Tenofovir Alafenamide vs. Tenofovir Disoproxil Fumarate
Tenofovir Alafenamide vs. Tenofovir Disoproxil Fumarate
Study 292-0102 is an ongoing randomized, double-blind, double dummy, active controlled, Phase 2 study being conducted in the United States that was approved by the US Food and Drug Administration and by institutional review boards at all sites. HIV-positive treatment-naive adults were considered eligible if they were ≥18 years of age with a plasma HIV-1 RNA ≥5000 copies per milliliter, a CD4 cell count >50 cells per microliter, an HIV-1 genotype showing sensitivity to TFV and emtricitabine (FTC), and an estimated glomerular filtration rate (eGFR; Cockcroft–Gault) of ≥70 mL/min. Patients were excluded if they were hepatitis B or C coinfected, had a new AIDS-defining condition within 30 days of screening, or were pregnant. The study was conducted from December 2011 through April 2013 (week 48 endpoint) and is posted on clinicaltrials.gov (NCT01497899).
Eligible participants were randomized centrally by a third party interactive voice/web response system, stratified by screening HIV-1 RNA (≤ or >,100,000 copies per milliliter), in a 2:1 fashion to receive treatment with either E/C/F/TAF or E/C/F/TDF administered once daily with food; all patients also received matching placebo tablets.
Randomized patients were seen at screening, baseline, and at weeks 2, 4, 8, 12, 16, and then every 8 weeks through week 48. Laboratory analyses (hematology, serum chemistries, CD4 cell count, and urinalysis; Covance Laboratories, Indianapolis, IN), HIV-1 RNA (TaqMan 2.0; Roche Diagnostics, Indianapolis, IN), and physical examinations were performed at all visits. HIV-1 genotype (reverse transcriptase and protease) was tested at screening (GenoSure MG, Monogram Biosciences, South San Francisco, CA). Any patient with confirmed virologic failure (2 consecutive viral load samples >50 copies/mL) and an HIV RNA >400 copies/mL at week 8 or later had the second, confirmatory, sample sent for resistance analysis by GeneSeq Integrase, PhenoSense GT, and PhenoSense Integrase (Monogram Biosciences).
Trough pharmacokinetic (PK) samples were collected at weeks 8, 24, and 48 visits, and population PK samples were collected at weeks 2, 4, 12, 16, 24, and 40. An intensive PK substudy was performed on a subset of patients at week 4 or 8 and included peripheral blood mononuclear cell (PBMC) sampling for intracellular TFV-DP levels.
Dual energy x-ray absorptiometry (DEXA) was used to measure BMD only at the hip and lumbar spine before study drug administration at baseline and every 24 weeks. These were read centrally by BioClinica (Newtown, PA), with investigators and patients blinded to the results. Patients were scanned with the same machine throughout the study, and phantom scans were used for quality assurance across sites. Blood and urine for selected bone and renal biomarkers were collected and analyzed at baseline and weeks 24 and 48.
The primary objective was to determine the efficacy of a regimen containing E/C/F/TAF vs. E/C/F/TDF in HIV-1 treatment-naive adults at week 24 (primary endpoint) and week 48 (secondary endpoint) according to US Food and Drug Administration snapshot analysis (the proportion of patients with HIV-1 RNA <50 copies per milliliter). The sample size of 150 patients (100 in the E/C/F/TAF arm) was chosen to estimate the response rate of HIV-1 RNA <50 copies per milliliter at week 24 and to have 76% power to detect a 1.5% (standard deviation of 3.2%) difference in hip BMD in the E/C/F/TAF arm relative to the E/C/F/TDF treatment group. The safety and tolerability of the 2 treatment arms through 48 weeks of treatment were assessed as secondary endpoints.
An individual patient was considered a treatment success if he or she had HIV-1 RNA <50 copies per milliliter at week 24 without virologic failure (confirmed >50 copies per milliliter in week 24 window). These criteria were also used for the week 48 secondary analysis. Safety analyses included available data from all participants who consented to participate, and who received at least 1 dose of study medication; patients who discontinued were followed up for 30 days after drug discontinuation. Demographic and baseline characteristics were summarized using standard descriptive methods.
Methods
Study Design
Study 292-0102 is an ongoing randomized, double-blind, double dummy, active controlled, Phase 2 study being conducted in the United States that was approved by the US Food and Drug Administration and by institutional review boards at all sites. HIV-positive treatment-naive adults were considered eligible if they were ≥18 years of age with a plasma HIV-1 RNA ≥5000 copies per milliliter, a CD4 cell count >50 cells per microliter, an HIV-1 genotype showing sensitivity to TFV and emtricitabine (FTC), and an estimated glomerular filtration rate (eGFR; Cockcroft–Gault) of ≥70 mL/min. Patients were excluded if they were hepatitis B or C coinfected, had a new AIDS-defining condition within 30 days of screening, or were pregnant. The study was conducted from December 2011 through April 2013 (week 48 endpoint) and is posted on clinicaltrials.gov (NCT01497899).
Eligible participants were randomized centrally by a third party interactive voice/web response system, stratified by screening HIV-1 RNA (≤ or >,100,000 copies per milliliter), in a 2:1 fashion to receive treatment with either E/C/F/TAF or E/C/F/TDF administered once daily with food; all patients also received matching placebo tablets.
Randomized patients were seen at screening, baseline, and at weeks 2, 4, 8, 12, 16, and then every 8 weeks through week 48. Laboratory analyses (hematology, serum chemistries, CD4 cell count, and urinalysis; Covance Laboratories, Indianapolis, IN), HIV-1 RNA (TaqMan 2.0; Roche Diagnostics, Indianapolis, IN), and physical examinations were performed at all visits. HIV-1 genotype (reverse transcriptase and protease) was tested at screening (GenoSure MG, Monogram Biosciences, South San Francisco, CA). Any patient with confirmed virologic failure (2 consecutive viral load samples >50 copies/mL) and an HIV RNA >400 copies/mL at week 8 or later had the second, confirmatory, sample sent for resistance analysis by GeneSeq Integrase, PhenoSense GT, and PhenoSense Integrase (Monogram Biosciences).
Trough pharmacokinetic (PK) samples were collected at weeks 8, 24, and 48 visits, and population PK samples were collected at weeks 2, 4, 12, 16, 24, and 40. An intensive PK substudy was performed on a subset of patients at week 4 or 8 and included peripheral blood mononuclear cell (PBMC) sampling for intracellular TFV-DP levels.
Dual energy x-ray absorptiometry (DEXA) was used to measure BMD only at the hip and lumbar spine before study drug administration at baseline and every 24 weeks. These were read centrally by BioClinica (Newtown, PA), with investigators and patients blinded to the results. Patients were scanned with the same machine throughout the study, and phantom scans were used for quality assurance across sites. Blood and urine for selected bone and renal biomarkers were collected and analyzed at baseline and weeks 24 and 48.
Statistical Methods
The primary objective was to determine the efficacy of a regimen containing E/C/F/TAF vs. E/C/F/TDF in HIV-1 treatment-naive adults at week 24 (primary endpoint) and week 48 (secondary endpoint) according to US Food and Drug Administration snapshot analysis (the proportion of patients with HIV-1 RNA <50 copies per milliliter). The sample size of 150 patients (100 in the E/C/F/TAF arm) was chosen to estimate the response rate of HIV-1 RNA <50 copies per milliliter at week 24 and to have 76% power to detect a 1.5% (standard deviation of 3.2%) difference in hip BMD in the E/C/F/TAF arm relative to the E/C/F/TDF treatment group. The safety and tolerability of the 2 treatment arms through 48 weeks of treatment were assessed as secondary endpoints.
An individual patient was considered a treatment success if he or she had HIV-1 RNA <50 copies per milliliter at week 24 without virologic failure (confirmed >50 copies per milliliter in week 24 window). These criteria were also used for the week 48 secondary analysis. Safety analyses included available data from all participants who consented to participate, and who received at least 1 dose of study medication; patients who discontinued were followed up for 30 days after drug discontinuation. Demographic and baseline characteristics were summarized using standard descriptive methods.