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| Name | Class |
|---|---|
| University of California, San Francisco | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Generic | Experimental | generic fixed dose combination of Stavudine, Lamivudine and Nevirapine (Triomune) |
|
| Brand | Active Comparator | 3 separate single pills of Zerit (Stavudine)Epivir (Lamivudine) Viramune (Nevirapine) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Triomune | Drug | Stavudine (40mg) Lamivudine (150mg) Nevirapine (200mg)All twice a day |
|
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Concentration-Time Curve(AUC) | Mean Area Under the Plasma Concentration-Time Curve for each drug, log transformed | Assessed at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 12 hr post-dosing |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Plasma Concentration of Drug | Maximum concentration of drug in plasma that was attained post dosing | Assessed at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 12 hr post-dosing |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jayne Tusiime, B Pharm, MSc | Makerere University | Principal Investigator |
| David R Bangsberg, MD,MPH | Harvard University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Makerere University | Kampala | Uganda |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19096711 | Result | Byakika-Tusiime J, Chinn LW, Oyugi JH, Obua C, Bangsberg DR, Kroetz DL. Steady state bioequivalence of generic and innovator formulations of stavudine, lamivudine, and nevirapine in HIV-infected Ugandan adults. PLoS One. 2008;3(12):e3981. doi: 10.1371/journal.pone.0003981. Epub 2008 Dec 19. |
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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).
Subjects were recruited from an ongoing cohort study in Kampala, Uganda. The first subject was recruited in Feb 2006.
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| ID | Title | Description |
|---|---|---|
| FG000 | Generic (Triomune) to Brand (Zerit/Epivir/Viramune) | Started with generic formulation (Triomune) then switched to brand formulation (Zerit/Epivir/Viramune). |
| FG001 | Brand (Zerit/Epivir/Viramune) to Generic (Triomune) | started with brand formulation(Zerit/Epivir/Viramune) then switched to generic formulation (Triomune) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Generic (Tr) First Then Brand (Ze/Ep/Vi) |
| |||||||||||||
| Washout Period of 30 Days |
| |||||||||||||
| Brand (Ze/Ep/Vi) First Then Generic (Tr) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Entire Study Population | Includes groups randomized to receive generic formulation and brand formulation |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Area Under the Concentration-Time Curve(AUC) | Mean Area Under the Plasma Concentration-Time Curve for each drug, log transformed | 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. | Posted | Geometric Mean | Standard Deviation | hour*milligram/liter | Assessed at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 12 hr post-dosing |
|
Patients were in the study for 60 days and this is the period over which they were monitored for any adverse events.
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Entire Study Population | Includes groups randomized to receive generic formulation and brand formulation |
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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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jayne Byakika Tusiime | University of California Berkeley | 1 510 219 7567 | tusiimej@berkeley.edu |
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| ID | Term |
|---|---|
| D000163 | Acquired Immunodeficiency Syndrome |
| ID | Term |
|---|---|
| D015658 | HIV Infections |
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
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| ID | Term |
|---|---|
| C516355 | stavudine, lamivudine, nevirapine drug combination |
| D018119 | Stavudine |
| D019259 | Lamivudine |
| D019829 | Nevirapine |
| ID | Term |
|---|---|
| D013936 | Thymidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
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| Zerit/Epivir/Viramune | Drug | Stavudine (40mg) Lamivudine (150mg) and Nevirapine (200mg) All taken twice daily. |
|
|
| NOT COMPLETED |
|
| NOT COMPLETED |
|
| Participants |
|
| Age Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Body Mass Index | Mean | Standard Deviation | kg/m2 |
|
| Weight | Mean | Standard Deviation | kg |
|
| OG002 | Generic Nevirapine | period when subjects were on generic nevirapine |
| OG003 | Brand Nevirapine | Period when subjects were on brand nevirapine |
| OG004 | Generic Lamivudine | period when subjects were on generic lamivudine |
| OG005 | Brand Lamivudine | Period when subjects were on brand lamivudine |
|
|
|
| Secondary | Maximum Plasma Concentration of Drug | Maximum concentration of drug in plasma that was attained post dosing | 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. | Posted | Geometric Mean | Standard Deviation | milligram/liter | Assessed at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 12 hr post-dosing |
|
|
|
|
| 0 |
| 20 |
| 0 |
| 20 |
| EG001 | Generic to Brand | Started with generic formulation then switched to brand formulation | 0 | 8 | 0 | 8 |
| EG002 | Brand to Generic | started with brand formulation then switched to generic formulation | 0 | 12 | 0 | 12 |
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| D015229 |
| Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D012897 | Slow Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| D006571 |
| Heterocyclic Compounds |
| D015224 | Dideoxynucleosides |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D016047 | Zalcitabine |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011725 | Pyridines |
Same for all three drugs. |
| Non-compartmental model |
Same for all three drugs. |
Same for all three drugs. |
| Geometric Mean Ratio |
| 1.1 |
| 90 |
| 0.95 |
| 1.23 |
Same for all three drugs. |
| Yes |
| Non-Inferiority or Equivalence |
same for all three drugs. |
| Same for all three drugs. | Non-compartmental model | Same for all three drugs. | Same for all three drugs. | Geometric Mean Ratio | 0.8 | 90 | 0.63 | 0.98 | Same for all three drugs. | Yes | Non-Inferiority or Equivalence | Same for all three drugs. |