A Study to Evaluate the Pharmacokinetic Profile (How the Body Absorbs, Distributes, Metabolizes and Eliminates a Drug) of TMC125 Plus Tenofovir/Emtricitabine Once Daily With or Without Darunavir/r Once Daily in Antiretroviral (ARV) Naive HIV-1 Patients (Patients Have Never Received ARV Treatment).

This study has been completed.
Sponsor:
Collaborator:
Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA
Information provided by:
Tibotec, Inc
ClinicalTrials.gov Identifier:
NCT00534352
First received: September 21, 2007
Last updated: October 18, 2010
Last verified: October 2010
Results First Received: May 6, 2009  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Pharmacokinetics Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: HIV-1 Infection
Intervention: Drug: TMC125; darunavir; ritonavir

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The 42-day open-label main treatment phase of this trial was conducted from 10 December 2007 to 27 May 2008. Four investigators from the US participated in this multicenter trial. A total of 35 subjects were screened and of these, 23 subjects entered the trial and started the first treatment phase

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
TDF/FTC +/- TMC125 +/- DRV/Rtv

In the first part of the trial (Days 1-14), all subjects received TMC125 400 mg once daily (qd) in combination with fixed dose combinations (FDC) of tenofovir disoproxil (TDF)/emtricitabine (FTC) 300/200 mg qd(Truvada®) for 14 days (Treatment A: TMC125 + TDF/FTC ). On Day 14, 24-hour intensive TMC125 pharmacokinetic sampling took place and fasting lipids were assessed.

In the second part of the trial (Days 15-28) darunavir (DRV)/ritonavir (rtv) 800/100 mg qd was added to the regimen (Treatment B: TMC 125 + TDF/FTC + DRV/rtv). On Day 28, 24-hour intensive pharmacokinetic sampling for TMC125, DRV and ritonavir took place and fasting lipids were assessed.

In the third part of the trial (Day 29-42), TMC125 was discontinued and subjects received treatment with DRV/rtv 800/100 mg q.d. and TDF/FTC FDC 300/200 mg qd (Treatment C: DRV/rtv + TDF/FTC).On Day 42, fasting lipids were assessed.

Subjects discontinued or entered the optional open-label extension period DRV/rtv + TDF/FTC.


Participant Flow for 4 periods

Period 1:   Treatment A: TMC125 + TDF/FTC
    TDF/FTC +/- TMC125 +/- DRV/Rtv  
STARTED     23  
COMPLETED     21  
NOT COMPLETED     2  
Physician Decision                 1  
Lost to Follow-up                 1  

Period 2:   Treatment B: TMC125 + TDF/FTC + DRV/Rtv
    TDF/FTC +/- TMC125 +/- DRV/Rtv  
STARTED     21  
COMPLETED     21  
NOT COMPLETED     0  

Period 3:   Treatment C: DRV/Rtv + TDF/FTC
    TDF/FTC +/- TMC125 +/- DRV/Rtv  
STARTED     21  
COMPLETED     20  
NOT COMPLETED     1  
Physician Decision                 1  

Period 4:   Optional Extension: DRV/Rtv + TDF/FTC
    TDF/FTC +/- TMC125 +/- DRV/Rtv  
STARTED     18  
COMPLETED     14  
NOT COMPLETED     4  
Physician Decision                 1  
Lost to Follow-up                 2  
Pregnancy                 1  



  Baseline Characteristics
  Hide 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
TDF/FTC +/- TMC125 +/- DRV/Rtv

In the first part of the trial (Days 1-14), all subjects received TMC125 400 mg once daily (qd) in combination with fixed dose combinations (FDC) of tenofovir disoproxil (TDF)/emtricitabine (FTC) 300/200 mg qd(Truvada®) for 14 days (Treatment A: TMC125 + TDF/FTC ). On Day 14, 24-hour intensive TMC125 pharmacokinetic sampling took place and fasting lipids were assessed.

In the second part of the trial (Days 15-28) darunavir (DRV)/ritonavir (rtv) 800/100 mg qd was added to the regimen (Treatment B: TMC 125 + TDF/FTC + DRV/rtv). On Day 28, 24-hour intensive pharmacokinetic sampling for TMC125, DRV and ritonavir took place and fasting lipids were assessed.

In the third part of the trial (Day 29-42), TMC125 was discontinued and subjects received treatment with DRV/rtv 800/100 mg q.d. and TDF/FTC FDC 300/200 mg qd (Treatment C: DRV/rtv + TDF/FTC).On Day 42, fasting lipids were assessed.

Subjects discontinued or entered the optional open-label extension period DRV/rtv + TDF/FTC.


Baseline Measures
    TDF/FTC +/- TMC125 +/- DRV/Rtv  
Number of Participants  
[units: participants]
  23  
Age  
[units: participants]
 
<=18 years     0  
Between 18 and 65 years     22  
>=65 years     1  
Age  
[units: years]
Mean ± Standard Deviation
  35.87  ± 13.264  
Gender  
[units: participants]
 
Female     3  
Male     20  
Race/Ethnicity, Customized  
[units: participants]
 
Black     9  
Caucasian / White     9  
Hispanic     5  
Region of Enrollment  
[units: participants]
 
United States     23  
CYP2C19 Genotyping [1]
[units: participants]
 
CYP2C19*1/CYP2C19*1 : Normal Phenotype     5  
CYP2C19*1/CYP2C19*17 : Rapid Phenotype     5  
CYP2C19*1/CYP2C19*2 : Intermediate Phenotype     7  
CYP2C19*17/CYP2C19*17 : Ultrarapid Phenotype     1  
CYP2C19*17/CYP2C19*2 : Normal Phenotype     2  
CYP2C19*2/CYP2C19*2 : Poor Phenotype     1  
No data     2  
CYP2C9 Genotyping [1]
[units: participants]
 
CYP2C9*1/CYP2C1*1 : Normal Phenotype     19  
CYP2C9*1/CYP2C1*3 : Intermediate Phenotype     2  
No data     2  
Family History Related to Skin Disease  
[units: participants]
 
No     18  
Yes     5  
Body Mass Index  
[units: kg/m2]
Mean ± Standard Deviation
  26.33  ± 4.629  
Height  
[units: cm]
Mean ± Standard Deviation
  172.73  ± 8.405  
Weight  
[units: kg]
Mean ± Standard Deviation
  78.58  ± 13.711  
[1] There are 21 participants with genotyping data.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Number of Participants Contributing to the Pharmacokinetic (PK) Evaluations: Cmin, Cmax, AUC24 & Css,av   [ Time Frame: 6 weeks ]
  Hide Outcome Measure 1

Measure Type Primary
Measure Title Number of Participants Contributing to the Pharmacokinetic (PK) Evaluations: Cmin, Cmax, AUC24 & Css,av
Measure Description At visit Days 14 & 28, samples were collected pre-dose and at 1, 2, 3, 4, 6, 9, and 12 hours post-dose. An additional sample was taken at 24 hours (Day 15 or 29 as applicable) post-dose.
Time Frame 6 weeks  
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.
Intention To Treat (ITT) population

Reporting Groups
  Description
Treatment A: TMC125 + TDF/FTC Treatment A: TMC125 + TDF/FTC.
Treatment B: TMC125 + TDF/FTC + DRV/Rtv Treatment B: TMC125 + TDF/FTC + DRV/rtv.

Measured Values
    Treatment A: TMC125 + TDF/FTC     Treatment B: TMC125 + TDF/FTC + DRV/Rtv  
Number of Participants Analyzed  
[units: participants]
  23     21  
Number of Participants Contributing to the Pharmacokinetic (PK) Evaluations: Cmin, Cmax, AUC24 & Css,av  
[units: participants]
  23     21  


Statistical Analysis 1 for Number of Participants Contributing to the Pharmacokinetic (PK) Evaluations: Cmin, Cmax, AUC24 & Css,av
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Mixed Models Analysis (Cmin)
P Value [4] NA
Least Square (LS) mean ratio [5] 95.47
90% Confidence Interval ( 82.77 to 110.1 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Previous studies showed that the intrasubject variability on the log transformed Cmax and AUC12h of TMC125 was less than or equal to 40%. Based on this and with complete data on 20 patients, the 90% CI of the true ratio of the means was expected to be contained within 81-124% of the observed ratio of the means.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Equivalence was shown for Cmin as the 90% confidence intervals (CI) of the LSmean ratio was within the 80-125% limits.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  The linear mixed effects model was controlled for treatment as fixed effects, and subject as a random effect.
[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 p-values.
[5] Other relevant estimation information:
  The results are for the mean ratio of Cmin. Numerator: Treatment B Denominator: Treatment A

Statistical Analysis 2 for Number of Participants Contributing to the Pharmacokinetic (PK) Evaluations: Cmin, Cmax, AUC24 & Css,av
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Mixed Models Analysis (Cmax)
P Value [4] NA
Least Square (LS) mean ratio [5] 102.6
90% Confidence Interval ( 92.91 to 113.3 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Previous studies showed that the intrasubject variability on the log transformed Cmax and AUC12h of TMC125 was less than or equal to 40%. Based on this and with complete data on 20 patients, the 90% CI of the true ratio of the means was expected to be contained within 81-124% of the observed ratio of the means.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Equivalence was shown for Cmax as the 90% confidence intervals (CI) of the LSmean ratio was within the 80-125% limits.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  The linear mixed effects model was controlled for treatment as fixed effects, and subject as a random effect.
[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 p-values.
[5] Other relevant estimation information:
  The results are for the mean ratio of Cmax. Numerator: Treatment B Denominator: Treatment A

Statistical Analysis 3 for Number of Participants Contributing to the Pharmacokinetic (PK) Evaluations: Cmin, Cmax, AUC24 & Css,av
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Mixed Models Analysis (AUC24)
P Value [4] NA
LS means of ratios [5] 98.97
90% Confidence Interval ( 89.23 to 109.8 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Previous studies showed that the intrasubject variability on the log transformed Cmax and AUC12h of TMC125 was less than or equal to 40%. Based on this and with complete data on 20 patients, the 90% CI of the true ratio of the means was expected to be contained within 81-124% of the observed ratio of the means.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Equivalence was shown for AUC24 as the 90% confidence intervals (CI) of the LSmean ratio was within the 80-125% limits.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  The linear mixed effects model was controlled for treatment as fixed effects, and subject as a random effect.
[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 p-values.
[5] Other relevant estimation information:
  The results are for the mean ratio of AUC24. Numerator: Treatment B Denominator: Treatment A

Statistical Analysis 4 for Number of Participants Contributing to the Pharmacokinetic (PK) Evaluations: Cmin, Cmax, AUC24 & Css,av
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Mixed Models Analysis (Css,av)
P Value [4] NA
Least Square (LS) mean ratio [5] 99.30
90% Confidence Interval ( 89.39 to 110.3 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Previous studies showed that the intrasubject variability on the log transformed Cmax and AUC12h of TMC125 was less than or equal to 40%. Based on this and with complete data on 20 patients, the 90% CI of the true ratio of the means was expected to be contained within 81-124% of the observed ratio of the means.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Equivalence was shown for Css,av as the 90% confidence intervals (CI) of the LSmean ratio was within the 80-125% limits.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  The linear mixed effects model was controlled for treatment as fixed effects, and subject as a random effect.
[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 p-values.
[5] Other relevant estimation information:
  The results are for the mean ratio of Css,av. Numerator: Treatment B Denominator: Treatment A



2.  Secondary:   Number of Participants With Treatment-Emergent Graded Laboratory Abnormalities (Worst Grade): Glucose-Hyperglycemia   [ Time Frame: Day 1 through 42 and Week 48 ]

3.  Secondary:   Number of Participants With Treatment-Emergent Graded Laboratory Abnormalities (Worst Grade): Glucose- Hypoglycemia   [ Time Frame: Day 1 through 42 and Week 48 ]

4.  Secondary:   Number of Participants With Treatment-Emergent Non-Graded Laboratory Abnormalities(Worst Abnormality): Glucose- Insulin   [ Time Frame: Day 1 through 42 and Week 48 ]

5.  Secondary:   Number of Participants With Treatment-Emergent Graded Laboratory Abnormalities (Worst Grade): Lipids- Total Cholesteral   [ Time Frame: Day 1 through 42 and Week 48 ]

6.  Secondary:   Number of Participants With Treatment-Emergent Non-Graded Laboratory Abnormalities(Worst Abnormality): Lipids- High-density Lipoprotein (HDL)   [ Time Frame: Day 1 through 42 and Week 48 ]

7.  Secondary:   Number of Participants With Treatment-Emergent Graded Laboratory Abnormalities(Worst Grade): Lipids- Low-density Lipoprotein (LDL) Direct   [ Time Frame: Day 1 through 42 and Week 48 ]

8.  Secondary:   Number of Participants With Treatment-Emergent Graded Laboratory Abnormalities(Worst Grade): Lipids- Triglycerides   [ Time Frame: Day 1 through 48 and Week 48 ]

9.  Secondary:   Virologic Response < 50 HIV-1 RNA Copies/mL (ITT-Observed Case)   [ Time Frame: Day 8, 14, 22, 28, 42 and Week 48 ]

10.  Secondary:   Log10 Viral Load (HIV-1 RNA Copies/mL): Mean Changes From Baseline(ITT-Observed Case)   [ Time Frame: Baseline, Day 8, 14, 22, 28 & 42 and Week 48 ]

11.  Secondary:   CD4+ Cell Count (x 10^6 Cell/L): Baseline and Median Changes From Baseline (ITT-Observed Case)   [ Time Frame: Baseline, Day 8, 14, 22, 28 & 42 ans Week 48 ]

12.  Secondary:   CD4+ Cell Count (Percent): Baseline and Median Changes From Baseline (ITT-Observed Case)   [ Time Frame: Baseline, Day 8, 14, 22, 28 & 42 and Week 48 ]


  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