and Mutagenesis
Glecaprevir and pibrentasvir were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rodent micronucleus assays.
Carcinogenicity studies with glecaprevir and pibrentasvir have not been conducted.
Impairment of Fertility
No effects on mating, female or male fertility, or early embryonic development were observed in rodents at up to the highest dose tested. Systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 63 and 102 times higher, respectively, than the exposure in humans at the recommended dose.
14 CLINICAL STUDIES
14.1 Description of Clinical Trials
TABLE 10 summarizes the clinical trials conducted to support the effectiveness of MAVYRET in subjects with HCV genotype 1, 2, 3, 4, 5 or 6 infection and compensated liver disease (including Child-Pugh A cirrhosis) according to treatment history and cirrhosis status.
Table 10. Clinical Trials Conducted with MAVYRET in Adults With HCV Genotype 1, 2, 3, 4, 5 or 6 Infection and Compensated Liver Disease
Genotype
(GT) Clinical Trial Treatment Duration*
TN and PRS-TE Subjects Without Cirrhosis
GT1 ENDURANCE-1 MAVYRET for 8 (n=351) or 12 weeks (n=352)
GT2 SURVEYOR-2 MAVYRET for 8 weeks (n=197)
GT3 ENDURANCE-3 MAVYRET for 8 (n=157) or 12 weeks (n=233)
sofosbuvir + daclatasvir for 12 weeks (n=115)
SURVEYOR-2 MAVYRET for 16 (PRS-TE only) weeks (n=22)
GT4, 5, 6 ENDURANCE-4 MAVYRET for 12 weeks (n=26, GT5; n=19, GT6)
SURVEYOR-1 MAVYRET for 12 weeks (n=1, GT5; n=11, GT6)
SURVEYOR-2 MAVYRET for 8 weeks (n=46, GT4; n=2, GT5; n=10 GT6)
TN and PRS-TE Subjects With Compensated Cirrhosis
GT1, 2, 4, 5, 6 EXPEDITION-1 MAVYRET for 12 weeks (n=146)
GT3 SURVEYOR-2 MAVYRET for 12 weeks (TN only) (n=40) or 16 weeks (PRS-TE only) (n=47)
Subjects With CKD Stage 4 and 5 Without Cirrhosis or With Compensated Cirrhosis
GT1-6 EXPEDITION-4 MAVYRET for 12 weeks (n=104)
NS5A Inhibitor or PI-Experienced Subjects Without Cirrhosis or With Compensated Cirrhosis
GT1 MAGELLAN-1 MAVYRET for 12 (n=25) or 16 weeks (n=17)
TN=treatment naïve; PI=protease inhibitor; CKD=chronic kidney disease
PRS-TE= defined as prior treatment experience with regimens containing interferon, pegylated interferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor.
* Treatment durations for some trial arms shown in this table do not reflect recommended dosing for the respective genotypes, prior treatment history, and/or cirrhosis status. For recommended dosing in adults [see Dosage and Administration (2.2)].
Serum HCV RNA values were measured during the clinical trials using the Roche COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL (except for SURVEYOR-1 and SURVEYOR-2 which used the Roche COBAS TaqMan real-time reverse transcriptase-PCR (RT-PCR) assay v. 2.0 with an LLOQ of 25 IU/mL). The primary endpoint across all clinical trials was sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment. Relapse was defined as HCV RNA ≥ LLOQ after end-of-treatment response among subjects who completed treatment. Subjects with missing HCV RNA data, such as thos |
