increases in the incidence of drug-related neoplasms were observed at the highest dose tested,resulting in dolutegravir AUC exposures 17 times higher than those in humans at therecommended dose.
Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed noevidence of carcinogenic potential at exposures up to 12 times (mice) and 57 times (rats) thehuman exposures at the recommended dose.
Mutagenicity
Dolutegravir: Dolutegravir was not genotoxic in the bacterial reverse mutation assay, in a mouselymphoma assay, or in the in vivo rodent micronucleus assay.
Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenicin a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in amicrobial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test,in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in ratliver.
Impairment of Fertility
Dolutegravir or lamivudine did not affect male or female fertility in rats at doses associated withexposures approximately 44 or 112 times, respectively, higher than the exposures in humans atthe recommended dose.
14 CLINICAL STUDIES
14.1 Clinical Trials in Adult Subjects
The efficacy of DOVATO is supported by data from 2 randomized, double-blind, controlledtrials (GEMINI-1 [NCT02831673] and GEMINI-2 [NCT02831764]) in HIV–1-infected adultswith no antiretroviral treatment history.
GEMINI-1 and GEMINI-2 are identical 148-week, Phase 3, randomized, multicenter, parallelgroup,non-inferiority trials. A total of 1,433 HIV-1–infected adults with no antiretroviraltreatment history received treatment in the trials. Subjects were enrolled with a screening plasma
HIV-1 RNA of 1,000 to ≤500,000 copies/mL and without evidence of major resistanceassociatedmutations or evidence of HBV infection. Subjects were randomized to receive a 2-drug regimen of TIVICAY 50 mg plus EPIVIR 300 mg administered once daily or TIVICAY
50 mg plus fixed-dose TRUVADA administered once daily. The primary efficacy endpoint foreach GEMINI trial was the proportion of subjects with plasma HIV-1 RNA <50 copies/mL atWeek 48 (Snapshot algorithm) who were randomized and treated.
At baseline, in the pooled analysis, the median age of subjects was 33 years, 15% female, 68%white, 9% were CDC Stage 3 (AIDS), the median plasma HIV-1 RNA was 4.4 log10 copies/mL,20% had HIV-1 RNA >100,000 copies/mL, the median CD4+ cell count was 432 cells/mm3
, and8% had CD4+
cell count ≤200 cells/mm3
; these characteristics were similar between trials and
treatment arms within each trial.
The primary endpoint and other outcomes (including outcomes by key baseline covariates) forthe pooled GEMINI-1 and GEMINI-2 trials are shown in Table 11. The results of the pooledanalysis are consistent with the results from the individual trials, for which the primary endpoint(difference in proportion <50 copies/mL plasma HIV-1 RNA at Week 48 based on the Snapshotalgorithm for TIVICAY plus EPIVIR versus TIVICAY plus TRUVADA) was met. The adjusted difference was -2.6 (95% CI: -6.7; 1.5) for GEMINI-1 and -0.7 (95% CI: -4.3; 2.9) for GEMINI-2 with a prespecified non-inferiority margin of 10%. At Week 48, no subjects had any detectabletreatment-emergent substitutions associated with resistance to dolutegravir or NRTIs.
Table 11. Pooled Virologic Outcomes of Randomized |
