Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials

Edward J. Gane; Stephen Pianko; Stuart K. Roberts; Alexander J. Thompson; Stefan Zeuzem; Eli Zuckerman; Ziv Ben-Ari; Graham R. Foster; Kosh Agarwal; Alex L. Laursen; Jan Gerstoft; Wei Gao; Hsueh Cheng Huang; Brian Fitzgerald; Doreen Fernsler; Jerry J. Li; Anjana Grandhi; Hong Liu; Feng Hsiu Su; Shuyan Wan; Zhen Zeng; Huei Ling Chen; Frank J. Dutko; Bach Yen T. Nguyen; Janice Wahl; Michael N. Robertson; Eliav Barr; Wendy W. Yeh; Rebeca M. Plank; Joan R. Butterton; Rafael Esteban

doi:10.1016/S2468-1253(17)30159-0

Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials

Edward J. Gane^*, Stephen Pianko, Stuart K. Roberts, Alexander J. Thompson, Stefan Zeuzem, Eli Zuckerman, Ziv Ben-Ari, Graham R. Foster, Kosh Agarwal, Alex L. Laursen, Jan Gerstoft, Wei Gao, Hsueh Cheng Huang, Brian Fitzgerald, Doreen Fernsler, Jerry J. Li, Anjana Grandhi, Hong Liu, Feng Hsiu Su, Shuyan WanZhen Zeng, Huei Ling Chen, Frank J. Dutko, Bach Yen T. Nguyen, Janice Wahl, Michael N. Robertson, Eliav Barr, Wendy W. Yeh, Rebeca M. Plank, Joan R. Butterton, Rafael Esteban

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

19 Citationer (Scopus)

Abstract

Background New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3. Methods Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. Findings 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [91%] of 22). In particular, among those with genotype 2 infection, the grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [94%] of 16) than the grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two (<1%) of 240 participants had serious adverse events (pharyngeal abscess and keratitis), which were not considered drug related by the respective investigators. Interpretation These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV–HIV co-infection. Funding Merck & Co, Inc.

Originalsprog	Engelsk
Tidsskrift	The Lancet Gastroenterology and Hepatology
Vol/bind	2
Udgave nummer	11
Sider (fra-til)	805-813
Antal sider	9
ISSN	2468-1253
DOI	https://doi.org/10.1016/S2468-1253(17)30159-0
Status	Udgivet - 2017

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Citationsformater

Gane, E. J., Pianko, S., Roberts, S. K., Thompson, A. J., Zeuzem, S., Zuckerman, E., Ben-Ari, Z., Foster, G. R., Agarwal, K., Laursen, A. L., Gerstoft, J., Gao, W., Huang, H. C., Fitzgerald, B., Fernsler, D., Li, J. J., Grandhi, A., Liu, H., Su, F. H., ... Esteban, R. (2017). Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials. The Lancet Gastroenterology and Hepatology, 2(11), 805-813. https://doi.org/10.1016/S2468-1253(17)30159-0

Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A) : two randomised, phase 2, open-label trials. / Gane, Edward J.; Pianko, Stephen; Roberts, Stuart K. et al.

I: The Lancet Gastroenterology and Hepatology, Bind 2, Nr. 11, 2017, s. 805-813.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Gane, EJ, Pianko, S, Roberts, SK, Thompson, AJ, Zeuzem, S, Zuckerman, E, Ben-Ari, Z, Foster, GR, Agarwal, K, Laursen, AL, Gerstoft, J, Gao, W, Huang, HC, Fitzgerald, B, Fernsler, D, Li, JJ, Grandhi, A, Liu, H, Su, FH, Wan, S, Zeng, Z, Chen, HL, Dutko, FJ, Nguyen, BYT, Wahl, J, Robertson, MN, Barr, E, Yeh, WW, Plank, RM, Butterton, JR & Esteban, R 2017, 'Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials', The Lancet Gastroenterology and Hepatology, bind 2, nr. 11, s. 805-813. https://doi.org/10.1016/S2468-1253(17)30159-0

Gane EJ, Pianko S, Roberts SK, Thompson AJ, Zeuzem S, Zuckerman E et al. Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials. The Lancet Gastroenterology and Hepatology. 2017;2(11):805-813. doi: 10.1016/S2468-1253(17)30159-0

Gane, Edward J. ; Pianko, Stephen ; Roberts, Stuart K. et al. / Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A) : two randomised, phase 2, open-label trials. I: The Lancet Gastroenterology and Hepatology. 2017 ; Bind 2, Nr. 11. s. 805-813.

@article{be6a11b016694ba9ac458fd2ce0db78d,

title = "Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials",

abstract = "Background New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3. Methods Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. Findings 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [91%] of 22). In particular, among those with genotype 2 infection, the grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [94%] of 16) than the grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two (<1%) of 240 participants had serious adverse events (pharyngeal abscess and keratitis), which were not considered drug related by the respective investigators. Interpretation These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV–HIV co-infection. Funding Merck & Co, Inc.",

author = "Gane, {Edward J.} and Stephen Pianko and Roberts, {Stuart K.} and Thompson, {Alexander J.} and Stefan Zeuzem and Eli Zuckerman and Ziv Ben-Ari and Foster, {Graham R.} and Kosh Agarwal and Laursen, {Alex L.} and Jan Gerstoft and Wei Gao and Huang, {Hsueh Cheng} and Brian Fitzgerald and Doreen Fernsler and Li, {Jerry J.} and Anjana Grandhi and Hong Liu and Su, {Feng Hsiu} and Shuyan Wan and Zhen Zeng and Chen, {Huei Ling} and Dutko, {Frank J.} and Nguyen, {Bach Yen T.} and Janice Wahl and Robertson, {Michael N.} and Eliav Barr and Yeh, {Wendy W.} and Plank, {Rebeca M.} and Butterton, {Joan R.} and Rafael Esteban",

year = "2017",

doi = "10.1016/S2468-1253(17)30159-0",

language = "English",

volume = "2",

pages = "805--813",

journal = "The Lancet Gastroenterology and Hepatology",

issn = "2468-1253",

publisher = "Elsevier Limited",

number = "11",

}

TY - JOUR

T1 - Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A)

T2 - two randomised, phase 2, open-label trials

AU - Gane, Edward J.

AU - Pianko, Stephen

AU - Roberts, Stuart K.

AU - Thompson, Alexander J.

AU - Zeuzem, Stefan

AU - Zuckerman, Eli

AU - Ben-Ari, Ziv

AU - Foster, Graham R.

AU - Agarwal, Kosh

AU - Laursen, Alex L.

AU - Gerstoft, Jan

AU - Gao, Wei

AU - Huang, Hsueh Cheng

AU - Fitzgerald, Brian

AU - Fernsler, Doreen

AU - Li, Jerry J.

AU - Grandhi, Anjana

AU - Liu, Hong

AU - Su, Feng Hsiu

AU - Wan, Shuyan

AU - Zeng, Zhen

AU - Chen, Huei Ling

AU - Dutko, Frank J.

AU - Nguyen, Bach Yen T.

AU - Wahl, Janice

AU - Robertson, Michael N.

AU - Barr, Eliav

AU - Yeh, Wendy W.

AU - Plank, Rebeca M.

AU - Butterton, Joan R.

AU - Esteban, Rafael

PY - 2017

Y1 - 2017

N2 - Background New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3. Methods Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. Findings 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [91%] of 22). In particular, among those with genotype 2 infection, the grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [94%] of 16) than the grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two (<1%) of 240 participants had serious adverse events (pharyngeal abscess and keratitis), which were not considered drug related by the respective investigators. Interpretation These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV–HIV co-infection. Funding Merck & Co, Inc.

AB - Background New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3. Methods Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. Findings 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [91%] of 22). In particular, among those with genotype 2 infection, the grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [94%] of 16) than the grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two (<1%) of 240 participants had serious adverse events (pharyngeal abscess and keratitis), which were not considered drug related by the respective investigators. Interpretation These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV–HIV co-infection. Funding Merck & Co, Inc.

U2 - 10.1016/S2468-1253(17)30159-0

DO - 10.1016/S2468-1253(17)30159-0

M3 - Journal article

AN - SCOPUS:85032275643

SN - 2468-1253

VL - 2

SP - 805

EP - 813

JO - The Lancet Gastroenterology and Hepatology

JF - The Lancet Gastroenterology and Hepatology

IS - 11

ER -