HIV/AIDS
Conditions
Keywords
HIV;Bioequivalence;Triomune
Brief summary
The null hypothesis is that there is a difference in the the relative rate and extent of absorption into the systemic circulation of Triomune and brand-name Stavudine/Lamivudine/Nevirapine in HIV-infected Africans and the alternative hypothesis is that there is no difference in the the relative rate and extent of absorption into the systemic circulation of Triomune and brand-name Stavudine/Lamivudine/Nevirapine in HIV-infected Africans. This is a non-inferiority study.
Detailed description
Generic antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of Lamivudine, Stavudine and Nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune®) or the corresponding brand formulations (Epivir®, Zerit®, and Viramune®). An open-label, randomized, crossover study was carried out in 18 HIV-infected Ugandan subjects stabilized on Triomune-40. Subjects received Lamivudine (150 mg), Stavudine (40 mg), and Nevirapine (200 mg) in either the generic or brand formulation twice a day for 30 days, before switching to the other formulation. At the end of each treatment period, blood samples were collected over 12 h for pharmacokinetic analysis. The main outcome measures were the mean AUC0-12h and Cmax. Bioequivalence was defined as a geometric mean ratio between the generic and brand-name within the 90% confidence interval of 0.8-1.25.
Interventions
DRUGTriomune
Stavudine (40mg) Lamivudine (150mg) Nevirapine (200mg)All twice a day
DRUGZerit/Epivir/Viramune
Stavudine (40mg) Lamivudine (150mg) and Nevirapine (200mg) All taken twice daily.
Sponsors
University of California, San Francisco
Makerere University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. HIV-infected men and non-pregnant women; 2. On Triomune for at least 4 weeks; 3. 18 years or greater; 4. Residing within 15km of Kampala city center
Exclusion criteria
1. Unable to sign or understand informed consent 2. Concurrent medication known to interact with any of the components of Triomune 3. Patients with active TB, malabsorption, nausea, emesis, abdominal discomfort, chronic diarrhoea, documented active clinically relevant hepatitis; 4. Patients expected to change their drug regimen or dosage during the study 5. Those planning to move out of Kampala in the next two months; 6. Hemoglobin \<7.0 mmol/l (men) or \<6.5 mmol/l (women); 7. Alanine aminotransferase or aspartate aminotransferase \>5 times the upper limit of normal; 8. Serum creatinine \> 1.5 times the upper limit of normal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-Time Curve(AUC) | Assessed at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 12 hr post-dosing | Mean Area Under the Plasma Concentration-Time Curve for each drug, log transformed |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration of Drug | Assessed at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 12 hr post-dosing | Maximum concentration of drug in plasma that was attained post dosing |
Countries
Uganda
Participant flow
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).
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes groups randomized to receive generic formulation and brand formulation | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age Continuous | 37.4 years STANDARD_DEVIATION 6 |
| Body Mass Index | 25.1 kg/m2 STANDARD_DEVIATION 3.4 |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 8 Participants |
| Weight | 68.3 kg STANDARD_DEVIATION 6.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 0 / 8 | 0 / 12 |
| serious Total, serious adverse events | 0 / 20 | 0 / 8 | 0 / 12 |
Outcome results
Primary
Area Under the Concentration-Time Curve(AUC)
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
Population: 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 | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Generic Stavudine | Area Under the Concentration-Time Curve(AUC) | 3.6 hour*milligram/liter | Standard Deviation 2.4 |
| Brand Stavudine | Area Under the Concentration-Time Curve(AUC) | 3.4 hour*milligram/liter | Standard Deviation 3.9 |
| Generic Nevirapine | Area Under the Concentration-Time Curve(AUC) | 85.8 hour*milligram/liter | Standard Deviation 35.2 |
| Brand Nevirapine | Area Under the Concentration-Time Curve(AUC) | 79.2 hour*milligram/liter | Standard Deviation 45.7 |
| Generic Lamivudine | Area Under the Concentration-Time Curve(AUC) | 5.2 hour*milligram/liter | Standard Deviation 2.5 |
| Brand Lamivudine | Area Under the Concentration-Time Curve(AUC) | 6.4 hour*milligram/liter | Standard Deviation 4.9 |
Comparison: 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 0.05.90% CI: [0.87, 1.38]Non-compartmental model
Comparison: 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 0.05.90% CI: [0.95, 1.31]Non-compartmental model
Comparison: 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 0.05.90% CI: [0.65, 0.99]Non-compartmental model
Secondary
Maximum Plasma Concentration of Drug
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
Population: 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 | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Generic Stavudine | Maximum Plasma Concentration of Drug | 1.6 milligram/liter | Standard Deviation 1.1 |
| Brand Stavudine | Maximum Plasma Concentration of Drug | 1.3 milligram/liter | Standard Deviation 2 |
| Generic Nevirapine | Maximum Plasma Concentration of Drug | 8.8 milligram/liter | Standard Deviation 3.1 |
| Brand Nevirapine | Maximum Plasma Concentration of Drug | 8.4 milligram/liter | Standard Deviation 5.5 |
| Generic Lamivudine | Maximum Plasma Concentration of Drug | 1.0 milligram/liter | Standard Deviation 0.5 |
| Brand Lamivudine | Maximum Plasma Concentration of Drug | 1.3 milligram/liter | Standard Deviation 1.4 |
Comparison: Same as for AUC90% CI: [0.99, 1.71]Non-compartmental model
Comparison: Same for all three drugs.90% CI: [0.95, 1.23]Non-compartmental model
Comparison: Same for all three drugs.90% CI: [0.63, 0.98]Non-compartmental model