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

• ClinicalTrials.gov Identifier: NCT01455090
• Recruitment Status: Completed
• First Posted: October 19, 2011
• Last Update Posted: April 27, 2017
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: October 18, 2011
• First Posted Date: October 19, 2011
• Last Update Posted Date: April 27, 2017
• Actual Study Start Date: November 30, 2011
• Actual Primary Completion Date: March 31, 2014 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: October 18, 2011): Sustained virologic response (SVR) at 12 weeks post-treatment (SVR12) [ Time Frame: 12 weeks post-treatment ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 2, 2012)

• Proportion of subjects with HCV ribonucleic acid (RNA) < limit of quantification (LOQ) (detectable and undetectable) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Formal analysis at SVR12, Week 48 of follow up period (or upon occurrence) ]
  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
• 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) [ Time Frame: End of treatment (Maximum up to 24 Weeks) ]
• Maximum observed plasma concentration (Cmax) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712 [ Time Frame: Day 1 and Day 14 ]
• Observed plasma concentration at 12 hours (C12) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712 [ Time Frame: Day 1 and Day 14 ]
• Observed plasma concentration at 24 hours (C24) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712 [ Time Frame: Day 1 and Day 14 ]
• Trough observed plasma concentration (Ctrough) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712 [ Time Frame: Day 1 and Day 14 ]
• Time of maximum observed plasma concentration (Tmax) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712 [ Time Frame: 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 [ Time Frame: Day 1 and Day 14 ]
• HCV genomic substitutions associated with exposure of BMS-650032, BMS-790052, and BMS-791325 [ Time Frame: 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 [ Time Frame: Formal analysis at week 48 of follow up period (or upon occurrence) ]

Original Secondary Outcome Measures (submitted: October 18, 2011)

• Proportion of subjects with HCV ribonucleic acid (RNA) < limit of quantification (LOQ) (detectable and undetectable) [ Time Frame: 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) < limit of detection (LOD) (detectable and undetectable) [ Time Frame: 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 [ Time Frame: Formal analysis at SVR12, Week 48 of follow up period (or upon occurrence) ]
  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
• Proportion of subjects who experience viral relapse defined as confirmed detectable HCV RNA in a subject with HCV RNA undetectable (or unconfirmed detectable HCV RNA [< 25 IU/mL]) [ Time Frame: End of treatment ]
• Maximum observed plasma concentration (Cmax) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712 [ Time Frame: Day 14 ]
• Trough observed plasma concentration (Cmin) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712 [ Time Frame: Day 14 ]
• Time of maximum observed plasma concentration (Tmax) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712 [ Time Frame: Day 14 ]
• Area under the concentration-time curve in one dosing interval (AUC(TAU)) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712 [ Time Frame: Day 14 ]
• HCV genomic substitutions associated with exposure of BMS-650032, BMS-790052, and BMS-791325 [ Time Frame: At the time of viral breakthrough or relapse ]
• Frequency of deaths, SAEs, discontinuations due to AEs, severity Grade 3/4 AEs, and severity Grade 3/4 laboratory abnormalities [ Time Frame: Formal analysis at week 48 of follow up period (or upon occurrence) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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
• Brief Summary: 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
• Detailed Description: IND numbers: 79,599; 101,943
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Hepatitis C

Intervention

• Drug: BMS-650032
  Other Name: Asunaprevir (ASV)
• Drug: BMS-790052
  Other Name: Daclatasvir (DCV)
• Drug: BMS-791325
• Drug: Ribavirin
  Other Name: Copegus®

Study Arms

• 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

  Interventions:

  • Drug: BMS-650032
  • Drug: BMS-790052
  • Drug: BMS-791325
• 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

  Interventions:

  • Drug: BMS-650032
  • Drug: BMS-790052
  • Drug: BMS-791325
• 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

  Interventions:

  • Drug: BMS-650032
  • Drug: BMS-790052
  • Drug: BMS-791325
• 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

  Interventions:

  • Drug: BMS-650032
  • Drug: BMS-790052
  • Drug: BMS-791325
• 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

  Interventions:

  • Drug: BMS-650032
  • Drug: BMS-790052
  • Drug: BMS-791325
• 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

  Interventions:

  • Drug: BMS-650032
  • Drug: BMS-790052
  • Drug: BMS-791325
• 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

  Interventions:

  • Drug: BMS-650032
  • Drug: BMS-790052
  • Drug: BMS-791325
• 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

  Interventions:

  • Drug: BMS-650032
  • Drug: BMS-790052
  • Drug: BMS-791325
• 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

  Interventions:

  • Drug: BMS-650032
  • Drug: BMS-790052
  • Drug: BMS-791325
• 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

  Interventions:

  • Drug: BMS-650032
  • Drug: BMS-790052
  • Drug: BMS-791325
• 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

  Interventions:

  • Drug: BMS-650032
  • Drug: BMS-790052
  • Drug: BMS-791325
• 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

  Interventions:

  • Drug: BMS-650032
  • Drug: BMS-790052
  • Drug: BMS-791325
• 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]

  Interventions:

  • Drug: BMS-650032
  • Drug: BMS-790052
  • Drug: BMS-791325
  • Drug: Ribavirin

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 10, 2015): 320
• Original Estimated Enrollment (submitted: October 18, 2011): 64
• Actual Study Completion Date: July 31, 2015
• Actual Primary Completion Date: March 31, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Puerto Rico, United States

Administrative Information

• NCT Number: NCT01455090
• Other Study ID Numbers: AI443-014; 2011-002788-11 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bristol-Myers Squibb
• Original Responsible Party: Same as current
• Current Study Sponsor: Bristol-Myers Squibb
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Bristol-Myers Squibb
• Verification Date: April 2017