Triomune Bioequivalence With Innovators

This study has been completed.
Sponsor:
Collaborator:
University of California, San Francisco
Information provided by:
Makerere University
ClinicalTrials.gov Identifier:
NCT01025830
First received: April 21, 2009
Last updated: December 31, 2009
Last verified: December 2009
Results First Received: April 21, 2009  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Bio-equivalence Study;   Intervention Model: Crossover Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: HIV/AIDS
Interventions: Drug: Triomune
Drug: Zerit/Epivir/Viramune

  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
Subjects were recruited from an ongoing cohort study in Kampala, Uganda. The first subject was recruited in Feb 2006.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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).

Reporting Groups
  Description
Generic (Triomune) to Brand (Zerit/Epivir/Viramune) Started with generic formulation (Triomune) then switched to brand formulation (Zerit/Epivir/Viramune).
Brand (Zerit/Epivir/Viramune) to Generic (Triomune) started with brand formulation(Zerit/Epivir/Viramune) then switched to generic formulation (Triomune)

Participant Flow for 3 periods

Period 1:   Generic (Tr) First Then Brand (Ze/Ep/Vi)
    Generic (Triomune) to Brand (Zerit/Epivir/Viramune)     Brand (Zerit/Epivir/Viramune) to Generic (Triomune)  
STARTED     8     12  
COMPLETED     8     12  
NOT COMPLETED     0     0  

Period 2:   Washout Period of 30 Days
    Generic (Triomune) to Brand (Zerit/Epivir/Viramune)     Brand (Zerit/Epivir/Viramune) to Generic (Triomune)  
STARTED     8     12  
COMPLETED     8     12  
NOT COMPLETED     0     0  

Period 3:   Brand (Ze/Ep/Vi) First Then Generic (Tr)
    Generic (Triomune) to Brand (Zerit/Epivir/Viramune)     Brand (Zerit/Epivir/Viramune) to Generic (Triomune)  
STARTED     8     12  
COMPLETED     8     12  
NOT COMPLETED     0     0  



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

Reporting Groups
  Description
Entire Study Population Includes groups randomized to receive generic formulation and brand formulation

Baseline Measures
    Entire Study Population  
Number of Participants  
[units: participants]
  20  
Age  
[units: participants]
 
<=18 years     0  
Between 18 and 65 years     20  
>=65 years     0  
Age  
[units: years]
Mean ± Standard Deviation
  37.4  ± 6.0  
Gender  
[units: participants]
 
Female     12  
Male     8  
Body Mass Index  
[units: kg/m2]
Mean ± Standard Deviation
  25.1  ± 3.4  
Weight  
[units: kg]
Mean ± Standard Deviation
  68.3  ± 6.6  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Area Under the Concentration-Time Curve(AUC)   [ Time Frame: Assessed at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 12 hr post-dosing ]
  Hide Outcome Measure 1

Measure Type Primary
Measure Title Area Under the Concentration-Time Curve(AUC)
Measure 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  
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.
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.

Reporting Groups
  Description
Generic Stavudine period when subjects were on generic stavudine
Brand Stavudine period when subjects were on brand stavudine
Generic Nevirapine period when subjects were on generic nevirapine
Brand Nevirapine Period when subjects were on brand nevirapine
Generic Lamivudine period when subjects were on generic lamivudine
Brand Lamivudine Period when subjects were on brand lamivudine

Measured Values
    Generic Stavudine     Brand Stavudine     Generic Nevirapine     Brand Nevirapine     Generic Lamivudine     Brand Lamivudine  
Number of Participants Analyzed  
[units: participants]
  7     11     7     11     7     11  
Area Under the Concentration-Time Curve(AUC)  
[units: hour*milligram/liter]
Geometric Mean ± Standard Deviation
  3.6  ± 2.4     3.4  ± 3.9     85.8  ± 35.2     79.2  ± 45.7     5.2  ± 2.5     6.4  ± 4.9  


Statistical Analysis 1 for Area Under the Concentration-Time Curve(AUC)
Groups [1] Generic Stavudine vs. Brand Stavudine
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Non-compartmental model
Geometric Mean Ratio [4] 1.1
90% Confidence Interval ( 0.87 to 1.38 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  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.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed random effects model was used to assess difference between treatments and intra- and inter-subject variances.
[4] Other relevant estimation information:
  the generic is the numerator while the brand is the denominator

Statistical Analysis 2 for Area Under the Concentration-Time Curve(AUC)
Groups [1] Generic Nevirapine vs. Brand Nevirapine
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Non-compartmental model
Geometric Mean Ratio [4] 1.1
90% Confidence Interval ( 0.95 to 1.31 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  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.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed random effects model was used to assess difference between treatments and intra- and inter-subject variances.
[4] Other relevant estimation information:
  the generic is the numerator while the brand is the denominator

Statistical Analysis 3 for Area Under the Concentration-Time Curve(AUC)
Groups [1] Generic Lamivudine vs. Brand Lamivudine
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Non-compartmental model
Geometric Mean Ratio [4] 0.8
90% Confidence Interval ( 0.65 to 0.99 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  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.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed random effects model was used to assess difference between treatments and intra- and inter-subject variances.
[4] Other relevant estimation information:
  the generic is the numerator while the brand is the denominator



2.  Secondary:   Maximum Plasma Concentration of Drug   [ Time Frame: Assessed at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 12 hr post-dosing ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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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
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.


  More Information
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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
e-mail: tusiimej@berkeley.edu


Publications of Results:

Responsible Party: Jayne Tusiime, University of California, Berkeley
ClinicalTrials.gov Identifier: NCT01025830     History of Changes
Other Study ID Numbers: BETr
Study First Received: April 21, 2009
Results First Received: April 21, 2009
Last Updated: December 31, 2009
Health Authority: Uganda: Research Ethics Committee