria ^† 1	0/279 (0.00%)	1/89 (1.12%)
Meningitis tuberculous ^† 1	1/279 (0.36%)	0/89 (0.00%)
Oral candidiasis ^† 1	1/279 (0.36%)	0/89 (0.00%)
Osteomyelitis ^† 1	1/279 (0.36%)	0/89 (0.00%)
Perianal abscess ^† 1	1/279 (0.36%)	0/89 (0.00%)
Pneumonia ^† 1	3/279 (1.08%)	0/89 (0.00%)
Pneumonia streptococcal ^† 1	1/279 (0.36%)	0/89 (0.00%)
Respiratory tract infection ^† 1	1/279 (0.36%)	0/89 (0.00%)
Sepsis syndrome ^† 1	1/279 (0.36%)	0/89 (0.00%)
Septic shock ^† 1	1/279 (0.36%)	0/89 (0.00%)
Subcutaneous abscess ^† 1	0/279 (0.00%)	2/89 (2.25%)
Injury, poisoning and procedural complications
Ankle fracture ^† 1	1/279 (0.36%)	0/89 (0.00%)
Brain contusion ^† 1	1/279 (0.36%)	0/89 (0.00%)
Drug toxicity ^† 1	1/279 (0.36%)	0/89 (0.00%)
Humerus fracture ^† 1	0/279 (0.00%)	1/89 (1.12%)
Muscle injury ^† 1	0/279 (0.00%)	1/89 (1.12%)
Road traffic accident ^† 1	1/279 (0.36%)	1/89 (1.12%)
Investigations
Alanine aminotransferase increased ^† 1	1/279 (0.36%)	0/89 (0.00%)
Aspartate aminotransferase increased ^† 1	1/279 (0.36%)	0/89 (0.00%)
Blood amylase increased ^† 1	1/279 (0.36%)	1/89 (1.12%)
Metabolism and nutrition disorders
Anorexia ^† 1	1/279 (0.36%)	0/89 (0.00%)
Dehydration ^† 1	1/279 (0.36%)	0/89 (0.00%)
Diabetes mellitus ^† 1	1/279 (0.36%)	0/89 (0.00%)
Metabolic acidosis ^† 1	1/279 (0.36%)	0/89 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	0/279 (0.00%)	1/89 (1.12%)
Back pain ^† 1	1/279 (0.36%)	0/89 (0.00%)
Costochondritis ^† 1	1/279 (0.36%)	0/89 (0.00%)
Lumbar spinal stenosis ^† 1	1/279 (0.36%)	0/89 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Burkitt's lymphoma ^† 1	2/279 (0.72%)	0/89 (0.00%)
Cervix cancer metastatic ^† 1	1/279 (0.36%)	1/89 (1.12%)
Chondrosarcoma metastatic ^† 1	0/279 (0.00%)	1/89 (1.12%)
Kaposi's sarcoma ^† 1	1/279 (0.36%)	0/89 (0.00%)
Lymphoma ^† 1	2/279 (0.72%)	0/89 (0.00%)
Squamous cell carcinoma ^† 1	1/279 (0.36%)	0/89 (0.00%)
Uterine leiomyoma ^† 1	1/279 (0.36%)	0/89 (0.00%)
Nervous system disorders
Epilepsy ^† 1	1/279 (0.36%)	0/89 (0.00%)
Headache ^† 1	0/279 (0.00%)	1/89 (1.12%)
Pregnancy, puerperium and perinatal conditions
Pregnancy ^† 1	0/279 (0.00%)	1/89 (1.12%)
Psychiatric disorders
Depression ^† 1	1/279 (0.36%)	0/89 (0.00%)
Intentional self-injury ^† 1	1/279 (0.36%)	0/89 (0.00%)
Major depression ^† 1	1/279 (0.36%)	0/89 (0.00%)
Suicide attempt ^† 1	1/279 (0.36%)	0/89 (0.00%)
Renal and urinary disorders
Renal failure ^† 1	1/279 (0.36%)	0/89 (0.00%)
Renal impairment ^† 1	1/279 (0.36%)	0/89 (0.00%)
Reproductive system and breast disorders
Ovarian cyst ^† 1	1/279 (0.36%)	0/89 (0.00%)
Prostatitis ^† 1	0/279 (0.00%)	1/89 (1.12%)
Respiratory, thoracic and mediastinal disorders
Alveolitis allergic ^† 1	1/279 (0.36%)	0/89 (0.00%)
Skin and subcutaneous tissue disorders
Rash maculo-papular ^† 1	1/279 (0.36%)	0/89 (0.00%)
Surgical and medical procedures
Ovarian cystectomy ^† 1	1/279 (0.36%)	0/89 (0.00%)
Penile prosthesis insertion ^† 1	1/279 (0.36%)	0/89 (0.00%)
Vascular disorders
Arterial occlusive disease ^† 1	1/279 (0.36%)	0/89 (0.00%)
Deep vein thrombosis ^† 1	0/279 (0.00%)	1/89 (1.12%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 11.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	All TMC278	Efavirenz
	Affected / at Risk (%)	Affected / at Risk (%)
Total	241/279 (86.38%)	82/89 (92.13%)
Blood and lymphatic system disorders
Anaemia ^† 1	24/279 (8.60%)	2/89 (2.25%)
Ear and labyrinth disorders
Vertigo ^† 1	4/279 (1.43%)	10/89 (11.24%)
Eye disorders
Conjunctivitis ^† 1	9/279 (3.23%)	5/89 (5.62%)
Gastrointestinal disorders
Abdominal pain ^† 1	20/279 (7.17%)	4/89 (4.49%)
Abdominal pain upper ^† 1	13/279 (4.66%)	5/89 (5.62%)
Diarrhoea ^† 1	33/279 (11.83%)	16/89 (17.98%)
Dyspepsia ^† 1	36/279 (12.90%)	7/89 (7.87%)
Haemorrhoids ^† 1	10/279 (3.58%)	7/89 (7.87%)
Nausea ^† 1	100/279 (35.84%)	26/89 (29.21%)
Vomiting ^† 1	33/279 (11.83%)	11/89 (12.36%)
General disorders
Fatigue ^† 1	23/279 (8.24%)	4/89 (4.49%)
Pyrexia ^† 1	19/279 (6.81%)	3/89 (3.37%)
Infections and infestations
Body tinea ^† 1	4/279 (1.43%)	7/89 (7.87%)
Bronchitis ^† 1	20/279 (7.17%)	3/89 (3.37%)
Condyloma acuminatum ^† 1	17/279 (6.09%)	3/89 (3.37%)
Gastroenteritis ^† 1	11/279 (3.94%)	5/89 (5.62%)
Herpes simplex ^† 1	25/279 (8.96%)	7/89 (7.87%)
Herpes zoster ^† 1	15/279 (5.38%)	4/89 (4.49%)
Influenza ^† 1	27/279 (9.68%)	8/89 (8.99%)
Nasopharyngitis ^† 1	45/279 (16.13%)	19/89 (21.35%)
Pharyngitis ^† 1	18/279 (6.45%)	4/89 (4.49%)
Respiratory tract infection ^† 1	9/279 (3.23%)	5/89 (5.62%)
Respiratory tract infection viral ^† 1	1/279 (0.36%)	7/89 (7.87%)
Rhinitis ^† 1	12/279 (4.30%)	5/89 (5.62%)
Sinusitis ^† 1	20/279 (7.17%)	3/89 (3.37%)
Tinea pedis ^† 1	8/279 (2.87%)	5/89 (5.62%)
Upper respiratory tract infection ^† 1	49/279 (17.56%)	9/89 (10.11%)
Urinary tract infection ^† 1	21/279 (7.53%)	6/89 (6.74%)
Investigations
Alanine aminotransferase increased ^† 1	21/279 (7.53%)	6/89 (6.74%)
Aspartate aminotransferase increased ^† 1	17/279 (6.09%)	5/89 (5.62%)
Blood cholesterol increased ^† 1	13/279 (4.66%)	11/89 (12.36%)
Low density lipoprotein increased ^† 1	16/279 (5.73%)	9/89 (10.11%)
Metabolism and nutrition disorders
Anorexia ^† 1	19/279 (6.81%)	7/89 (7.87%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	39/279 (13.98%)	11/89 (12.36%)
Back pain ^† 1	31/279 (11.11%)	5/89 (5.62%)
Myalgia ^† 1	18/279 (6.45%)	3/89 (3.37%)
Nervous system disorders
Dizziness ^† 1	31/279 (11.11%)	27/89 (30.34%)
Headache ^† 1	62/279 (22.22%)	15/89 (16.85%)
Somnolence ^† 1	10/279 (3.58%)	10/89 (11.24%)
Psychiatric disorders
Abnormal dreams ^† 1	6/279 (2.15%)	5/89 (5.62%)
Depression ^† 1	19/279 (6.81%)	9/89 (10.11%)
Insomnia ^† 1	23/279 (8.24%)	6/89 (6.74%)
Nightmare ^† 1	1/279 (0.36%)	5/89 (5.62%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	29/279 (10.39%)	12/89 (13.48%)
Skin and subcutaneous tissue disorders
Dry skin ^† 1	14/279 (5.02%)	1/89 (1.12%)
Pruritus ^† 1	18/279 (6.45%)	4/89 (4.49%)
Rash ^† 1	5/279 (1.79%)	7/89 (7.87%)
Seborrhoeic dermatitis ^† 1	7/279 (2.51%)	5/89 (5.62%)
Vascular disorders
Hypertension ^† 1	22/279 (7.89%)	3/89 (3.37%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 11.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

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Name/Title:	Director
Organization:	Janssen-Virco BE
Phone:	32 14 641418

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Pozniak AL, Morales-Ramirez J, Katabira E, Steyn D, Lupo SH, Santoscoy M, Grinsztejn B, Ruxrungtham K, Rimsky LT, Vanveggel S, Boven K; TMC278-C204 Study Group. Efficacy and safety of TMC278 in antiretroviral-naive HIV-1 patients: week 96 results of a phase IIb randomized trial. AIDS. 2010 Jan 2;24(1):55-65. doi: 10.1097/QAD.0b013e32833032ed.

Layout table for additonal information

Responsible Party:	Tibotec Pharmaceuticals, Ireland
ClinicalTrials.gov Identifier:	NCT00110305
Obsolete Identifiers:	NCT00980837
Other Study ID Numbers:	CR006760 TMC278-C204 ( Other Identifier: Tibotec Pharmaceuticals, Ireland ) R278474-C204 ( Other Identifier: Tibotec Pharmaceuticals, Ireland )
First Submitted:	May 5, 2005
First Posted:	May 6, 2005
Results First Submitted:	April 26, 2013
Results First Posted:	October 28, 2013
Last Update Posted:	June 25, 2014

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