This study was conducted to evaluate the efficacy, safety, and tolerability of switching to a FDC tablet of EVG/COBI/FTC/TAF from regimens containing TDF in virologically suppressed HIV-1 infected adults.
The primary objective was to evaluate the non-inferiority of switching to a TAF containing FDC relative to maintaining TDF containing regimens in virologically suppressed, HIV infected subjects as determined by having HIV-1 RNA ˂ 50 copies/mL at Week 48 (US Food and Drug Administration (FDA) defined snapshot algorithm).
Secondary objectives were similar to studies GS-US-292-0104 and GS-US-292-0111.
The primary efficacy endpoint was the percentage of subjects with HIV-1 RNA < 50 copies/mL at Week 48 using the FDA-defined snapshot algorithm. Secondary endpoints are described in Attachment 2.
All subjects were HIV infected adults drawn from a predefined set of Gilead Sciences (Gilead) clinical studies and were virologically suppressed on one of the following FTC/TDF regimens:
Efavirenz (EFV)/FTC/TDF (Atripla; ATR)
COBI-boosted atazanavir (ATV/co) + FTC/TDF (Truvada; TVD)
Ritonavir (RTV)-boosted atazanavir (ATV/r) + Truvada.
Subjects were randomised in a 2:1 ratio to one of the following two treatment groups: Treatment Group 1: Switch to EVG/COBI/FTC/TAF (n = 1,000), Treatment Group 2: Stay on pre-existing Truvada (FTC/TDF) + 3rd Agent regimen (Stribild, ATR, ATV/co+TVD, or ATV/r+TVD) (n = 500).
Results for primary efficacy outcome
Virologic outcomes at Week 48 were similar between the two treatment groups for the primary endpoint analysis using the Week 48 Full Analysis Set. Virologic success rates at Week 48 were high in both groups (EVG/COBI/FTC/TAF 95.6%; FTC/TDF + 3rd Agent 92.9%; difference in percentages: 2.7%, 95.01% CI: -0.3% to 5.6%), indicating that EVG/COBI/FTC/TAF was non-inferior to FTC/TDF + 3rd Agent. As the lower bound of the 2 sided 95.01% CI of the difference in response rate was greater than the pre-specified -12% margin, switching to EVG/COBI/FTC/TAF was non-inferior to maintaining FTC/TDF + 3rd Agent at Week 48.
Study GS-US-292-0106 was conducted to evaluate the PK, safety, tolerability, and antiviral activity of EVG/COBI/FTC/TAF in HIV-1 infected, antiretroviral treatment (ART) naive adolescents.
Entry criteria included ART naive adolescents, 12 to < 18 years of age, weight ≥ 35 kg, with plasma HIV-1 RNA levels ≥ 1,000 copies/mL, CD4 cell counts > 100 cells/µL, and eGFR ≥ 90 mL/min/1.73 m2 at screening.
The primary objectives were
Part A: To evaluate the steady state PK for EVG and TAF and confirm the dose of the EVG/COBI/FTC/TAF fixed dose combination in HIV-1 infected ART naive adolescents.
Part B: To evaluate the safety and tolerability of the EVG/COBI/FTC/TAF fixed dose combination through Week 24 in HIV-1 infected ART naive adolescents.
The secondary objectives were:
To evaluate the safety and tolerability of the EVG/COBI/FTC/TAF FDC through Week 48 in HIV-1 infected ART naive adolescents and to evaluate the antiviral activity of the EVG/COBI/FTC/TAF FDC through Week 48 in HIV-1 infected, ART naive adolescents.
For Part B, following confirmation of EVG and TAF exposures in at least 18 subjects in Part A and independent data monitoring committee review of preliminary safety and efficacy data, subjects were enrolled in Part B to evaluate the safety, tolerability, and antiviral activity of EVG/COBI/FTC/TAF.
PK results were summarised in the study report. Interim 24 week conclusions by the sponsor included the following:
Based on PK analyses of 24 subjects, the dose of EVG/COBI/FTC/TAF (150/150/200/10 mg) was appropriate for adolescent use
EVG exposure in adolescents administered EVG/COBI/FTC/TAF was similar to that in adults
TAF exposure in adolescents was consistent with the range of exposure associated with antiviral activity in adults despite being lower than that in the adult comparator see Table 15
TFV exposure in adolescents was similar to that in adults
FTC exposure in adolescents was consistent with adult data. COBI exposure in adolescents was lower compared with the adult comparator, but was consistent with historical data and in the range of exposure associated with robust pharmaco-enhancement (boosting)
Nearly all ART naive adolescents who received EVG/COBI/FTC/TAF achieved virologic suppression to < 50 copies/mL at Week 24 (91.3% virologic success rate), further confirming the EVG/COBI/FTC/TAF 150/150/200/10 mg dose in adolescents
The safety profile was acceptable
Few subjects experienced a clinically relevant decrease from baseline in BMD at Week 24
Changes from baseline in serum creatinine and eGFR were consistent with the inhibitory effect of COBI on renal tubular secretion of creatinine, and were not considered reflective of changes in actual glomerular filtration.
Table 15. Pharmacokinetic parameters for EVG, TAF, TFV, COBI, and FTC from adolescent subjects with an adult comparator