Christophe Hézode1, Gideon M Hirschfield2, Wayne Ghesquiere3, William Sievert4, Maribel Rodriguez-Torres5, Stephen D Shafran6, Paul J Thuluvath7, Harvey A Tatum8, Imam Waked9, Gamal Esmat10, Eric J Lawitz11, Vinod K Rustgi12, Stanislas Pol13, Nina Weis14, Paul J Pockros15, Marc Bourlière16, Lawrence Serfaty17, John M Vierling18, Michael W Fried19, Ola Weiland20, Maurizia R Brunetto21, Gregory T Everson22, Stefan Zeuzem23, Paul Y Kwo24, Mark Sulkowski25, Norbert Bräu26, Dennis Hernandez27, Fiona McPhee27, Megan Wind-Rotolo28, Zhaohui Liu29, Stephanie Noviello28, Eric A Hughes28, Philip D Yin27, Steven Schnittman27. 1. Hôpital Henri Mondor, AP-HP, Université Paris-Est, Inserm U955, Créteil, France. 2. Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK. 3. Vancouver Island Health Authority & University of British Columbia, Victoria, British Columbia, Canada. 4. Monash University and Monash Health, Melbourne, Australia. 5. Fundacion De Investigacion, San Juan Bautista School of Medicine, San Juan, Puerto Rico. 6. University of Alberta Hospital, Edmonton, Canada. 7. Mercy Medical Center, Baltimore, Maryland, USA. 8. Options Health Research, LLC, Tulsa, Oklahoma, USA. 9. National Liver Institute, Shebin Elkom, Egypt. 10. Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt. 11. Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA. 12. Metropolitan Research, Fairfax, Virginia, USA. 13. Inserm U1016 and Liver Unit, Université Paris Descartes, Hôpital Cochin, Paris, France. 14. Copenhagen University Hospital, Hvidovre, Denmark. 15. Scripps Clinic, La Jolla, California, USA. 16. Hôpital Saint Joseph, Marseille, France. 17. Hôpital Saint-Antoine, Paris, France. 18. Baylor College of Medicine, Houston, Texas, USA. 19. University of North Carolina, Chapel Hill, North Carolina, USA. 20. Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. 21. Hepatology Unit, University Hospital of Pisa, Pisa, Italy. 22. University of Colorado Denver, Aurora, Colorado, USA. 23. Goethe University, Frankfurt, Germany. 24. Indiana University, Indianapolis, Indiana, USA. 25. Johns Hopkins University, Baltimore, Maryland, USA. 26. James J. Peters VA Medical Center, Bronx, New York, USA. 27. Bristol-Myers Squibb, Clinical Research and Development, Wallingford, Connecticut, USA. 28. Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA. 29. Bristol-Myers Squibb Research and Development, Hopewell, New Jersey, USA.
Abstract
OBJECTIVE: To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. DESIGN: In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA<lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients. RESULTS: Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups. CONCLUSIONS: The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4. TRIAL REGISTRATION NUMBER: NCT01125189. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
RCT Entities:
OBJECTIVE: To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. DESIGN: In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA<lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infectedpatients. RESULTS: Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infectedpatients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups. CONCLUSIONS: The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4. TRIAL REGISTRATION NUMBER: NCT01125189. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Mark S Sulkowski; Walford J Fessel; Adriano Lazzarin; Juan Berenguer; Natalia Zakharova; Hugo Cheinquer; Pierre Côté; Douglas Dieterich; Adrian Gadano; Gail Matthews; Jean-Michel Molina; Christophe Moreno; Juan Antonio Pineda; Federico Pulido; Antonio Rivero; Jurgen Rockstroh; Dennis Hernandez; Fiona McPhee; Timothy Eley; Zhaohui Liu; Patricia Mendez; Eric Hughes; Stephanie Noviello; Peter Ackerman Journal: Hepatol Int Date: 2017-02-16 Impact factor: 6.047
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