| Protocol No: | ECCT/12/07/03 | Date of Protocol: | 25-08-2010 |
| Study Title: | A5278 - Pharmacology Substudies of A5263 and A5264 |
| Study Objectives: | Primary Objectives
The overall objective of ACTG 5278s/AMC074 is to investigate the potential for drug-drug interactions among agents used for the chemotherapy of KS and co-formulated EFV/TDF/FTC.
To investigate the effects of the concomitant EFV/TDF/FTC antiretroviral regimen on ET, VCR, and PTX PK in A5263, and assess these concentrations relative to historical controls (which do not include CYP3A inducers such as EFV).
To investigate the effects of the KS chemotherapy used in Arms A, B, and C of A5263 on the PK of EFV regimen and assess these concentrations relative to historical controls.
To investigate the effects of the concomitant EFV/TDF/FTC antiretroviral regimen on ET in A5264 Arm 1B, and assess these concentrations relative to historical controls.
To investigate the effects of ET on the PK parameters of EFV, TDF, and FTC, by comparing PK parameters obtained in A5264 without ET (Arm 1A) versus with ET (Arm 1B).
1.2 Secondary Objectives
1.2.1 To investigate exposure-response relationships between EFV, TDF, and FTC PK parameters and markers of response (including adverse reactions) to HIV and KS treatment, and to investigate exposure-response relationships between ET, VCR, and PTX PK parameters and markers of response (including adverse reactions) to KS treatment.
1.2.2 To compare the effects of the EFV/TDF/FTC antiretroviral regimen in
1.2.3 To investigate the effects of ET on EFV, TDF, and FTC PK through within-subject comparisons of EFV, TDF, and FTC PK parameters, among participants randomized to A5264 Arm 1A who go on to provide PK samples on Arm 2A.
1.2.4 To investigate the effects of the KS chemotherapy used in Arms A, B, and C of A5263 on the PK of TDF and FTC by comparing PK parameters obtained in A5263 Arms A, B and C with those obtained in A5264 Arm 1A.
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| Laymans Summary: | A5278s/AMC 074 will investigate the potential for drug-drug interactions among agents used for the chemotherapy of KS when given with the ART regimen, EFV/TDF/FTC. These investigations will occur as a substudy to the parent protocols A5263 and A5264. In A5263, the primary question to be evaluated is whether KS chemotherapy with ET, BV, and PLD and ART with EFV/TDF/FTC given concomitantly affects the PK characteristics of each other when compared with historical controls (when examining the PK of KS agents) and PK parameters obtained from participants randomized on A5264 to Arm 1A (ARV agents). In A5264, the primary question of whether co administration of ET with EFV/TDF/FTC alters the PK of ET when compared with historical controls will be addressed as well. Additionally, the question of whether the PK of EFV/TDF/FTC is altered in the presence of ET will be investigated in a direct comparison of participants who are randomized to receive initially only the ART regimen, or the ART regimen and ET. PK samples will be collected using a sparse sampling strategy at one specified study day when the participants are receiving concomitant therapy. PK data analysis strategies using nonlinear mixed effects modeling and Bayesian-estimation will be used to obtain estimates of individual and population PK parameters for statistical comparisons. To date, no PK evaluations of these KS and ART regimens have been performed. Therefore, this substudy will provide the first PK data for these agents when used in combination. |
| Abstract of Study: | DESIGN A5278s/AMC 074 is designed to assess the direction and magnitude of pharmacokinetic (PK) interactions between the antiretroviral agents efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) and the Kaposi’s sarcoma (KS) chemotherapy agents etoposide (ET), vincristine (VCR), and pegylated liposomal doxorubicin (PLD). This substudy will coenroll a subset of participants randomized on ACTG parent studies A5263 and A5264 for PK sampling on no more than two occasions. Estimates of participant-specific PK parameters for the parent study agents, obtained by maximum a posteriori (MAP) Bayesian estimation, will be compared to historical control data (KS agents) or estimates obtained for participants on A5264 Arm 1A (antiretroviral agents).
DURATION One or two day PK visit(s)
SAMPLE SIZE A5263: 45 participants who complete the PK blood draw visit; 15 participants in each A5263 arm. Participants enrolled who do not complete the PK visit will be replaced. A5264: 60 participants who complete the PK blood draw; 30 participants in each A5264 arm. Participants enrolled who do not complete the PK visit will be replaced.
POPULATION HIV-1 infected men and women enrolled in A5263 or A5264 |