Michael Manns1, Stanislas Pol2, Ira M Jacobson3, Patrick Marcellin4, Stuart C Gordon5, Cheng-Yuan Peng6, Ting-Tsung Chang7, Gregory T Everson8, Jeong Heo9, Guido Gerken10, Boris Yoffe11, William J Towner12, Marc Bourliere13, Sophie Metivier14, Chi-Jen Chu15, William Sievert16, Jean-Pierre Bronowicki17, Dominique Thabut18, Youn-Jae Lee19, Jia-Horng Kao20, Fiona McPhee21, Justin Kopit21, Patricia Mendez22, Misti Linaberry22, Eric Hughes22, Stephanie Noviello22. 1. Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany. Electronic address: manns.michael@mh-hannover.de. 2. Hôpital Cochin, Paris, France. 3. Weill Cornell Medical College, New York, NY, USA. 4. Hôpital Beaujon, Clichy, France. 5. Henry Ford Health Systems, Detroit, MI, USA. 6. School of Medicine, China Medical University, Taichung, Taiwan. 7. National Cheng Kung University Hospital, Tainan, Taiwan. 8. University of Colorado Denver, Aurora, CO, USA. 9. Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, South Korea. 10. University of Duisburg-Essen, Essen, Germany. 11. VAMC, Baylor College of Medicine, Houston, TX, USA. 12. Kaiser Permanente, Los Angeles, CA, USA. 13. Hôpital Saint Joseph, Marseille, France. 14. CHU Purpan, Toulouse, France. 15. Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan. 16. Monash Health and Monash University, Melbourne, VIC, Australia. 17. INSERM Unité 954, Centre Hospitalier Universitaire de Nancy and Université de Lorraine, Vandoeuvre-lès-Nancy, France. 18. Hôpital Pitié-Salpêtrière, Paris, France. 19. Inje University Busan Paik Hospital, Busan, South Korea. 20. National Taiwan University Hospital, Taipei, Taiwan. 21. Bristol-Myers Squibb Research and Development, Wallingford, CT, USA. 22. Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
Abstract
BACKGROUND: An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. METHODS: We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders topeginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant ofpeginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. FINDINGS: This study included 307 treatment-naive patients (205 receiveddaclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85-94) patients in the treatment-naive cohort, 168 (82%, 77-87) in the non-responder cohort, and 192 (82%, 77-87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (≤2% each). INTERPRETATION:Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis. FUNDING: Bristol-Myers Squibb.
RCT Entities:
BACKGROUND: An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. METHODS: We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. FINDINGS: This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85-94) patients in the treatment-naive cohort, 168 (82%, 77-87) in the non-responder cohort, and 192 (82%, 77-87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (≤2% each). INTERPRETATION:Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis. FUNDING: Bristol-Myers Squibb.
Authors: Cindy J Bednasz; Joshua R Sawyer; Anthony Martinez; Patrick G Rose; Samantha S Sithole; Holly R Hamilton; Farzia S Kaufman; Charles S Venuto; Qing Ma; Andrew Talal; Gene D Morse Journal: Future Virol Date: 2015 Impact factor: 1.831
Authors: Stuart C Gordon; Sheri Trudeau; Jia Li; Yueren Zhou; Loralee B Rupp; Scott D Holmberg; Anne C Moorman; Philip R Spradling; Eyasu H Teshale; Joseph A Boscarino; Yihe G Daida; Mark A Schmidt; Mei Lu Journal: J Clin Gastroenterol Date: 2019-01 Impact factor: 3.062