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Original Research |

Grazoprevir–Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized TrialC-EDGE Treatment-Naive Trial of Grazoprevir–Elbasvir

Stefan Zeuzem, MD; Reem Ghalib, MD; K. Rajender Reddy, MD; Paul J. Pockros, MD; Ziv Ben Ari, MD; Yue Zhao, PhD; Deborah D. Brown, BS; Shuyan Wan, PhD; Mark J. DiNubile, MD; Bach-Yen Nguyen, MD; Michael N. Robertson, MD; Janice Wahl, MD; Eliav Barr, MD; and Joan R. Butterton, MD
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 24 April 2015.


From Goethe University Hospital, Frankfurt, Germany; Texas Clinical Research Institute, Dallas, Texas; University of Pennsylvania, Philadelphia, Pennsylvania; Scripps Translational Science Institute, La Jolla, California; Sheba Medical Center, Ramat Gan, Israel; and Merck & Co., Kenilworth, New Jersey.

Disclaimer: The opinions expressed in this report represent the consensus of the authors and do not necessarily reflect the formal position of Merck & Co.

Acknowledgment: The authors thank all of the patients, health care providers, and investigators (Appendix 2) involved with the C-EDGE Treatment-Naive study. They are indebted to Drs. Fred Lahser and Anita Howe of Merck for performing the sequencing analyses and to Karyn Davis of Merck for technical assistance in preparing this manuscript. Medical writing and editorial assistance was provided by Tim Ibbotson, PhD, and Beth McMahon-Wise, PhD, of ApotheCom. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Kenilworth, New Jersey.

Financial Support: The C-EDGE Treatment-Naive study was sponsored and funded by Merck & Co.

Disclosures: Dr. Zeuzem reports personal fees from AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Janssen, Merck, Novartis, and Roche outside the submitted work. Dr. Reddy reports a grant and a consulting fee/honorarium from Merck during the conduct of the study and board membership with the Chronic Liver Disease Foundation; consultancies with AbbVie, Idenix, Genentech-Roche, Gilead Sciences, Vertex Pharmaceuticals, Janssen, and Bristol-Myers Squibb; grants from AbbVie, Genentech-Roche, Gilead Sciences, Vertex Pharmaceuticals, Janssen, and Bristol-Myers Squibb; royalties from UpToDate; payment from ViralEd for development of educational presentations; and other activities with DSMB-Novartis outside the submitted work. Dr. Pockros reports grants and personal fees from Merck, Gilead Sciences, Bristol-Myers Squibb, AbbVie, and Janssen and other support from Merck and Gilead Sciences outside the submitted work. Dr. Ben Ari reports personal fees from Merck, Gilead Sciences, AbbVie, Bristol-Myers Squibb, and Janssen outside the submitted work. Dr. Wan reports that she is an employee and shareholder at Merck. Dr. DiNubile reports support for travel to meetings for the study or other purposes; an employee salary from Merck during the conduct of the study with stock options; and an employee salary from Merck outside the submitted work. Dr. Robertson reports employment with and stock in Merck during the conduct of the study and outside the submitted work. Dr. Wahl reports employment with Merck during the conduct of the study and outside the submitted work. Dr. Barr reports employment and stock options with Merck and study sponsorship from Merck outside the submitted work. Dr. Butterton reports employment with, salary support from, and stock in Merck during the conduct of the study and outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0785.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.

Requests for Single Reprints: Stefan Zeuzem, MD, Goethe University Hospital, Theodor-Stern-Kai 7, Frankfurt 60590, Germany; e-mail, zeuzem@em.uni-frankfurt.de.

Reproducible Research Statement:Study protocol: See the Appendix. Statistical code: Not available. Data set: Merck's data-sharing policy, including restrictions, is available at http://engagezone.merck.com/ds_documentation.php. Requests for access to the study data can be submitted through the EngageZone site or via e-mail (dataaccess@merck.com).

Current Author Addresses: Dr. Zeuzem: Goethe University Hospital, Theodor-Stern-Kai 7, Frankfurt 60590, Germany.

Dr. Ghalib: Texas Clinical Research Institute, 1009 Magnolia Street, Arlington, TX 76012.

Dr. Reddy: Division of Gastroenterology and Hepatology, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104.

Dr. Pockros: Scripps Translational Science Institute, 3344 North Torrey Pines Court, La Jolla, CA 92037.

Dr. Ari: Sheba Medical Center, Chaim Sheba Medical Center - Tel Hashome, Ramat Gan, Israel 972-3-530-3030.

Drs. Zhao, Wan, DiNubile, Nguyen, Robertson, Wahl, Barr, and Butterton and Ms. Brown: Merck & Co., 2000 Galloping Hill Road, Kenilworth, NJ 07033.

Author Contributions: Conception and design: E. Barr, D.D. Brown, J.R. Butterton, M.N. Robertson, J. Wahl, Y. Zhao.

Analysis and interpretation of the data: E. Barr, Z. Ben Ari, D.D. Brown, J.R. Butterton, M.J. DiNubile, B. Nguyen, P.J. Pockros, K.R. Reddy, M.N. Robertson, J. Wahl, S. Wan, S. Zeuzem, Y. Zhao.

Drafting of the article: D.D. Brown, J.R. Butterton, M.J. DiNubile, B. Nguyen, M.N. Robertson, S. Zeuzem.

Critical revision for important intellectual content: E. Barr, Z. Ben Ari, J.R. Butterton, M.J. DiNubile, R. Ghalib, B. Nguyen, K.R. Reddy, M.N. Robertson, S. Wan, S. Zeuzem.

Final approval of the article: E. Barr, Z. Ben Ari, D.D. Brown, J.R. Butterton, M.J. DiNubile, R. Ghalib, B. Nguyen, P.J. Pockros, K.R. Reddy, M.N. Robertson, J. Wahl, S. Wan, S. Zeuzem.

Provision of study materials or patients: R. Ghalib, K.R. Reddy, S. Zeuzem.

Statistical expertise: R. Ghalib, S. Wan, Y. Zhao.

Obtaining of funding: E. Barr, J. Wahl.

Administrative, technical, or logistic support: E. Barr, D.D. Brown, M.J. DiNubile.

Collection and assembly of data: D.D. Brown, J.R. Butterton, R. Ghalib, P.J. Pockros, K.R. Reddy, S. Zeuzem, Y. Zhao.


Ann Intern Med. 2015;163(1):1-13. doi:10.7326/M15-0785
Text Size: A A A

Background: Novel interferon- and ribavirin-free regimens are needed to treat hepatitis C virus (HCV) infection.

Objective: To evaluate the safety and efficacy of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor) in treatment-naive patients.

Design: Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02105467)

Setting: 60 centers in the United States, Europe, Australia, Scandinavia, and Asia.

Patients: Cirrhotic and noncirrhotic treatment-naive adults with genotype 1, 4, or 6 infection.

Intervention: Oral, once-daily, fixed-dose grazoprevir 100 mg/elbasvir 50 mg for 12 weeks, stratified by fibrosis and genotype. Patients were randomly assigned 3:1 to immediate or deferred therapy.

Measurements: Proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after treatment (SVR12); adverse events in both groups.

Results: Among 421 participants, 194 (46%) were women, 157 (37%) were nonwhite, 382 (91%) had genotype 1 infection, and 92 (22%) had cirrhosis. Of 316 patients receiving immediate treatment, 299 of 316 (95% [95% CI, 92% to 97%]) achieved SVR12, including 144 of 157 (92% [CI, 86% to 96%]) with genotype 1a, 129 of 131 (99% [CI, 95% to 100%]) with genotype 1b, 18 of 18 (100% [CI, 82% to 100%]) with genotype 4, 8 of 10 (80% [CI, 44% to 98%]) with genotype 6, 68 of 70 (97% [CI, 90% to 100%]) with cirrhosis, and 231 of 246 (94% [CI, 90% to 97%]) without cirrhosis. Virologic failure occurred in 13 patients (4%), including 1 case of breakthrough infection and 12 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or both. Serious adverse events occurred in 9 (2.8%) and 3 (2.9%) patients in the active and placebo groups, respectively (difference <0.05 percentage point [CI, −5.4 to 3.1 percentage points]); none were considered drug related. The most common adverse events in the active group were headache (17%), fatigue (16%), and nausea (9%).

Limitation: The study lacked an active-comparator control group and included relatively few genotype 4 and 6 infections.

Conclusion: Grazoprevir–elbasvir achieved high SVR12 rates in treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 infection. This once-daily, all-oral, fixed-combination regimen represents a potent new therapeutic option for chronic HCV infection.

Primary Funding Source: Merck & Co.

Figures

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Figure 1.

Diagram of study design.

DFW = deferred follow-up week; DTW = deferred-treatment week; FU = follow-up; FW = follow-up week; GZR–EBR = grazoprevir–elbasvir; TW = treatment week.

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Grahic Jump Location
Figure 2.

Study flow diagram.

FW12 = follow-up week 12; GZR–EBR = grazoprevir–elbasvir; SVR12 = sustained virologic response at 12 weeks after the end of treatment.

* Three patients in the immediate-treatment group discontinued use of the study drug because of adverse events. One patient discontinued use because of palpitations and anxiety on treatment day 4. Two patients had elevated liver aminotransferase levels: 1 at treatment week 8 and 1 at treatment week 10; they discontinued use of the study drug per protocol. Both remained in the study for follow-up and achieved SVR12.

† One patient in the immediate-treatment group was lost to follow-up after treatment week 6.

‡ One patient had virologic breakthrough at treatment week 8.

§ One patient in the deferred-treatment group discontinued use of the study drug on treatment day 10 because of a rash that developed on treatment day 2.

|| Two patients in the immediate-treatment group died: 1 of an incarcerated hiatal hernia between treatment weeks 2 and 4 and 1 found dead after treatment but before follow-up week 4 (death presumed to be due to an arrhythmia from autopsy-documented coronary disease).

¶ One patient in the deferred-treatment group withdrew from the study after completing 12 weeks of placebo treatment but before receiving active study drug in the deferred active-treatment period.

Grahic Jump Location
Grahic Jump Location
Figure 3.

Rates of sustained virologic response at the primary end point (12 weeks after cessation of study therapy).

For intermittently missing data points, a success was imputed only if both values immediately before or after the missing value were successes. For this study, there were no intermittently missing SVR12 data, so no outcome was imputed as a success for the primary SVR12 end point based on the data analysis plan. There were 2 patients with SVR at 4 weeks after end of treatment imputed as successes, 1 patient with treatment week 4 imputed as a success, and 1 patient with both SVR4 and treatment week 12 imputed as successes by this predetermined rule. All other intermittently missing or nonintermittently missing data were imputed as failures. GT = genotype; SVR12 = sustained virologic response at 12 weeks after the end of treatment.

* Four patients had nonvirologic failure: 2 non–drug-related deaths (strangulated hiatal hernia and presumed cardiac arrhythmia from autopsy-documented coronary disease), 1 drug-related adverse event (palpitations and anxiety on treatment day 4), and 1 dropout.

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Grahic Jump Location
Figure 4.

Subgroup analysis.

Number of patients in the analysis who achieved sustained virologic response. Two patients were missing data for IL28B genotype and were not included in the forest plot. SVR12 was achieved in 1 of these 2 patients (50.0% [CI, 1.3% to 98.7%]). Patients were deemed ineligible for interferon treatment by the investigator if they had comorbid conditions (including autoimmune disorders, inflammatory bowel disease, interstitial lung disease, interstitial nephritis, sarcoidosis, significant psychiatric disease, a seizure disorder, uncontrolled thyroid disease, retinal disease, or poorly controlled diabetes) and were considered at risk for worsening during therapy with interferon. IFN = interferon; SVR12 = sustained virologic response (HCV RNA less than the lower limit of quantitation [<15 IU/mL]) at 12 weeks after the end of treatment.

* Based on the Clopper–Pearson method.

Grahic Jump Location
Grahic Jump Location
Appendix Figure.

Treatment response during the blinded period at treatment weeks (TWs) 2, 4, and 12 and follow-up week (FW) 4 visits by cirrhotic status for full analysis set population.

Top. Proportion of patients with undetectable HCV RNA levels. Bottom. Analysis of the proportion of patients with HCV RNA levels less than the LLOQ. LLOQ = lower limit of quantification; TND = target not detected; TDu = target detected unquantifiable.

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