Study to Determine the Effectiveness of Antiviral Combination Therapy to Treat Hepatitis C Virus (HCV) Infected Patients Who Have Previously Failed Standard of Care

Parallel, Open-Label, Randomized, Multiple-Dose Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of BMS-790052 and BMS-650032 in Combination in Null Responders to Standard of Care Infected With Chronic Hepatitis C Virus Genotype 1

The purpose of this study is to determine whether BMS-650032 and BMS-790052 in combination alone, together with Ribavirin, or together with Interferon and Ribavirin are effective in the treatment of Hepatitis C in patients who have not responded to prior therapy.

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis C
• Intervention / Treatment: Drug: BMS-790052; Drug: BMS-650032; Drug: BMS-650032; Drug: BMS-650032; Drug: Pegylated-interferon alfa-2a; Drug: Ribavirin

• Study Type: Interventional
• Enrollment (Actual): 215
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Clichy Cedex, France, 92118
    • Local Institution
  • Creteil Cedex, France, 94010
    • Local Institution
  • Marseille Cedex 08, France, 13285
    • Local Institution
  • Paris Cedex 12, France, 75571
    • Local Institution
  • Paris Cedex 13, France, 75651
    • Local Institution
  • Paris Cedex 14, France, 75679
    • Local Institution
  • Pessac, France, 33604
    • Local Institution
• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • Local Institution
• United States
  • California
    • Anaheim, California, United States, 92801
      • Advanced Clinical Research Institute
    • Coronado, California, United States, 92118
      • Southern California Liver Centers
    • San Jose, California, United States, 95128
      • San Jose Gastroenterology
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University Of Colorado Denver & Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
  • North Carolina
    • Statesville, North Carolina, United States, 28677
      • Carolinas Center For Liver Disease
  • Texas
    • Arlington, Texas, United States, 76012
      • Texas Clinical Research Institute, LLC
    • San Antonio, Texas, United States, 78215
      • Alamo Medical Research
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Metropolitan Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female subjects ages 18 to 70 years
• HCV-Infected Genotype 1 Null responders to current standard of care
• Expansion Cohorts A1 and A2 are restricted to patients infected with HCV Genotype 1b only.

Exclusion Criteria:

• Evidence of a medical condition associate with chronic liver disease other than HCV
• History of variceal bleeding, hepatic encephalopathy, or ascites requiring management with diuretics or paracentesis
• History of Cancer within 5 years of enrollment
• History of gastrointestinal disease or surgical procedure (except Cholecystectomy)
• History of clinically significant cardiac disease
• History of Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Documented cirrhosis within 12 months prior to dosing
• Positive for Human Immunodeficiency Virus (HIV) or Hepatitis B Virus (HBV)
• Pregnant

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

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Sentinel A; BMS-790052 (60mg) once daily + BMS-650032 (600 mg) twice daily	Drug: BMS-790052; Tablets, Oral, 60 mg, once daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 600 mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200 mg, once daily, 24 weeks
Experimental: Arm 2: Sentinel B; BMS-790052 (60mg) once daily + BMS-650032 (600mg) twice daily + Pegylated-interferon alfa-2a + Ribavirin	Drug: BMS-790052; Tablets, Oral, 60 mg, once daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 600 mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200 mg, once daily, 24 weeks; Drug: Pegylated-interferon alfa-2a; Syringe, Subcutaneous Injection, 180 µg, once weekly; Other Names: Pegasys; Drug: Ribavirin; Tablets, Oral For subjects weighing < 75 kg: 1000 mg; For subjects weighing ≥ 75 kg: 1200 mg Twice daily (< 75 kg: 400 mg in ante meridian (AM) and 600 mg in post meridian (PM); ≥ 75 kg: 600 mg in AM and PM), 24 weeks; Other Names: Copegus
Experimental: Arm 3: Expansion A1; BMS-790052 (60mg) once daily + BMS-650032 (200mg) twice daily	Drug: BMS-790052; Tablets, Oral, 60 mg, once daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 600 mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200 mg, once daily, 24 weeks
Experimental: Arm 4: Expansion A2; BMS-790052 (60mg) once daily + BMS-650032 (200mg) once daily	Drug: BMS-790052; Tablets, Oral, 60 mg, once daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 600 mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200 mg, once daily, 24 weeks
Experimental: Arm 5: Expansion B1; BMS-790052 (60mg) once daily + BMS-650032 (200 mg) twice daily + Pegylated-interferon alfa-2a + Ribavirin	Drug: BMS-790052; Tablets, Oral, 60 mg, once daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 600 mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200 mg, once daily, 24 weeks; Drug: Pegylated-interferon alfa-2a; Syringe, Subcutaneous Injection, 180 µg, once weekly; Other Names: Pegasys; Drug: Ribavirin; Tablets, Oral For subjects weighing < 75 kg: 1000 mg; For subjects weighing ≥ 75 kg: 1200 mg Twice daily (< 75 kg: 400 mg in ante meridian (AM) and 600 mg in post meridian (PM); ≥ 75 kg: 600 mg in AM and PM), 24 weeks; Other Names: Copegus
Experimental: Arm 6: Expansion B2; BMS-790052 (60mg) once daily + BMS-650032 (200 mg) once daily + Pegylated-interferon alfa-2a + Ribavirin	Drug: BMS-790052; Tablets, Oral, 60 mg, once daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 600 mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200 mg, once daily, 24 weeks; Drug: Pegylated-interferon alfa-2a; Syringe, Subcutaneous Injection, 180 µg, once weekly; Other Names: Pegasys; Drug: Ribavirin; Tablets, Oral For subjects weighing < 75 kg: 1000 mg; For subjects weighing ≥ 75 kg: 1200 mg Twice daily (< 75 kg: 400 mg in ante meridian (AM) and 600 mg in post meridian (PM); ≥ 75 kg: 600 mg in AM and PM), 24 weeks; Other Names: Copegus
Experimental: Arm 7: Expansion B3; BMS-790052 (60 mg) once daily + BMS-650032 (200 mg) twice daily + Ribavirin	Drug: BMS-790052; Tablets, Oral, 60 mg, once daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 600 mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200mg, twice daily, 24 weeks; Drug: BMS-650032; Tablets, Oral, 200 mg, once daily, 24 weeks; Drug: Ribavirin; Tablets, Oral For subjects weighing < 75 kg: 1000 mg; For subjects weighing ≥ 75 kg: 1200 mg Twice daily (< 75 kg: 400 mg in ante meridian (AM) and 600 mg in post meridian (PM); ≥ 75 kg: 600 mg in AM and PM), 24 weeks; Other Names: Copegus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Hepatitis C virus (HCV) ribonucleic acid (RNA) levels in subjects' blood before, during and after treatment	12 weeks post treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety assessments will be based on medical review of the frequency of SAEs and AEs, discontinuations due to AEs, and abnormalities observed from vital sign and ECG measurements, physical examinations and clinical laboratory results	Serious Adverse Events (SAEs), Adverse Events (AEs), Electrocardiogram (ECG)	12 weeks post-treatment
Pharmacokinetic parameter maximum observed concentration [Cmax] will be derived from plasma concentration versus time. Trough concentration (Ctrough) and sparse Pharmacokinetics (PK) samples will also be collected.		Day 1 and Day 14
Pharmacokinetic parameter trough observed concentration [Cmin] will be derived from plasma concentration versus time. Trough concentration (Ctrough) and sparse Pharmacokinetics (PK) samples will also be collected.		Days 1, Days 7, Days 14, Weeks 4, Weeks 8, Weeks 12, Weeks 16
Pharmacokinetic parameter time of maximum observed concentration [Tmax] will be derived from plasma concentration versus time. Trough concentration (Ctrough) and sparse Pharmacokinetics (PK) samples will also be collected.		Day 1 and Day 14
Pharmacokinetic parameter area under the concentration-time curve in one dosing interval [AUC(TAU)] will be derived from plasma concentration versus time. Trough concentration (Ctrough) and sparse Pharmacokinetics (PK) samples will also be collected.		Day 1 and Day 14

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Kao JH, Jensen DM, Manns MP, Jacobson I, Kumada H, Toyota J, Heo J, Yoffe B, Sievert W, Bessone F, Peng CY, Roberts SK, Lee YJ, Bhore R, Mendez P, Hughes E, Noviello S. Daclatasvir plus asunaprevir for HCV genotype 1b infection in patients with or without compensated cirrhosis: a pooled analysis. Liver Int. 2016 Jul;36(7):954-62. doi: 10.1111/liv.13049. Epub 2016 Jan 24.
• McPhee F, Hernandez D, Yu F, Ueland J, Monikowski A, Carifa A, Falk P, Wang C, Fridell R, Eley T, Zhou N, Gardiner D. Resistance analysis of hepatitis C virus genotype 1 prior treatment null responders receiving daclatasvir and asunaprevir. Hepatology. 2013 Sep;58(3):902-11. doi: 10.1002/hep.26388. Epub 2013 Jul 16.
• Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, Reindollar R, Rustgi V, McPhee F, Wind-Rotolo M, Persson A, Zhu K, Dimitrova DI, Eley T, Guo T, Grasela DM, Pasquinelli C. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med. 2012 Jan 19;366(3):216-24. doi: 10.1056/NEJMoa1104430.

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: November 12, 2009
• First Submitted That Met QC Criteria: November 12, 2009
• First Posted (Estimate): November 13, 2009

Study Record Updates

• Last Update Posted (Estimate): October 9, 2015
• Last Update Submitted That Met QC Criteria: September 23, 2015
• Last Verified: September 1, 2015

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; Hepatitis A; Hepatitis C; Hepatitis, Chronic; Hepatitis C, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Protease Inhibitors; Interferons; Interferon-alpha; Ribavirin; Peginterferon alfa-2a; Interferon alpha-2; Asunaprevir
• Other Study ID Numbers: AI447-011; 2010-024637-23 (EudraCT Number)