Study to Determine the Effectiveness and Safety of a Three Drug Antiviral Combination Therapy to Treat Hepatitis C Virus (HCV) Infected Patients Not Previously Treated With Currently Available Medications

Open-Label, Multiple-Dose, Dose Escalation Study to Evaluate the Pharmacodynamics, Pharmacokinetics, and Safety of Coadministration of BMS-650032, BMS-790052, and BMS-791325 When Administered for 24 or 12 Weeks in Treatment-Naïve Subjects Infected With Hepatitis C Virus Genotype 1

The purpose of this study is to estimate the rate of sustained virologic response (SVR) SVR12, where SVR12 is defined as HCV RNA < LOQ (detectable or undetectable) 12 weeks post-treatment in Genotype 1 & Genotype 4 treatment naive patients, and Genotype (GT1) infected patients who are prior null responders to pegIFN/ribavirin

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis C
• Intervention / Treatment: Drug: BMS-791325; Drug: Ribavirin; Drug: BMS-650032; Drug: BMS-790052

Detailed Description

IND numbers: 79,599; 101,943

• Study Type: Interventional
• Enrollment (Actual): 320
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Clichy Cedex, France, 92118
    • Local Institution
  • Creteil Cedex, France, 9410
    • Local Institution
  • Limoges, France, 87042
    • Local Institution
  • Marseille Cedex 08, France, 13285
    • Local Institution
  • Paris Cedex 14, France, 75679
    • Local Institution
• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • Fundacion de Investigacion de Diego
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • The Kirklin Clinic
  • California
    • Coronado, California, United States, 92118
      • Southern California Research Center
    • Los Angeles, California, United States, 90073
      • VA Greater Los Angeles Healthcare System
    • Los Angeles, California, United States, 90036
      • Peter J Ruane Md Inc
    • San Diego, California, United States, 92105
      • Research and Education, Inc.
    • San Diego, California, United States, 92123
      • Medical Associates Research Group
    • San Diego, California, United States, 92114
      • Precision Research Institute, LLC
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver and Hospital
  • District of Columbia
    • Washington, D.C., District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Orlando, Florida, United States, 32803
      • Orlando Immunology Center
    • South Miami, Florida, United States, 33143
      • Miami Research Associates
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Atlanta Gastroenterology Associates, Llc
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center, Inc.
    • Lutherville, Maryland, United States, 21093
      • Johns Hopkins University
  • New Jersey
    • Hillsborough, New Jersey, United States, 08844
      • ID Care
  • New Mexico
    • Santa Fe, New Mexico, United States, 87505
      • Southwest CARE Center
  • New York
    • The Bronx, New York, United States, 10468
      • James J Peters VAMC
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • Options Health Research, LLC
    • Tulsa, Oklahoma, United States, 74135
      • Healthcare Research Consultants
  • Texas
    • Arlington, Texas, United States, 76012
      • Texas Clinical Research Institute
    • Houston, Texas, United States, 77030
      • Research Specialists of Texas
    • San Antonio, Texas, United States, 78215
      • Alamo Medical Research
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • Lifetree Clinical Research
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Metropolitan Research
    • Falls Church, Virginia, United States, 22042
      • Inova Fairfax Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53715
      • Dean Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men and women, ages ≥18 years of age
• Subjects who are naive to HCV treatment, defined as no previous exposure to an Interferon (IFN), Ribavirin (RBV); or any HCV-specific direct acting antiviral or experimental therapy or subjects who are null responders to previous pegylated Interferon alfa (pegIFNα) plus Ribavirin (RBV) treatment

• Subjects should have chronic hepatitis C (CHC) as documented by:

  1. Positive for anti-HCV antibody, HCV RNA, or a positive HCV genotype test at least 6 months prior to screening, and positive for HCV RNA and Anti-HCV antibody at the time of screening, or
  2. Positive for anti-HCV antibody and HCV RNA at the time of screening with a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed prior to enrollment with evidence of CHC disease, such as the presence of fibrosis)
• HCV genotype 1a, 1b or 4 only
• HCV RNA viral load of ≥10,000 IU/mL at screening

• Have one of the following:

  1. Documented Fibrotest score of ≤0.72 and aspartate transferase (transminase) to platelet ratio index (APRI) ≤2; OR
  2. Documented liver biopsy within 36 months preceding Day 1 showing absence of cirrhosis OR
  3. Documented Fibroscan® ultrasound (where approved) within 12 months of screening showing absence of cirrhosis
• Body mass index (BMI) of 18.0 to 35.0 kg/m2, inclusive
• Subjects with compensated Child-Pugh A cirrhosis as documented by history of cirrhosis with any prior liver biopsy or Fibroscan® ultrasound (where approved) within 12 months prior to screening

Exclusion Criteria:

• Evidence of a medical condition associated with chronic liver disease other than HCV (such as but not limited to: hemochromatosis, autoimmune hepatitis,metabolic liver disease, alcoholic liver disease, toxin exposures)
• History of variceal bleeding, hepatic encephalopathy, or ascites requiring management with diuretics or paracentesis
• Current or known history of cancer (except in situ carcinoma of the cervix or adequately treated basal or squamous cell carcinoma of the skin) within 5 years prior to enrollment
• Documented or suspected hepatocellular carcinoma (HCC)
• Positive for hepatitis B surface antigen (HBsAg)
• Positive for Human Immunodeficiency Virus-1 (HIV-1) and/or Human Immunodeficiency Virus-2 (HIV-2) antibodies
• Alanine transferase (transminase) (ALT) >5x upper limit of normal (ULN)
• Total Bilirubin ≥2 mg/dL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

13

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1:BMS-650032(200 mg)+BMS-790052(60 mg)+BMS-791325(75mg); BMS-650032 200 mg tablet by mouth twice daily for 24 Weeks BMS-790052 60 mg tablet by mouth once daily for 24 Weeks BMS 791325 75 mg table by mouth twice daily for 24 Weeks	Drug: BMS-791325; Drug: BMS-650032; Other Names: Asunaprevir (ASV); Drug: BMS-790052; Other Names: Daclatasvir (DCV)
Experimental: Group 2:BMS-650032(200 mg)+BMS-790052(60 mg)+BMS-791325(75mg); BMS-650032 200 mg tablet by mouth twice daily for 12 Weeks BMS-790052 60 mg tablet by mouth once daily for 12 Weeks BMS 791325 75 mg table by mouth twice daily for 12 Weeks	Drug: BMS-791325; Drug: BMS-650032; Other Names: Asunaprevir (ASV); Drug: BMS-790052; Other Names: Daclatasvir (DCV)
Experimental: Group 3:BMS-650032(200 mg)+BMS-790052(60 mg)+BMS-791325(150mg); * Contingent upon review of safety data from all available treated subjects from Groups 1 and 2 BMS-650032 200 mg tablet by mouth twice daily for 24 Weeks BMS-790052 60 mg tablet by mouth once daily for 24 Weeks BMS 791325 150 mg table by mouth twice daily for 24 Weeks	Drug: BMS-791325; Drug: BMS-650032; Other Names: Asunaprevir (ASV); Drug: BMS-790052; Other Names: Daclatasvir (DCV)
Experimental: Group 4:BMS-650032(200 mg)+BMS-790052(60 mg)+BMS-791325(150mg); * Contingent upon review of safety data from all available treated subjects from Groups 1 and 2 BMS-650032 200 mg tablet by mouth twice daily for 12 Weeks BMS-790052 60 mg tablet by mouth once daily for 12 Weeks BMS 791325 150 mg table by mouth twice daily for 12 Weeks	Drug: BMS-791325; Drug: BMS-650032; Other Names: Asunaprevir (ASV); Drug: BMS-790052; Other Names: Daclatasvir (DCV)
Experimental: Group 5:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(75mg); * Genotype 1 treatment-naive subjects BMS-650032 200 mg tablet by mouth twice daily for 12 Weeks BMS-790052 30 mg tablet by mouth twice daily for 12 Weeks BMS 791325 75 mg table by mouth twice daily for 12 Weeks	Drug: BMS-791325; Drug: BMS-650032; Other Names: Asunaprevir (ASV); Drug: BMS-790052; Other Names: Daclatasvir (DCV)
Experimental: Group 6:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(150mg); * Genotype 1 treatment-naive subjects BMS-650032 200 mg tablet by mouth twice daily for 12 Weeks BMS-790052 30 mg tablet by mouth twice daily for 12 Weeks BMS 791325 150 mg table by mouth twice daily for 12 Weeks	Drug: BMS-791325; Drug: BMS-650032; Other Names: Asunaprevir (ASV); Drug: BMS-790052; Other Names: Daclatasvir (DCV)
Experimental: Group 7:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(75mg); * Genotype 4 treatment-naive subjects BMS-650032 200 mg tablet by mouth twice daily for 12 Weeks BMS-790052 30 mg tablet by mouth twice daily for 12 Weeks BMS 791325 75 mg table by mouth twice daily for 12 Weeks	Drug: BMS-791325; Drug: BMS-650032; Other Names: Asunaprevir (ASV); Drug: BMS-790052; Other Names: Daclatasvir (DCV)
Experimental: Group 8:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(150mg); * Genotype 4 treatment-naive subjects BMS-650032 200 mg tablet by mouth twice daily for 12 Weeks BMS-790052 30 mg tablet by mouth twice daily for 12 Weeks BMS 791325 150 mg table by mouth twice daily for 12 Weeks	Drug: BMS-791325; Drug: BMS-650032; Other Names: Asunaprevir (ASV); Drug: BMS-790052; Other Names: Daclatasvir (DCV)
Experimental: Group 9:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(75mg); * Genotype 1 treatment-null/non-responder subjects BMS-650032 200 mg tablet by mouth twice daily for 12 Weeks BMS-790052 30 mg tablet by mouth twice daily for 12 Weeks BMS 791325 75 mg table by mouth twice daily for 12 Weeks	Drug: BMS-791325; Drug: BMS-650032; Other Names: Asunaprevir (ASV); Drug: BMS-790052; Other Names: Daclatasvir (DCV)
Experimental: Group10:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(150mg); * Genotype 1 treatment-null/non-responder subjects BMS-650032 200 mg tablet by mouth twice daily for 12 Weeks BMS-790052 30 mg tablet by mouth twice daily for 12 Weeks BMS 791325 150 mg table by mouth twice daily for 12 Weeks	Drug: BMS-791325; Drug: BMS-650032; Other Names: Asunaprevir (ASV); Drug: BMS-790052; Other Names: Daclatasvir (DCV)
Experimental: Group11:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(75mg); * Genotype 1 treatment-null/non-responder subjects BMS-650032 200 mg tablet by mouth twice daily for 24 Weeks BMS-790052 30 mg tablet by mouth twice daily for 24 Weeks BMS 791325 75 mg table by mouth twice daily for 24 Weeks	Drug: BMS-791325; Drug: BMS-650032; Other Names: Asunaprevir (ASV); Drug: BMS-790052; Other Names: Daclatasvir (DCV)
Experimental: Group12:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(150mg); * Genotype 1 treatment-null/non-responder subjects BMS-650032 200 mg tablet by mouth twice daily for 24 Weeks BMS-790052 30 mg tablet by mouth twice daily for 24 Weeks BMS 791325 150 mg table by mouth twice daily for 24 Weeks	Drug: BMS-791325; Drug: BMS-650032; Other Names: Asunaprevir (ASV); Drug: BMS-790052; Other Names: Daclatasvir (DCV)
Experimental: Grp13:BMS-650032(200mg)+BMS-790052(30mg)+BMS-791325(75mg)+RBV; * Genotype 1 treatment-naive subjects BMS-650032 200 mg tablets orally twice daily 12 weeks BMS-790052 30 mg tablets orally twice daily 12 weeks BMS-791325 75 mg tablets orally twice daily 12 weeks Ribavirin (RBV) tablets orally weight based dosing daily 12 weeks [if subject is < 75 kg: 1000 mg per day orally (2 x 200 mg tablets in AM and 3 x 200 mg tablets in PM), or if ≥ 75 kg: 1200 mg per day orally (3 x 200 mg tablets in AM and 3 x 200 mg tablets in PM]	Drug: BMS-791325; Drug: Ribavirin; Other Names: Copegus®; Drug: BMS-650032; Other Names: Asunaprevir (ASV); Drug: BMS-790052; Other Names: Daclatasvir (DCV)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Sustained virologic response (SVR) at 12 weeks post-treatment (SVR12)	12 weeks post-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with HCV ribonucleic acid (RNA) < limit of quantification (LOQ) (detectable and undetectable)		Weeks 1, 2, 4, 6, 8, 10, 12,14, 16, 18, 20, 22 and 24 weeks of therapy; at end of treatment (EOT) (following 12 or 24 weeks of treatment, by Group); and Weeks 4, 12, 24, 36, and 48 weeks post-treatment
Proportion of subjects with HCV ribonucleic acid (RNA) undetectable		Weeks 1, 2, 4, 6, 8, 10, 12,14, 16, 18, 20, 22 and 24 weeks of therapy; at end of treatment (EOT) (following 12 or 24 weeks of treatment, by Group); and Weeks 4, 12, 24, 36, and 48 weeks post-treatment
Proportion of subjects who experience viral breakthrough	viral breakthrough defined as: Any increase in HCV RNA ≥ 1 log10 from nadir or; Any quantifiable HCV RNA ≥ 25 IU/mL (> LOQ) on or after Week 8	Formal analysis at SVR12, Week 48 of follow up period (or upon occurrence)
Proportion of subjects who experience viral relapse defined as confirmed quantifiable HCV RNA ≥ 25 IU/mL (>LOQ) in a subject with HCV RNA < LOQ or undetectable at End of treatment (EOT)		End of treatment (Maximum up to 24 Weeks)
Maximum observed plasma concentration (Cmax) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712		Day 1 and Day 14
Observed plasma concentration at 12 hours (C12) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712		Day 1 and Day 14
Observed plasma concentration at 24 hours (C24) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712		Day 1 and Day 14
Trough observed plasma concentration (Ctrough) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712		Day 1 and Day 14
Time of maximum observed plasma concentration (Tmax) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712		Day 1 and Day 14
Area under the concentration-time curve in one dosing interval [AUC(TAU)] of BMS-650032, BMS-790052, BMS 791325, and BMS-794712		Day 1 and Day 14
HCV genomic substitutions associated with exposure of BMS-650032, BMS-790052, and BMS-791325		At the time of viral breakthrough or relapse
Frequency of deaths, serious adverse events (SAEs), discontinuations due to adverse events (AEs), severity Grade 3/4 AEs, and severity Grade 3/4 laboratory abnormalities		Formal analysis at week 48 of follow up period (or upon occurrence)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Everson GT, Sims KD, Thuluvath PJ, Lawitz E, Hassanein T, Rodriguez-Torres M, Desta T, Hawkins T, Levin JM, Hinestrosa F, Rustgi V, Schwartz H, Younossi Z, Webster L, Gitlin N, Eley T, Huang SP, McPhee F, Grasela DM, Gardiner DF. Daclatasvir + asunaprevir + beclabuvir +/- ribavirin for chronic HCV genotype 1-infected treatment-naive patients. Liver Int. 2016 Feb;36(2):189-97. doi: 10.1111/liv.12964. Epub 2015 Dec 6.
• Everson GT, Sims KD, Rodriguez-Torres M, Hezode C, Lawitz E, Bourliere M, Loustaud-Ratti V, Rustgi V, Schwartz H, Tatum H, Marcellin P, Pol S, Thuluvath PJ, Eley T, Wang X, Huang SP, McPhee F, Wind-Rotolo M, Chung E, Pasquinelli C, Grasela DM, Gardiner DF. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology. 2014 Feb;146(2):420-9. doi: 10.1053/j.gastro.2013.10.057. Epub 2013 Oct 30.

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2011
• Primary Completion (Actual): March 31, 2014
• Study Completion (Actual): July 31, 2015

Study Registration Dates

• First Submitted: October 18, 2011
• First Submitted That Met QC Criteria: October 18, 2011
• First Posted (Estimate): October 19, 2011

Study Record Updates

• Last Update Posted (Actual): April 27, 2017
• Last Update Submitted That Met QC Criteria: April 26, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites; Protease Inhibitors; Ribavirin; Asunaprevir
• Other Study ID Numbers: AI443-014; 2011-002788-11 (EudraCT Number)