Clinical trial NCT01455090: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Hepatitis C
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2011-10-19
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

Primary outcomes:
measure: Sustained virologic response (SVR) at 12 weeks post-treatment (SVR12)
timeFrame: 12 weeks post-treatment
Secondary outcomes:
measure: Proportion of subjects with HCV ribonucleic acid (RNA) < limit of quantification (LOQ) (detectable and undetectable)
timeFrame: 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
measure: Proportion of subjects with HCV ribonucleic acid (RNA) undetectable
timeFrame: 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
measure: Proportion of subjects who experience viral breakthrough
timeFrame: Formal analysis at SVR12, Week 48 of follow up period (or upon occurrence)
measure: 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)
timeFrame: End of treatment (Maximum up to 24 Weeks)
measure: Maximum observed plasma concentration (Cmax) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712
timeFrame: Day 1 and Day 14
measure: Observed plasma concentration at 12 hours (C12) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712
timeFrame: Day 1 and Day 14
measure: Observed plasma concentration at 24 hours (C24) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712
timeFrame: Day 1 and Day 14
measure: Trough observed plasma concentration (Ctrough) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712
timeFrame: Day 1 and Day 14
measure: Time of maximum observed plasma concentration (Tmax) of BMS-650032, BMS-790052, BMS 791325, and BMS-794712
timeFrame: Day 1 and Day 14
measure: Area under the concentration-time curve in one dosing interval [AUC(TAU)] of BMS-650032, BMS-790052, BMS 791325, and BMS-794712
timeFrame: Day 1 and Day 14
measure: HCV genomic substitutions associated with exposure of BMS-650032, BMS-790052, and BMS-791325
timeFrame: At the time of viral breakthrough or relapse
measure: 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
timeFrame: Formal analysis at week 48 of follow up period (or upon occurrence)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: The Kirklin Clinic
state: Alabama
city: Coronado
country: United States
facility: Southern California Research Center
state: California
city: Los Angeles
country: United States
facility: Peter J Ruane Md Inc
state: California
city: Los Angeles
country: United States
facility: Va Greater Los Angeles Healthcare System
state: California
city: San Diego
country: United States
facility: Research And Education, Inc.
state: California
city: San Diego
country: United States
facility: Precision Research Institute, Llc
state: California
city: San Diego
country: United States
facility: Medical Associates Research Group
state: California
city: Aurora
country: United States
facility: University Of Colorado Denver And Hospital
state: Colorado
city: Washington, D.C.
country: United States
facility: Medstar Georgetown University Hospital
state: District of Columbia
city: Orlando
country: United States
facility: Orlando Immunology Center
state: Florida
city: South Miami
country: United States
facility: Miami Research Associates
state: Florida
city: Atlanta
country: United States
facility: Atlanta Gastroenterology Associates, Llc
state: Georgia
city: Baltimore
country: United States
facility: Mercy Medical Center, Inc.
state: Maryland
city: Lutherville
country: United States
facility: Johns Hopkins University
state: Maryland
city: Hillsborough
country: United States
facility: Id Care
state: New Jersey
city: Santa Fe
country: United States
facility: Southwest Care Center
state: New Mexico
city: The Bronx
country: United States
facility: James J Peters Vamc
state: New York
city: Tulsa
country: United States
facility: Options Health Research, Llc
state: Oklahoma
city: Tulsa
country: United States
facility: Healthcare Research Consultants
state: Oklahoma
city: Arlington
country: United States
facility: Texas Clinical Research Institute
state: Texas
city: Houston
country: United States
facility: Research Specialists Of Texas
state: Texas
city: San Antonio
country: United States
facility: Alamo Medical Research
state: Texas
city: Salt Lake City
country: United States
facility: Lifetree Clinical Research
state: Utah
city: Fairfax
country: United States
facility: Metropolitan Research
state: Virginia
city: Falls Church
country: United States
facility: Inova Fairfax Hospital
state: Virginia
city: Madison
country: United States
facility: Dean Clinic
state: Wisconsin
city: Clichy Cedex
country: France
facility: Local Institution
city: Creteil Cedex
country: France
facility: Local Institution
city: Limoges
country: France
facility: Local Institution
city: Marseille Cedex 08
country: France
facility: Local Institution
city: Paris Cedex 14
country: France
facility: Local Institution
city: San Juan
country: Puerto Rico
facility: Fundacion De Investigacion De Diego
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.