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Triomune Bioequivalence With Innovators

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ClinicalTrials.gov Identifier: NCT01025830
Recruitment Status : Completed
First Posted : December 4, 2009
Results First Posted : December 4, 2009
Last Update Posted : January 5, 2010
Sponsor:
Collaborator:
University of California, San Francisco
Information provided by:
Makerere University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition HIV/AIDS
Interventions Drug: Triomune
Drug: Zerit/Epivir/Viramune
Enrollment 20
Recruitment Details Subjects were recruited from an ongoing cohort study in Kampala, Uganda. The first subject was recruited in Feb 2006.
Pre-assignment Details Participants received a medical and laboratory examination before assignment. Subjects were excluded if they had active tuberculosis or were anemic. 22 participants were recruited; 22 were screened,2 were excluded (1 did not meet inclusion criteria and 1 refused participation).
Arm/Group Title Generic (Triomune) to Brand (Zerit/Epivir/Viramune) Brand (Zerit/Epivir/Viramune) to Generic (Triomune)
Hide Arm/Group Description Started with generic formulation (Triomune) then switched to brand formulation (Zerit/Epivir/Viramune). started with brand formulation(Zerit/Epivir/Viramune) then switched to generic formulation (Triomune)
Period Title: Generic (Tr) First Then Brand (Ze/Ep/Vi)
Started 8 12
Completed 8 12
Not Completed 0 0
Period Title: Washout Period of 30 Days
Started 8 12
Completed 8 12
Not Completed 0 0
Period Title: Brand (Ze/Ep/Vi) First Then Generic (Tr)
Started 8 12
Completed 8 12
Not Completed 0 0
Arm/Group Title Entire Study Population
Hide Arm/Group Description Includes groups randomized to receive generic formulation and brand formulation
Overall Number of Baseline Participants 20
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants
<=18 years
0
   0.0%
Between 18 and 65 years
20
 100.0%
>=65 years
0
   0.0%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 20 participants
37.4  (6.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants
Female
12
  60.0%
Male
8
  40.0%
Body Mass Index  
Mean (Standard Deviation)
Unit of measure:  Kg/m2
Number Analyzed 20 participants
25.1  (3.4)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 20 participants
68.3  (6.6)
1.Primary Outcome
Title Area Under the Concentration-Time Curve(AUC)
Hide Description Mean Area Under the Plasma Concentration-Time Curve for each drug, log transformed
Time Frame Assessed at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 12 hr post-dosing
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analyzed population consists only of participants who had sufficient plasma samples for analysis.Intent to treat analysis was used. Separate analyses provided for each drug. Results of such a study are not combined.
Arm/Group Title Generic Stavudine Brand Stavudine Generic Nevirapine Brand Nevirapine Generic Lamivudine Brand Lamivudine
Hide Arm/Group Description:
period when subjects were on generic stavudine
period when subjects were on brand stavudine
period when subjects were on generic nevirapine
Period when subjects were on brand nevirapine
period when subjects were on generic lamivudine
Period when subjects were on brand lamivudine
Overall Number of Participants Analyzed 7 11 7 11 7 11
Geometric Mean (Standard Deviation)
Unit of Measure: hour*milligram/liter
3.6  (2.4) 3.4  (3.9) 85.8  (35.2) 79.2  (45.7) 5.2  (2.5) 6.4  (4.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Generic Stavudine, Brand Stavudine
Comments The null hypothesis was that there is a difference in the relative bioavailability of Triomune and brand-name stavudine/lamivudine/nevirapine in HIV-infected Africans. 18 participants were required to provide 80% power to detect approximately a 20% difference on a log scale in AUC0-12h between the brand formulation and the generic formulation. Alpha level of 0.05.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Bioequivalence was defined as a 90% Confidence Interval of the geometric mean ratio between 0.8 and 1.25. Differences between treatments with respect to the outcome and intra- and inter-subject variances were assessed using the mixed effects model. Bootstrapped random errors were used.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments p value not required for this analysis. What counts is the 90% confidence interval of the geometric mean ratio between the two formulation parameters.
Method Non-compartmental model
Comments Mixed random effects model was used to assess difference between treatments and intra- and inter-subject variances.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.1
Confidence Interval 90%
0.87 to 1.38
Estimation Comments the generic is the numerator while the brand is the denominator
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Generic Nevirapine, Brand Nevirapine
Comments The null hypothesis was that there is a difference in the relative bioavailability of Triomune and brand-name stavudine/lamivudine/nevirapine in HIV-infected Africans. 18 participants were required to provide 80% power to detect approximately a 20% difference on a log scale in AUC0-12h between the brand formulation and the generic formulation. Alpha level of 0.05.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Bioequivalence was defined as a 90% Confidence Interval of the geometric mean ratio between 0.8 and 1.25. Differences between treatments with respect to the outcome and intra- and inter-subject variances were assessed using the mixed effects model. Bootstrapped random errors were used.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments p value not required for this analysis. What counts is the 90% confidence interval of the geometric mean ratio between the two formulation parameters.
Method Non-compartmental model
Comments Mixed random effects model was used to assess difference between treatments and intra- and inter-subject variances.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.1
Confidence Interval 90%
0.95 to 1.31
Estimation Comments the generic is the numerator while the brand is the denominator
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Generic Lamivudine, Brand Lamivudine
Comments The null hypothesis was that there is a difference in the relative bioavailability of Triomune and brand-name stavudine/lamivudine/nevirapine in HIV-infected Africans. 18 participants were required to provide 80% power to detect approximately a 20% difference on a log scale in AUC0-12h between the brand formulation and the generic formulation. Alpha level of 0.05.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Bioequivalence was defined as a 90% Confidence Interval of the geometric mean ratio between 0.8 and 1.25. Differences between treatments with respect to the outcome and intra- and inter-subject variances were assessed using the mixed effects model. Bootstrapped random errors were used.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments p value not required for this analysis. What counts is the 90% confidence interval of the geometric mean ratio between the two formulation parameters.
Method Non-compartmental model
Comments Mixed random effects model was used to assess difference between treatments and intra- and inter-subject variances.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 0.8
Confidence Interval 90%
0.65 to 0.99
Estimation Comments the generic is the numerator while the brand is the denominator
2.Secondary Outcome
Title Maximum Plasma Concentration of Drug
Hide Description Maximum concentration of drug in plasma that was attained post dosing
Time Frame Assessed at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 12 hr post-dosing
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analysis used including only participants with sufficient plasma samples for analysis. Separate analyses are given for each drug. Results for this kind of study are not combined.
Arm/Group Title Generic Stavudine Brand Stavudine Generic Nevirapine Brand Nevirapine Generic Lamivudine Brand Lamivudine
Hide Arm/Group Description:
period when subjects were on generic stavudine
period when subjects were on brand stavudine
period when subjects were on generic nevirapine
Period when subjects were on brand nevirapine
period when subjects were on generic lamivudine
Period when subjects were on brand lamivudine
Overall Number of Participants Analyzed 7 11 7 11 7 11
Geometric Mean (Standard Deviation)
Unit of Measure: milligram/liter
1.6  (1.1) 1.3  (2.0) 8.8  (3.1) 8.4  (5.5) 1.0  (0.5) 1.3  (1.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Generic Stavudine, Brand Stavudine
Comments Same as for AUC
Type of Statistical Test Non-Inferiority or Equivalence
Comments same as for AUC
Statistical Test of Hypothesis P-Value [Not Specified]
Comments same as for AUC
Method Non-compartmental model
Comments same as for AUC
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.3
Confidence Interval 90%
0.99 to 1.71
Estimation Comments same as AUC
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Generic Nevirapine, Brand Nevirapine
Comments Same for all three drugs.
Type of Statistical Test Non-Inferiority or Equivalence
Comments same for all three drugs.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments Same for all three drugs.
Method Non-compartmental model
Comments Same for all three drugs.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.1
Confidence Interval 90%
0.95 to 1.23
Estimation Comments Same for all three drugs.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Generic Lamivudine, Brand Lamivudine
Comments Same for all three drugs.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Same for all three drugs.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments Same for all three drugs.
Method Non-compartmental model
Comments Same for all three drugs.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 0.8
Confidence Interval 90%
0.63 to 0.98
Estimation Comments Same for all three drugs.
Time Frame Patients were in the study for 60 days and this is the period over which they were monitored for any adverse events.
Adverse Event Reporting Description After 30 days of taking each formulation subjects were asked if they had experienced any unwanted effects since they started taking the study drug. Responses were recorded in their study charts. During the blood draw period patients were watched for any adverse events.
 
Arm/Group Title Entire Study Population Generic to Brand Brand to Generic
Hide Arm/Group Description Includes groups randomized to receive generic formulation and brand formulation Started with generic formulation then switched to brand formulation started with brand formulation then switched to generic formulation
All-Cause Mortality
Entire Study Population Generic to Brand Brand to Generic
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Entire Study Population Generic to Brand Brand to Generic
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/20 (0.00%)   0/8 (0.00%)   0/12 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Entire Study Population Generic to Brand Brand to Generic
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/20 (0.00%)   0/8 (0.00%)   0/12 (0.00%) 
Stavudine (40mg) was used whereas currently it is Stavudine(30mg) that is recommended for usage. So our results may not be applicable to patients on Stavudine 30mg.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT 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
Name/Title: Jayne Byakika Tusiime
Organization: University of California Berkeley
Phone: 1 510 219 7567
Responsible Party: Jayne Tusiime, University of California, Berkeley
ClinicalTrials.gov Identifier: NCT01025830     History of Changes
Other Study ID Numbers: BETr
First Submitted: April 21, 2009
First Posted: December 4, 2009
Results First Submitted: April 21, 2009
Results First Posted: December 4, 2009
Last Update Posted: January 5, 2010